TW202517637A - Sarm1 inhibitors - Google Patents

Abstract

The invention provides compounds having the general formula (I) wherein X, Y, Z, U, V, and R1 to R7 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with SARM1.

Description

SARM1 inhibitors

The present invention relates to organic compounds for use in treatment or prevention in mammals, and in particular to Sterile Alpha And TIR Motif Containing 1 (SARM1) inhibitors for use in the treatment or prevention of muscular dystrophy, spinal muscular atrophy, chemotherapy-induced peripheral neuropathy, diabetes-induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury and Chamadryna disease.

Axonal degeneration is a core driver of disability and disease progression in neurodegenerative and neurological diseases, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, Alzheimer's disease, and peripheral neuropathies. Due to the high energy requirements of axons to propagate action potentials and ensure protein transport over distances of sometimes meters, they are particularly sensitive to metabolic stresses such as those following mitochondrial rupture or microtubule disassembly. However, the resulting axonal degeneration is not a passive death process, and is now understood to involve key molecular components and steps. Programmed axonal degeneration, also known as Wallerian degeneration, is a key molecular mechanism driving axonal loss. As an early pathological feature of many neurological disorders associated with increasing social and economic burdens, therapies aimed at preventing axonal degeneration therefore have significant therapeutic potential.

In a first aspect, the present invention provides a compound of formula (I): (I) wherein X, Y, Z, U, V and ^R1 to ^R7 are as defined herein.

In a further aspect, the present invention provides compositions comprising compounds of formula (I), methods of making compounds of formula (I), and methods of using compounds of formula (I).

Definition

Features, integers, properties, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention should be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstracts and drawings) and/or all steps of any method or process so disclosed may be combined in any combination, except for at least some mutually exclusive combinations of such features and/or steps. The invention is not limited to the details of any foregoing embodiment. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings) or to any novel step or any novel combination of steps of any method or process so disclosed.

The term "alkyl" refers to a monovalent or polyvalent group having 1 to 6 carbon atoms, such as a monovalent or divalent linear or branched saturated alkyl group ("C _1-6 -alkyl"), such as 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. In yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, dibutyl, tertiary butyl, and 2,2-dimethylpropyl. Particularly preferred but non-limiting examples of alkyl groups are methyl, tertiary butyl, and 2,2-dimethylpropyl.

The term "alkoxy" refers to an alkyl group as previously defined attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C _1-6 -alkoxy"). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. In yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy group is methoxy.

The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably by fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably by fluorine. Particularly preferred but non-limiting examples of haloalkoxy are trifluoromethoxy, 3,3,3-trifluoropropoxy, 2,2,2-trifluoro-1-methyl-ethoxy and 3-fluoro-2-fluoro-propoxy.

The term "alkoxyalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group has been replaced by an alkoxy group. Some particularly preferred but non-limiting examples of alkoxyalkyl groups are 2-methoxy-2,2-dimethyl-ethyl, methoxymethyl and 2-methoxyethyl.

The term "haloalkoxyalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group. Preferably, "haloalkoxyalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group has been replaced by a haloalkoxy group. Particularly preferred but non-limiting examples of haloalkoxyalkyl groups are difluoromethoxymethyl and trifluoromethoxymethyl.

The term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halogenated" are fluorine (F) and chlorine (Cl).

The term "cyano" refers to the -CN (nitrile) group.

The term "hydroxy" refers to the −OH group.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or bicyclic alkyl group having 3 to 10 ring carbon atoms (" _C3-10 -cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a monocyclic alkyl group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and is a spirocyclic moiety, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic alkyl group having 3 to 6 ring carbon atoms, for example, 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentyl, norbornyl, and 1-bicyclo[2.2.2]octyl. Particularly preferred but non-limiting examples of cycloalkyl groups are cyclopropyl, bicyclo[1.1.1]pentyl, and cyclohexyl.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbon ring system having a total of 6 to 10 ring members (" _C6 - _C10 -aryl"), and wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting example of aryl is phenyl.

The term "aryl" refers to an aryl moiety attached to the parent moiety through a carbonyl group. A preferred but non-limiting example of aryl is benzoyl.

The term "heteroaryl" refers to a heteroaryl moiety attached to the parent moiety through a carbonyl group. A preferred but non-limiting example of heteroaryl is pyridine-3-carbonyl.

The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic, bicyclic or tricyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, such as 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7 or 5 to 6 ring members, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 9-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, "heteroaryl" refers to a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrazolyl, triazolyl, 1,3-benzoazol-2-yl, 1,3-benzoazol-4-yl, 1,3-benzoazol-5-yl, 1,3-benzoazol-6-yl, 1,3-benzoazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), pyrazolyl (e.g., 1H-pyrazol-4-yl), triazolyl (e.g., 1H-1,2,4-triazol-3-yl, 1H-triazol-4-yl, 2H-triazol-4-yl), and tetrazolyl (e.g., 2H-tetrazol-5-yl).

The term "heterocyclic group" as used herein refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system having 3 to 14 ring atoms, such as 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6 or 3 to 5 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 10 ring atoms, most preferably 3 to 8 ring atoms, wherein 1, 2 or 3 of the ring atoms are selected from N, O and S. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclic group" refers to a heterocyclic group consisting of two rings having two common ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and is a spirocyclic group, i.e., the two rings are connected via a common ring atom. Some non-limiting examples of monocyclic heterocyclic groups include tetrahydroazacyclopentane-3-yl, tetrahydroazacyclopentane-2-yl, 2-azaspiro[3.3]heptane-2-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2-azaspiro[3.4]octane-2-yl, 5-oxa-2-azaspiro[3.4]octane-2-yl, pyrrolidinyl (e.g., pyrrolidin-1-yl), thiophene, oxacyclobutane-3-yl, oxacyclobutane-2-yl, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl), tetrahydropyranyl. In some embodiments, the present invention comprises 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperidinyl (e.g., piperidin-1-yl), N-morpholinyl, morpholin-2-yl, and morpholin-3-yl.

The term "haloalkyl" refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably by fluorine. Preferably, "haloalkyl" refers to an alkyl group wherein 1, 2 or 3 of the hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably by fluorine. Particularly preferred but non-limiting examples of haloalkyl groups are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.

The term "hydroxyalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group has been replaced by a hydroxy group. Preferred but non-limiting examples of hydroxyalkyl groups are 2-hydroxy-1,1-dimethylethyl, 2-hydroxy-2-methyl-propyl, hydroxymethyl and hydroxyethyl (e.g., 2-hydroxyethyl).

The term "pharmaceutically acceptable salt" means a salt which retains the biological effectiveness and properties of the free base or free acid and which is not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. Alternatively, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimide resins, and the like.

The compounds of formula (I) described herein may contain several asymmetric centers and may be in the form of pure mirror image isomers, mixtures of mirror image isomers, such as racemates, optically pure non-mirror image isomers, mixtures of non-mirror image isomers, non-mirror image isomers, or mixtures of non-mirror image isomers.

The abbreviation "SARM1" refers to sterile alpha and TIR motif-containing 1.

As used herein, the term "treating" includes: (1) inhibiting a disease, symptom or condition (e.g., arresting, reducing or delaying the development of at least one clinical or subclinical symptom of a disease or its recurrence, while maintaining treatment); and/or (2) relieving a disease (i.e., causing regression of the disease, symptom or condition or at least one of its clinical or subclinical symptoms). The benefit to the patient being treated is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a drug is administered to a patient to treat a disease, the result may not always be an effective treatment.

As used herein, the term "prophylaxis" includes preventing or delaying the onset of clinical symptoms of a disease, disorder or condition in a mammal, especially a human, that may be susceptible to or susceptible to the disease, disorder or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease, disorder or condition.

SARM1

Axonal disruption distal to the site of injury is a key feature of programmed axonal degeneration or Wallerian degeneration and is characterized by mitochondrial fragmentation, loss of nicotinamide adenine dinucleotide (NAD+), increased intracellular calcium levels, and axonal fragmentation (Conforti, L. et al., Nat. Rev. Neurosci., 2014, 15, 394–409). A core component of the programmed axonal degeneration mechanism is sterile alpha and TIR motif 1 (SARM1) (Osterloh, JM et al., Science, 2012, 337, 481-484). SARM1 is a NAD+ hydrolase that depletes NAD+ levels by cleaving NAD+ into its metabolites: nicotinamide (NAM) and adenosine diphosphate ribose (ADPR) or cyclic ADPR. The resulting loss of NAD+ (an essential metabolite involved in energy metabolism and axonal homeostasis) (Hopkins, EL et al., 2021, Front. Mol. Biosci. , 8:703532) and increase in cADPR (a regulator of intra-axonal calcium levels) (Li, Y. et al., 2022, J. Cell Biol. , 221, e202106080) contribute to the subsequent axonal degeneration process.

Other molecular components of the Wallerian axonal degeneration pathway have been identified, including axon survival factors such as nicotinamide mononucleotide adenosyltransferase 2 (NMNAT2). Under normal circumstances, axon survival factors such as NMNAT2 are continuously renewed and replenished by anterograde transport along the axon from the cell body (Gilley, J. & Coleman, MP, 2010, PLoS Biol ., 8, e1000300). NMNAT2 maintains axon energetics by catalyzing the formation of NAD+ from nicotinamide mononucleotide (NMN) and adenosine triphosphate (ATP). However, during injury or disease, disruption of microtubule assembly or mitochondrial depolarization in axons leads to loss of NMNAT2 trafficking, which then leads to NMNAT2 depletion. This in turn activates SARM1 by reducing NMNAT2 levels due to loss of NAD+ (a negative SARM1 ligand) and accumulation of NMN (a positive SARM1 ligand) (Figley, MD et al., 2021, Neuron , 109, 1118-1136).

SARM1 is a multidomain protein consisting of an autoinhibitory ARM domain, a tandem oligomerizing SAM domain, and a catalytic TIR domain. Although initially thought to exist as a monomer in solution, recent high-resolution cryo-EM structures have revealed that SARM1 exists as an octamer in which the ARM domain locks the TIR domain in an inactive conformation (Bratkowski, M. et al., 2020, Cell Rep. , 32, 107999). Allosteric sites were then identified where both NMN and NAD+ can bind (Jiang, Y. et al. , 2020, Nature , 588, 658-663; Figley, MD et al., 2021, Neuron , 109, 1118-1136). The increase in NMN/NAD+ during axonal injury and the higher affinity of NMN for SARM1 lead to the displacement of NAD+ in the allosteric pocket, thereby releasing the ARM domain and allowing the TIR domain to be catalytically active.

Both in vitro and in vivo studies of SARM1 loss of function have highlighted the central role of SARM1 in programmed axonal degeneration. SARM1 gene knockout has been shown to protect axons in both human and rodent neuron cultures after physical (axonal severing) or chemical damage (e.g. caused by chemotherapeutic drugs such as vincristine) (Osterloh, JM et al., Science, 2012, 337, 481-484; Chen, Y. et al., 2021, Exp. Neurol. , 339, 113636). In vivo , SARM1 deficiency prevents neurofibrillary loss and restores normal pain sensitivity in models of chemotherapy-induced peripheral neuropathy (Geisler, S. et al., 2016, Brain, 139, 3092-3108) and diabetic peripheral neuropathy (Cheng, Y. et al., 2019, Diabetes , 68, 2120-2130). SARM1 deficiency also attenuates axonal degeneration in preclinical models of ALS (White, MA et al., Acta Neuropathol. Commun. , 7, 166) and MS (Viar, K. et al., 2020, PLoS One , 15, e0235110). In models of ocular disease, SARM1 deficiency has been found to prevent axonal loss in retinal ganglion cells in a glaucoma model (Finnegan, LK et al., 2022, Int. J. Mol. Sci., 23, 1606) and photoreceptor loss in a pigmentary retinitis model (Ozaki, E. et al., 2020, Life Sci. Alliance. , 3, e201900618). These combined studies highlight the therapeutic potential of blocking SARM1 activity to improve various neurological diseases associated with axonal loss.

Compounds of the present invention

In a first aspect, the present invention provides a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are each selected from CR ^Z and N, provided that at most two of X, Y and Z are N; U is selected from O, S and NR ^U ; V is a covalent bond or C( ^RV ) ₂ ; A is selected from 3- to 14-membered heterocyclic groups, 5- to 14-membered heteroaryl groups, C ₆ -C ₁₀ -aryl groups and C ₃ -C ₁₀ -cycloalkyl groups; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is selected from hydrogen and C ₁ -C ₆ -alkyl groups; ^RU is selected from hydrogen, C ₁ -C ₆ -alkyl groups and cyano groups; each ^RV is independently selected from hydrogen, C ₁ -C ₆ -alkyl groups and halogen-C ₁ -C ₆ -alkyl; R ^Z is selected from hydrogen and C ₁ -C ₆ -alkyl; R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy and a group R ^1a is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl; R ^2a and R ^2b are each independently selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₆ -C ₁₀ -aryl-C ₁ -C ₆ -alkyl and R ^2c -OC ₁ -C ₆ -alkyl; wherein each C ₆ -C ₁₀ -aryl and C ₃ -C R ^2c is selected from hydrogen, C ₁ ^-C 6 -alkyl, halogen-C ₁ -C 6 -alkyl and C 6 -C ₁₀ -aryl, wherein the C ₆ -C ₁₀ -aryl is optionally substituted with 1 to 2 halogen substituents; R ³ is selected from hydrogen, C _{1 -C 6 -alkyl} , halogen-C ₁ -C 6 -alkyl and C _{3 -C 10} -cycloalkyl; R ^{4a and} R _4b are each independently selected from hydrogen, halogen _{, hydroxyl, C 1 -C 6 -alkyl , 5} to ₁₄ membered cycloalkyl ^; wherein the 5- to 14-membered heteroaryl, C ₆ -C ₁₀ -aryl, C ₆ -C ₁₀ -aroyl, or 5- to 14-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen and hydroxy-C _{1 -C 6 -alkyl} ; or R ^4a and R ^4b together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl or a 3- to 14-membered heterocyclic group, wherein the C ₃ -C ₁₀ -cycloalkyl and the 3- to 14-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from halogen and hydroxy-C ₁ -C ₆ -alkyl. or R ^4a and R ⁷ together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group or a pendoxy group; R ^6a and R ^6b are each independently selected from hydrogen, a 5- to 14-membered heteroaryl group and a C ₆ -C ₁₀ -aryl group; wherein the 5- to 14-membered heteroaryl group and the C ₆ -C ₁₀ -aryl group are optionally substituted by 1 to 3 halogen substituents independently selected from halogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In one embodiment, the invention provides a compound of formula (I) as described herein, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are N; U is selected from O, S and NR ^U ; V is a covalent bond or C( ^RV ) ₂ ; A is selected from 3-14 membered heterocyclic groups, 5-14 membered heteroaryl groups, _C6 - _C10 -aryl groups and _C3 - _C10 -cycloalkyl groups; L is selected from a covalent bond and -NR ^L -; ^RL is selected from hydrogen and _C1 - _C6 -alkyl; ^RU is selected from hydrogen, _C1 - _C6 -alkyl and cyano; each ^RV is independently selected from hydrogen, _C1 - _C6 -alkyl and halogen- _C1 - _C6 -alkyl; ^R1 is selected from hydrogen, halogen, cyano, _C1 - _C6 -alkyl, halogen- _C1 - _C6 -alkyl, hydroxy- _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, halogen- _C1 - _C6 -alkoxy and a group R ^1a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^2a and R ^2b are each independently selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy, C 1 -C ₆ -alkyl-NH-C ₁ -C 6 -alkyl-, C ₃ -C ₁₀ -cycloalkyl and R ^2c -OC ₁ -C ₆ -alkyl; or R ^2a and R ^2b together with the carbon atom to which they are attached form C ₃ -C ₁₀ -cycloalkyl; R 2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C 6 -alkyl and C 6 -C ₁₀ -aryl; R ³ is selected from hydrogen, C ₁ -C 6 -alkyl, halogen-C ¹ -C ₆ -alkyl and C ₆ -C ₁₀ -aryl. R ^4a and R ^4b are each independently selected from hydrogen, halogen, hydroxyl, C _{1 -C 6 -alkyl, 5- to 14-membered heteroaryl, C 6 -C 10 -aryl , C 6} -C ₁₀ -aroyl, 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl, C ₆ -C ₁₀ -aryl, C _{6 -C 10} -aroyl, 5- to ₁₄ -membered heteroaroyl is optionally substituted with 1 to 3 substituents independently selected from halogen and hydroxyl- _{C 1} -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form C ₃ -C ₁₀ -cycloalkyl or 3 to 14 membered heterocyclic group, wherein the C ₃ -C ₁₀ -cycloalkyl and 3 to 14 membered heterocyclic group are optionally substituted with 1 to 3 halogen substituents; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^6a and R ^6b are each independently selected from hydrogen, 5 to 14 membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5 to 14 membered heteroaryl and C ₆ -C ₁₀ -aryl is optionally substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (I) is a compound of formula (Ia) (Ia) or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are N; ^R1 is selected from hydrogen, halogen, cyano, _C1 - _C6 -alkyl, halogen- _C1 - _C6 -alkyl and _C3 - _C10 -cycloalkyl; ^R2a and ^R2b are each independently selected from hydrogen, _C1 - _C6 -alkyl, halogen- _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, halogen- _C1 - _C6 -alkoxy, _C1 - _C6 -alkyl-NH- _C1 - _C6 -alkyl-, _C1 - _C6 -alkoxy- _{C1-C6-alkyl and halogen-C1 - C6 -} alkoxy-C1- _C6 -alkyl. or R ^2a and R ^2b together with the carbon atom to which they are attached form a C _{3 -C 10} -cycloalkyl group; R ³ is selected from hydrogen, C ₁ -C ₆ -alkyl and C ₃ -C ₁₀ -cycloalkyl group; R ^4a and R ^4b are each independently selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl, C ₆ -C ₁₀ -aryl, C ₆ -C ₁₀ -aromatic, 5- to 14-membered heteroaromatic; wherein the 5- to 14-membered heteroaryl, C ₆ -C ₁₀ -aryl, C ₆ -C ₁₀ -aromatic, 5- to 14-membered heteroaromatic is optionally 1 to 3 R ^4a and R ^4b together with the carbon atoms to which they are attached form a C 3 -C ₁₀ -cycloalkyl group or a 3- to 14 _- membered heterocyclic group, wherein the C ₃ -C ₁₀ -cycloalkyl group and the 3- to ₁₄ -membered heterocyclic group are optionally substituted with 1 to 3 halogen substituents; R ^5a and R ^5b are each independently selected from hydrogen and C _{1 -C 6} -alkyl; or R ^5a and R ^5b together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group; R ^6a and R ^6b are each independently selected from hydrogen, a 5- to 14-membered heteroaryl group and a C ₆ -C ₁₀ -aryl group; wherein the 5 The C ₆ -C ₁₀ -aryl group is optionally substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5 to 14 membered heteroaryl groups; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5 to 14 membered heteroaryl groups.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i)   X, Y and Z are CH; or (ii)   X and Z are CH and Y is N; or (iii)  X is N and Y and Z are CH; or (iv)  X is CH and Y and Z are N; or (v)   X and Y are N and Z is CH; or (vi)  X and Z are N and Y is CH.

In one embodiment, the invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR ^Z ; wherein R ^Z is selected from hydrogen and C ₁ -C ₆ -alkyl; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i)   X, Y and Z are CH; or (ii)   X and Z are CH and Y is N; or (iii)  X is N and Y and Z are CH.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y are CH and Z is CR ^Z ; wherein R ^Z is selected from hydrogen and methyl; or (ii) X and Z are CH and Y is N.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: (i)   X, Y and Z are CH; or (ii)   X and Z are CH and Y is N.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are CH.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein X and Z are CH and Y is N.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: ^R1 is selected from hydrogen, halogen, cyano, _C1 - _C6 -alkyl, _C2 - _C6 -alkynyl, halogen- _C1 - _C6 -alkyl, hydroxy- _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy and a group ; A is selected from a 3- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, a phenyl group and a C ₃ -C ₆ -cycloalkyl group; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; and R ^1a is selected from hydrogen, a halogen, a C ₁ -C ₆ -alkyl group and a halogen-C ₁ -C ₆ -alkyl group.

In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, prop-1-ynyl, hydroxymethyl, CHF ₂ , methoxy and a group ; A is selected from tetrahydroacrylamide, tetrahydrofuran, tetrahydropyran, pyrrolidine, pyrazole, phenyl, pyridyl and cyclopropyl; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; and R ^1a is selected from hydrogen, chlorine, methyl and CF ₃ .

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: ^R1 is selected from hydrogen, halogen, cyano, _C1 - _C6 -alkyl, halogen- _{C1-C6 -} alkyl, hydroxy- _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy and a group ; A is selected from a 3- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, a phenyl group and a C ₃ -C ₆ -cycloalkyl group; L is selected from a covalent bond and -NR ^L -; ^RL is hydrogen; and R ^1a is selected from hydrogen, a halogen and a C ₁ -C ₆ -alkyl group.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl and C ₃ -C ₁₀ -cycloalkyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, hydroxymethyl, CHF ₂ , methoxy and a group ; A is selected from tetrahydroacrylamide, pyrrolidine, pyrazole, phenyl and cyclopropyl; L is selected from a covalent bond and -NR ^L -; ^RL is hydrogen; and R ^1a is selected from hydrogen, chloro and methyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen, fluorine, chlorine, cyano, methyl and cyclopropyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen, fluorine and methyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, phenyl-C ₁ -C ₆ -alkyl and R ^2c -OC ₁ -C ₆ -alkyl; wherein the phenyl is optionally substituted with 1 halogen substituent; R ^2b is hydrogen; and R ^2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and phenyl; wherein the phenyl is optionally substituted with 1 halogen substituent; or R ^2a and R ^2b together with the carbon atom to which it is attached forms a C ₃ -C ₆ -cycloalkyl group.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CHF ₂ , CH ₃ N-CH ₂ -, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF ₂ -O-CH ₂ -, CF ₃ -O-CH ₂ - and cyclopropyl; and R ^2b is hydrogen; or R ^2a and R ^2b together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl and R ^2c -OC ₁ -C ₆ -alkyl; R ^2b is hydrogen; and R ^2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and phenyl; or R ^2a and R ^2b together with the carbon atom to which they are attached form a C ₃ -C ₆ -cycloalkyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl; and R ^2b is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₃ N-CH ₂ -, hydroxymethyl, methoxymethyl, phenoxymethyl, CHF ₂ -O-CH ₂ -, CF ₃ -O-CH ₂ - and cyclopropyl; and R ^2b is hydrogen; or R ^2a and R ^2b together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group.

In one embodiment, the invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₃ N-CH ₂ -, methoxymethyl, CHF ₂ -O-CH ₂ - and CF ₃ -O-CH ₂ -; and R ^2b is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is C ₁ -C ₆ -alkyl; and R ^2b is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^2a is methyl; and R ^2b is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from methyl and CHF ₂ .

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is C ₁ -C ₆ -alkyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxyl-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a C ₃ -C ₆ -cycloalkyl; R ^{R 5a} and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl or a pendoxy group; R ^6a is selected from hydrogen, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl are substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl. Heteroaryl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted with a substituent selected from chlorine, bromine and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a cyclopropyl group; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group; R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R ^5a and R ^{R 5b} together with the carbon atom to which it is attached forms a cyclopropyl group or an oxo group; R ^6a is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, methyl, CHF ₂ , CF ₃ and imidazolyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxyl-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a C ₃ -C ₆ -cycloalkyl; R ^{R 5a} and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^6a is selected from hydrogen, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl are substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxy-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^R5b together with the carbon atom to which it is attached forms a _C3 - _C10 -cycloalkyl group; ^R6a is selected from hydrogen, 5- to 14-membered heteroaryl groups and _C6 - _C10 -aryl groups; wherein the 5- to 14-membered heteroaryl groups and _C6 - _C10 -aryl groups are substituted with 1 to 3 substituents independently selected from halogen, _C1 - _C6 -alkyl, _C3 - _C10 -cycloalkyl groups and 5- to 14-membered heteroaryl groups; ^R6b is hydrogen; and ^R7 is selected from hydrogen, halogen- _C1 - _C6 -alkyl groups and 5- to 14-membered heteroaryl groups.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted with a substituent selected from chlorine, bromine and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a cyclopropyl group; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group; R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R ^5a and R R ^5b together with the carbon atom to which it is attached forms a cyclopropyl group; R ^6a is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, methyl, CHF ₂ , CF ₃ and imidazolyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted with 1 substituent selected from chlorine, bromine and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a cyclopropyl group; R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a cyclopropyl group; R ^{R 6a} is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^4b is selected from hydrogen and halogen; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen and 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl is substituted with one substituent selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, fluorine and methyl; R ^4b is selected from hydrogen and fluorine; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen, pyridyl and pyrazolyl; wherein the pyridyl and pyrazolyl are substituted with a substituent selected from bromine, methyl, cyclopropyl and pyridyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen and halogen; R ^4b is selected from hydrogen and halogen; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen and 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is substituted with 1 halogen substituent; R ^6b is hydrogen; and R ⁷ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are each independently selected from hydrogen and halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein both R ^5a and R ^5b are hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ^6a is selected from hydrogen and 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is substituted with 1 halogen substituent; and R ^6b is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen and fluorine; R ^4b is selected from hydrogen and fluorine; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen and bromopyridyl; R ^6b is hydrogen; and R ⁷ is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are each independently selected from hydrogen and fluorine.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: R ^6a is selected from hydrogen and bromopyridinyl; and R ^6b is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the group for .

In one embodiment, the invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; ^RU is cyano; and ^RV is halo-C ₁ -C ₆ -alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; ^RU is cyano; and ^RV is CF ₃ .

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein U is O and V is a covalent bond, which is represented by formula (Ia): (Ia) wherein X, Y, Z and R ¹ to R ⁷ are as defined herein.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR ^Z ; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; A is selected from a 3- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, a phenyl group and a C ₃ -C ₆ -cycloalkyl group; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; R ^U is cyano; ^RV is halogen-C ₁ -C ₆ -alkyl; ^RZ is selected from hydrogen and C ₁ -C ₆ -alkyl; ^R1 is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, halogen-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and the group ; R ^1a is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl; R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, phenyl-C ₁ -C ₆ -alkyl and R ^2c -OC ₁ -C ₆ -alkyl; wherein the phenyl is optionally substituted with 1 halogen substituent; R ^2b is hydrogen; and R ^2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and phenyl; wherein the phenyl is optionally substituted with 1 halogen substituent; or R ^2a and R ^{R 2b} together with the carbon atom to which it is attached forms a C ₃ -C ₆ -cycloalkyl group; R ³ is selected from C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl; R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxyl-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group; or R ^4a and R ^{R 7} together with the carbon atom to which it is attached forms a C ₃ -C ₆ -cycloalkyl group; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group or a pendoxy group; R ^6a is selected from hydrogen, 5- to 14-membered heteroaryl groups and C ₆ -C ₁₀ -aryl groups; wherein the 5- to 14-membered heteroaryl groups and C ₆ -C ₁₀ -aryl groups are substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl groups and 5- to 14-membered heteroaryl groups; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR ^Z ; or (ii) X and Z are CH and Y is N ; or (iii) X is N and Y and Z are CH ; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; A is selected from tetrahydroazine, tetrahydrofuran, tetrahydropyran, pyrrolidine, pyrazole, phenyl, pyridyl and cyclopropyl; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; ^RU is cyano; ^RV is CF ₃ ; ^RZ is selected from hydrogen and methyl; R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, prop-1-ynyl, hydroxymethyl, CHF ₂ , methoxy and a group ; R ^1a is selected from hydrogen, chlorine, methyl and CF ₃ ; R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CHF ₂ , CH ₃ N-CH ₂ -, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF ₂ -O-CH ₂ -, CF ₃ -O-CH ₂ - and cyclopropyl; and R ^2b is hydrogen; or R ^2a and R ^2b together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group; R ³ is selected from methyl and CHF ₂ ; R ^{R 4a} is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted with 1 substituent selected from chlorine, bromine and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a cyclopropyl group; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group; R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a cyclopropyl group or a pendoxy group; R ^{R 6a} is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, methyl, CHF ₂ , CF ₃ and imidazolyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; A is selected from a 3- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, a phenyl group and a C ₃ -C ₆ -cycloalkyl group; L is selected from a covalent bond and -NR ^L -; ^RL is hydrogen; ^RU is cyano; ^RV is a halogen-C ₁ -C ₆ -alkyl; R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and a group ; R ^1a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl and R ^2c -OC ₁ -C ₆ -alkyl; R ^2b is hydrogen; and R ^2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and phenyl; or R ^2a and R ^2b together with the carbon atom to which they are attached form a C ₃ -C ₆ -cycloalkyl; R ³ is C ₁ -C ₆ -alkyl; R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5 wherein the 5- to 14-membered heteroaryl group is optionally substituted with 1 substituent selected from halogen and hydroxy-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; or R ^4a and R ⁷ together with the carbon atom to which they are attached form _{a C 3 -C 6 -cycloalkyl ; R} ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^{R 6a} is selected from hydrogen, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl are substituted by 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; A is selected from tetrahydroazine, pyrrolidine, pyrazole, phenyl and cyclopropyl; L is selected from a covalent bond and -NR ^L -; ^RL is hydrogen; ^RU is cyano; ^RV is CF ₃ ; R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, hydroxymethyl, CHF ₂ , methoxy and a group ; R ^1a is selected from hydrogen, chlorine and methyl; R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₃ N-CH ₂ -, hydroxymethyl, methoxymethyl, phenoxymethyl, CHF ₂ -O-CH ₂ -, CF ₃ -O-CH ₂ - and cyclopropyl; and R ^2b is hydrogen; or R ^2a and R ^2b together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl group; R ³ is methyl; R ^4a is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted by 1 R 4a and R ^4b are each independently selected from hydrogen and methyl; or R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R 5a and R 5b are each independently selected from hydrogen and methyl; or R ^6a and R ^6a are selected from hydrogen, pyrazolyl, pyridinyl, pyrimidine, isothiocyanate, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidine, isothiocyanate, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents selected from chlorine ^{, bromine} and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b are taken together with the carbon atom to which they are attached to form a cyclopropyl group; or R 4a and R 7 are taken together with the carbon atom to which they are attached to form a cyclopropyl group; R 5a and R 5b are each independently selected from hydrogen and methyl; or R 5a and R 5b are taken together with the carbon atom to which they are attached to form a cyclopropyl group; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, methyl, CHF ₂ , CF ₃ and imidazolyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; U is O; V is a covalent bond; R ¹ is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^2a is C ₁ -C ₆ -alkyl; and R ^2b is hydrogen; R ³ is C ₁ -C ₆ -alkyl; R ^4a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^4b is selected from hydrogen and halogen; R 5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen and 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl is selected from hydrogen ^and halogen; The 5-membered heteroaryl is substituted with 1 substituent selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5-membered to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, halogen-C ₁ -C ₆ -alkyl and 5-membered to 14-membered heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; U is O; V is a covalent bond; R ¹ is selected from hydrogen, fluorine and methyl; R ^2a is methyl; and R ^2b is hydrogen; R ³ is methyl; R ^4a is selected from hydrogen, fluorine and methyl; R ^4b is selected from hydrogen and fluorine; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen, pyridyl and pyrazolyl; wherein the pyridyl and pyrazolyl are substituted with a substituent selected from bromine, methyl, cyclopropyl and pyridyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; ^RU is cyano; and ^RV is halogen-C ₁ -C ₆ -alkyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; ^RU is cyano; and ^RV is CF ₃ .

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein: (i)   X, Y and Z are CH; or (ii)   X and Z are CH and Y is N; U     is O; and V     is a covalent bond.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl and C ₃ -C ₁₀ -cycloalkyl; R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl; R ^2b is hydrogen; R ³ is C ₁ -C ₆ -alkyl; R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxy-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; R ^6a is selected from hydrogen, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl are substituted by 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; R ¹ is selected from hydrogen, fluorine, chlorine, cyano, methyl and cyclopropyl; R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₃ N-CH ₂ -, methoxymethyl, CHF ₂ -O-CH ₂ - and CF ₃ -O-CH ₂ -; R ^2b is hydrogen; R ³ is methyl; R ^4a is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted by 1 R 4a ^and R ^4b are each independently selected from hydrogen and methyl; or R ^5a and R ^5b are together with the carbon atom to which they are attached to form a cyclopropyl group; R ^6a is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidine, isothiocyanate, 1,2,4-oxadiazolyl and phenyl; wherein the ^pyrazolyl , ^pyridinyl , pyrimidine, isothiocyanate, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents ^{independently} selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH; ^R1 is hydrogen; ^R2a is _C1 - _C6 -alkyl; and ^R2b is hydrogen; ^R3 is C1- _C6 -alkyl; ^R4a is selected from hydrogen, halogen and _C1 - _C6 - _alkyl ; ^R4b is selected from hydrogen and halogen; ^R5a is hydrogen; ^R5b is hydrogen; ^R6a is selected from hydrogen and 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl is substituted with 1 alkyl radical selected from halogen, _C1 - _C6 -alkyl, _C3 - _C10 -cycloalkyl and 5- to 14-membered heteroaryl. R ^6b is hydrogen; and R ⁷ is selected from hydrogen, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH; R ¹ is hydrogen; R ^2a is methyl; and R ^2b is hydrogen; R ³ is methyl; R ^4a is selected from hydrogen, fluorine and methyl; R ^4b is selected from hydrogen and fluorine; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen, pyridyl and pyrazolyl; wherein the pyridyl and pyrazolyl are substituted with a substituent selected from bromine, methyl, cyclopropyl and pyridyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl.

In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)urea; 1-[(3-chloro-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-fluoro-4-pyridyl)methyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-(4-pyridylmethyl)urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridinylmethyl)urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridinylmethyl)urea; 3-(4-Benzyltetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 1-[(3-bromo-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[[3-(hydroxymethyl)-4-pyridinyl]methyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]urea; 1-[(3-cyclopropyl-4-pyridinyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(tetrahydroacrif-1-yl)-4-pyridinyl]methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[2-methoxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-methoxy-4-pyridyl)methyl]-1-methyl-urea; 1-[1-(3-chloro-4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-pyrrolidin-1-yl-4-pyridyl)methyl]urea; 1-[(S)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(S)-cyclopropyl(4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 3-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-chloro-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridinyl)cyclopropyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 1-[[3-(3-chloroanilino)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(3-chloroanilino)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 1-methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-3-[(1S,5S)-3-oxabicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1R,5R)-3-oxobicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1S,5S)-3-oxobicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(1H-pyrazol-5-yl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[3-(difluoromethyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]thiourea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(3-methyl-1H-pyrazol-5-yl)-4-pyridyl]methyl]urea; 2-cyano-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]guanidine; 1-methyl-3-(5-hydroxytetrahydrofuran-3-yl)-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(4-pyridyl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(3-pyridyl)-4-pyridyl]methyl]urea; 1-[[3-(4-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(2-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(3-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[2-(3-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-prop-1-ynyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(2-pyridyl)-4-pyridyl]methyl]urea; 1-[2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S,4R)-4-Hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R,4S)-4-Hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[4-(trifluoromethyl)phenyl]-4-pyridinyl]methyl]urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; 1-[(1S)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-(difluoromethyl)-3-(4,4-difluorotetrahydrofuran-3-yl)-1-(4-pyridylmethyl)urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; and 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2,2,2-trifluoro-1-(4-pyridinyl)ethyl]urea].

In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-tetrahydrofuran-3-yl]urea; 1-methyl-3-[(3RS,4RS)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-3-[(3RS,4SR)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3RS)-3-(1H-imidazol-2-yl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(3RS)-3-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2RS,3SR)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2RS,3SR)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2RS,3SR)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2R,3S)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2R,3S)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2S,3R)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2R,3S)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; and 3-[(2S,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea.

In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridinylmethyl)urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridinylmethyl)urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridinyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridinyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea; and 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridinyl)methyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridamole-4-ylethyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridamole-4-ylethyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridamole-4-ylethyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridamole-4-ylethyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridinyl)methyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridinyl)methyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea.

In a particular embodiment, the present invention provides a pharmaceutically acceptable salt of a compound according to formula (I) as described herein. In a further particular embodiment, the present invention provides a compound according to formula (I) as described herein as a free base.

In some embodiments, the compounds of Formula (I) are isotopically labeled wherein one or more atoms are replaced by atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of Formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that may be incorporated into compounds of Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ^{17 O, 18 O} , ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. Certain isotopically labeled compounds of formula (I) (e.g., those incorporating radioactive isotopes) are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose due to their ease of incorporation and ready means of detection. For example, a compound of formula (I) may be enriched in 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

Substitution with heavier isotopes such as deuterium (i.e., ^2H ) may provide certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements. Thus, in one embodiment, the invention provides a compound of formula (I) as described herein, wherein one or more hydrogen atoms are replaced by deuterium, preferably wherein 1 to 4 hydrogen atoms are replaced by deuterium, and more preferably wherein 1 to 3 hydrogen atoms are replaced by deuterium.

Substitution with positron emitting isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N) may be useful in positron emission tomography (PET) studies for examining receptor occupancy. Isotopically labeled compounds of formula (I) may generally be prepared by techniques known to those of ordinary skill in the art or by methods analogous to those described in the Examples as illustrated below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

Manufacturing method

The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for the reaction and purification of the obtained products are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the description of the following methods have the meanings given herein.

If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced prior to the key steps using methods well known in the art (e.g., as described in T. W. Greene and P. G. M. Wutts, "Protective Groups in Organic Chemistry", 5th edition, 2014, John Wiley & Sons, N.Y.). Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature.

If the starting materials or intermediates contain stereocenters, the compounds of formula (I) can be obtained in the form of non-mirror image isomers or mixtures of mirror image isomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can be separated into their mirror image isomers, for example, via non-mirror image isomer salts by crystallization with optically pure acids or by mirror image isomer separation by specific analytical methods, using chiral adsorbents or chiral eluents. Likewise, it is possible to separate starting materials and intermediates containing stereocenters to obtain non-mirror image isomerically/mirror image enriched starting materials and intermediates. The use of such non-imagerally/imagerally enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally produce the corresponding non-imagerally/imagerally enriched compounds of formula (I).

The person skilled in the art will recognize that in the synthesis of compounds of formula (I) - if this is not desired - an "orthogonal protection group strategy" will be employed, which allows the cleavage of several protection groups at once without affecting other protection groups in the molecule. The principle of orthogonal protection is well known in the art and is also described in the literature (e.g. Barany and RB Merrifield, J. Am. Chem. Soc. 1977 , 99 , 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996 , 35 , 2056).

Those skilled in the art will recognize that the order of the reactions may vary depending on the reactivity and nature of the intermediates.

In more detail, the compounds of formula (I) can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art in the art to which the present invention belongs. In addition, for reaction conditions affecting the described reactions described in the literature, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999) . It has been found that it is appropriate to carry out the reaction in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be used, provided that the solvent has no adverse reaction to the reaction or reagent involved and that it can dissolve the reagent at least to a certain extent. The described reactions can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the invention. It is convenient to carry out the described reactions at a temperature range between -78°C and reflux. The time required for the reaction may also vary greatly, depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to obtain the described intermediates and compounds. The reaction sequence is not limited to the sequence presented in the scheme, however, depending on the starting materials and their respective reactivity, the order of the reaction steps can be freely varied.

If starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared in an analogous manner to existing procedures for close analogs or as outlined in the experimental part.

The following abbreviations are used herein: °C = degrees Celsius; Boc ₂ O = di - tributyl dicarbonate; CataCXium Pd G4 = [di(adamantan-1-yl)(butyl)phosphine](mesylate-κ O )[2'-(methylamino)-2-biphenyl]palladium; CDT = 1,1'-carbonyl-bis-(1,2,4-triazole); CH ₃ CN = acetonitrile; CHCl ₃ = chloroform; Cs ₂ CO ₃ = cesium carbonate; CuI = cuprous iodide; DCE = dichloroethane; DCM = dichloromethane; DIPEA = N , N -diisopropylethylamine; DMF = N , N -dimethylformamide; ESI = electrospray ionization; Et ₂ O = diethyl ether; EtOAc = ethyl acetate; EtOH = = ethanol; FC = flash chromatography; h = hour; H ₂ = hydrogen; H ₂ O = water; HCl = hydrogen chloride; HCOOH = formic acid; HPLC = high performance liquid chromatography; IPA = propan-2-ol; i- PrMgCl·LiCl = isopropylmagnesium chloride/lithium chloride complex; K ₂ CO ₃ = potassium carbonate; KHMDS = potassium bis(trimethylsilyl)amide; KH ₂ PO ₄ = potassium dihydrogen phosphate; KI = potassium iodide; LiAlH ₄ = lithium aluminum hydroxide; LiCl = lithium chloride; M = molar; MeMgBr = methylmagnesium bromide; MeNH ₂ = methylamine; MeOH = methanol; 2-Me-TFH = 2-methyltetrahydrofuran; mg = mg; MgSO ₄ = magnesium sulfate; min = minute; mL = milliliter; mm = millimeter; mmHg = millimeter of mercury; MS = mass spectrometer; Ms ₂ O = methanesulfonic anhydride; MTBE = 2-methoxy-2-methylpropane; m/z = mass-to-charge ratio; NaBH ₃ CN = sodium cyanoborohydride; NaBH ₄ = sodium borohydride; NaHSO ₄ = sodium hydrogen sulfate; NaNO ₂ = sodium nitrite; NaOAc = sodium acetate; Na ₂ SO ₄ = sodium sulfate; NH ₄ Cl = ammonium chloride; nm = nanometer; PE = petroleum ether; Pd/C = palladium on carbon; Pd ₂ (dba) ₃ = tris(dibenzylideneacetone)dipalladium; Pd(OAc) ₂ = =Palladium(II) acetate; (PPh ₃ ) ₂ PdCl ₂ ·DCM = bis(triphenylphosphine)palladium chloride in dichloromethane; ppm = parts per million; RP = reversed phase; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; SFC = supercritical fluid chromatography; SiO ₂ = silicon dioxide; SOCl ₂ = sulfenyl chloride; ^t BuOH = tert- butyl alcohol; TEA = trimethylamine; THF = tetrahydrofuran; Ti(O ⁱ Pr) ₄ = titanium isopropoxide; t _R = retention time; Xantphos = (9,9-dimethyl-9 H -xanthene-4,5-diyl)bis(diphenylphosphine); µL = Microliter, µm = micrometer.

The compounds of the general formula (I) of the present invention (wherein U = O or S and V = a covalent bond or C( ^RV ) ₂ ) can be prepared starting from intermediates of formula 1 as shown in Scheme 1. Intermediate 1 can be activated with coupling agents such as CDT (U = O) or 1,1'-thiocarbonyldiimidazole (U = S) in the presence of a base (e.g., TEA, DIPEA) in a solvent such as DMF, DCM or _CH3CN to produce activated intermediate 2 in situ . Addition of intermediate 3 to the reaction mixture will produce compounds of the general formula (I). In some cases, intermediate 2 can be isolated and then converted to the corresponding urea using the above-mentioned reaction conditions. Furthermore, the order of addition can be interchanged, and in some cases, the intermediate of Formula 3 can be activated first, and the amine of Formula 1 can be added to the reaction mixture a second time. Those skilled in the art will recognize that when the amines of Formula 1 are not commercially available, they can be prepared from the corresponding formic acid via Curtius rearrangement using standard reaction conditions.

plan 1

The building blocks of formula 1 are commercially available or can be prepared by methods known to those skilled in the art. The building blocks of formula 3 are commercially available or can be prepared by methods known to those skilled in the art (e.g., from the corresponding ketone or aldehyde and amine or by reductive amination using Ellman-type chemistry followed by a reduction or alkylation step).

Alternatively, amines of general formula 3 , wherein ^R1 = _CH2OH , X = C, ^R2a , ^R2b = hydrogen, _C1 - _C6 -alkyl and ^R3 = _C1 - _C6 -alkyl or C3- _{C10 -} cycloalkyl, are depicted in Scheme 2 as compounds 4 , and can be prepared starting from appropriately protected aryl bromides 5. Esters 6 can be prepared by carbonylation of bromides 5 in the presence of bases such as TEA and MeOH using a palladium catalyst in a carbon monoxide atmosphere. Hydroxylmethyl intermediates 7 can be prepared from esters 6 using standard reaction conditions such as _LiAlH4 in polar aprotic solvents such as THF. Deprotection of the amines using conditions known to those skilled in the art affords amines of general formula 4 .

plan 2

Alternatively, amines of general formula 3 (wherein L = covalent bond, A = 3- to 14-membered heterocyclic group, R ^1a = H, halogen, C ₁ -C ₆ -alkyl, X = C, R ^2a , R ^2b = hydrogen, C ₁ -C ₆ -alkyl and R ³ = C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl) are depicted in Scheme 3 as compounds 8 and can be prepared from appropriately protected commercially available bromides 5 . Buchwald-Hartwig cross coupling of bromide 5 with commercially available amine ₉ in the presence of a ligand such as Xantphos and a base such as but not limited to _Cs2CO3 in a polar aprotic solvent such as 1,4-dioxane using a Pd catalyst such as _Pd2 (dba) ₃ at elevated temperature followed by deprotection affords amines of general formula 8. Those skilled in the art will recognize that amine 8 may be prepared using alternative methods such as _SN Ar or Chan-Lam couplings.

plan 3

Alternatively, amines of general formula 3 (wherein L = covalent bond, A = 5- to 14-membered heteroaryl, C ₆ -C ₁₀ -aryl and C ₃ -C ₁₀ -cycloalkyl, R ^1a = H, halogen, C ₁ -C ₆ -alkyl, X = C, R ^2a , R ^2b = hydrogen, C ₁ -C ₆ -alkyl and R ³ = C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl) are depicted in Scheme 3 as compounds 10 and can be prepared from appropriately protected commercially available bromides 5 . Bromide 5 is subjected to Suzuki-Miyaura _cross coupling with commercially available potassium trifluoroborate 11 in the presence of a ligand such as RuPhos or a catalytic system such as CataCXium Pd _G4 and a base such as but not limited to _KH2PO4 or _Cs2CO3 at elevated temperature in toluene and water using a Pd catalyst such as Pd(OAc) ₂ , followed by deprotection to afford amines of general formula 10. One skilled in the art will recognize that potassium trifluoroborate 11 can be replaced by the corresponding boronic acid or boronic ester. One skilled in the art will also recognize that the electrophile and nucleophile can be interchanged depending on the substituents to yield the same compound 10 .

plan 4

Alternatively, amines of Formula 3 (wherein R ^2a = hydrogen, R ^2b = hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C 6 -alkoxy, halogen-C 1 -C ₆ -alkoxy, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, and R ^2c -OC ₁ -C _{6 -alkyl} ) are depicted in Scheme 5 as compounds 12 , which can be prepared from the corresponding commercially available ketones (wherein R ^2b = C ₁ -C ₆ -alkyl, halogen-C 1 -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C 1 -C ₆ -alkoxy, C ₁ -C 6 -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, and R 2c -OC ₁ -C _{6 -alkyl)} -alkyl-, C ₃ -C ₁₀ -cycloalkyl and R ^2c -OC ₁ -C ₆ -alkyl) or aldehyde (when R ^2b = hydrogen) 13. Treatment of 13 with an amine R ³ NH ₂ ( 14 ) in a polar protic solvent such as 2-propanol or EtOH followed by reduction of the in situ generated imine by a reducing agent such as NaBH ₄ or sodium triacetoxyborohydride affords amines of general formula 12. In some cases, Ti(O ⁱ Pr) ₄ may be added to aid imine formation. Those skilled in the art will recognize that ketones of general formula 13 can be prepared starting from the corresponding bromides using standard chemistry (such as, but not limited to, the Grignard reaction or the Weinreb ketone synthesis).

plan 5

Alternatively, amines of general formula 3 (wherein L = NH, A = 3- to 14-membered heterocyclic group, R ^1a = H, halogen, C ₁ -C ₆ -alkyl, X = C, R ^2a , R ^2b = hydrogen, C ₁ -C ₆ -alkyl and R ³ = C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl) are depicted in Scheme 6 as compounds 15 and can be prepared from appropriately protected commercially available bromides 5 . Buchwald-Hartwig cross coupling of suitably protected bromide 5 with commercially available amine 16 in the presence of a ligand such as Xantphos or 2,2'-bis( _{diphenylphosphino} )-1,1'-binaphthyl and a base such as but not limited to _Cs2CO3 in a solvent such as 1,4-dioxane or toluene at elevated temperature using a Pd catalyst such as _Pd2 (dba) ₃ or Pd(OAc) ₂ followed by deprotection affords amines of general formula 15. Those skilled in the art will recognize that amine 15 may be prepared using alternative methods such as _SNAr or Chan-Lam couplings.

plan 6

Alternatively, amines of Formula 3 (wherein R ^2a = hydrogen, R ^2b = hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C 6 -alkoxy, halogen-C 1 -C ₆ -alkoxy, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, and R ^2c -OC ₁ -C _{6 -alkyl} ) are depicted in Scheme 7 as compounds 12 , which can be prepared from the corresponding commercially available ketones (when R ^2b = C ₁ -C ₆ -alkyl, halogen-C 1 -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C 1 -C ₆ -alkoxy, C ₁ -C 6 -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, and R 2c -OC ₁ -C _{6 -alkyl)} -alkyl-, C ₃ -C ₁₀ -cycloalkyl and R ^2c -OC ₁ -C ₆ -alkyl) or aldehyde (when R ^2b = hydrogen) 13. Building block 13 is treated with a reducing agent such as NaBH ₄ or sodium triacetoxyborohydride to give alcohols of general formula 17. The alcohol is converted to a better leaving group using, for example but not limited to, MeSO ₂ Cl and then substituted with amine 14 in the presence of a base such as DIPEA or TEA to give amines of general formula 12. One skilled in the art will recognize that, when not commercially available, ketones of general formula 13 can be prepared starting from the corresponding bromides using standard chemistry (such as but not limited to the Grignard reaction or the Weinreb ketone synthesis).

plan 7

Amines of general formula 1 (wherein V = covalent bond, R ^4a = R ^4b = R ^5a = R ^5b = R ^6b = R ⁷ = hydrogen, R ^6a = 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl) are depicted in Scheme 8 as compounds 18 , which can be prepared starting from aldehyde 19. Treatment of aldehyde 19 with methyl 4-chlorobutyrate in THF followed by NaO ^t Bu affords the corresponding tetrahydrofuran 20. Tetrahydrofuran 20 can be converted to the corresponding amine 18 by Curtius rearrangement (e.g. using TEA, tert-butyl alcohol and diphenylphosphohydride at 80°C) followed by deprotection.

plan 8

Compounds of general formula (I) (wherein U = N-CN) are depicted in Scheme 9 as compounds 21 , which can be prepared starting from thiourea 22. Thiourea 22 can be prepared as described in Scheme 1. Methylation of 22 with MeI followed by methylation with _NH3 in MeOH affords thioether 23. Treatment of thioether 23 with cyanamide in THF in the presence of a base such as DIPEA affords compounds of general formula 21 .

plan 9

Alternatively, amines of general formula 3 , wherein L = CH ₂ and A = C ₃ -C ₁₀ -cycloalkyl, depicted in Scheme 10 as compounds 24 , can be prepared from appropriately protected commercially available bromides 5. Bromide 5 is subjected to Suzuki-Miyaura cross coupling with commercially available esters 25 in the presence of ligands such as RuPhos or catalytic systems such as CataCXium Pd G4 and a base such as, but not limited to, KH ₂ PO ₄ or Cs ₂ CO ₃ at elevated temperatures in toluene and water using a Pd catalyst such as Pd(OAc) ₂ to afford olefins 26 . Hydrogenation of olefins 26 using Pd/C in EtOAc under hydrogen atmosphere affords compounds of general formula 24. If not commercially available, esters 25 can be prepared as reported by Kovalenko et al. , EJOC 2019 , 33 , 5624-5635).

plan 10

Alternatively, amines of general formula 3 (wherein ^R2a = hydrogen) are depicted as compounds 3 in Scheme 11 and can be prepared starting from commercially available aldehydes 27. Aldehydes 27 can be treated with a Grignard reagent to give diols 17. Alcohols 17 can be treated with _SOCl2 to produce the corresponding chlorides 28. Chlorides 28 can be displaced by amines 14 in the presence of bases such as _K2CO3 , optionally in the presence of additives such as KI, in polar solvents such as but not limited to DMF to give amines of general formula 12. If not commercially available, aldehydes 27 can be prepared _from the corresponding heterocycles or halides using methods known to those skilled in the art. Similarly, the alcohol of formula 17 can be converted to other leaving groups such as bromides or mesylate using standard methods.

plan 11

Alternatively, amines of general formula 3 , wherein ^R2a = hydrogen and ^R2b = C6- _{C10 -} aryl- _C1 - _C6 -alkyl and C = a heteroaromatic ring optionally substituted with 1 to 2 halogen substituents, depicted in Scheme 12 as compound 29 , can be prepared starting from homobenzylic aldehydes of general formula 30. Treatment of aldehyde 30 in MeOH at 60 °C with 4-methylbenzenesulfonylhydrazine ( 31 ) yields compounds of general formula 32. Treatment of 32 with aldehyde 27 in the presence of a base such as _Cs2CO3 at elevated temperature in _a polar aprotic solvent such as 1,4-dioxane affords ketone 33 . Condensation of amine 14 with ketone 33 in THF, optionally in the presence of an acid such as acetic acid, followed by reduction of the in situ generated imine (using, for example but not limited to, NaBH ₃ CN) yields amines of general formula 29 .

plan 12

Alternatively, amines of general formula 3 , wherein ^R2a = H and ^R2b = halo- _C1 - _C6 -alkyl, depicted in Scheme 13 as compound 12 , can be prepared starting from esters of general formula 34. Ester 34 yields alkylated product 35 upon treatment with LDA and triflate 36 in THF at -40 °C. Treatment of ester 35 with hydrazine in EtOH at elevated temperature affords hydrazide 37. Hydrazide 37 affords carbamate 38 in a Curtius rearrangement upon treatment with an acid such as HCl followed by _NaNO2 , water and tBuOH. Carbamate 38 can be alkylated with an alkylating agent R ³ -X (X = halide) and a base such as but not limited to NaH in a polar aprotic solvent such as THF to give carbamate 39 . Deprotection of 39 gives amines of general formula 12 .

plan 13

Alternatively, amines of general formula 3 where R ³ = halo-C ₁ -C ₆ -alkyl can be prepared from benzylamine 40 (Scheme 14). Treatment of amine 40 with (2,5-dioxopyrrolidin-1-yl)carboxylate ( 41 ) in THF followed by addition of a base such as TEA affords formamide 42. Treatment of formamide 42 with Lawson's reagent followed by TEA and H ₂ O affords thioformamide 43. Treatment of thioformamide 43 with AgOCF ₃ affords amines of general formula 3 .

plan 14

Alternatively, amines of general formula 3 can be prepared starting from commercially available benzylamines 40 (Scheme 15). Amines 40 can be protected using standard conditions (such as, but not limited to, Boc) to produce protected amines 44. Alkylation of such amines 44 using a base (such as NaH or KHMDS) and a methylating agent ^R3 -X (X = halide) affords tertiary amines 45. Deprotection using standard conditions yields amines of general formula 3. If not commercially available, benzylamines 40 can be prepared using techniques known to those skilled in the art.

plan 15

Alternatively, amines of general formula 3 , wherein ^R2a = hydrogen and ^R2b = ^R2c - _OC1 - _C6 -alkyl, depicted in Scheme 16 as compound 46 , can be prepared starting from commercially available phenol 47. Phenol 47 is treated with acetyl bromide 48 and a base such as _K2CO3 in a polar aprotic solvent such as MeCN to produce _ether 49. Ether 49 can be converted to amines of general formula 46 via reductive amination using standard reaction conditions (e.g., NaOAc or TEA as base and _NaNH3CN as reducing agent).

plan 16

Alternatively, compounds of formula (I) (wherein U = O, V = covalent bond, A = 3- to 14-membered heterocyclic, 5- to 14-membered heteroaryl or C ₆ -C ₁₀ -aryl) depicted in Scheme 17 as compound 50 can be generated from compounds of formula 51. Bromides of formula 51 can be prepared as described in Scheme 1. Suzuki-Miyaura cross coupling between bromide 51 and commercially available ester 52 using a catalyst such as cataCXium Pd G4 and a base such as Cs ₂ CO ₃ in 1,4-dioxane/H ₂ O affords compounds of formula 50 . Those skilled in the art will recognize that alternative aryl halides may be used for the cross coupling, such as aryl chlorides or aryl iodides.

plan 17

Alternatively, compounds of formula (I) wherein ^R1 = _C2 - _C6 -alkynyl, depicted as compound 53 in Scheme 18, can be prepared from bromide 51. Bromide 51 can be coupled with alkyne 54 in a Sonogashira cross coupling using, for example, CuI, bis(triphenylphosphine)palladium(II) chloride, TEA in THF to give alkyne-containing compounds of formula 53 .

plan 18

Alternatively, compounds of general formula (I) wherein A = 3- to 14-membered heterocyclic, 5- to 14-membered heteroaryl or C ₆ -C ₁₀ -aryl, depicted in Scheme 19 as compound 50 , can be prepared from bromide 51. Bromide 51 can be coupled with commercially available stannae 55 in a Stille cross coupling at elevated temperature using, for example, LiCl, Pd(PPh ₃ ) ₄ in 1,4-dioxane to give compounds of general formula 51. If not commercially available, stannae 55 can be prepared using methods known to those skilled in the art.

plan 19

In one embodiment, the present invention provides a method for preparing a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as described herein, comprising: reacting a first amine 1 , wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b and R ⁷ are as defined herein, and a second amine 3 , wherein R ¹ , R ^2a , R ^2b , R ³ , X, Y and Z are as defined herein, The reaction is carried out in the presence of a base and a urea-forming reagent to form the compound of formula (Ia).

In one embodiment, the base is selected from TEA, DIPEA and sodium bicarbonate.

In a preferred embodiment, the base is selected from TEA and DIPEA.

In a particularly preferred embodiment, the base is selected from DIPEA.

In one embodiment, the urea-forming reagent is selected from bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, 1,1'-carbonyl-bis-imidazole and 1,1'-carbonyl-bis-(1,2,4-triazole).

In a preferred embodiment, the urea-forming reagent is 1,1'-carbonyl-bis-(1,2,4-triazole).

In one aspect, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when produced according to any of the methods described herein.

SARM1 inhibitory activity

The compounds of the present invention are SARM1 inhibitors. Therefore, in one aspect, the present invention provides the use of a compound of formula (I) as described herein for inhibiting the function of human SARM1 in a subject in need thereof.

In a further aspect, the invention provides a compound of formula (I) as described herein for use in a method of inhibiting the function of human SARM1 in a subject in need thereof.

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting the function of human SARM1 in a subject in need thereof.

In a further aspect, the present invention provides a method of inhibiting the function of human SARM1 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as described herein.

The SARM1 inhibitory potency of the compounds of formula (I) according to the present invention was measured using the following assay.

The enzyme reaction was run in a 10µL volume consisting of 8nM human SARM1 (aa28-724), 100µM nicotinamide (NMN) and 30µM nicotinamide adenine dinucleotide (NAD). The assay reagent was prepared in 25mM HEPES pH 7.2, 50mM NaCl, 1mM EDTA and 0.0025% Tween20. To determine compound _IC50 , the reaction was incubated for 60 minutes at room temperature in the presence of a 12-point concentration response curve of the compound (starting concentration 100µM; 1:3 dilutions between each point; 2% DMSO) and then quenched with 40µL of 0.125% formic acid. The peak areas of NAD and linear ADPR were measured by RapidFire High-Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API5000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA). The ratio of linear ADPR to NAD peak areas was then plotted against compound concentration to obtain the IC50 fitted by nonlinear regression.

The SARM1 inhibitory potency of the compounds of formula (I) according to the present invention measured in the above assay is presented in Table 1.

surface 1 Examples IC ₅₀ hSARM1 [µM] 1 2.335 2 2.341 3 2.210 4 3.904 5 2.998 6 0.892 7 1.425 8 3.617 9 0.343 10 4.235 11 0.442 12 0.529 13 1.135 14 7.295 15 1.394 16 1.289 17 0.544 18 0.520 19 0.708 20 6.260 twenty one 0.689 twenty two 1.783 twenty three 0.262 twenty four 2.805 25 1.126 26 1.873 27 0.328 28 0.822 29 2.366 30 0.373 31 5.008 32 2.355 33 1.074 34 0.762 35 0.539 36 4.704 37 1.070 38 3.612 39 7.541 40 4.386 41 3.489 42 1.895 43 7.485 44 0.671 45 2.753 46 4.902 47 2.351 48 1.024 49 0.385 50 4.498 51 7.784 52 1.861 53 5.912 54 5.631 55 2.767 56 7.088 57 0.619 58 0.977 59 7.217 60 2.536 61 4.127 62 5.611 63 2.363 64 2.565 65 0.730 66 5.939 67 1.084 68 1.232 69 2.722 70 3.155 71 1.215 72 1.260 73 9.991 74 1.540 75 3.199 76 1.145 77 0.263 78 9.115 79 5.297 80 0.991 81 4.612 82 3.292

Use of the compounds of the present invention

In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

In a further aspect, the present invention provides a method for treating or preventing a SARM1-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In a further aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in a method for treating or preventing a disease associated with SARM1 in a subject in need thereof.

In a further aspect, the present invention provides a method for treating or preventing a SARM1-related disorder in a subject in need thereof using a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the preparation of a medicament for use in a method of treating or preventing a SARM1-related disorder in a subject in need thereof.

In one embodiment, the SARM1-associated disorder is a disorder affecting the nervous system, including the central nervous system and the peripheral nervous system.

In one embodiment, the disorder affecting the nervous system is a neurodegenerative disease.

In one embodiment, the SARM1-associated disorder is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy-induced peripheral neuropathy, diabetes-induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury and Chamadryl disease.

In a preferred embodiment, the SARM1-related disease is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy-induced peripheral neuropathy, diabetes-induced peripheral neuropathy and multiple sclerosis.

In a particularly preferred embodiment, the SARM1-related disease is amyotrophic lateral sclerosis.

In a particularly preferred embodiment, the SARM1-related disease is spinal muscular atrophy.

In a particularly preferred embodiment, the SARM1-related disorder is chemotherapy-induced peripheral neuropathy.

In a particularly preferred embodiment, the SARM1-related disorder is diabetes-induced peripheral neuropathy.

In a particularly preferred embodiment, the SARM1-associated disease is multiple sclerosis.

Pharmaceutical compositions and administration

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

In one embodiment, a pharmaceutical composition according to Example 83 or 84 is provided.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

The compound of formula (I) and its pharmaceutically acceptable salt can be processed with pharmaceutically inert, inorganic or organic adjuvants to produce tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols.

Suitable adjuvants for producing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will of course be adapted to the individual requirements of each particular case. In general, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg/kg body weight, preferably about 0.5 mg to 4 mg/kg body weight (e.g. about 300 mg/individual), divided into preferably 1 to 3 individual doses (which may consist, for example, of the same amount) should be appropriate. However, it should be clear that the upper limits given herein may be exceeded when indicated.

Examples

The present invention will be more fully understood by referring to the following examples. However, the scope of the application should not be interpreted as being limited to the scope of the examples.

If the preparation is a mixture of mirror image isomers, the pure mirror image isomers can be separated by methods described herein or methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

The compounds of formula I may contain several asymmetric centers and may exist as optically pure mirror image isomers, mixtures of mirror image isomers (such as, for example, racemates), optically pure non-mirror image isomers or mixtures of non-mirror image isomers. According to the Cahn-Ingold-Prelog order rules, asymmetric carbon atoms may be in the "R" or "S" configuration. For the compounds described in the patents, the absolute stereochemistry is arbitrarily specified. The relative configuration of the tetrahydrofuran ring may be cis or trans and is arbitrarily specified.

If not stated otherwise, all reaction examples and intermediates were prepared under an argon atmosphere.

The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. When more than one name is associated with a compound of formula (I) or an intermediate, the chemical structure should define the compound. Example 1 1- Methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-[(3RS) -tetrahydrofuran -3- yl ] urea

To a solution of tetrahydrofuran-3-ylamine; hydrochloride (CAS RN: 204512-94-7; 45.37 mg, 367.13 µmol) in DMF (734.27 µL) was added DIPEA (192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was stirred at 70 °C for 20 hours and then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) and chiral SFC (column chiral OZ-H, 5 µm, 250x20 mm, 25% EtOH) gave the title compound as a mixture of non-mirror isomers (39.8 mg, 43%, t _R = 2.485 min) and a colorless oil. MS (ESI): m/z = 250.2 [M+H] ⁺ Example 2 1- Methyl -3-[(3RS, 4RS or 3RS,4SR)-4 -methyltetrahydrofuran -3- yl ]-1-[(1S)-1-(4- pyridyl ) ethyl ] urea

To a solution of (4-methyltetrahydrofuran-3-yl)amine (CAS RN: 1527863-66-63; 7.14 mg, 367.13 µmol) in DMF (734.27 µL) was added DIPEA (192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at room temperature for 30 min and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was stirred at 70 °C for 30 min and then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm, 40 mL/min, MeOH/H ₂ O+0.1% TEA) gave the title compound as a white oil (20.3 mg, 20%, t _R = 2.017 min). MS (ESI): m/z = 264.1 [M+H] ⁺ Example 3 1- Methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-[(3RS)-3-( trifluoromethyl ) tetrahydrofuran -3- yl ] urea

To a solution of [3-(trifluoromethyl)tetrahydrofuran-3-yl]amine; hydrochloride (CAS RN: 1638269-35-8, 68 mg, 354.94 µmol) in DCM (860 µL) was added DIPEA (220 µL, 1.29 mmol) and then CDT (75 mg, 456.97 µmol). The mixture was stirred at room temperature for 1 hour and then methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 48 mg, 50 µL, 352.45 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with DCM. The organic layer was washed with water and brine. The combined organic layers were dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) gave the title compound (67 mg, 57%) as a mixture of non-mirror isomers and an off-white solid. MS (ESI): m/z = 318.1 [M+H] ⁺ Example 4 3-[(3RS)-3-(1H- imidazol -2- yl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of [3-(1H-imidazol-2-yl)tetrahydrofuran-3-yl]amine; dihydrochloride (CAS RN 2031269-25-5, 99.61 mg, 440.56 µmol) in DMF (881.12 uL) was added DIPEA (230.83 µL, 1.32 mmol) followed by CDT (79.54 mg, 484.62 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 60 mg, 440.56 µmol). The resulting mixture was heated at 75°C for 20 hours, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over _Na2SO4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5μm, 100x30mm, _CH3CN / _H2O ) gave the title compound as a mixture _of non-mirror isomers (9.2 mg, 6%) and a colorless oil. MS (ESI): m/z = 316.1 [M+H] ⁺ Example 5 1- Methyl -3-[(3RS)-3-(1- methylpyrazol -4- yl ) tetrahydrofuran -3- yl ]-1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of [rac-(2S,3R)-2-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]amine; dihydrochloride (CAS RN 1807941-18-9, 88.16 mg, 367.13 µmol) in DMF (734.27 µL) was added DIPEA (192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 75 °C for 30 min and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was heated at 70°C for 30 minutes, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over _Na2SO4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100x30 mm, _CH3CN / _H2O +0.1% HCOOH) gave the title compound as a mixture _of non-mirror isomers (70.9 mg, 53%) and a white viscous oil. MS (ESI): m/z = 330.2 [M+H] ⁺ Example 6 3-[(2RS,3SR)-2-(5- bromo -3- pyridinyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ] urea

To a solution of [rac-(2S,3R)-2-(5-bromo-3-pyridinyl)tetrahydrofuran-3-yl]amine; dihydrochloride (CAS RN: 1955553-29-3; 116.02 mg, 367.13 µmol) in DMF (734.27 µL) was added DIPEA (142.35 mg, 192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 75 °C for 30 min and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was heated at 70°C for 30 min, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over _Na2SO4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm, 40 mL/min, _CH3CN / _H2O +0.1% HCOOH) gave the title compound _as a mixture of non-mirror isomers (80.2 mg, 53%) and an off-white viscous oil. MS (ESI): m/z = 405.1 [M+H] ⁺ Example 7 1- Methyl- 1-[(1S)-1-(4 -pyridyl ) ethyl ]-3-[(2RS,3SR)-2-[5-(3 -pyridyl )-3 -pyridyl ] tetrahydrofuran -3- yl ] urea

To a solution of [rac-(2S,3R)-2-[5-(3-pyridinyl)-3-pyridinyl]tetrahydrofuran-3-yl]amine; trihydrochloride (CAS RN: 2241139-77-3; 128.74 mg, 367.13 µmol) in DMF (734.27 µL) was added DIPEA (192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 75 °C for 30 min and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was heated at 70°C for 30 min, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over _Na2SO4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm, 40 mL/min, _CH3CN / _H2O +0.1% HCOOH) gave the title compound as _a mixture of non-mirror isomers (107 mg, 71%) as a white solid. MS: (ESI): m/z = 404.2 [M+H] ⁺ Example 8 3-[(2RS,3SR)-2-(5 -cyclopropyl -3 -pyridyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of [rac-(2S,3R)-2-(5-cyclopropyl-3-pyridinyl)tetrahydrofuran-3-yl]amine; dihydrochloride (CAS RN: 2241140-72-5; 59 mg, 212.85 µmol) in DMF (350 µL) was added DIPEA (0.140 µL, 817.84 µmol) followed by CDT (39 mg, 237.62 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 28.8 mg, 30 µL, 211.47 µmol). The mixture was heated at 70°C for 30 min and then poured into EtOAc and 5% LiCl-H ₂ O aqueous solution. The aqueous layer was back extracted with EtOAc. The organic layer was washed twice with 5% LiCl aqueous solution, once with water, and once with brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) gave the title compound (43 mg, 53%) as a mixture of non-mirror isomers and as an off-white solid. MS (ESI): m/z = 367.2 [M+H] ⁺ Example 9 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4- pyridyl ) ethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 58.58 mg, 367.13 µmol) in DMF (734.27 uL) was added DIPEA (192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 75°C for 30 minutes and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was heated at 75°C for 1 hour and then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100x30 mm, MeOH/H ₂ O+0.1% TEA) gave the title compound as a colorless oil (20.6 mg, 19%, t _R = 1.993 min). MS (ESI): m/z = 286.1 [M+H] ⁺ Example 10 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 58.58 mg, 367.13 µmol) and DIPEA (192.36 µL, 1.1 mmol) in DMF (734.27 uL) was added CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 75°C for 30 minutes and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was heated at 75°C for 1 hour and then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100x30 mm, MeOH/H ₂ O+0.1% TEA) gave the title compound as a colorless oil (23.2 mg, 21%, t _R = 2.048 min). MS (ESI): m/z = 286.1 [M+H] ⁺ Example 11 3-[(2S,3R)-2-(5- bromo -3 -pyridyl ) tetrahydrofuran -3 -yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or 3-[(2R,3S)-2-(5 -bromo -3 -pyridyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

Starting from 92 mg of Example 6: 3-[(2RS,3SR)-2-(5- bromo -3 -pyridinyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ] urea , chiral SFC (column chiral IA, 5 µm, 250x20 mm, 25% MeOH) gave the title compound (3.8 mg, 2%, _tR = 2.549 min) as a yellow viscous oil. MS (ESI): m/z = 405.1 [M+H] ⁺ Example 12 1- Methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ]-3-[(2R,3S)-2-[5-(3 -pyridyl )-3 -pyridyl ] tetrahydrofuran -3- yl ] urea or 1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ]-3-[(2S,3R)-2-[5-(3 -pyridyl )-3 -pyridyl ] tetrahydrofuran -3- yl ] urea

Starting from 52.6 mg of Example 7: 1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-[(2RS,3SR)-2-[5-(3 -pyridinyl )-3 -pyridinyl ] tetrahydrofuran -3 -yl ] urea , chiral SFC (column chiral Lux C4, 5 µm, 250x20 mm, 40% MeOH) gave the title compound (21.8 mg, 39%, _tR = 3.746 min) as a yellow viscous oil. MS (ESI): m/z = 404.2 [M+H] ⁺ Example 13 3-[(2R,3S)-2-(5 -cyclopropyl -3 -pyridyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or 3-[(2S,3R)-2-(5 -cyclopropyl -3 -pyridyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

Starting from 30 mg of Example 8 below: 3-[(2RS,3SR)-2-(5 -cyclopropyl- 3 -pyridinyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ] urea , chiral SFC (column chiral Lux C4, 5 µm, 250x20 mm, 30% MeOH) afforded the title compound (13.4 mg, 42%, t _R = 2.601 min) as a colorless oil. MS (ESI): m/z = 367.3 [M+H] ⁺ Example 14 1- Methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-(2,2,2- trifluoro -1- tetrahydrofuran -3- yl - ethyl ) urea

To a solution of (2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)amine (CAS RN: 1342056-79-4; 37.26 mg, 220.28 µmol) in DMF (300 µL) was added DIPEA (76.94 µL, 440.56 µmol) followed by CDT (52.22 mg, 286.36 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 30 mg, 31.25 µL, 220.28 µmol). The mixture was heated at 70 °C for 16 h, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried _{over Na2SO4} and evaporated. Purification by RP-HPLC gave the title compound as a non-mirror isomeric mixture (39 mg, 51% yield) and a colorless amorphous solid. MS (ESI): m/z = 332.2 [M+H] ⁺ Example 15 1-[(3- chloro -4 -pyridinyl ) methyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 20 mg, 125.34 µmol) in DMF (200 µL) was added DIPEA (109.46 µL, 626.72 µmol) followed by CDT (29.71 mg, 162.95 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with (3-chloro-4-pyridinyl)methyl-methyl-amine; dihydrochloride (CAS RN: 2270911-80-1; 31.65 mg, 137.88 µmol). The mixture was heated at 70 °C for 16 hours. Purification by RP-HPLC gave the title compound as a racemic mixture (24 mg, 60% yield) and an off-white solid. MS (ESI): m/z = 306.1 [M+H] ⁺ Example 16 3-(4,4 -difluorotetrahydrofuran -3 -yl )-1-[(3- fluoro -4 -pyridinyl ) methyl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 20 mg, 125.34 µmol) in DMF (200 µL) was added DIPEA (109.46 µL, 626.72 µmol) followed by CDT (29.71 mg, 162.95 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with (3-fluoro-4-pyridinyl)methyl-methyl-amine; dihydrochloride (CAS RN: 2460754-71-4; 26.71 mg, 125.34 µmol). The mixture was heated at 80 °C for 16 hours and then cooled. Purification by RP-HPLC gave the title compound as a racemic mixture (24 mg, 63% yield) and a white solid. MS (ESI): m/z = 290.2 [M+H] ⁺ Example 17 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-(4 -pyridylmethyl ) urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 17 mg, 106.54 µmol) in DMF (170 µL) was added DIPEA (55.82 µL, 319.63 µmol) followed by CDT (25.26 mg, 138.51 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl(4-pyridylmethyl)amine (CAS RN: 6971-44-4; 13.02 mg, 106.54 µmol). The mixture was heated at 80 °C for 16 hours. Purification by RP-HPLC gave the title compound as a racemic mixture (10 mg, 33% yield) and as a colorless amorphous solid. MS (ESI): m/z = 272.2 [M+H] ⁺ Example 18 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) propyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1R)-1-(4 -pyridyl ) propyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran - 3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) propyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1R)-1-(4 -pyridyl ) propyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 86 mg, 538.98 µmol) in DCM (1.2 mL) was added DIPEA (0.320 mL, 1.87 mmol) followed by CDT (113 mg, 688.5 µmol). The reaction mixture was stirred at 23 °C for 1 hour and then treated dropwise with a solution of methyl(4-pyridylmethyl)amine (CAS RN: 6971-44-4; 80 mg, 532.55 µmol) in DCM (0.200 mL). The mixture was stirred at 23 °C for 3 hours and then poured into DCM and washed with water and brine. The aqueous layer was back extracted twice with DCM. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ , heptane/EtOAc) gave two non-mirror isomers A (70 mg) and B (57 mg).

Starting from 70 mg of non-mirror isomer A, chiral SFC (column chiral Wrr C4, 5 µm, 250x20 mm, 15% MeOH) afforded the title compound as an off-white solid (30 mg, 18%, t _R = 4.280 min). MS (ESI): m/z = 300.3 [M+H] ⁺ Example 19 3-(4,4 -difluorotetrahydrofuran -3 -yl )-1- methyl -1-[(3- methyl -4 -pyridyl ) methyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 90 mg, 564.05 µmol) in DMF (800 µL) was added DIPEA (246.28 µL, 1.41 mmol) followed by CDT (133.72 mg, 733.27 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl-[(3-methyl-4-pyridinyl)methyl]amine (CAS RN: 915919-59-4; 76.82 mg, 564.05 µmol). The mixture was heated at 70 °C for 1 hour. Purification by RP-HPLC gave the title compound as a racemic mixture (117 mg, 69% yield) and as a colorless amorphous solid. MS (ESI): m/z = 286.2 [M+H] ⁺ Example 20 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyridinium - 4 -ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyridinium -4- ylethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3 - yl ]-1- methyl -1-[(1R)-1 -pyridinium -4- ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1R)-1- pyridinium -4 - ylethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 75.94 mg, 475.96 µmol) in DMF (952 µL) was added DIPEA (498.76 µL, 2.86 mmol) followed by CDT (85.93 mg, 523.56 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl(1-tetrahydrofuran-4-ylethyl)amine; dihydrochloride (CAS RN: 2913244-09-2; 100 mg, 475.96 µmol). The mixture was heated at 70 °C for 2 h, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture (92 mg, 68% yield) as a white solid. MS (ESI): m/z 287.1 [M+H] ⁺

Starting from 92 mg of the non-mirror isomeric mixture, chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 25% EtOH) afforded the title compound as a white solid (12.8 mg, 9% yield, t _R = 2,572 min). MS (ESI): m/z = 287.1 [M+H] ⁺ Example 21 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyridinium - 4 -ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyridinium -4- ylethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3 - yl ]-1- methyl -1-[(1R)-1 -pyridinium -4- ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1R)-1- pyridinium -4 - ylethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 75.94 mg, 475.96 µmol) in DMF (952 µL) was added DIPEA (498.76 µL, 2.86 mmol) followed by CDT (85.93 mg, 523.56 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl(1-tetrahydrofuran-4-ylethyl)amine; dihydrochloride (CAS RN: 2913244-09-2; 100 mg, 475.96 µmol). The mixture was heated at 70 °C for 2 h, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture (92 mg, 68% yield) as a white solid. MS (ESI): m/z = 287.1 [M+H] ⁺

Starting from 92 mg of the non-mirror isomeric mixture, chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 25% EtOH) afforded the title compound as a colorless oil (13 mg, 9%, t _R = 3.038 min). MS (ESI): m/z = 287.1 [M+H] ⁺ Example 22 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyridinium - 4 -ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyridinium -4- ylethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3 - yl ]-1- methyl -1-[(1R)-1 -pyridinium -4- ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1R)-1- pyridinium -4 - ylethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 75.94 mg, 475.96 µmol) in DMF (952 µL) was added DIPEA (498.76 µL, 2.86 mmol) followed by CDT (85.93 mg, 523.56 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl(1-tetrahydrofuran-4-ylethyl)amine; dihydrochloride (CAS RN: 2913244-09-2; 100 mg, 475.96 µmol). The mixture was heated at 70 °C for 2 h, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture (92 mg, 68% yield) as a white solid. MS (ESI): m/z = 287.1 [M+H] ⁺

Starting from 92 mg of the non-mirror isomeric mixture, chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 25% EtOH) afforded the title compound as a light yellow oil (14 mg, 10% yield, t _R = 3.373 min). MS (ESI): m/z = 287.1 [M+H] ⁺ Example 23 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-(4 -pyridylmethyl ) urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-(4 -pyridylmethyl ) urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 70 mg, 438.71 µmol) in DMF (700 µL) was added DIPEA (229.86 µL, 1.32 mmol) followed by CDT (104 mg, 570.32 µmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl(4-pyridylmethyl)amine (CAS RN: 6971-44-4; 53.6 mg, 438.71 µmol). The mixture was heated at 80 °C for 1 hour. Purification by HPLC (Gemini NX, 12 nm, 5 µm, 100x30 mm, ACN/H ₂ O+0.1% TEA) gave the title compound as a racemic mixture (72 mg, 57% yield) as a white solid. MS (ESI): m/z = 272.2 [M+H] ⁺

Starting from 72 mg of the racemic mixture, chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 23% EtOH) afforded the light yellow title compound (32 mg, 44% yield, t _R = 2.265 min). MS (ESI): m/z = 272.2 [M+H] ⁺ Example 24 3-(4- Benzyltetrahydrofuran- 3 -yl )-1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ] urea

To a solution of (4-aminotetrahydrofuran-3-yl)-phenyl-methanone; hydrochloride (EN300-1693205; 83.59 mg, 367.13 µmol) in DMF (734.27 µL) was added DIPEA (192.36 µL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 µmol). The mixture was stirred at 75 °C for 30 min and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was heated at 75 °C for 3 h and then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over _Na2SO4 and evaporated. Purification by RP-HPLC gave the title compound as _a non-mirror isomeric mixture (33 mg, 24% yield) as a colorless oil. MS (ESI): m/z = 354.3 [M+H] ⁺ Example 25 1- Methyl -1-[(1S)-1-(4- pyridinyl ) ethyl ]-3-[(3R)-3-( trifluoromethyl ) tetrahydrofuran -3- yl ] urea or 1- Methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-[(3S)-3-( trifluoromethyl ) tetrahydrofuran -3 -yl ] urea

Starting from 30.49 mg of Example 3: 1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-[(3RS)-3-( trifluoromethyl ) tetrahydrofuran -3- yl ] urea , chiral SFC (column chiral IC, 5 µm, 250x20 mm, 15% MeOH) gave the title compound (6.7 mg, 21% yield, t _R = 3.717 min) as a colorless oil. MS (ESI): m/z = 318.1 [M+H] ⁺ Example 26 1- Methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ]-3-[(3R)-3-( trifluoromethyl ) tetrahydrofuran - 3- yl ] urea or 1- Methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ]-3-[(3S)-3-( trifluoromethyl ) tetrahydrofuran -3- yl ] urea

Starting from 30.49 mg of Example 3: 1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ]-3-[(3RS)-3-( trifluoromethyl ) tetrahydrofuran -3- yl ] urea , chiral SFC (column chiral IC, 5 µm, 250x20 mm, 15% MeOH) gave the title compound (5.1 mg, 16% yield, t _R = 4.155 min) as a colorless oil. MS (ESI): m/z = 318.1 [M+H] ⁺ Example 27 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(3- methyl -4 -pyridinyl ) methyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 - yl ]-1- methyl -1-[(3- methyl -4 -pyridinyl ) methyl ] urea

Starting from 117 mg of Example 19 below: 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-[(3- methyl -4 -pyridinyl ) methyl ] urea , chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 25% MeOH) afforded the title compound (54 mg, 46% yield, t _R = 2.493 min) as a colorless amorphous solid. MS (ESI): m/z = 286.1 [M+H] ⁺ Example 28 1-[(3- bromo -4 -pyridinyl ) methyl ]-3-(4,4 -difluorotetrahydrofuran -3 -yl )-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 500 mg, 3.13 mmol) in DMF (6.93 mL) was added DIPEA (2.53 mL, 14.51 mmol) followed by CDT (436.48 mg, 2.66 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with methyl-[1-(3-bromo-4-pyridinyl)ethyl-]amine (CAS RN: 463941-58-4; 453.63 mg, 2.26 mmol). The mixture was heated at 70 °C for 16 hours and then poured into 2-Me-THF and washed with water and brine. The organic layer was dried _{over Na2SO4} and evaporated. Purification by FC ( _SiO2 , heptane/EtOAc/EtOH) gave the title compound as a racemic mixture (358.7 mg, 31% yield) as a light yellow gum. MS (ESI): m/z = 350.1 [M+H] ⁺ Example 29 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1- pyrimidin -4- ylethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1R)-1- pyrimidin -4- ylethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea or 3-[(3R)-4,4-difluorotetrahydrofuran - 3 - yl ] -1 - methyl - 1 - [ ( 1R ) -1 - pyrimidin -4 - ylethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 93.87 mg, 588.29 µmol) in DCM (5 mL) was added DIPEA (410.97 µL, 2.35 mmol) and CDT (115.86 mg, 705.94 µmol). The mixture was stirred at 23 °C for 1 hour and then treated with methyl-[1-(4-pyrimidinyl)ethyl]amine; hydrochloride (102.15 mg, 588.29 µmol). The mixture was stirred at 23 °C for 15 hours. The solvent was removed in vacuo . Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture.

Starting from the non-mirror isomeric mixture, chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 15% EtOH) afforded the title compound as a colorless oil (33 mg, 19% yield, t _R = 3.983 min). MS (ESI): m/z = 287.3 [M+H] ⁺

Steps a) : N- methyl -1- Pyrimidine -4- base - Ethylamine

To a solution of 1-pyrimidin-4-ylethanone (CAS RN: 39870-05-8; 500.0 mg, 4.09 mmol) in DCE (2 mL) was added DIPEA (2.18 mL, 12.28 mmol) and _MeNH2 ·HCl (822.89 mg, 12.28 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with sodium cyanoborohydride (771.8 mg, 12.28 mmol). The reaction was stirred at 50 °C for 12 hours and then filtered. The filtrate was washed with DCM and concentrated to give the title compound as a dark green oil (1856.0 mg, 83% yield). MS (ESI): m/z = 138.1 [M+H] ⁺

Steps b) : N- methyl -N-(1- Pyrimidine -4- Ethyl ) Tributyl carbamate

To a solution of N-methyl-1-pyrimidin-4-yl-ethylamine (8150.0 mg, 11.88 mmol) in MeOH (40 mL) was added Boc ₂ O (3889.6 mg, 17.82 mmol) and DIPEA (4.14 mL, 23.76 mmol). The mixture was stirred at 25° C. for 1 h. Purification by FC (SiO ₂ , PE/EtOAc) gave the title compound as a light yellow oil (2324.0 mg, 82% yield). MS (ESI): m/z = 182.1 [MC ₄ H ₈ +H] ⁺

Steps c) : N- methyl -1- Pyrimidine -4- base - Ethylamine; Hydrochloride

A solution of tributyl N-methyl-N-(1-pyrimidin-4-ylethyl)carbamate (2815.0 mg, 11.86 mmol) in dioxane/HCl (30.0 mL, 60.0 mmol) was stirred at 25°C for 2 hours. The precipitate was collected by filtration, washed with PE and dried under high vacuum to give the title compound as a light brown solid (1.77 g, 80% yield). MS (ESI): m/z = 138.2 [M+H] ⁺ Example 30 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-1-(3- fluoro -4 -pyridinyl ) ethyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 - yl ]-1-[(1S)-1-(3- fluoro -4 -pyridinyl ) ethyl ]-1- methyl - urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1R)-1-(3- fluoro -4 -pyridinyl ) ethyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3- fluoro -4 -pyridinyl ) ethyl ]-1- methyl - urea

Starting from 127 mg of the non-mirror isomeric mixture (step d, 3-(4,4 -difluorotetrahydrofuran -3- yl ) -1-[1-(3- fluoro -4 -pyridinyl ) ethyl ]-1 - methylurea ), chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 11% EtOH) afforded the title compound as a colorless oil (31 mg, 21% yield, t _R = 2.071 min). MS (ESI): m/z = 304.3 [M+H] ⁺

Steps a) : 1-(3- fluorine -4- Pyridyl )-N- methyl - Ethylamine

To a solution of 1-(3-fluoro-4-pyridinyl)ethanone (2.0 g, 14.38 mmol) and _MeNH2 ·HCl (2.9 g, 43.13 mmol) in DCE (20 mL) was added DIPEA (7.64 mL, 43.13 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with sodium cyanoborohydride (2.7 g, 43.13 mmol). The mixture was stirred at 70 °C for 12 hours and then concentrated under reduced pressure to give the title compound as a yellow oil (2.0 g, 90% yield), which was used in the next step without any further purification. MS (ESI): m/z = 155.2 [M+H] ⁺

Steps b) : N-[1-(3- fluorine -4- Pyridyl ) Ethyl ]-N- methyl - Tributyl carbamate

To a solution of 1-(3-fluoro-4-pyridinyl)-N-methyl-ethylamine (2 g, 12.97 mmol) in MeOH (20 mL) and TEA (1.3 g, 12.97 mmol) was added Boc ₂ O (5662.62 mg, 25.94 mmol). The mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. Purification by FC (SiO ₂ , PE/EtOAc) gave the title compound as a yellow oil (1.2 g, 36% yield). MS (ESI): m/z = 255.1 [M+H] ⁺

Step c) : 1-(3- fluoro -4 -pyridyl )-N- methyl - ethylamine; dihydrochloride

To a solution of N-[1-(3-fluoro-4-pyridinyl)ethyl]-N-methyl-carbamic acid tributyl ester (1.2 g, 4.72 mmol) in 1,4-dioxane (2 mL) was added a solution of HCl in 1,4-dioxane (20.0 mL, 40.0 mmol). The mixture was stirred at 25°C for 1 hour, then filtered and the filter cake was dried under reduced pressure to give the title compound as a yellow solid (710.31 mg, 66% yield). MS (ESI): m/z = 155.2 [M+H] ⁺

Steps d) : 3-(4,4- Difluorotetrahydrofuran -3- base )-1-[1-(3- fluorine -4- Pyridyl ) Ethyl ]-1- methyl - Urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 89 mg, 557.78 µmol) in DCM (1.4 mL) was added DIPEA (380 µL, 2.22 mmol) followed by CDT (117 mg, 712.87 µmol). The mixture was stirred at 23°C for 1 hour. 1-(3-Fluoro-4-pyridinyl)-methyl-ethylamine; dihydrochloride (105 mg, 462.33 mmol) was then added and the reaction mixture was stirred at 23°C for 16 hours. The reaction mixture was extracted with DCM. The organic layer was washed with water and brine. The aqueous layer was back extracted twice with DCM. The combined org. layers were dried _{over Na2SO4} and evaporated. Purification by FC ( _SiO2 ; heptane/EtOAc) gave the title compound (127 mg, 90% yield) as a non-mirror isomeric mixture. Example 31 3-[(3S)-4,4 -difluorotetrahydrofuran - 3-yl ]-1-[(1S)-1-(3- fluoro -4 -pyridyl ) ethyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran - 3- yl ]-1-[(1S)-1-(3- fluoro -4 -pyridyl ) ethyl ]-1- methyl - urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3 - yl ]-1-[(1R)-1-(3- fluoro -4 -pyridyl ) ethyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran - 3 -yl ]-1-[(1R)-1-(3- fluoro -4 -pyridyl ) ethyl ]-1 - methyl - urea

Starting from 127 mg of the non-mirror isomeric mixture ( 3-(4,4 -difluorotetrahydrofuran -3- yl )-1-[1-(3- fluoro -4 -pyridinyl ) ethyl ]-1- methyl - urea ) of Example 30 , step d , chiral SFC (column chiral Whelk (r,r), 5 µm, 250x20 mm, 11% EtOH) afforded the title compound as a colorless oil (29 mg, 19%, t _R = 2.250 min). MS (ESI): m/z = 304.3 [M+H] ⁺ Example 32 3-(4,4 -difluorotetrahydrofuran -3- yl )-1-[[3-( hydroxymethyl )-4 -pyridinyl ] methyl ]-1- methyl - urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 90.0 mg, 0.56 mmol) and DIPEA (0.59 mL, 3.38 mmol) in DMF (1 mL) was added CDT (120.34 mg, 0.73 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with [4-(methylaminomethyl)-3-pyridinyl]methanol; dihydrochloride (126.97 mg, 0.56 mmol). The mixture was stirred at 80 °C for 2 hours and at 23 °C for 18 hours. Purification by RP-HPLC gave the title compound as a colorless oil (10.1 mg, 6% yield). MS (ESI): m/z = 302.2 [M+H] ⁺

Steps a) : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

A solution of Boc ₂ O (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3-bromo-4-pyridinyl)-N-methyl-methylamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25°C. The mixture was stirred at 23°C for 18 hours and then evaporated to give the title compound as a light yellow oil (9.0 g, 96% yield). MS (ESI): m/z = 301.0/303.0 [M+H] ⁺

Steps b) : 4-[[ Tertiary Butoxycarbonyl ( methyl ) Amine ] methyl ] Pyridine -3- Methyl formate

A mixture of tributyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (4.0 g, 13.28 mmol), triethylamine (2.22 mL, 15.94 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex (325.12 mg, 0.4 mmol) and MeOH (800 mL) was stirred at 130°C for 28 hours under carbon monoxide atmosphere (15000 mmHg), then cooled and evaporated. The residue was diluted with EtOAc (100 mL) and washed with water (2x 50 mL). The organic layer was dried over _Na2SO4 , _filtered and evaporated to give the title compound (2.4 g, 59% yield). MS (ESI): m/z = 281.0 [M+H] ⁺

Steps c) : N-[[3-( Hydroxymethyl )-4- Pyridyl ] methyl ]-N- methyl - Tributyl carbamate

A solution of methyl 4-[[tri-butyloxycarbonyl(methyl)amino]methyl]pyridine-3-carboxylate (500.0 mg, 1.78 mmol) in THF (5 mL) was added dropwise to a suspension of LiAlH ₄ (54.15 mg, 1.43 mmol) in THF (5 mL) at 0°C. The mixture was stirred at 0°C for 2 hours and then allowed to warm to 23°C. Water (0.06 mL), 15% aqueous sodium hydroxide solution (0.06 mL), and then water (0.2 mL) were added to the reaction mixture at 0°C, which was stirred at 23°C for 1 hour. The precipitate was then filtered off. The filtrate was evaporated to give the title compound (470.0 mg, 99% yield). MS (ESI): m/z = 253.2 [M+H] ⁺

Steps d) : [4-( Methylaminomethyl )-3- Pyridyl ] Methanol; dihydrochloride

To a solution of tributyl N-[[3-(Hydroxymethyl)-4-pyridinyl]methyl]-N-methyl-carbamate (250.0 mg, 0.79 mmol) in DCM (4.44 mL) was added a solution of 4 M HCl in 1,4-dioxane (2.38 mL, 9.51 mmol). The mixture was stirred at 23 °C for 18 h and then evaporated to give the title compound as a light yellow oil (130.0 mg, 73% yield). MS (ESI): m/z = 153.2 [M+H] ⁺ Example 33 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(3- methyl -4 - pyridyl ) ethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1R)-1-(3- methyl -4 -pyridyl ) ethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1S)-1-(3- methyl - 4-pyridyl ) ethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1R)-1-(3- methyl -4 -pyridyl ) ethyl ] urea or or or

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 46.91 mg, 293.97 µmol) in DMF (587.94 µL) was added DIPEA (308.05 µL, 1.76 mmol) followed by CDT (53.07 mg, 323.37 µmol). The mixture was stirred at 50 °C for 1 h and then treated with methyl-[1-(3-methyl-4-pyridinyl)ethyl]amine (CAS RN: 1550152-27-6; 55.2 mg, 293.97 µmol). The mixture was stirred at 70 °C for 15 h, then poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) and chiral SFC (column chiral IF, 5 µm, 250 x 20 mm, 15% MeOH) gave the title compound as a colorless oil (7.7 mg, 9% yield, t _R = 1.27 min). MS (ESI): m/z = 300.3 [M+H] ⁺ Example 34 1-[(3 -cyclopropyl -4 -pyridinyl ) methyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 68.75 mg, 0.43 mmol) and DIPEA (0.45 mL, 2.59 mmol) in DMF (0.625 mL) at 23° C. was added 1-(3-cyclopropyl-4-pyridinyl)-N-methyl-methylamine; dihydrochloride (101.32 mg, 0.43 mmol). The mixture was stirred at 50° C. for 1 hour and then treated with 1-(3-cyclopropyl-4-pyridinyl)-N-methyl-methylamine; dihydrochloride (101.32 mg, 0.43 mmol). The mixture was stirred at 80°C for 2 hours and then cooled. Purification by RP-HPLC gave the title compound as a yellow liquid (77.4 mg, 58% yield). MS (ESI): m/z = 312.2 [M+H] ⁺

Steps a) : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

A solution of Boc ₂ O (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3-bromo-4-pyridinyl)-N-methyl-methylamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25°C. The mixture was stirred at 23°C for 18 hours and then evaporated to give the title compound as a light yellow oil (9.0 g, 96% yield). MS (ESI): m/z = 301.0/303.0 [M+H] ⁺

Steps b) : N-[(3- Cyclopropyl -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

A solution of tributyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (300.0 mg, 1.0 mmol), potassium cyclopropyltrifluoroborate (515.9 mg, 3.49 mmol), tripotassium phosphate (634.32 mg, 2.99 mmol) and RuPhos (46.48 mg, 0.1 mmol) in toluene (4.8 mL) and water (1.2 mL) was degassed. Palladium (II) acetate (11.18 mg, 0.05 mmol) was added and the mixture was stirred at 100 °C in a sealed tube for 18 h and then cooled. The mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous KH ₂ PO ₄ solution (50 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RP-HPLC gave the title compound (174.1 mg, 67% yield) as a light yellow oil. MS (ES): m/z = 263.2 [M+H] ⁺

Steps c) : 1-(3- Cyclopropyl -4- Pyridyl )-N- methyl - Methylamine; dihydrochloride

To a solution of tributyl N-[(3-cyclopropyl-4-pyridinyl)methyl]-N-methyl-carbamate (110.0 mg, 0.42 mmol) in DCM (2.44 mL) was added a solution of 4 M HCl in 1,4-dioxane (1.26 mL, 5.03 mmol). The mixture was stirred at 23 °C for 18 h and then evaporated to give the title compound as a white solid (98.0 mg, 99% yield). MS (ESI): m/z = 163.0 [M+H] ⁺ Example 35 1-[(3 -Bromo - 4 -pyridinyl ) methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1 - methyl - urea or 1-[(3- Bromo -4 -pyridinyl ) methyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran - 3 - yl ]-1- methyl - urea or

Starting from 162 mg of Example 28: 1-[(3- bromo -4 -pyridinyl ) methyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea , chiral SFC (column chiral IF, 5 µm, 250x20 mm, 25% MeOH) afforded the title compound as a colorless oil (63 mg, 39% yield, t _R = 1.553 min). MS (ESI): m/z = 350. [M+H] ⁺ Example 36 1-[[3-( tetrahydroazolidin- 1- yl )-4 -pyridinyl ] methyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 46.0 mg, 0.29 mmol) and DIPEA (0.3 mL, 1.73 mmol) in DMF (0.50 mL) was added CDT (61.51 mg, 0.37 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with 1-[3-(tetrahydroazolidin-1-yl)-4-pyridinyl]-N-methyl-methylamine; 2,2,2-trifluoroacetic acid (149.72 mg, 0.29 mmol). The mixture was stirred at 80 °C for 2 hours and then cooled. Purification by RP-HPLC gave the title compound (15.6 mg, 17% yield) as a yellow oil. MS (ESI): m/z = 327.2 [M+H] ⁺

Steps a) : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

A solution of Boc ₂ O (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3-bromo-4-pyridinyl)-N-methyl-methylamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25°C. The mixture was stirred at 23°C for 18 hours and then evaporated to give the title compound as a light yellow oil (9.0 g, 96% yield). MS (ESI): m/z = 301.0/303.0 [M+H] ⁺

Steps b) : N-[[3-( Four Hydrogen -1- base )-4- Pyridyl ] methyl ]-N- methyl - Tributyl carbamate

A solution of tributyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (300.0 mg, 1.0 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)dibenzopyran (57.64 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (45.61 mg, 0.05 mmol), tetrahydroacalkonium chloride (279.55 mg, 2.99 mmol) and cesium carbonate (1947.26 mg, 5.98 mmol) in 1,4-dioxane (15 mL) was bubbled with Ar and then stirred at 100°C for 18 hours. The mixture was cooled and filtered. The filtrate was evaporated. Purification by RP-HPLC gave the title compound (72.2 mg, 26% yield) as a light yellow oil. MS (ESI): m/z = 278.2 [M+H] ⁺

Steps c) : 1-[3-( Four Hydrogen -1- base )-4- Pyridyl ]-N- methyl - Methylamine; 2,2,2- Trifluoroacetic acid

To a solution of tributyl N-[[3-(tetrahydroazir-1-yl)-4-pyridinyl]methyl]-N-methyl-carbamate (85.0 mg, 0.31 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.12 mL, 1.53 mmol). The mixture was stirred at 23 °C for 18 h and then evaporated to give the title compound as a light yellow oil (150.0 mg, 90% yield). MS (ESI): m/z = 178.0 [M+H] ⁺ Example 37 3-(4,4 -Difluorotetrahydrofuran -3- yl )-1- methyl -1-[2- phenoxy -1-(4 -pyridinyl ) ethyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (34.96 mg, 219.07 µmol) in dichloromethane (1100 µL) was added DIPEA (250 µL, 1.46 mmol) followed by CDT (46.61 mg, 283.97 µmol). The mixture was stirred at 23 °C for 1 h and then treated with methyl-[2-phenoxy-1-(4-pyridinyl)ethyl]amine (50 mg, 219.02 µmol). The mixture was stirred at 23 °C for 16 h and then evaporated. Purification by RP-HPLC gave the title compound as a white powder (14.7 mg, 18% yield). MS (ESI): m/z = 378.3 [M+H] ⁺

Step a ): N- methyl -2- phenoxy -1-(4 -pyridyl ) ethylamine

Titanium isopropoxide (2.1 mL, 7.09 mmol) was added to a solution of 2-phenoxy-1-(4-pyridyl)ethanone (CAS RN: 1574141-85-7; 1440.0 mg, 6.75 mmol) in 2-propanol (9.65 mL) at 0°C over 2-5 minutes. Methylamineethanol (2.52 mL, 20.26 mmol) was then added and the mixture was allowed to warm to 23°C and stirred at that temperature for another 18 hours before cooling to 0°C. Sodium borohydride (383.2 mg, 10.13 mmol) was added portionwise and the mixture was stirred at 0°C for 1 hour before being diluted with EtOAc (2 mL) and brine (2 mL). The mixture was stirred at 23 °C for 10 min and then filtered through celite. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH 9:1) gave the title compound as a yellow oil (550 mg, 36% yield). MS (ESI): m/z = 229.2 [M+H] ⁺ Example 38 3-(4,4 -difluorotetrahydrofuran -3- yl )-1-[2- methoxy -1-(4 -pyridinyl ) ethyl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 42.71 mg, 267.69 µmol) in dichloromethane (1 mL) was added DIPEA (305.48 µL, 1.78 mmol) followed by CDT (56.95 mg, 346.99 µmol). The mixture was stirred at 23 °C for 1 h and then treated with 2-methoxy-1-(4-pyridinyl)ethanol (75 mg, 267.63 µmol). The mixture was stirred at 23 °C for another 16 h and then evaporated. Purification by RP-HPLC gave the title compound as a light yellow solid (15 mg, 17% yield). MS (ESI): m/z = 316.2 [M+H] ⁺

Steps a) : 2- Methoxy -1-(4- Pyridyl ) Ethyl Ketone

To a solution of 4-bromopyridine (CAS RN: 1120-87-2; 6.5 g, 41.14 mmol) in THF (70 mL) was added dropwise a solution of i-PrMgCl·LiCl in THF (79.11 mL, 102.85 mmol) at -20°C under _N2 atmosphere. The mixture was stirred at this temperature for 1 hour and then treated with a solution of N,2-dimethoxy-N-methyl-acetamide (CAS RN: 132289-57-7; 13.7 g, 102.85 mmol) in THF (15 mL). The mixture was stirred at 0°C for 1 hour and then quenched with 30 mL of saturated aqueous _NH4Cl solution and poured into water. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FC (SiO ₂ ; PE/EtOAc 1:1) gave the title compound as a colorless oil (5.0 g, 80% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.85 - 8.76 (m, 2H), 7.77 - 7.66 (m, 2H), 4.67 (s, 2H), 3.50 ppm (s, 3H).

Steps b) : 2- Methoxy -1-(4- Pyridyl ) Ethanol

To a solution of 2-methoxy-1-(4-pyridyl)ethanone (3.0 g, 19.85 mmol) in MeOH (30 mL) was added NaBH ₄ (1.5 g, 39.69 mmol) at 0°C. The mixture was stirred at 23°C for 2 h and then evaporated. Purification by FC (SiO ₂ ; PE/EtOAc) gave the title compound (1.5 g, 49% yield) as a yellow oil. MS (ESI): m/z = 154.4 [M+H] ⁺

Steps c) : [2- Methoxy -1-(4- Pyridyl ) Ethyl ] Mesylate

To a solution of 2-methoxy-1-(4-pyridinyl)ethanol (1.5 g, 9.79 mmol) in DCM (15 mL) and TEA (6.79 mL, 48.96 mmol) at 0°C was added Ms ₂ O (5.1 g, 29.38 mmol). The mixture was stirred at 25°C for 12 h and then evaporated. Purification by FC (SiO ₂ ; PE/EtOAc) gave the title compound (1.0 g, 44% yield) as a yellow oil. MS (ESI): m/z = 232.1 [M+H] ⁺

Steps d) : 2- Methoxy -N- methyl -1-(4- Pyridyl ) Ethylamine

A solution of [2-methoxy-1-(4-pyridinyl)ethyl]methanesulfonate (1.0 g, 4.32 mmol) in 2 M MeNH ₂ in THF (32.43 mL, 64.86 mmol). The mixture was stirred at 70 °C for 12 h and then evaporated to give the crude title compound as a yellow oil (846.0 mg, 82% yield). MS (ESI): m/z = 167.2 [M+H] ⁺ Example 39 3-(4,4 -difluorotetrahydrofuran -3- yl )-1-[(3- methoxy -4 -pyridinyl ) methyl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 30 mg, 188.02 µmol) and DIPEA (82 µL, 469.51 µmol) in DCM (450 µL) was treated with CDT (45 mg, 246.77 µmol). The mixture was stirred at 23 °C for 1 hour and then treated with (3-methoxy-4-pyridinyl)methyl-methyl-amine (29 mg, 190.55 µmol). The mixture was stirred at 23 °C for 16 hours and then poured into EtOAc (10 mL). The mixture was washed three times with water and brine. The aqueous layer was back extracted with EtOAc (20 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FC (SiO ₂ ; heptane/EtOAc/MeOH) gave the title compound as a white powder (33.5 mg, 56% yield). MS (ESI): m/z = 302.2 [M+H] ⁺

Steps a) : (3- Methoxy -4- Pyridyl ) methyl - methyl - amine

To a solution of 3-methoxyisonicotinaldehyde (CAS RN: 1849-52-1; 100 mg, 729.18 µmol) and methylamine hydrochloride (247 mg, 3.66 mmol) in MeOH (2 mL) was added sodium triacetyloxyborohydride (473 mg, 2.23 mmol). The mixture was stirred at 23 °C for 18 h, then treated with 2 M HCl (2 mL) and evaporated. The residue was dissolved in 2 M NaOH. The aqueous phase was extracted with DCM and the combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the crude title compound (60 mg, 52% yield) as a light yellow liquid. MS (ESI): m/z = 153.2 [M+H] ⁺ Example 40 1-[1-(3- chloro -4 -pyridinyl ) ethyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 38.53 mg, 241.49 µmol) in DCM (599.38 µL) was added DIPEA (144.65 µL, 845 µmol) followed by CDT (59.44 mg, 362.14 µmol). The mixture was stirred at 23°C for 1 hour and then treated with 1-(3-chloro-4-pyridinyl)-N-methyl-ethylamine; dihydrochloride (50 mg, 241.43 µmol) and stirred at 23°C for another 16 hours. The mixture was extracted with DCM and water. The aqueous layer was back extracted twice with DCM. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification by RP-HPLC gave the title compound as a white oil (22.4 mg, 28% yield). MS (ESI): m/z = 320.1 [M+H] ⁺

Steps a) : N-[1-(3- chlorine -4- Pyridyl ) Ethyl ]-N- methyl - Tributyl carbamate

A mixture of 1-(3-chloro-4-pyridinyl)-N-methyl-ethylamine (CAS RN: 1602674-56-5; 2194.0 mg, 12.86 mmol), Boc ₂ O (4.2 g, 19.29 mmol) in MeOH (60 mL) was stirred at 25°C for 1 hour and then evaporated. Purification by FC (SiO ₂ ; PE/EtOAc) gave the title compound (2.0 g, 57% yield) as a colorless oil. MS (ESI): m/z = 271.0 [M+H] ⁺

Steps b) : 1-(3- chlorine -4- Pyridyl )-N- methyl - Ethylamine; dihydrochloride

A solution of N-[1-(3-chloro-4-pyridinyl)ethyl]-N-methyl-carbamic acid tributyl ester (1.0 g, 3.69 mmol) in 2 M HCl in 1,4-dioxane (30.0 mL, 60.0 mmol) was stirred at 23°C for 4 h. The resulting precipitate was filtered and the filter cake was dissolved in MeOH (40 mL) and evaporated to give the title compound as a light yellow solid (812.1 mg, 90% yield). MS (ESI): m/z = 171.1 [M-2 HCl + H] ⁺ Example 41 3-(4,4 -Difluorotetrahydrofuran -3 -yl )-1- methyl -1-[(3 -pyrrolidin -1- yl -4 -pyridinyl ) methyl ] urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 265.0 mg, 1.66 mmol) and DIPEA (1.74 mL, 9.96 mmol) in DMF (3.13 mL) was added CDT (354.35 mg, 2.16 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with N-methyl-1-(3-pyrrolidin-1-yl-4-pyridinyl)methanamine; trihydrochloride (499.32 mg, 1.66 mmol). The mixture was heated to 80 °C and stirred at that temperature for 2 hours and then cooled. Purification by RP-HPLC gave the title compound (53.8 mg, 9% yield) as a yellow oil. MS (ESI): m/z = 341.4 [M+H] ⁺

Steps a) : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

A solution of Boc ₂ O (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3-bromo-4-pyridinyl)-N-methyl-methylamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25°C. The mixture was stirred at 23°C for 18 hours and then evaporated to give the title compound as a light yellow oil (9.0 g, 96% yield). MS (ESI): m/z = 301.0/303.0 [M+H] ⁺

Steps b) : N- methyl -N-[(3- Pyrrolidine -1- base -4- Pyridyl ) methyl ] Tributyl carbamate

A solution of tributyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (1.6 g, 5.31 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)dibenzopyran (153.7 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (243.23 mg, 0.27 mmol), pyrrolidine (1133.46 mg, 15.94 mmol) and cesium carbonate (5.19 g, 15.94 mmol) in 1,4-dioxane (80 mL) was stirred at 100°C for 18 hours. Purification by FC (SiO ₂ ; MTBE/MeOH) gave the title compound (500.0 mg, 32% yield) as a light yellow oil. MS (ESI): m/z = 292.2 [M+H] ⁺

Steps c) : N- methyl -1-(3- Pyrrolidine -1- base -4- Pyridyl ) Methylamine trihydrochloride

To a solution of tributyl N-methyl-N-[(3-pyrrolidin-1-yl-4-pyridinyl)methyl]carbamate (500.0 mg, 1.72 mmol) in DCM (10 mL) was added a solution of 4 M HCl in 1,4-dioxane (5.15 mL, 20.59 mmol). The mixture was stirred at 23 °C for 18 h and then evaporated to give the title compound as a light yellow solid (500.0 mg, 87% yield). MS (ESI): m/z = 192.0 [M+H] ⁺ Example 42 1-[(S) -Cyclopropyl (4 -pyridyl ) methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(S) -Cyclopropyl (4 -pyridyl ) methyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(R) -Cyclopropyl (4 -pyridyl ) methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(R) -Cyclopropyl (4 -pyridyl ) methyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or or or

1-[Cyclopropyl(4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea (52.0 mg, 0.17 mmol) was separated by chiral SFC (column CHIRALCEL OJ-H5, 5 µm, 250x20 mm, hexane:IPA:MeOH 90:5:5) to give the title compound as a colorless oil (6.3 mg, 12% yield, t _R = 0.695 min). MS (ESI): m/z = 312.2 [M+H] ⁺

Steps a) : 1- Cyclopropyl -N- methyl -1-(4- Pyridyl ) Methylamine

A solution of cyclopropyl(4-pyridyl)methanone (CAS RN: 39512-48-6; 900.0 mg, 6.11 mmol) and monomethylamine in THF (20% wt, 1.81 mL, 9.17 mmol) in THF (10 mL) was cooled to 0°C and then treated dropwise with titanium(IV) isopropoxide (2.61 g, 9.17 mmol). The mixture was stirred at 23°C for 16 hours, then cooled to 0°C and treated with sodium borohydride (462.69 mg, 12.23 mmol). The mixture was stirred for 16 h and then treated with MeOH (10 mL) and sodium borohydride (102.82 mg, 2.72 mmol) at 0 °C. The reaction was stirred for another 2 h at 23 °C and then treated with ice-cold water. The mixture was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound as a light yellow oil (800.0 mg, 57% yield). MS (ESI): m/z = 163.0 [M+H] ⁺

Steps b) : 1-[ Cyclopropyl (4- Pyridyl ) methyl ]-3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl - Urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 50.0 mg, 0.31 mmol) and DIPEA (0.14 mL, 0.78 mmol) in DMF (0.500 mL) at 23°C was added CDT (66.86 mg, 0.41 mmol). The mixture was stirred at 50°C for 1 hour and then treated with 1-cyclopropyl-N-methyl-1-(4-pyridinyl)methanamine (101.68 mg, 0.31 mmol). The mixture was stirred at 80°C for 2 hours and at 23°C for 18 hours. Purification by RP-HPLC gave the title compound as a light brown oil (28.0 mg, 27% yield). MS (ESI): m/z = 312.2 [M+H] ⁺ Example 43 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-[1-(4 -pyridyl ) cyclopropyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (36.08 mg, 226.11 µmol) (CAS RN: 2408969-70-8) in dichloromethane (452.22 µL) was added DIPEA (96.43 mg, 130.32 µL, 746.17 µmol) followed by CDT (55.66 mg, 339.17 µmol). The mixture was stirred at 23 °C for 1 hour and then treated with methyl-[1-(4-pyridyl)cyclopropyl]amine; dihydrochloride (CAS RN: 2416728-56-6; 50 mg, 226.11 µmol). The mixture was stirred at 23°C for 48 hours and then extracted with 2-Me-THF. The organic layer was washed with water and brine. The combined organic layers were dried _{over Na2SO4} and evaporated. Purification by RP-HPLC gave the title compound as a white oil (29.3 mg, 41% yield). MS (ESI): m/z = 298.3 [M+H] ⁺ Example 44 3-[(2R,3S)-2-(5- bromo -2- methyl -3 -pyridyl ) tetrahydrofuran -3 -yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or 3-[(2S,3R)-2-(5- bromo -2- methyl -3 -pyridyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or

A suspension of (2R,3S)-2-(5-bromo-2-methyl-3-pyridinyl)tetrahydrofuran-3-amine; dihydrochloride (62.0 mg, 0.19 mmol) in DCM (2 mL) was cooled to 0°C and then treated with triethylamine (0.1 mL, 0.75 mmol) and CDT (33.51 mg, 0.21 mmol). The mixture was stirred at this temperature for 1 hour and (1S)-N-methyl-1-(4-pyridinyl)ethylamine (CAS RN: 42732-16-1; 25.59 mg, 0.19 mmol) was added. The mixture was stirred at 20°C for 15 hours and concentrated. Purification by RP-HPLC gave 50.5 mg of the racemic mixture. Purification by chiral SFC (column: CHIRALPAK IС, 250x21 mm, 5 µm, hexane:IPA:MeOH 70:15:15, 18 mL/min) gave the title compound as a light brown solid (16.1 mg, 20% yield, t _R = 24.47 min). MS (ESI): m/z = 419.0/421.0 [M+H] ⁺

Steps a) : (2S,3S)-2-(5- bromine -2- methyl -3- Pyridyl ) Tetrahydrofuran -3- Formic acid

A solution of 5-bromo-2-methyl-pyridine-3-carbaldehyde (CAS RN: 1211532-24-9; 250.0 mg, 1.25 mmol) and methyl 4-chlorobutyrate (CAS RN: 3153-37-5; 187.75 mg, 1.37 mmol) in THF (3 mL) was cooled to -30 °C and then treated with sodium tributyl oxide (180.16 mg, 1.87 mmol). The mixture was stirred at this temperature for 1 hour, then warmed to 25 °C and stirred for another 15 hours. The mixture was evaporated and dissolved in MeOH (2 mL). A solution of potassium hydroxide (105.18 mg, 1.87 mmol) in water (2 mL) was added. The resulting mixture was stirred at 23 °C for 2 h and then evaporated. The residue was dissolved in water (2 mL) and the aqueous layer was extracted with MTBE. The aqueous layer was separated and acidified to pH = 4 with saturated aqueous NaHSO _4. The mixture was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the crude title compound (260.0 mg, 55% yield) as a white solid. MS (ESI): m/z = 286.0/288.0 [M+H] ⁺

Steps b) : N-[(2R,3S)-2-(5- bromine -2- methyl -3- Pyridyl ) Tetrahydrofuran -3- base ] Tributyl carbamate

To a solution of (2S,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-carboxylic acid (260.0 mg, 0.91 mmol) and triethylamine (0.19 mL, 1.36 mmol) in tert- butanol (7.8 mL, 82.19 mmol) at 23°C was added diphenylphosphoric acid azide (0.2 mL, 0.91 mmol) dropwise. The mixture was heated at 80°C for 15 h and evaporated. The residue was dissolved in EtOAc and the solution was washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated. Purification by FC (SiO ₂ ; hexane/EtOAc 3:1) afforded the title compound as a white solid (110.0 mg, 33% yield). MS (ESI): m/z = 356.7/358.7 [M+H] ⁺

Steps c) : (2R,3S)-2-(5- bromine -2- methyl -3- Pyridyl ) Tetrahydrofuran -3- Amine; dihydrochloride

To a solution of tributyl N-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]carbamate (72.0 mg, 0.2 mmol) in DCM (2 mL) was added a solution of 4 M HCl in 1,4-dioxane (0.5 mL, 10.0 eq). The mixture was stirred at 20 °C for 15 h and then evaporated to give the crude title compound (64.0 mg, 96% yield) as a white solid. MS (ESI): m/z = 257.0/259.0 [M+H] ⁺ Example 45 1-[(1S)-1-(3- chloro -4 -pyridinyl ) ethyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl - urea or 1-[(1S)-1-(3- chloro - 4 -pyridinyl ) ethyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(1R)-1-(3- chloro -4 -pyridinyl ) ethyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl - urea or 1-[(1R)-1-(3- chloro - 4 -pyridinyl ) ethyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or or or

Starting from 22.4 mg of Example 40: 1-[1-(3- chloro -4 -pyridinyl ) ethyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea , chiral SFC (chiral Whelk(r,r), 12 nm, 5 µm, 250 x 20 mm, W(r,r) 80 mL 18% EtOH) gave the title compound as a white oil (0.95 mg, 5% yield, t _R = 2.11 min). MS (ESI): m/z = 320.1 [M+H] ⁺ Example 46 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[1-(4 -pyridyl ) cyclopropyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[1-(4 -pyridyl ) cyclopropyl ] urea or

Starting from 40.0 mg of Example 43: 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-[1-(4- pyridinyl ) cyclopropyl ] urea , chiral SFC (chiral Whelk(r,r), 5 µm, 250 x 20 mm, 30% MeOH) gave the title compound as a white oil (8.0 mg, 40% yield, t _R = 2.15 min). MS (ESI): m/z = 298.1 [M+H] ⁺ Example 47 1-[[3-(3- Chloroanilino )-4 -pyridinyl ] methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1 - methyl - urea or 1-[[3-(3- Chloroanilino )-4 -pyridinyl ] methyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 48.44 mg, 303.57 µmol) in DCM (940 µL) at 23°C was added DIPEA (212.07 µL, 1.21 mmol) followed by CDT (59.79 mg, 364.28 µmol). The mixture was stirred at 23°C for 1 hour and then treated with a solution of [3-(3-chloroanilino)-4-pyridinyl]methyl-methyl-amine (75.2 mg, 303.57 µmol) in DCM (940 µL). The mixture was stirred at 23°C for another 1.5 hours and then treated with water and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) followed by chiral SFC (column chiral AD-H, 5 µm, 250 x 20 mm, 18% MeOH) afforded the title compound as a white solid (24.4 mg, 22% yield). MS (ESI): m/z = 397.3 [M+H] ⁺

Steps a) : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

A solution of Boc ₂ O (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3-bromo-4-pyridinyl)-N-methyl-methylamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25°C. The mixture was stirred at 23°C for 18 hours and then evaporated to give the title compound as a light yellow oil (9.0 g, 96% yield). MS (ESI): m/z = 301.0/303.0 [M+H] ⁺

Steps b) : N-[[3-(3- Chloroaniline )-4- Pyridyl ] methyl ]-N- methyl - Tributyl carbamate

A solution of 3-chloroaniline (58.76 µL, 557.31 µmol), N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamic acid tributyl ester (111.9 mg, 371.54 µmol) and cesium carbonate (302.64 mg, 928.85 µmol) in toluene (1.17 mL) was degassed under nitrogen and then treated with sodium diacetate (8.34 mg, 37.15 µmol) and racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (46.27 mg, 74.31 µmol). The mixture was stirred at 100°C for 16 hours and then poured into 2-methyl-THF and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FC (SiO ₂ ; heptane/EtOAc) gave the title compound as a light brown oil (65.7 mg, 50.84% yield). MS (ESI): m/z = 348.3 [M+H] ⁺

Steps c) : [3-(3- Chloroaniline )-4- Pyridyl ] methyl - methyl - amine

A solution of tributyl N-[[3-(3-chloroanilino)-4-pyridinyl]methyl]-N-methyl-carbamate (175.6 mg, 504.83 µmol) in 4 M HCl in 1,4-dioxane (2.52 mL, 10.1 mmol) was stirred at 23°C for 18 h, then diluted with DCM, filtered through celite and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) gave the title compound as a light brown oil (83.9 mg, 60.38% yield). MS (ESI): m/z = 248.1 [M+H] ⁺ Example 48 3-[(3S)-4,4 -difluoro -3- methyl - tetrahydrofuran -3 -yl ]-1- methyl -1-[(1S)-1-(4- pyridyl ) ethyl ] urea or 3-[(3R)-4,4 -difluoro -3 - methyl - tetrahydrofuran -3 - yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or

To a solution of 4,4-difluoro-3-methyl-tetrahydrofuran-3-carboxylic acid (CAS RN: 1782346-79-5; 100.0 mg, 0.6 mmol) and triethylamine (0.13 mL, 0.9 mmol) in 1,4-dioxane (1.25 mL) at 23° C. was added diphenylphosphatidylhydrazine (182.23 mg, 0.66 mmol). The mixture was stirred at 60° C. for 1 hour and at 80° C. for 2 hours, then cooled and treated with (1S)-N-methyl-1-(4-pyridyl)ethylamine (CAS RN: 42732-16-1; 81.99 mg). The mixture was stirred at 23 °C for 1 hour and then purified by RP-HPLC. Chiral SFC (column Chiralpak IG, 250x20 mm, 5 µm, hexane/IPA/MeOH 70:15:15, 14 mL/min) afforded the title compound as a yellow oil (36.5 mg, 20.26% yield, t _R = 16.17 min). MS (ESI): m/z = 300.0 [M+H] ⁺ Example 49 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1R)-2- phenoxy- 1-(4 -pyridyl ) ethyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran - 3- yl ]-1- methyl -1-[(1S)-2- phenoxy -1-(4 -pyridyl ) ethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[(1R)-2- phenoxy- 1-(4 -pyridyl ) ethyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-2- phenoxy -1-(4 -pyridyl ) ethyl ] urea or or or

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 174.78 mg, 1.1 mmol) in DCM (5.5 mL) was added DIPEA (1.25 mL, 7.3 mmol) followed by CDT (233.03 mg, 1.42 mmol). The mixture was stirred at 23°C for 1 h and then treated with N-methyl-2-phenoxy-1-(4-pyridinyl)ethanamine (250 mg, 1.1 mmol) and stirred at 23°C for 16 h. Purification by FC (SiO ₂ ; DCM/MeOH) gave 340 mg of the racemic mixture. Purification by chiral SFC (column chiral Whelk (r,r), 5 µm, 250 x 20 mm, 25% MeOH) gave the title compound as a white powder (46 mg, 11% yield, t _R = 3.06 min). MS (ESI): m/z = 378.2 [M+H] ⁺

Step a ): N- methyl -2- phenoxy -1-(4 -pyridyl ) ethylamine

Titanium isopropoxide (2.1 mL, 7.09 mmol) was added to a solution of 2-phenoxy-1-(4-pyridyl)ethanone (CAS RN: 1574141-85-7; 1440.0 mg, 6.75 mmol) in 2-propanol (9.65 mL) at 0°C over 2-5 minutes. Methylamineethanol (2.52 mL, 20.26 mmol) was then added and the mixture was allowed to warm to 23°C and stirred at that temperature for another 18 hours before cooling to 0°C. Sodium borohydride (383.2 mg, 10.13 mmol) was added portionwise and the mixture was stirred at 0°C for 1 hour before being diluted with EtOAc (2 mL) and brine (2 mL). The mixture was stirred at 23 °C for 10 min _and then filtered through celite. The organic layer was washed with brine, dried over _Na2SO4 , filtered and evaporated. Purification by FC ( _SiO2 ; DCM/MeOH) gave the title compound as a yellow oil (550 mg, 36% yield). MS (ESI): m/z = 229.2 [M+H] ⁺ Example 50 1- methyl -3-[(1R,5R)-3- oxabicyclo [3.1.0] hex -1- yl ]-1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or 1- methyl -3-[(1S,5S)-3- oxabicyclo [3.1.0] hex -1- yl ]-1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of [3-oxabicyclo[3.1.0]hexan-1-yl]amine; hydrochloride (CAS RN: 2307776-44-7; 49.78 mg, 367.13 µmol) in DCM (734.27 µL) was added DIPEA (147.47 µL, 844.41 µmol) followed by CDT (90.38 mg, 550.7 µmol). The mixture was stirred at 23 °C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was stirred at 23°C for 16 h, then poured into 2-Me-THF and washed with water and brine. The combined organic layers were dried over _Na2SO4 and evaporated. Purification by (Gemini NX, 12 nm, 5 μm, 100 x 30 mm, ACN/ _H2O + 0.1% TEA) gave the title compound as a mixture _of non-mirror isomers (55.3 mg, 55% yield) and as a white oil. MS (ESI): m/z = 262.3 [M+H]+

Starting from 40 mg of the non-image-bearing isomeric mixture, chiral SFC (column chiral AD-H, 5 µm, 250 x 20 mm, 15% MeOH) afforded the title compound as a light yellow oil (9.3 mg, 23% yield, t _R = 3.420 min). MS (ESI): m/z = 262.2 [M+H] ⁺ Example 51 1- Methyl -3-[(1R,5R)-3- oxabicyclo [3.1.0] hex -1- yl ]-1-[(1S)-1-(4 -pyridinyl ) ethyl ] urea or 1- Methyl -3-[(1S,5S)-3- oxabicyclo [3.1.0] hex -1- yl ]-1-[(1S)-1-(4- pyridinyl ) ethyl ] urea

To a solution of [3-oxabicyclo[3.1.0]hexan-1-yl]amine; hydrochloride (CAS RN: 2307776-44-7; 49.78 mg, 367.13 µmol) in DCM (734.27 µL) was added DIPEA (147.47 µL, 844.41 µmol) followed by CDT (90.38 mg, 550.7 µmol). The mixture was stirred at 23 °C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 µmol). The mixture was stirred at 23 °C for 16 h, then poured into 2-Me-THF and washed with water and brine. The combined organic layers were dried over Na ₂ SO ₄ and evaporated. Purification by (Gemini NX, 12 nm, 5 μm, 100 x 30 mm, ACN/H ₂ O + 0.1% TEA) gave the title compound as a mixture of non-mirror isomers (55.3 mg, 55% yield) and as a white oil. MS (ESI): m/z = 262.3 [M+H] ⁺

Starting from 40 mg of the non-mirror isomeric mixture, chiral SFC (column chiral AD-H, 5 µm, 250 x 20 mm, 15% MeOH) afforded the title compound as a light yellow oil (10.1 mg, 25% yield, t _R = 3.610 min). MS (ESI): m/z = 262.2 [M+H] ⁺ Example 52 1-[[3-( Difluoromethyl )-4 - pyridinyl ] methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1 - methyl - urea or 1-[[3-( Difluoromethyl )-4 -pyridinyl ] methyl ] -3 -[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 40 mg, 250.69 µmol) in DCM (600 µL) was added DIPEA (110 µL, 629.84 µmol) and CDT (60 mg, 329.03 µmol). The mixture was stirred at 23 °C for 1 hour. [3-(Difluoromethyl)-4-pyridinyl]methyl-methyl-amine (44 mg, 255.55 µmol) was added. The reaction mixture was stirred at 23 °C for 16 hours. The combined organic layers were dried over Na ₂ SO ₄ and evaporated. Purification by (SiO ₂ , DCM/MeOH) and SFC (chiral Whelk (r,r), 12 nm, 5 µm, 250 x 20 mm, 20% MeOH) afforded the title compound as a light yellow viscous oil (32.3 mg, 38% yield, t _R = 1.853 min). MS (ESI): m/z = 322.1 [M+H] ⁺

Steps a) : [3-( Difluoromethyl )-4- Pyridyl ] Methanol

A solution of 3-(difluoromethyl)isonicotinaldehyde (CAS RN: 1211541-96-6; 70 mg, 445.52 µmol) and methylamine hydrochloride (CAS RN: 593-51-1; 152 mg, 2.25 mmol) in MeOH (1.25 mL) was stirred at 23°C for 1 hour and then treated with sodium triacetoxyborohydride (290 mg, 1.37 mmol). The mixture was stirred at 23°C for 2 hours and then poured into MeOH, washed with NH ₄ Cl and neutralized with NaOH. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound (54 mg, 72% yield) as a colorless crystalline solid. MS (ESI): m/z = 160.1 [M+H] ⁺

Steps b) : [3-( Difluoromethyl )-4- Pyridyl ] methyl - methyl - amine

To a solution of [3-(difluoromethyl)-4-pyridinyl]methanol (54 mg, 339.35 µmol) in anhydrous THF was added DIPEA (209 µL, 713.96 µmol). The solution was cooled to 0°C and then treated with methanesulfonyl chloride (66 µL, 853.02 µmol). The mixture was stirred at 0°C for 1 hour and then treated with a 2.0 M solution of MeNH ₂ (850 µL, 1.7 mmol). The mixture was stirred at 23°C for 4 hours and then additional 2.0 M solution of MeNH ₂ (850 µL, 1.7 mmol) was added. The mixture was heated to 60°C for 18 hours and then poured onto EtOAc (20 mL) and washed with water and brine. The combined organic layers were dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a light yellow liquid (44 mg, 72% yield). MS (ESI): m/z = 173.1 [M+H] ⁺ Example 53 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[1-(4 -pyridyl ) cyclobutyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran - 3- yl ]-1- methyl -1-[1-(4 -pyridyl ) cyclobutyl ] urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN:2408969-70-8; 165.22 mg, 1.04 mmol) in DMF (0.500 mL) was added DIPEA (0.45 mL, 2.59 mmol) and CDT (220.93 mg, 1.35 mmol). The mixture was stirred at 50 °C for 1 hour and then treated with N-methyl-1-(4-pyridyl)cyclobutanamine (CAS RN: 1500790-86-2; 210.0 mg, 1.04 mmol). The mixture was then heated at 80 °C for 2 hours and then at 23 °C for 18 hours. Purification by RP-HPLC gave 167 mg of the racemic mixture. Further separation by chiral HPLC (column chiral IF, 5 µm, 250 x 21 mm, hexane/IPA/MeOH) gave the title compound as a light brown oil (61.8 mg, 19% yield, t _R = 11.89 min). MS (ESI): m/z = 312.2 [M+H] ⁺ Example 54 3-(4,4 -difluorotetrahydrofuran -3 -yl )-1- methyl -1-[[3-(1H -pyrazol -5- yl )-4 -pyridinyl ] methyl ] urea

To a solution of 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[2-(2-trimethylsilanylethoxymethyl)pyrazol-3-yl]-4-pyridinyl]methyl]urea and 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[2-(2-trimethylsilanylethoxymethyl)pyrazol-3-yl]-4-pyridinyl]methyl]urea (14.76 mg, 29.04 µmol) in DCM (232.99 µL) was added TFA (11.19 µL, 145.21 µmol) under hydrogen. The mixture was stirred at 23 °C for 1.5 h, then additional TFA (33.56 µL, 435.62 µmol) was added. The mixture was stirred at 23 °C for 3.5 h, then additional TFA (11.19 µL, 145.21 µmol) was added. The mixture was stirred at 23 °C for 1 h, then additional TFA (9.6 µL, 124.65 µmol) was added, and the mixture was stirred at 23 °C for 2 h, then additional TFA (44.75 µL, 580.83 µmol) was added. The mixture was stirred at 23 °C for 3 h, then concentrated in vacuo . Purification by FC (SiO ₂ , heptane/EtOAc/EtOH) gave the title compound as a racemic mixture (9.69 mg, 99% yield) and as a white solid. MS (ESI): m/z = 338.2 [M+H] ⁺

Steps a) ：Trimethyl -[2-[[5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Pyrazole -1- base ] Methoxy ] Ethyl ] Silane and trimethyl -[3-[[5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborane -2- base ) Pyrazole -1- base ] Methoxy ] Ethyl ] Silane

To a solution of 1H-pyrazole-5-boronic acid ester (CAS RN: 844501-71-9; 300 mg, 1.55 mmol) in extra dry THF (3 mL) at 0°C was added a solution of NaH 60% in mineral oil (68.03 mg, 1.7 mmol) under argon. The mixture was stirred at 23°C for 90 min and then treated with 2-(trimethylsilyl)ethoxymethyl chloride (329.06 µL, 1.86 mmol) at 0°C. The mixture was stirred at 23°C for 28 h and then quenched with water, extracted with EtOAc and washed with brine. The combined organic layers were dried over MgSO ₄ and evaporated to give the title compound as a mixture of two pyrazole positional isomers (766.45 mg, quantitative) as a yellow oil. The crude product was directly used in the next conversion. MS (ESI): m/z = 243.2 [M+H-(CH ₃ ) ₂ CC(CH ₃ ) ₂ ] ⁺

Steps b) : 3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl -1-[[3-[2-(2- Trimethylsilylethoxymethyl ) Pyrazole -3- base ]-4- Pyridyl ] methyl ] Urea and 3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl -1-[[3-[3-(2- Trimethylsilylethoxymethyl ) Pyrazole -3- base ]-4- Pyridyl ] methyl ] Urea

Under argon in a vial, trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (56.32 mg, 128.51 µmol), Cs ₂ CO ₃ (125.62 mg, 385.54 µmol), cataCXium Pd G4 (9.54 mg, 12.85 µmol) and 1-[(3- bromo -4 -pyridyl ) methyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea from Example 28 (50 mg, 128.51 µmol) were suspended in 1,4-dioxane (321 µL) and water (321 µL). The mixture was stirred at 100 °C for 3 h, then poured into EtOAc, filtered through Celite and evaporated. Purification by FC (SiO ₂ , heptane/EtOAc/EtOH) gave the title compound as a mixture of two pyrazole positional isomers (14.76 mg, 22% yield) as a colorless oil. MS (ESI): m/z = 468.4 [M+H] ⁺ Example 55 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1R)-2- hydroxy -1-(4 -pyridyl ) ethyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuranpyrimidin - 3- yl ]-1-[(1R)-2- hydroxy -1-(4 -pyridyl ) ethyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran - 3 -yl ]-1-[(1S)-2- hydroxy -1-(4 -pyridyl ) ethyl ]-1- methyl - urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-2- hydroxy -1-(4 -pyridyl ) ethyl ]-1- methyl - urea

To a solution of a non-mirror isomeric mixture of 1-[2-[tributyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea (48.6 mg, 0.111 mmol) in DCM (250 µL) was added TFA (42.8 µL, 555.53 µmol). The reaction mixture was stirred at 23 °C for 1 h and then evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture.

Starting from the non-mirror isomeric mixture, chiral SFC (column chiral Amyl, 5 µm, 250 x 20 mm, 15 % MeOH) afforded the title compound as a colorless oil (3.4 mg, 9.55%, t _R = 3.972 min). MS (ESI): m/z = 284.1 [M+H] ⁺

Steps a) : N-[2- Hydroxyl -1-(4- Pyridyl ) Ethyl ] Tributyl carbamate

To a solution of 2-amino-2-(4-pyridinyl)ethanol (CAS RN: 100-43-6; 25.0 g, 180.94 mmol) in MeOH (700 mL) was added TEA (75.66 mL, 542.81 mmol) and Boc ₂ O (39.49 g, 180.94 mmol). The mixture was stirred at 25 °C for 2 h. Purification by FC (PE/EtOAc) gave the title compound as a racemic mixture (22.3 g, 52% yield) and as a white solid. MS (ESI): m/z = 239.0 [M+H] ⁺

Steps b) : N-[2-[ Tertiary Butyl ( Dimethyl ) Silane ] oxygen -1-(4- Pyridyl ) Ethyl ] Tributyl carbamate

To a solution of tributyl N-[2-hydroxy-1-(4-pyridinyl)ethyl]carbamate (750.0 mg, 3.15 mmol) in DCM (20 mL) were added 1H-imidazole (535.38 mg, 7.87 mmol) and tributyl-chloro-dimethylsilane (1181.54 mg, 7.87 mmol). The mixture was stirred at 20 °C for 16 h. Purification by FC (PE/EtOAc) gave the title compound as a racemic mixture (1090.0 mg, 98% yield) and as a white solid. MS (ESI): m/z = 353.1 [M+H] ⁺

Steps c) ：Tributyl N-[2-[ Tertiary Butyl ( Dimethyl ) Silane ] oxygen -1-(4- Pyridyl ) Ethyl ]-N- methyl - Tributyl carbamate

To a solution of tributyl N-[2-[tributyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]carbamate (100 mg, 283.66 µmol) in DMF (3 mL) at 0°C was added a solution of NaH 60% in mineral oil (13.62 mg, 567.31 µmol). The mixture was stirred at 0°C for 30 min and then treated with iodomethane (35.47 µL, 567.31 µmol). The mixture was stirred at 0°C for 45 min and then poured into EtOAc and washed with water and brine. The combined organic layers were dried over MgSO ₄ and evaporated. Purification by FC (SiO ₂ , heptane/EtOAc) gave the title compound as a racemic mixture (91 mg, 83% yield) as a yellow liquid. MS (ESI): m/z = 367.3 [M+H] ⁺

Steps d) : [2-[ Tertiary Butyl ( Dimethyl ) Silane ] oxygen -1-(4- Pyridyl ) Ethyl ]- methyl - amine. 1:1 2,2,2- Trifluoroacetic acid

To a solution of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]-N-methyl-carbamic acid tert-butyl ester (91 mg, 0.236 mmol) in DCM (1.2 mL) was added TFA (134.45 mg, 90.84 µL, 1.18 mmol). The mixture was stirred at 23 °C for 1.8 h and then concentrated under vacuum to give the title compound as a racemic mixture (123.9 mg, 97%, 70% purity) as a light yellow liquid, which was used directly in the next step without further purification. MS (ESI): m/z = 267.3 [M+H] ⁺

Steps e) : 1-[2-[ Tertiary Butyl ( Dimethyl ) Silane ] oxygen -1-(4- Pyridyl ) Ethyl ]-3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl - Urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 60.54 mg, 384.16 µmol) in DCM (1 mL) was added DIPEA (268.37 µL, 1.54 mmol) and CDT (75.66 mg, 460.99 µmol). The mixture was stirred at 23 °C for 1 h and then treated with a solution of [2-[tributyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]-methyl-amine 1:1 TFA (208.8 mg, 384.16 µmol) in DCM (1 mL) and DMF (100 µL). The mixture was stirred at 23 °C for 17 h and then evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture (48.6 mg, 29% yield) as a light yellow oil. MS (ESI): m/z = 416.3 [M+H] ⁺ Example 56 3-[3-( Difluoromethyl ) tetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of [3-(difluoromethyl)tetrahydrofuran-3-yl]amine; hydrochloride (CAS RN: 2742653-30-9; 76.48 mg, 440.56 µmol) in DMF (2.2 mL) was added DIPEA (307.77 µL, 1.76 mmol) and CDT (79.54 mg, 484.62 µmol). The mixture was stirred at 75°C for 1 hour and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 60 mg, 440.56 µmol). The mixture was stirred at 75°C for 16 hours. Purification by RP-HPLC gave the title compound as a non-mirror isomeric mixture (73.2 mg, 53% yield ) as a colorless gum. MS (ESI): m/z = 298.2 [MH] ^˗Example 57 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(3- phenyl -4 -pyridinyl ) methyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[(3- phenyl -4 -pyridinyl ) methyl ] urea

Phenylboronic acid, ester (34.2 mg, 162.78 µmol), Cs ₂ CO ₃ (159.11 mg, 488.35 µmol), cataCXium Pd G4 (12.08 mg, 16.27 µmol) and 1-[(3- bromo -4 -pyridyl ) methyl ] -3- (4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea (60 mg, 162.78 µmol) from Example 28 were suspended in 1,4-dioxane (405 µL) and water (405 µL) in a vial under argon. The mixture was stirred at 100 °C for 4 hours, then poured into EtOAc, filtered through celite and concentrated in vacuo. Purification by FC (SiO ₂ , heptane/EtOAc/EtOH) gave the title compound as a racemic mixture (45.13 mg, 80% yield) and as an off-white oil. MS (ESI): m/z = 348.2 [M+H] ⁺

Starting from 45.13 mg of the non-mirror isomeric mixture, chiral SFC (column chiral OZ, 5 µm, 250 x 20 mm, 20% MeOH) afforded the title compound as a white solid (24.29 mg, 54% yield, t _R = 1.953 min). MS (ESI): m/z = 348.2 [M+H] ⁺ Example 58 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] thiourea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 117.16 mg, 734.27 µmol) in extra dry DCM (2.38 mL) was added DIPEA (384.72 µL, 2.2 mmol) and 1,1'-thiocarbonyldiimidazole (143.94 mg, 807.7 µmol). The mixture was stirred at 23 °C for 30 min and then treated with methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 100 mg, 734.27 µmol). The mixture was stirred at 23 °C for 16 h and then poured into MeOH and evaporated. Purification by FC (SiO ₂ , DCM/MeOH) gave the title compound as a non-mirror isomeric mixture (25.1 mg, 10.89% yield) as a light yellow oil. MS (ESI): m/z = 302.2 [M+H] ⁺ Example 59 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-[[3-(3- methyl -1H -pyrazol -5- yl )-4 -pyridinyl ] methyl ] urea

To a solution of 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[5-methyl-2-(2-trimethylsilanylethoxymethyl)pyrazol-3-yl]-4-pyridinyl]methyl]urea and 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[5-methyl-1-(2-trimethylsilanylethoxymethyl)pyrazol-3-yl]-4-pyridinyl]methyl]urea (41.87 mg, 0.080 mmol) in extra dry DCM (400 µL) was added TFA (123.24 µL, 1.6 mmol) under hydrogen. The mixture was stirred at 23 °C for 4 h, then additional TFA (61.62 µL, 789.83 µmol) was added. The mixture was stirred at 23 °C for 1.5 h, then the mixture was concentrated in vacuo . Purification by FC (SiO ₂ , heptane/EtOAc/EtOH) gave the title compound as a racemic mixture (27.68 mg, 98% yield) as a white solid. MS (ESI): m/z = 352.2 [M+H] ⁺

Steps a) ：Trimethyl -[2-[[3- methyl -5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborane -2- base ) Pyrazole -1- base ] Methoxy ] Ethyl ] Silane and trimethyl -[2-[[5- methyl -3-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Pyrazole -1- base ] Methoxy ] Ethyl ] Silane

To a solution of 1H-pyrazole-5-boronic acid ester (CAS RN: 1888441-67-5; 300 mg, 1.44 mmol) in extra dry THF (2.5 mL) at 0°C was added a solution of NaH 60% in mineral oil (63.44 mg, 1.586 mmol) under argon. The mixture was stirred at 23°C for 90 min and then treated with 2-(trimethylsilyl)ethoxymethyl chloride (306.87 µL, 1.73 mmol) at 0°C. The mixture was stirred at 23°C for 28 h and then quenched with water, extracted with EtOAc and washed with brine. The combined organic layers were dried over MgSO ₄ and evaporated to give the title compound as a mixture of two pyrazole positional isomers (437.06 mg, 79% yield) as a colorless oil. The crude product was directly carried forward to the next transformation. MS (ESI): m/z = 256.4 [M+H-(CH ₃ ) ₂ CC(CH ₃ ) ₂ ] ⁺

Steps b) : 3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl -1-[[3-[5- methyl -2-(2- Trimethylsilylethoxymethyl ) Pyrazole -3- base ]-4- Pyridyl ] methyl ] Urea and 3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl -1-[[3-[5- methyl -1-(2- Trimethylsilylethoxymethyl ) Pyrazole -3- base ]-4- Pyridyl ] methyl ] Urea

Trimethyl-[2-[[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane and trimethyl-[2-[[5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (two pyrazole positional isomers) (100 mg, 260.1 µmol), Cs ₂ CO ₃ (254.24 mg, 780.3 µmol), cataCXium Pd G4 (19.3 mg, 26.01 µmol) were added to a small vial under an atmosphere of argon. and 1-[(3- bromo -4 -pyridinyl ) methyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea from Example 28 (95.87 mg, 260.1 µmol) were suspended in 1,4-dioxane (650.25 µL) and water (650.25 µL). The mixture was stirred at 100 °C for 3 h, then poured into EtOAc, filtered through celite and concentrated in vacuo. Purification by FC (SiO ₂ , heptane/EtOAc/EtOH) gave the title compound as a mixture of two pyrazole positional isomers (41.87 mg, 31% yield) and as a colorless oil. MS (ESI): m/z = 482.3 [M+H] ⁺ Example 60 2- Cyano -3-(4,4 -difluorotetrahydrofuran -3 -yl )-1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ] guanidine

To a solution of 3-(4,4-difluorotetrahydrofuran-3-yl)-1,2-dimethyl-1-[(1S)-1-(4-pyridyl)ethyl]isothiourea (48 mg, 152.2 µmol) in extra dry THF (500 µL) at 23°C was added cyanamide (63.98 mg, 1.52 mmol). The mixture was stirred at 23°C for 16 h, then additional DIPEA (53.16 µL, 304.39 µmol) was added. The reaction was heated to 45°C for 32 h, then concentrated under reduced pressure. Purification by FC (SiO ₂ , DCM/MeOH) followed by RP FC (MeCN/H ₂ O) gave the title compound as a non-mirror isomeric mixture (7.4 mg, 15% yield) as a colorless oil. MS (ESI): m/z = 310.1 [M+H] ⁺

Steps a) : 3-(4,4- Difluorotetrahydrofuran -3- base )-1,2- Dimethyl -1-[(1S)-1-(4- Pyridyl ) Ethyl ] Isothiourea

To a solution of Example 58 : 3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl -1-[(1S)-1-(4 -pyridinyl ) ethyl ] thiourea (46.1 mg, 152.97 µmol) in extra dry MeOH (1 mL) at -78 °C was added iodomethane (309 µL, 4.94 mmol) dropwise. The mixture was stirred at 23 °C for 16 h. It was then treated with 2 M _NH3 in MeOH and evaporated to give the crude title compound (45 mg, 47% yield) as a light yellow oil which was used directly in the next step. MS (ESI): m/z = 316.1 [M+H] ⁺ Example 61 1- methyl -3-(5 -oxotetrahydrofuran -3- yl )-1-[(1S)-1-(4- pyridyl ) ethyl ] urea

To a solution of 4-aminotetrahydrofuran-2-one; hydrochloride (CAS RN: 138846-59-0; 100 mg, 726.96 µmol) in DCM (5 mL) at 23°C was added DIPEA (507.85 µL, 2.91 mmol) followed by CDT (143.17 mg, 872.35 µmol). The reaction mixture was stirred at 23°C for 1 hour. Then, a solution of methyl-[(1S)-1-(4-pyridinyl)ethyl]amine; dihydrochloride (CAS RN: 42732-16-1; 152.02 mg, 726.96 µmol) in DCM (5 mL) was added and the reaction mixture was stirred at 23°C for 15 hours. The solvent was evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) and by RP-HPLC (YMC-Triart C18, 12 nm, 5 μm, 100 x 30 mm, CH ₃ CN/H ₂ O+0.1% TEA) gave the title compound as a mixture of non-mirror isomers (171.9 mg, 88% yield, t _R = 0.825 min) as a colorless oil. MS (ESI): m/z = 264.2 [M+H] ⁺ Example 62 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[[3-[[(3S) -tetrahydrofuran -3- yl ] methyl ]-4 -pyridinyl ] methyl ] urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[[3-[[(3R) -tetrahydrofuran - 3- yl ] methyl ]-4 -pyridinyl ] methyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[[3-[[(3S) -tetrahydrofuran -3- yl ] methyl ]-4 -pyridyl ] methyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[[3-[[(3R) -tetrahydrofuran -3- yl ] methyl ]-4 -pyridyl ] methyl ] urea

To a solution of 4,4-difluorotetrahydrofuran-3-amine; hydrochloride (CAS RN: 2408969-70-8; 171.45 mg, 1.07 mmol) in DCM (25 mL) was added DIPEA (0.75 mL, 4.3 mmol) followed by CDT (193.99 mg, 1.18 mmol). The reaction mixture was stirred at 23 °C for 2 hours and then treated with N-methyl-1-[3-(tetrahydrofuran-3-ylmethyl)-4-pyridinyl]methanamine; dihydrochloride (300.0 mg, 1.07 mmol). The mixture was stirred at 23 °C for 20 hours and then treated with water. The aqueous layer was back extracted three times with DCM. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by RP-HPLC (XBridge BEH C18, 100 x 19 mm, 5 µM, MeCN/H ₂ O+0.1% HCl) and chiral SFC (column Chiralpak IF, 250x20 mm, 5 µm, 25%/25% IPA/MeOH) gave the title compound as a yellow oil (16.5 mg, 4% yield, t _R = 21.23 min). MS (ESI): m/z = 356.2 [M+H] ⁺

Steps a : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

Boc ₂ O (7.16 g, 32.82 mmol) was added dropwise to a solution of 1-(3-bromo-4-pyridinyl)-N-methyl-methylamine (CAS RN: 73335-64-5; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25°C. After stirring for 18 hours, the solvent was evaporated to give the title compound as a light yellow oil (9.0 g, 96% yield). MS (ESI): m/z = 303.0 [M+H] ⁺

Steps b : N- methyl -N-[[3-[(E)- Tetrahydrofuran -3- Methylene ]-4- Pyridyl ] methyl ] Tributyl carbamate

Under nitrogen in a vial, 4,4,5,5-tetramethyl-2-[(Z)-tetrahydrofuran-3-ylidenemethyl]-1,3,2-dioxaborolane (CAS RN: 2365173-52-8; 800.0 mg, 3.81 mmol), N-[(3-bromo-4-pyridinyl)methyl]-N-methyl-carbamic acid tributyl ester (1.147 g, 3.81 mmol), K ₂ CO ₃ (1.053 g, 7.62 mmol) and (PPh ₃ ) ₂ PdCl ₂ ·DCM complex (466.11 mg, 0.57 mmol) were suspended in 1,4-dioxane (32 mL) and water (8 mL). The mixture was bubbled with argon for 10 min and then stirred vigorously at 90 °C for 16 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiO ₂ ; PE/THF) gave the title compound as a light brown solid (760 mg, 60% yield). MS (ESI): m/z = 305.2 [M-Bu+H] ⁺

Steps c : N- methyl -N-[[3-( Tetrahydrofuran -3- Methyl )-4- Pyridyl ] methyl ] Tributyl carbamate

N-Methyl-N-[[3-[(E)-tetrahydrofuran-3-ylidenemethyl]-4-pyridinyl]methyl]carbamic acid tributyl ester (100.0 mg, 0.33 mmol) was dissolved in EtOAc (15 mL) and hydrogenated over Pd/C 10% (14.14 mg, 0.01 mmol) at 3800 mmHg for 48 h. The reaction mixture was filtered to remove Pd/C and the solvent was evaporated to give the title compound as a light yellow oil (100.0 mg, 93% yield). MS (ESI): m/z = 307.2 [M+H] ⁺

Steps d : N- methyl -1-[3-( Tetrahydrofuran -3- Methyl )-4- Pyridyl ] Methylamine; dihydrochloride

Tributyl N-methyl-N-[[3-(tetrahydrofuran-3-ylmethyl)-4-pyridinyl]methyl]carbamate (600.0 mg, 1.96 mmol) was dissolved in MeOH (25 mL) and HCl (4 N in 1,4-dioxane) (0.49 mL, 1.96 mmol) was added. The reaction was stirred at 25 °C for 16 h. The solvent was evaporated and the residue was triturated with _Et2O , filtered and dried to give the title compound as a yellow solid (350.0 mg, 61% yield). MS (ESI): m / z = 207.2 [M+H] ⁺ Synthesis of the most common intermediate 1-[(3- bromo-4-pyridinyl) methyl ] -3 - [ (3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea Int-1 for Examples 63 , 64, 65 , 66 , 67, 70 and 74

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 474.78 mg, 2.98 mmol) in DCM (7 mL) was added DIPEA (1.56 mL, 8.93 mmol) followed by CDT (732.54 mg, 4.46 mmol). The mixture was stirred at 23 °C for 2 hours. 1-(3-bromopyridin-4-yl)-n-methylmethanamine (CAS RN: 463941-58-4; 418.08 µL, 2.98 mmol) was then added. The reaction mixture was stirred at 23 °C for 20 hours and then treated with water. The aqueous layer was back extracted three times with DCM. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; EtOAc/EtOH/heptane) and by chiral SFC (column Chiralpak IF, 250x20 mm, 5 µm, 26% MeOH) gave the title compound as an off-white semisolid (383.43 mg, 49% yield, t _R = 1.512 min). MS (ESI): m/z = 352.0 [M+H] ⁺ Example 63 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[[3-(4 -pyridinyl )-4 -pyridinyl ] methyl ] urea

In a vial under hydrogen, 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 (63.91 mg, 182.5 µmol), pyridine-4-boronic acid, ester (CAS RN: 181219-01-2; 41.17 mg, 200.75 µmol), Cs ₂ CO ₃ (178.39 mg, 547.51 µmol) and cataCXium Pd G4 (13.55 mg, 18.25 µmol) were suspended in 1,4-dioxane (456.26 µL) and water (456.26 µL). The reaction mixture was bubbled with argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiO ₂ ; EtOAc/EtOH/heptane) gave the title compound as a white solid (39.78 mg, 61% yield). MS (ESI): m/z = 349.2 [M+H] ⁺ Example 64 3-[(3S)-4,4 -difluorotetrahydrofuran -3 - yl ]-1- methyl -1-[[3-(3 -pyridinyl )-4 -pyridinyl ] methyl ] urea

In a vial under argon, 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methylurea Int-1 (63.91 mg, 182.5 µmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS RN: 329214-79-1; 41.17 mg, 200.75 µmol), Cs ₂ CO ₃ (178.39 mg, 547.51 µmol) and cataCXium Pd G4 (13.55 mg, 18.25 µmol) were suspended in 1,4-dioxane (456.26 µL) and water (456.26 µL). The mixture was bubbled with argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiO ₂ ; EtOAc/EtOH/heptane) gave the title compound as a white solid (43.08 mg, 68% yield). MS (ESI): m/z 349.2 [M+H] ⁺ Example 65 1-[[3-(4- chlorophenyl )-4 -pyridinyl ] methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

In a vial under nitrogen, 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 (63.91 mg, 182.5 µmol), 4-chlorophenylboronic acid (CAS RN: 1679-18-1; 31.39 mg, 200.75 µmol), Cs ₂ CO ₃ (178.39 mg, 547.51 µmol) and cataCXium Pd G4 (13.55 mg, 18.25 µmol) were suspended in 1,4-dioxane (456.26 µL) and water (456.26 µL). The reaction mixture was bubbled with argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by RP (C18, MeCN/H ₂ O) gave the title compound as a white solid (19.31 mg, 28% yield). MS (ESI): m/z = 382.1 [M+H] ⁺ Example 66 1-[[3-(2- Chlorophenyl )-4 - pyridinyl ] methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

In a vial under nitrogen, 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 (63.91 mg, 182.5 µmol), 2-chlorophenylboronic acid (CAS RN: 3900-89-8; 41.17 mg, 200.75 µmol), Cs ₂ CO ₃ (178.39 mg, 547.51 µmol) and cataCXium Pd G4 (13.55 mg, 18.25 µmol) were suspended in 1,4-dioxane (456.26 µL) and water (456.26 µL). The mixture was bubbled with argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiO ₂ ; EtOAc/EtOH/heptane) gave the title compound as a white solid (46.94 mg, 67% yield). MS (ESI): m/z 382.1 [M+H] ⁺ Example 67 1-[[3-(3- chlorophenyl )-4 -pyridinyl ] methyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

In a vial under nitrogen, 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 (63.91 mg, 182.5 µmol), 3-chlorophenylboronic acid (CAS RN: 63503-60-6; 31.39 mg, 200.75 µmol), Cs ₂ CO ₃ (178.39 mg, 547.51 µmol) and cataCXium Pd G4 (13.55 mg, 18.25 µmol) were suspended in 1,4-dioxane (456.26 µL) and water (456.26 µL). The reaction mixture was bubbled with argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by RP (C18, MeCN/H ₂ O) gave the title compound as a white solid (30.25 mg, 43% yield). MS (ESI): m/z = 382.1 [M+H] ⁺ Example 68 1-[2-(3- Chlorophenoxy )-1-(4 -pyridinyl ) ethyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 26.67 mg, 167.15 µmol) in DCM (840 µL) was added DIPEA (190.75 µL, 1.11 mmol) followed by CDT (35.56 mg, 216.7 µmol). The mixture was stirred at 23 °C for 2 h. Then, [2-(3-chlorophenoxy)-1-(4-pyridinyl)ethyl]-methyl-amine; hydrochloride (50 mg, 167.11 µmol) was added. The reaction mixture was stirred at 23 °C for 16 h. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12nm, 5μm, 100 x 30mm, CH ₃ CN/H ₂ O+0.1% HCOOH) gave the title compound as a non-mirror isomeric mixture (13 mg, 19% yield) as an off-white semisolid. MS (ESI): m/z = 412.2 [M+H] ⁺

Steps a : 2-(3- Chlorophenoxy )-1-(4- Pyridyl ) Ethyl Ketone

To a solution of 3-chlorophenol (CAS RN: 108-43-0; 22.65 g, 176.19 mmol) in MeCN (150 mL) at 25°C was added K ₂ CO ₃ (24.35 g, 176.19 mmol). Then 4-(bromoacetyl)pyridinium hydrobromide (CAS RN: 5349-17-7; 3.0 g, 10.68 mmol) was added and the reaction was stirred at 60°C for 0.15 h. Then a second portion of 4-(bromoacetyl)pyridinium hydrobromide (CAS RN: 5349-17-7; 5.0 g, 17.8 mmol) was added and the reaction was stirred at 60°C for another 0.15 h. A third portion of 4-(bromoacetyl)pyridinium hydrobromide (CAS RN: 5349-17-7; 8.0 g, 28.48 mmol) was then added and the reaction was stirred at 60 °C for another 30 min. The solvent was evaporated. Purification by FC (SiO ₂ ; PE/EtOAc) gave the title compound as a pink solid (10.76 g, 74% yield). MS (ESI): m/z = 248.0 [M+H] ⁺

Steps b : 2-(3- Chlorophenoxy )-N- methyl -1-(4- Pyridyl ) Ethylamine; dihydrochloride

A mixture of 2-(3-chlorophenoxy)-1-(4-pyridyl)ethanone (2.0 g, 8.07 mmol), MeNH ₂ ·HCl (CAS RN: 593-51-1; 1.09 g, 16.15 mmol), NaOAc (1.373 g, 20.19 mmol) in DCE (20 mL) was stirred at 70°C for 2 hours. NaBH ₃ CN (1.526 g, 24.22 mmol) was added to the reaction and the resulting mixture was stirred at 25°C for 12 hours. The precipitate was filtered off and the filtrate was evaporated. Purification by RP-HPLC (Phenomenex Luna C18, 15 μm, 150 x 40 mm, CH ₃ CN/H ₂ O+0.1% HCO ₂ H) and titration with HCl afforded the title compound as a yellow solid (253.11 mg, 12% yield). MS (ESI): m/z = 263.1 [M-2HCl+H] ⁺ Example 69 3-(4,4- difluorotetrahydrofuran -3- yl )-1- methyl -1-[(3 -prop -1- ynyl -4- pyridinyl ) methyl ] urea

In a vial under argon, bis(triphenylphosphine)palladium(II) chloride (3.06 mg, 4.36 µmol), TEA (91.21 µL, 654.39 µmol) and 1-[(3-bromo-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea (80.4 mg, 0.218 mmol) were dissolved in extra dry THF (1.09 mL). Then 1 M prop-1-yne solution (261.75 µL, 261.75 µmol) and CuI (1.66 mg, 8.73 µmol) were added and the mixture was heated to 65°C. After 1.5 hours, more 1 M prop-1-yne solution (218.13 µL, 218.13 µmol) was added and the mixture was heated to 65°C. After 4.5 hours, more 1 M prop-1-yne solution (436.26 µL, 436.26 µmol) was added and the mixture was heated to 65°C. After 25 hours, more 1 M prop-1-yne solution (436.26 µL, 436.26 µmol) was added. After 26 hours, bis(triphenylphosphine)palladium(II) chloride (15.31 mg, 21.81 µmol), CuI (8.31 mg, 43.63 µmol), TEA (91.21 µL, 654.39 µmol) and 1 M prop-1-yne solution (436.26 µL, 436.26 µmol) were added. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The combined filtrate was evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12nm, 5μm, 100 x 30mm, CH ₃ CN/H ₂ O+0.1% HCOOH) gave the title compound as a light yellow oil (1.1 mg, 2% yield). MS (ESI): m/z = 310.1 [M+H] ⁺

Steps a : 1-[(3- bromine -4- Pyridyl ) methyl ]-3-(4,4- Difluorotetrahydrofuran -3- base )-1- methyl - Urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 39.68 mg, 248.68 µmol) in DCM (800 µL) was added DIPEA (130 µL, 746.05 µmol) followed by CDT (44.9 mg, 273.55 µmol). The reaction mixture was stirred at 23°C for 16 hours. Then 1-(3-bromopyridin-4-yl)-n-methylmethanamine (CAS RN: 463941-58-4; 50 mg, 248.68 µmol) was added. The reaction mixture was stirred at 23°C for 4 hours. MeOH and Isolute were added. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) gave the title compound as a colorless oil (80.4 mg, 88% yield). Example 70 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl -1-[[3-(2 -pyridinyl )-4 -pyridinyl ] methyl ] urea

1-[(3-Bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 (30.47 mg, 87.02 µmol), 2-tri-n-butyltinylpyridine (CAS RN: 17997-47-6; 69.64 µL, 174.03 µmol) and LiCl (7.38 mg, 174.03 µmol) and tetrakis(triphenylphosphine)palladium (20.11 mg, 17.4 µmol) were suspended in 1,4-dioxane (1.5 mL) in a vial under argon. The mixture was bubbled with argon for 10 minutes and then vigorously stirred at 100 °C for 15 hours. After cooling to 23°C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by RP (C18, MeCN:H ₂ O) and FC (SiO ₂ ; EtOAc/EtOH/heptane) gave the title compound as a white solid (5.79 mg, 19% yield). MS (ESI): m/z = 349.1 [M+H] ⁺ Example 71 1-[2-(4- chlorophenoxy )-1-(4 -pyridinyl ) ethyl ]-3-(4,4 -difluorotetrahydrofuran -3- yl )-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 30.37 mg, 190.35 µmol) in DCM (956 µL) was added DIPEA (217.23 µL, 1.27 mmol) followed by CDT (40.5 mg, 246.75 µmol). The reaction mixture was stirred at 23 °C for 1 hour. Then, [2-(4-chlorophenoxy)-1-(4-pyridinyl)ethyl]-methyl-amine (50 mg, 190.31 µmol) was added. The reaction mixture was stirred at 23 °C for 16 hours. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12nm, 5μm, 100 x 30mm, CH ₃ CN/H ₂ O+0.1% HCOOH) gave the title compound as a non-mirror isomeric mixture (23 mg, 29% yield) as a white powder. MS (ESI): m/z = 412.1 [M+H] ⁺

Steps a : 2-(4- Chlorophenoxy )-1-(4- Pyridyl ) Ethyl Ketone

To a solution of 4-chlorophenol (CAS RN: 106-48-9; 2.75 g, 21.36 mmol) in MeCN (10 mL) at 25 °C was added K ₂ CO ₃ (6.18 g, 44.5 mmol). Then 4-(bromoacetyl)pyridinium hydrobromide (CAS RN: 5349-17-7; 5.0 g, 17.8 mmol) was added and the reaction was stirred at 25 °C for 12 h. The solvent was evaporated. Purification by RP-HPLC (CH ₃ CN/H ₂ O+0.1% NH ₃ .H ₂ O) gave the title compound as a white solid (3.0 g, 68% yield). MS (ESI): m/z = 248.6 [M+H] ⁺

Steps b : 2-(4- Chlorophenoxy )-N- methyl -1-(4- Pyridyl ) Ethylamine

A mixture of 2-(4-chlorophenoxy)-1-(4-pyridinyl)ethanone (3.0 g, 12.11 mmol), MeNH ₂ .HCl (CAS RN: 593-51-1; 1.7 g, 24.22 mmol), NaOAc (2.06 g, 30.28 mmol) in DCE (20 mL) was stirred at 70°C for 2 hours. NaBH ₃ CN (2.29 g, 36.34 mmol) was added to the reaction and the resulting mixture was stirred at 25°C for 12 hours. The precipitate was filtered off and the filtrate was evaporated. Purification by RP-HPLC (CH ₃ CN/H ₂ O+0.1% TEA) and trituration with HCl gave the title compound as a yellow solid (590.66 mg, 18% yield). MS (ESI): m/z = 263.2 [M+H] ⁺ Example 72 3-[(3S,4R)-4 -Hydroxytetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea or 3-[(3R, 4S)-4 -Hydroxytetrahydrofuran -3- yl ]-1- methyl -1-[(1S)-1-(4 -pyridyl ) ethyl ] urea

To a solution of (trans-4-amino-tetrahydrofuran-3-ol (CAS RN: 330975-13-8; 57.55 mg, 558.04 µmol) in DMF (1.12 mL) was added DIPEA (382.11 µL, 2.23 mmol) and TMSCl (72.78 µL, 558.04 µmol). The reaction was stirred at 23 °C for 30 min and then treated with CDT (137.38 mg, 837.07 µmol). The reaction mixture was stirred at 75 °C for 40 min. Then, methyl-[(1S)-1-(4-pyridinyl)ethyl]amine (CAS RN: 42732-16-1; 80 mg, 558.04 µmol) was added. The mixture was stirred at 75 °C for 5 min. Stir for 16 hours. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by RP (C18, CH ₃ CN/H ₂ O) and chiral SFC (column chiral Amy1, 5 µm, 250x20 mm, 28% MeOH) gave the title compound as a light brown solid (8.7 mg, 6% yield, t _R = 3.695 min). MS (ESI): m/z = 266.2 [M+H] ⁺ Example 73 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[[3-( tetrahydropyran- 4- ylmethyl )-4 - pyridinyl ] methyl ] urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 - yl ]-1- methyl -1-[[3-( tetrahydropyran- 4 -ylmethyl )-4 -pyridinyl ] methyl ] urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 166.3 mg, 1.04 mmol) in DCM (5 mL) was added DIPEA (910 µL, 5.21 mmol) and then CDT (205.2 mg, 1.25 mmol). The reaction mixture was stirred at 23°C for 40 min. Then, methyl-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridinyl]methyl]amine.2,2,2-trifluoroacetic acid (1.16 g, 1.04 mmol) was added. The reaction mixture was stirred at 23°C for 16 h. The organic layer was dried over Na ₂ SO ₄ , mixed with Isolute and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) and by chiral SFC (chiral column OZ-H, 5 μm, 250 x 20 mm, 25% MeOH) afforded the title compound as a yellow gel (24.9 mg, 6% yield, t _R = 1.780 min). MS (ESI): m/z = 370.2 [M+H] ⁺

Steps a : N-[(3- bromine -4- Pyridyl ) methyl ]-N- methyl - Tributyl carbamate

To a solution of (3-bromo-4-pyridinyl)methyl-methyl-amine (CAS RN: 463941-58-4; 2500 mg, 12.43 mmol) in DCM (60 mL) was added DIPEA (8.69 mL, 49.74 mmol) and then Boc ₂ O (4.33 mL, 18.65 mmol) at 23°C. The mixture was maintained at this temperature for 17 h and then treated with water and diluted with DCM. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by FC (SiO ₂ ; heptane/EtOAc) gave the title compound as an orange oil (3078 mg, 80.55%). MS (ESI): m/z = 301.1 [M+H] ⁺

Steps b : N- methyl -N-[[3-( Tetrahydropyran -4- Methylene )-4- Pyridyl ] methyl ] Tributyl carbamate

To a solution of tributyl N-[(3-bromo-4-pyridinyl)methyl]-N-methyl-carbamate (500 mg, 1.63 mmol) and 4,4,5,5-tetramethyl-2-(tetrahydropyran-4-ylidenemethyl)-1,3,2-dioxaborolane (364.6 mg, 1.63 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) under argon was added K ₂ CO ₃ (674.58 mg, 4.88 mmol) followed by dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (120.68 mg, 162.69 μmol). The mixture was stirred at 90°C for 15 h, then cooled to 23°C, filtered and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) gave the title compound as an orange oil (413.8 mg, 75.89%). MS (ESI): m/z = 319.2 [M+H] ⁺

Steps c : N- methyl -N-[[3-( Tetrahydropyran -4- Methyl )-4- Pyridyl ] methyl ] Tributyl carbamate

A solution of tributyl N-methyl-N-[[3-(tetrahydropyran-4-ylidenemethyl)-4-pyridinyl]methyl]carbamate (515 mg, 1.54 mmol) in MeOH (8 mL) was purged with argon and then Pd/C (163.52 mg, 153.65 µmol) was added. The system was then purged with _H2 . The reaction mixture was stirred at 23 °C for 3 h and then filtered on a celite pad, washed with MeOH and evaporated to give the title compound as an orange oil (433.8 mg, 79.3%). MS (ESI): m/z = 321.2 [M+H] ⁺

Steps d :methyl -[[3-( Tetrahydropyran -4- Methyl )-4- Pyridyl ] methyl ] amine 1:1 2,2,2- Trifluoroacetic acid

To a solution of tributyl N-methyl-N-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridinyl]methyl]carbamate (433.8 mg, 1.22 mmol) in DCM (6 mL) at 23°C was added TFA (938.68 µL, 12.18 mmol). The mixture was stirred at this temperature for 3 hours and then treated with more TFA (469.34 µL, 6.09 mmol). The mixture was stirred at 23°C for another 2 hours and then evaporated to give the title compound as a brown oil (1.16 g, 85.52%). MS (ES): m/z = 221.2 [M+H] ⁺ Example 74 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl -1-[[3-[4-( trifluoromethyl ) phenyl ]-4 -pyridinyl ] methyl ] urea

In a vial under nitrogen, 1-[(3-bromo-4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 (60.0 mg, 171.35 µmol), 4-(trifluoromethyl)phenylboronic acid (CAS RN: 128796-39-4; 36.91 mg, 188.49 µmol), Cs ₂ CO ₃ (167.49 mg, 514.05 µmol) and cataCXium Pd G4 (12.72 mg, 17.14 µmol) were suspended in 1,4-dioxane (400 µL) and water (400 µL). The mixture was bubbled with argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiO ₂ ; EtOAc/EtOH/heptane) gave the title compound as a white solid (48.57 mg, 68% yield). MS (ESI): m/z 416.0 [M+H] ⁺ Example 75 [3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea ] or [3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3,5- dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea and 3-[(3S)-4,4 -difluorotetrahydrofuran - 3-yl ]-1-[(1R)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea ] or [3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1 - methyl - urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3,5- dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea ] or [3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-1-(3,5- dimethyl -4- pyridyl ) ethyl ]-1- methyl - urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea ] or [3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1 - methyl- Urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1R)-1-(3,5- dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea ] or [3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea and 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3,5 -dimethyl -4 -pyridyl ) ethyl ]-1- methyl - urea ]

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 195 mg, 1.22 mmol) in DCM (2.5 mL) was added DIPEA (534 µL, 3.06 mmol) and then CDT (251 mg, 1.53 mmol). The reaction mixture was stirred at 23 °C for 2 hours. Then, 1-(3,5-dimethyl-4-pyridinyl)ethyl-methyl-amine (167.3 mg, 1.02 mmol) was added. The reaction mixture was stirred at 23 °C for 17 hours. The mixture was treated with H ₂ O and extracted with EtOAc. The organic layer was dried over MgSO ₄ and evaporated. Purification by FC (SiO ₂ ; heptane/EtOAc/EtOH) and by SFC (chiral column OZ-H, 5 μm, 250 x 20 mm, 25% MeOH + 0.2% DIPEA) gave the title compound as a mixture of two structural isomers (4.34 mg, 1.32% yield, t _R = 0.981 min) as an off-white solid. MS (ESI): m/z = 314.2 [M+H] ⁺

Steps a : 1-(3,5- Dimethyl -4- Pyridyl ) Ethanol

To a solution of 3,5-dimethylpyridine-4-carbaldehyde (CAS RN: 201286-64-8; 150 mg, 1.11 mmol) in THF (8 mL) at -78 °C was added dropwise a solution of 3.4 M MeMgBr in 2-Me-THF (816.03 µL, 2.77 mmol) under argon at -78 °C. The reaction mixture was slowly warmed to 0 °C over 3.5 h. The reaction was quenched with saturated aqueous NH ₄ Cl solution. The aqueous phase was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and evaporated to give the title compound as a yellow solid (184.2 mg, over quantitative). The crude product was directly used in the next transformation without further purification. MS (ESI): m/z = 152.1 [M+H] ⁺

Steps b : 4-(1- Chloroethyl )-3,5- Dimethyl - Pyridine

To a solution of 1-(3,5-dimethyl-4-pyridinyl)ethanol (184.2 mg, 1.16 mmol) in extra dry DCM (5 mL) was added SOCl ₂ (253.4 µL, 3.47 mmol) in a flask at 0°C under argon. The reaction mixture was stirred at 23°C for 20 h. The mixture was quenched with saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to give the title compound as a yellow oil (261.78 mg, in excess of quantitative). The crude product was directly used in the next transformation without further purification. MS (ESI): m/z = 170.0 [M+H] ⁺

Steps c : 1-(3,5- Dimethyl -4- Pyridyl ) Ethyl - methyl - amine

4-(1-Chloroethyl)-3,5-dimethyl-pyridine (261.78 mg, 1.48 mmol), 2 M MeNH ₂ in THF (888.8 µL, 1.78 mmol) and K ₂ CO ₃ (409.47 mg, 2.96 mmol) were suspended in DMF (7 mL) in a flask under argon. The mixture was stirred at 100 °C for 14 h. The reaction was cooled to 50 °C. Additional 2 M MeNH ₂ in THF (2.96 mL, 5.93 mmol) and KI (12.3 mg, 74.07 µmol) were added and the mixture was stirred at 50 °C for 18 h. The mixture was treated with H ₂ O and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to give the title compound as a brown oil (167.3 mg, 57% yield). MS (ESI): m/z = 165.2 [M+H] ⁺ Example 76 1-[(1S)-1-(3- bromo -4 -pyridinyl ) ethyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl - urea or 1-[(1S)-1-(3- bromo - 4 -pyridinyl ) ethyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(1R)-1-(3- bromo -4 -pyridinyl ) ethyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl - urea or 1-[(1R)-1-(3- bromo - 4 -pyridinyl ) ethyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 277 mg, 1.74 mmol) in DCM (3.5 mL) was added DIPEA (758 µL, 4.34 mmol) and then CDT (356 mg, 2.17 mmol). The reaction mixture was stirred at 23 °C for 2 hours. Then, 1-(3-bromo-4-pyridinyl)ethyl-methyl-amine (611 mg, 1.45 mmol) was added. The reaction mixture was stirred at 23 °C for 20 hours. The mixture was treated with H ₂ O and extracted with EtOAc. The organic layer was dried over MgSO ₄ and evaporated. Purification by FC (SiO ₂ ; heptane/EtOAc/EtOH) and by chiral SFC (chiral column Whelk01 r,r, 5 μm, 250 x 20 mm, 20% MeOH) gave the title compound (4.34 mg, 1.32% yield, t _R = 2.181 min) as an off-white solid. MS (ESI): m/z = 364.1 [M+H] ⁺

Steps a : 1-(3- bromine -4- Pyridyl ) Ethyl - methyl - amine

A solution of 1-(3-bromopyridin-4-yl)ethanone (CAS RN: 111043-06-2; 325.95 µL, 2.5 mmol), 2 M MeNH ₂ in THF (1.5 mL, 3.00 mmol) and Ti(O ⁱ Pr) ₄ (740.05 µL, 2.5 mmol) were dissolved in extra dry THF (6 mL). The mixture was stirred at 23 °C for 20 h. NaBH ₄ (283.68 mg, 7.5 mmol) was added at 0 °C and the mixture was stirred at 23 °C for 4.5 h. The reaction was quenched with 12 mL of 25% aqueous NH ₃ solution and the mixture was stirred at 23 °C for 1 h. The mixture was filtered through celite and the solvent was evaporated. The crude product was partitioned between EtOAc and 1 M aqueous NaOH. The aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO ₄ and evaporated to give the title compound as a yellow oil (610.48 mg, 58% yield). MS (ESI): m/z 215.0 [M+H] ⁺ Example 77 1-[(1R)-2-(4- chlorophenoxy )-1-(4 -pyridinyl ) ethyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(1R)-2-(4- chlorophenoxy )-1-(4 -pyridinyl ) ethyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(1S)-2-(4- chlorophenoxy )-1-(4 -pyridinyl ) ethyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(1S)-2-(4- chlorophenoxy )-1-(4 -pyridinyl ) ethyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 30.37 mg, 190.35 µmol) in DCM (956 µL) was added DIPEA (217 µL, 1.27 mmol) followed by CDT (40.5 mg, 247 µmol). The reaction mixture was stirred at 23 °C for 1 hour. Then, [2-(4-chlorophenoxy)-1-(4-pyridinyl)ethyl]-methyl-amine (50.0 mg, 190 µmol) was added. The reaction mixture was stirred at 23 °C for 16 hours. The organic layer was dried over MgSO ₄ and evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12 nm, 5 μm, 100 x 30 mm, CH ₃ CN/H ₂ O+0.1% HCOOH) and chiral SFC (chiral column Wrr, 5 μm, 250 x 20 mm, 24% MeOH+0.2% TEA) gave the title compound (5.6 mg, 25% yield, t _R = 3.069 min) as a white powder. MS (ESI): m/z = 412.1 [M+H] ⁺

Steps a : 2-(4- Chlorophenoxy )-1-(4- Pyridyl ) Ethyl Ketone

To a solution of 4-chlorophenol (CAS RN: 106-48-9; 2.75 g, 21.36 mmol) in MeCN (10 mL) was added K ₂ CO ₃ (6.18 g, 44.49 mmol) and 4-(bromoacetyl)pyridinium hydrobromide (CAS RN: 5349-17-7; 5 g, 17.8 mmol). The mixture was stirred at 25 °C for 12 h. The solvent was removed in vacuo. Purification by RP-HPLC (0.1% NH ₃ .H ₂ O) gave the title compound (3.0 g, 68% yield) as a white solid. MS (ESI): m/z = 248.6 [M+H] ⁺

Steps b : 2-(4- Chlorophenoxy )-N- methyl -1-(4- Pyridyl ) Ethylamine

A mixture of 2-(4-chlorophenoxy)-1-(4-pyridinyl)ethanone (3.0 g, 12.11 mmol), MeNH ₃ HCl (1.7 g, 24.22 mmol), NaOAc (2.06 g, 30.28 mmol) in DCE (20 mL) was stirred at 70°C for 2 hours. Then NaBH ₃ CN (2.29 g, 36.34 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction was filtered and evaporated. Purification by RP-HPLC (0.1% NH ₃ ·H ₂ O) gave the title compound as a brown oil (590.66 mg, 19% yield). MS (ESI): m/z = 263.2 [M+H] ⁺ Example 78 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-3-(4- fluorophenyl )-1-(4 -pyridyl ) propyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-3-(4- fluorophenyl )-1-(4 -pyridyl ) propyl ]-1- methyl - urea or 3-[(3R)-4,4 -difluorotetrahydrofuran - 3-yl ]-1-[(1R)-3-(4- fluorophenyl )-1-(4 -pyridyl ) propyl ]-1- methyl - urea or 3-[(3S)-4,4 -difluorotetrahydrofuran -3 - yl ]-1-[(1R)-3-(4- fluorophenyl )-1-(4 -pyridyl ) propyl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 102 mg, 639.26 µmol) in DCM (2.3 mL) was added DIPEA (280 µL, 1.6 mmol) followed by CDT (152 mg, 926 µmol). The reaction mixture was stirred at 23 °C for 1 hour. Then, [3-(4-fluorophenyl)-1-(4-pyridinyl)propyl]-methyl-amine (150.0 mg, 614 µmol) was added. The reaction mixture was stirred at 23 °C for 16 hours. The organic layer was dried over MgSO ₄ and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) and by chiral SFC (chiral column Wrr, 5 μm, 250 x 20 mm, 29% EtOH) afforded the title compound as a white powder (25 mg, 14% yield, t _R = 3.005 min). MS (ESI): m/z = 394.2 [M+H] ⁺

Steps a : N-[(E)-2-(4- Fluorophenyl ) Ethyleneamino ]-4- methyl - Benzenesulfonamide

To a solution of (4-fluorophenyl)acetaldehyde (CAS RN: 1736-67-0; 3.5 g, 25.34 mmol) in MeOH (100 mL) was added 4-toluenesulfonylhydrazine (CAS RN: 1576-35-8; 4.8 g, 25.34 mmol) and the mixture was stirred at 60°C for 0.4 h. The mixture was evaporated. Purification by FC (SiO ₂ ; PE/EtOAc) gave the title compound as a yellow oil (7.8 g, quantitative). MS (ESI): m/z = 307.0 [M+H] ⁺

Steps b : 3-(4- Fluorophenyl )-1-(4- Pyridyl ) C -1- ketone

To a solution of 4-pyridinecarboxaldehyde (CAS RN: 872-85-5; 1.56 mL, 16.32 mmol) in 1,4-dioxane (100 mL) was added N-[( E )-2-(4-fluorophenyl)ethyleneamino]-4-methyl-benzenesulfonamide (5.0 g, 16.32 mmol) and _Cs2CO3 (1.6 g, 48.96 mmol). The mixture was stirred at 110°C for 12 h. The mixture was evaporated. Purification by FC ( _SiO2 ; PE/EtOAc) gave the title _compound as a yellow oil (2.8 g, 75% yield). MS (ESI): m/z = 230.1 [M+H] ⁺

Steps c : 3-(4- Fluorophenyl )-N- methyl -1-(4- Pyridyl ) C -1- Amine; dihydrochloride

To a solution of 3-(4-fluorophenyl)-1-(4-pyridinyl)propan-1-one (2.8 g, 12.2 mmol) in THF (100 mL) was added AcOH (70 µL, 1.22 mmol) and the reaction was stirred at 25 °C for 15 min. Then a solution of MeNH ₂ in THF (73.28 mL, 146.56 mmol) was added and the resulting mixture was stirred at 25 °C for 4 h. NaBH ₃ CN (3.8 g, 61.07 mmol) was added portionwise at 0 °C and the mixture was stirred at 25 °C for 12 h. The mixture was evaporated. Purification by RP-HPLC (C18, CH ₃ CN/H ₂ O) gave the title compound as a yellow solid (983.7 mg, 25% yield). MS (ESI): m/z = 245.1 [M+H] ⁺ Example 79 1-[(1S)-3,3 -difluoro -1-(4 -pyridyl ) propyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl - urea or 1-[(1S)-3,3 -difluoro -1-(4 -pyridyl ) propyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea or 1-[(1R)-3,3 -difluoro -1-(4 -pyridyl ) propyl ]-3-[(3R)-4,4 -difluorotetrahydrofuran -3 -yl ]-1- methyl - urea or 1-[(1R)-3,3 -difluoro -1-(4 -pyridyl ) propyl ]-3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1- methyl - urea

To a 0°C solution of 3,3-difluoro-N-methyl-1-(4-pyridinyl)propan-1-amine; 2,2,2-trifluoroacetic acid (0.3 g, 0.72 mmol) in DCM (25 mL) was added TEA (710 µL, 5.07 mmol) followed by CDI (180 mg, 1.09 mmol). The reaction mixture was stirred at 25°C for 1 hour. Then, (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 130.0 mg, 800 µmol) was added. The mixture was stirred at 23°C for 18 hours. The organic layer was dried over MgSO ₄ and evaporated. Purification by RP-HPLC (C18 Chromatorex SMB, CH ₃ CN/H ₂ O) and by chiral HPLC (Chiralpack IG, 5 μm, 250 x 20 mm, hexane/MeOH/IPA 50%/25%/25%) afforded the title compound as a yellow solid (17.6 mg, 7% yield, t _R = 15.46 min). MS (ESI): m/z = 336.0 [M+H] ⁺

Steps a : 4,4- Difluoro -2-(4- Pyridyl ) Methyl butyrate

To a solution of bis(isopropyl)amine (4.65 mL, 33.19 mmol) in THF (60 mL) was added dropwise a solution of n -BuLi 1 M in THF (14.34 mL, 35.84 mmol) at 0°C. The reaction was stirred at 0°C for 30 min. Then, a solution of methyl 2-(pyridin-4-yl)acetate (CAS RN: 29800-89-3; 4.01 g, 26.55 mmol) in THF (60 mL) was added at -40°C. The mixture was stirred at 0°C for 1 h. Then, a solution of 2,2-difluoroethyl trifluoromethanesulfonate (3.87 mL, 29.2 mmol) in THF (40 ml) was added dropwise, and the resulting mixture was stirred at -40°C for 1 hour. Then, the reaction was warmed to 23°C and stirred for 18 hours. The mixture was poured into saturated aqueous NH ₄ Cl solution (100 mL) and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; PE/EtOAc) gave the title compound (2.3 g, 38% yield). MS (ESI): m/z = 216.2 [M+H] ⁺

Steps b : 4,4- Difluoro -2-(4- Pyridyl ) Butyl hydrazine

To a solution of methyl 4,4-difluoro-2-(4-pyridyl)butanoate (2.3 g, 10.05 mmol) and hydrazine hydrate (CAS RN: 7803-57-8; 1.18 mL, 30.14 mmol) in EtOH (25 mL) was stirred at 75 °C for 18 h and then evaporated. Purification by FC (SiO ₂ ; CH ₃ CN/MeOH) gave the title compound (1.18 g, 49% yield). MS (ESI): m/z = 216.2 [M+H] ⁺

Steps c : N-[3,3- Difluoro -1-(4- Pyridyl ) Propyl ] Tributyl carbamate

4,4-Difluoro-2-(4-pyridyl)butanehydrazide (2.4 g, 11.15 mmol) was dissolved in HCl (64.0 mL, 182.6 mmol) and the solution was cooled to 0°C. A solution of NaNO ₂ (2.31 g, 33.46 mmol) in H ₂ O (12 mL) was added dropwise over 40 min. The reaction was stirred at 0°C for 1 h. Et ₂ O (100 mL) was added and the mixture was slowly neutralized with saturated aqueous NaHCO ₃ at the same temperature. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , and evaporated. The residue was diluted in ^t BuOH (40 mL) and heated at 82°C for 2 h. The solvent was removed in vacuo by azeotropic distillation with toluene. Purification by FC (SiO ₂ ; CHCl ₃ /CH ₃ CN) gave the title compound (1.1 g, 33% yield). MS (ESI): m/z = 273.2 [M+H] ⁺

Steps d : N-[3,3- Difluoro -1-(4- Pyridyl ) Propyl ]-N- methyl - Tributyl carbamate

Sodium hydride (60% solution in mineral oil) (8.08 mg, 0.2 mmol) was added portionwise to a solution of tributyl N-[3,3-difluoro-1-(4-pyridyl)propyl]carbamate (50.0 mg, 0.18 mmol) in THF (1 mL) at 0°C. The reaction mixture was stirred for 30 minutes then iodomethane (10 µL, 0.2 mmol) was added dropwise and the reaction was stirred at 23°C for 18 hours. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (30 mL). The organic phase was washed with water (2 x 50 mL) and brine (30 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FC (SiO ₂ ; heptane/EtOAc) gave the title compound as a dark brown viscous oil (30.0 mg, 17% yield). MS (ESI): m/z = 287.2 [M+H] ⁺

Steps e : [3,3- Difluoro -1-(4- Pyridyl ) Propyl ]- methyl - ammonium; 2,2,2- Trifluoroacetate

TFA (3.75 mL, 48.56 mmol) was added to a stirred solution of N-[3,3-difluoro-1-(4-pyridinyl)propyl]-N-methyl-carbamic acid tributyl ester (0.68 g, 2.36 mmol) in DCM (7 mL) at 20°C. The mixture was then stirred at 20°C for 18 hours. The solvent was evaporated to give the title compound (1.3 g, 87% yield). MS (ESI): m/z = 187.2 [M+H] ⁺ Example 80 1-( Difluoromethyl )-3-(4,4 -difluorotetrahydrofuran -3- yl )-1-(4 -pyridinylmethyl ) urea

N-(4-pyridylmethyl)thiocarboxamide (200.0 mg, 1.31 mmol) was dissolved in CH ₃ CN (5 mL) in a vial under argon. A solution of AgOCF ₃ in CH ₃ CN (3.94 mL, 3.94 mmol) was added. The mixture was stirred at 50°C for 2 hours. The resulting suspension was diluted with DCM and filtered through celite. The filtrate was evaporated. The residue was diluted with DCM/CH ₃ CN 1/1 (20 mL), filtered through celite and concentrated. The residue was dissolved in CH ₃ CN (5 mL), DIPEA (0.92 mL, 5.26 mmol) and (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 209.66 mg, 1.31 mmol) was added. The mixture was stirred at 20° C. for 15 h. The solvent was evaporated. Purification by HPLC (Chromatorex 18, CH ₃ CN/H ₂ O) gave the title compound (15.9 mg, 4% yield) as a white solid. MS (ESI): m/z = 308.2 [M+H] ⁺

Steps a : N-(4- Pyridylmethyl ) Formamide

To a solution of 4-(aminomethyl)pyridine (CAS RN: 3731-53-1; 1.00 g, 9.25 mmol) in THF (20 mL) was added (2,5-dioxopyrrolidin-1-yl)carboxylate (CAS RN: 17592-54-0; 1.324 g, 9.25 mmol) dropwise at 0°C. The mixture was stirred at 20°C for 5 h. The mixture was evaporated. The residue was diluted with CH ₃ CN (10 mL) and TEA (1.5 mL) was added. The precipitated solid was filtered off and the filtrate was evaporated to give the title compound as a light brown oil (800.0 mg, 57% yield). MS (ESI): m/z = 137.0 [M+H] ⁺

Steps b : N-(4- Pyridylmethyl ) Thiomethamide

To a solution of N-(4-pyridylmethyl)formamide (800.0 mg, 5.88 mmol) in THF (20 mL) was added Lawson's reagent (CAS RN: 19172-47-5; 1.307 g, 3.23 mmol) in one portion. The mixture was heated at 55 °C for 15 h. The mixture was evaporated. The residue was diluted with water (10 mL) and TEA (2 mL) was added. The resulting solution was extracted with DCM (2×20 mL). The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by RP-HPLC (XBridge BEH C18, H ₂ O/CH ₃ CN+0.1% NH ₄ OH) gave the title compound as a white solid (29.0 mg, 3% yield). MS (ESI): m/z = 153.0 [M+H] ⁺ Example 81 [3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea ] or [3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1S)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea and 3-[(3S)-4,4 -difluorotetrahydrofuran -3 -yl ]-1-[(1R)-1-(3- ethyl -4- pyridinyl ) ethyl ]-1- methyl - urea ] or [3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3- ethyl -4- pyridinyl ) ethyl ]-1 - methyl - urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3 - yl ]-1-[(1R)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea ] or [3-[(3R)-4,4 -difluorotetrahydrofuran - 3-yl ]-1-[(1S)-1-(3- ethyl -4- pyridinyl ) ethyl ]-1- methyl - urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea ] or [3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1 - methyl- Urea and 3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea ] or [3-[(3R)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1S)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea and 3-[(3S)-4,4 -difluorotetrahydrofuran -3- yl ]-1-[(1R)-1-(3- ethyl -4 -pyridinyl ) ethyl ]-1- methyl - urea

To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 151.55 mg, 949.77 µmol) in DCM (1.3 mL) was added DIPEA (581 µL, 3.2 mmol) followed by CDT (234 mg, 1.42 mmol). The reaction mixture was stirred at 23 °C for 1 hour. Then, 1-(3-ethyl-4-pyridinyl)ethyl-methyl-amine (156 mg, 950 µmol) was added. The reaction mixture was stirred at 23 °C for 16 hours. The organic layer was dried over MgSO ₄ and evaporated. Purification by SFC (chiral column Wrr, 5 μm, 250 x 20 mm, 15% MeOH) gave the title compound as a mixture of non-mirror isomers (0.8 mg, 0.25% yield, t _R = 1.834 min) as a colorless oil. MS (ESI): m/z = 412.1 [M+H] ⁺

Steps a : N-[1-(3- Ethyl -4- Pyridyl ) Ethyl ] Tributyl carbamate

To a solution of 1-(3-ethyl-4-pyridinyl)ethanamine (CAS RN: 56129-55-6; 500 mg, 3.16 mmol) in DCM (16 mL) was added TEA (1.76 mL, 12.65 mmol) followed by (Boc) ₂ O (1.04 g, 4.74 mmol). The reaction was stirred at 23 °C for 18 h. The reaction was quenched with brine and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ and evaporated. Purification by FC (SiO ₂ ; DCM/MeOH) gave the title compound as an orange gum (337 mg, 41% yield). MS (ESI): m/z = 251.2 [M+H] ⁺

Steps b : N-[1-(3- Ethyl -4- Pyridyl ) Ethyl ]-N- methyl - Tributyl carbamate

To a solution of tributyl N-[1-(3-ethyl-4-pyridinyl)ethyl]carbamate (230 mg, 872.81 µmol) in extra dry THF (8.73 mL) was added 0.5 M KHMDS (3.49 mL, 1.75 mmol) at 0 °C under argon and the mixture was stirred for 1 hour. CH ₃ I (81.86 µL, 1.31 mmol) was then added and the reaction was stirred at 50 °C for 3 hours. The solution was quenched with saturated aqueous NH ₄ Cl and extracted with DCM to give the title compound as a light brown oil (253.1 mg, 88% yield, 80% purity). MS (ESI): m/z = 265.2 [M+H] ⁺

Steps c : 1-(3- Ethyl -4- Pyridyl ) Ethyl - methyl - amine

To a solution of tributyl N-[1-(3-ethyl-4-pyridinyl)ethyl]-N-methyl-carbamate (253.1 mg, 0.957 mmol) in DCM (4.8 mL) was added TFA (737.56 µL, 9.57 mmol). The resulting solution was stirred at 23 °C overnight. The mixture was neutralized to pH 8/9 with NaOH. The aqueous phase was extracted with DCM and further washed with water. The organic layer was dried over Na ₂ SO ₄ and evaporated to give the title compound as a light brown oil (156 mg, 79% yield, 80% purity). MS (ESI): m/z = 165.1 [M+H] ⁺ Example 82 3-(4,4 -difluorotetrahydrofuran -3 -yl )-1- methyl -1-[2,2,2- trifluoro -1-(4 -pyridyl ) ethyl ] urea ]

Triphosgene (CAS RN: 32315-10-9; 74.9 mg, 0.25 mmol) was dissolved in DCM (6 mL) at 0°C. (4,4-Difluorotetrahydrofuran-3-yl)amine; hydrochloride (CAS RN: 2408969-70-8; 0.1 g, 0.63 mmol) and DIPEA (0.4 mL, 2.27 mmol) were dissolved in DCM (6 ml) and added dropwise. The reaction mixture was allowed to warm to 23°C and stirred for 30 minutes. Afterwards, the solution was cooled to 0°C, and a solution of 2,2,2-trifluoro-N-methyl-1-(4-pyridyl)ethanamine (0.12 g, 0.63 mmol) and DIPEA (0.4 mL, 2.27 mmol) in DCM (6 mL) was added dropwise. The mixture was stirred at 20°C for 18 h. The solvent was evaporated. Purification by RP-HPLC (CROMATOREX SMB C18, CH ₃ CN/H ₂ O) and chiral RP-HPLC (column Chiralpak AD-H, 250x4.6 mm, 5 µm, 50%/25%/25% hexane/IPA/MeOH) gave the title compound (4.2 mg, 1.47% yield) as an orange oil. MS (ESI): m/z = 340.2 [M+H] ⁺

Steps a : 2,2,2- Trifluoro -N- methyl -1-(4- Pyridyl ) Ethylamine

MeNH ₂ ·HCl (CAS RN: 593-51-1; 0.62 g, 9.14 mmol) and TEA (1.27 mL, 9.14 mmol) were added to a stirred solution of 2,2,2-trifluoro-1-(4-pyridyl)ethanone (0.8 g, 4.57 mmol) in THF (15 mL). A solution of Ti(O ⁱ Pr) ₄ (4.06 mL, 13.71 mmol) was added to the mixture. The reaction was stirred at 70 °C for 16 hours. NaBH ₄ (0.02 g, 0.57 mmol) was added and the reaction was stirred at 23 °C for 16 hours. The reaction was quenched by counter addition of NH ₃ ·H ₂ O solution (1% in 20 mL water), extracted with EtOAc (20 mL), and filtered. The organic layer was dried over Na ₂ SO ₄ and the solvent was evaporated. Purification by FC (SiO ₂ ; CHCl ₃ /CH ₃ CN) gave the title compound as a light red oil (0.1 g, 10% yield). MS (ESI): m/z = 191.2 [M+H] ⁺ Example 83

The compound of formula (I) itself can be used as an active ingredient in a known manner to prepare tablets of the following composition: Per tablet Active ingredients 200 mg Microcrystalline Cellulose 155 mg Corn starch 25 mg talcum powder 25 mg Hydroxypropyl methylcellulose 20 mg 425 mg Example 84

The compound of formula (I) itself can be used as an active ingredient in a known manner to prepare capsules of the following composition: Each capsule Active ingredients 100.0 mg Corn starch 20.0 mg lactose 95.0 mg talcum powder 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims (40)

A compound of formula (I), (I) or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are each selected from CR ^Z and N, provided that at most two of X, Y and Z are N; U is selected from O, S and NR ^U ; V is a covalent bond or C( ^RV ) ₂ ; A is selected from 3- to 14-membered heterocyclic groups, 5- to 14-membered heteroaryl groups, C ₆ -C ₁₀ -aryl groups and C ₃ -C ₁₀ -cycloalkyl groups; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is selected from hydrogen and C ₁ -C ₆ -alkyl groups; ^RU is selected from hydrogen, C ₁ -C ₆ -alkyl groups and cyano groups; each ^RV is independently selected from hydrogen, C ₁ -C ₆ -alkyl groups and halogen-C ₁ -C ₆ -alkyl; R ^Z is selected from hydrogen and C ₁ -C ₆ -alkyl; R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy and a group R ^1a is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl; R ^2a and R ^2b are each independently selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₆ -C ₁₀ -aryl, C ₆ -C ₁₀ -aryl-C ₁ -C ₆ -alkyl and R ^2c -OC ₁ -C ₆ -alkyl; wherein each C ₆ -C ₁₀ -aryl and C ₃ -C R ^2c is selected from hydrogen, C ₁ ^-C 6 -alkyl, halogen-C ₁ -C 6 -alkyl and C 6 -C ₁₀ -aryl, wherein the C ₆ -C ₁₀ -aryl is optionally substituted with 1 to 2 halogen substituents; R ³ is selected from hydrogen, C _{1 -C 6 -alkyl} , halogen-C ₁ -C 6 -alkyl and C _{3 -C 10} -cycloalkyl; R ^{4a and} R _4b are each independently selected from hydrogen, halogen _{, hydroxyl, C 1 -C 6 -alkyl , 5} to ₁₄ membered cycloalkyl ^; wherein the 5- to 14-membered heteroaryl, C ₆ -C ₁₀ -aryl, C ₆ -C ₁₀ -aroyl, or 5- to 14-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen and hydroxy-C _{1 -C 6 -alkyl} ; or R ^4a and R ^4b together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl or a 3- to 14-membered heterocyclic group, wherein the C ₃ -C ₁₀ -cycloalkyl and the 3- to 14-membered heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from halogen and hydroxy-C ₁ -C ₆ -alkyl. or R ^4a and R ⁷ together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atoms to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group or a pendoxy group; R ^6a and R ^6b are each independently selected from hydrogen, a 5- to 14-membered heteroaryl group and a C ₆ -C ₁₀ -aryl group; wherein the 5- to 14-membered heteroaryl group and the C ₆ -C ₁₀ -aryl group are optionally substituted by 1 to 3 halogen substituents independently selected from halogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl. The compound of claim 1, wherein: (i) X and Y are CH and Z is CR ^Z ; wherein R ^Z is selected from hydrogen and C ₁ -C ₆ -alkyl; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH. The compound of claim 2, wherein: (i) X and Y are CH and Z is CR ^Z ; wherein R ^Z is selected from hydrogen and methyl; or (ii) X and Z are CH and Y is N. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein X, Y and Z are CH. A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: ^R1 is selected from hydrogen, halogen, cyano, _C1 - _C6 -alkyl, _C2 - _C6 -alkynyl, halogen- _C1 - _C6 -alkyl, hydroxy- _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy and a group ; A is selected from a 3- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, a phenyl group and a C ₃ -C ₆ -cycloalkyl group; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; and R ^1a is selected from hydrogen, a halogen, a C ₁ -C ₆ -alkyl group and a halogen-C ₁ -C ₆ -alkyl group. The compound of claim 5 of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, prop-1-ynyl, hydroxymethyl, CHF ₂ , methoxy and a group ; A is selected from tetrahydroacrylamide, tetrahydrofuran, tetrahydropyran, pyrrolidine, pyrazole, phenyl, pyridyl and cyclopropyl; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; and R ^1a is selected from hydrogen, chlorine, methyl and CF ₃ . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ¹ is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 7, wherein R ¹ is selected from hydrogen, fluorine and methyl. The compound of formula (I) of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, phenyl-C ₁ -C ₆ -alkyl and R ^2c -OC ₁ -C ₆ -alkyl; wherein the phenyl is optionally substituted with 1 halogen substituent; R ^2b is hydrogen; and R ^2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and phenyl; wherein the phenyl is optionally substituted with 1 halogen substituent; or R ^2a and R ^2b together with the carbon atom to which they are attached form a C ₃ -C ₆ -cycloalkyl. The compound of formula (I) of claim 9 or a pharmaceutically acceptable salt thereof, wherein: R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CHF ₂ , CH ₃ N-CH ₂ -, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF ₂ -O-CH ₂ -, CF ₃ -O-CH ₂ - and cyclopropyl; and R ^2b is hydrogen; or R ^2a and R ^2b together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein: R ^2a is C ₁ -C ₆ -alkyl; and R ^2b is hydrogen. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein: R ^2a is methyl; and R ^2b is hydrogen. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ³ is selected from C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ³ is selected from methyl and CHF ₂ . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein R ³ is C ₁ -C ₆ -alkyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 15, wherein R ³ is methyl. The compound of formula (I) of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxyl-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a C ₃ -C ₆ -cycloalkyl; R ^5a and R ^{R 5b} is each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl or a pendoxy group; R ^6a is selected from hydrogen, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl are substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl. The compound of formula (I) of claim 17 or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted with a substituent selected from chlorine, bromine and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a cyclopropyl group; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group; R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a cyclopropyl group or a pendoxy group; R ^{R 6a} is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, methyl, CHF ₂ , CF ₃ and imidazolyl. The compound of formula (I) of claim 17 or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^4b is selected from hydrogen and halogen; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen and 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl is substituted with one substituent selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl. The compound of formula (I) of claim 19 or a pharmaceutically acceptable salt thereof, wherein: R ^4a is selected from hydrogen, fluorine and methyl; R ^4b is selected from hydrogen and fluorine; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen, pyridyl and pyrazolyl; wherein the pyridyl and pyrazolyl are substituted with a substituent selected from bromine, methyl, cyclopropyl and pyridyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein: U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; ^RU is cyano; and ^RV is halogen-C ₁ -C ₆ -alkyl. The compound of claim 21, wherein: U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; ^RU is cyano; and ^RV is CF ₃ . The compound of formula (I) or a pharmaceutically acceptable salt thereof of claim 22, wherein U is O and V is a covalent bond, is represented by formula (Ia): (Ia) wherein X, Y, Z and ^R1 to ^R7 are as defined in any one of claims 1 to 20. The compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR ^Z ; or (ii) X and Z are CH and Y is N ; or (iii) X is N and Y and Z are CH ; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; A is selected from a 3- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, a phenyl group and a C ₃ -C ₆ -cycloalkyl group; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; ^RU is cyano; ^RV is a halogen-C R ^Z is selected from hydrogen and _{C 1} -C ₆ -alkyl; R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, halogen-C ₁ -C ₆ -alkyl, hydroxy-C _{1 -C 6} -alkyl, C ₁ -C ₆ -alkoxy and the group ; R ^1a is selected from hydrogen, halogen, C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl; R ^2a is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl-NH-C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, phenyl-C ₁ -C ₆ -alkyl and R ^2c -OC ₁ -C ₆ -alkyl; wherein the phenyl is optionally substituted with 1 halogen substituent; R ^2b is hydrogen; and R ^2c is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and phenyl; wherein the phenyl is optionally substituted with 1 halogen substituent; or R ^2a and R ^{R 2b} together with the carbon atom to which it is attached forms a C ₃ -C ₆ -cycloalkyl group; R ³ is selected from C ₁ -C ₆ -alkyl and halogen-C ₁ -C ₆ -alkyl; R ^4a is selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkyl, 5- to 14-membered heteroaryl and C ₆ -C ₁₀ -aryl; wherein the 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxyl-C ₁ -C ₆ -alkyl; and R ^4b is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group; or R ^4a and R ^{R 7} together with the carbon atom to which it is attached forms a C ₃ -C ₆ -cycloalkyl group; R ^5a and R ^5b are each independently selected from hydrogen and C ₁ -C ₆ -alkyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a C ₃ -C ₁₀ -cycloalkyl group or a pendoxy group; R ^6a is selected from hydrogen, 5- to 14-membered heteroaryl groups and C ₆ -C ₁₀ -aryl groups; wherein the 5- to 14-membered heteroaryl groups and C ₆ -C ₁₀ -aryl groups are substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl groups and 5- to 14-membered heteroaryl groups; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl and 5- to 14-membered heteroaryl. The compound of claim 24, wherein: (i) X and Y are CH and Z is CR ^Z ; or (ii) X and Z are CH and Y is N ; or (iii) X is N and Y and Z are CH ; U is selected from O, S and NR ^U ; V is a covalent bond or CHR ^V ; A is selected from tetrahydroazine, tetrahydrofuran, tetrahydropyran, pyrrolidine, pyrazole, phenyl, pyridyl and cyclopropyl; L is selected from a covalent bond, -CH ₂ - and -NR ^L -; ^RL is hydrogen; ^RU is cyano; ^RV is CF ₃ ; ^RZ is selected from hydrogen and methyl; ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, prop-1-ynyl, hydroxymethyl, CHF ₂ , methoxy and a group ; R ^1a is selected from hydrogen, chlorine, methyl and CF ₃ ; R ^2a is selected from hydrogen, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CHF ₂ , CH ₃ N-CH ₂ -, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF ₂ -O-CH ₂ -, CF ₃ -O-CH ₂ - and cyclopropyl; and R ^2b is hydrogen; or R ^2a and R ^2b together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group; R ³ is selected from methyl and CHF ₂ ; R ^{R 4a} is selected from hydrogen, fluorine, hydroxyl, methyl, benzyl, pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl; wherein the pyridinyl, triazolyl, 1,2,4-triazolyl and pyrazolyl are optionally substituted with 1 substituent selected from chlorine, bromine and hydroxymethyl; and R ^4b is selected from hydrogen, fluorine and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a cyclopropyl group; or R ^4a and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group; R ^5a and R ^5b are each independently selected from hydrogen and methyl; or R ^5a and R ^5b together with the carbon atom to which they are attached form a cyclopropyl group or a pendoxy group; R ^{R 6a} is selected from hydrogen, pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyrimidinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, methyl, CHF ₂ , CF ₃ and imidazolyl. The compound of claim 24, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; U is O; V is a covalent bond; R ¹ is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^2a is C ₁ -C ₆ -alkyl; and R ^2b is hydrogen; R ³ is C ₁ -C ₆ -alkyl; R ^4a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; R ^4b is selected from hydrogen and halogen; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen and a 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl is 1- R ^6b is hydrogen; and _R ⁷ is selected from hydrogen, halogen-C ₁ -C ₆ -alkyl, _{C 3} -C ₁₀ -cycloalkyl and 5- to 14-membered heteroaryl. The compound of formula (I) of claim 26 or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y and Z are CH; or (ii) X and Z are CH and Y is N; U is O; V is a covalent bond; R ¹ is selected from hydrogen, fluorine and methyl; R ^2a is methyl; and R ^2b is hydrogen; R ³ is methyl; R ^4a is selected from hydrogen, fluorine and methyl; R ^4b is selected from hydrogen and fluorine; R ^5a is hydrogen; R ^5b is hydrogen; R ^6a is selected from hydrogen, pyridyl and pyrazolyl; wherein the pyridyl and pyrazolyl are substituted with a substituent selected from bromine, methyl, cyclopropyl and pyridyl; R ^6b is hydrogen; and R ⁷ is selected from hydrogen, CF ₃ and imidazolyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound of formula (I) is selected from: 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-tetrahydrofuran-3-yl]urea; 1-methyl-3-[(3RS,4RS)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-3-[(3RS,4SR)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3RS)-3-(1H-imidazol-2-yl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-3-[(3RS)-3-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2RS,3SR)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2RS,3SR)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2RS,3SR)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2R,3S)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2R,3S)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2S,3R)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2R,3S)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)urea; 1-[(3-chloro-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-fluoro-4-pyridyl)methyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-(4-pyridylmethyl)urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridinium-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridinylmethyl)urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridinylmethyl)urea; 3-(4-Benzyltetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 1-[(3-bromo-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridinyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[[3-(hydroxymethyl)-4-pyridinyl]methyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridinyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridinyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridinyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]urea; 1-[(3-cyclopropyl-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 1-[(3-bromo-4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(3-bromo-4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(tetrahydrofuran-1-yl)-4-pyridinyl]methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2-phenoxy-1-(4-pyridinyl)ethyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[2-methoxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-methoxy-4-pyridinyl)methyl]-1-methyl-urea; 1-[1-(3-chloro-4-pyridinyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-pyrrolidin-1-yl-4-pyridinyl)methyl]urea; 1-[(S)-cyclopropyl(4-pyridinyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(S)-cyclopropyl(4-pyridinyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 3-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridinyl)cyclopropyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridinyl)cyclopropyl]urea; 1-[[3-(3-chloroanilino)-4-pyridinyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(3-chloroanilino)-4-pyridinyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea; 3-[(3R)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridinyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 1-methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1S,5S)-3-oxobicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1R,5R)-3-oxobicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1S,5S)-3-oxobicyclo[3.1.0]hex-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-[[3-(difluoromethyl)-4-pyridinyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(difluoromethyl)-4-pyridinyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridinyl)cyclobutyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridinyl)cyclobutyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(1H-pyrazol-5-yl)-4-pyridinyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridinyl)ethyl]-1-methyl-urea; 3-[3-(difluoromethyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridinyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridinyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridinyl)methyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]thiourea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(3-methyl-1H-pyrazol-5-yl)-4-pyridyl]methyl]urea; 2-cyano-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]guanidine; 1-methyl-3-(5-hydroxytetrahydrofuran-3-yl)-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(4-pyridyl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(3-pyridyl)-4-pyridyl]methyl]urea; 1-[[3-(4-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(2-chlorophenyl)-4-pyridinyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(3-chlorophenyl)-4-pyridinyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[2-(3-chlorophenoxy)-1-(4-pyridinyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-prop-1-ynyl-4-pyridinyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(2-pyridyl)-4-pyridyl]methyl]urea; 1-[2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridinyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridinyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[4-(trifluoromethyl)phenyl]-4-pyridinyl]methyl]urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridinyl)ethyl]-1-methyl-urea]; 1-[(1S)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridinyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-(difluoromethyl)-3-(4,4-difluorotetrahydrofuran-3-yl)-1-(4-pyridylmethyl)urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridinyl)ethyl]-1-methyl-urea]; and 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2,2,2-trifluoro-1-(4-pyridinyl)ethyl]urea]. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, for use as a therapeutically active substance. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. A method for treating or preventing a SARM1-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30. The method of claim 31, wherein the SARM1-related disorder is a disorder affecting the nervous system, including the central nervous system and the peripheral nervous system. The method of claim 32, wherein the disorder affecting the nervous system is a neurodegenerative disease. The method of claim 31, wherein the SARM1-related disorder is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy-induced peripheral neuropathy, diabetes-induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury and Charcot-Marie-Tooth disease. A compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30, for use in a method according to any one of claims 31 to 34. Use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30, in a method according to any one of claims 31 to 34. A use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used in a method according to any one of claims 31 to 34. A method for preparing a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as claimed in claim 23, comprising: reacting a first amine 1, wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b and R ⁷ are as defined in any one of claims 1 to 28, and a second amine 3, wherein R ¹ , R ^2a , R ^2b , R ³ , X, Y and Z are as defined in any one of claims 1 to 28, The reaction is carried out in the presence of a base and a urea-forming reagent to form the compound of formula (Ia). A compound of formula (I) according to any one of claims 1 to 28, which is prepared according to the method of claim 38. The present invention as described above.