N-(4-aminocyclohexyl)pyrimidine-4-carboxamide derivatives as CD38 inhibitors

Abstract

The present invention relates to a compound of formula (I): [Formula 1] TIFF2024540318000061.tif53159[where, Het, X 1 , X 2 , L, R 1 , R 2 and R 3 [0023] The present invention provides compounds of the formula: [wherein x is as defined herein] and their pharma- ceutically acceptable salts, solvates and prodrugs, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in the treatment of disorders associated with CD38 activity.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to N-(4-aminocyclohexyl)pyrimidine-4-carboxamide and related compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in the treatment of disorders associated with CD38 activity. [Background technology]

[0002] NAD + Homeostasis, Aging and Disease Nicotinamide adenine dinucleotide (NAD + NAD is an essential cellular component that is highly abundant in most living cells. + and its close analogue, NADP + Although NAD fulfills similar redox functions in cells, the latter is more often restricted to biosynthetic pathways and redox protective roles (Ying, 2008, Antioxidant Redox Signal 10:179). + NADH and NADH (NAD(H)) are essential redox systems for various electron exchange-dependent biochemical reactions, especially redox reactions involving oxidoreductase-mediated hydride transfer. Thus, NAD(H) plays an important role in the mitochondrial electron transport system and cellular energy metabolism, as well as in eukaryotic cells as a coenzyme involved in catabolism and metabolic energy acquisition. However, NAD + The role of NAD + Beyond its function as a coenzyme, its metabolites also serve 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 functions that they link cellular metabolism to altered signaling and transcriptional events and thus play a central role in the regulation of cellular homeostasis and signaling.

[0003] NAD + Levels remain largely constant when used as a coenzyme, but in non-redox reactions, their levels are depleted from cellular pools and therefore require continual resynthesis and replenishment (Nikiforov et al, 2015, Crit Rev Biochem Mol Biol 50:284). NAD + There are two main pathways for the synthesis of quinolinic acid (QA), which utilizes the essential amino acid L-tryptophan to produce quinolinic acid (QA), which is then converted to NAD + The so-called de novo pathway, which further metabolizes NAD to nicotinamide (NAM), nicotinic acid (NA), and nicotinamide riboside (NR) (Imai & Yoshino, 2013, Diabetes Obes Metab Suppl. 3:26). The salvage pathway is the major NAD metabolizer in most cell types. + Source of NAD + Levels of NAD in cells change during many physiological processes. + Increasing evidence indicates that NAD levels are greatly influenced by nutritional and environmental stimuli. + These changes in NAD + This reflects the dependent enzyme function, which in turn leads to cellular metabolism, gene expression, and protein function. Thus, optimal NAD + Maintenance of these concentrations appears to be essential for the maintenance of long-term tissue homeostasis.

[0004] cellular NAD +It has been clearly shown that levels of NAD 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, cellular NAD + Decreasing levels of NAD have emerged as potentially central to 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, + Maintenance of NAD levels and subsequent cellular homeostasis may be a means to attenuate aging and age-related diseases such as Alzheimer's and Parkinson's (Chini et al, 2017, Mol Cell Endocrinol 455:62). In support of this, numerous studies have demonstrated that elevated NAD in multiple model organisms and humans + demonstrated that NAD levels are associated with improved health and longer life spans (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, Mech Ag & Dev 197:111499). As a result, the role of NAD in age-related diseases is unclear. + Characterization of the metabolic role of NAD + There has been growing interest in developing pharmacological or nutraceutical interventions to increase NAD levels, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). +NAD by precursor + Restoring NAD levels has attracted considerable interest (for reviews, see Covarrubias et al., 2021, Nat Rev Mol Cell Biol 22:119; Perez et al., 2021, Mech Ag & Dev 197:111499), and studies have also shown that NAD levels, e.g., by suppressing CD38, may be reduced. + Consumption control has emerged as a useful therapeutic approach for age-related disorders and neurological diseases.

[0005] CD38 Cluster of differentiation (CD38) mediates cell and tissue NAD via its hydrolase function + CD38 is a multifunctional protein involved in ii) homeostasis (Chini, 2009, Curr Pharm Des 15:57) and ii) generation of the second messengers ADPR and cyclic ADPR (cADPR) through CD38s cyclase enzymatic activity, and subsequently, intracellular calcium signaling (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 is somewhat paradoxical, given that most substrates for NAD nucleosidase-CD38 would be predicted to be intracellular, however, it is now believed that NAD + as well as circulating NADs such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). + The precursors also act as NAD +It is evident that CD38 degrades NAD before it can be incorporated into the biosynthetic pathway (Yoshino et al, 2018, Cell Metab 27:513). In addition, CD38 has also been observed in intracellular membranes such as the nuclear membrane, mitochondria, and endoplasmic reticulum (Zhao et al, 2012, Sci Signal 5:ra67; Shrimp et al, 2014, J Am Chem Soc 136:5656), and a small amount 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 Sci USA. 114:8283), and even intracellular and extracellular forms of CD38 have been reported (Chini, 2009, Curr Pharm Des 15:57; Malavasi et al, 2008, Physiol Rev 88:841). + The relative roles and contributions of different cellular pools of CD38 in regulating homeostasis, calcium signaling, and subsequent cellular functions are thus complex and not yet clearly understood. CD38 requires the synthesis of approximately 100 NADPH molecules to generate one cADPR molecule. + It appears to be an extremely inefficient second messenger generating enzyme, since it hydrolyzes the molecule (Beers et al, 1995, J Clin Invest 95:2385; Kim et al, 1993, Science 261:1330), and therefore + Its role in homeostasis is similar to that of other NAD + This may be its primary function as reflected by its high substrate affinity and turnover rate compared to the utilized enzyme.

[0006] 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). It is interesting to note that in the human brain, CD38 is expressed in virtually all brain regions, with the highest expression levels in the caudate, pallidum, olfactory bulb, putamen, thalamus, and anterior cingulate gyrus (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, J Neurosci 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, applicants' own data indicate that CD38 expression predominates in astrocytes of human forebrain structures.

[0007] CD38 function has been linked to effects on immune, metabolic dysfunction, and behavioral disorders in mice (Barbosa et al., 2007, FASEB J 21:3629; Lopatina et al., 2012, Front Neurosci 6:182). + The levels were found to be significantly higher in CD38-deficient mice, indicating that CD38 is the major NAD molecule in mammalian tissues. + These results suggest that CD38 is a metabolic enzyme (NAD nucleosidase) that mediates aging. +It has been demonstrated that reduced NAD is the cause of subsequent mitochondrial dysfunction (Camacho-Pereira et al., 2016, Cell Metab 23:1127). + Decreased NAD levels are a common observation among neurodegenerative diseases, including Alzheimer's disease (Sonntag et al., 2017, Sci Rep 7:14038), Parkinson's disease (Wakade et al., 2014, PLoS ONE 9:e109818), 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, reduced CD38 activity, NAD + Increased cellular levels of NAD and subsequent + Modulation of related pathways may be a promising therapeutic approach for a range of brain and inflammatory diseases.

[0008] Therapeutic utility of CD38 inhibitors Several experimental data using CD38 knockout (KO) mice have shown favorable 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, Sci Rep 10:17795) and neuroinflammation (Choe et al., 2011, PLoS ONE 6:e19046; Raboon et al., 2019, Front Cell Neurosci 13:258; for review see Guerreiro et al., 2020, Cells 9:471), and furthermore, CD38 inhibitor molecules have been shown to reduce aging-associated NAD in mice. +CD38 KO mice reversed the decline and physiological aging effects of Alzheimer's disease (Tarrago et al., 2018, Cell Metab 27:1081). Crossbreeding CD38 KO mice with the APPswePS1DE9 model of Alzheimer's disease reduced amyloid plaque deposition and soluble Aβ levels, effects that correlated with improved functional characteristics in the Morris water maze behavioral task (Blacher et al., 2015, Ann Neurol 78:88).

[0009] In stroke models, CD38-deficient mice showed reduced local expression of proinflammatory cytokines as well as reduced ischemic injury and neurological impairment (Choe et al., 2011, PLoS ONE 6:e19046), while Long et al. (Long et al., 2017, Neurochem Res 42:283) showed improved histological and neurological outcomes after ischemic insults in CD38 KO mice. In models of multiple sclerosis, CD38 deficiency reduced the severity of the outcome of experimental autoimmune encephalomyelitis (EAE) in mice (Herrmann et al., 2016, Dis Mods Mechs 9:1211) and suppressed neuroinflammation in a mouse model of demyelination (Raboon et al., 2019, Front Cell Neurosci 13:258). Similarly, CD38 deletion or NAD +Supplementation of CD38 reduces axonal degeneration in a mouse facial nerve transection model (Takaso et al., 2020, Sci Rep 10:17795). Interestingly, transcriptome-wide association studies have 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, which are recognized as risk factors for Alzheimer's disease (Barbosa et al., 2007, FASEB J 21:3629; Chiang et al., 2015, PLoS ONE 10:e0134927). Because neuroinflammation has been shown to be a major contributor to many of these diseases (Ransohoff, 2016, Science 353:777), the regulatory influence of CD38 on immune cells in the brain and periphery is also likely to be a contributor to the beneficial effects of CD38 deletion or blockade on various preclinical seizure models (for reviews, see Guerreiro et al., 2020, Cells 9:471; Piedra-Quintero et al., 2020, Front Immunol 11:597959).

[0010] In summary, blocking CD38 and inhibiting its degradation reduces cellular NAD + There is significant preclinical evidence supporting the usefulness of enhancing CD38 levels. The therapeutic utility in CNS diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke and other neurodegenerative conditions will depend on achieving CNS penetration of CD38 inhibitors. However, CD38 inhibitors may also be useful in other conditions such as autoimmune diseases, obesity and metabolic syndrome.

[0011] Brain Penetration of Small Molecules The central nervous system (CNS) is shielded from exposure to unwanted substances by the blood-brain barrier (BBB). This restriction protects neurons from harmful interactions with toxins and other potentially harmful molecules. The BBB is composed of brain capillary endothelial cells that have several unique attributes and functions: they have tight junctions that result in extremely low permeability via paracellular pathways, they have a low rate of endocytosis, and, importantly, they highly express efflux transport proteins that have the specific function of recognizing and transporting foreign substances back out of the CNS (Gloor et al, 2001, Brain Res Rev 36:258).

[0012] Importantly, the unbound drug concentration in brain compartments is a key parameter considered necessary when evaluating the suitability of a molecule as a potential therapeutic drug for neurological and neurodegenerative diseases: it is usually only acceptable if the unbound portion of the drug is available to occupy the desired target in order to express a pharmacological effect.

[0013] There is a need for treatment of the above diseases and conditions, as well as other conditions described herein, with compounds that are CD38 inhibitors.The present invention provides such CD38 inhibitors, including brain-penetrant CD38 inhibitors. Summary of the Invention

[0014] The first aspect of the present invention relates to a compound of formula (I): [ka] [In the formula, Het is a 5-membered heteroaryl group containing 2 heteroatoms independently selected from N and S, which 5-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 hydroxyalkyl; X 1 is CH or N, and X 2 is CH or N, and X 1and X 2 at least one of is N; L is a bond, CH2, CHMe, CMe2, or CO; R 1 is C1-C4 alkyl, C3-C6 cycloalkyl, hydroxyl, -O-(C1-C4 alkyl), or -O-(C3-C6 cycloalkyl), each of which may be optionally fluoro-substituted; R 2 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CHO, -CO-(C1-C3 alkyl) or -CO-(C1-C3 fluoroalkyl); R 3 is hydrogen or methyl; or R 2 and R 3 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0015] The first aspect of the present invention also relates to a compound of formula (I): [ka] [In the formula, Het is a 5-membered heteroaryl group containing 2 heteroatoms independently selected from N and S, which 5-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 hydroxyalkyl; X 1 is CH or N, and X 2 is CH or N, and X 1 and X 2 at least one of is N; L is a bond, CH2, CHMe, CMe2, or CO; R 1is C1-C4 alkyl, C3-C6 cycloalkyl, hydroxyl, -O-(C1-C4 alkyl), or -O-(C3-C6 cycloalkyl), each of which may be optionally fluoro-substituted; R 2 is C1-C3 alkyl, C1-C3 fluoroalkyl, -CHO, -CO-(C1-C3 alkyl) or -CO-(C1-C3 fluoroalkyl); R 3 is hydrogen or methyl; or R 2 and R 3 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0016] In one embodiment of the compound of formula (I), Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group, each of which may be optionally substituted with one or two substituents independently selected from C1-C3 alkyl, C1-C3 fluoroalkyl and C1-C3 hydroxyalkyl. In one embodiment, Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group, each of which may be optionally substituted with one substituent independently selected from C1-C3 alkyl and C1-C3 fluoroalkyl. In one embodiment, Het is an imidazolyl, pyrazolyl or thiazolyl group, each of which may be optionally substituted with one substituent independently selected from methyl or ethyl. In one embodiment, Het is an imidazol-1-yl, 1-methylimidazol-5-yl, pyrazol-4-yl or thiazol-5-yl group. In a preferred embodiment, Het is an imidazol-1-yl, 1-methylimidazol-5-yl or thiazol-5-yl group.

[0017] In one embodiment of the compound of formula (I), X 1 is N and X2 is CH. In another embodiment, X 1 is CH, X 2 is N. In a preferred embodiment, X 1 is N and X 2 is N. In one embodiment of the compound of formula (I), L is a bond, CH2 or CO. In a preferred embodiment, L is a bond. In one embodiment of the compound of formula (I), R 1 is C1-C4 alkyl or C3-C6 cycloalkyl, each of which may be optionally fluoro-substituted. In one embodiment, R 1 is C1-C4 alkyl or C3-C4 cycloalkyl, each of which may be optionally fluoro-substituted. In one embodiment, R 1 is C1-C3 alkyl or cyclopropyl, each of which may be optionally fluoro-substituted. In one embodiment, R 1 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl. In a preferred embodiment, R 1 is methyl, ethyl or cyclopropyl. In one embodiment of the compound of formula (I), R 2 is C1-C3 alkyl or C1-C3 fluoroalkyl. 2 is C1-C3 fluoroalkyl. In one embodiment, R 2 is C1-C2 fluoroalkyl. In a preferred embodiment, R 2 is -CHCF, -CHCHF or -CHCHF. In another preferred embodiment, R 2 is -CH2CF3, or -CH2CHF2. In one embodiment of the compound of formula (I), R 2 and R 3 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally substituted with 1, 2, 3, or 4 fluoro substituents. 2 and R 3together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which may be optionally substituted with 1, 2, 3 or 4 fluoro substituents. In a preferred embodiment, R 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which is substituted with 1, 2, or 3 fluoro substituents. In another preferred embodiment, R 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which is substituted with two or three fluoro substituents. In a preferred embodiment of the compounds of formula (I), the two substituents on the cyclohexyl group (-NH- and -L-) are trans to each other.

[0018] The first aspect of the present invention relates to a compound represented by formula (II): [ka] [In the formula, Het is a 5-membered heteroaryl group containing 2 heteroatoms independently selected from N and S, which 5-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 hydroxyalkyl; X 1 is CH or N, and X 2 is CH or N, and X 1 and X 2 at least one of is N; R 1 is C1-C4 alkyl, C3-C6 cycloalkyl, hydroxyl, -O-(C1-C4 alkyl), or -O-(C3-C6 cycloalkyl), each of which may be optionally fluoro-substituted; R 2 is C1-C3 alkyl or C1-C3 fluoroalkyl; R 3 is hydrogen or methyl; or R 2 and R 3together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0019] In one embodiment of the compound of formula (II), Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group, each of which may be optionally substituted with one or two substituents independently selected from C1-C3 alkyl, C1-C3 fluoroalkyl and C1-C3 hydroxyalkyl. In one embodiment, Het is an imidazolyl, pyrazolyl, thiazolyl or isothiazolyl group, each of which may be optionally substituted with one substituent independently selected from C1-C3 alkyl and C1-C3 fluoroalkyl. In one embodiment, Het is an imidazolyl, pyrazolyl or thiazolyl group, each of which may be optionally substituted with one substituent independently selected from methyl or ethyl. In one embodiment, Het is an imidazol-1-yl, 1-methylimidazol-5-yl, pyrazol-4-yl or thiazol-5-yl group. In a preferred embodiment, Het is an imidazol-1-yl, 1-methylimidazol-5-yl or thiazol-5-yl group. In one embodiment of the compound of formula (II), X 1 is N and X 2 is CH. In another embodiment, X 1 is CH and X 2 is N. In a preferred embodiment, X 1 is N and X 2 is N. In one embodiment of the compound of formula (II), R 1 is C1-C4 alkyl or C3-C6 cycloalkyl, each of which may be optionally fluoro-substituted. In one embodiment, R 1 is C1-C4 alkyl or C3-C4 cycloalkyl, each of which may be optionally fluoro-substituted. In one embodiment, R1 is C1-C3 alkyl or cyclopropyl, each of which may be optionally fluoro-substituted. In one embodiment, R 1 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl. In a preferred embodiment, R 1 is methyl, ethyl or cyclopropyl. In one embodiment of the compound of formula (II), R 2 is C1-C3 fluoroalkyl. In one embodiment, R 2 is C1-C2 fluoroalkyl. In a preferred embodiment, R 2 is -CHCF, -CHCHF or -CHCHF. In another preferred embodiment, R 2 is -CH2CF3, or -CH2CHF2. In one embodiment of the compound of formula (II), R 2 and R 3 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally substituted with 1, 2, 3, or 4 fluoro substituents. 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which may be optionally substituted with 1, 2, 3 or 4 fluoro substituents. In a preferred embodiment, R 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which is substituted with 1, 2, or 3 fluoro substituents. In another preferred embodiment, R 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which is substituted with two or three fluoro substituents. In a preferred embodiment of the compound of formula (II), the two substituents on the cyclohexyl group (-NH- and -NR 2 R 3 ) are trans to each other.

[0020] The first aspect of the present invention relates to a compound represented by formula (III): [ka] [In the formula, each W, X, Y and Z is independently CH, CMe, N, NH, NMe or S, two of W, X, Y and Z are CH or CMe, and the other two of W, X, Y and Z are N, NH, NMe or S; R 1 is C1-C4 alkyl or C3-C4 cycloalkyl; R 2 is C1-C3 alkyl or C1-C3 fluoroalkyl; R 3 is hydrogen or methyl; or R 2 and R 3 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0021] To avoid any misunderstanding, [ka] is a 5-membered heteroaryl group containing two heteroatoms independently selected from N and S, and it is noted that the 5-membered heteroaryl group may be optionally substituted with one or two methyl groups.

[0022] In one embodiment of the compound of formula (III), W is CH, N or NH; X is CH, N or NH; Y is CH, N, NH, NMe or S; and Z is C or N. In one embodiment, W is CH or N; X is CH, N or NH; Y is CH, NMe or S; and Z is C or N. In one embodiment, the group [ka] is an imidazol-1-yl, 1-methylimidazol-5-yl, pyrazol-4-yl, or thiazol-5-yl group. In a preferred embodiment, the group [ka] is an imidazol-1-yl, 1-methylimidazol-5-yl, or thiazol-5-yl group. In one embodiment of the compound of formula (III), R 1 is C1-C3 alkyl or cyclopropyl. 1 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl. In a preferred embodiment, R 1 is methyl, ethyl or cyclopropyl. In one embodiment of the compound of formula (III), R 2 is C1-C3 fluoroalkyl. In one embodiment, R 2 is C1-C2 fluoroalkyl. In a preferred embodiment, R 2 is -CHCF, -CHCHF or -CHCHF. In another preferred embodiment, R 2 is -CH2CF3, or -CH2CHF2. In one embodiment of the compound of formula (III), R 2 and R 3 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally substituted with 1, 2, 3, or 4 fluoro substituents. 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which may be optionally substituted with 1, 2, 3 or 4 fluoro substituents. In a preferred embodiment, R 2 and R 3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which is substituted with 1, 2, or 3 fluoro substituents. In another preferred embodiment, R 2 and R3 together with the nitrogen to which they are attached form a pyrrolidin-1-yl group, which is substituted with two or three fluoro substituents. In a preferred embodiment of the compound of formula (III), the two substituents on the cyclohexyl group (-NH- and -NR 2 R 3 ) are trans to each other.

[0023] A second aspect of the present invention provides a compound selected from: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; 6-Cyclopropyl-N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide; 6-Methyl-2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 6-Methyl-2-(thiazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 6-Ethyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(thiazol-5-yl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2-fluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; 6-Methyl-2-(1H-pyrazol-4-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(1H-pyrazol-4-yl)pyrimidine-4-carboxamide; 4-Cyclopropyl-N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-(1H-imidazol-1-yl)picolinamide; N-((1r,4r)-4-(ethylamino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide; 4-Cyclopropyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)picolinamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1S,4r)-4-(((S)-1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1R,4r)-4-(((R)-1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide; 6-Methyl-2-(5-methyl-1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-aminocyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl-1,1-d2)amino)cyclohexyl)pyrimidine-4-carboxamide; or an enantiomer of any of the foregoing; or a pharma- ceutically acceptable salt, solvate or prodrug of any of the foregoing.

[0024] 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. 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.

[0025] 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, the process comprising reacting a compound of formula (IV) with a compound of formula (V): [ka] [where Het, X 1 , X 2 , L, R 1 , R 2 and R 3 is as defined in the first or second aspect of the invention; Y is -OH, -OR 4 , -O-CO-R 4 or -Cl; and R 4 is C1-C3 alkyl], and then optionally carrying out one or more of the following procedures: - converting a compound of formula (I), (II) or (III) into another compound of formula (I), (II) or (III); - a procedure for removing all protecting groups; - A procedure for forming a pharma- ceutically acceptable salt. When Y is -OH, the compound of formula (IV) is a carboxylic acid (IVA). 4 When Y is -CO-R, the compound of formula (IV) is the ester (IVB). 4When Y is -Cl, the compound of formula (IV) is an anhydride (IVC). When Y is -Cl, the compound of formula (IV) is an acid chloride (IVD).

[0026] The step of reacting the carboxylic acid (IVA) with the amine of formula (V) may be carried out in the presence of a coupling agent such as HATU or T3P, and a base such as DIPEA or TEA. Typically, DMF, NMP or DCM is used as the solvent, but other polar aprotic solvents can also be used. Usually, the reaction is carried out at about 20-50° C. (typically, about 25° C.) and takes 0.5-5 hours (typically, about 1-2 hours).

[0027] The step of reacting the ester (IVB) with the amine of formula (V) may be carried out in the presence of trimethylaluminum in a non-polar solvent such as toluene. Typically, the reaction is carried out at about 70-100° C. (typically about 90° C.) and takes 0.5-5 hours (typically about 1-2 hours).

[0028] The step of reacting the anhydride (IVC) with the amine of formula (V) may be carried out in the presence of a base such as DIPEA or TEA. Typically, DMF, NMP or DCM is used as the solvent, although other polar aprotic solvents can also be used. Usually, the reaction is carried out at about 20-50° C. (typically about 25° C.) and takes 0.5-5 hours (typically about 1-2 hours).

[0029] Carboxylic acids of formula (IVA) and esters of formula (IVB) may be prepared as shown in Scheme 1. [ka]

[0030] In step (a), ester (VI) (where Z is a leaving group such as chlorine) is reacted with a heteroaryl compound such as imidazole, typically in the presence of a base such as DIPEA or TEA, to give ester (IVB). Typically, DMF is used as the solvent. Typically, the reaction is carried out at about 90-110° C. (typically, about 100° C.) and takes 2-24 hours (typically, about 4-12 hours). The reaction may be carried out under an atmosphere of nitrogen. In step (b), the ester (IVB) is converted to the carboxylic acid (IVA) by treatment with a base such as LiOH. Typically, THF and water are used as solvents. The reaction is usually carried out at about 20-50° C. (typically, about 25° C.) and takes 0.5-5 hours (typically, about 1-2 hours). Alternatively, carboxylic acid (IVA) can be prepared from ester (VI) in a one-step process. In step (c), ester (VI) is reacted with a heteroaryl compound activated with, for example, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group, for example, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole or 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole to directly obtain carboxylic acid (IVA). Ester (VI) and activated heteroaryl compound can be reacted in the presence of Cs2CO3 and Pd(dppf)Cl2. Typically, dioxane and water are used as solvents. The reaction is usually carried out at about 80 to 100° C. (typically, about 90° C.) and takes 0.5 to 5 hours (typically, about 1 to 2 hours). The reaction is usually carried out under a nitrogen atmosphere.

[0031] X 1 is N and X 2 When is CH, the methyl ester of formula (IVB′) and the carboxylic acid of formula (IVA′) may be prepared as shown in Scheme 2. [ka]

[0032] In step (d), 2,6-dichloro-4-iodopyridine (VIII) is reacted with a heteroaryl salt, such as sodium imidazole, to give compound (IX). Typically, THF is used as a solvent. The reaction is usually carried out at about 50-70° C. (typically, about 60° C.) and takes about 6-24 hours (typically, about 12 hours). The required heteroaryl salt can be prepared by treating a heteroaryl compound, such as imidazole, with a base, such as NaH. Typically, THF is used as a solvent; the reaction is typically carried out at about 0° C. and takes about 0.1-2 hours (typically, about 0.5 hours). In step (e), compound (IX) is usually reacted with a boronic acid R in the presence of K3PO4, PCy3·BF4, and Pd(OAc)2. 1 -B(OH)2 to obtain compound (X). Typically, water and toluene are used as solvents. Typically, the reaction is carried out at about 100-120°C (typically, about 110°C) and takes about 3-12 hours (typically, about 6 hours). Typically, the reaction is carried out under a nitrogen atmosphere. In step (f), compound (X) can be treated with carbon monoxide and methanol, typically in the presence of TEA and Pd(dppf)Cl2, to obtain methyl ester (IVB'). Typically, the reaction is carried out at about 70-90°C (typically, about 80°C) and takes about 12-24 hours (typically, about 16 hours). In step (g), methyl ester (IVB') is converted to carboxylic acid (IVA') by treatment with a base such as LiOH. Typically, THF and water are used as solvents. Usually, the reaction is carried out at about 20 to 30° C. (typically, about 25° C.) and takes about 0.5 to 5 hours (typically, about 1 to 2 hours).

[0033] An example of the conversion of a compound of formula (I), (II) or (III) to another compound of formula (I), (II) or (III) can be found in Example 28. The step of converting a compound of formula (I), (II) or (III) to another compound of formula (I), (II) or (III) can be carried out by an alkylation reaction, where R is hydrogen. 2 is another R 2 R is substituted with a group or is hydrogen. 3 is another R 3 Typically, in alkylation reactions, R 2 or R 3 The compound of formula (I), (II) or (III) in which is hydrogen is the compound LG-R 2 or LG-R 3 where LG is a leaving group, e.g., halo, such as fluoro, chloro, bromo, or iodo-, a sulfate group (e.g., methyl sulfate), or a sulfonate group (e.g., mesylate, triflate, or tosylate); 2 and R 3 may be combined with a carboxyl group (as defined in the first or second aspect of the invention). Usually, the reaction is carried out in the presence of a base such as K2CO3, typically in the further presence of KI and 1,4,7,10,13,16-hexaoxacyclooctadecane. Usually, the reaction is carried out in a solvent such as DMF at about 80-100°C (typically about 90°C) and takes about 1 hour.

[0034] Those skilled in the art will understand that in the methods 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. Examples of the introduction and / or removal of one or more protecting groups can be found in Example 28.

[0035] 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. Huts, Wiley-Interscience (2007); and "Protecting Groups", 3rd edition, P.J. Kocienski, Thieme (2005).

[0036] The compounds of the first and second aspects of the invention can be converted into their pharma- ceutically acceptable salts, preferably acid addition salts, such as formate, hemiformate, hydrochloride, hydrobromide, benzenesulfonate (besylate), saccharinate (e.g. monosaccharinate), trifluoroacetate, sulfate, nitrate, phosphate, acetate, fumarate, hemifumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy-2-naphthoate (xinafoate), methanesulfonate or p-toluenesulfonate. In one embodiment of the invention, the compounds of the first and second aspects are in the form of hydrochloride, formate or fumarate. Examples of pharma-ceutically acceptable salts of the compounds of the first and second aspects of the invention can be found in Examples 9, 19 and 27. Salts of the compounds of the first or second aspect of the present invention can also be formed between the protonic acidic functional group of the compounds 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 present invention, the salt is a sodium or potassium salt. The compounds of the first and second aspects of the invention and their salts may be in the form of hydrates or solvates, which constitute another embodiment of the invention. Such solvates may be formed with common organic solvents, including but not limited to alcoholic solvents, such as methanol, ethanol or isopropanol. In one embodiment of the present invention, therapeutically inactive prodrugs are provided. Prodrugs are compounds that, 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. In general, prodrugs are pharmacologically inactive chemical derivatives that can be converted to an active drug molecule in vivo to exert a therapeutic effect. Any compound of the first and second aspects 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 the functional moieties 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 generate an active compound. The present invention also encompasses salts and solvates of the prodrugs as described above.

[0037] It will be understood that when the compounds, salts, solvates and prodrugs of the present invention can exist in stereoisomeric forms, the present invention encompasses the use of all geometric and optical isomers (including atropisomers) and mixtures thereof. The use of tautomers and mixtures thereof also form an embodiment of the present invention. The compounds, salts, solvates and prodrugs of the present invention can contain at least one chiral center. The compounds, salts, solvates and prodrugs can 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. In the present invention, an "enantiomerically substantially pure" isomer of a compound contains less than 5% by weight, more typically less than 2% by weight, more typically less than 1% by weight, and most typically less than 0.5% by weight of other isomers of the same compound. Enantiomerically pure isomers are particularly desirable.

[0038] The compounds, salts, solvates and prodrugs of the present invention include, but are not limited to, 12 C. 13 C. 1 H, 2 H(D), 14 N, 15 N, 16 O. 17 O. 18 O. 19 F and 127 Any stable isotope, including but not limited to I, 11 C. 14 C. 3 H(T), 13 N, 15 O. 18 F, 123 I, 124 I, 125 I and 131 The term "hydrogen" may include any radioisotope, including I. Thus, the term "hydrogen" may include, for example, 1 H, 2 H(D) and 3 H(T). Similarly, the carbon atom is 11 C. 12 C. 13 C and14 C, and the nitrogen atom is 13 N, 14 N and 15 N should be understood to include the oxygen atom. 15 O. 16 O. 17 O and 18 O, and fluorine atoms are 18 F and 19 F, and the iodine atom is understood to include 123 I, 124 I, 125 I, 127 I and 131 It should be understood to include I.

[0039] In one embodiment, the compounds, salts, solvates and prodrugs of the present invention may be isotopically labeled. As used herein, an "isotopically labeled" compound is a compound in which the abundance of a particular nuclide at a particular atomic position in the molecule is increased above the naturally occurring level. Any of the compounds, salts, solvates and prodrugs of the present invention, for example, any of Examples 1-16 or 19-28, may be isotopically labeled.

[0040] In one embodiment, the compounds, salts, solvates and prodrugs of the present invention can have one or more radiolabels.Such radiolabels can be introduced by using radiolabel-containing reagents during the synthesis of compounds, salts, solvates or prodrugs, or can be introduced by binding compounds, salts, solvates or prodrugs to chelating moieties that can bind to radioactive metal atoms.Such radiolabeled compounds, salts, solvates and prodrugs can be used, for example, in imaging diagnostic tests.

[0041] In one embodiment, the compounds, salts, solvates and prodrugs of the present invention may be tritium-labeled, i.e., they may contain one or more 3 Any of the compounds, salts, solvates and prodrugs of the invention, for example any of Examples 1-16 or 19-28, can be tritium-labeled.

[0042] The compounds, salts, solvates and prodrugs of the present invention may be in amorphous or polymorphic form, or any mixture thereof, each of which is an embodiment of the present invention.

[0043] The compounds, salts, solvates and prodrugs of the present invention have pharmaceutical activity and may be used in the treatment or prevention of diseases, disorders or conditions associated with CD38 activity, including: -CNS diseases and diseases requiring CNS-mediated therapy, including: Parkinson's disease (Camacho-Pereira et al, 2016, Cell Metab 23:1127; Perez et al, 2021, Mech Ag & Dev 197:111499; Wakade et al, 2014, PLoS ONE 9:e109818; Yao et al, 2021, npj Parkinsons Dis 7:79); Alzheimer's disease (Blacher et al, 2015, Ann Neurol 78:88; Sonntag et al, 2017, Sci Rep 7:14038); frontotemporal dementia; progressive supranuclear palsy (PSP); tauopathies; other non-Alzheimer's dementias; stroke and ischemic attacks (Choe et al, 2011, PLoS ONE 6:e19046); traumatic brain injury (TBI) (Long et al,2017,Neurochem Res 42:283;Takaso et al,2020,Sci Rep 10:17795);multiple sclerosis (Herrmann et al,2016,Dis Mods Mechs 9:1211;Raboon et al,2019,Front Cell Neurosci 13:258);autoimmune diseases with associated neuronal damage such as Muckle-Wells syndrome;motor neuron diseases such as amyotrophic lateral sclerosis (ALS) (Wang et al,2017,Cell Rep 20:2184);axonal degeneration such as axonal neuropathy and diabetic neuropathy (Lin et al,2016,Cell Rep 17:69);Wallerian degeneration (Essuman et al,2017,Neuron 93:1334;Takaso et al,2019,Cell Rep 13:258); al,2020,Sci Rep 10:17795; Krauss et al,2020,TiPS 41:281); other ataxias such as ataxia-telangiectasia, Friedreich's ataxia and spinocerebellar ataxia 7 (SCA7) (Fang et al,2016,Cell Metab 24:566); - Aging and aging (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); -Neuroinflammation (Choe et al,2011,PLoS ONE 6:e19046;Raboon et al,2019,Front Cell Neurosci 13:258;Guerreiro et al,2020,Cells 9:471;Najjar et al,2013,J Neuroinflamm 10:43); - Depression, schizophrenia, anxiety, stress and post-traumatic stress disorder (PTSD) (Tabak et al, 2016, Clin Psychol Sci 4:17); -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); -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 6:1); - Autoimmune diseases, e.g., 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:e0134927).

[0044] Thus, a fourth aspect of the invention provides a compound, salt, solvate or prodrug according to the first or second aspects of the invention for use in therapy, in particular in the treatment or prophylaxis of a disease, disorder or condition associated with CD38 activity.

[0045] A fourth aspect of the invention provides a compound, salt, solvate or prodrug according to the first or second aspect of the invention for use in the treatment or prophylaxis of a CNS disease, a disease requiring CNS mediated therapy, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disease. The fourth aspect of the invention also provides a compound, salt, solvate or prodrug according to the first or second aspect of the invention for use in the treatment or prevention of Parkinson's disease; Alzheimer's disease; frontotemporal dementia; progressive supranuclear palsy; tauopathy; another non-Alzheimer's dementia; stroke; ischemic attack; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated neuronal damage such as Muckle-Wells syndrome; a motor neuron disease such as amyotrophic lateral sclerosis; axonal degeneration such as axonal neuropathy or diabetic neuropathy; Wallerian degeneration; another ataxia such as ataxia-telangiectasia; Friedreich's ataxia; spinocerebellar ataxia; ageing; aging; 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.

[0046] A fifth aspect of the invention provides the use of a compound, salt, solvate or prodrug according to the first or second aspect of the invention for the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition associated with CD38 activity. The fifth aspect of the invention also provides the use of a compound, salt, solvate or prodrug according to the first or second aspect of the invention for the manufacture of a medicament for the treatment or prevention of a CNS disease, a disease requiring CNS mediated therapy, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disease. The fifth aspect of the invention also provides the use of a compound, salt, solvate or prodrug according to the first or second aspect of the invention for the manufacture of a medicament for the treatment or prevention of Parkinson's disease; Alzheimer's disease; frontotemporal dementia; progressive supranuclear palsy; tauopathy; another non-Alzheimer's dementia; stroke; ischemic attack; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated neuronal damage such as Muckle-Wells syndrome; a motor neuron disease such as amyotrophic lateral sclerosis; axonal degeneration such as axonal neuropathy or diabetic neuropathy; Wallerian degeneration; ataxia-telangiectasia; Friedreich's ataxia; another ataxia such as spinocerebellar ataxia7; ageing; 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.

[0047] A sixth aspect of the invention provides a method for the treatment or prevention of a disease, disorder or condition associated with CD38 activity, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound, salt, solvate or prodrug according to the first or second aspect of the invention. The sixth aspect of the invention also provides a method of treatment or prophylaxis of a CNS disease, a disease requiring CNS mediated therapy, a neurodegenerative condition, a neurological disease, an age-related disorder or an inflammatory disease, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound, salt, solvate or prodrug according to the first or second aspect of the invention. A sixth aspect of the invention also relates to a method for treating Parkinson's disease; Alzheimer's disease; frontotemporal dementia; progressive supranuclear palsy; tauopathy; another non-Alzheimer's dementia; stroke; ischemic attack; traumatic brain injury; multiple sclerosis; autoimmune diseases with associated neuronal damage such as Muckle-Wells syndrome; motor neuron diseases such as amyotrophic lateral sclerosis; axonal degeneration such as axonal neuropathy or diabetic neuropathy; Wallerian degeneration; ataxia telangiectasia; Friedreich's dementia. The present invention provides a method for the treatment or prevention of: ataxia; another ataxia such as spinocerebellar ataxia7; aging; ageing; 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 to a patient in need thereof a therapeutically or prophylactically effective amount of a compound, salt, solvate or prodrug according to the first or second aspect of the invention.

[0048] Unless otherwise specified, in any of the fourth, fifth or sixth aspects of the present 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.

[0049] As used herein, unless specifically indicated to the contrary, the term "therapy" also includes "prophylaxis." The terms "therapeutic" and "therapeutically" should be construed accordingly.

[0050] It is expected that prophylaxis will be particularly relevant to the treatment of persons who have experienced previous symptoms of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at increased risk of developing a particular disorder or condition will usually include those who have a family history of the disorder or condition, or who have been identified by genetic testing or screening as being particularly susceptible to developing the disorder or condition.

[0051] The terms "treat", "treatment" and "treating" include amelioration of the conditions described herein. The terms "treat", "treatment" and "treating" do not necessarily indicate complete disappearance of all symptoms or a cure of a condition, but include any process that slows, interrupts, hinders, or halts the progression or progression of a condition described herein. The terms "treat", "treatment" and "treating" are intended to include therapeutic as well as prophylactic measures for such conditions.

[0052] In the case of the above-mentioned therapeutic use, the dosage will of course vary depending on the compound used, the method of administration, the desired treatment and the disorder to be treated. For example, the daily dosage of the compound of the present invention (i.e., the compound of formula (I), (II) or (III), or its pharma-ceutically acceptable salt, solvate or prodrug) by oral or parenteral administration can be in the range of 0.01 (μg / kg body weight) to 500 (mg / kg body weight). The desired dosage may be given at suitable intervals, such as once every other day, once a day, twice a day, three times a day, or four times a day.

[0053] The compounds and their acceptable salts, solvates and prodrugs may be used alone, but the active ingredient is usually administered in the form of a pharmaceutical composition together with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0054] Thus, a seventh aspect of the invention provides a pharmaceutical composition comprising a compound, salt, solvate or prodrug according to the first or second aspects of the invention together with a pharma- ceutically acceptable adjuvant, diluent or carrier and, optionally, one or more other therapeutic agents.

[0055] The present invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises admixing a compound, salt, solvate or prodrug according to the first or second aspect of the invention with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0056] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in “Pharmaceutics—The Science of Dosage Form Design”, MEAulton, Churchill Livingstone, 1988.

[0057] The pharma- ceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the present invention are those conventionally used in the field of pharmaceutical formulations and include, but are not limited to, sugars, sugar alcohols, starches, ion exchange materials, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerin, 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.

[0058] The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, rectally, nasally, bucally, vaginally, ophthalmically, topically, or via an implanted reservoir. Oral administration is preferred. The pharmaceutical composition of the present invention may contain any conventional non-toxic pharma- ceutical acceptable adjuvant, diluent, or carrier. As used herein, the term parenteral includes subcutaneous, intradermal, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratracheal, intraperitoneal, intraarticular, and epidural injection or infusion techniques. As used herein, the term topical includes transdermal, mucosal, sublingual, and topical ocular administration.

[0059] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous solution. Suspensions 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. Sterile injectable preparations may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, 1,3-butanediol. Among the acceptable diluents and solvents that may be used, mannitol, water, Ringer's solution, and isotonic sodium chloride solution may be employed. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland, fixed oil may be employed, such as synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharma-ceutically acceptable natural oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants.

[0060] The pharmaceutical composition of the present 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 by techniques known in the art of pharmaceutical formulation. In the case of tablets for oral use, commonly used carriers include lactose, sodium and calcium carbonate, sodium and calcium phosphate, and cornstarch. Lubricants, such as magnesium stearate, stearic acid, or talc, are also commonly added. If necessary, the tablet may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The tablet may also be an effervescent and / or dissolving tablet. Useful diluents for oral administration in capsule form include lactose and dried cornstarch. When aqueous suspensions are orally administered, the active ingredient may be mixed with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents and / or preservatives may be added to any oral dosage form.

[0061] The pharmaceutical composition of the present invention may also be administered in the form of suppositories for rectal administration of the drug.These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

[0062] The pharmaceutical compositions of the invention may be administered by nasal aerosol or inhalation. Such compositions are prepared by techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0063] For ocular administration, the compound, salt, solvate or prodrug of the present invention will generally be provided in a form suitable for topical administration, such as eye drops.Suitable forms may include eye drops, gel-forming solutions, sterile powders for reconstitution, eye drop suspensions, eye drop ointments, eye drop emulsions, eye drop gels and ocular inserts.Alternatively, the compound, salt, solvate or prodrug of the present invention may be provided in a form suitable for other types of ocular administration, such as intraocular preparations (such as irrigation solutions, intraocular, intravitreal or juxtascleral injection preparations, or intravitreal implants), as packs or corneal shields, as intracameral, subconjunctival or retrobulbar injection preparations, or as iontophoretic preparations.

[0064] For transdermal and other topical administration, the compounds, salts, solvates or prodrugs of the invention will generally be provided in the form of an ointment, poultice, paste, powder, bandage, cream, plaster or patch.

[0065] Depending on the method of administration, all pharmaceutical compositions contain, by weight based on the total composition, preferably 0.05-99% by weight, more preferably 0.05-80% by weight, even more preferably 0.1-70% by weight, and still more preferably 0.1-50% by weight of the active ingredient.

[0066] The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions. The present invention therefore further relates to combination therapy, in which the compound of the present invention or pharmaceutical composition or formulation containing the compound of the present invention is administered together with another therapeutic agent or agent for the treatment of one or more conditions previously indicated.The compound of the present invention or pharmaceutical composition or formulation containing the compound of the present invention can be administered simultaneously with one or more other therapeutic agents, separately therewith, or sequentially therewith.The compound of the present invention and one or more other therapeutic agents can be included in the same pharmaceutical composition or formulation, or in separate pharmaceutical compositions or formulations, i.e., in the form of a kit.

[0067] Typically, the method of administration selected is the one most suitable for the disorder, disease or condition to be treated or prevented. When one or more additional active agents are administered, the method of administration may be the same as or different from the method of administration of the compound or pharmaceutical composition of the present invention. Such combination products employ the compounds of this invention within the dosage range described herein, and the other pharma- ceutical active agent within its approved dosage range. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] definition An "alkyl" group may be linear (i.e., straight-chain) or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, and 2,2-dimethyl-1-propyl groups. Unless otherwise specified, the term "alkyl" does not include "cycloalkyl". Typically, alkyl groups are C1-C 12 An alkyl group is more typically a C1-C6 alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.

[0069] 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 otherwise specified, the term "alkenyl" does not include "cycloalkenyl". Typically, an alkenyl group is a C2-C 12 alkenyl groups. More typically, the alkenyl group is a C2-C6 alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.

[0070] 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-C 12 An alkynyl group is a C2-C6 alkynyl group. More typically, the alkynyl group is a C2-C6 alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.

[0071] A "cycloalkyl" group is a saturated hydrocarbyl ring containing, for example, 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a cycloalkyl group may be monocyclic, bicyclic (e.g., bridged, fused, or spiro) or polycyclic.

[0072] A "cycloalkenyl" group is a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohexa-1,3-dien-1-yl. Unless otherwise specified, cycloalkenyl groups can be monocyclic, bicyclic (e.g., bridged, fused, or spiro) or polycyclic.

[0073] 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 otherwise specified, the term "aryl" does not include "heteroaryl."

[0074] A "heterocyclic" group is a non-aromatic cyclic group that contains one or more carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as N, O, or S, in the ring structure. Heterocyclic groups can be monocyclic, bicyclic (e.g., bridged, fused, or spiro) or polycyclic. Typically, a heterocyclic group is a 4-14 membered heterocyclic group, meaning it contains 4 to 14 ring atoms. More typically, a heterocyclic group is a 4-10 membered heterocyclic group, meaning it contains 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 include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups. Examples of saturated bicyclic heterocyclic groups include quinuclidinyl, 8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 6-azaspiro[2.5]octanyl and hexahydro-1H-pyrrolidinyl groups.

[0075] A "heteroaryl group" is an aromatic cyclic group that contains one or more carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, such as N, O or S, in the ring structure. Typically, a heteroaryl group is a 5- to 14-membered heteroaryl group, which means it contains 5-14 ring atoms. More typically, a heteroaryl group is a 5- to 10-membered heteroaryl group, which means it contains 5-10 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, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzimidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, and cinnolinyl. Examples of heteroaryl groups include: [ka] Wherein G=O, S or NH. Thus, a 5-membered heteroaryl group containing two heteroatoms independently selected from N and S can be a pyrazolyl, imidazolyl, thiazolyl or isothiazolyl group.

[0076] As used herein, when a combination of moieties is referred to as a group, such as arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl, the last-listed moiety contains the atom by which the group is attached to the remainder of the molecule. An example of an arylalkyl group is benzyl.

[0077] The term "halo" encompasses fluoro, chloro, bromo and iodo, hi one embodiment, halo is fluoro.

[0078] Unless otherwise noted, when a group is prefixed with the term "halo", such as a haloalkyl or halomethyl group, it is to be understood that the group is substituted with one or more (e.g., 1, 2, 3, 4, or 5) 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 in the corresponding group without the halo prefix. For example, a "halomethyl" group may contain 1, 2, or 3 halo substituents. A "haloethyl" or "halophenyl" group may contain 1, 2, 3, 4, or 5 halo substituents. Similarly, unless otherwise noted, when a group is prefixed with a particular halo group, it is to be understood that the group is substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the particular halo group. For example, the term "fluoromethyl" refers to a methyl group substituted with 1, 2 or 3 fluoro groups, and the term "fluoroethyl" refers to an ethyl group substituted with 1, 2, 3, 4 or 5 fluoro groups.

[0079] Similarly, unless otherwise indicated, when a group is said to be "halo-substituted," it is to be understood that the group is substituted with one or more (e.g., 1, 2, 3, 4, or 5) 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 in the corresponding group that does not contain halo substitution. For example, a "halo-substituted methyl" group may contain 1, 2, or 3 halo substituents. A "halo-substituted ethyl" or a "halo-substituted phenyl" group may contain 1, 2, 3, 4, or 5 halo substituents. Similarly, unless otherwise indicated, when a group is said to be substituted with a particular halo group, such as a "fluoro-substituted" group, it is to be understood that the group is substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the particular halo group. For example, the term "fluoro-substituted methyl" means a methyl group substituted with 1, 2 or 3 fluoro groups, and the term "fluoro-substituted ethyl" means an ethyl group substituted with 1, 2, 3, 4 or 5 fluoro groups.

[0080] A "hydroxyalkyl" group refers to an alkyl group substituted with one or more (e.g., 1, 2 or 3) hydroxyl (-OH) groups. Typically, a hydroxyalkyl group has one or two hydroxyl substituents, and more typically, a hydroxyalkyl has one hydroxyl substituent.

[0081] Unless otherwise specified, any reference to an element should be taken to refer to all isotopes of that element. Thus, for example, unless otherwise specified, any reference to hydrogen is 1 H, 2 H(D) and 3 All hydrogen isotopes are considered to be encompassed, including H(T). Thus, for the avoidance of doubt, it is noted that, for example, the terms "alkyl" and "methyl" include, for example, trideuteriomethyl.

[0082] Unless otherwise stated, any reference to a compound or group should include a reference to all tautomers of that compound or group.

[0083] It will be understood that when any chemical group or moiety is described as substituted, the number and nature of the substituents will be selected to avoid sterically unfavorable combinations.

[0084] Working Example The invention will now be further described by reference to the following illustrative examples, in which starting materials and reagents used are either obtained from commercial suppliers or prepared by literature procedures similar to those described in this application. Abbreviation DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide EtOAc Ethyl acetate EtOH Ethanol h time HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography MeCN Acetonitrile MeOH Methanol min NMP N-methyl-2-pyrrolidine PCy3·BF4 Tricyclohexylphosphine Tetrafluoroborate Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) RT room temperature SFC Supercritical Fluid Chromatography T3P Propylphosphonic anhydride TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran UPLC High Performance Liquid Chromatography

[0085] Basic steps Unless otherwise stated, nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz, 298.2 K or 294.1 K as indicated; chemical shifts (δ) were reported in parts per million. Spectra were recorded using a Bruker® 400 AVANCE instrument equipped with a 5 mm iprobe or smart probe with the instrument controlled by Bruker TopSpin 4.0.9 or Bruker TopSpin 4.1.1 software. Reactions were monitored using one or more of the following: Agilent 1290 infinity II UPLC coupled to a 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): 220nm and 254nm; Flow rate: 1.0mL min-1; Analysis time: 4.0min; Mass range: 100-1500m / z. Purity was assessed using: UPLC with UV (photodiode array) detection over a wide range of wavelengths, typically 220-254 nm, using a Shimadzu® Nexera X2 UPLC equipped with an Acquity UPLC BEH, HSS or HSS T3 C18 column (2.1 mm idx50 mm length) operated at 50°C and controlled by Lab Solution software. Unless otherwise stated, the mobile phase typically consisted of CH3CN mixed with H2O containing 0.037% TFA or 0.225% HCOOH. Mass spectra were recorded on a Shimadzu single mass spectrometer using DUIS ionization. Compounds were purified using normal phase silica chromatography on a Biotage or ISCO® instrument, or by preparative high performance liquid chromatography (HPLC). Preparative HPLC was performed at room temperature using a Gilson GX-281 system with Phenomenex C18 75x30mm, 3μm; Xtimate C18 100x30mm, 10μm; Xtimate C18 150x40mm, 10μm; Xtimate C18 150x40mm, 10μm; Phenomenex C18 75x30mm, 3μm or Gemini NX C18 10x150mm, 5μm columns. Unless otherwise noted, the mobile phase typically consisted of CH3CN mixed with H2O containing 0.225% formic acid or 0.05% ammonia + 10nM NH4HCO3. Supercritical fluid chromatography (SFC) chiral analysis was performed on a Waters UPCC equipped with a PDA Detector using a flow rate of 4 mL / min, temperatures between RT and 35° C. and a pressure of 1500 psi. The mobile phase typically consists of supercritical CO2 and a polar solvent such as CH3CN, MeOH, EtOH or isopropanol. Column types and eluents 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-0-1.8 50x4.6mm, 1.8μm; Chiralpak OJ-3 100x4.6mm, 3μm.; Detection: 220nm; Sample diluent: CH3CN, MeOH; Injection: 9μl; Isocratic ratio: 5%-40% of mobile phase. As used herein, "room temperature" means a temperature ranging from about 18°C ​​to about 25°C.

[0086] Synthesis of intermediates Intermediate 1:(1r,4r)-N 1 -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine [ka] Step 1: A solution of (1r,4r)-N1,N1-dibenzylcyclohexane-1,4-diamine hydrochloride (6.30 g, 18.7 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.21 g, 22.5 mmol) and NEt3 (9.47 g, 93.6 mmol) in CH3CN (60 mL) was stirred at 70 °C for 12 h and extracted with EtOAc (80 mL x 3). The combined organic layers were dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-20%, 80 mL / min) to give (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (4.20 g, 10.9 mmol, 58.4%) was obtained as a white solid. 1 H NMR(400MHz;DMSO-d6):7.16-7.38(m,10H),3.56(s,4H),3.12-3.23(m,2H),2.28-2.43(m,2H),2.02- 2.13(m,1H),1.90(d,J=11.8Hz,2H),1.80(d,J=11.5Hz,2H),1.29-1.45(m,2H),0.77-0.91(m,2H).MS E.S. + :377.4. Step 2: (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 A solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (4.10 g, 10.9 mmol) in EtOH (40 mL) was treated with Pd(OH)2 (956 mg, 1.36 mmol, 20% purity), degassed, and purged with H2 three times. The mixture was stirred under H2 atmosphere (40 psi) at 25 °C for 12 h and filtered through Celite®. The filtrate was concentrated to give the title compound (2.10 g, 89.1%) as a white solid. 1H NMR(400MHz;DMSO-d6):3.09-3.25(m,2H),2.51(s,1H),2.33(s,1H),2.10(d,J=4.6Hz,1H),1.68-1.84(m,4H),0.89-1.03(m,4H).

[0087] Intermediate 2: (1r,4r)-N 1 -(2,2-difluoroethyl)cyclohexane-1,4-diamine [ka] (1r,4r)-N 1 ,N 1 Prepared as described in Intermediate 1 using -dibenzylcyclohexane-1,4-diamine hydrochloride (prepared as described in US Patent Application Publication No. 2011 / 0034470, 7.00 g, 20.9 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (5.36 g, 25.1 mmol) to give the title compound (1.30 g, 35%) as a white solid.

[0088] Intermediate 3: (1r,4r)-N 1 -Methyl-N 1 -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine [ka] Step 1: (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4A solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (500 mg, 1.33 mmol) in THF (10 mL) was treated with NaH (159 mg, 3.98 mmol, 60% dispersion in oil) followed by dropwise addition of CHI (226 mg, 1.59 mmol). The mixture was stirred at 25° C. for 12 h and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (20 mL), dried (NaSO), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-50%, 35 mL / min) to give (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 -Methyl-N 4 -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (250 mg, 48%) was obtained as an off-white solid. Step 2: (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 -Methyl-N 4 A solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (250 mg, 0.640 mmol) in MeOH (10 mL) was treated with 10% palladium on carbon (wet with ca. 55% H2O) (100 mg), degassed, and purged with H2 three times. The mixture was stirred at 50° C. under an atmosphere of H2 (40 psi) for 12 h and filtered through Celite®. The filtrate was concentrated to give the title compound (70 mg, 52%) as an off-white solid, which was used in the next step without further purification.

[0089] Intermediate 4: 4-(Dibenzylamino)cyclohexanone [ka] Prepared as described in WO2018 / 114700 using 1,4-dioxaspiro[4.5]decan-8-one (5.00 g, 32.0 mmol) and dibenzylamine (6.32 g, 32.0 mmol) to give the title compound (2.75 g, 21%) as a yellow oil. MS ES + :294.1.

[0090] Intermediate 5: 4-Cyclopropyl-6-(1H-imidazol-1-yl)picolinic acid [ka] Step 1: A solution of imidazole (1.24 g, 18.3 mmol) in THF (50 mL) was treated with NaH (876 mg, 21.91 mmol, 60% dispersion in oil) at 0° C., stirred for 0.5 h, treated with 2,6-dichloro-4-iodopyridine (5.00 g, 18.3 mmol), stirred at 60° C. for 12 h, and cooled to room temperature. The mixture was quenched with saturated NH4Cl (aq, 50 mL) at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-50%, 100 mL / min) to give 2-chloro-6-(1H-imidazol-1-yl)-4-iodopyridine (1.45 g, 26%) as a yellow solid. 1 H NMR(400MHz;DMSO-d6):8.53(s,1H),8.33(d,J=0.8Hz,1H),7.96(d,J=0.8Hz,1H),7.95(t,J=1.4Hz,1H),7.13(s,1H).MS ES + :305.9. Step 2: A mixture of 2-chloro-6-(1H-imidazol-1-yl)-4-iodopyridine (1.15 g, 3.76 mmol), cyclopropylboronic acid (647 mg, 7.53 mmol), KPO (4.79 g, 22.59 mmol), and PCy·BF (277 mg, 0.753 mmol) in HO (5 mL) and toluene (20 mL) was treated with Pd(OAc) (169.02 mg, 0.753 mmol), degassed, purged with N three times, stirred at 110 °C for 6 h under N atmosphere, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-35%, 80 mL / min) to give 2-chloro-4-cyclopropyl-6-(1H-imidazol-1-yl)pyridine (750 mg, 3.41 mmol, 90.7%) as a yellow solid. MS ES + :220.0. Step 3: A mixture of 2-chloro-4-cyclopropyl-6-(1H-imidazol-1-yl)pyridine (750 mg, 3.41 mmol) and NEt3 (1.04 g, 10.2 mmol) in MeOH (10 mL) was treated with Pd(dppf)Cl2 (250 mg, 0.341 mmol), degassed, purged with carbon monoxide three times, stirred under carbon monoxide atmosphere (50 psi) at 80 °C for 16 h, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-60%, 80 mL / min) to give methyl 4-cyclopropyl-6-(1H-imidazol-1-yl)picolinate (650 mg, 2.67 mmol, 78.3%) as a brown solid. 1H NMR(400MHz,CDCl3):8.50(s,1H),7.72(s,1H),7.66(d,J=1.2Hz,1H),7.29(d,J=1.2Hz,1 H),7.23(s,1H),4.00(s,3H),2.09-2.01(m,1H),1.28-1.22(m,2H),1.00-0.94(m,2H).MS E.S. + :244.2. Step 4: A solution of methyl 4-cyclopropyl-6-(1H-imidazol-1-yl)picolinate (650 mg, 2.67 mmol) and LiOH·HO (336 mg, 8.02 mmol) in THF (12 mL) and HO (4 mL) was stirred at 25 °C for 1 h, acidified to pH = 3-4 with 1 M aqueous HCl, and concentrated under reduced pressure to give the title compound (1.00 g, crude) as a grey solid, which was used in the next step without further purification. MS ES + :230.2.

[0091] Intermediate 6: (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexane-1-amine and Intermediate 7: (1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexane-1-amine [ka] Step 1: A solution of 4-(dibenzylamino)cyclohexanone (Intermediate 4) (0.50 g, 1.70 mmol), 3,3-difluoropyrrolidine hydrochloride (269 mg, 1.87 mmol) and acetic acid (102 mg, 1.70 mmol) in CHCl (25 mL) was stirred at 25 °C for 1 h, treated with NaBHCN (214 mg, 3.41 mmol) at 0 °C, warmed to 25 °C and stirred for 3 h. The mixture was treated with 1 M NaOH (aq, 75 mL) and extracted with CHCl (75 mL x 3). The combined organic layers were washed with brine (75 mL), dried (Na2SO4), filtered, concentrated and purified by preparative HPLC (Column: Xtimate C18 150x40mm 10μm, Mobile phase A: H2O (0.05% NH3·H2O + 10mM NH4HCO3), Mobile phase B: CH3CN, 55-95%, Flow rate: 60mL / min). The product was partitioned between CH3CN (20mL) and H2O (100mL). The aqueous solution was lyophilized to dryness to give (1r,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexan-1-amine (480 mg, 36%) and (1s,4s)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexan-1-amine (322 mg, 0.752 mmol, 22.1%), both as white solids. (1r,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexan-1-amine: 1 H NMR(400MHz;DMSO-d6):7.42-7.14(m,10H),3.56(s,4H),2.88(t,J=13.6Hz,2H),2.69(t,J=6.6Hz,2H),2.37(t,J=10.9Hz,1H),2 .23-2.10(m,2H),2.10-2.02(m,1H),1.90(d,J=11.5Hz,2H),1.82(d,J=11.5Hz,2H),1.38(q,J=11.5Hz,2H),1.04-0.89(m,2H).MS E.S. + :385.1. (1s,4s)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexan-1-amine: 1H NMR(400MHz;DMSO-d6):7.53-7.10(m,10H),3.57(s,4H),2.85(t,J=13.8Hz,2H),2.65(t,J=6.8Hz,2H),2.46-2.40(m,1H) ),2.31-2.19(m,2H),2.16(s,1H),1.82(d,J=13.3Hz,2H),1.75-1.60(m,2H),1.52(d,J=10.1Hz,2H),1.26-1.14(m,2H). Step 2a: A solution of (1r,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexane-1-amine (300 g, 0.780 mmol) in MeOH (10 mL) was treated with Pd(OH)2 (300 mg, 0.427 mmol, 20% purity), degassed, and purged with H2 three times. The mixture was stirred at 50° C. under 40 psi H2 atmosphere for 12 h, filtered through Celite®, and concentrated under reduced pressure to give (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexane-1-amine (Intermediate 6) (158 mg, 0.619 mmol, 99.1% yield, 80% purity) as a yellow solid, which was used in the next step without further purification. 1 H NMR(400MHz;DMSO-d6):2.93-2.83(m,2H),2.69(t,J=7.0Hz,2H),2.48-2.40(m,1H),2.25 -2.11(m,2H),2.04-1.94(m,1H),1.86-1.68(m,3H),1.66-1.26(m,1H),1.26-0.80(m,4H). Step 2b: A solution of (1s,4s)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexane-1-amine (320 g, 0.832 mmol) in MeOH (10 mL) was treated with Pd(OH)2 (200 mg, 0.285 mmol, 20% purity), degassed, and purged with H2 three times. The mixture was stirred at 50° C. under 40 psi H2 atmosphere for 12 h, filtered through Celite®, and concentrated under reduced pressure to give (1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexane-1-amine (Intermediate 7) (168 mg, 0.822 mmol, 98.8%) as a white gum. 1 H NMR(400MHz;DMSO-d6):3.16(s,1H),2.96-2.81(m,2H),2.73-2.62(m,3H), 2.29-2.15(m,2H),2.14-2.06(m,1H),1.73-1.56(m,2H),1.50-1.32(m,5H).

[0092] Intermediate 8:(1r,4r)-N 1 -Ethylcyclohexane-1,4-diamine [ka] Step 1: To a solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (20 g, 93.3 mmol) in N,N-dimethylformamide (250 mL) was added K2CO3 (19.6 g, 140 mmol) and bromomethylbenzene (35.1 g, 205 mmol). At the same time, the internal temperature was maintained in the range of 25-30 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was slowly poured into water (600 mL), while maintaining the temperature in the range of 25-35 °C. A white precipitate was formed and filtered. The filter cake was suspended in water (400 mL), stirred for 20 min, the suspension was filtered, and this procedure was repeated three times. Then, the suspension was filtered and the filter cake was washed with water (150 mL) and n-hexane (150 mL). The filter cake was collected and dried under reduced pressure to give tert-butyl ((1r,4r)-4-(dibenzylamino)cyclohexyl)carbamate (30 g, 74.1 mmol, 79.4% yield, 97.5% chemical purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 7.09-7.41 (m, 10H) 6.58 (br d, J = 8.00 Hz, 1H) 3.56 (s, 4H) 3.16 (br d, J = 8.13 Hz, 1H) 2.23-2.40 (m, 1H) 1.78 (br d, J = 9.76 Hz, 4H) 1.38-1.49 (m, 2H) 1.35 (s, 9H) 0.92-1.06 (m, 2H). Step 2: To a solution of tert-butyl ((1r,4r)-4-(dibenzylamino)cyclohexyl)carbamate (19 g, 48.16 mmol) in dichloromethane (50 mL) was added 4 M hydrochloric acid in dioxane (4 M, 240.78 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product (1r,4r)-N 1 ,N 1 -Dibenzylcyclohexane-1,4-diamine hydrochloride (21 g, 47.6 mmol, 98.8% yield, 75% chemical purity), a white solid, was used in the next step without further purification. MS ES + :295.2. Step 3: (1r,4r)-N 1 ,N 1To a solution of 1r,4r-dibenzylcyclohexane-1,4-diamine hydrochloride (2 g, 6.79 mmol) and triethylamine (2.06 g, 20.4 mmol) in acetonitrile (20 mL) was added ethyl trifluoromethanesulfonate (1.09 g, 6.11 mmol). The mixture was stirred at 75 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and then extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (30 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®; 20 g SepaFlash® Silica Flash Column, eluent ethyl acetate:methanol=10:1, flow rate 45 mL / min) to give (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 -Ethylcyclohexane-1,4-diamine (2.1 g, crude) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)7.2-7.4(m,10H),3.58(d,4H,J=4.9Hz),3.1-3.3(m,1H),3.06(br s,1H),2.93(q,1H,J=7.3Hz),2.3-2.5(m,1H),1.8-2.1(m,4H),1.2-1.6(m,4H),1.1-1.2(m,3H). Step 4: (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 To a solution of -ethylcyclohexane-1,4-diamine (2.1 g, 6.51 mmol) in MeOH (23 mL) was added Pd(OH)2 (571.58 mg, 0.814 mmol, 20% purity). The reaction mixture was degassed and purged with H2 (13.15 mg, 6.51 mmol) three times. The mixture was stirred under H2 atmosphere (50 psi) at 50 °C for 12 h. The reaction mixture was filtered through Celite and the filtrate was concentrated to give the title compound (1.2 g, crude) as a white solid, which was used in the next step without further purification. 1H NMR(400MHz,DMSO-d6)4.91(br s,2H),2.8-2.9(m,1H),2.66(q,1H,J=7.1Hz),2.45(q,2H,J=7.2Hz),1.7-1.9(m,4H),1.1-1.3(m,4H),0.93(t,3H,J=7.1Hz).

[0093] Intermediate 9:N 1 -(1,1,1-trifluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride [ka] 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), titanium(IV) propane-2-oleate (1.33 g, 4.69 mmol) was added and stirred for 1 h, followed by sodium cyanotrihydroborate (442 mg, 7.03 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (30 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 with 0-100% ethyl acetate / petroleum ether gradient, flow rate 50 mL / min) to give tert-butyl (4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate (168 mg, 0.518 mmol, 22.1% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)4.35(br d,J=7.0Hz,1H),3.43-3.26(m,1H),2.77-2.60(m,1H),2.00-1.92(m,2H),1.86(br d,J=12.2Hz,2H),1.69-1.58(m,4H),1.52(s,1H),1.44(s,15H). Step 2: To a solution of tert-butyl (4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate (160 mg, 0.493 mmol) in dichloromethane (2 mL) was added 4M HCl in dioxane (4 M, 1.97 mL). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (120 mg, 0.460 mmol, 93.3% yield) as a white solid which was used without further purification. 1 H NMR(400MHz,DMSO-d6)2.52(br s,1H),2.13(br d,J=12.2Hz,2H),2.02(br d,J=12.4Hz,2H),1.94-1.85(m,2H),1.81-1.71(m,3H),1.62(br s,6H),1.42(br s,1H).

[0094] Intermediate 10:(1r,4S)-N 1 -((S)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine [ka] Step 1: To a solution of (S)-1,1,1-trifluoropropan-2-amine·hydrochloride (500 mg, 3.34 mmol) in dichloromethane (10 mL), triethylamine (846 mg, 8.36 mmol) was added and the reaction mixture was stirred for 0.5 h, after which 4-(dibenzylamino)cyclohexan-1-one (818 mg, 2.79 mmol) and titanium(IV) propane-2-oleate (1.58 g, 5.57 mmol) were added. The reaction was stirred for 1 h, after which sodium cyanotrihydroborate (525 mg, 8.36 mmol) was added. The mixture was stirred at 25 °C for 13.5 h. The mixture was quenched with EtOH (30 mL) and then concentrated to give the crude product. The crude product was purified by FCC (ISCO®; 4 g SepaFlash® Silica Flash Column, elution with a gradient of 0–16% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain (1S,4r)-N 1 ,N 1 -Dibenzyl-N4 -((S)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine (300 mg, 0.768 mmol, 27.6% yield) was obtained as a white solid. 1 H NMR(400MHz;DMSO-d6):7.37-7.25(m,8H),7.22-7.15(m,2H),3.55(s,4H),3.31-3.19(m,1H),2.45-2.31(m,2H),1.93(br d,J=12.4Hz,1H),1.87-1.73(m,3H),1.63(br s,1H),1.44-1.29(m,2H),1.10(d,J=6.8Hz,3H),0.92-0.76(m,2H). Step 2: (1S,4r)-N 1 ,N 1 -Dibenzyl-N 4 To a solution of -((S)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine (300 mg, 0.768 mmol) in EtOH (4 mL) under N2 atmosphere was added Pd(OH)2 (107.89 mg, 0.154 mmol, 20% purity). The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 atmosphere (40 psi) at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (115 mg, 0.547 mmol, 71.2% yield) as a white solid, which was used without further purification. 1 H NMR (400MHz; DMSO-d6): 2.40 (br s, 3H), 1.95-1.58 (m, 5H), 1.56-1.26 (m, 1H), 1.17-1.08 (m, 3H), 1.07-0.76 (m, 4H).

[0095] Intermediate 11:(1r,4R)-N 1 -((R)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine [ka] Step 1: To a solution of (R)-1,1,1-trifluoropropan-2-amine·hydrochloride (500 mg, 3.34 mmol) in dichloromethane (10 mL), triethylamine (846 mg, 8.36 mmol) was added and the reaction mixture was stirred for 0.5 h, after which 4-(dibenzylamino)cyclohexan-1-one (818 mg, 2.79 mmol) and titanium(IV) propane-2-oleate (1.58 g, 5.57 mmol) were added. The reaction was stirred for 1 h, after which sodium cyanotrihydroborate (525 mg, 8.36 mmol) was added. The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give (1R,4r)-N 1 ,N 1 -Dibenzyl-N 4 -((R)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine (425 mg, 1.09 mmol, 39.1% yield) was obtained as a colorless oil. 1 H NMR(400MHz,CDCl3)7.27(s,10H),3.62(s,4H),3.21(td,J=7.0,14.0Hz,1H),2.63-2.44(m, 2H),1.98-1.87(m,4H),1.44-1.37(m,2H),1.21(d,J=6.9Hz,3H),1.05-0.93(m,2H),0.79(br s,1H). Step 2: (1R,4r)-N 1 ,N 1 -Dibenzyl-N 4 To a solution of -((R)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine (425.00 mg, 1.09 mmol) in EtOH (10 mL) was added Pd(OH)2 (200 mg, 0.285 mmol, 20% purity). The reaction mixture was degassed and purged with H2 three times. The mixture was stirred under H2 atmosphere (40 psi) at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound (45 mg, 0.214 mmol, 19.7% yield) as a colorless solid, which was used without further purification. 1H NMR(400MHz,DMSO-d6)3.26(br s,1H),2.48-2.35(m,2H),2.14-1.98(m,1H),1.87-1.61(m,6H),1.42(br dd,J=10.4,13.3Hz,1H),1.17-1.10(m,3H).

[0096] Intermediate 12: 2,2,2-trifluoroethyl-1,1-d2-4-methylbenzenesulfonate [ka] To a solution of 2,2,2-trifluoroethane-1,1-d2-1-ol-d (100 mg, 0.970 mmol) in dichloromethane (1 mL) was added triethylamine (353 mg, 3.49 mmol). Then, 4-methylbenzenesulfonyl chloride (231 mg, 1.21 mmol) was added at 0° C. The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=5:1, Rf=0.48) to give the title compound (190 mg, 0.742 mmol, 76.4% yield) as a pale yellow liquid. 1 H NMR (400MHz, CDCl3)7.88-7.78(m,2H),7.44-7.34(m,2H),2.51-2.45(m,3H).

[0097] Synthesis of Examples Example 1: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: A solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (2.00 g, 10.7 mmol), imidazole (875 mg, 12.8 mmol) and DIPEA (4.16 g, 32 mmol) in DMF (20 mL) was stirred at 100 °C for 4 h and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc: 0-60%, 100 mL / min) to give methyl 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (1.35 g, 6.19 mmol, 58%) as a pale yellow solid. MS ES + :219.0. Step 2: A solution of methyl 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (1.35 g, 6.19 mmol) in THF (15 mL) was treated with 2M LiOH (aq, 6.19 mL), stirred at 25 °C for 2 h, and concentrated under reduced pressure. The residue was neutralized to pH = 2-3 with 1M HCl (aq) and concentrated under reduced pressure to give 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (2.75 g, crude, 50% purity) as an off-white solid, which was used in the next step without further purification. MS ES + :205.0. Step 3: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (49.9 mg, 0.122 mmol, 50% purity), (1r,4r)-N 1A solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (intermediate 1) (20 mg, 0.102 mmol) and NEt3 (30.9 mg, 0.306 mmol) in DMF (2 mL) was treated with HATU (46.5 mg, 0.122 mmol), stirred at 25 °C for 1 h, cooled to room temperature, and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (column: Gemini NX C18 10x150 mm 5 μm, mobile phase A: H2O (0.225% HCOOH), mobile phase B: CH3CN, 0-30% B, flow rate: 25 mL / min). The purified product was partitioned between CH3CN (2 mL) and H2O (10 mL) and lyophilized to give the title compound (11.4 mg. 0.029 mmol, 28.8%) as an off-white solid. 1 H NMR(400MHz;DMSO-d6):8.95(d,J=1.3Hz,1H),8.79(d,J=8.6Hz,1H),8.21(s,1H),7.82(s,1H),7.18(s,1H),3.84-3.80(m,1H),3.26(d,J=10. MS E.S. + : 383.0. UPLC purity: 98.6%. SFC chiral purity: 99.2%.

[0098] Example 2: N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (55 mg, 0.135 mmol, 50% purity), (1r,4r)-N 1A solution of -(2,2-difluoroethyl)cyclohexane-1,4-diamine (intermediate 2) (20 mg, 0.112 mmol) and NEt3 (34 mg, 0.337 mmol) in DMF (3 mL) was treated with HATU (51.2 mg, 0.135 mmol), stirred at 25 °C for 1 h and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated and purified by preparative HPLC (column: Gemini NX C18 10x150 mm 5 μm, mobile phase A: H2O (0.225% HCOOH), mobile phase B: CH3CN, 0-30% B, flow rate: 25 mL / min). The product was partitioned between CH3CN (2 mL) and H2O (10 mL) and lyophilized to give the title compound (15.9 mg. 0.044 mmol, 39%) as an off-white solid. 1 H NMR(400MHz;DMSO-d6):8.95(s,1H),8.80(d,J=8.6Hz,1H),8.20(s,1H),7.82(s,1H),7.17(s,1H),6.10-5.82(m,1H),3.87-3.76(m,1H),2.93( dt,J=4.3,15.9Hz,2H),2.63(s,3H),2.49-2.38(m,2H),1.96(d,J=10.9 Hz,2H),1.82(d,J=10.3Hz,2H),1.60-1.48(m,2H),1.18-1.07(m,2H).MS E.S. + : 365.4. UPLC purity: 99.4%. SFC chiral purity: 99.3%.

[0099] Example 3: 6-Cyclopropyl-N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide [ka] Step 1: A solution of methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate (3.60 g, 16.9 mmol) in DMF (20 mL) was treated with DIPEA (6.56 g, 50.8 mmol) and imidazole (3.46 g, 50.79 mmol), stirred at 100° C. for 12 h, cooled to room temperature and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, EtOAc in petroleum ether: 0-100%, 35 mL / min) to give methyl 6-cyclopropyl-2-(1H-imidazol-1-yl)pyrimidine-4-carboxylate (1.60 g, 6.55 mmol, 38%) as an off-white solid. Step 2: A solution of methyl 6-cyclopropyl-2-(1H-imidazol-1-yl)-methylpyrimidine-4-carboxylate (1.60 g, 6.55 mmol) in THF (10 mL) was treated with LiOH (157 mg, 6.55 mmol) and HO (118 mg, 6.55 mmol) and stirred at 25° C. for 2 h. The mixture was adjusted to pH<7 with 1 M HCl (aq). The resulting white precipitate was collected by filtration to give 6-cyclopropyl-2-(1H-imidazol-1-yl)-pyrimidine-4-carboxylic acid (1.40 g, 6.08 mmol, 93%) as an off-white solid, which was used in the next step without further purification. MS ES + :230.9. Step 3: 6-Cyclopropyl-2-(1H-imidazol-1-yl)-pyrimidine-4-carboxylic acid (50 mg, 0.217 mmol) and (1r,4r)-N 1 Prepared as described in Example 2 using -(2,2-difluoroethyl)cyclohexane-1,4-diamine (Intermediate 2) (38.7 mg, 0.217 mmol) to afford the title compound (30.5 mg, 0.076 mmol, 35%) as an off-white solid. 1H NMR(400MHz;DMSO-d6):8.90(s,1H),8.76(d,J=8.8Hz,1H),8.16(t,J=1.3Hz,1H),7.86(s,1H), 7.14(s,1H),6.09(t,J=4.3Hz,0.25H),5.95(t,J=4.3Hz,0.5H),5.81(t,J=4.3Hz,0.25H),3.87- 3.76(m,1H),3.34(s,1H),2.92(dt,J=4.3,15.9Hz,2H),2.43-2.34(m,2H),1.95(d,J=11.4Hz,2 H),1.82(d,J=10.5Hz,2H),1.54(d,J=12.5Hz,2H),1.24-1.18(m,4H),1.12(d,J=13.4Hz,2H).MS E.S. + : 391.2. UPLC purity: 98.0%. SFC chiral purity: 100%.

[0100] Example 4: 6-Methyl-2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (200 mg, 0.961 mmol), methyl 2-chloro-6-methylpyrimidine-4-carboxylate (149 mg, 0.801 mmol) and Cs2CO3 (522 mg, 1.60 mmol) in dioxane (8 mL) and HO (2 mL) was treated with Pd(dppf)Cl2·CHCl2 (65.4 mg, 0.080 mmol) and stirred at 90 °C under N2 for 2 h, cooled to room temperature and filtered. The filtrate was concentrated to dryness to give 6-methyl-2-(1-methyl-1H-imidazol-5-yl)-pyrimidine-4-carboxylic acid (175 mg, crude) as a black solid, which was used in the next step without further purification. Step 2: 6-Methyl-2-(1-methyl-1H-imidazol-5-yl)-pyrimidine-4-carboxylic acid (158 mg, 0.724 mmol) and (1r,4r)-N 1 A mixture of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (Intermediate 1) (170.49 mg, 0.869 mmol) in CHCl (6 mL) was treated with DIPEA (281 mg, 2.17 mmol) and T3P (921 mg, 1.45 mmol, 50% purity in EtOAc), stirred at 25 °C for 0.5 h, and extracted with CHCl (3x30 mL). The organic layers were combined, dried (NaSO) and filtered. The filtrate was evaporated and the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc: 0-100%, 45 mL / min) to give the title compound (59.7 mg, 0.150 mmol, 21%) as a white solid. 1 H NMR(400MHz;DMSO-d6):8.44(d,J=8.6Hz,1H),8.00(s,1H),7.85(s,1H),7.66(s,1H),4.05(s,3H),3.88-3.71(m,1H),3.29-3.21(m,2) MS E.S. + : 397.0. UPLC purity: 99.3%. SFC chiral purity: 100%.

[0101] Example 5: 6-Methyl-2-(thiazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: A mixture of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (300 mg, 1.61 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (408 mg, 1.93 mmol) and Cs2CO3 (1.05 g, 3.22 mmol) in dioxane (12 mL) and HO (3 mL) was treated with Pd(dppf)Cl2·CHCl2 (131 mg, 0.161 mmol), stirred at 90 °C under N2 for 1 h, cooled to room temperature and filtered. The filtrate was concentrated to dryness to give 6-methyl-2-(thiazol-5-yl)-pyrimidine-4-carboxylic acid (360 mg, crude) as a black solid, which was used in the next step without further purification. Step 2: 6-Methyl-2-(thiazol-5-yl)-pyrimidine-4-carboxylic acid (140 mg, 0.633 mmol) and (1r,4r)-N 1 A mixture of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (Intermediate 1) (149 mg, 0.759 mmol) in CHCl (2 mL) was treated with DIPEA (245 mg, 1.90 mmol) and T3P (805 mg, 1.27 mmol, 50% purity in EtOAc), stirred at 25° C. for 0.5 h, and extracted with CHCl (30 mL×3). The organic layers were combined, dried (NaSO), and filtered. The filtrate was evaporated and the residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-100%, 45 mL / min) to give the title compound (39.5 mg, 14.9%) as a white solid. 1 H NMR(400MHz;DMSO-d6):9.28(s,1H),9.06(s,1H),8.68(d,J=8.6Hz,1H),7.78(s,1H),3.86-3.76(m,1H),3.30-3.21( m,2H),2.60(s,3H),2.46-2.40(m,1H),2.30-2.19(m,1H),1.97-1.81(m,4H),1.61-1.48(m,2H),1.18-1.08(m,2H).MS E.S. +: 400.1. UPLC purity: 95.7%. SFC chiral purity: 100%.

[0102] Example 6: 6-Ethyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: A mixture of methyl 2-chloro-6-vinylpyrimidine-4-carboxylate (1.02 g, 5.14 mmol) and PtO2 (116.62 mg, 0.514 mmol) in EtOAc (20 mL) was degassed, purged with H2 three times, and stirred at 25 °C for 1 h under H2 atmosphere. The mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give methyl 2-chloro-6-ethylpyrimidine-4-carboxylate (780 mg, 3.89 mmol, 76%) as a brown liquid, which was used in the next step without further purification. Step 2: A mixture of methyl 2-chloro-6-ethylpyrimidine-4-carboxylate (780 mg, 3.89 mmol), imidazole (265 mg, 3.89 mmol) and DIPEA (1.51 g, 11.66 mmol) in DMF (10 mL) was stirred at 100 °C for 12 h under N2, cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-100%, 80 mL / min) to give methyl 6-ethyl-2-(1H-imidazol-1-yl)-pyrimidine-4-carboxylate (340 mg, 1.46 mmol, 38%) as a brown solid. 1 H NMR(400MHz;DMSO-d6):8.58(s,1H),7.94(s,1H),7.87(s,1H),7.16(s,1H),3.95(s,3H),2.93(q,J=7.4Hz,2H),1.30(t,J=7.6Hz,3H). Step 3: A solution of methyl 6-ethyl-2-(1H-imidazol-1-yl)-pyrimidine-4-carboxylate (340 mg, 1.46 mmol) in THF (3 mL) was treated with 1 M LiOH (aq, 4.39 mL) and stirred at 25° C. for 1 h. The pH of the mixture was adjusted to pH<7 with 1 M HCl (aq). The mixture was concentrated under reduced pressure to give 6-ethyl-2-(1H-imidazol-1-yl)-pyrimidine-4-carboxylic acid (556 mg, crude) as a yellow solid, which was used in the next step without further purification. Step 4: 6-Ethyl-2-(1H-imidazol-1-yl)-pyrimidine-4-carboxylic acid (100 mg, 0.458 mmol) and (1r,4r)-N 1 A solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (intermediate 1) (89.92 mg, 0.458 mmol) in DMF (1 mL) was treated with DIPEA (177.68 mg, 1.37 mmol) followed by dropwise addition of T3P (437.44 mg, 0.687 mmol, 50% purity in EtOAc). The resulting mixture was stirred at 25 °C for 1 h, diluted with saturated NaHCO3 (aq, 10 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were washed with 4% LiCl aq, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Xtimate C18 100x30 10 μm, mobile phase A: H2O (HCOOH), mobile phase B: CH3CN, 0-30% B, flow rate: 25 mL / min). The product was partitioned between CH3CN (2 mL) and H2O (10 mL) and lyophilized to give the title compound (40 mg. 0.099 mmol, 22%) as a white solid. 1H NMR(400MHz;DMSO-d6):8.95(s,1H),8.79(d,J=8.76Hz,1H),8.21(s,1H),7.81(s,1H) ),7.16(s,1H),3.81(dd,J=7.88,4.13Hz,1H),3.26(dd,J=10.19,4.69Hz,2H),2.91( q,J=7.50Hz,2H),2.41-2.45(m,1H),2.16-2.29(m,1H),1.95(d,J=12.13Hz,2H),1.8 1(d,J=10.13Hz,2H),1.47-1.61(m,2H),1.29(t,J=7.57Hz,3H),1.07-1.18(m,2H).MS E.S. + : 397.4. UPLC purity: 97.4%. SFC chiral purity: 100%.

[0103] Example 7: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (81.6 mg, 0.400 mmol), (1r,4r)-N 1 -Methyl-N 1 A solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (intermediate 3) (70 mg, 0.333 mmol) and NEt3 (101 g, 0.999 mmol) in DMF (1 mL) was treated with HATU (189 mg, 0.499 mmol) and stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC (column: Phenomenex C18 75x30 mm 3 μm, mobile phase A: H2O (NH3·H2O+NH4HCO3), mobile phase B: CH3CN, 7-37% B, flow rate: 25 mL / min). The product was partitioned between CH3CN (2 mL) and H2O (10 mL). The aqueous solution was lyophilized to dryness to give the title compound (10.09 mg, 0.025 mmol, 7.4%) as a white solid. 1H NMR(400MHz;CD3OD):8.92(s,1H),8.19(s,1H),7.86(s,1H),7.15(s,1H),3.82-3.96(m,1H),3.06-3.16(m,2H),2.68(s,3H),2. 52-2.61(m,1H),2.47(s,3H),2.04(br.d,J=11.26Hz,2H),1.93(br.d,J=11.76Hz,2H),1.52-1.65(m,2H),1.39-1.51(m,2H).MS E.S. + : 397.2. UPLC purity: 96.5%. SFC chiral purity: 100%.

[0104] Example 8: N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(thiazol-5-yl)pyrimidine-4-carboxamide [ka] 6-Methyl-2-(thiazol-5-yl)-pyrimidine-4-carboxylic acid (140 mg, 0.633 mmol) and (1r,4r)-N 1 Prepared as described in Example 5 using -(2,2-difluoroethyl)cyclohexane-1,4-diamine (Intermediate 2) (135 mg, 0.759 mmol) to afford the title compound (13.0 mg, 0.033 mmol, 5.2%) as a white solid. 1 H NMR(400MHz;DMSO-d6):9.27(s,1H),9.05(s,1H),8.71-8.62(m,1H),7.78(s,1H),6.12-5.79(m,1H),3.87-3.74(m, MS E.S. + : 382.1. UPLC purity: 96.7%. SFC chiral purity: 100%.

[0105] Example 9: N-((1r,4r)-4-((2-fluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide formate [ka] Step 1: A solution of tert-butyl ((1r,4r)-4-(dibenzylamino)cyclohexyl)carbamate (19 g, 48.2 mmol) in CHCl (50 mL) was treated with 4 M HCl (241 mL), stirred at 25 °C for 0.5 h, and concentrated under reduced pressure to give (1r,4r)-N 1 ,N 1 -Dibenzylcyclohexane-1,4-diamine hydrochloride (21 g, 98.8% yield, 75% purity) was obtained as a white solid. MS ES + :295.2. Step 2: (1r,4r)-N 1 ,N 1 A mixture of 1r,4r-dibenzylcyclohexane-1,4-diamine hydrochloride (1.50 g, 4.53 mmol) in CH3CN (15 mL) was treated with K2CO3 (1.25 g, 9.07 mmol) and 1-fluoro-2-iodoethane (789 mg, 4.53 mmol), stirred at 45 °C for 16 h, and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, dichloromethane / MeOH: 1 / 0 to 10 / 1) to give (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 -(2-Fluoroethyl)cyclohexane-1,4-diamine (1.3 g, 72.4% yield, 86% purity) was obtained as a yellow oil. 1H NMR(400MHz;DMSO-d6):7.38-7.25(m,8H),7.22-7.16(m,2H),4.45(t,J=5.2Hz,1H),4.33(t,J=5.2Hz,1H),3.56(s,4H),2 .79(t,J=5.2Hz,1H),2.72(t,J=5.2Hz,1H),2.43-2.24(m,2H),1.94-1.75(m,4H),1.47-1.31(m,2H),0.90-0.76(m,2H).MS E.S. + :341.4. Step 3: (1r,4r)-N 1 ,N 1 -Dibenzyl-N 4 A mixture of 1r,4r-(2-fluoroethyl)cyclohexane-1,4-diamine (1.30 g, 3.82 mmol) in MeOH (15 mL) was treated with Pd(OH)2 (600 mg, 0.854 mmol, 20% purity), degassed, purged with H2 three times, stirred under H2 atmosphere (40 psi) at 50 °C for 12 h, and filtered. The filtrate was concentrated under reduced pressure to afford (1r,4r)-N 1 -(2-fluoroethyl)cyclohexane-1,4-diamine (550 mg, 90%) was obtained as a yellow oil. 1 H NMR(400MHz;DMSO-d6):4.47(t,J=5.2Hz,1H),4.35(t,J=5.2Hz,1H),3.42-3.33(m,1H),2.81(t,J=5.3Hz,1H),2.74(t, J=5.3Hz,1H),2.54-2.51(m,1H),2.34-2.25(m,1H),1.81(d,J=10.3Hz,2H),1.72(d,J=10.4Hz,2H),1.08-0.92(m,4H). Step 4: 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (212 mg, 0.624 mmol, 60% purity) and (1r,4r)-N 1A mixture of -(2-fluoroethyl)cyclohexane-1,4-diamine (100 mg, 0.624 mmol) in CHCl (2.5 mL) was treated with NEt (189 mg, 1.87 mmol) followed by dropwise addition of TP (476 mg, 0.749 mmol, 50% purity in EtOAc), stirred at 25° C. for 2 h, and extracted with CHCl (3 mL). The organic layers were combined, dried (NaSO), filtered, concentrated, and purified by preparative HPLC (column: Xtimate C18 100x30 mm 10 μm, mobile phase A: HCOOH (0.225% HCOOH), mobile phase B: CHCN, 0-20% B, flow rate 25 mL / min). The product was partitioned between CH3CN (2 mL) and H2O (10 mL) and lyophilized to dryness to give the title compound (26.3 mg, 10.7%) as a white solid. 1 H NMR(400MHz;DMSO-d6):8.93(s,1H),8.80(d,J=8.6Hz,1H),8.24-8.17(m, 2H),7.82(s,1H),7.16(s,1H),4.63-4.41(m,2H),3.81(ddd,J=4.1,7.9,11 .7Hz,1H),3.00-2.88(m,2H),2.62(s,3H),2.53-2.52(m,1H),1.99(d,J=11 .6Hz,2H),1.84(d,J=11.1Hz,2H),1.63-1.48(m,2H),1.27-1.12(m,2H).MS E.S. + : 347.4. UPLC purity: 99.4%. SFC chiral purity: 98.9%.

[0106] Example 10: N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] A solution of (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexan-1-amine (Intermediate 6) (50.0 mg, 0.196 mmol, 80% purity) and 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (57.1 mg, 0.196 mmol, 70% purity) in CHCl (0.5 mL) was treated with NEt (59.5 mg, 0.588 mmol), followed by dropwise addition of TP (149.5 mg, 50% purity in EtOAc), stirred at 25 °C for 2 h, and extracted with CHCl (30 mL x 3). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure and purified by preparative HPLC (column: Xtimate C18 100x30mm 10μm, mobile phase A: H2O (0.225% HCOOH), mobile phase B: CH3CN, 0-20% B, flow rate: 25mL / min). The product was partitioned between CH3CN (20mL) and H2O (100mL) and lyophilized to dryness to give the title compound (37mg, 21%) as a white solid. 1 H NMR(400MHz;DMSO-d6):8.94(s,1H),8.81(d,J=8.6Hz,1H),8.19(s,1H),7 .82(s,1H),7.16(s,1H),3.87-3.76(m,1H),2.95(t,J=13.7Hz,2H),2.75(t ,J=6.8Hz,2H),2.62(s,3H),2.28-2.15(m,2H),2.11(s,1H),1.97(d,J=12 .3Hz,2H),1.83(d,J=10.8Hz,2H),1.61-1.48(m,2H),1.30-1.18(m,2H).MS E.S. + : 391.0. UPLC purity: 98.4%. SFC chiral purity: 100%.

[0107] Example 11: N-((1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] A mixture of (1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)-cyclohexan-1-amine (Intermediate 7) (120 mg, 0.529 mmol) and 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (180 mg, 0.529 mmol, 60% purity) in CHCl (0.5 mL) was treated with NEt (161 mg, 1.59 mmol) followed by dropwise addition of TP (404 mg, 0.634 mmol, 50% purity in EtOAc), stirred at 25 °C for 2 h and extracted with CHCl (9 mL x 3). The combined organic layers were dried, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by preparative HPLC (column: Xtimate C18 100x30mm 10μm, mobile phase A: HO (0.225% HCOOH), mobile phase B: CH3CN, 0-20% B, flow rate: 25mL / min). The product was partitioned between CH3CN (20mL) and HO (100mL) and lyophilized to dryness to give the title compound (65.0mg, 0.166mmol, 31.5%) as a white powder. 1 H NMR(400MHz;DMSO-d6):8.99-8.86(m,2H),8.23-8.13(m,1H),7.81(s,1H),7.14(s,1H),3.94-3.85(m,1H),2.92( MS E.S. + : 391.4. UPLC purity: 100%. SFC chiral purity: 100%.

[0108] Example 12: N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] Step 1: A solution of 4-(dibenzylamino)cyclohexanone (Intermediate 4) (500 mg, 1.70 mmol), (3S)-3-fluoropyrrolidine hydrochloride (214 mg, 1.70 mmol) and acetic acid (471 mg, 1.70 mmol) in CHCl (5 mL) was stirred at 25° C. for 1 h, treated with NaBH(OAc) (1.08 g, 5.11 mmol) and stirred at 25° C. for 4 h. The pH was adjusted to about 8 by addition of saturated NaHCO (aq) and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether: 0-40%, 40 mL / min) to give (1s,4r)-N,N-dibenzyl-4-((S)-3-fluoropyrrolidin-1-yl)-(cyclohexan-1-amine) (190 mg, 30%) as a white solid. 1 H NMR(400MHz;DMSO-d6):7.15-7.38(m,10H),5.01-5.23(m,1H),3.57(s,4H),2.69-2.85(m,2H),2.53-2.69(m,1H), 2.26-2.44(m,2H),1.99-2.12(m,2H),1.88-1.95(m,2H),1.70-1.87(m,3H),1.31-1.47(m,2H),0.91-1.05(m,2H). Step 2: A mixture of (1s,4r)-N,N-dibenzyl-4-((S)-3-fluoropyrrolidin-1-yl)-cyclohexan-1-amine (190 mg, 0.518 mmol) in EtOH (2 mL) was treated with Pd(OH)2 (190 mg, 0.271 mmol, 20% purity), degassed, purged with H2 three times, and stirred under H2 atmosphere (40 psi) at 50° C. for 12 h. The mixture was filtered under reduced pressure and concentrated under reduced pressure to give (1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)-cyclohexan-1-amine (105 mg, crude) as a white solid, which was used in the next step without purification. Step 3: A solution of (1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)-cyclohexan-1-amine (100 mg, 0.537 mmol) and 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (131 mg, 0.644 mmol) in CHCl (2 mL) was treated with DIPEA (208 mg, 1.61 mmol) followed by dropwise addition of TP (512 mg, 0.805 mmol, 50% purity in EtOAc), stirred at 25 °C for 1 h and extracted with CHCl (5 mL x 3). The combined organic layers were dried, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex C18 75x30mm 3μm, mobile phase A: HO (0.05% NH3·HO+10mM NH4HCO3), mobile phase B: CH3CN, 18-48% B, flow rate: 25mL / min). The product was partitioned between CH3CN (2mL) and HO (10mL) and lyophilized to dryness to give the title compound (28mg, 14%) as a white solid. 1 H NMR(400MHz;DMSO-d6):8.94(s,1H),8.80(d,J=8.6Hz,1H),8.20(s,1H),7.83(s,1H),7.16(s,1H),5.07-5.31(m,1H),3.74-3.90(m,1H),2.78- 2.94(m,2H),2.67-2.74(m,1H),2.62(s,3H),2.35-2.41(m,1H),1.95-2 .15(m,4H),1.79-1.94(m,3H),1.47-1.65(m,2H),1.22-1.32(m,2H).MS E.S. + : 373.1. UPLC purity: 99.6%. SFC chiral purity: 100%.

[0109] Example 13: N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] Prepared as described in Example 12 using 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (100 mg, 0.343 mmol, 70% purity) and (1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)-cyclohexan-1-amine (70.2 mg, 0.377 mmol) to give the title compound (55 mg, 43%) as a white solid. 1 H NMR(400MHz;DMSO-d6):8.94(s,1H),8.80(d,J=8.6Hz,1H),8.19(s,1H),7.82(s,1H),7.16(s,1H),5.34-5.01(m,1H),3.91-3.72(m,1H),2.93- 2.78(m,2H),2.74-2.64(m,1H),2.62(s,3H),2.42-2.34(m,1H),2.15-1 .94(m,4H),1.94-1.76(m,3H),1.62-1.47(m,2H),1.28-1.22(m,2H).MS E.S. + :373.2. UPLC purity: 99.2%. SFC chiral purity: 99.8%.

[0110] Example 14: 6-Methyl-2-(1H-pyrazol-4-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: A mixture of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (500 mg, 2.68 mmol), 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (894 mg, 3.22 mmol) and CsCO (1.75 g, 5.36 mmol) in HO (2 mL) and dioxane (8 mL) was treated with Pd(dppf)Cl·CHCl (219 mg, 0.268 mmol), stirred at 90 °C under N for 2 h, cooled to room temperature and filtered. The filtrate was concentrated to dryness to give 6-methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid (810 mg, crude) as a black solid, which was used in the next step without further purification. Step 2: 6-Methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid (365 mg, 1.27 mmol) and (1r,4r)-N 1 A mixture of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (Intermediate 1) (299 mg, 1.52 mmol) in CHCl (4 mL) was treated with DIPEA (492 mg, 3.81 mmol) followed by dropwise addition of TP (1.62 g, 2.54 mmol, 50% purity in EtOAc), stirred at 25° C. for 0.5 h, and extracted with CHCl (40 mL×3). The combined organic layers were dried (NaSO) and filtered. The filtrate was evaporated to dryness to give 6-methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-N-(trans-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxylic acid (420 mg, crude) as a black oil, which was used in the next step without further purification. Step 3: A mixture of 6-methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-N-(trans-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide (420 mg, 0.90 mmol, crude) in CHCl (5 mL) was treated with 4 M HCl in dioxane (5 mL), stirred at 25 °C for 0.5 h, concentrated and purified by preparative HPLC (column: Xtimate C18 150x30 mm 5 μm, mobile phase A: HO (10 mM NHHCO), mobile phase B: CHCN, 20-55% B, flow rate: 25 mL / min). The product was partitioned between CH3CN (2 mL) and H2O (10 mL) and lyophilized to dryness to give the title compound (111 mg, 32%) as a white solid. 1 H NMR(400MHz;DMSO-d6):13.47-13.17(m,1H),8.69(d,J=8.8Hz,1H),8.63-8. 37(m,2H),7.71-7.64(m,1H),3.91-3.80(m,1H),3.32(dd,J=7.8,10.1Hz,2H ),2.61(s,3H),2.52(dd,J=6.3,10.5Hz,1H),2.36-2.25(m,1H),2.01(d,J=1 1.3Hz,2H),1.89(d,J=10.1Hz,2H),1.65-1.54(m,2H),1.25-1.14(m,2H).MS E.S. + : 383.3. UPLC purity: 99.2%. SFC chiral purity: 100%.

[0111] Example 15: N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(1H-pyrazol-4-yl)pyrimidine-4-carboxamide [ka] 6-Methyl-2-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid (80 mg, 0.277 mmol) and (1r,4r)-N 1Prepared as described in Example 14 using -(2,2-difluoroethyl)cyclohexane-1,4-diamine (Intermediate 2) (59 mg, 0.33 mmol) to give the title compound (25 mg, 24.2%) as a white solid. 1 H NMR(400MHz;DMSO-d6):13.26(s,1H),8.61(d,J=8.4Hz,2H),8.46-8.17(m,1H),7.62(s,1H),6.13-5.79(m,1H),3.86-3. 73(m,1H),2.97-2.86(m,2H),2.55(s,3H),2.46-2.38(m,1H),2.03-1.76(m,5H),1.61-1.47(m,2H),1.20-1.06(m,2H).MS E.S. + : 365.1. UPLC purity: 98.7%. SFC chiral purity: 100%.

[0112] Example 16: 4-Cyclopropyl-N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-(1H-imidazol-1-yl)picolinamide [ka] Step 5: 4-Cyclopropyl-6-(1H-imidazol-1-yl)picolinone (Intermediate 5) (150 mg, 0.654 mmol), (1r,4r)-N 1 A solution of -(2,2-difluoroethyl)cyclohexane-1,4-diamine (Intermediate 2) (117 mg, 0.654 mmol) and NEt3 (199 mg, 1.96 mmol) in CHCl2 (3 mL) was treated with HATU (373 mg, 0.982 mmol), stirred at 25 °C for 2 h, and extracted with CHCl2 (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried (NaSO4), filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, MeOH / CHCl2: 0-3%, 40 mL / min) to give the title compound (60.6 mg, 24%) as a pale yellow solid. 1H NMR(400MHz;DMSO-d6):8.91(s,1H),8.49(d,J=8.6Hz,1H),8.24(s,1H),7.64(d,J =20.0Hz,2H),7.13(s,1H),5.95(tt,J=4.4,56.6Hz,1H),3.87-3.71(m,1H),2.91( dt,J=4.4,15.8Hz,2H),2.40(t,J=10.8Hz,1H),2.18-2.10(m,1H),1.97-1.76(m,5 H),1.59-1.47(m,2H),1.19-1.13(m,2H),1.13-1.05(m,2H),1.02-0.96(m,2H).MS E.S. + : 390.2. UPLC purity: 97.1%. SFC chiral purity: 100%.

[0113] Example 17 (Comparative Example): N-((1r,4r)-4-(difluoromethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] A solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (100 mg, 0.245 mmol, 50% purity), (1r,4r)-4-(difluoromethoxy)cyclohexamine (40.5 mg, 0.245 mmol) and NEt (74.3 mg, 0.735 mmol) in CHCl (2 mL) was treated with TP (234 mg, 0.367 mmol, 50% purity in EtOAc) and stirred at 25 °C for 5 h, extracted with CHCl (20 mL x 3), washed with brine (40 mL), dried (NaSO), filtered, concentrated under reduced pressure and purified by preparative TLC (SiO, CHCl / MeOH = 20:1) to give the title compound (10.7 mg, 11.6%) as a white solid. 1H NMR(400MHz;DMSO-d6):8.93(s,1H),8.80(d,J=8.6Hz,1H),8.19(s,1H),7.83(s,1H),7.17(s,1H),6.95-6.56(m,1H),4.1 1-4.00(m,1H),3.88(dd,J=3.4,7.4Hz,1H),2.63(s,3H),2.04(d,J=11.0Hz,2H),1.92-1.84(m,2H),1.69-1.48(m,4H).MS E.S. + : 352.1. UPLC Purity: 93.3. SFC Chiral Purity: 98.1%.

[0114] Example 18 (Comparative Example): N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide [ka] A mixture of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (530 mg, 2.60 mmol), (1r,4r)-4-amino-1-methylcyclohexanol (402 mg, 3.11 mmol) and DIPEA (1.01 g, 7.79 mmol) in CHCl (5 mL) was treated with HATU (1.48 g, 3.89 mmol), stirred at 25 °C for 12 h, extracted with EtOAc (20 mL x 3), washed with brine, dried (NaSO), filtered, concentrated under reduced pressure and purified by preparative HPLC (column: Xtimate C18 150 x 40 mm 10 μm, mobile phase A: H2O (0.05% NH3·H2O), mobile phase B: CH3CN, 15-45% B, flow rate: 25 mL / min). The product was partitioned between CH3CN (2 mL) and H2O (10 mL) and lyophilized to dryness to give the title compound (6.8 mg, 1%) as a white solid. 1H NMR(400MHz;DMSO-d6):8.92(s,1H),8.73(d,J=8.4Hz,1H),8.18(s,1H),7.82(s,1H),7.16(s,1H),4.39(s,1H),3 .90-3.77(m,1H),2.62(s,3H),1.77-1.70(m,2H),1.65-1.57(m,4H),1.49(dd,J=3.6,13.2Hz,2H),1.20(s,3H).MS E.S. + :316.1. UPLC purity: 95.3%. SFC chiral purity: 100%.

[0115] Example 19: N-((1r,4r)-4-(ethylamino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide formate [ka] 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (239.25 mg, 0.703 mmol) and (1r,4r)-N 1To a solution of -ethylcyclohexane-1,4-diamine (Intermediate 8) (100 mg, 0.703 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine (213.42 mg, 2.11 mmol), followed by T3P (537 mg, 0.844 mmol, 50% purity). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and then extracted with EtOAc (3x10 mL). The combined organic layers were washed with 4% LiCl(aq) (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (column: Xtimate C18 100*30mm*10μm, mobile phase A: water (HCOOH), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition: 0%~30%): Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to obtain the residue. The residue was purified by preparative HPLC (column: Xtimate C18 100*30mm*10μm, mobile phase A: water (HCOOH), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition: 0%~30%): Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The aqueous solution was lyophilized to dryness to give the title compound (3.36 mg, 0.009 mmol, 1.9%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)10.30(s,1H),9.18(d,J=8.4Hz,1H),8.99(s,2H),8.62(s,1H),8.04(s,1H),7.81(s,1H),3.86(dd,J=3.6,7.8Hz,1H),2.98 (d,J=6.8Hz,3H),2.69(s,3H),2.17(d,J=10.6Hz,2H),1.91(d,J=10.6Hz ,2H),1.71-1.61(m,2H),1.53(q,J=11.4Hz,2H),1.24(t,J=7.2Hz,3H).MS E.S. + : 329.4. UPLC purity: 97.4%. SFC chiral purity: 100%.

[0116] Example 20: 4-Cyclopropyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)picolinamide [ka] Step 1: To a solution of imidazole (1.24 g, 18.3 mmol) in THF (50 mL) was added NaH (8763 mg, 21.9 mmol, 60% purity) in small portions. After stirring for 0.5 h, 2,6-dichloro-4-iodopyridine (5 g, 18.3 mmol) was added and the mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched by adding 50 mL of saturated aqueous NH4Cl at 0 °C, then diluted with H2O (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (100 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®; 80 g SepaFlash® Silica Flash Column, elution with a 0-50% ethyl acetate / petroleum ether gradient, flow rate 100 mL / min) to give 2-chloro-6-(1H-imidazol-1-yl)-4-iodopyridine (1.45 g, 4.75 mmol, 26.0% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)8.53(s,1H),8.33(d,J=0.8Hz,1H),7.96(d,J=0.8Hz,1H),7.95(t,J=1.4Hz,1H),7.13(s,1H). Step 2: A mixture of 2-chloro-6-(1H-imidazol-1-yl)-4-iodopyridine (1.15 g, 3.76 mmol), cyclopropylboronic acid (647 mg, 7.53 mmol), K3PO4 (4.79 g, 22.6 mmol), tricyclohexylphosphonium tetrafluoroborate (277 mg, 0.753 mmol) and Pd(OAc)2 (169 mg, 0.753 mmol) in HO (5 mL) and toluene (20 mL) was degassed and purged with N2 three times. The mixture was stirred at 110 °C under N2 atmosphere for 6 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, elution with a gradient of 0-35% ethyl acetate / petroleum ether, flow rate 80 mL / min) to give 2-chloro-4-cyclopropyl-6-(1H-imidazol-1-yl)pyridine (750 mg, 3.41 mmol, 90.7% yield) as a yellow solid. MS ES + :220.0. Step 3: A mixture of 2-chloro-4-cyclopropyl-6-(1H-imidazol-1-yl)pyridine (750 mg, 3.41 mmol), triethylamine (1.04 g, 10.24 mmol) and Pd(dppf)Cl2 (250 mg, 0.341 mmol) in MeOH (10 mL) was degassed and purged with CO three times, after which the mixture was stirred under CO atmosphere (50 psi) at 80 °C for 16 h. The reaction mixture was 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 0-60% ethyl acetate / petroleum ether gradient, flow rate 80 mL / min) to give 4-cyclopropyl-6-imidazol-1-yl-pyridine-2-carboxylate (650 mg, 2.67 mmol, 78.3% yield) as a brown solid. 1H NMR(400MHz,CDCl3)8.50(s,1H),7.72(s,1H),7.66(d,J=1.2Hz,1H),7.29(d,J=1.2Hz, 1H),7.23(s,1H),4.00(s,3H),2.09-2.01(m,1H),1.28-1.22(m,2H),1.00-0.94(m,2H). Step 4: To a solution of methyl 4-cyclopropyl-6-(1H-imidazol-1-yl)picolinate (650 mg, 2.67 mmol) in THF (12 mL) was added a solution of LiOH·HO (336.38 mg, 8.02 mmol) in HO (4 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified with 1N HCl (aq) to pH = 3-4 and then concentrated under reduced pressure to give a residue. The crude 4-cyclopropyl-6-(1H-imidazol-1-yl)picolinate (1 g, crude), a grey solid, was used in the next step without further purification. Step 5: 4-Cyclopropyl-6-(1H-imidazol-1-yl)picolinic acid (150 mg, 0.654 mmol) and (1r,4r)-N 1 To a solution of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (intermediate 1) (128 mg, 0.654 mmol) in dichloromethane (2 mL) was added triethylamine (199 mg, 1.96 mmol), followed by T3P (625 mg, 0.981 mmol, 50% purity). The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The product was then further purified by preparative HPLC (column: C18-6 100*30 mm*5 μm, mobile phase A: water (HCOOH), mobile phase B: acetonitrile, flow rate: 25 mL / min, 5%-35% gradient condition). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the title compound (73.46 mg, 0.180 mmol, 27.5% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)8.91(s,1H),8.50(d,J=8.6Hz,1H),8.24(s,1H),7.6 6(s,1H),7.61(s,1H),7.12(s,1H),3.87-3.70(m,1H),3.25(d,J=10.2Hz,3H ),2.45-2.37(m,1H),2.19-2.08(m,1H),1.99-1.88(m,2H),1.79(d,J=10.6 Hz,2H),1.53(q,J=11.6Hz,2H),1.19-1.08(m,4H),0.99(d,J=2.6Hz,2H).MS E.S. + : 408.4. UPLC purity: 99.8%. SFC chiral purity: 100%.

[0117] Example 21: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (109 mg, 0.535 mmol) and N 1To a solution of -(1,1,1-trifluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine·hydrochloride (Intermediate 9) (120 mg, 0.535 mmol) in N,N-dimethylformamide (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (207 mg, 1.61 mmol) and HATU (305 mg, 0.803 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (50 mL) and extracted with dichloromethane (30 mL). The reaction mixture was washed with NaHCO3 (3x30 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 preparative HPLC (column: Phenomenex C18 75*30mm*3μm, mobile phase A: water (NH3·H2O+NH4HCO3) mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition: 33%-63%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to give the title compound (52.16mg, 0.122mmol, 22.8% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)8.93(t,J=1.0Hz,1H),8.74(d,J=8.8Hz,1H),8.19(t,J=1.4Hz,1H),7.82(s,1H),7.20-7.1 3(m,1H),3.87-3.69(m,1H),2.68-2.64(m,1H),2.63(s,3H),1.87-1.76(m,5H),1.65-1.52(m,2H),1.22(s,8H).MS E.S. + : 411.2. UPLC purity; 95.9%. SFC chiral purity: 100%.

[0118] Example 22: 2-(1H-imidazol-1-yl)-6-methyl-N-((1S,4r)-4-(((S)-1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] (1r,4S)-N 1To a mixture of -((S)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine (intermediate 10) (100 mg, 0.476 mmol) and 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (80.93 mg, 0.396 mmol) in dichloromethane (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (154 mg, 1.19 mmol) followed by T3P (504 mg, 0.793 mmol, 50% purity in EtOAc) at 25° C. The mixture was stirred at 25° C. for 0.5 h. Water (15 mL) was added and the mixture was extracted with DCM (3×15 mL) and the organic phase was concentrated to give the crude product. The product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm, mobile phase A: water (NH3·H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition: 25%-55%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to give the title compound (20.83mg, 0.517mmol, 13.0% yield) as a white solid. 1 H NMR(400MHz,CDCl3):8.72(s,1H),7.96-7.84(m,2H),7.61(br d,J=8.2Hz,1H),7.24-7.16(m,1H),4.02-3.90(m,1H),3.28(spt,J=6.9Hz,1H),2.76-2.65(m,4H),2.18- 2.11(m,2H),2.06-1.97(m,2H),1.89(s,1H),1.48-1.39(m,2H),1.39-1.30(m,2H),1.28-1.26(m,3H).MS E.S. + : 397.4. UPLC purity: 98.3%. SFC chiral purity: 100%.

[0119] Example 23: 2-(1H-imidazol-1-yl)-6-methyl-N-((1R,4r)-4-(((R)-1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (43.7 mg, 0.214 mmol), (1r,4R)-N 1 To a mixture of -((R)-1,1,1-trifluoropropan-2-yl)cyclohexane-1,4-diamine (Intermediate 11) (45 mg, 0.214 mmol), N-ethyl-N-isopropylpropan-2-amine (83.0 mg, 0.642 mmol) in dichloromethane (0.5 mL) was added T3P (272 mg, 0.428 mmol, 50% purity in EtOAc) and the mixture was stirred at 25° C. for 0.5 h. The reaction mixture was diluted with H2O (3 mL) and dichloromethane (3×3 mL). The aqueous phase was filtered to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm, mobile phase A: water (NH3·H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition: 25%B to 55%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to give the title compound (6.59mg, 0.166mmol, 7.7% yield) as an off-white powder. 1 H NMR(400MHz,DMSO-d6)8.93(s,1H),8.78(d,J=8.8Hz,1H),8.19(t,J=1.3Hz,1H),7.82(s,1H),7.15(s,1H),3.86-3.74(m,2H),2.62(s,3H),2.52(br MS ES + : 397.4. UPLC purity: 99.7%. SFC chiral purity: 97.61%.

[0120] Example 24: 6-Methyl-2-(5-methyl-1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1 g, 5.36 mmol) and 5-methyl-1H-imidazole (440.01 mg, 5.36 mmol) in N,N-dimethylformamide (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.08 g, 16.1 mmol) at 25° C. The mixture was stirred at 100° C. for 12 h. The mixture was poured into H2O (10 mL), extracted with EtOAc (3×20 mL), and the combined organic layers were concentrated to give a residue. The residue was purified by flash column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, elution with a 0-50% ethyl acetate / petroleum ether gradient, flow rate 60 mL / min) to give methyl 6-methyl-2-(5-methyl-1H-imidazol-1-yl)pyrimidine-4-carboxylate (0.1 g, 0.415 mmol, 7.7% yield, 96.3% chemical purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)8.43(s,1H),7.84(s,1H),7.67-7.61(m,1H),3.95(s,3H),2.63(s,3H),2.50(br s,3H). Step 2: A solution of methyl 6-methyl-2-(5-methyl-1H-imidazol-1-yl)pyrimidine-4-carboxylate (40 mg, 0.172 mmol) in 1M LIOH(aq) (1M, 0.861 mL) in THF (2 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated to give the crude product. The crude product 6-methyl-2-(5-methyl-1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (36 mg, crude), a yellow solid, was used in the next step without further purification. MS ES + :219.0. Step 3: 6-Methyl-2-(5-methyl-1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (28 mg, 0.128 mmol) and (1r,4r)-N 1To a mixture of -(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (Intermediate 1) (252 mg, 1.28 mmol) in dichloromethane (0.5 mL) was added triethylamine (130 mg, 1.28 mmol) and T3P (306 mg, 0.962 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was poured into H2O (5 mL), extracted with dichloromethane (3x5 mL), and the combined organic layers were concentrated to give the crude product. The residue was purified by preparative TLC (SiO2, PE:EA=0:1, Rf=0.5) to give the crude product. The crude product was purified by preparative HPLC (DAICEL CHIRALCEL OD (250*30mm), 10μm): Mobile phase A: [0.1% NH3·H2O ETOH]; Mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition from 30%B to 30%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to give the title compound (12.8mg, 0.031mmol, 46.8% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)8.86(d,J=1.1Hz,1H),8.63(d,J=8.5Hz,1H),7.82(s,1H),6.85(t,J=1.1Hz,1H),3.89-3.71(m,1H),3.26(br dd,J=7.9,10.3Hz,2H),2.62(s,3H),2.56(d,J=0.9Hz,3H),2.24(br d,J=6.4Hz,1H),1.94(br d,J=11.4Hz,2H),1.82(br d,J=10.4Hz,2H),1.61-1.41(m,2H),1.13(br d,J=13.8Hz,2H).MS ES + : 397.2. UPLC purity: 95.4%. SFC chiral purity: 100%.

[0121] Example 25: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: To a solution of 2-imidazol-1-yl-6-methylpyrimidine-4-carboxylic acid (50 mg, 0.245 mmol), tert-butyl (((1r,4r)-4-aminocyclohexyl)methyl)carbamate (55.91 mg, 0.245 mmol), N-ethyl-N-isopropylpropan-2-amine (94.9 mg, 0.735 mmol) and dichloromethane (1 mL) was added T3P (233.7 mg, 0.367 mmol, 50% purity in EtOAc). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product tert-butyl (((1r,4r)-4-(2-1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamido)cyclohexyl)methyl)carbamate (102 mg, crude), a yellow solid, was used in the next step without further purification. MS ES + :415.2. Step 2: To a solution of tert-butyl (((1r,4r)-4-(2-1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexyl)methyl)carbamate (100 mg, 0.241 mmol) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetic acid (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product N-((1r,4r)-4-(aminomethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide trifluoroacetate (105 mg, crude), a yellow solid, was used in the next step without further purification. MS ES + :315.1. Step 3: To a solution of N-((1r,4r)-4-(aminomethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide trifluoroacetate (105 mg, 0.245 mmol), triethylamine (124 mg, 1.23 mmol) and N,N-dimethylformamide (1 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (56.9 mg, 0.245 mmol) was added. The mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The product was then further purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm, mobile phase A: water (NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient condition from 27% B to 68%). The pure fractions were collected and the volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the title compound (3.77 mg, 0.009 mmol, 3.7% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)8.94(s,1H),8.81(d,J=8.8Hz,1H),8.22-8.18(m,1H),7.82(s,1H),7.15(s,1H),3.86-3.76(m,1H),3.24-3.17(m MS E.S. + :397.2. UPLC purity: 95.3%. SFC chiral purity: 100%.

[0122] Example 26: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: To a solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (2 g, 5.58 mmol) and methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (1.19 g, 6.14 mmol) in dichloromethane (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.16 g, 16.8 mmol) and T3P (5.33 g, 8.37 mmol, 50% purity in EtOAc). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with dichloromethane (3x20 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 (SiO2, petroleum ether:ethyl acetate=1 / 0 to 0 / 1) to give methyl (1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexane-1-carboxylate (400 mg, 1.16 mmol, 20.9% yield) as a yellow solid. MS ES + :343.9. Step 2: To a solution of methyl (1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexane-1-carboxylate (200 mg, 0.582 mmol) in THF (2 mL) was added 1M LiOH(aq) (1M, 1.75 mL). The mixture was stirred at 25 °C for 1 h. The pH of the mixture was adjusted to 5-6 by addition of 1M HCl(aq). The mixture was concentrated under reduced pressure to give the crude product. The crude product (1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexane-1-carboxylic acid (236 mg, 0.573 mmol, 98.4% yield), an off-white solid, was used in the next step without further purification. MS ES + :330.0. Step 3: To a solution of (1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexane-1-carboxylic acid (50 mg, 0.121 mmol), 2,2,2-trifluoroethan-1-amine (13.2 mg, 0.134 mmol) in dichloromethane (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (47.1 mg, 0.364 mmol) and T3P (116 mg, 0.182 mmol, 50% purity in EtOAc). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100*30mm*10μm, mobile phase A: water (HCOOH), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition: 5%-35%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to give the title compound (7.21mg, 0.017mmol, 14.3% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)9.05(s,1H),8.84(d,J=8.6Hz,1H),8.49(t,J=6.3Hz,1H),8.24(s,1H),7.85(s,1H),7.22(s,1H),3.95 -3.86(m,2H),3.85-3.80(m,1H),2.63(s,3H),2.27-2.18(m,1H),1.88-1.80(m,3H),1.57-1.46(m,4H),0.98-0.91(m,1H).MS E.S. + : 411.1. UPLC purity: 98.8%. SFC chiral purity: 98.34%.

[0123] Example 27: N-((1r,4r)-4-aminocyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide formate [ka] Step 1: To a solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (500 mg, 2.33 mmol), 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (476 mg, 2.33 mmol) and triethylamine (708 mg, 7.00 mmol) in dichloromethane (10 mL) was added T3P (2.23 g, 3.50 mmol, 50% purity in EtOAc). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and then extracted with EtOAc (3x20 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®; 20 g SepaFlash® Silica Flash Column, eluent of petroleum ether:ethyl acetate=0:1, flow rate 35 mL / min) to give tert-butyl ((1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexyl)carbamate (570 mg, 1.19 mmol, 51.1% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)8.94(s,1H),8.81(d,1H,J=8.6Hz),8.20(t,1H,J=1.2Hz),7.82(s,1H),7.1-7.2(m,1H),6.77(d,1H,J=7.8Hz) ),3.79(dd,1H,J=3.8,7.8Hz),3.2-3.3(m,1H),2.62(s,3H),1.83(t,4H,J=12.2Hz),1.5-1.6(m,2H),1.38(s,9H),1.2-1.3(m,2H). Step 2: tert-Butyl ((1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexyl)carbamate (50 mg, 0.125 mmol) was added to a solution of 4M HCl in dioxane (1 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 100*30 mm*10 μm, mobile phase A: water (HCOOH), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient condition 0% to 20%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the title compound (18.09 mg, 0.520 mmol, 41.6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)8.92(s,1H),8.82(d,J=8.6Hz,1H),8.42(s,1H),8.18(s,1H),7.82(s,1H),7.16(s,1H),3.89-3.75(m,1H), 3.30-3.22(m,2H),2.97-2.81(m,1H),2.62(s,3H),2.02-1.94(m,2H),1.90-1.82(m,2H),1.64-1.50(m,2H),1.45-1.33(m,2H).MS E.S. + :301.4. UPLC purity: 99.5%. SFC chiral purity: 96.89%.

[0124] Example 28: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl-1,1-d2)amino)cyclohexyl)pyrimidine-4-carboxamide [ka] Step 1: To a solution of 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylic acid (4.84 g, 23.7 mmol), tert-butyl ((trans)-4-aminocyclohexyl)carbamate (6.10 g, 28.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (9.19 g, 71.11 mmol) in dichloromethane (50 mL), T3P (22.63 g, 35.56 mmol, 50% purity in EtOAc) was added. The mixture was then stirred at 25° C. for 1 h. The reaction mixture was diluted with 50 mL of saturated NaHCO3 and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent: dichloromethane / methanol=20 / 1, flow rate 80 mL / min) afforded tert-butyl ((1r,4r)-4-(2-(1H-imidazol-1-yl)methylpyrimidine-4-carboxamide)cyclohexyl)carbamate (5.89 g, 13.02 mmol, 54.9% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)8.94(s,1H),8.82(d,J=8.8Hz,1H),8.20(s,1H),7.82(s,1H),7.16(s,1H),6.78(d,J=8.0Hz,1H),3. 88-3.68(m,1H),3.26-3.20(m,1H),2.62(s,3H),1.83(t,J=11.9Hz,4H),1.62-1.51(m,2H),1.38(s,9H),1.32-1.22(m,2H). Step 2: To a solution of tert-butyl ((1r,4r)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide)cyclohexyl)carbamate (2 g, 4.99 mmol) in dichloromethane (10 mL) was added 4 M HCl in dioxane (4 M, 20 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give ((1r,4r)-4-aminocyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide hydrochloride (0.89 g, 1.97 mmol, 39.4% yield) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)10.23(s,1H),9.13(d,J=8.5Hz,1H),8.60(s,1H),8.10(d,J=4.1Hz,3H),8.03(s,1H),7.79(s,1H),3.88-3.8 3(m,1H),2.99(d,J=5.1Hz,1H),2.69(s,3H),2.05(d,J=11.4Hz,2H),1.89(d,J=10.5Hz,2H),1.72-1.59(m,2H),1.56-1.42(m,2H). Step 3: To a solution of N-((1r,4r)-4-aminocyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide hydrochloride (20 mg, 0.594 mmol) and 2,2,2-trifluoroethyl-1,1-d2-4-methylbenzenesulfonate (Intermediate 12) (22.8 mg, 0.891 mmol) in DMF (0.2 mL) was added KI (9.86 mg, 0.594 mmol), K2CO3 (24.6 mg, 0.178 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (3.14 mg, 0.119 mmol). The mixture was stirred at 90 °C for 1 h. The combined reaction mixture was poured into saturated KHCO3(aq) (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness. The product was purified by preparative HPLC (column: Xtimate C18 150*40mm*10μm, mobile phase A: water (NH3·H2O+NH4HCO3), mobile phase B: acetonitrile, flow rate: 25mL / min, gradient condition 14%-54%). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was partitioned between acetonitrile (2mL) and water (10mL). The solution was lyophilized to dryness to give the title compound (5mg, 3.5% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)8.96-8.91(m,1H),8.82-8.76(m,1H),8.21-8.17(m,1H),7.84-7.80(m,1H),7.17-7.14(m,1H),3.88-3.76(m,1H) MS E.S. + : 385.1. UPLC purity: 97.5%. SFC chiral purity: 100%.

[0125] Example 29 (Comparative Example): 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide [ka] The compound of Example 29 was prepared as described in Example 101 of International Publication No. WO2021 / 021986A1.

[0126] biological activity Human CD38 hydrolase assay non-physiological NAD + Substrate analog 1,N 6 -Etheno NAD + The ability of test compounds to inhibit human CD38 hydrolase activity was measured in a fluorescence-based assay using ε-NAD. 2+ / Mg 2+ Recombinant human CD38 (0.8 nM) in a 384-well black microplate was preincubated in 100 mM NaCl (pH 7.4) for 30 min at 25 °C. CD38 hydrolase activity was determined by the addition of 4 μM ε-NAD (which produces a fluorescent product, 1,N 6 -etheno-ADP-ribose was generated. Fluorescent product formation was followed by fluorescence readings (excitation λ=300 nm; emission λ=410 nm) at two time points, one after substrate addition (t=0) and one 10 min later (t=10) using a ClarioStar Plus (BMG) microplate reader. To correct for baseline fluorescence variations, data were analyzed by subtracting values ​​detected at t = 0 from values ​​detected at t = 10. Fluorescence values ​​were converted to percent inhibition using the average of high signal (CD38 and ε-NAD) and low signal (CD38 and ε-NAD in the presence of tool CD38 inhibitor) control wells. IC 50 Values ​​were determined from a 10-point half-log concentration-response curve with a four-parameter logistic equation.

[0127] Mouse CD38 hydrolase assay non-physiological NAD + Substrate analog 1,N 6 -Etheno NAD + The ability of test compounds to inhibit mouse CD38 hydrolase activity was measured in a fluorescence-based assay using ε-NAD. 2+ / Mg 2+ Recombinant mouse CD38 (0.4 nM) in a 384-well black microplate was preincubated in 10 mM NaCl (pH 7.4) for 30 min at 25 °C. CD38 hydrolase activity was determined by the addition of 12 μM ε-NAD (which produces a fluorescent product, 1,N 6 -etheno-ADP-ribose was generated. Fluorescent product formation was followed by fluorescence readings (excitation λ=300 nm; emission λ=410 nm) at two time points, one after substrate addition (t=0) and one 6 min later (t=6) using a ClarioStar Plus (BMG) microplate reader.

[0128] To correct for baseline fluorescence variations, values ​​detected at t = 0 were subtracted from values ​​detected at t = 6. Data were analyzed and fluorescence values ​​were converted to percent inhibition using the average of high signal (CD38 and ε-NAD) and low signal (CD38 and ε-NAD in the presence of tool CD38 inhibitor) control wells. IC 50 Values ​​were determined from a 10-point half-log concentration-response curve with a four-parameter logistic equation. Data for human and mouse CD38 activity are summarized in Table 1. [Table 1]

[0129] Pharmacokinetics Tissue binding assay Buffer preparation. The basic solution was prepared by dissolving 14.2 g / L Na2HPO4 and 8.77 g / L NaCl in deionized H2O. The acidic solution was prepared by dissolving 15.6 g / L NaH2PO4·2H2O and 8.77 g / L NaCl in deionized H2O. The basic solution was titrated to pH 7.4 ± 0.1 with the acidic solution and stored at 4 °C for up to 1 month. The stop solution was 100% CH3CN containing 200 ng / mL tolbutamide, 200 ng / mL labetalol, and 50 ng / mL metformin.

[0130] Test method. Dialysis membrane strips were soaked in ultrapure water for approximately 1 hour at room temperature. Each membrane strip containing 2 membranes was separated and soaked in 20:80 EtOH / H2O (vol / vol) for approximately 20 minutes, after which they were either ready to use or stored in solution at 2-8 °C for up to 1 month. Prior to the experiment, the membranes were rinsed in ultrapure water and soaked for 20 minutes. On the day of the experiment, brain homogenates were thawed in a water bath at room temperature and incubated at 37 °C for 10 minutes before use. Test and control compounds were dissolved in DMSO to obtain 10 mM stock solutions. DMSO working solutions were prepared at 400 μM by diluting 10 μL of the stock solutions. To prepare the time zero (t=0) samples used for recovery measurements, 50 μL aliquots of the loading matrix were transferred in triplicate to the sample collection plate. Samples were immediately matched with the corresponding blank buffer to obtain a final volume of 100 μL with 1:1 matrix / dialysis buffer (vol / vol) in each well. 500 μL of stop solution was added to these t=0 samples. They were then stored at 2-8 °C with other post-dialysis samples pending further processing. To load the dialysis devices, 150 μL aliquots of loading matrix were transferred in triplicate to the donor side of each dialysis well, and 150 μL of dialysis buffer was added to the acceptor side of the well. The dialysis plate was placed in a humidified incubator at 37 °C with 5% CO2 on a slowly rotating (approximately 100 rpm) shaking platform for 4 hours. At the end of dialysis, 50 μL aliquots of samples were taken from both the buffer and matrix sides of the dialysis devices. These samples were transferred to a new 96-well plate. Each sample was mixed with an equal volume of the corresponding blank matrix (buffer or matrix) to reach a final volume of 100 μL in each well with 1:1 matrix / dialysis buffer (vol / vol). All samples were further processed by adding 500 μL of stop solution containing internal standards. The mixtures were vortexed and centrifuged at 4000 rpm for approximately 20 min. Then, 100 μL aliquots of the supernatant of all samples were removed for LC-MS / MS analysis. A single blank sample was prepared by transferring 50 μL of blank matrix to a 96-well plate and adding 50 μL of blank PBS buffer to each well.The matrix-matched samples were then further processed by adding 500 μL of stop solution containing the internal standard, following the same processing method as the dialyzed samples.

[0131] Data Analysis % Undiluted Unbound, % Undiluted Bound and % Recovery were calculated using the following formulas: %undiluted unbound=100*1 / D / ((1 / (F / T)-1)+1 / D) % undiluted bound = 100 - % undiluted unbound %Recovery=100*(F+T) / T0 where F is the analyte concentration or analyte / internal standard peak area ratio on the buffer (acceptor) side of the membrane; T is the analyte concentration or analyte / internal standard peak area ratio on the matrix (donor) side of the membrane; T0 is the analyte concentration or analyte / internal standard peak area ratio in the loading matrix at time zero; and D is the dilution factor, specified as 4 in this assay.

[0132] Percent unbound in brain homogenates and plasma for selected compounds are summarized in Table 2. [Table 2]

[0133] PK brain penetrant The in vivo brain distribution of compounds was measured in C57BL / 6 mice after a single oral (po) gavage dose. Test compounds were formulated at 1 mg / mL in 0.5% HPMC E4M, 0.2% Tween 80 in water to obtain a solution or homogenous suspension suitable for po administration. A volume of 10 mL / kg of the formulation was administered to three male C57BL / 6 mice to give a dose level of 10 mg / kg. Blood samples were collected 1 and 2 hours after dosing into tubes containing K2EDTA as an anticoagulant, processed to plasma, and stored at -60°C or below until LC-MS / MS analysis. Brains were collected 2 hours after dosing, rinsed with saline, dried, weighed, and homogenized under ice-cold conditions. Brain homogenates were stored at -60°C or below until LC-MS / MS analysis. Dose formulation concentrations were verified using LC-UV or LC-MS / MS methods. Test compound concentrations in plasma and brain homogenate were quantitatively measured using LC-MS / MS methods developed in individual matrices against calibration curves using included QC samples and acceptance standards according to CRO SOPs. Concentrations in brain homogenate were corrected for the dilution factor used to prepare the homogenate to obtain concentrations in whole brain tissue. Plasma and brain concentration data versus time were reported and plotted in Excel. Brain to plasma ratios 2 hours post-dose were calculated for each animal using the following formula: Brain: Plasma = brain concentration at 2 hours (ng / g) / plasma concentration at 2 hours (ng / mL) Since only unbound test compound was available to affect the target, unbound plasma (Cp,u) and unbound brain (Cb,u) concentrations were calculated by correcting the total concentration to the unbound fraction in plasma (fu,p) or brain (fu,b) determined from in vitro plasma protein or brain tissue assays using the following formula: Cp,u=plasma concentration*fu,p Cb,u = Brain concentration * fu,b Next, the non-bonded partition coefficient (Kp u,u ) to Cp, u For Cb, u The ratio was calculated using the following formula: Kp u,u =Cb, u / Cp, u

[0134] Selected data from the pharmacokinetic studies are summarized in Table 3. In these studies, mice were orally administered a dose of 10 mg / kg, sacrificed 2 hours after dosing, and tissue samples (brain homogenates and plasma) were then analyzed as described above. [Table 3]

[0135] The data in Table 3 show that N-(4-aminocyclohexyl)pyrimidine-4-carboxamides, such as Examples 1-3, 10, and 21, exhibit excellent brain penetration, whereas the analogous cyclohexyl ethers or alcohols, such as Comparative Examples 17-18, and the analogous pyrrolopyrimidines, such as Comparative Example 29 (included for illustrative purposes), exhibit much lower brain exposure and Kp u,u This is a surprising observation, especially since the additional hydrogen bond donors in Examples 1-3 and 21 would be expected to reduce brain exposure compared to Comparative Examples 17-18.

[0136] It will be understood that the 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 solely by the following claims.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Het is a 5-membered heteroaryl group containing two heteroatoms independently selected from N and S, said 5-membered heteroaryl group being C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl and C １ -C ３ optionally substituted with 1 or 2 substituents independently selected from hydroxyalkyl; X １ is CH or N, and X ２ is CH or N, and X １ and X ２ at least one of is N; L is a bond, CH ２ , CHMe, CMe ２ or CO; R １ is C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, hydroxyl, —O—(C １ -C ４ alkyl), or —O—(C ３ -C ６ cycloalkyl), each of which may be optionally fluoro-substituted; R ２ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, —CHO, —CO—(C １ -C ３ alkyl) or -CO-(C １ -C ３ fluoroalkyl); R ３ is hydrogen or methyl; or R ２ and R ３ together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. L is a bond, CH ２ or CO.

3. The compound has the formula (II): 【Chemistry 2】 [In the formula, Het is a 5-membered heteroaryl group containing two heteroatoms independently selected from N and S, said 5-membered heteroaryl group being C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl and C １ -C ３ optionally substituted with 1 or 2 substituents independently selected from hydroxyalkyl; X １ is CH or N, and X ２ is CH or N, and X １ and X ２ at least one of is N; R １ is C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, hydroxyl, —O—(C １ -C ４ alkyl), or —O—(C ３ -C ６ cycloalkyl), each of which may be optionally fluoro-substituted; R ２ is C １ -C ３ Alkyl or C １ -C ３ is fluoroalkyl; R ３ is hydrogen or methyl; or R ２ and R ３ and R 1 and R 2 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

4. X １ is N and X ２ The compound, salt, solvate or prodrug of claim 1 , wherein is N.

5. The compound has the formula (III): 【Transformation 3】 [In the formula, each W, X, Y, and Z is independently CH, CMe, N, NH, NMe, or S, where two of W, X, Y, and Z are CH or CMe, and the other two of W, X, Y, and Z are N, NH, NMe, or S; R １ is C １ -C ４ Alkyl or C ３ -C ４ is cycloalkyl; R ２ is C １ -C ３ Alkyl or C １ -C ３ is fluoroalkyl; R ３ is hydrogen or methyl; or R ２ and R ３ and R 1 and R 2 together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally fluoro-substituted, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

6. Het or group 【Chemistry 4】 The compound, salt, solvate or prodrug of claim 1, wherein is an imidazol-1-yl, 1-methylimidazol-5-yl, pyrazol-4-yl, or thiazol-5-yl group.

7. R １ 2. The compound, salt, solvate or prodrug of claim 1, wherein is methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

8. R ２ is C １ -C ３ 2. The compound, salt, solvate or prodrug of claim 1, which is fluoroalkyl.

9. R ２ and R ３ together with the nitrogen to which they are attached form an azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl group, each of which may be optionally substituted with 1, 2, 3, or 4 fluoro substituents.

10. 2. The compound, salt, solvate or prodrug of claim 1, wherein the two substituents on the cyclohexyl group are trans to each other.

11. 2. The compound of claim 1, a salt, solvate, or prodrug thereof, selected from the following: 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; 6-cyclopropyl-N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)pyrimidine-4-carboxamide; 6-methyl-2-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 6-methyl-2-(thiazol-5-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 6-ethyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(thiazol-5-yl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2-fluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1s,4s)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1s,4r)-4-((S)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; N-((1r,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxamide; 6-methyl-2-(1H-pyrazol-4-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-methyl-2-(1H-pyrazol-4-yl)pyrimidine-4-carboxamide; 4-cyclopropyl-N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-6-(1H-imidazol-1-yl)picolinamide; N-((1r,4r)-4-(ethylamino)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide; 4-cyclopropyl-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)picolinamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1S,4r)-4-(((S)-1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1R,4r)-4-(((R)-1,1,1-trifluoropropan-2-yl)amino)cyclohexyl)pyrimidine-4-carboxamide; 6-methyl-2-(5-methyl-1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)pyrimidine-4-carboxamide; N-((1r,4r)-4-aminocyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-6-methyl-N-((1r,4r)-4-((2,2,2-trifluoroethyl-1,1-d ２ )amino)cyclohexyl)pyrimidine-4-carboxamide; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.

12. The compound of formula (IV) is reacted with an amine of formula (V): 【Transformation 5】 [In the formula, Het, １ , X ２ , L, R １ , R ２ and R ３ is as defined in any one of claims 1 to 11; Y is -OH, -OR ４ , —O—CO—R ４ or —Cl; and R ４ is C １ -C ３ alkyl] and then optionally reacting with: - a process for converting a compound of formula (I), (II) or (III) into another compound of formula (I), (II) or (III); - a procedure to remove all protecting groups; - carrying out one or more of the following procedures to form a pharmaceutically acceptable salt:

13. A pharmaceutical composition comprising a compound, salt, solvate or prodrug according to any one of claims 1 to 11 together with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

14. A compound, salt, solvate or prodrug according to any one of claims 1 to 11 for use in therapy.

15. 12. A compound, salt, solvate or prodrug according to any one of claims 1 to 11 for use in the treatment or prevention of a disease, disorder or condition associated with CD38 activity.

16. 12. A compound, salt, solvate or prodrug according to any one of claims 1 to 11 for use in the treatment or prevention of a CNS disease, a disease requiring treatment via the CNS, a neurodegenerative condition, a neurological disease, an age-related disorder, or an inflammatory disease.

17. 12. The compound, salt, solvate or prodrug of any one of claims 1 to 11 for use in the treatment or prevention of Parkinson's disease; Alzheimer's disease; frontotemporal dementia; progressive supranuclear palsy; a tauopathy; another non-Alzheimer's dementia; stroke; ischemic attack; traumatic brain injury; multiple sclerosis; an autoimmune disease with associated nerve damage such as Muckle-Wells syndrome; a motor neuron disease such as amyotrophic lateral sclerosis; axonal degeneration such as axonal neuropathy or diabetic neuropathy; Wallerian degeneration; another ataxia such as ataxia-telangiectasia, Friedreich's ataxia, or 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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