1,3-thiazole and 1,2,4-thiadiazole derivatives for use as cd38 inhibitors for the treatment of CNS disorders

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof: Formula (I) wherein Het, X1, X2, Cy, L and R1 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with CD38 activity.

Description

[0001] 1 ,3-THIAZOLE AND 1 ,2,4-THIADIAZOLE DERIVATIVES FOR USE AS CD38 INHIBITORS FOR THE TREATMENT OF CNS DISORDERS

[0002] Field of the invention

[0003] The present invention relates to thiazole-carboxamides, thiadiazole-carboxamides and related compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with CD38 activity.

[0004] Background of the invention

[0005] NAD+ homeostasis, aging & disease

[0006] Nicotinamide adenine dinucleotide (NAD+) is an essential cellular component being extremely abundant in most living cells. NAD+and its close analogue NADP+ perform similar redox functions within the cell, the latter being more confined to biosynthetic pathways and redox protective roles (Ying, 2008, Antioxid Redox Signal 10: 179). NAD+ and NADH (NAD(H)) are redox essential for a variety of electron-exchange- dependent biochemical reactions, particularly redox reactions involving oxidoreductase-mediated hydride transfer. Thus NAD(H) plays a vital role in the mitochondrial electron transport chain and cellular energy metabolism and as a co- enzyme linked to catabolism and harvesting of metabolic energy in all eukaryotic cells. However, the roles of NAD+expand beyond its function as a co-enzyme, as NAD+and its metabolites also act as degradation substrates for a wide range of enzymes, such as sirtuins (Hall et al, 2013, J Clin Invest 123: 973), SARM1 (Essuman et al, 2017, Neuron 93: 1334) and PARP enzymes (Murata et al, 2019, Mol Biol Cell 30: 2584). It is through these activities that NAD+ also links cellular metabolism to changes in signalling and transcriptional events and thus plays a central role in regulating cellular homeostasis and signalling.

[0007] NAD+levels largely remain constant when used as a co-enzyme, but in non-redox reactions its levels are depleted from the cellular pool, thus requiring continuous re- synthesis and replenishment (Nikiforov et al, 2015, Crit Rev Biochem Mol Biol 50: 284). There are two main pathways for the synthesis of NAD+, the so called de novo pathway that utilizes the essential amino acid L-tryptophan to generate quinolinic acid (QA) that is further metabolized into NAD+ (Nikiforov et al, 2015, Crit Rev Biochem Mol Biol 50: 284), and the salvage pathway that utilizes nicotinamide (NAM), nicotinic acid (NA), and nicotinamide riboside (NR) (Imai & Yoshino, 2013, Diabetes Obes Metab Suppl. 3: 26). The salvage pathway is the main source of NAD+in most cell types. NAD+levels change during many physiological processes. Mounting evidence indicates that intracellular NAD+levels are significantly affected by nutritional and environmental stimuli. These changes in NAD+content are reflected into NAD+- dependent enzymatic activities, which in turn lead to changes in cellular metabolism, gene expression, and protein function. Therefore, maintenance of an optimal NAD+concentration appears critical to maintain long term tissue homeostasis.

[0008] It has been clearly demonstrated that cellular NAD+ levels decline during chronological aging (Chini et al, 2017, Mol Cell Endocrinol 455: 62). This decline appears to play a crucial role in the development of metabolic dysfunction in aging and importantly, decline in cellular NAD+levels has emerged as a potential key player in the pathogenesis of age-related conditions (Chini et al, 2017, Mol Cell Endocrinol 455: 62; Verdin, 2015, Science 350: 1208; Imai & Guarente, 2014, Trends Cell Biol 24: 464; Schultz & Sinclair, 2016, Cell Metab 23: 965); thus, maintaining NAD+levels and subsequent cellular homeostasis may be a means of attenuating aging and age-related diseases such as Alzheimer’s disease and Parkinson’s disease (Chini et al, 2017, Mol Cell Endocrinol 455: 62). In support of this many studies have demonstrated that elevated NAD+ levels are associated with improved health and longer life span in multiple model organisms and humans (Fang et al, 2016, Cell Metab 24: 566; Fang et al, 2019, Nat Comms 10: 5284; Lehmann et al, 2017, Biol Open, 6: 141; Martens et al, 2018, Nat Comms 9: 1286; Mitchell et al, 2018, Cell Metab 27: 667; Covarrubias et al, 2021, Nat Rev Mol Cell Biol 22: 119; Perez et al, 2021, MechAg & Dev 197: 111499). As a result, there has been a growing interest in characterizing the role of NAD+metabolism in age- related diseases and in developing pharmacological or nutraceutical interventions that increase NAD+ levels. In this regard, restoring NAD+ levels with NAD+ precursors, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), has received some clinical interest (for reviews see Covarrubias et al, 2021, Nat Rev Mol Cell Biol 22: 119; Perez et al, 2021, Meeh Ag & Dev 197: 111499) and inhibiting NAD+ consumption, e.g. by inhibiting CD38, has emerged as valuable therapeutic approach for age-related disorders and neurological diseases.

[0009] CD38

[0010] Cluster of differentiation (CD38) is a multifunctional protein involved in i) cellular and tissue NAD+ homeostasis via its hydrolase function (Chini, 2009, Curr Pharm Des 15: 57) and ii) the generation of the second messengers ADPR and cyclic-ADPR (cADPR), via CD38S cyclase enzyme activity, that are subsequently involved in intracellular calcium signalling (Lee & Aarhus, 1991, Cell Regul 3: 203; Malavasi et al, 2008, Physiol Rev 88: 841). CD38 has a type II membrane orientation, with the catalytic site facing the outside of the cell (Chini, 2009, Curr Pharm Des 15: 57; Malavasi et al, 2008, Physiol Rev 88: 841). This was somewhat of a paradox given most substrates for NADase- CD38 are expected to be intracellular, however, it is now evident that CD38 degrades not only NAD+, but also circulating NAD+precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), before they can be incorporated into intracellular NAD+biosynthetic pathways (Yoshino et al, 2018, Cell Metab 27: 513). Furthermore, CD38 has also been observed in intracellular membranes, such as in the nuclear membrane, mitochondria, and endoplasmic reticulum (Zhao et al, 2012, Sei Signal 5: ra6y; Shrimp et al, 2014, J Am Chem Soc 136: 5656), a small fraction of CD38 is also expressed as a type III plasma membrane protein with the catalytic site facing the inside of the cell (Lui et al, 2017, Proc Natl Acad Sei USA. 114: 8283), and intra- and extracellular forms of CD38 have also been described (Chini, 2009, Curr Pharm Des 15: 57; Malavasi et al, 2008, Physiol Rev 88: 841). The relative roles and contributions of the different cellular pools of CD38 in the regulation of NAD+homeostasis, calcium signalling, and subsequent cellular function is thus complex and still not clearly understood. It is apparent that CD38 is a very inefficient second messenger-generating enzyme, as it will hydrolyze almost a hundred molecules of NAD+ in order to generate one molecule of cADPR (Beers et al, 1995, J Clin Invest 95: 2385; Kim et al, 1993, Science 261: 1330), thus its role in NAD+homeostasis may be its primary function reflected by its high substrate affinity and turnover rate compared to other NAD+utilizing enzymes. CD38 is expressed in the brain across species including mouse (Ceni et al, 2003, Biochem J 370: 175), rat (Yamada et al, 1997, Brain Res 756: 52; Braidy et al, 2014, Biogerontology 15: 177) and human (Mizuguchi et al, 1995, Brain Res 697: 235). In the human brain, it is interesting to note that CD38 is expressed in virtually all brain areas, with the highest expression levels in the caudate, pallidum, olfactory bulb, putamen, thalamus, and cingulate anterior (Quintana et al, 2019, Nat Comms 10: 668). Literature evidence suggests that CD38 is expressed in neurons (Yamada et al, 1997, Brain Res 756: 52; Mizuguchi et al, 1995, Brain Res 697: 235), astrocytes (Yamada et al, 1997, Brain Res 756: 52; Kou et al, 2009, JNeurosci Res 87: 2326), and microglial cells (Ma et al, 2012, Biochem Biophys Res Commun 418: 714; Mayo et al, 2008, J Immunol 181: 92). However, the applicant’s in-house data suggest that CD38 expression predominates in the astrocytes of the human forebrain structures. CD38 function is associated with effects on immunity, metabolic dysfunction, and behavioural deficits in mice (Barbosa et al, 2007, FASEB J 21: 3629; Lopatina et al, 2012, Front Neurosci 6: 182). Tissue NAD+ levels were found to be significantly higher in CD38-deficient mice suggesting that CD38 is the main NAD+metabolising enzyme (NADase) in mammalian tissues. Concurrently it has been demonstrated that the expression and activity of CD38 increases with aging and that CD38 is at least in part the cause for the age-related NAD+decline and subsequent mitochondrial dysfunction (Camacho-Pereira et al, 2016, Cell Metab 23: 1127). Furthermore, reduced NAD+levels are a common observation among neurodegenerative diseases including Alzheimer’s disease (Sonntag et al, 2017, Sei Rep 7: 14038), Parkinson’s disease (Wakade et al, 2014, PLoS ONE 9: 0109818), amyotrophic lateral sclerosis (Wang et al, 2017, Cell Rep 20: 2184), as well as multiple sclerosis (Braidy et al, 2013, Brain Res 1537: 267). Thus, attenuating CD38 activity, enhancing cellular levels of NAD+and subsequent modulation of the diverse NAD+related pathways could be a therapeutically viable approach to a range of brain and inflammatory disorders.

[0011] Therapeutic utility of CD38 inhibitors

[0012] Several experimental data using CD38 knockout mice (KO) mice have demonstrated positive effects of CD38 deletion in models of neurodegeneration (Blacher et al, 2015, Ann Neurol 78: 88; Long et al, 2017, Neurochem Res 42: 283; Takaso et al, 2020, Sei Rep 10: 17795) and neuroinflammation (Choe et al, 2011, PLoS ONE 6: 019046; Raboon et al, 2019, Front Cell Neurosci 13: 258; for review see Guerreiro et al, 2020, Cells 9: 471), and a CD38 inhibitor molecule reversed age-related NAD+decline and physiological effects of aging in mice (Tarrago et al, 2018, Cell Metab 27: 1081). Crossing of CD38 KO mouse with the APPswePSiDEg model of Alzheimer’s disease mouse model reduced amyloid plaque load and soluble Ap levels, an effect that correlated with improved functional performance in a Morris water maze behavioural task (Blacher et al, 2015, Ann Neurol 78: 88).

[0013] In stroke models CD38-deficient mice showed decreased local expression of the proinflammatory cytokines and reduced ischemic injury and neurological deficits (Choe et al, 2011, PLoS ONE 6: 019046), whilst Long et al (Long et al, 2017, Neurochem Res 42: 283) showed an amelioration of histological and neurologic outcome following ischemic insult in CD38 KO mice. In models of multiple sclerosis, CD38 deficiency reduced severity of outcome in mouse experimental autoimmune encephalomyelitis (EAE) (Herrmann et al, 2016, Dis Mods Meehs 9: 1211) and suppressed neuroinflammation in a mouse model of demyelination (Raboon et al, 2019, Front Cell Neurosci 13: 258). Similarly, deletion of CD38 or supplementation of NAD+attenuate axon degeneration in a mouse facial nerve axotomy model (Takaso et al, 2020, Sei Rep 10: 17795). Interestingly, a transcriptome-wide association study has identified CD38 as a potential susceptibility gene for Parkinson’s disease (Yao et al, 2021, npj Parkinsons Dis 7: 79). In addition, CD38 KO mice are protected against obesity and metabolic syndrome (Barbosa et al, 2007, FASEB J 21: 3629; Chiang et al, 2015, PLoS ONE 10: 00134927) which are recognised risk factors for Alzheimer’s disease. The regulatory impact of CD38 on the immune cells of the brain and periphery are also likely to be contributors to the beneficial impact of CD38 deletion or blockade on the various preclinical insult models (for reviews see Guerreiro et al, 2020, Cells 9: 471;

[0014] Piedra-Quintero et al, 2020, Front Immunol 11: 597959) as neuroinflammation has been shown to be a major contributor across many of these diseases (Ransohoff, 2016, Science 353: 777).

[0015] Taken together, there is significant preclinical evidence to support the utility of augmenting cellular NAD+levels by inhibiting its breakdown via blockade of CD38. The therapeutic utility in CNS diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke and other neurodegenerative conditions will be reliant on achieving CNS penetration by the CD38 inhibitors. However, CD38 inhibitors will also likely have utility in other conditions such as autoimmune diseases, obesity and metabolic syndrome.

[0016] Brain permeability of small molecules

[0017] The central nervous system (CNS) is shielded from exposure to undesired substances by the blood-brain barrier (BBB). This restriction protects neurons from harmful interactions with toxins and other potentially harmful molecules. The BBB consists of brain capillary endothelial cells which have several unique attributes and functions: they have tight junctions leading to extremely low permeability via a paracellular route, they have low rates of endocytosis and, importantly, they highly express efflux transporter proteins with the specific function of recognizing and shuttling foreign substances out of the CNS (Gloor et al, 2001, Brain Res Rev 36: 258).

[0018] Importantly, the unbound drug concentration in the brain compartment is a critical parameter that needs to be considered when evaluating the suitability of molecules as potential therapies for neurological and neurodegenerative disorders: it is generally accepted that only the unbound fraction of drug may be available for occupying the desired target in order to exert a pharmacological effect. There is a need for treatment of the above diseases and conditions and others described herein with compounds that are CD38 inhibitors. The present invention provides such CD38 inhibitors, including brain permeable CD38 inhibitors. Summary of the invention

[0019] A first aspect of the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0020] Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; one of X1and X2is S and the other of X1and X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0021] Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0022] L is a bond, CH2, CHMe, CMe2or CO;

[0023] R1is -NR2R3, halo or C1-C4fluoroalkyl;

[0024] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0025] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0026] Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S. In one embodiment, Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group.

[0027] In another embodiment, Het is an imidazolyl, thiazolyl or isothiazolyl group.

[0028] In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl).

[0029] Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl.

[0030] In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl. In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0031] In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl.

[0032] One of X1and X2is S and the other of X1and X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl. In a preferred embodiment, one of X1and X2is S and the other of X1and X2is CH or N.

[0033] Cy is a C3-C8cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6- membered heteroaryl group. The C3-C8cycloalkyl group and the 3- to 9-membered saturated heterocyclyl group may be monocyclic or bicyclic (including bridged, fused and spiro).

[0034] In one embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro [3.3]heptanyl, azaspiro [2.5] octanyl azaspiro [3.4]octanyl, azaspiro[2.6]nonanyl, azaspiro [3 -5]nonanyl azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro [2.3] hexanyl oxaspiro[2.4]heptanyl, oxaspiro [3.3]heptanyl, oxaspiro[2.5]octanyl oxaspiro[3.4]octanyl, oxaspiro[2.6]nonanyl, oxaspiro [3.5]nonanyl oxaspiro[4.4]nonanyl, quinuclidinyl, 8-azabicyclo[3.2.i]octanyl, 2- azabicyclo[2.2.2]octanyl, hexahydro-1H-pyrrolizinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

[0035] In another embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl azaspiro [3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl azaspiro[2.6]nonanyl, azaspiro [3.5] nonanyl, azaspiro[4.4]nonanyl. oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro[3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[2.6]nonanyl, oxaspiro[3.5]nonanyl, oxaspiro[4.4]nonanyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0036] In a preferred embodiment, Cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, piperidinyl, tetrahydropyranyl, azaspiro[3.5]nonanyl, phenyl, pyridinyl, and pyrimidinyl.

[0037] Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl.

[0038] In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl.

[0039] L is a bond, CH2[including CHD and CD2], CHMe [including CDMe, CH(CD3) and CD(CD3)], CMe2[including CMe(CD3) and C(CD3)2] or CO. In one embodiment, L is a bond, CH2or CO. In a preferred embodiment, L is a bond or CH2.

[0040] R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0041] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);

[0042] R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl. In one embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0043] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0044] R3is hydrogen or methyl; or

[0045] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl. In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0046] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl; R3is hydrogen or methyl; or

[0047] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0048] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH2, -NHMe, -NHEt, -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe2, -NMeEt, -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is optionally fluoro-substituted and / or optionally substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3).

[0049] In a first specific preferred embodiment, the first aspect of the present invention provides a compound of formula (II): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0050] Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; X1is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0051] Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl; L is a bond, CH2, CHMe, CMe2or CO;

[0052] R1is -NR2R3, halo or C1-C4fluoroalkyl;

[0053] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not: (i) N-(2-bromophenyl)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-

[0054] 2-carboxamide;

[0055] (ii) N-(3-bromophenyl)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole- 2-carboxamide;

[0056] (iii) 4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-2-carboxamide; or

[0057] (iv) 4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(2- (trifluoromethyl)phenyl)thiazole-2-carboxamide.

[0058] In the first specific preferred embodiment, Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S.

[0059] In one embodiment, Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group.

[0060] In another embodiment, Het is an imidazolyl, thiazolyl or isothiazolyl group.

[0061] In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl).

[0062] In the first specific preferred embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl. In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0063] In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0064] In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl.

[0065] In the first specific preferred embodiment, X1is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl.

[0066] In a preferred embodiment, X1is CH or N.

[0067] In the first specific preferred embodiment, Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group. The C3-C9cycloalkyl group and the 3- to 9-membered saturated heterocyclyl group may be monocyclic or bicyclic (including bridged, fused and spiro).

[0068] In one embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro [3.3]heptanyl, azaspiro [2.5] octanyl, azaspiro [3.4]octanyl, azaspiro[2.6]nonanyl, azaspiro [3.5]nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro [3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[2.6]nonanyl, oxaspiro [3.5]nonanyl, oxaspiro[4.4]nonanyl, quinuclidinyl, 8-azabicyclo[3.2.i]octanyl, 2- azabicyclo[2.2.2]octanyl, hexahydro-1H-pyrrolizinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

[0069] In another embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro [3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl, azaspiro[2.6]nonanyl, azaspiro [3.5] nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro[3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro [3.4] octanyl, oxaspiro[2.6]nonanyl, oxaspiro[3.5]nonanyl, oxaspiro[4.4]nonanyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0070] In a preferred embodiment, Cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, piperidinyl, tetrahydropyranyl, azaspiro[3.5]nonanyl, phenyl, pyridinyl, and pyrimidinyl. In the first specific preferred embodiment, Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl.

[0071] In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl.

[0072] In the first specific preferred embodiment, L is a bond, CH2[including CHD and CD2], CHMe [including CDMe, CH(CD3) and CD(CD3)], CMe2[including CMe(CD3) and C(CD3)2] or CO. In one embodiment, L is a bond, CH2or CO. In a preferred embodiment, L is a bond or CH2.

[0073] In the first specific preferred embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0074] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);

[0075] R3is hydrogen or methyl; or

[0076] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0077] In one embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0078] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0079] R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl. In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0080] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0081] R3is hydrogen or methyl; or

[0082] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0083] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH2, -NHMe, -NHEt, -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe2, -NMeEt, -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is optionally fluoro-substituted and / or optionally substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3).

[0084] In a second specific preferred embodiment, the first aspect of the present invention provides a compound of formula (III): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0085] Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0086] Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0087] L is a bond, CH2, CHMe, CMe2or CO; R1is -NR2R3, halo or C1-C4fluoroalkyl;

[0088] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or

[0089] -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0090] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not:

[0091] (i) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0092] (ii) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0093] (iii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (iv) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0094] (v) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;

[0095] (vi) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide; (vii) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0096] (viii) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0097] (ix) 2-(1H-imidazol-1-yl)-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;

[0098] (x) 2-(1H-imidazol-1-yl)-N-(4-(piperazin-1-yl)pyridin-3-yl)thiazole-4-carboxamide; (xi) N-(4-acetamidocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0099] (xii) N-(4-(dimethylamino)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0100] (xiii) 2-(1H-imidazol-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole-4- carboxamide;

[0101] (xiv) 2-(1H-imidazol-5-yl)-N-(4-(pyrrolidin-1-yl)pyrimidin-5-yl)thiazole-4- carboxamide;

[0102] (xv) 2-(1H-imidazol-5-yl)-N-(3-(pyrrolidin-1-yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;

[0103] (xvi) 2-(1H-imidazol-5-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)thiazole-4- carboxamide; (xvii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0104] (xviii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0105] (xix) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0106] (xx) 2-(1H-imidazol-5-yl)-N-(1-(methylcarbamoyl)cyclohexyl)thiazole-4- carboxamide; or (xxi) N-(3-(dimethylcarbamoyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide.

[0107] In the second specific preferred embodiment, Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl.

[0108] In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl). In the second specific preferred embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl.

[0109] In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0110] In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0111] In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl. In the second specific preferred embodiment, X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl. In a preferred embodiment, X2is CH or N.

[0112] In the second specific preferred embodiment, Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group.

[0113] In one embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

[0114] In another embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In a preferred embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, and pyrimidinyl.

[0115] In the second specific preferred embodiment, Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl.

[0116] In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl.

[0117] In the second specific preferred embodiment, L is a bond, CH2[including CHD and CD2], CHMe [including CDMe, CH(CD3) and CD(CD3)], CMe2[including CMe(CD3) and

[0118] C(CD3)2] or CO. In one embodiment, L is a bond, CH2or CO. In a preferred embodiment, L is a bond or CH2.

[0119] In the second specific preferred embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0120] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);

[0121] R3is hydrogen or methyl; or

[0122] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0123] In one embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein: R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0124] R3is hydrogen or methyl; or

[0125] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0126] In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0127] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl; R3is hydrogen or methyl; or

[0128] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0129] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH2, -NHMe, -NHEt, -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe2, -NMeEt, -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is optionally fluoro-substituted and / or optionally substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3).

[0130] In a third specific preferred embodiment, the first aspect of the present invention provides a compound of formula (III): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0131] Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;

[0132] X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl; Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0133] L is a bond, CH2, CHMe, CMe2or CO;

[0134] R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl; R2is C1-C4fluoroalkyl or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0135] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not:

[0136] (i) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(4- (trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0137] (ii) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0138] (iii) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(2- (trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0139] (iv) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0140] (v) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (vi) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0141] (vii) 2-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0142] (viii) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (ix) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;

[0143] (x) 2-(1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0144] (xi) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;

[0145] (xii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4- carboxamide;

[0146] (xiii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4- carboxamide; (xiv) 2-(1-methyl-1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4- carboxamide;

[0147] (xv) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0148] (xvi) 2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide; (xvii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(2-((2,2,2- trifluoroethyl)amino)phenyl)thiazole-4-carboxamide;

[0149] (xviii) N-(4-chlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0150] (xix) N-(3-chlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0151] (xx) N-(2-chlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0152] (xxi) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(2-fluorophenyl)thiazole-4- carboxamide; (xxii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0153] (xxiii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0154] (xxiv) N-(3-chlorophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

[0155] (xxv) N-(3-fluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

[0156] (xxvi) N-((1R,2R)-2-fluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0157] (xxvii) N-(4-fluorophenyl)-2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)thiazole-4- carboxamide;

[0158] (xxviii)N-(3,5-dichlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide; (xxix) N-(3,4-dichlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide; (xxx) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(3,4,5- trifluorophenyl)thiazole-4-carboxamide;

[0159] (xxxi) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0160] (xxxii) N-(3,3-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0161] (xxxiii)N-(4,4-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0162] (xxxiv)N-(5-chloro-2-fluorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide; (xxxv) N-(5-bromo-2-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0163] (xxxvi) N-(4-bromo-2-chloro-6-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0164] (xxxvii) N-(2-chloro-4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0165] (xxxviii) N-(4-fluoro-4-methylcyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-

[0166] 4-carboxamide;

[0167] (xxxix) N-(2,5-dichlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

[0168] (xl) N-(6-bromo-2-chloro-pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;

[0169] (xli) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0170] (xlii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)thiazole- 4-carboxamide; or (xliii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiazole- 4-carboxamide.

[0171] In the third specific preferred embodiment, Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S.

[0172] In one embodiment, Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group.

[0173] In another embodiment, Het is an imidazolyl, thiazolyl or isothiazolyl group. In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl). In the third specific preferred embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl.

[0174] In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0175] In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0176] In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl.

[0177] In the third specific preferred embodiment, X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl. In a preferred embodiment, X2is CH or N.

[0178] In the third specific preferred embodiment, Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group. In one embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. In another embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0179] In a preferred embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, and pyrimidinyl.

[0180] In the third specific preferred embodiment, Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl. In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl.

[0181] In the third specific preferred embodiment, L is a bond, CH2[including CHD and CD2], CHMe [including CDMe, CH(CD3) and CD(CD3)], CMe2[including CMe(CD3) and C(CD3)2] or CO. In one embodiment, L is a bond, CH2or CO. In a preferred embodiment, L is a bond or CH2.

[0182] In the third specific preferred embodiment, R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl; wherein: R2is C1-C4fluoroalkyl or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0183] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0184] In one embodiment, R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl; wherein:

[0185] R2is C1-C4fluoroalkyl;

[0186] R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0187] In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0188] R2is C1-C4fluoroalkyl;

[0189] R3is hydrogen or methyl; or

[0190] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0191] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin- 1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is fluoro-substituted and / or substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3).

[0192] In a fourth specific preferred embodiment, the first aspect of the present invention provides a compound of formula (III): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0193] Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0194] Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl; L is a bond;

[0195] R1is -NR2R3, halo or C1-C4fluoroalkyl;

[0196] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not: (i) 2-(1H-imidazol-1-yl)-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;

[0197] (ii) 2-(1H-imidazol-1-yl)-N-(4-(piperazin-1-yl)pyridin-3-yl)thiazole-4-carboxamide;

[0198] (iii) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0199] (iv) N-(3,3-dichlorocyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (v) N-(3,3-difluoro-1-methylcyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0200] (vi) N-(6,6-difluorobicyclo[3.i.o]hexan-3-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0201] (vii) N-(i,i-difluorospiro[2.5]octan-6-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0202] (viii) N-(3-(dimethylamino)-2,2-dimethylcyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0203] (ix) 2-(1H-imidazol-5-yl)-N-((1R,2R)-2-(trifluoromethyl)cyclopropyl)thiazole-4- carboxamide; (x) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclobutyl)thiazole-4-carboxamide;

[0204] (xi) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0205] (xii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0206] (xiii) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0207] (xiv) N-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide; (xv) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0208] (xvi) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;

[0209] (xvii) 2-(1H-imidazol-5-yl)-N-(1-(trifluoromethyl)cyclopropyl)thiazole-4- carboxamide;

[0210] (xviii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0211] (xix) N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0212] (xx) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0213] (xxi) 2-(1H-imidazol-5-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)thiazole-4- carboxamide;

[0214] (xxii) 2-(1H-imidazol-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole-4- carboxamide;

[0215] (xxiii) N-(1-(difluoromethyl)cyclopentyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0216] (xxiv) 2-(1H-imidazol-5-yl)-N-(4-(pyrrolidin-1-yl)pyrimidin-5-yl)thiazole-4- carboxamide;

[0217] (xxv) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0218] (xxvi) 2-(1H-imidazol-5-yl)-N-(3-(piperidin-1-yl)cyclobutyl)thiazole-4-carboxamide;

[0219] (xxvii) N-(3-(dimethylamino)cyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0220] (xxviii)N-(1-(fluoromethyl)cyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0221] (xxix) N-((1R,2R)-2-(dimethylamino)cyclopentyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0222] (xxx) N-(4-acetamidocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0223] (xxxi) N-(4-(dimethylamino)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0224] (xxxii) 2-(1H-imidazol-5-yl)-N-(3-(pyrrolidin-1-yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;

[0225] (xxxiii)N-(3-(dimethylamino)spiro[3.3]heptan-1-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide; (xxxiv)N-(5-(azetidin-1-yl)-i,3-dimethyl-1H-pyrazol-4-yl)-2-(1H-imidazol-5- yl)thiazole-4-carboxamide;

[0226] (xxxv) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0227] (xxxvi) N-((1R,2R)-2-(fluoromethyl)cyclopropyl)-2-(1H-imidazol-2-yl)thiazole-4- carboxamide; (xxxvii) N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-2-(1H-imidazol-2-yl)thiazole-

[0228] 4-carboxamide; (xxxviii) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H- pyran-4-yl)thiazole-4-carboxamide;

[0229] (xxxix) N-(3,3-dichlorocyclobutyl)-2-(1H-imidazol-2-yl)thiazole-4-carboxamide; or

[0230] (xl) N-((1R,2R)-2-(dimethylamino)cyclopentyl)-2-(1H-imidazol-2-yl)thiazole-4- carboxamide.

[0231] In the fourth specific preferred embodiment, Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl. In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl).

[0232] In the fourth specific preferred embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl.

[0233] In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0234] In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0235] In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl. In the fourth specific preferred embodiment, X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl. In a preferred embodiment, X2is CH or N.

[0236] In the fourth specific preferred embodiment, Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group. The C3-C9cycloalkyl group and the 3- to 9-membered saturated heterocyclyl group may be monocyclic or bicyclic (including bridged, fused and spiro).

[0237] In one embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro [3.3]heptanyl, azaspiro [2.5] octanyl, azaspiro [3.4]octanyl, azaspiro[2.6]nonanyl, azaspiro [3-5]nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro [3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[2.6]nonanyl, oxaspiro [3.5]nonanyl, oxaspiro[4.4]nonanyl, quinuclidinyl, 8-azabicyclo[3.2.i]octanyl, 2- azabicyclo[2.2.2]octanyl, hexahydro-1H-pyrrolizinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

[0238] In another embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl azaspiro [3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl azaspiro[2.6]nonanyl, azaspiro[3.5]nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl oxaspiro[3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro [3.4] octanyl oxaspiro[2.6]nonanyl, oxaspiro[3.5]nonanyl, oxaspiro[4.4]nonanyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0239] In a preferred embodiment, Cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, piperidinyl, tetrahydropyranyl, azaspiro[3.5]nonanyl, phenyl, pyridinyl, and pyrimidinyl.

[0240] In the fourth specific preferred embodiment, Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl.

[0241] In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl.

[0242] In the fourth specific preferred embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0243] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);

[0244] R3is hydrogen or methyl; or

[0245] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0246] In one embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0247] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0248] R3is hydrogen or methyl; or

[0249] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0250] In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0251] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0252] R3is hydrogen or methyl; or

[0253] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0254] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH2, -NHMe, -NHEt, -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe2, -NMeEt, -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is optionally fluoro-substituted and / or optionally substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3). In a fifth specific preferred embodiment, the first aspect of the present invention provides a compound of formula (III): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;

[0255] X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0256] Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0257] L is a bond;

[0258] R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl;

[0259] R2is C1-C4fluoroalkyl or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0260] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not:

[0261] (i) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0262] (ii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0263] (iii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0264] (iv) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (v) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0265] (vi) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;

[0266] (vii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (viii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0267] (ix) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0268] (x) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; or

[0269] (xi) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide.

[0270] In the fifth specific preferred embodiment, Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl.

[0271] In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl). In the fifth specific preferred embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl. In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

[0272] In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl. In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl.

[0273] In the fifth specific preferred embodiment, X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl.

[0274] In a preferred embodiment, X2is CH or N.

[0275] In the fifth specific preferred embodiment, Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group.

[0276] In one embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. In another embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0277] In a preferred embodiment, Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, and pyrimidinyl.

[0278] In the fifth specific preferred embodiment, Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl.

[0279] In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl. In the fifth specific preferred embodiment, R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl; wherein:

[0280] R2is C1-C4fluoroalkyl or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0281] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0282] In one embodiment, R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl; wherein: R2is C1-C4fluoroalkyl;

[0283] R3is hydrogen or methyl; or

[0284] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0285] In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0286] R2is C1-C4fluoroalkyl; R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0287] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin- 1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is fluoro-substituted and / or substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3).

[0288] In a sixth specific preferred embodiment, the first aspect of the present invention provides a compound of formula (IV): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0289] Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;

[0290] Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0291] L is a bond, CH2, CHMe, CMe2or CO;

[0292] R1is -NR2R3, halo or C1-C4fluoroalkyl; R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; or

[0293] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0294] In the sixth specific preferred embodiment, Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S.

[0295] In one embodiment, Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group.

[0296] In another embodiment, Het is an imidazolyl, thiazolyl or isothiazolyl group.

[0297] In a preferred embodiment, Het is an imidazolyl group (including imidazol-1-yl and imidazol-5-yl).

[0298] In the sixth specific preferred embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl.

[0299] In one embodiment, Het is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl. In another embodiment, Het is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl. In a preferred embodiment, Het is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl.

[0300] In the sixth specific preferred embodiment, Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group. The C3-C9cycloalkyl group and the 3- to 9-membered saturated heterocyclyl group may be monocyclic or bicyclic (including bridged, fused and spiro).

[0301] In one embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro [3.3]heptanyl, azaspiro [2.5] octanyl, azaspiro [3.4]octanyl, azaspiro[2.6]nonanyl, azaspiro [3-5]nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro [3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[2.6]nonanyl, oxaspiro [3.5]nonanyl, oxaspiro[4.4]nonanyl, quinuclidinyl, 8-azabicyclo[3.2.i]octanyl, 2- azabicyclo[2.2.2]octanyl, hexahydro-1H-pyrrolizinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

[0302] In another embodiment, Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl azaspiro [3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl azaspiro[2.6]nonanyl, azaspiro [3.5] nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl oxaspiro[3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro [3.4] octanyl oxaspiro[2.6]nonanyl, oxaspiro[3.5]nonanyl, oxaspiro[4.4]nonanyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0303] In a preferred embodiment, Cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, piperidinyl, tetrahydropyranyl, azaspiro[3.5]nonanyl, phenyl, pyridinyl, and pyrimidinyl.

[0304] In the sixth specific preferred embodiment, Cy is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl.

[0305] In one embodiment, Cy is optionally substituted with one or two substituents (preferably one substituent) independently selected from fluoro, chloro and methyl.

[0306] In the sixth specific preferred embodiment, L is a bond, CH2[including CHD and CD2], CHMe [including CDMe, CH(CD3) and CD(CD3)], CMe2[including CMe(CD3) and C(CD3)2] or CO. In one embodiment, L is a bond, CH2or CO. In a preferred embodiment, L is a bond or CH2.

[0307] In the sixth specific preferred embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0308] R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);

[0309] R3is hydrogen or methyl; or

[0310] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl. In one embodiment, R1is -NR2R3, halo or C1-C4fluoroalkyl; wherein:

[0311] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl; R3is hydrogen or methyl; or

[0312] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

[0313] In another embodiment, R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:

[0314] R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl; R3is hydrogen or methyl; or

[0315] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0316] In a preferred embodiment, R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including CH2CF3), -NH2, -NHMe, -NHEt, -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe2, -NMeEt, -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is optionally fluoro-substituted and / or optionally substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3). In a seventh specific preferred embodiment, the first aspect of the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0317] Het is imidazolyl (including imidazol-1-yl and imidazol-5-yl) optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl; one of X1and X2is S and the other of X1and X2is CH or N; Cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, piperidinyl, tetrahydropyranyl, azaspiro[3.5]nonanyl, phenyl, pyridinyl, and pyrimidinyl, each of which is optionally substituted with one or two substituents independently selected from fluoro, chloro and methyl;

[0318] L is a bond or CH2; and R1is fluoro, chloro, fluoromethyl (including CF3), fluoroethyl (including

[0319] CH2CF3), -NH2, -NHMe, -NHEt, -NH-fluoroethyl (including -NH-CH2CF3, -NH-CH2CHF2, and -NH-CH2CH2F), -NH-fluoropropyl (including -NH-CH2CF2CH3and -NH-CHMeCF3), -NH-fluorobutyl (including -NH-CMe2CF3), -NMe2, -NMeEt, -NMe-fluoroethyl (including -NMe-CH2CF3, -NMe-CH2CHF2, and -NMe-CH2CH2F), -NMe-fluoropropyl (including -NMe-CH2CF2CH3and -NMe-CHMeCF3), -NMe-fluorobutyl (including -NMe-CMe2CF3), or an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group is optionally fluoro-substituted and / or optionally substituted with one substituent selected from fluoromethyl (including CF3) and fluoroethyl (including CH2CF3); provided that the compound is not:

[0320] (i) N-(3-(dimethylamino)-2,2-dimethylcyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0321] (ii) N-(3,3-difluoro-1-methylcyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0322] (iii) N-(3-(dimethylamino)cyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (iv) N-((1R,2R)-2-(dimethylamino)cyclopentyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0323] (v) N-(4-(dimethylamino)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0324] (vi) 2-(1H-imidazol-5-yl)-N-(3-(piperidin-1-yl)cyclobutyl)thiazole-4-carboxamide; (vii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclobutyl)thiazole-4-carboxamide;

[0325] (viii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0326] (ix) N-(1-(fluoromethyl)cyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0327] (x) 2-(1H-imidazol-5-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)thiazole-4- carboxamide; (xi) 2-(1H-imidazol-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole-4- carboxamide;

[0328] (xii) N-(3-(dimethylamino)spiro[3.3]heptan-1-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0329] (xiii) 2-(1H-imidazol-5-yl)-N-(3-(pyrrolidin-1-yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;

[0330] (xiv) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0331] (xv) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0332] (xvi) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (xvii) 2-(1H-imidazol-5-yl)-N-(4-(pyrrolidin-1-yl)pyrimidin-5-yl)thiazole-4- carboxamide;

[0333] (xviii) N-(1-(difluoromethyl)cyclopentyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0334] (xix) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide; (xx) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0335] (xxi) 2-(1H-imidazol-1-yl)-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;

[0336] (xxii) 2-(1H-imidazol-1-yl)-N-(4-(piperazin-1-yl)pyridin-3-yl)thiazole-4-carboxamide;

[0337] (xxiii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (xxiv) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;

[0338] (xxv) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0339] (xxvi) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0340] (xxvii) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (xxviii)N-(3,3-dichlorocyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0341] (xxix) N-(3,3-dichlorocyclobutyl)-2-(1H-imidazol-2-yl)thiazole-4-carboxamide; or (xxx) N-((1R,2R)-2-(dimethylamino)cyclopentyl)-2-(1H-imidazol-2-yl)thiazole-4- carboxamide.

[0342] In an eighth specific preferred embodiment, the first aspect of the present invention provides a compound of formula (II): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0343] Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl;

[0344] X1is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0345] Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro [3-5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro [3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl, azaspiro[2.6]nonanyl, azaspiro [3.5]nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, oxaspiro [3-3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[2.6]nonanyl, oxaspiro [3.5]nonanyl, oxaspiro[4.4]nonanyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0346] L is a bond, CH2or CO;

[0347] R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;

[0348] R3is hydrogen or methyl; or

[0349] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

[0350] In a ninth specific preferred embodiment, the first aspect of the present invention provides a compound of formula (III): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0351] Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoromethyl, fluoroethyl (including CH2CF3, CH2CHF2, and CH2CH2F), hydroxymethyl, hydroxyethyl (including CH2CH2OH), azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl;

[0352] X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;

[0353] Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;

[0354] L is a bond;

[0355] R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl;

[0356] R2is C1-C4fluoroalkyl; R3is hydrogen or methyl; or

[0357] R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C3fluoroalkyl; provided that the compound is not:

[0358] (i) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0359] (ii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;

[0360] (iii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (iv) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;

[0361] (v) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;

[0362] (vi) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide; (vii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0363] (viii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0364] (ix) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;

[0365] (x) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; or

[0366] (xi) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide.

[0367] A second aspect of the present invention provides a compound selected from:

[0368] 4-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide; 3-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide;

[0369] 4-(1-(2-fluoroethyl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide;

[0370] 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide;

[0371] 4-(1-(2,2-difluoroethyl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide;

[0372] 4-(1-methyl-1H-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2- azaspiro[3.5]nonan-7-yl)thiazole-2-carboxamide; 4-(1-methyl-1H-imidazol-5-yl)-N-(6-((2,2,2- trifluoroethyl)amino)spiro[3.3]heptan-2-yl)thiazole-2-carboxamide; N-((1S,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-4-(1-methyl-1H-imidazol- 5-yl)thiazole-2-carboxamide;

[0373] N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-4-(1-methyl-1H-imidazol- 5-yl)thiazole-2-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxamide;

[0374] N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-4-(1-methyl-1H-imidazol- 5-yl)thiazole-2-carboxamide;

[0375] 4-(1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide;

[0376] N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1H-imidazol-1- yl)thiazole-2-carboxamide;

[0377] N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxamide; 4-(1H-imidazol-1-yl)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-3- yl)thiazole-2-carboxamide;

[0378] N-(4-chloro-3-fluorophenyl)-2-(1H-imidazol-1-yl)thiazole-4-carboxamide;

[0379] 3-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-methyl-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide; 3-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-methyl-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide;

[0380] 3-(5-methyl-1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide;

[0381] 4-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((1,i,i-trifluoro-2-methylpropan-2- yl)amino)cyclohexyl)thiazole-2-carboxamide;

[0382] 4-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-((1,i,i-trifluoro-2-methylpropan-2- yl)amino)cyclohexyl)thiazole-2-carboxamide;

[0383] N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-3-(1-methyl-1H-imidazol-5- yl)-1,2,4-thiadiazole-5-carboxamide; N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-3-(1-methyl-1H-imidazol-

[0384] 5-yl)-1,2,4-thiadiazole-5-carboxamide;

[0385] N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxamide; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing. Preferably the compound of the first or second aspect has a chemical purity of 95% or more, preferably 96% or more, preferably 97% or more, preferably 98% or more, preferably 99% or more, preferably 99.5% or more, preferably 99.8% or more, preferably 99.9% or more, as measured by HPLC or UPLC.

[0386] Preferably the compound of the first or second aspect has a stereochemical purity of 95% or more, preferably 96% or more, preferably 97% or more, preferably 98% or more, preferably 99% or more, preferably 99.5% or more, preferably 99.8% or more, preferably 99.9% or more, as measured by XRPD or SFC.

[0387] A third aspect of the present invention provides a process for the preparation of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, wherein the process comprises the step of: (a) reacting a compound of formula (V) or a salt thereof with an amine of formula

[0388] (VI) or a salt thereof or protected derivative thereof: wherein:

[0389] Rs is -OH, -OR6, -O-CO-R6, -F or -Cl; R6is C1-C3alkyl; and

[0390] Het, X1, X2, Cy, L and R1are as defined in the first or second aspect of the present invention; or

[0391] (b) reacting a compound of formula (VII) or a salt thereof with a compound of formula (VIII) or a salt thereof:

[0392] wherein:

[0393] R7is a leaving group (such as halo);

[0394] R8is a leaving group (such as halo), -B(R9)2or -Sn(C1-C4alkyl)3; each R9is independently selected from hydroxyl, C1-C5alkoxy and C1-C5alkyl, or two R9together with the boron atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclic group; and

[0395] Het, X1, X2, Cy, L and R1are as defined in the first or second aspect of the present invention; or

[0396] (c) reacting a compound of formula (IX) or a salt thereof with an amine of formula (VI) or a salt thereof or protected derivative thereof: wherein: R10is a leaving group (such as halo); and

[0397] Het, X1, X2, Cy, L and R1are as defined in the first or second aspect of the present invention; or

[0398] (d) the step of reacting a compound of formula (VII) or a salt thereof with a compound of formula (X) or a salt thereof:

[0399] wherein:

[0400] R7is a leaving group (such as halo);

[0401] X1is CR4or N; X2is S;

[0402] Het-H is a heteroaryl compound selected from iW-imidazole and iW-pyrazole, wherein the heteroaryl compound is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; and Cy, L, R1and R4are as defined in the first or second aspect of the present invention; and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (I), (II), (III) or (IV) into another compound of formula (I), (II), (III) or (IV); removing any protecting groups; forming a pharmaceutically acceptable salt.

[0403] An example of converting a compound of formula (I), (II), (III) or (IV) into another compound of formula (I), (II), (III) or (IV) can be found in Example 17.

[0404] In one embodiment of the process of the present invention, a compound of formula (V) or a salt thereof is reacted with an amine of formula (VI) or a salt thereof or protected derivative thereof: wherein:

[0405] Rs is -OH, -OR6, -O-CO-R6, -F or -Cl;

[0406] R6is C1-C3alkyl; and

[0407] Het, X1, X2, Cy, L and R1are as defined in the first or second aspect of the present invention.

[0408] When R5is -OH, the compound of formula (V) is a carboxylic acid (VA). When R5is -OR6, the compound of formula (V) is an ester. When R5is -O-CO-R6, the compound of formula (V) is an anhydride. When Rs is -Cl, the compound of formula (V) is an acid chloride. When Rs is -F, the compound of formula (V) is an acid fluoride.

[0409] The step of reacting a carboxylic acid (VA) or a salt thereof with an amine of formula

[0410] (VI) or a salt thereof or protected derivative thereof may be carried out in the presence of uronium-type coupling reagents, such as HATU, or phosphonic anhydrides, such as T4P or T3P, and a base, such as DIPEA or triethylamine. Typically, DMF or DCM is used as a solvent, although other polar aprotic solvents can also be used. Typically, the reaction is carried out at a temperature of about 20-50 °C (typically about 25 °C) and takes about 1-12 hours (typically about 1-6 hours). The salt of the amine of formula (VI) may be a hydrochloride salt. The reaction may be carried out under an atmosphere of nitrogen. The amine of formula (VI) may be derivatised with a protecting group. The protecting group may be, for example, a tert-butyloxycarbonyl (Boc) group, a fluorenylmethoxycarbonyl (Fmoc) group, an acetamide group, a benzyloxycarbonyl (CBz) group or a para-toluenesulfonamide (Ts) group, although other protecting groups can be used. Conveniently, the amine of formula (VI) may be derivatised with a tert- butyloxycarbonyl (Boc) group.

[0411] In another embodiment of the process of the present invention, a compound of formula

[0412] (VII) or a salt thereof is reacted with a compound of formula (VIII) or a salt thereof: wherein: R7is a leaving group (such as halo);

[0413] R8is a leaving group (such as halo), -B(R9)2or -Sn(C1-C4alkyl)3; each Rs is independently selected from hydroxyl, C1-C5alkoxy and C1-C5alkyl, or two R9together with the boron atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclic group; and

[0414] Het, X1, X2, Cy, L and R1are as defined in the first or second aspect of the present invention.

[0415] The compound of formula (VIII) is a heteroaiyl compound activated with, for example, a boron-containing group, a tin-containing group or a leaving group. The activated heteroaiyl compound of formula (VIII) may be used in metal-catalysed cross coupling reactions.

[0416] The compound of formula (VIII) may be a heteroaiyl compound activated with a tin- containing group, such as an organotin group. When R8is a group -Sn(C1-C4alkyl)3, the reaction may conveniently be carried out by a Stille reaction. Typically, R8may be -SnMe3or -SnBu3. The reaction is carried out in the presence of a palladium catalyst, such as Pd(PPh3)4, and in a solvent such as dioxane or DMF. The reaction may be carried out in the presence of copper iodide (Cui) and caesium fluoride. Typically, the reaction is carried out at a temperature of about 90-110 °C (typically about 100 °C) for about 10-16 hours (typically about 12 hours). Typically, the reaction is carried out under an atmosphere of nitrogen.

[0417] The compound of formula (VIII) may be a heteroaiyl compound activated with a boron- containing group, such as a boronic acid or boronic ester group. When R8is a group -B(R9)2, the reaction may conveniently be carried out by a Suzuki reaction. R9may be selected such that the heteroaiyl compound of formula (VIII) is activated, for example, by a boronic acid group or a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group. The activated heteroaiyl compound of formula (VIII) may be, for example, i-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole. The reaction is carried out with a palladium catalyst, such as Pd(dppf)Cl2, in the presence of a base, such as K2CO3or CsCO3. Typically, the reaction is carried out in a solvent such as dioxane or water or a mixture thereof. Typically, the reaction is carried out at a temperature of about 80-110 °C (typically about 90-100 °C) for about 1-12 hours. Typically, the reaction is carried out under an atmosphere of nitrogen. The compound of formula (VIII) may be a heteroaryl compound activated with a leaving group such as fluorine, chlorine or bromine. Typically, R8is chlorine or bromine. When R8is a leaving group, the compound of formula (VIII) may be, for example, 5-bromo-1-(2-fluoroethyl)-1H-imidazole, 5-bromo-1-(2,2-difluoroethyl)-1H- imidazole or 5-bromo-1-(oxetan-3-yl)-1H-imidazole.

[0418] When R8is a leaving group, step (b) may be carried out by combining a compound of formula (VIII) or a salt thereof with a compound of formula (VII) or a salt thereof and a diboron compound such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-i,3,2-dioxaborolane (bis(pinacolato) diboron) in the presence of a palladium catalyst such as palladium (II) acetate or chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (cataCXium-A-Pd-G2).

[0419] The reaction is typically carried out in the presence of a base such as caesium fluoride or CsCO3and typically in the presence of a ligand such as di(1-adamantyl)-n- butylphosphine. Typically, the reaction is carried out under an atmosphere of nitrogen in a solvent such as toluene, dioxane, methanol or water. Typically, the reaction is carried out in a mixture of dioxane and water or a mixture of methanol and toluene. The reaction is typically carried out at a temperature of about 80-120 °C (typically about 90 °C) for about 6-20 hours (typically about 8-16 hours).

[0420] In another embodiment of the present invention, a compound of formula (IX) or a salt thereof is reacted with an amine of formula (VI) or a salt thereof or protected derivative thereof: wherein:

[0421] R10is a leaving group (such as halo); and

[0422] Het, X1, X2, Cy, L and R1are as defined in the first or second aspect of the present invention. The amine of formula (VI) may be derivatised with a protecting group. The protecting group may be, for example, a tert-butyloxycarbonyl (Boc) group, a fluorenylmethoxycarbonyl (Fmoc) group, an acetamide group, a benzyloxycarbonyl (CBz) group or a para-toluenesulfonamide (Ts) group, although other protecting groups can be used. Conveniently, the amine of formula (VI) may be derivatised with a tertbutyloxycarbonyl (Boc) group.

[0423] The reaction is carried out under an atmosphere of carbon monoxide. The reaction is typically carried out in the presence of a palladium catalyst, such as Pd(dppf)Cl2, and in the presence of sodium acetate (AcONa) or Na2CO3. The reaction may be carried out in the presence of Pd(0Ac)2with a ligand such as i,3-bis(diphenylphosphino)propane (DPPP) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). Typically, the reaction is carried out in a solvent such as DMF or toluene. Typically, the reaction is carried out at a temperature of about 70-110 °C (typically about 80-100 °C) for about 12-72 hours.

[0424] In another embodiment of the process of the present invention, a compound of formula (VII) or a salt thereof is reacted with a compound of formula (X) or a salt thereof: wherein:

[0425] R7is a leaving group (such as halo);

[0426] X1is CR4or N;

[0427] X2is S;

[0428] Het-H is a heteroaryl compound selected from iW-imidazole and iW-pyrazole, wherein the heteroaryl compound is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; and

[0429] Cy, L, R1and R4are as defined in the first or second aspect of the present invention. The heteroaryl compound of formula (X) may be substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl. For the avoidance of doubt, said substitution does not replace the hydrogen atom in the N-H bond, such that the heteroaryl compound of formula (X) has the N-H to act as a nucleophile in step (d).

[0430] When X1is N in the compound of formula (VII), the reaction is typically carried out in the presence of a base such as DIPEA or triethylamine and in a solvent such as DMF or DMSO. Typically, the reaction is carried out a temperature of about 100-130 °C (typically about 120 °C) for about 5-15 hours (typically about 12 hours).

[0431] When X1is CR4in the compound of formula (VII), the reaction is typically carried out in the presence of a copper compound, such as Cui, and in the presence of a base such as K2CO3, optionally in the presence of a ligand, such as N1,N2-dimethylethane-i,2- diamine. Typically, the reaction is carried out in a solvent such as DMSO for about 1-4 hours (typically about 2 hours). The reaction is typically carried out under microwave irradiation at a temperature of about 100-130 °C (typically about 120 °C).

[0432] It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as phenol, hydroxy or amino groups in the reagents may need to be 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. An example of the introduction and / or removal of one or more protecting groups can be found in Examples 6, 17 and 18.

[0433] 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.

[0434] Kocienski, Thieme (2005).

[0435] The compounds of the first and second aspect of the present invention may be converted into a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi-formate, hydrochloride, hydrobromide, benzenesulfonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulfate, nitrate, phosphate, acetate, fumarate, semi-fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, i-hydroxy-2-naphthoate (xinafoate), methanesulfonate or p-toluenesulfonate salt. In one embodiment of the invention, the compounds of the first and second aspect are in the form of a hydrochloride, formate or fumarate salt. Examples of pharmaceutically acceptable salts of the compounds of the first and second aspect of the present invention may be found in Examples 17 and 18.

[0436] A salt of a compound of the first or second aspect of the present invention may also be formed between a protic acid functionality of a compound of the first or second aspect 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 sodium or potassium salt. Compounds of the first and second aspect of the present invention 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. In 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 the first or second aspect. Generally, the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds of the first and second aspect of the present invention can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound. 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%, more typically less than 1%, and most typically less than 0.5% by weight. Enantiomerically pure isomers are particularly desired.

[0437] The compounds, salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to12C,13C,XH,2H (D),14N,15N,160,170,180,19F and127I, and any radioisotope including, but not limited tonC,14C,3H (T),13N,150,18F, 1231,1241,1231 and131I. Therefore, the term “hydrogen”, for example, encompasses H,2H (D) and3H (T). Similarly, carbon atoms are to be understood to includeUC,12C,13C and14C, nitrogen atoms are to be understood to include13N,14N and15N, oxygen atoms are to be understood to include15O,160,17O and18O, fluorine atoms are to be understood to include18F and19F, and iodine atoms are to be understood to include1231,1241,1251,127I and131I.

[0438] 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 1-24.

[0439] In 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.

[0440] In one embodiment, the compounds, salts, solvates and prodrugs of the present invention may be tritiated, i.e. they contain one or more3H (T) atoms. Any of the compounds, salts, solvates and prodrugs of the present invention can be tritiated, for example, any of Examples 1-24.

[0441] 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.

[0442] 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 associated with CD38 activity. Diseases, disorders and conditions associated with CD38 activity include:

[0443] - CNS diseases and diseases requiring treatment via the CNS, including Parkinson’s disease (Camacho-Pereira et al, 2016, Cell Metab 23: 1127; Perez et al, 2021, Meeh Ag & Dev 197: 111499; Wakade et al, 2014, PLoS ONE 9: 0109818; Yao et al, 2021, rtpj Parkinsons Dis 7: 79); Alzheimer’s disease (Blacher et al, 2015, Ann Neurol 78: 88;

[0444] Sonntag et al, 2017, Sei Rep 7: 14038); frontotemporal dementia; progressive supranuclear palsy (PSP); tauopathies; other non-Alzheimer’s dementias; stroke and ischemic insults (Choe et al, 2011, PLoS ONE 6: 019046); traumatic brain injury (TBI) (Long et al, 2017, Neurochem Res 42: 283; Takaso et al, 2020, Sei Rep 10: 17795); multiple sclerosis (Herrmann et al, 2016, Dis Mods Meehs 9: 1211; Raboon et al, 2019, Front Cell Neurosci 13: 258); autoimmune diseases with associated neuronal damage such as Muckle-Wells syndrome; motor neuron disease such as amyotrophic lateral sclerosis (ALS) (Wang et al, 2017, Cell Rep 20: 2184); axonal neuropathy and axonal degeneration such as diabetic neuropathy (Lin et al, 2016, Cell Rep 17: 69); Wallerian degeneration (Essuman et al, 2017, Neuron 93: 1334; Takaso et al, 2020, Sei Rep 10: 17795; Krauss et al, 2020, TiPS 41: 281); ataxia telangiectasia, Friedreich’s ataxia and other ataxias such as spinocerebellar ataxia 7 (SCA7) (Fang et al, 2016, Cell Metab 24: 566);

[0445] - aging and senescence (Chini et al, 2017, Mol Cell Endocrinol 455: 62; Verdin, 2015, Science 350: 1208; Imai & Guarente, 2014, Trends Cell Biol 24: 464; Schultz &

[0446] Sinclair, 2016, Cell Metab 23: 965); - neuroinflammation (Choe et al, 2011, PLoS ONE 6: 019046; Raboon et al, 2019, Front Cell Neurosci 13: 258; Guerreiro et al, 2020, Cells 9: 471; Najjar et al, 2013, J Neuroinflamm 10: 43);

[0447] - depression, schizophrenia, anxiety, stress and post-traumatic stress disorder (PTSD) (Tabak et al, 2016, Clin Psychol Sci 4: 17);

[0448] - glaucoma and age-related macular degeneration (AMD) (Cimaglia et al, 2020, Nutrients 12: 2871; Jadeja et al, 2020, Oxidative Medicine and Cellular Longevity article 2692794);

[0449] - hearing loss (Brown et al, 2014, Cell Metab 20: 1059; Nakanishi et al, 2020, Frontiers in Neurology 11: article 141; Okur et al, 2020, npj Aging and Mechanisms of Disease

[0450] 6: 1);

[0451] - autoimmune diseases such as rheumatoid arthritis (RA) and Lupus (Cole et al, 2018, Arthritis Research & Therapy 20: 85; Garcia-Rodriguez et al, 2018, Scientific Reports 8: 3357); - obesity and metabolic syndrome (Barbosa et al, 2007, FASEB J 21: 3629; Chiang et al, 2015, PLoS ONE 10: 00134927).

[0452] Therefore, a fourth aspect of the present invention provides a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, for use in therapy, in particular for use in treating or preventing a disease, disorder or condition associated with CD38 activity.

[0453] The fourth aspect of the present invention also provides a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, for use in treating or preventing a CNS disease, a disease requiring treatment via the CNS, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disorder.

[0454] The fourth aspect of the present invention also provides a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, for use in treating or preventing Parkinson’s disease; Alzheimer’s disease; frontotemporal dementia; progressive supranuclear palsy; a tauopathy; another non-Alzheimer’s dementia; stroke; ischemic insult; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated neuronal damage such as Muckle-Wells syndrome; motor neuron disease such as amyotrophic lateral sclerosis; axonal neuropathy or axonal degeneration such as diabetic neuropathy; Wallerian degeneration; ataxia telangiectasia; Friedreich’s ataxia; another ataxia such as spinocerebellar ataxia 7; aging; senescence; neuroinflammation; depression; schizophrenia; anxiety; stress; post-traumatic stress disorder; glaucoma; age-related macular degeneration; hearing loss; an autoimmune disease such as rheumatoid arthritis or Lupus; obesity; or metabolic syndrome.

[0455] A fifth aspect of the present invention provides a use of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, for the manufacture of a medicament for treating or preventing a disease, disorder or condition associated with CD38 activity.

[0456] The fifth aspect of the present invention also provides a use of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, for the manufacture of a medicament for treating or preventing a CNS disease, a disease requiring treatment via the CNS, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disorder.

[0457] The fifth aspect of the present invention also provides a use of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, for the manufacture of a medicament for treating or preventing Parkinson’s disease;

[0458] Alzheimer’s disease; frontotemporal dementia; progressive supranuclear palsy; a tauopathy; another non-Alzheimer’s dementia; stroke; ischemic insult; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated neuronal damage such as Muckle-Wells syndrome; motor neuron disease such as amyotrophic lateral sclerosis; axonal neuropathy or axonal degeneration such as diabetic neuropathy;

[0459] Wallerian degeneration; ataxia telangiectasia; Friedreich’s ataxia; another ataxia such as spinocerebellar ataxia 7; aging; senescence; neuroinflammation; depression; schizophrenia; anxiety; stress; post-traumatic stress disorder; glaucoma; age-related macular degeneration; hearing loss; an autoimmune disease such as rheumatoid arthritis or Lupus; obesity; or metabolic syndrome.

[0460] A sixth aspect of the present invention provides a method of treating or preventing a disease, disorder or condition associated with CD38 activity; the method comprising administering a therapeutically or prophylactically effective amount of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, to a patient in need thereof. The sixth aspect of the present invention also provides a method of treating or preventing a CNS disease, a disease requiring treatment via the CNS, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disorder; the method comprising administering a therapeutically or prophylactically effective amount of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, to a patient in need thereof.

[0461] The sixth aspect of the present invention also provides a method of treating or preventing Parkinson’s disease; Alzheimer’s disease; frontotemporal dementia; progressive supranuclear palsy; a tauopathy; another non-Alzheimer’s dementia; stroke; ischemic insult; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated neuronal damage such as Muckle-Wells syndrome; motor neuron disease such as amyotrophic lateral sclerosis; axonal neuropathy or axonal degeneration such as diabetic neuropathy; Wallerian degeneration; ataxia telangiectasia; Friedreich’s ataxia; another ataxia such as spinocerebellar ataxia 7; aging; senescence; neuroinflammation; depression; schizophrenia; anxiety; stress; post-traumatic stress disorder; glaucoma; age-related macular degeneration; hearing loss; an autoimmune disease such as rheumatoid arthritis or Lupus; obesity; or metabolic syndrome; the method comprising administering a therapeutically or prophylactically effective amount of a compound, salt, solvate or prodrug according to the first or second aspect of the present invention, to a patient in need thereof.

[0462] Unless stated otherwise, in any of the fourth, fifth or sixth aspects of the invention, the subject or patient may be any human or other animal. Typically, the subject or patient is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Most typically, the subject is a human. 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.

[0463] 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 the disorder or condition or those in the prodromal phase of a disorder.

[0464] 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.

[0465] 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 a compound of the invention (that is, a compound of formula (I), (II), (III), (IV) or a pharmaceutically acceptable salt, solvate or prodrug thereof) by oral or parenteral administration may be in the range from 0.01 micrograms per kilogram body weight (pg / kg) to 500 milligrams per kilogram body weight (mg / kg). The desired dosage may be presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day.

[0466] The compounds 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.

[0467] Therefore, a seventh aspect of the present invention provides a pharmaceutical composition comprising a compound, salt, solvate or prodrug according to the first or second 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, salt, solvate or prodrug according to the first or second aspect of the present invention, with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0468] 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. Aulton, Churchill Livingstone, 1988.

[0469] 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 sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-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, ocularly, topically 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, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratracheal, intraperitoneal, intraarticular, and epidural injection or infusion techniques. The term topical as used herein includes transdermal, mucosal, sublingual and topical ocular administration.

[0470] The pharmaceutical compositions maybe in the form of a sterile injectable preparation, for 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 form including, but not limited to capsules, tablets, caplets, troches, lozenges, powders, granules, and aqueous suspensions, solutions, and dispersions. 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, sodium and calcium carbonate, sodium and calcium phosphate, and corn starch. Lubricating agents, such as magnesium stearate, stearic acid or talc, are also typically added. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and / or dissolving tablets. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavouring and / or colouring agents and / or preservatives may be added to any oral dosage form.

[0471] 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.

[0472] The pharmaceutical compositions of this invention may be administered by nasal aerosol 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.

[0473] For ocular administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in a form suitable for topical administration, e.g. as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels, and ocular inserts. Alternatively, the compounds, salts, solvates or prodrugs of the invention may be provided in a form suitable for other types of ocular administration, for example as intraocular preparations (including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants), as packs or corneal shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.

[0474] For transdermal and other topical administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches. 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 0.1 to 70% by weight, and even more preferably from 0.1 to 50% by weight of active ingredient, all percentages by weight being based on total composition.

[0475] The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.

[0476] 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, i.e. in the form of a kit.

[0477] Typically, the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented. Where one or more further active agents are administered, the mode of administration may be the same as or different to the mode of administration of the compound or pharmaceutical composition of the invention. Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent(s) within approved dosage ranges.

[0478] Definitions

[0479] An “alkyl” group may be linear (i.e. straight-chained) or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, zso-propyl, n-butyl, iso-butyl, sec-butyl, tertbutyl, n-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, and 2,2- dimethyl-1-propyl groups. Unless stated otherwise, the term “alkyl” does not include “cycloalkyl”. Typically an alkyl group is a C1-C12alkyl group. More typically an alkyl group is a C1-C6alkyl group. An “alkylene” group is similarly defined as a divalent alkyl group.

[0480] An “alkenyl” group is an unsaturated alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, 1-butenyl, 2- butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”. Typically an alkenyl group is a C2-C12alkenyl group. More typically an alkenyl group is a C2-C6alkenyl group. An “alkenylene” group is similarly defined as a divalent alkenyl group.

[0481] An “alkynyl” group is an unsaturated alkyl group having one or more carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups. Typically an alkynyl group is a C2-C12alkynyl group. More typically an alkynyl group is a C2-C6 alkynyl group. An “alkynylene” group is similarly defined as a divalent alkynyl group. A “cycloalkyl” group is a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl group maybe monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic.

[0482] A “cycloalkenyl” group is a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex- 1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic.

[0483] An “aryl” group is an aromatic hydrocarbyl ring. The term “aryl” includes monocyclic aromatic hydrocarbons (such as phenyl) and polycyclic fused-ring aromatic hydrocarbons (such as naphthyl, anthracenyl and phenanthrenyl). Unless stated otherwise, the term “aryl” does not include “heteroaryl”.

[0484] A “heterocyclic” group is a non-aromatic cyclic group which includes one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure. A heterocyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. Typically, a heterocyclic group is a 4- to 14- membered heterocyclic group, which means it contains from 4 to 14 ring atoms. More typically, a heterocyclic group is a 4- to 10-membered heterocyclic group, which means it contains from 4 to 10 ring atoms. Heterocyclic groups include unsaturated heterocyclic groups (such as azetinyl, tetrahydropyridinyl, and 2-oxo-1H-pyridinyl) and saturated heterocyclic groups. Examples of saturated monocyclic heterocyclic groups are azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups. Examples of saturated bicyclic heterocyclic groups are quinuclidinyl, 8-azabicyclo[3.2.i]octanyl, 2-azaspiro[3.3]heptanyl, 6-azaspiro[2.5]octanyl and hexahydro-1H-pyrrolizinyl groups.

[0485] A “heteroaryl” group is an aromatic cyclic group which includes one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure. Typically, a heteroaryl group is a 5- to 14-membered heteroaryl group, which means it contains from 5 to 14 ring atoms. More typically, a heteroaryl group is a 5- to 10-membered heteroaryl group, which means it contains from 5 to 10 ring atoms. The term “heteroaryl” includes monocyclic aromatic heterocycles (such as pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl) and polycyclic fused-ring aromatic heterocycles (such as indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzimidazolyl, 1H- imidazo[4,5-b]pyridinyl, iH-imidazo[4,5-c]pyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl and cinnolinyl). Examples of heteroaryl groups include the following: wherein G = O, S or NH.

[0486] Accordingly, a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, may be a pyrazolyl, imidazolyl, thiazolyl or isothiazolyl group.

[0487] For the purposes of the present specification, where a combination of moieties is referred to as one group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl.

[0488] The term “halo” includes fluoro, chloro, bromo and iodo. In one embodiment, halo is fluoro. Unless stated otherwise, where a group is prefixed by the term “halo”, such as a “haloalkyl” or “halomethyl” group, it is to be understood that the group in question is substituted with one or more (such as one, two, three, four or five) halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix. For example, a “halomethyl” group may contain one, two or three halo substituents. A “haloethyl” or “halophenyl” group may contain one, two, three, four or five halo substituents. Similarly, unless stated otherwise, where a group is prefixed by a specific halo group, it is to be understood that the group in question is substituted with one or more (such as one, two, three, four or five) of the specific halo groups. For example, the term “fluoromethyl” refers to a methyl group substituted with one, two or three fluoro groups, and the term “fluoroethyl” refers to an ethyl group substituted with one, two, three, four or five fluoro groups.

[0489] Similarly, unless stated otherwise, where a group is said to be “halo-substituted”, it is to be understood that the group in question is substituted with one or more (such as one, two, three, four or five) halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without halo substitution. For example, a “halo-substituted methyl” group may contain one, two or three halo substituents. A “halo-substituted ethyl” or “halo-substituted phenyl” group may contain one, two, three, four or five halo substituents. Similarly, unless stated otherwise, where a group is said to be substituted with a specific halo group, such as a “fluoro-substituted” group, it is to be understood that the group in question is substituted with one or more (such as one, two, three, four or five) of the specific halo groups. For example, the term “fluoro-substituted methyl” refers to a methyl group substituted with one, two or three fluoro groups, and the term “fluoro- substituted ethyl” refers to an ethyl group substituted with one, two, three, four or five fluoro groups.

[0490] A “hydroxyalkyl” group is an alkyl group substituted with one or more (such as one, two or three) hydroxyl (-OH) groups. Typically a hydroxyalkyl group has one or two hydroxyl substituents, more typically a hydroxyalkyl group has one hydroxyl substituent. Unless stated otherwise, any reference to an element is to be considered a reference to all isotopes of that element. Thus, for example, unless stated otherwise, any reference to hydrogen is considered to encompass all isotopes of hydrogen including H,2H (D) and3H (T). Therefore, for the avoidance of doubt, it is noted that, for example, the terms “alkyl” and “methyl” include, for example, trideuteriomethyl.

[0491] Unless stated otherwise, any reference to a compound or group is to be considered a reference to all tautomers of that compound or group. When any chemical group or moiety 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.

[0492] Examples

[0493] 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 or procedures similar to the ones described in this application.

[0494] Abbreviations

[0495] General procedures

[0496] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as stated and at 298.2K or 294.1K unless otherwise stated; the chemical shifts (8) are reported in parts per million. Spectra were recorded using a Bruker® 400 AVANCE instrument fitted with a 5 mm iprobe or smart probe with instrument controlled by Bruker TopSpin 4.0.9 or Bruker TopSpin 4.1.1 software.

[0497] Reactions were monitored using one or more of the following: Agilent 1290 infinity II UPLC coupled with 6130 quadrupole LCMS: mobile phase A: 0.037% TFA in H2O; mobile phase B: 0.018% TFA in CH3CN; column: Xtimate® C18 2.1x30mm, 3μm; column temperature: 50 °C; sample temperature: RT; detection (nm): 220 nm and 254 nm; flow rate: 1.0 mL / min; analysis time: 4.0 min.; measured mass range: 100 to 1500 m / z.

[0498] Purity was assessed using the following: UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-254 nm, using Shimadzu® Nexera X2 UPLC controlled by Lab Solution software equipped with Acquity UPLC BEH, HSS or HSS T3 C18 columns (2.1mm id x 50 mm long) operated at 50 °C. Unless stated otherwise, mobile phases typically consisted of CH3CN mixed with H2O containing either 0.037% TFA or 0.225% HCOOH. Mass spectra were recorded with a Shimadzu single quadrupole mass spectrometer using DUIS ionisation.

[0499] Compounds were purified using Biotage or ISCO® instrument using normal phase chromatography on silica or by preparative high performance liquid chromatography (HPLC).

[0500] Preparative HPLC was performed using Gilson GX-281 system using Phenomenex C18 75x30mm, 3μm; Xtimate C18 100x30mm, 10μm; Xtimate C18 150x40mm, 10μm;

[0501] Xtimate C18 150x40mm, 10μm; Phenomenex C18 75x30mm, 3μm or Gemini NX C18 10x150mm, 5μm columns at RT. Mobile phases typically consisted of CH3CN mixed with H2O containing either 0.225% formic acid or 0.05% ammonia + 10 nM NH4HCO3, unless otherwise stated. Super Critical Fluid Chromatography (SFC) chiral analysis were performed on a Waters UPCC with PDA Detector, using a flow rate of 4 mL / min, temperature of RT to 35 °C and a pressure of 1500 psi. Mobile phases typically consisted of supercritical C02and a polar solvent such as CH3CN, MeOH, EtOH or isopropanol. Column type and eluent are detailed for individual examples. Columns: Chiralpak OD-3 50x4.6mm, 3μm; Chiralpak AD-3 50x4.6mm, 3μm; Chiral NS-3 100x4.6mm, 3μm; Chiral MD-3 100x4.6mm, 3μm; Chiralpak IG 50x4.6mm, 3μm; (S,S)-Whelk-o-1.8 50x4.6mm,

[0502] 1.8μm; Chiralpak OJ-3100x4.6mm, 3μm.; Detection: 220 nm; sample diluent: CH3CN, MeOH; injection: 9 μl; isocratic ratio: 5% to 40% of mobile phase.

[0503] ‘Room temperature’, as used in the present specification, means a temperature in the range from about 18 °C to about 25 °C.

[0504] Synthesis of Intermediates

[0505] Intermediate 1: 4-(1-methyl-iH-imidazol-5-yl)thiazole-2-carboxylic acid Step 1: A mixture of methyl 4-bromothiazole-2-carboxylate (100 mg, 0.450 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)imidazole (93.7 mg, 0.450 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride (36.8 mg, 0.045 mmol) and K2CO3(187 mg, 1.35 mmol) in 1,4-dioxane (0.6 mL) and H2O (0.2 mL) was degassed and purged with N2(3x), and the reaction mixture was stirred at 90 °C for 1 h under N2atmosphere. Then the reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4and filtered. The filtrate was evaporated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of o~ioo% EtOAc / petroleum ether @ 30 mL / min) to give methyl 4-(3-methylimidazol-4-yl)thiazole-2-carboxylate (17 mg, 0.076 mmol, 16.9% yield) as a black solid.1H NMR (400 MHz, DMSO-d6) 8.32-8.21 (m, 1H), 7.80-7.67 (m, 1H), 7-41-7-34 (m, 1H), 3.99-3.82 (m, 6H).

[0506] Step 2: A solution of methyl 4-(3-methylimidazol-4-yl)thiazole-2-carboxylate (17 mg, 0.076 mmol) in THF (0.1 mL) was treated with 1M LiOH aq. solution (0.228 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with 1M HC1 aq. solution to adjust the pH to 6-7 at o °C and concentrated under reduced pressure to give the title compound (15 mg, crude, as a yellow solid) which was used without further purification. MS ES+: 209.9. Intermediate 2: 3-(1-methyl-1H-imidazol-5-yl)-i,2,4-thiadiazole-5- carboxylic acid Step 1: A mixture of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (1 g, 5.01 mmol) and tributyl(1-ethoxyvinyl)stannane (2.17 g, 6.02 mmol) in DMF (10 mL) was treated with Pd(PPh3)2Cl2(352 mg, 0.501 mmol), added in one portion at 25 °C under N2. The mixture was stirred at 60 °C for 4 h. The reaction solution was quenched with excess sat. KF aq. solution. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL), the combined organic layers were concentrated to afford crude product which was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent of 0-15% EtOAc / petroleum ether @ 40 mL / min) to give 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (710 mg, 3.02 mmol, 60.2% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5.45 (d, J = 3.0 Hz, 1H), 4.92-4.83 (m, 1H), 4.13-3.98 (m, 2H), 1.39-1-31 (m, 3H).

[0507] Step 2: To a solution of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (710 mg, 3.02 mmol) in 1,4-dioxane (5.3 mL) was added KMnO4(716 mg, 4.53 mmol) and NaIO4(1.94 g, 9.06 mmol) in H2O (1.7 mL), in one portion at o °C. The mixture was stirred at 25 °C for 17 h. After this time, the pH was adjusted to 7-8 by slowly controlling the pH with sat. sodium bicarbonate aq. solution. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were concentrated to afford crude product which was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent of 0-15% EtOAc / petroleum ether @ 40 mL / min) to give ethyl 3-bro mo-1,2, 4-thiadiazole-5- carboxylate (250 mg, 1.05 mmol, 34.9% yield) as a colourless liquid.1H NMR (400 MHz, DMSO-d6) 4-44 (q, J = 7-1 Hz, 2H), 1.35 (t, J = 7-1 Hz, 3H).

[0508] Step 3: To a mixture of ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate (100 mg, 0.422 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (105 mg, 0.506 mmol) and K2CO3(175 mg, 1.27 mmol) in 1-4, dioxane (0.75 mL) and H2O (0.25 mL) was added Pd(dppf)Cl2·CH2Cl2(34.5 mg, 0.0422 mmol) in one portion at 25

[0509] °C under N2. The mixture was stirred at 110 °C for 12 h. The reaction mixture was quenched with 1M HC1 aq. solution to pH = 6-7 at 0 °C and diluted with H2O (20 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (too mg, crude) as a black solid, which was used without further purification. MS ES+: 210.2. Intermediate 3: 4-bromo-N-((ir,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide

[0510] A solution of 4-bromothiazole-2-carboxylic acid (3.4 g, 16.3 mmol) and (trans)-N1- (2,2,2-trifluoroethyl)cyclohexane-1,4-diamine hydrochloride (3.85 g, 19.6 mmol) in DMF (35 mL) was treated with TEA (4.96 g, 49.0 mmol) and HATU (9.32 g, 24.5 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to afford crude product which was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, eluent of o~75% EtOAc / petroleum ether, gradient @ 50 mL / min) to give the title compound (3.6 g, 22.8% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.78 (br d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 3.75-3.67 (m, 1H), 3.23 (br dd, J = 5.4, 9.8 Hz, 2H), 2.37 (br s, 1H), 2.16 (br d, J = 15.3 Hz, 1H), 1.93-1.88 (m, 2H), 1.77 (br d, J = 10.5 Hz, 2H), 1.54-1.41 (m, 2H), 1.11-1.01 (m, 2H).

[0511] Intermediate 4: 5-bromo-1-(2-fluoroethyl)-iH-imidazole

[0512] A solution of 5-bromo-1H-imidazole (2 g, 13.6 mmol) in MeCN (40 mL) was treated with Cs2CO3(4.43 g, 13.6 mmol) and 1-fluoro-2-iodoethane (2.37 g, 13.6 mmol). The mixture was stirred at 50 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep. HPLC (Column: Welch Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 0% B to 36%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give crude product which was purified by SFC separation (separation condition: Daicel ChiralPak IG (250 x 30mm, 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% NH3H2O), A:B = 20:20 at 80 mL / min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C;

[0513] Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the solution was lyophilized to dryness to give the title compound (492 mg, 17.8% yield) as a yellow oil. MS ES+: 194.0.

[0514] Intermediate 5: 2-bromo-N-((ir,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide A solution of 2-bromothiazole-4-carboxylic acid (1 g, 4.81 mmol), (ir,4r)-N1-(2,2,2- trifluoroethyl)cyclohexane-i,4-diamine hydrochloride (1.12 g, 4.81 mmol) and TEA (1.46 g, 14.4 mmol) in DMF (10 mL) was treated with HATU (2.74 g, 7.21 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was poured into sat. NaHCO3aq. solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent of 0~20% EtOAc / petroleum ether, gradient @ 60 mL / min) to give the title compound (1.13 g, 47.4% yield) as a white solid. MS ES+: 387-9-

[0515] Intermediate 6: 5-bromo-1-(2,2-difluoroethyl)-iH-imidazole

[0516] A solution of 5-bromo-1H-imidazole (2 g, 13.6 mmol) in MeCN (30 mL) was treated with Cs2CO3(8.87 g, 27.22 mmol) and 1,1-difluoro-2-iodoethane (2.61 g, 13.61 mmol). The mixture was stirred at 50 °C for 12 h. The reaction mixture was extracted with EtOAc (3 x 30 mL) and water (30 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of o~35% EtOAc / petroleum ether, gradient @ 50 mL / min) to give crude product which was purified by SFC separation (separation condition: Daicel ChiralCel OD (250 x 50mm, 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% NH3H2O), A:B = 55:45 at 80 mL / min; Column Temp: 38 °C; Nozzle Pressure: too Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to diyness to give the title compound (170 mg, 6.0% yield) as yellow oil. MS ES+: 211.0.

[0517] Intermediate 7: N2-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2,6-diamine hydrochloride

[0518] Step 1: A solution of tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (1 g, 4.44 mmol) and 2,2,2-trifluoroethan-1-amine (528 mg, 5.33 mmol) in dichloromethane (10 mL) was treated with Ti(i-PrO)4(1.26 g, 4.44 mmol). After stirring for 1 h, NaBH3CN (279 mg, 4.44 mmol) was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®, 12g Sepa Flash® Silica Flash Column, eluent of o~45% EtOAc / petroleum ether, gradient @ 35 mL / min) to give tert- butyl (6-((2,2,2-trifluoroethyl)amino)spiro[3.3]heptan-2-yl)carbamate (880 mg, crude) as a white solid.1H NMR (400 MHz, CDCl3) 4.54 (br d, J = 2.0 Hz, 1H), 4.00-3.89 (m, 1H), 3.18 (quin, J = 7.7 Hz, 1H), 3.05-2.96 (m, 2H), 2.51-2.07 (m, 5H), 1.78-1.70 (m, 2H), 1.69-1.63 (m, 2H), 1.36 (s, 9H).

[0519] Step 2: A solution of tert-butyl (6-((2,2,2-trifluoroethyl)amino)spiro[3.3]heptan-2- yl)carbamate (830 mg, 2.69 mmol) in dichloromethane (8 mL) was treated with 4M HC1 in dioxane (8.30 mL). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (355 mg, crude) as an off-white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 8.28-7.95 (m, 3H), 3.94- 3-8O (m, 1H), 3.69-3.53 (m, 2H), 3.20-3.07 (m, 1H), 2.43-2.27 (m, 4H), 2.26-2.11 (m,4H).

[0520] Intermediate 8: (1S,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexan-1-amine

[0521] Step 1: A solution of 4-(dibenzylamino)cyclohexanone (4.5 g, 15.3 mmol) and (3S)-3- fluoropyrrolidine hydrochloride (1.93 g, 15.3 mmol) in dichloromethane (60 mL) was treated with AcOH (921 mg, 15.3 mmol) until the pH was adjusted to around 5. The mixture was stirred at 25 °C for 1 h. Then NaBH(OAc)3(4.88 g, 23.0 mmol) was added and the mixture was stirred at 25 °C for 11 h. The reaction mixture was quenched with sat. NaHCO3aq. solution (120 mL), and then diluted with H2O (130 mL) and extracted with dichloromethane (3 x 250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, eluent of o~ioo% EtOAc / petroleum ether, gradient @ 70 mL / min) to give (1S,4r)-N,N-dibenzyl-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexan-1- amine (5.9 g, 50.5% yield) as white solid.1H NMR (400 MHz, DMSO-d6) 7.36-7.16 (m, 10H), 5.21-5.03 (m, 1H), 3.56 (s, 4H), 2.87-2.72 (m, 2H), 2.69-2.55 (m, 1H), 2.44-2.27 (m, 2H), 2.11-1.91 (m, 4H), 1.87-1.70 (m, 3H), 1.38 (dq, J = 2.4, 12.4 Hz, 2H), 1.08-0.90 (m, 2H).

[0522] Step 2: A solution of (iS,4r)-N,N-dibenzyl-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexan-1- amine (5.9 g, 16.10 mmol) in MeOH (60 mL) was treated with Pd(OH)2(2.26 g, 3.22 mmol, 20% purity). The reaction mixture was degassed and purged with H2(3x). The mixture was stirred at 50 °C for 12 h under H2atmosphere (50 psi). The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated to afford the title compound (3 g, crude) a white solid.1H NMR (400 MHz, DMSO-d6) 6.79 (br s, 2H), 5.26-5.03 (m, 1H), 2.91-2.54 (m, 4H), 2.38-2.27 (m, 1H), 2.12-1.93 (m, 2H), 1.87 (br t, J = 12.4 Hz, 4H), 1.70 (s, 1H), 1.33-1.04 (m, 4H). Intermediate 9: (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine

[0523] Step 1: A solution of 4-(dibenzylamino)cyclohexan-1-one (2.91 g, 9.92 mmol) and 3,3- difluoropyrrolidine hydrochloride (1.71 g, 11.90 mmol) in CHC13(30 mL) was treated with AcOH (596 mg, 9.92 mmol) and after 1 h was treated with NaBH(OAc)3(3.15 g, 14.9 mmol). The mixture was stirred at 25 °C for 5 h. Then the mixture was treated with

[0524] 1M NaHCO3aq. solution (300 mL), and extracted with dichloromethane (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether: EtOAc = 1: o to o: 1) to give (ir,4r)-N,N- dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (1.65 g, 43.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 7.35-7.26 (m, 8H), 7.23-7.14 (m, 2H), 3.57 (s, 4H), 2.91-2.65 (m, 6H), 2.17 (dt, J = 7.4, 15.0 Hz, 2H), 1.93-1.79 (m, 4H), 1.44-1.33 (m, 2H), 1.02-0.89 (m, 2H).

[0525] Step 2: A mixture of (ir,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1- amine (1 g, 2.60 mmol), Pd(OH)2(913 mg, 1.30 mmol) in EtOH (10 mL) was degassed and purged with H2(3x), and then the mixture was stirred at 50 °C for 17 h under H2(50 psi) atmosphere. The mixture was concentrated under reduced pressure to give the title compound (510 mg, crude), which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 3.44 (q, J = 7.0 Hz, 1H), 2.88 (t, J = 13.8 Hz, 2H), 2.70 (t, J = 7.0 Hz, 2H), 2.50 -2.41 (m, 2H), 2.26-2.11 (m, 2H), 2.04-1.95 (m, 1H), 1.90-1.67 (m, 4H), 1.14-0.95 (m, 4H).

[0526] Intermediate 10: N1-(2,2-difluoroethyl)cyclohexane-i,4-diamine hydrochloride

[0527] Step 1: A solution of 2,2-difluoroethan-1-amine (1 g, 12.3 mmol) and tert-butyl (4- oxocyclohexyl)carbamate (2.19 g, 10.3 mmol) in dichloromethane (20 mL) was treated with Ti(i-PrO)4(5.84 g, 20.6 mmol). After stirring for 1 h, NaBH3CN (1.94 g, 30.8 mmol) was added. The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were concentrated to afford a residue which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of O~5O% EtOAc / petroleum ether, gradient @ 50 mL / min) to give tert-butyl (4-((2,2- difluoroethyl)amino)cyclohexyl)carbamate (1.9 g, 66.4% yield) as a colourless oil.1H NMR (400 MHz, DMSO-d6) 6.78-6.61 (m, 1H), 6.10-5.70 (m, 1H), 4.18-4.04 (m, 1H),

[0528] 3.17-3.16 (m, 1H), 2.90-2.79 (m, 2H), 2.38-2.19 (m, 1H), 1.86-1.65 (m, 4H), 1.58-1.42 (m, 2H), 1.39-1.34 (m, 9H), 1.13-0.96 (m, 2H).

[0529] Step 2: A solution of tert-butyl (4-((2,2-difluoroethyl)amino)cyclohexyl)carbamate (1.9 g, 6.83 mmol) in dichloromethane (10 mL) was treated with 4M HC1 in dioxane (20 mL). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated under reduced pressure to give the title compound (1.75 g, crude) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 6.80-6.27 (m, 1H), 3.57 (s, 3H), 3.42-3.41 (m, 2H), 3.20-2.81 (m, 2H),

[0530] 2.18-1.37 (m, 8H).

[0531] Intermediate 11: N1-(2,2-difluoropropyl)cyclohexane-i,4-diamine hydrochloride Step 1: A solution of tert-butyl (4-oxocyclohexyl)carbamate (1 g, 4.69 mmol) and 2,2- difluoropropan-1-amine hydrochloride (945 mg, 5.63 mmol) in dichloromethane (20 mL) was treated with Ti(i-PrO)4(2.67 g, 9.38 mmol). After stirring for 1 h, NaBH3CN (884 mg, 14.1 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then the mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to afford a residue which was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, eluent of 20~30% EtOAc / petroleum ether, gradient @ 20 mL / min) to give tert-butyl (4-((2,2- difluoropropyl)amino)cyclohexyl)carbamate (180 mg, 2.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 6.68 (br d, J = 7.9 Hz, 1H), 3.34 (s, 1H), 3.18-3.09 (m, 1H), 2.84 (t, J = 14.1 Hz, 2H), 2.30-2.23 (m, 1H), 1.88-1.80 (m, 2H), 1.72 (br d, J = 11.0 Hz,

[0532] 2H), 1.56 (t, J = 19.1 Hz, 3H), 1.36 (s, 9H), 1.17-1.07 (m, 2H), 1.05-0.93 (m, 2H).

[0533] Step 2: To a mixture of tert-Butyl (4-((2,2-difluoropropyl)amino)cyclohexyl)carbamate (180 mg, 0.616 mmol) in dichloromethane (1 mL) was added 4M HC1 in dioxane (2 mL) and then stirred at 25 °C for 0.5 h. Then the reaction mixture was concentrated under reduced pressure to give the title compound (130 mg, crude), which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 9.44 (br s, 1H), 8.20 (br d, J = 1.8 Hz, 2H), 3.62-3.54 (m, 2H), 3.06-2.91 (m, 2H), 2.20-2.00 (m, 4H), 1.78 (t, J = 194 Hz, 3H), 1.58-1.32 (m, 4H).

[0534] Intermediate 12: 4-(1H-imidazol-1-yl)thiazole-2-carboxylic acid

[0535] A mixture of 4-bromothiazole-2-carboxylic acid (500 mg, 2.40 mmol), 1H-imidazole (164 mg, 2.40 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (342 mg, 2.40 mmol), Cs2CO3(2.35 g, 7.21 mmol) and Cui (229 mg, 1.20 mmol) in DMF (5 mL) was degassed and purged with N2(3x), and then the mixture was stirred at 90 °C for 2 h under microwave irradiation. The reaction mixture was quenched with NH3H2O (3 mL), and then extracted with dichloromethane (3 x 3 mL). The aqueous phase was freeze-dried to give a residue which was further purified by prep. HPLC (Column: Xtimate C18 150 x 40mm x 10 μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 0% B to 18%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (160 mg, 33.2% yield) as a blue solid.1H NMR (400 MHz, D2O) 8.58-8.32 (m, 1H), 7.71-7.64 (m, 2H), 7.48-7.33 (m, 1H), 7.29-7.10 (m, 1H).

[0536] Intermediate 13: 4-((3,3-difluoropyrrolidin-1-yl)methyl)aniline

[0537] Step 1: A solution of 1-(bromomethyl)-4-nitrobenzene (5 g, 23.1 mmol) in THF (50 mL) was treated with 3,3-difluoropyrrolidine (2.97 g, 27.8 mmol) and TEA (7.03 g, 69.4 mmol). The mixture was stirred at 25 °C for 1 h. Then the mixture was filtered, and the filter liquor was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0~50% EtOAc / petroleum ether, gradient @ 50 mL / min) to give 3,3- difluoro-1-(4-nitrobenzyl)pyrrolidine (3.96 g, 68.2% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.26-8.11 (m, 2H), 7.58 (d, J = 8.8 Hz, 2H), 3.76 (s, 2H), 2.88 (t, J = 13.3 Hz, 2H), 2.71 (t, J = 7.0 Hz, 2H), 2.34-2.17 (m, 2H).

[0538] Step 2: A solution of 3,3-difluoro-1-(4-nitrobenzyl)pyrrolidine (500 mg, 2.06 mmol) and NH4CI (2.21 g, 41.3 mmol) in H20 (2 mL) and EtOH (10 mL) was treated with iron powder (576 mg, 10.3 mmol). The mixture was stirred at 95 °C for 1 h. Then the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saline (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~50% EtOAc / petroleum ether, gradient @ 30 mL / min) to give the title compound (143 mg, 23.3% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 6.92 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 8.3 Hz, 2H), 4.97 (s, 2H), 3.40 (s, 2H), 2.76 (t, J = 13.4 Hz, 2H), 2.61 (t, J = 6.9 Hz, 2H), 2.27-2.13 (m, 2H).

[0539] Intermediate 14: 6-(4-(2,2,2-trifluoroethyl)piperazin-i-yl)pyridin-3-amine

[0540] Step 1: A solution of 2-bromo-5-nitropyridine (1.00 g, 4.93 mmol) in DMSO (10 mL) was treated with K2CO3(2.04 g, 14.8 mmol) and i-(2,2,2-trifluoroethyl)piperazine (828 mg, 4-93 mmol). The mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with H20 (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(5-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.4 g, 89.9% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) 9.04 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.5 Hz, 1H), 6.57 (d, J = 9.5 Hz, 1H), 3.86-3.76 (m, 4H), 3.06 (q, J = 9.5 Hz, 2H), 2.84-2.75 (m, 4H).

[0541] Step 2: To a solution of 1-(5-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (500 mg, 1.72 mmol) in MeOH (5 mL) was added Pd / C (200 mg, 0.188 mmol, 10% purity). The mixture was stirred at 25 °C for 12 h under H2(15 psi). The mixture was filtered and concentrated under reduced pressure to give the title compound (410 mg, 91.5% yield) as a white solid.1H NMR (400 MHz, CDCl3) 7.80 (d, J = 2.9 Hz, 1H), 7.04-6.96 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 3.45-3.36 (m, 4H), 3.03 (q, J = 9.6 Hz, 2H), 2.84-2.75 (m, 4H).

[0542] Intermediate 15: 2-(iH-imidazol-1-yl)thiazole-4-carboxylic acid

[0543] Step 1: A mixture of methyl 2-bromothiazole-4-carboxylate (2 g, 9.01 mmol), 1H- imidazole (736 mg, 10.81 mmol), Cs2CO3(8.80 g, 27.0 mmol) and RuPhos Pd G3 (753 mg, 0.901 mmol) in 1,4-dioxane (30 mL) was degassed and purged with N2(3x), and then the mixture was stirred at 100 °C for 12 h under N2atmosphere. The reaction mixture was partitioned between water (50 ml) and EtOAc (3 x 50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of o~ioo% EtOAc / petroleum ether, gradient @ 80 mL / min) to give methyl 2-(IH- imidazol-1-yl)thiazole-4-carboxylate (166 mg, 7.3% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.49-8.41 (m, 2H), 7.89 (s, 1H), 7.19 (s, 1H), 3.85 (s, 3H).

[0544] Step 2: A solution of methyl 2-(1H-imidazol-1-yl)thiazole-4-carboxylate (166 mg, 0.793 mmol) in THF (2 mL) was treated with 1M NaOH aq. solution (1.59 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was acidified by 1M HC1 aq. solution until pH = 5-6 and then concentrated under reduced pressure to give the title compound (357 mg, crude) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 7.14 (s, 1H). Intermediate 16: 3-(5-methyl-iH-imidazol-1-yl)-i,2,4-thiadiazole-5- carboxylic acid

[0545] A solution of ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (300 mg, 1.56 mmol) in MeCN (0.5 mL) was treated with K2CO3(646 mg, 4.67 mmol) and 5-methyl-1H- imidazole (153 mg, 1.87 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with 1M HC1 aq. solution to pH = 7-8 at 0 °C and concentrated under reduced pressure to give the title compound (205 mg, crude) as a yellow oil, which was used into the next step without further purification.

[0546] Intermediate 17: N1-(1,1,1-trifluoro-a-methylpropan-a-yDcyclohexane-i^- diamine hydrochloride

[0547] Step 1: To a solution of tert-butyl (4-oxocyclohexyl)carbamate (500 mg, 2.34 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride (460.17 mg, 2.81 mmol) in dichloromethane (5 mL) was added titanium(IV) propan-2-olate (1.33 g, 4.69 mmol) and after stirring for 1 h, sodium cyanotrihydroborate (442 mg, 7.03 mmol) was added.

[0548] The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of o~ioo% EtOAc / petroleum ether, gradient @ 50 mL / min) to give tert-butyl (4-(( 1,1,1-trifluoro- 2-methylpropan-2-yl)amino)cyclohexyl)carbamate (168 mg, 22.1% yield) as a colourless solid.1H NMR (400 MHz, CDCl3) 4.35 (br d, J = 7.0 Hz, 1H), 3.43-3.26 (m, 1H), 2.77-2.60 (m, 1H), 2.00-1.92 (m, 2H), 1.86 (br d, J = 12.2 Hz, 2H), 1.69-1.58 (m, 4H), 1.52 (s, 1H), 1.44 (s, 15H).

[0549] Step 2: To a solution of tert-butyl (4-((1,i,i-trifluoro-2-methylpropan-2- yl)amino)cyclohexyl)carbamate (160 mg, 0.493 mmol) in dichloromethane (2 mL) was added 4M HC1 in dioxane (1.97 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (120 mg, 93.3% yield) as a white solid which was used without further purification.1H

[0550] NMR (400 MHz, DMSO-d6) 2.52 (br s, 1H), 2.13 (br d, J = 12.2 Hz, 2H), 2.02 (br d, J = 12.4 Hz, 2H), 1.94-1.85 (m, 2H), 1.81-1.71 (m, 3H), 1.62 (br s, 6H), 1.42 (br s, 1H).

[0551] Intermediate 18: (ir,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1-amine Step 1: A solution of 4-(dibenzylamino)cyclohexan-1-one (5 g, 17.0 mmol) and 3,3- difluoroazetidine hydrochloride (2.65 g, 20.5 mmol) in chloroform (30 mL) was treated with AcOH (1.02 g, 17.04 mmol). The mixture was stirred at 25 °C for 1 h. Then sodium triacetoxyborohydride (5.42 g, 25.6 mmol) was added and the mixture was stirred at 25 °C for 4 h. The mixture was treated with 1M aq. NaOH solution (20 mL), and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 8~10% EtOAc / petroleum ether, gradient @ 50 mL / min) to give N,N-dibenzyl-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1-amine (2.78 g, 27.3% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 7.36-7.25 (m, 8H), 7.22-7.16 (m, 2H), 3.56 (s, 4H), 3.47 (t, J = 12.4 Hz, 4H), 2.43-2.32 (m, 1H), 2.07-1.95 (m, 1H), 1.84-1.67 (m, 4H), 1.44-1.29 (m, 2H), 0.89-0.71 (m, 2H).

[0552] Step 2: A solution of N,N-dibenzyl-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1-amine (2.78 g, 7.50 mmol) in MeOH (30 mL) was treated with Pd(OH)2(527 mg, 0.750 mmol,

[0553] 20% purity). The mixture was stirred at 50 °C for 12 h under H2atmosphere (50 psi). Then the reaction mixture was filtered, washed with MeOH (3 x 50 mL) and the combined organics were concentrated under reduced pressure to give the title compound (1.25 g, 87.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 3.49 (t, J = 12.4 Hz, 4H), 2.48-2.39 (m, 1H), 2.00 (br d, J = 3.6 Hz, 1H), 1.74-1.59 (m, 4H), 1.07-0.81 (m, 4H).

[0554] Synthesis of Examples Example 1: 4-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide

[0555] A solution of 4-(1-methyl-1H-imidazol-5-yl)thiazole-2-carboxylic acid (Intermediate

[0556] 1) (15 mg, 0.071 mmol) in dichloromethane (0.1 mL) was treated with N4-(2,2,2- trifluoroethyl)cyclohexane-1,4-diamine hydrochloride (17.0 mg, 0.086 mmol), HATU (40.9 mg, 0.107 mmol) and TEA (21.7 mg, 0.215 mmol). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated under reduced pressure. The product was purified by prep. HPLC (Column: Welch Xtimate C18 150 x 30mm x 5μm, Mobile Phase A: water (NH4HCO3-MeCN) Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 10% B to 50%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (1.10 mg, 3.9% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 8.54-8.42 (m, 1H), 8.11-8.04 (m, 1H), 7.82-7.68 (m, 1H), 7.47-7.25 (m, 1H), 3.88-3.84 (m, 3H), 3.80-3.70 (m, 1H), 3.24 (br dd, J = 7.7, 10.1 Hz, 2H), 2.46-2.36 (m, 1H), 2.25-

[0557] 2.16 (m, 1H), 1.96-1.80 (m, 4H), 1.55-1.45 (m, 2H), 1.16-1.05 (m, 2H). MS ES+: 387.9. SFC: Rt = 2.108 min, 100% chiral purity.

[0558] Example 2: 3-(1-methyl-1H-imidazol-5-yl)-N-((ir,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide

[0559] Following the procedure as described for Example 1 using 3-(1-methyl-1H-imidazol-5- yl)-1,2,4-thiadiazole-5-carboxylic acid (Intermediate 2) (100 mg, 0.476 mmol) and (trans)-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine hydrochloride (111 mg, 0.478 mmol) gave the title compound (12.70 mg, 6.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 9. oo (br d, J = 8.4 Hz, 1H), 7.92-7.84 (m, 1H), 7.78-7.69 (m, 1H), 4.01 (s, 3H), 3.81-3.70 (m, 1H), 3.29-3.14 (m, 3H), 2.41 (br t, J = 10.9 Hz, 1H), 1.93 (br d, J = 12.0 Hz, 2H), 1.83 (br d, J = 10.9 Hz, 2H), 1.58-1.43 (m, 2H), 1.12-0.99 (m, 2H). MS ES+: 388.4.

[0560] Example 3: 4-(1-(2-fluoroethyl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide

[0561]

[0562] A mixture of 5-bromo-1-(2-fluoroethyl)-1H-imidazole (Intermediate 4) (200 mg, 1.04 mmol), 4-bromo-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2- carboxamide (Intermediate 3) (400 mg, 1.04 mmol), bis(pinacolato)diboron (526 mg, 2.07 mmol), bis(1-adamantyl)-butyl-phosphane (37.2 mg, 0.104 mmol), CsF (315 mg, 2.07 mmol) and Pd(OAc)2(23.3 mg, 0.104 mmol) in toluene (4 mL) and MeOH (4 mL) was degassed and purged with N2(3x), and then the mixture was stirred at 80 °C for 16 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep. HPLC (Column: Phenomenex Luna C18 150 x 40mm x 10 μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 16% B to 56%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (28.18 mg, 6.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.43 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 4.75-4.63 (m, 3H), 4.59-4.54 (m, 1H), 3.79- 3.67 (m, 1H), 3.25 (q, J = 10.3 Hz, 3H), 2.46-2.38 (m, 1H), 1.93 (br d, J = 12.0 Hz, 2H), 1.82 (br d, J = 10.3 Hz, 2H), 1.53-1.42 (m, 2H), 1.16-1.06 (m, 2H). MS ES+: 420.1. SFC: Rt = 2.12 min, 100% chiral purity.

[0563] Example 4: 2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide

[0564] A mixture of 2-bromo-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-4- carboxamide (Intermediate 5) (200 mg, 0.518 mmol), 1-methyl-5-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (108 mg, 0.518 mmol) and K2CO3(215 mg, 1.55 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.5 mL) was degassed and purged with N2(3x), and then [1,1-[1,1- bis(diphenylphosphino)ferrocene]palladium(II)chloride (37.9 mg, 0.052 mmol) was added and the resulting mixture was stirred at 110 °C for 2 h under N2atmosphere. Then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep. HPLC (column: Welch Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 8% B to 48%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (40.53 mg, 20.2% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) 8.20 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.59 (d, J = 0.8 Hz, 1H), 3-99 (s, 3H), 3.83-3.67 (m, 1H), 3.28-3.18(111, 2H), 2.46-2.36 (m, 1H), 2.28-2.17 (m, 1H), 1.92 (br d, J = 11.6 Hz, 2H), 1.86-1.75 (m, 2H), 1.52-1.37 (m, 2H), 1.19-1.04 (m, 2H). MS ES+: 387.9- Example 5: 4-(1-(2,2-difluoroethyl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide

[0565] A mixture of 5-bromo-1-(2,2-difluoroethyl)-1H-imidazole (Intermediate 6) (170 mg, 0.81 mmol), 4-bromo-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2- carboxamide (Intermediate 3) (311 mg, 0.806 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-i,3,2-dioxaborolan-2-yl)-113,2-dioxaborolane (409 mg, 1.61 mmol), chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium-A-Pd-G2) (108 mg, 0.16 mmol) and Cs2CO3(656 mg, 2.01 mmol) in dioxane:H2O 3:1 (8 mL) was degassed and purged with N2(3x), and then the mixture was stirred at 110 °C for 12 h under N2atmosphere. Then the reaction mixture was extracted with EtOAc (3 x 10 mL) and water (10 mL). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep. HPLC (Column: Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH1H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 30 mL / min, gradient condition from 16% B to 56%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (36.09 mg, 10.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.45 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.80 (s, 1H), 7.40 (d, J = 0.9 Hz, 1H), 6.58-6.15 (m, 1H), 4.90 (dt, J = 3-3, 15-5 Hz, 2H), 3.80-3.66 (m, 1H), 3.24 (br dd, J = 7.8, 10.1 Hz, 2H), 2.44-2.37 (m,

[0566] 1H), 2.22 (br d, J = 6.8 Hz, 1H), 1.96-1.80 (m, 4H), 1.53-1.37 (m, 2H), 1.18-1.04 (m, 2H). MS ES+: 438.1. SFC: Rt = 2.41 min, 100% chiral purity.

[0567] Example 6: 4-(1-methyl-iH-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2- azaspiro[3.5]nonan-7-yl)thiazole-2-carboxamide

[0568] Step 1: Following the procedure as described for Example 1 using 4-(1-methyl-1H- imidazol-5-yl)thiazole-2-carboxylic acid (Intermediate 1) (145 mg, 0.693 mmol) and tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (200 mg, 0.832 mmol) gave tert-butyl 7-(4-(1-methyl-1H-imidazol-5-yl)thiazole-2-carboxamido)-2- azaspiro[3.5]nonane-2-carboxylate (280 mg, 90.5% yield) as a black oil. MS ES+: 432.1. Step 2: A solution of tert-butyl 7-(4-(1-methyl-1H-imidazol-5-yl)thiazole-2- carboxamido)-2-azaspiro[3.5]nonane-2-carboxylate (280 mg, 0.649 mmol) in dichloromethane (3 mL) was treated with 4M HC1 in dioxane (1.62 mL). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated under reduced pressure to give 4-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)thiazole- 2-carboxamide hydrochloride (300 mg, crude) as a black oil, which was used in the next step without further purification.

[0569] Step 3: A solution of 4-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7- yl)thiazole-2-carboxamide hydrochloride (250 mg, 0.754 mmol) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (210 mg, 0.905 mmol) in MeCN (2.5 mL) was treated with DIPEA (292 mg, 2.26 mmol). The mixture was stirred at 70 °C for 2 h. Then the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 16% B to 56%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (15.32 mg, 4.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.46 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 3.86 (s, 3H), 3.77-3.69 (m, 1H), 3.22-3.13 (m, 4H),3-O5 (s, 2H), 1.90 (br d, J = 8.4 Hz, 2H), 1.73-1.64 (m, 2H), 1.52-1.40 (m, 4H). MS ES+: 413.9.

[0570] Example 7: 4-(1-methyl-iH-imidazol-5-yl)-N-(6-((2,2,2- trifluoroethyl)amino)spiro[3.3]heptan-2-yl)thiazole-2-carboxamide Following the procedure as described for Example 1 using N2-(2,2,2- trifluoroethyl)spiro[3.3]heptane-2,6-diamine hydrochloride (Intermediate 7) (355 mg, 1.45 mmol) and 4-(1-methyl-1H-imidazol-5-yl)thiazole-2-carboxylic acid (Intermediate 1) (337 mg, 1.21 mmol) gave the title compound (5.18 mg, 1.0% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) 8.87 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 7.72. (s, 1H), 7.36 (s, 1H), 4.36-4.25 (m, 1H), 3.87 (s, 3H), 3.17-3.14 (m, 1H), 3.13 (br d, J

[0571] = 4.0 Hz, 2H), 3.08-3.03 (m, 1H), 2.31 (td, J = 3.8, 10.7 Hz, 2H), 2.22-2.11 (m, 4H), 1.77-1.70 (m, 2H). MS ES+400.1. SFC: Peak 1 = 1.298 min, 41.83% chiral purity; Peak 2 = 1.383 min, 58.17% chiral purity. Example 8: N-((1S,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-4-(1- methyl-1H-imidazol-5-yl)thiazole-2-carboxamide

[0572] Following the procedure as described for Example 1 using 4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxylic acid (Intermediate 1) (20 mg, 0.096 mmol) and (iS,4r)-4- ((S)-3-fluoropyrrolidin-1-yl)cyclohexan-1-amine (Intermediate 8) (25.6111g, 0.115 mmol) gave the title compound (3.52 mg, 9.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.60 (br d, J = 8.3 Hz, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.36 (d, J = 0.9 Hz, 1H), 5.46-5.18 (m, 1H), 3.86 (s, 3H), 3.79-3.73 (m, 1H), 3.26-2.81 (m, 4H), 2.52 (br s, 1H), 2.19-1.96 (m, 4H), 1.87 (br d, J= 11.0 Hz, 2H), 1.61-1.34 (m, 4H). MS ES+: 378.2.

[0573] Example 9: N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-4-(1- methyl-1H-imidazol-5-yl)thiazole-2-carboxamide

[0574] Following the procedure as described for Example 1 using 4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxylic acid (Intermediate 1) (60.1 mg, 0.245 mmol) and (ir,4r)-4- (3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (Intermediate 9) (50 mg, 0.245 mmol) gave the title compound (1.79 mg, 1.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.55-8.49 (m, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.35 (s, 1H), 3.85 (s, 3H), 3.76-3.73 (m, 1H), 2.93 (br t, J = 13.7 Hz, 2H), 2.74 (br t, J = 6.9 Hz, 2H), 2.24-2.15 (m, 2H), 2.09 (br t, J = 11.1 Hz, 1H), 1.93 (br d, J = 11.9 Hz, 2H), 1.83 (br d, J = 11.0 Hz, 2H), 1.55-1.47 (m, 2H), 1.25-1.19 (m, 2H). MS ES+: 396.2. SFC: Rt = 2.144 min, 100% chiral purity.

[0575] Example 10: N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-4-(1- methyl-1H-imidazol-5-yl)thiazole-2-carboxamide A solution of N1-(2,2-difluoroethyl)cyclohexane-i,4-diamine hydrochloride (Intermediate 10) (1.7 g, 7.92 mmol) and 4-(1-methyl-1H-imidazol-5-yl)thiazole-2- carboxylic acid (Intermediate 1) (2.21 g, 7.92 mmol) in dichloro methane (20 mL) was treated with DIPEA (4.09 g, 31.7 mmol) and T3P (7.56 g, 11.9 mmol, 50% purity). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was evaporated to dryness. The residue was purified by prep. HPLC (Column: Xtimate C18150 x 40mm x 10μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 8% B to 48%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the product which was further purified by SFC separation (separation condition: Daicel ChiralPak AD (250 x 30mm, 10μm); Mobile phase: A: Supercritical CO2, B: i- PrOH (0.1% NH3H2O), A:B = 65:35 at 80 mL / min; Column Temp: 38 °C; Nozzle Pressure: too Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (15.92 mg, 0.5% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 6.76-6.53 (m, 1H), 3.22-3.08 (m, 2H), 2.45-2.39 (m, 1H), 1.69 (br d, J = 10.5 Hz, 4H), 1.41-1.31 (m, 9H), 1.15-0.90 (m, 4H). MS ES+: 370.1. SFC: Rt = 1.874 min, 100% chiral purity. Example 11: N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-4-(1- methyl-1H-imidazol-5-yl)thiazole-2-carboxamide

[0576] Following the procedure as described for Example 1 using 4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxylic acid (Intermediate 1) (119 mg, 0.568 mmol) and N1-(2,2- difluoropropyl)cyclohexane-1,4-diamine hydrochloride (Intermediate 11) (130 mg, 0.568 mmol) gave the title compound (2.29 mg, 1.0% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.51 (br d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.36 (s, 1H), 3.86 (s, 3H), 3.79-3.70 (m, 1H), 2.89 (br t, J = 14.1 Hz, 2H), 2.53-2.51 (m, 1H), 2.38 (br t, J = 10.8 Hz, 1H), 1.93 (br d, J = 11.5 Hz, 2H), 1.81 (br d, J = 10.5 Hz, 2H), 1.58 (t, J = 19.1 Hz, 3H), 1.53-1.43 (m, 2H), 1.16-1.05 (m, 2H). MS ES+: 384.1. SFC: Rt = 1.71 min,

[0577] 100% chiral purity.

[0578] Example 12: 4-(1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide

[0579] Step 1: A solution of 1H-imidazole (5 g, 73.5 mmol) in MeCN (100 mL) was treated with NaOH (5.88 g, 147 mmol) and 3-bromooxetane (12.1 g, 88.1 mmol). The mixture was stirred at 90 °C for 8 h. Then the reaction mixture was concentrated under reduced pressure to remove MeCN. The residue was diluted with H2O (150 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent of o~4% methanol / di chloromethane @ 40 mL / min) to give 1-(oxetan-3-yl)-1H-imidazole (2 g, 21.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 7.82 (s, 1H), 7.52 (t, J =

[0580] 1.2 Hz, 1H), 6.98 (s, 1H), 5.55-5.42 (m, 1H), 4.92 (t, J = 7.4 Hz, 2H), 4.80-4.68 (m, 2H). Step 2: A solution of i-(oxetan-3-yl)-1H-imidazole (1 g, 8.06 mmol) in CHC13(10 mL) was treated with NBS (1.15 g, 6.44 mmol). The mixture was stirred at 40 °C for 2 h. The residue was diluted with H2O (20 ml) and extracted with di chloro methane (3 x 15 mL). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0~30% EtOAc / petroleum ether, gradient @ 40 mL / min) to give 5-bromo-1-(oxetan-3-yl)-1H-imidazole (350 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.23 (s, 1H), 7.07 (d, J = 0.9 Hz, 1H), 5.42- 5.35 (m, 1H), 4.96 (t, J = 7.4 Hz, 2H), 4.88-4.83 (m, 2H).

[0581] Step 3: A mixture of 5-bromo-1-(oxetan-3-yl)-1H-imidazole (280 mg, 1.38 mmol), 4- bromo-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide (Intermediate 3) (533 mg, 1.38 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (525 mg, 2.07 mmol), Cs2CO3(1.35 g, 4.14 mmol) and chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) (cataCXium-A-Pd-G2) (92.2 mg, 0.138 mmol) in 1,4- dioxane (0.5 mL) and H2O (0.05 mL) was degassed and purged with N2(3x), and then the mixture was stirred at 110 °C for 8 h under N2atmosphere. Then the product was further purified by prep. HPLC (Column: Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 10% B to 50%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (74.52 mg, 12.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.42 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.42 (s, 1H), 5.93-5.73 (m, 1H), 4.97- 4.88 (m, 2H), 4.87-4.79 (m, 2H), 3.74 (tdt, J = 4.0, 7.8, 11.8 Hz, 1H), 3.30-3.19 (m, 2H),

[0582] 2.46-2.36 (m, 1H), 2.28-2.18 (m, 1H), 1.93 (br d, J = 11.5 Hz, 2H), 1.84 (br d, J = 10.5 Hz, 2H), 1.59-1.40 (m, 2H), 1.19-1.03 (m, 2H). MS ES+: 430.4. SFC: Rt = 1.76 min, 100% chiral purity. Example 13: N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1H- imidazol-1-yl)thiazole-2-carboxamide

[0583] Following the procedure as described for Example 1 using 4-(1H-imidazol-1- yl)thiazole-2-carboxylic acid (Intermediate 12) (30 mg, 0.15 mmol) and 4-((3,3- difluoropyrrolidin-1-yl)methyl)aniline (Intermediate 13) (39.1 mg, 0.18 mmol) gave the title compound (10.56 mg, 17.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 10.62 (br s, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.33 (br d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 3.60 (s, 2H), 2.85 (t, J = 13.4 Hz, 2H), 2.69 (br t, J = 6.9 Hz, 2H), 2.32-2.18 (m, 2H). MS ES+: 390.1.

[0584] Example 14: N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1- methyl-1H-imidazol-5-yl)thiazole-2-carboxamide

[0585] Following the procedure as described for Example 1 using 4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxylic acid (Intermediate 1) (13.1 mg, 0.062 mmol) and 4-((3,3- difluoropyrrolidin-1-yl)methyl)aniline (Intermediate 13) (20 mg, 0.094 mmol) gave the title compound (5.59 mg, 21.6% yield) as a white solid.1H NMR (400 MHz, DMSO- cU) 10.53 (br s, 1H), 8.19 (s, 1H), 7.81-7.72 (m, 3H), 7.43 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 3.60 (s, 2H), 2.85 (t, J = 13.3 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 2.31-2.17 (m, 2H). MS ES+: 404.3. Example 15: 4-(1H-imidazol-1-yl)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1- yl)pyridin-3-yl)thiazole-2-carboxamide Following the procedure as described for Example 1 using 4-(1H-imidazol-1- yl)thiazole-2-carboxylic acid (Intermediate 12) (120 mg, 0.12 mmol) and 6-(4-(2,2,2- trifluoroethyl)piperazin-1-yl)pyridin-3-amine (Intermediate 14) (38.4 mg, 0.15 mmol) gave the title compound (3.82 mg, 6.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 10.60 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.97- 7.90 (m, 2H), 7-25-7-11 (m, 1H), 7.01-6.87 (m, 1H), 3-51-3-45 (m, 4H), 3-23 (q, J = 10.3

[0586] Hz, 2H), 2.77-2.68 (m, 4H). MS ES+: 438.1.

[0587] Example 16: N-(4-chloro-3-fluorophenyl)-2-(1H-imidazol-1-yl)thiazole-4- carboxamide

[0588] Following the procedure as described for Example 1 using 2-(1H-imidazol-1- yl)thiazole-4-carboxylic acid (Intermediate 15) (120 mg, 0.246 mmol) and 4-chloro- 3-fluoroaniline (43.0 mg, 0.295 mmol) gave the title compound (29.91 mg, 37.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 10.42 (s, 1H), 8.58 (t, J = 1.0 Hz, 1H), 8.35 (s, 1H), 8.02-7.96 (m, 2H), 7.74-7.66 (m, 1H), 7.64-7.56 (m, 1H), 7.25-7.18 (m,

[0589] 1H). MS ES+: 323.1.

[0590] Example 17: 3-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-methyl-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-i,2,4-thiadiazole-5-carboxamide 0.6 eq. formate Step 1: A mixture of 3-(1-methyl-1H-imidazol-5-yl)-1,2,4-thiadiazole-5-carboxylic acid (Intermediate 2) (500 mg, 1.19 mmol), tert-butyl ((1s,4s)-4-amino-1- methylcyclohexyl)carbamate (272 mg, 1.19 mmol), T3P (1.14 g, 1.78 mmol, 1.06 mL, 50% purity in EtOAc) and DIPEA (461 mg, 3.57 mmol) in dichloromethane (5 mL) was degassed and purged with N2(3x), and then the mixture was stirred at 25 °C for 2 h under N2atmosphere. The reaction mixture was quenched with sat. NaHCO3aq. solution (1 mL) at 25 °C, and then diluted with water (1 mL) and extracted with dichloro methane (3 x 1 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether: EtOAc = 1:1 to 0:1) to give tert-butyl ((1s,4s)-1-methyl-4-(3-(1-methyl-1H- imidazol-5-yl)-1,2,4-thiadiazole-5-carboxamido)cyclohexyl)carbamate (80 mg, 16.0% yield) as a white solid, which was used in the next step without further purification.

[0591] Step 2: A mixture of tert-butyl ((1s,4s)-1-methyl-4-(3-(1-methyl-1H-imidazol-5-yl)- i,2,4-thiadiazole-5-carboxamido)cyclohexyl)carbamate (80 mg, 0.190 mmol) in 4M HC1 in dioxane (2 mL) and dichloromethane (2 mL) was degassed, and then the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with sat. NaHCO3aq. solution to pH = 7-8 at o °C. The mixture was added to H2O (5 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude N-((1s,4s)-4-amino-4-methylcyclohexyl)-3-(1-methyl-1H-imidazol-5-yl)-1,2,4- thiadiazole-5-carboxamide (60 mg, crude) as a brown solid which was used for the next step without further purification.

[0592] Step 3: A mixture of N-((1s,4s)-4-amino-4-methylcyclohexyl)-3-(1-methyl-1H-imidazol- 5-yl)-1,2,4-thiadiazole-5-carboxamide (20 mg, 0.062 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.24 mg, 0.031 mmol) and DIPEA (40.3 mg, 0.312 mmol) in MeCN (0.1 mL) was degassed, and then the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue which was purified by prep. HPLC (Column: Xtimate C18150 x 40mm x loμm, Mobile Phase A: water (HCOOH), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 0% B to 24%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture was lyophilized to dryness to give the title compound (2.03 mg, 7.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.97- 8.86 (m, 1H), 8.36-8.29 (m, 0.6H), 7.92-7.83 (m, 1H), 7.79-7.70 (m, 1H), 4.02 (s, 3H),

[0593] 3-83-3.74 (m, 1H), 3.17-3.14 (m, 2H), 2.03-1.98 (m, 1H), 1.87-1.79 (m, 2H), 1.69 (br s, 2H), 1.58-1.52 (m, 2H), 1.36-1.28 (m, 2H), 0.99 (s, 3H). MS ES+: 403.2. SFC: Rt = 1.667 min, 100% chiral purity.

[0594] Example 18: 3-(1-methyl-iH-imidazol-5-yl)-N-((1r,4r)-4-methyl-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-i,2,4-thiadiazole-5-carboxamide 1.1 eq. formate

[0595] Following the procedure as described for Example 17 using 3-(1-methyl-1H-imidazol- 5-yl)-1,2,4-thiadiazole-5-carboxylic acid (Intermediate 2) (450 mg, 1.07 mmol) and tert-butyl ((1r,4r)-4-amino-1-methylcyclohexyl)carbamate (244 mg, 1.07 mmol) gave the title compound (1.1 mg, 3.0% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 9.00-8.78 (m, 1H), 8.36 (br s, 1.1H), 7.89 (br s, 1H), 7.81-7.71 (m, 1H), 4.02 (s, 3H), 3.80-3.71 (m, 1H), 3.15 (br s, 2H), 1.89-1.86 (m, 1H), 1.85-1.79 (m, 2H), 1.69-1.64 (m, 2H), 1.57-1.52 (m, 2H), 1.35-1.29 (m, 2H), 1.02-0.95 (m, 3H). MS ES+: 403.2. SFC: Rt = 1-434 min, 100% chiral purity.

[0596] Example 19: 3-(5-methyl-1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide A solution of 3-(5-methyl-1H-imidazol-1-yl)-1,2,4-thiadiazole-5-carboxylic acid (Intermediate 16) (205 mg, 0.975 mmol), (1r,4r)-N1-(2,2,2- trifluoroethyl)cyclohexane-i,4-diamine hydrochloride (174 mg, 0.749 mmol) and DIPEA (323 mg, 2.50 mmol) in dichloromethane (2 mL) was treated with T4P (540 mg, 0.749 mmol, 50% purity in EtOAc). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organics were then concentrated under reduced pressure and the resulting residue was purified by prep. HPLC (Column: Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 18% B to 58%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between MeCN (2 mL) and water (10 mL) and the mixture as lyophilized to dryness to give the title compound (0.94 mg, 0.2% yield) as a white solid1.H NMR (400 MHz, DMSO-d6) 9.06 (br d, J = 8.3 Hz, 1H), 8.39 (d, J = 0.9 Hz, 1H), 6.88 (s, 1H), 3.76 (dtd, J = 4.3, 7.8, 11.7 Hz, 1H), 3.24 (br dd, J = 7.6, 10.1 Hz, 2H), 2.52 (d, J = 0.8 Hz, 3H), 2.43-2.38 (m, 1H), 2.27-2.18 (m, 1H), 1.94 (br d, J = 11.4 Hz, 2H), 1.89-1.80 (m, 2H), 1.54-1.44 (m,

[0597] 2H), 1.11 (br d, J = 13.6 Hz, 2H). MS ES+: 389.3. SFC: Rt = 1.316 min, 95.97% chiral purity.

[0598] Example 20: 4-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((1,1,1-trifluoro-2- methylpropan-2-yl)amino)cyclohexyl)thiazole-2-carboxamide

[0599] Example 21: 4-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-((1,1,1-trifluoro-2- methylpropan-2-yl)amino)cyclohexyl)thiazole-2-carboxamide

[0600] A solution of N1-(1,1,1-trifluoro-2-methylpropan-2-yl)cyclohexane-i,4-diamine hydrochloride (Intermediate 17) (187 mg, 0.717 mmol), 4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxylic acid (Intermediate 1) (100 mg, 0.478 mmol) and DIPEA (309 mg, 2.39 mmol) in dichloromethane (1 mL) was treated with T4P (517 mg, 0.717 mmol, 50% purity in EtOAc). The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were reduced and pressure and the resulting residue was purified by prep. HPLC (Column: Xtimate C18 150 x 40mm x 10μm, Mobile Phase A: water (NH3H2O+NH4HCO3), Mobile Phase B: MeCN, Flow rate: 25 mL / min, gradient condition from 20% B to 60%). Two peaks were observed and both pure fractions were collected and the volatiles were removed under vacuum. The residues were partitioned between MeCN (2 mL) and water (10 mL) and the mixtures were lyophilized to dryness to give the two title compounds.

[0601] Example 20: 4-(1-Methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((1,1,1-trifluoro-2- methylpropan-2-yl)amino)cyclohexyl)thiazole-2-carboxamide (21.79mg, 10.5% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) 7.70 (br s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.25 (br s, 1H), 4.12 (br s, 1H), 3.91 (s, 4H), 3.02 (br s, 1H), 1.82-1.78 (m, 4H), 1.77-1.73 (m, 2H), 1.53-1.47 (m, 2H), 1.29 (s, 6H). MS ES+: 416.2. SFC: Rt = 1.467 min, 100% chiral purity. Example 21: 4-(1-Methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-((1,1,1-trifluoro-2- methylpropan-2-yl)amino)cyclohexyl)thiazole-2-carboxamide (44.75 mg, 22.2% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) 7.70 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 6.98 (br d, J = 8.4 Hz, 1H), 3.89 (s, 4H), 2.82-2.73 (m, 1H), 2.15-2.08 (m, 2H),

[0602] 1.94 (br d, J = 12.4 Hz, 2H), 1.43-1.28 (m, 4H), 1.27 (s, 6H). MS ES+: 416.2. SFC: Rt = 1.110 min, 99.73% chiral purity.

[0603] Example 22: N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-3-(1- methyl-1H-imidazol-5-yl)-1,2,4-thiadiazole-5-carboxamide

[0604] Following the procedure as described for Example 19 using 3-(1-methyl-1H-imidazol- 5-yl)-1,2,4-thiadiazole-5-carboxylic acid (Intermediate 2) (50 mg, 0.238 mmol) and (1r,4r)-N1-(2,2-difluoroethyl)cyclohexane-i,4-diamine (prepared as described in US20210032251) (50.9 mg, 285 mmol) gave the title compound (2.05 mg, 2.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.98 (br d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 6.14-5.72 (m, 1H), 4.02 (s, 3H), 3.76 (tdt, J = 4.0, 7.9, 11.8 Hz, 1H), 2.90 (dt, J = 4.1, 15.9 Hz, 2H), 2.43-2.34 (m, 1H), 1.93 (br d, J = 12.3 Hz, 2H), 1.83 (br d, J = 10.3 Hz, 2H), 1.58-1.43 (m, 2H), 1.17-1.02 (m, 2H). MS ES+: 371.2. SFC: Rt = 1.978 min, 98.90% chiral purity.

[0605] Example 23: N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-3-(1- methyl-1H-imidazol-5-yl)-1,2,4-thiadiazole-5-carboxamide Following the procedure as described for Example 19 using 3-(1-methyl-1H-imidazol- 5-yl)-1,2,4-thiadiazole-5-carboxylic acid (Intermediate 2) (600 mg, 0.799 mmol) and (ir,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (Intermediate 9) (245 mg, 1.20 mmol) gave the title compound (12.51 mg, 3.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 9.00 (d, J = 8.4 Hz, 1H), 8.00-7.84 (m, 1H), 7.84-7.66 (m, 1H),

[0606] 4.02 (s, 3H), 3.77 (tdt, J = 3.9, 7.9, 11.7 Hz, 1H), 2.94 (t, J = 13.8 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.28-2.14 (m, 2H), 2.14-2.05 (m, 1H), 1.95 (br d, J = 12.1 Hz, 2H), 1.86 (br d, J = 10.8 Hz, 2H), 1.59-1.46 (m, 2H), 1.29-1.16 (m, 2H). MS ES+: 397.2. SFC: Rt = 1.898 min, 100% chiral purity.

[0607] Example 24: N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-4-(1- methyl-1H-imidazol-5-yl)thiazole-2-carboxamide

[0608] Following the procedure as described for Example 19 using 4-(1-methyl-1H-imidazol- 5-yl)thiazole-2-carboxylic acid (Intermediate 1) (100 mg, 0.478 mmol) and (ir,4r)-4- (3,3-difluoroazetidin-1-yl)cyclohexan-1-amine (Intermediate 18) (136 mg, 0.717 mmol) gave the title compound (21.7 mg, 11.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8.60-8.52 (m, 1H), 8.12-8.05 (m, 1H), 7.74-7.68 (m, 1H), 7.41-7.31 (m, 1H), 3.88-3.85 (m, 3H), 3.54 (t, J = 12.3 Hz, 4H), 2.52 (br s, 1H), 2.15-2.06 (m, 1H), 1.84-1.74 (m, 4H), 1.53-1.44 (m, 2H), 1.11-1.00 (m, 2H). MS ES+: 382.1. SFC: Rt = 2.613 min, 100% chiral purity.

[0609] Biological Activity Human CD38 Hydrolase Assay

[0610] The ability of test compounds to inhibit human CD38 hydrolase activity was measured in a fluorescence-based assay using non-physiological NAD+substrate analogue 1, N6- etheno NAD+(s-NAD). Recombinant human CD38 (0.8 nM) was preincubated with test compounds in 384-well black microplates for 30 min at 25 °C in PBS (-Ca2+ / Mg2+) containing 0.005% BSA (pH 7.4). CD38 hydrolase activity was initiated by addition of 4 μM ε-NAD, which yields the fluorescent product 1, N6-etheno ADP-ribose. Formation of fluorescent product was followed using ClarioStar Plus (BMG) microplate reader by reading fluorescence (excitation X = 300 nm; emission X = 410 nm) at two time points, one immediately after substrate addition (t = o) and one at 10 min (t = 10).

[0611] Data was analysed by subtracting the values detected at t = o from t = 10 to correct for variation in baseline fluorescence. Fluorescence values were converted to percent inhibition using the average of high signal (CD38 and s-NAD) and low signal (CD38 and s-NAD in the presence of a tool CD38 inhibitor) control wells. IC50values were determined from a 10-point, half log concentration response curve with a four- parameter logistic equation. Mouse CD38 Hydrolase Assay

[0612] The ability of test compounds to inhibit mouse CD38 hydrolase activity was measured in a fluorescence-based assay using non-physiological NAD+substrate analogue 1, N6- etheno NAD+(s-NAD). Recombinant mouse CD38 (0.4 nM) was preincubated with test compounds in 384-well black microplates for 30 min at 25 °C in PBS (-Ca2+ / Mg2+) containing 0.005% BSA (pH 7.4). CD38 hydrolase activity was initiated by addition of 12 μM s-NAD, which yields the fluorescent product 1, N6-etheno ADP-ribose. Formation of fluorescent product was followed using ClarioStar Plus (BMG) microplate reader by reading fluorescence (excitation X = 300 nm; emission X = 410 nm) at two time points, one immediately after substrate addition (t = o) and one at 6 min (t = 6). Data was analysed by subtracting the values detected at t = o from t = 6 to correct for variation in baseline fluorescence, and fluorescence values were converted to percent inhibition using the average of high signal (CD38 and s-NAD) and low signal (CD38 and s-NAD in the presence of a tool CD38 inhibitor) control wells. IC50values were determined from a 10-point, half log concentration response curve with a four- parameter logistic equation.

[0613] The data for human and mouse CD38 activity is summarized in Table 1.

[0614] Table 1: IC50 (<iopM = <ipM = <o.ipM = '+++’;

[0615] <0.04pM = ‘++++’; not determined = ‘ND’)

[0616] Pharmacokinetics

[0617] Tissue Binding Assays

[0618] Buffer preparation. A basic solution was prepared by dissolving 14.2 g / L Na2HPO4and 8.77 g / L NaCl in deionized H2O. An acidic solution was prepared by dissolving 15.6 g / L NaH2PO4-2H2O and 8.77 g / L NaCl in deionized H2O. Using the acidic solution, the basic solution was then titrated to pH 7.4 ± 0.1 and stored at 4 °C for up to 1 month.

[0619] The stop solution was 100% CH3CN containing 200 ng / mL tolbutamide, 200 ng / mL labetalol and 50 ng / mL metformin.

[0620] Test method. Dialysis membrane strips were soaked in ultra-pure water at room temperature for ~i hour. Each membrane strip containing 2 membranes was separated and soaked in 20:80 EtOH / H2O (v / v) for ~20 min, after which they were ready for use or were stored in the solution at 2-8 °C for up to 1 month. Prior to the experiment, the membrane was rinsed and soaked for 20 min in ultra-pure water. On the day of experiment, brain homogenate was thawed in a water bath at room temperature and incubated at 37 °C for 10 min before use. Test and control compounds were dissolved in DMSO to achieve 10 mM stock solutions. DMSO working solutions were prepared at 400 μM by diluting 10 μL of stock solution. To prepare the time zero (t = o) samples to be used for recovery determination, 50 μL aliquots of loading matrix were transferred in triplicate to the sample collection plate. The samples were immediately matched with opposite blank buffer to obtain a final volume of too μL of 1:1 matrix / dialysis buffer (v / v) in each well. 500 μL of stop solution were added to these t = o samples. They were then stored at 2-8 °C pending further processes along with other post-dialysis samples. To load the dialysis device, an aliquot of 150 μL of the loading matrix was transferred to the donor side of each dialysis well in triplicate, and 150 μL of the dialysis buffer was loaded to the receiver side of the well. The dialysis plate was placed in a humidified incubator at 37 °C with 5% CO2on a shaking platform that rotated slowly (about too rpm) for 4 hours. At the end of the dialysis, aliquots of 50 μL of samples were taken from both the buffer side and the matrix side of the dialysis device. These samples were transferred into new 96-well plates. Each sample was mixed with an equal volume of opposite blank matrix (buffer or matrix) to reach a final volume of too μL of 1:1 matrix / dialysis buffer (v / v) in each well. All samples were further processed by adding 500 μL of stop solution containing internal standards. The mixture was vortexed and centrifuged at 4000 rpm for about 20 min. An aliquot of too μL of supernatant of all the samples was then removed for LC-MS / MS analysis. The single blank samples were prepared by transferring 50 μL of blank matrix to a 96-well plate and adding 50 μL of blank PBS buffer to each well. Then the matrix-matched samples were further processed by adding 500 μL of stop solution containing internal standards, following the same sample processing method as the dialysis samples. Data analysis. The % undiluted unbound, % undiluted bound and % recovery were calculated using the following equations:

[0621] % Undiluted Unbound = 100*1 / D / ((1 / (F / T)-i)+i / D)

[0622] % Undiluted Bound = too - % Undiluted Unbound

[0623] % Recovery = 100 * (F+T) / To where F is the analyte concentration or peak area ratio of analyte / internal standard on the buffer (receiver) side of the membrane; T is the analyte concentration or peak area ratio of analyte / internal standard on the matrix (donor) side of the membrane; To is the analyte concentration or the peak area ratio of analyte / internal standard in the loading matrix sample at time zero; and D is the dilution factor determined as 4 in this assay.

[0624] Unbound fractions in brain homogenate and plasma for selected compounds are summarized in Table 2.

[0625] Table 2 PK brain permeability

[0626] The distribution of compounds into the brain in vivo was determined in C57BL / 6 mice following single oral (po) gavage administration. Test compounds were formulated at 1 mg / mL in 0.5% HPMC E4M, 0.2% Tween 80 in water to achieve solutions or homogenous suspensions suitable for po administration. Formulations were administered to 3 male C57BL / 6 mice at a volume of 10 mL / kg resulting in a dose level of 10 mg / kg. Blood samples were collected at 1 and 2 hours post dose into tubes containing K2EDTA as anticoagulant, processed to plasma and stored at -60 °C or lower until LC-MS / MS analysis. Brains were harvested 2 hours post dose, rinsed with saline, dried, weighed and homogenised under ice cold conditions. Brain homogenates were stored at -60 °C or lower until LC-MS / MS analysis.

[0627] Dose formulation concentrations were verified using a LC-UV or LC-MS / MS method. Test compound concentrations in plasma and brain homogenate were quantitatively determined using LC-MS / MS methods developed in individual matrices against calibration curves with QC samples included and acceptance criteria as per CRO SOPs. Concentrations in brain homogenate were corrected for the dilution factor used to prepare the homogenate to give concentrations in whole brain tissue.

[0628] Plasma and brain concentration versus time data were reported and plotted in excel. The brain to plasma ratio at 2 hours post dose was calculated for each animal using the following equation:

[0629] Brain :plasma = brain concentration (ng / g) at 2 h / plasma concentration (ng / mL) at 2 h As only unbound test compound is available to exert an effect on the target, unbound plasma (Cp,u) and unbound brain (Cb,u) concentrations were calculated by correcting the total concentrations for the unbound fraction in plasma (fu,p) or brain (fu,b) determined from in vitro plasma protein or brain tissue binding assays using the following equations: The unbound partitioning coefficient (Kpu,u) was then calculated based on the ratio of Cb,uto Cp,uusing the following equation:

[0630] Selected data from pharmacokinetic studies are summarized in Table 3. In these studies, mice were orally administrated a 10 mg / kg dose and sacrificed 2 hours post dose and tissue samples (brain homogenate and plasma) were analyzed subsequently as described above.

[0631] Table 3

[0632] The data in Table 3 illustrates that compounds disclosed herein such as Examples 1, 2, 4 and 9 display good brain permeability.

[0633] 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 of the invention, which is defined by the following claims only.

Claims

Claims1. A compound of formula (I):or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; one of X1and X2is S and the other of X1and X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond, CH2, CHMe, CMe2or CO;R1is -NR2R3, halo or C1-C4fluoroalkyl;R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

2. The compound, salt, solvate or prodrug as claimed in claim 1, wherein the compound, salt, solvate or prodrug is a compound of formula (II):or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;X1is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl; Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond, CH2, CHMe, CMe2or CO;R1is -NR2R3, halo or C1-C4fluoroalkyl; R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or-CO-(C1-C3fluoroalkyl);R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not:(i) N-(2-bromophenyl)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-2-carboxamide; (ii) N-(3-bromophenyl)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-2-carboxamide;(iii) 4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-2-carboxamide; or(iv) 4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(2- (trifluoromethyl)phenyl)thiazole-2-carboxamide.

3. The compound, salt, solvate or prodrug as claimed in claim 1, wherein the compound, salt, solvate or prodrug is a compound of formula (III):or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond, CH2, CHMe, CMe2or CO; R1is -NR2R3, halo or C1-C4fluoroalkyl;R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not:(i) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide; (ii) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(iii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(iv) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(v) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide; (vi) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(vii) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(viii) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(ix) 2-(1H-imidazol-1-yl)-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;(x) 2-(1H-imidazol-1-yl)-N-(4-(piperazin-1-yl)pyridin-3-yl)thiazole-4-carboxamide; (xi) N-(4-acetamidocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xii) N-(4-(dimethylamino)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xiii) 2-(1H-imidazol-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole-4- carboxamide;(xiv) 2-(1H-imidazol-5-yl)-N-(4-(pyrrolidin-1-yl)pyrimidin-5-yl)thiazole-4- carboxamide;(xv) 2-(1H-imidazol-5-yl)-N-(3-(pyrrolidin-1-yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;(xvi) 2-(1H-imidazol-5-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)thiazole-4- carboxamide; (xvii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xviii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xix) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xx) 2-(1H-imidazol-5-yl)-N-(1-(methylcarbamoyl)cyclohexyl)thiazole-4- carboxamide; or(xxi) N-(3-(dimethylcarbamoyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide.

4. The compound, salt, solvate or prodrug as claimed in claim 1, wherein the compound, salt, solvate or prodrug is a compound of formula (III):or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;Cy is a cyclohexyl, 6-membered saturated heterocyclyl, phenyl, or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond, CH2, CHMe, CMe2or CO;R1is -NR2R3, fluoro, chloro, or C1-C4fluoroalkyl;R2is C1-C4fluoroalkyl or -CO-(C1-C3fluoroalkyl); R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not:(i) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(4- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(ii) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (iii) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(2-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(iv) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(v) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(vi) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (vii) 2-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(viii) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(ix) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(x) 2-(1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide; (xi) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide;(xii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4- carboxamide;(xiii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4- carboxamide;(xiv) 2-(1-methyl-1H-pyrazol-4-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4- carboxamide;(xv) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xvi) 2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-N-(3- (trifluoromethyl)phenyl)thiazole-4-carboxamide;(xvii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(2-((2,2,2- trifluoroethyl)amino)phenyl)thiazole-4-carboxamide;(xviii) N-(4-chlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xix) N-(3-chlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xx) N-(2-chlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxi) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(2-fluorophenyl)thiazole-4- carboxamide;(xxii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xxiii) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xxiv) N-(3-chlorophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;(xxv) N-(3-fluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(xxvi) N-((1R,2R)-2-fluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxvii) N-(4-fluorophenyl)-2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)thiazole-4- carboxamide;(xxviii)N-(3,5-dichlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide;(xxix) N-(3,4-dichlorophenyl)-2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide;(xxx) 2-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-N-(3,4,5- trifluorophenyl)thiazole-4-carboxamide; (xxxi) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xxxii) N-(3,3-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxiii)N-(4,4-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide; (xxxiv)N-(5-chloro-2-fluorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxv) N-(5-bromo-2-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxvi) N-(4-bromo-2-chloro-6-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide; (xxxvii) N-(2-chloro-4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xxxviii) N-(4-fluoro-4-methylcyclohexyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(xxxix) N-(2,5-dichlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; (xl) N-(6-bromo-2-chloro-pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide;(xli) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xlii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)thiazole- 4-carboxamide; or(xliii) 2-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiazole- 4-carboxamide.

5. The compound, salt, solvate or prodrug as claimed in claim 1, wherein the compound, salt, solvate or prodrug is a compound of formula (III):or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:Het is a 5-membered heteroaryl group selected from imidazolyl, thiazolyl, and isothiazolyl, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;X2is CR4or N, wherein R4is hydrogen, halo, CH3, CF3, or cyclopropyl;Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond;R1is -NR2R3, halo or C1-C4fluoroalkyl;R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);R3is hydrogen or methyl; or R2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl; provided that the compound is not: (i) 2-(1H-imidazol-1-yl)-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide or the hydrochloride salt thereof;(ii) 2-(1H-imidazol-1-yl)-N-(4-(piperazin-1-yl)pyridin-3-yl)thiazole-4-carboxamide;(iii) N-(3,3-difluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(iv) N-(3,3-dichlorocyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (v) N-(3,3-difluoro-1-methylcyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(vi) N-(6,6-difluorobicyclo[3.i.o]hexan-3-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(vii) N-(i,i-difluorospiro[2.5]octan-6-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(viii) N-(3-(dimethylamino)-2,2-dimethylcyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(ix) 2-(1H-imidazol-5-yl)-N-((1R,2R)-2-(trifluoromethyl)cyclopropyl)thiazole-4- carboxamide; (x) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclobutyl)thiazole-4-carboxamide;(xi) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(xii) 2-(1H-imidazol-5-yl)-N-(3-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(xiii) 2-(1H-imidazol-5-yl)-N-(4-(trifluoromethyl)cyclohexyl)thiazole-4-carboxamide;(xiv) N-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xv) N-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xvi) 2-(1H-imidazol-5-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H-pyran-4- yl)thiazole-4-carboxamide; (xvii) 2-(1H-imidazol-5-yl)-N-(1-(trifluoromethyl)cyclopropyl)thiazole-4- carboxamide;(xviii) N-((1R,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xix) N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xx) N-((1S,2R)-2-fluorocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (xxi) 2-(1H-imidazol-5-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)thiazole-4- carboxamide;(xxii) 2-(1H-imidazol-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)thiazole-4- carboxamide;(xxiii) N-(1-(difluoromethyl)cyclopentyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (xxiv) 2-(1H-imidazol-5-yl)-N-(4-(pyrrolidin-1-yl)pyrimidin-5-yl)thiazole-4- carboxamide;(xxv) N-(1-(difluoromethyl)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xxvi) 2-(1H-imidazol-5-yl)-N-(3-(piperidin-1-yl)cyclobutyl)thiazole-4-carboxamide;(xxvii) N-(3-(dimethylamino)cyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (xxviii)N-(1-(fluoromethyl)cyclobutyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xxix) N-((1R,2R)-2-(dimethylamino)cyclopentyl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xxx) N-(4-acetamidocyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide;(xxxi) N-(4-(dimethylamino)cyclohexyl)-2-(1H-imidazol-5-yl)thiazole-4-carboxamide; (xxxii) 2-(1H-imidazol-5-yl)-N-(3-(pyrrolidin-1-yl)tetrahydro-2H-pyran-4-yl)thiazole- 4-carboxamide;(xxxiii)N-(3-(dimethylamino)spiro[3.3]heptan-1-yl)-2-(1H-imidazol-5-yl)thiazole-4- carboxamide;(xxxiv)N-(5-(azetidin-1-yl)-i,3-dimethyl-1H-pyrazol-4-yl)-2-(1H-imidazol-5- yl)thiazole-4-carboxamide;(xxxv) 2-(1H-imidazol-2-yl)-N-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(xxxvi) N-((1R,2R)-2-(fluoromethyl)cyclopropyl)-2-(1H-imidazol-2-yl)thiazole-4- carboxamide;(xxxvii) N-((3S,4S)-4-fluorotetrahydrofuran-3-yl)-2-(1H-imidazol-2-yl)thiazole- 4-carboxamide;(xxxviii) 2-(1H-imidazol-2-yl)-N-((3S,4S)-3-(trifluoromethyl)tetrahydro-2H- pyran-4-yl)thiazole-4-carboxamide;(xxxix) N-(3,3-dichlorocyclobutyl)-2-(1H-imidazol-2-yl)thiazole-4-carboxamide; or(xl) N-((1R,2R)-2-(dimethylamino)cyclopentyl)-2-(1H-imidazol-2-yl)thiazole-4- carboxamide.

6. The compound, salt, solvate or prodrug as claimed in claim 1, wherein the compound, salt, solvate or prodrug is a compound of formula (IV):or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:Het is a 5-membered heteroaryl group comprising two heteroatoms independently selected from N and S, wherein the 5-membered heteroaryl group is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl;Cy is a C3-C9cycloalkyl, 3- to 9-membered saturated heterocyclyl, phenyl, or 5- or 6-membered heteroaryl group, each of which is optionally substituted with one, two or three substituents independently selected from halo and C1-C3alkyl;L is a bond, CH2, CHMe, CMe2or CO; R1is -NR2R3, halo or C1-C4fluoroalkyl;R2is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, -CHO, -CO-(C1-C3alkyl) or -CO-(C1-C3fluoroalkyl);R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is optionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C4fluoroalkyl.

7. The compound, salt, solvate or prodrug as claimed in any one of the preceding claims, wherein Het is selected from imidazolyl, thiazolyl, and isothiazolyl, each of which is optionally substituted with one substituent selected from methyl, ethyl, fluoromethyl, fluoroethyl, hydroxymethyl, hydroxyethyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, and piperazinyl.

8. The compound, salt, solvate or prodrug as claimed in any one of the preceding claims, wherein one of X1and X2is S and the other of X1and X2is CH or N.

9. The compound, salt, solvate or prodrug as claimed in any one of claims 1, 2 or 5-8, wherein Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl. azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl azaspiro [3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl azaspiro[2.6]nonanyl, azaspiro [3.5] nonanyl, azaspiro[4.4]nonanyl, oxaspiro[2.2]pentanyl, oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl oxaspiro[3.3]heptanyl, oxaspiro[2.5]octanyl, oxaspiro [3.4] octanyl oxaspiro[2.6]nonanyl, oxaspiro[3.5]nonanyl, oxaspiro[4.4]nonanyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with one or two substituents independently selected from fluoro, chloro and methyl.

10. The compound, salt, solvate or prodrug as claimed in any one of the preceding claims, wherein Cy is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, thiomorpholinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with one or two substituents independently selected from fluoro, chloro and methyl.

11. The compound, salt, solvate or prodrug as claimed in any one of claims 1-4 or 6- 10, wherein L is a bond, CH2or CO.

12. The compound, salt, solvate or prodrug as claimed in any one of claims 1-3 or 5-11, wherein R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:R2is hydrogen, C1-C4alkyl or C1-C4fluoroalkyl;R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which isoptionally fluoro-substituted and / or optionally substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

13. The compound, salt, solvate or prodrug as claimed in any one of the preceding claims, wherein R1is -NR2R3, fluoro, chloro, fluoromethyl or fluoroethyl; wherein:R2is C1-C4fluoroalkyl;R3is hydrogen or methyl; orR2and R3, together with the nitrogen to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl group, each of which is fluoro-substituted and / or substituted with one or two substituents independently selected from C1-C3fluoroalkyl.

14. The compound, salt, solvate or prodrug as claimed in any one of the preceding claims, wherein the compound is selected from: 4-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide;3-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide;4-(1-(2-fluoroethyl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide;2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-4-carboxamide;4-(1-(2,2-difluoroethyl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide; 4-(1-methyl-1H-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2- azaspiro[3.5]nonan-7-yl)thiazole-2-carboxamide;4-(1-methyl-1H-imidazol-5-yl)-N-(6-((2,2,2- trifluoroethyl)amino)spiro[3.3]heptan-2-yl)thiazole-2-carboxamide;N-((1S,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-4-(1-methyl-1H-imidazol- 5-yl)thiazole-2-carboxamide;N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-4-(1-methyl-1H-imidazol-5-yl)thiazole-2-carboxamide;N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxamide; N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-4-(1-methyl-1H-imidazol-5-yl)thiazole-2-carboxamide;4-(1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)thiazole-2-carboxamide;N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1H-imidazol-1- yl)thiazole-2-carboxamide; N-(4-((3,3-difluoropyrrolidin-1-yl)methyl)phenyl)-4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxamide; 4-(1H-imidazol-1-yl)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-3- yl)thiazole-2-carboxamide; N-(4-chloro-3-fluorophenyl)-2-(1H-imidazol-1-yl)thiazole-4-carboxamide; 3-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-methyl-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide; 3-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-methyl-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide;3-(5-methyl-1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2- trifluoroethyl)amino)cyclohexyl)-1,2,4-thiadiazole-5-carboxamide;4-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((1,i,i-trifluoro-2-methylpropan-2- yl)amino)cyclohexyl)thiazole-2-carboxamide;4-(1-methyl-1H-imidazol-5-yl)-N-((1s,4s)-4-((1,i,i-trifluoro-2-methylpropan-2- yl)amino)cyclohexyl)thiazole-2-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-3-(1-methyl-1H-imidazol-5- yl)-1,2,4-thiadiazole-5-carboxamide; N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-3-(1-methyl-1H-imidazol- 5-yl)-1,2,4-thiadiazole-5-carboxamide;N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-4-(1-methyl-1H-imidazol-5- yl)thiazole-2-carboxamide; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.

15. A process for the preparation of a compound, salt, solvate or prodrug as claimed in any one of claims 1 to 14, wherein the process comprises the step of:(a) reacting a compound of formula (V) or a salt thereof with an amine of formula (VI) or a salt thereof or protected derivative thereof:wherein:Rs is -OH, -OR6, -O-CO-R6, -F or -Cl;R6is C1-C3alkyl; andHet, X1, X2, Cy, L and R1are as defined in any one of claims 1 to 14; or(b) reacting a compound of formula (VII) or a salt thereof with a compound of formula (VIII) or a salt thereof:wherein:R7is a leaving group (such as halo);R8is a leaving group (such as halo), -B(R9)2or -Sn(C1-C4alkyl)3; each Rs is independently selected from hydroxyl, C1-C5alkoxy and C1-C5alkyl, or two R9together with the boron atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclic group; andHet, X1, X2, Cy, L and R1are as defined in any one of claims 1 to 14; or(c) reacting a compound of formula (IX) or a salt thereof with an amine of formula (VI) or a salt thereof or protected derivative thereof:wherein:R10is a leaving group (such as halo); andHet, X1, X2, Cy, L and R1are as defined in any one of claims 1 to 14; or(d) the step of reacting a compound of formula (VII) or a salt thereof with a compound of formula (X) or a salt thereof:wherein:R7is a leaving group (such as halo);X1is CR4or N; X2is S;Het-H is a heteroaryl compound selected from 1H-imidazole and 1H-pyrazole, wherein the heteroaryl compound is optionally substituted with one or two substituents independently selected from C1-C3alkyl, C1-C3fluoroalkyl, C1-C3hydroxyalkyl, and 3- to 6-membered saturated heterocyclyl; and Cy, L, R1and R4are as defined in any one of claims 1 to 14; and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (I), (II), (III) or (IV) into another compound of formula (I), (II), (III) or (IV); - removing any protecting groups; forming a pharmaceutically acceptable salt.

16. A pharmaceutical composition comprising a compound, salt, solvate or prodrug as claimed in any one of claims 1 to 14, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

17. The compound, salt, solvate or prodrug as claimed in any one of claims 1 to 14, for use in therapy.

18. The compound, salt, solvate or prodrug as claimed in any one of claims 1 to 14, for use in treating or preventing a disease, disorder or condition associated with CD38 activity.

19. The compound, salt, solvate or prodrug as claimed in any one of claims 1 to 14, for use in treating or preventing a CNS disease, a disease requiring treatment via the CNS, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disorder.

20. The compound, salt, solvate or prodrug as claimed in any one of claims 1 to 14, for use in treating or preventing Parkinson’s disease; Alzheimer’s disease; frontotemporal dementia; progressive supranuclear palsy; a tauopathy; another nonAlzheimer’s dementia; stroke; ischemic insult; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated neuronal damage such as Muckle- Wells syndrome; motor neuron disease such as amyotrophic lateral sclerosis; axonal neuropathy or axonal degeneration such as diabetic neuropathy; Wallerian degeneration; ataxia telangiectasia; Friedreich’s ataxia; another ataxia such as spinocerebellar ataxia 7; aging; senescence; neuroinflammation; depression; schizophrenia; anxiety; stress; post-traumatic stress disorder; glaucoma; age-related macular degeneration; hearing loss; an autoimmune disease such as rheumatoid arthritis or Lupus; obesity; or metabolic syndrome.

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