RU2794334C2 - Oxazinmonoacylglycerin lipase (magl) inhibitors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to new heterocyclic compounds having the general formula (Ic), as well as to compositions comprising these compounds, methods for the manufacture of these compounds and methods of using these compounds.

EFFECT: new compounds have been obtained that can be used to inhibit the activity of monoacylglycerol lipase (MAGL).

44 cl, 3 tbl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to useful organic compounds for therapy or prevention in a mammal, and in particular to inhibitors of monoacylglycerol lipase (MAGL) for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, lateral amyotrophic sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine and/or depression in a mammal.

PRIOR ART

Endocannabinoids (EC) are signaling lipids that exert their biological effects through interaction with cannabinoid receptors (CBR) - CB1 and CB2. They modulate numerous physiological processes including neuroinflammation, neurodegeneration and tissue regeneration (Iannotti, FA, et al., Progress in lipid research 2016, 62, 107-28.). In the brain, the major endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipases (DAGL) and hydrolyzed by monoacylglycerol lipase, MAGL. MAGL hydrolyzes 85% 2-AG; with the remaining 15% being hydrolyzed by ABHD6 and ABDH12 (Nomura, DK, et al., Science 2011, 334, 809.). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, PK, et al., Molecular pharmacology 2010, 78, 996; Viader, A., et al., Cell reports 2015 , 12, 798.). Hydrolysis of 2-AG leads to the formation of arachidonic acid (AA) - a precursor of prostaglandins (PG) and leukotrienes (LT). Oxidative metabolism of AA is enhanced in inflamed tissues. There are two main enzymatic pathways for the oxygenation of arachidonic acid involved in inflammatory processes: cyclooxygenase, which produces PG, and 5-lipoxygenase, which produces LT. Of the various cyclooxygenase products produced during inflammation, RGE2 is one of the most important. These products have been identified at sites of inflammation, such as the cerebrospinal fluid of patients suffering from neurodegenerative disorders, and are believed to contribute to the inflammatory response and disease progression. MAGL-deficient mice (MgII-/-) show dramatically reduced 2-AG hydrolase activity and increased levels of 2-AG in the nervous system, while other arachidonoil-containing phospho- and neutral lipid species, including anandamide (AEA), as well as other free fatty acids acids are unchanged. Conversely, levels of AA, AA-derived prostaglandins, and other eicosanoids, including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2), are greatly reduced. Phospholipase A ₂ (PLA ₂ ) enzymes have been considered as the main source of AA, but cPLA ₂ -deficient mice have unchanged levels of AA in their brain, reinforcing the key role of MAGL in the brain in relation to AA production and regulation of brain inflammation.

Neuroinflammation is a common pathological change characteristic of diseases of the brain, including neurodegenerative diseases (for example, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, and psychiatric disorders such as anxiety and migraine) but not limited to. In the brain, the formation of eicosanoids and prostaglandins controls the process of neuroinflammation. The pro-inflammatory agent lipopolysaccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is markedly attenuated in MgII −/− mice. LPS treatment also induces a widespread increase in pro-inflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a), which is prevented in MgII-/- mice. .

Neuroinflammation is characterized by activation of cells of the innate immune system of the central nervous system, microglia and astrocytes. It has been reported that in preclinical models, anti-inflammatory drugs can suppress glial cell activation and disease progression, including Alzheimer's disease and multiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403.). Importantly, genetic and/or pharmacological disruption of MAGL activity also blocks LPS-induced activation of microglial cells in the brain (Nomura, D.K., et al., Science 2011, 334, 809.).

Furthermore, genetic and/or pharmacological disruption of MAGL activity has been shown to be protective in several animal models of neuroinflammation, including but not limited to Alzheimer's disease, Parkinson's disease and multiple sclerosis. For example, an irreversible inhibitor of MAGL has been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, J.Z., et al., Nature chemical biology 2009, 5, 37.). Systemic injection of such an inhibitor mimics the brain phenotype of MgII-/- mice, including increased levels of 2-AG, decreased levels of AA and production of related eicosanoids, and prevention of cytokine production and microglial activation following LPS-induced neuroinflammation (Nomura, D.K., et al. , Science 2011, 334, 809.), collectively confirming that MAGL is a drug-targeted target.

Following a genetic and/or pharmacological disruption of MAGL activity, endogenous levels of the brain's natural MAGL substrate, 2-AG, increase. 2-AG has been reported to show beneficial effects on pain, such as antinociceptive effects in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424.), and on psychiatric disorders. such as depression in models of chronic stress (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763.).

In addition, oligodendrocytes (OL), myelinating cells of the central nervous system and their progenitors (ORCs) express the cannabinoid receptor 2 (CB2) on their membrane. 2-AG is an endogenous ligand for the CB1 and CB2 receptors. Both cannabinoids and pharmacological inhibition of MAGL have been reported to attenuate the susceptibility of OL and ORF to excitotoxic strokes and therefore may be neuroprotective (Bernal-Chico, A., et al., Glia 2015, 63, 163.). In addition, pharmacological inhibition of MAGL increases the number of myelinating OLs in the mouse brain, suggesting that MAGL inhibition can stimulate ORF differentiation into myelinating OLs in vivo (Alpar, A., et al., Nature communications 2014, 5, 4421.). Inhibition of MAGL has also been shown to stimulate remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. et al., Journal of Neuroscience 2017, 37 (35), 8385.).

Finally, in recent years it has been said that metabolism, especially lipid metabolism, is very important in cancer research. Researchers believe that de novo fatty acid synthesis plays an important role in the development of tumors. Many studies have illustrated that endocannabinoids have anti-oncogenic effects, including anti-proliferative, apoptosis-inducing, and antimetastatic effects. MAGL is an important degrading enzyme with respect to both lipid metabolism and the endocannabinoid system, furthermore, as part of the gene expression signature, it promotes various aspects of oncogenesis (Qin, H., et al., Cell Biochem. Biophys. 2014, 70 , 33; Nomura DK et al., Cell 2009, 140(1), 49-61; Nomura DK et al., Chem biol 2011, 18(7), 846-856).

In conclusion, the suppression of the action and/or activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and mental disorders. In addition, inhibition of MAGL action and/or activation is a promising new therapeutic strategy for neuroprotection and myelin regeneration. Accordingly, there is a large unmet medical need for new MAGL inhibitors.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides compounds of Formula (Ic)

in which A, L, X, m, n and R ²⁰ -R ²³ are as defined in this document.

In another aspect, the present invention provides a process for the manufacture of compounds of formula (Ic) as described herein, comprising:

implementation of the interaction of 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (1),

with a heterocyclic amine 2a, in which A, L, X, m, n and R ²⁰ -R ²³ are as defined in this document

in the presence of a reagent that forms a base and urea,

to form said compounds of formula (Ic).

In another aspect, the present invention provides a compound of formula (Ic) as described herein when manufactured according to the methods described herein.

In another aspect, the present invention provides a compound of formula (Ic) as described herein for use as a therapeutically active agent.

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

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the inhibition of monoacylglycerol lipase (MAGL) in a mammal.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine , depression, hepatocellular carcinoma, colon oncogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-associated spasticity in a mammal.

In another aspect, the present invention provides a compound of formula (Ic) as described herein for use in a method for inhibiting monoacylglycerol lipase in a mammal.

In another aspect, the present invention provides a compound of formula (Ic) as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal.

In another aspect, the present invention provides a compound of formula (Ic) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon oncogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-associated spasticity in a mammal.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the preparation of a medicament for inhibiting monoacylglycerol lipase in a mammal.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the manufacture of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the manufacture of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy , anxiety, migraine, depression, hepatocellular carcinoma, colon oncogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-associated spasticity in a mammal.

In another aspect, the present invention provides a method for inhibiting monoacylglycerol lipase in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (Ic) as described herein.

In another aspect, the present invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (Ic) as described herein.

In another aspect, the present invention provides a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon oncogenesis, cancer. ovarian pain, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-associated spasticity in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (Ic) as described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Properties, integers, characteristics, compounds, chemical moieties, or groups described in conjunction with a particular aspect, embodiment, or example of this invention are to be understood as applicable to any other aspect, embodiment, or example described herein, unless otherwise incompatible. with him. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings) and/or all of the steps of any method or process thus disclosed may be combined in any combination, except for combinations where at least some of these features and/or steps are mutually exclusive. The present invention is not limited to the details of any of the above embodiments. This invention extends to any new feature or any new combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any new step or any new combination of steps of any method or process so disclosed. .

The term "alkyl" refers to a mono- or multivalent, for example, mono- or divalent, linear or branched hydrocarbon group of 1-12 carbon atoms. In some preferred embodiments, the alkyl group contains from 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. In other embodiments, the alkyl group contains from 1 to 3 carbon atoms, such as 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, t-butyl, and 2,2-dimethylpropyl. A particularly preferred, however, non-limiting example of alkyl is methyl. The alkyl group may be substituted. Thus, the term "substituted alkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been substituted with a substituent as described herein, preferably with a substituent selected from halogen, hydroxy, alkoxy, arylalkoxy, trialkylsilyloxy, substituted or unsubstituted cycloalkyl; and substituted or unsubstituted heterocyclyl. Most preferably, "substituted alkyl" refers to an alkyl group in which 1, 2, or 3 hydrogen atoms of the alkyl group have been replaced with a substituent selected from halo, hydroxy, alkoxy, arylalkoxy, trialkylsilyloxy, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In particular, however, non-limiting examples of substituted alkyl are 2-hydroxyethyl, 2-methoxyethyl, hydroxymethyl, methoxymethyl, trifluoromethyl, oxethan-3-yl-methyl, (1-tert-butoxycarbonylazetidin-3-yl)methyl, cyclopropylmethyl, 1 -(chloromethyl)-2-hydroxy-ethyl, 2-[tert-butyl(dimethyl)silyl]oxethyl and benzyloxymethyl.

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 from 1 to 12 carbon atoms. In some preferred embodiments, the alkoxy group contains from 1 to 6 carbon atoms. In other embodiments, the alkoxy group contains from 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains from 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and t-butoxy. A particularly preferred, however, non-limiting example of alkoxy is methoxy.

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

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group of 3-10 ring carbon atoms. In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3-8 ring carbon atoms. The term "bicyclic cycloalkyl" refers to cycloalkyl moieties consisting of two saturated carbocycles sharing two carbon atoms, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic groups, i.e. two rings are connected through one common ring atom. Preferably the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3-6 ring carbons, eg 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "cycloalkyloxy" refers to the group cycloalkyl-O-, ie. a cycloalkyl group substituted with an hydroxy group and attached to the parent molecular moiety through said hydroxy group.

The term "heterecyclyl" as used herein refers to a saturated or partially unsaturated mono- or bicyclic, preferably monocyclic ring system of 3-10 ring atoms, preferably 3-8 ring atoms, in which 1, 2 or 3 of said ring atoms are heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Preferably 1-2 of said ring atoms are selected from N and O, with the remaining ring atoms being carbon. The term "bicyclic heterocyclyl" refers to heterocyclic moieties consisting of two rings sharing two ring atoms, i.e. the bridge separating the two given rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic groups, i.e. two rings are connected through one common ring atom. Some non-limiting examples of monocyclic heterocyclic groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidine -2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3 -piperidyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl and morpholin-3-yl. The heterocyclyl group may be substituted. Thus, the term "substituted heterocyclyl" refers to a heterocyclyl group in which at least one of the hydrogen atoms of that heterocyclyl group has been substituted with a substituent as described herein, preferably with a substituent selected from saturated or unsaturated alkyl, halogen and alkoxy, where said substituted alkyl is substituted with 1-3 substituents selected from hydroxy, halo, alkoxy, arylalkoxy and cycloalkyl. Most preferably, the term "substituted heterocyclyl" refers to a heterocyclyl group in which 1-2 of the hydrogen atoms of a given heterocyclyl group have been substituted with a substituent selected from substituted or unsubstituted alkyl, halogen and alkoxy, wherein said substituted alkyl is substituted with 1-3 substituents selected from from hydroxy, halogen, alkoxy, arylalkoxy and cycloalkyl. Specific, however, non-limiting examples of substituted heterocyclyl are 2-methyl-5-oxo-pyrrolidin-1-yl, 4,4-difluoro-1-piperidyl, 1-tert-butoxycarbonylazeidin-3-yl, and 1-tert- butoxycarbonylazeidin-2-yl.

The term "heterocyclyloxy" refers to the heterocyclyl-O- group, i.e. a heterocyclyl group substituted with an hydroxy group and attached to the parent molecular moiety through said hydroxy group. A non-limiting example of a heterocyclyloxy group is oxethanyloxy, such as oxethan-3-yloxy.

The term "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably 6 to 12 ring members, and more preferably 6 to 10 ring members, and in which at least one the ring in this system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (eg, 9H-fluoren-9-yl). A particularly preferred, however, non-limiting example of an aryl is phenyl. The aryl group may be substituted. Thus, the term "substituted aryl" refers to an aryl group in which at least one of the hydrogen atoms of that aryl group has been substituted with a substituent as described herein, e.g., a substituent selected from halogen, cyano, alkoxy, heloalkoxy, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkyloxyalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted aryl, and substituted or unsubstituted aryloxy. Preferably, the term "substituted aryl" refers to an aryl group in which at least one of the hydrogen atoms of the aryl group has been replaced by a substituent selected from halo and haloalkyl. Most preferably, the term "substituted aryl" refers to an aryl group in which 1-3 hydrogen atoms of the aryl group have been replaced with a substituent selected from halo and haloalkyl. Specific, however, non-limiting examples of substituted aryl are 4-fluorophenyl, 4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-(trifluoromethyl)phenyl, and 3,4-difluorophenyl.

The term "heteroaryl" refers to a mono- or multivalent, monocyclic, bicyclic or tricyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 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, the term "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, the term "heteroaryl" refers to a 5-10 membered heteroaryl containing 1 -2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include spiro[cyclopropan-1,3'-indoline] (e.g., spiro[cyclopropan-1,3'-indoline]-1'-yl), 2- pyridyl, 3-pyridyl, 4-pyridyl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H- indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol- 6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol- 7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H- imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl and oxazol-5-yl. A particularly preferred, however, non-limiting example of heteroaryl is indolyl, in particular 1H-indol-3-yl. The heteroaryl group may be substituted. Thus, the term "substituted heteroaryl" refers to a heteroaryl group in which at least one of the hydrogen atoms of that heteroaryl group has been substituted with a substituent as described herein, preferably with a substituent selected from halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl and heterocyclyl substituted with alkoxycarbonyl, wherein the substituted alkyl is substituted with 1-3 substituents selected from halogen, hydroxy, heterocyclyl, trialkylsilyloxy, cycloalkyl, and heterocyclyl substituted with alkoxycarbonyl. Most preferably, the term "substituted heteroaryl" refers to a heteroaryl group in which 1-2 hydrogen atoms of the heteroaryl group have been substituted with a substituent selected from halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, and heterocyclyl substituted with alkoxycarbonyl, where substituted alkyl is substituted with 1 -3 substituents selected from halogen, hydroxy, heterocyclyl, trialkylsilyloxy, cycloalkyl, and heterocyclyl substituted with alkoxycarbonyl. Specific, however, non-limiting examples of substituted heteroaryl are 5-methyl-1,2,4-oxadiazol-3-yl, 5-fluoro-1-methyl-indol-3-yl, 5-chloro-1-methyl-indole -3-yl, 5-chloro-1-cyclopropyl-indol-3-yl, 5-chloro-1-oxethanyl-indol-3-yl, 5-chloro-1-(oxethan-3-ylmethyl)indol-3- yl, 5-chloro-1-(2-hydroxyethyl)indol-3-yl, 1-(1-tert-butoxycarbonylazetidin-3-yl)-5-chloro-indol-3-yl, 1-[(1-tert -butoxycarbonylazetidin-3-yl)-5-chloro-indol-3-yl, 5-(trifluoromethyl)-2-pyridyl, 5-(trifluoromethyl)-3-pyridyl, 4-(trifluoromethyl)imidazol-1-yl, 4 -(trifluoromethyl)pyrazol-1-yl, 4-tert-butylpyrazol-1-yl, 4-tert-butyloxazol-2-yl, 5-chloro-1-(cyclopropylmethyl)indol-3-yl, 6-fluoro-1H -indol-3-yl, 5-fluoro-1,2-benzoxazol-3-yl, 5-chloro-1H-indol-3-yl, 1-methylindazol-5-yl, 5-chloro-1-[1- (chloromethyl)-2-hydroxy-ethyl]indol-3-yl; and 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-indol-3-yl.

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

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

The term "cycloalkylalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been replaced by a cycloalkyl group. Preferably the term "cycloalkylalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of this alkyl group has been replaced by a cycloalkyl group. A particularly preferred, however, non-limiting example of cycloalkyl is cyclopropylmethyl.

The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, the term "haloalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms of the given alkyl group have been replaced by a halogen atom, most preferably fluorine. Particularly preferred, however, non-limiting examples of haloalkyl are trifluoromethyl and trifluoroethyl.

The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, the term "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 fluorine. A particularly preferred, however, non-limiting example of a haloalkyl is trifluoromethoxy (-OCF ₃ ).

The term "cycloalkylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of this alkoxy group has been replaced by a cycloalkyl group. Preferably the term "cycloalkylalkoxy" refers to an alkoxy group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of this alkoxy group, have been replaced by a cycloalkyl group. A particularly preferred, however, non-limiting example of cycloalkyl alkoxy is cyclopropyl methoxy.

The term "cycloalkyloxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been replaced by a cycloalkyloxy group, as defined herein. Preferably the term "cycloalkyloxyalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the given alkyl group, have been replaced by a cycloalkyloxy group. A particularly preferred, however, non-limiting example of cycloalkyloxyalkyl is cyclopropoxymethyl.

The term "hydroxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been replaced by a hydroxy group. Preferably the term "hydroxyalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the given alkyl group, have been replaced by a hydroxy group. Preferred, however, non-limiting examples of hydroxyalkyl are hydroxymethyl and hydroxyethyl (eg, 2-hydroxyethyl). A particularly preferred, however, non-limiting example of hydroxyalkyl is hydroxymethyl.

The term "arylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by an aryl group. Preferably the term "arylalkoxy" refers to an alkoxy group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of this alkoxy group, have been replaced by an aryl group. A particularly preferred, however, non-limiting example of an arylalkoxy is benzyloxy.

The term "arylalkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been replaced by an arylalkoxy group, as defined herein. Preferably the term "arylalkoxyalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the given alkyl group, have been replaced by an arylalkoxy group. A particularly preferred, however, non-limiting example of arylalkoxyalkyl is benzyloxymethyl.

The term "alkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the given alkyl group has been replaced by an alkoxy group. Preferably, the term "alkoxyalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the given alkyl group, have been replaced by an alkoxy group. A particularly preferred, however, non-limiting example of alkoxyalkyl is 2-methoxyethyl.

The term "alkoxycarbonyl" refers to an alkyl-O-C(O)- (ie alkyl ester) group.

The term "trialkylsilyloxy" refers to the group (alkyl) ₃ SiO-. A particularly preferred, however, non-limiting example of a trialkylsilyloxy is [tert-butyl(dimethyl)silyl]oxy.

The term "haloaryl" refers to an aryl group in which at least one of the hydrogen atoms of the aryl group has been replaced by a halogen atom. Preferably the term "haloaryl" refers to an aryl group in which 1, 2 or 3 hydrogen atoms, more preferably 1 or 2 hydrogen atoms, most preferably 1 hydrogen atom of this aryl group, has been replaced by a halogen atom. A particularly preferred, though non-limiting, example of a haloaryl is fluorophenyl, in particular 4-fluorophenyl.

The term "pharmaceutically acceptable salt" refers to those salts that retain the biological efficacy and free base or free acid properties that are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular with hydrochloric acid, and with 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. In addition, these salts can be obtained by adding an inorganic base or an organic base to the free acid. Salts derived from an inorganic base 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, polyimine resins, and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride salts.

The term "pharmaceutically acceptable ester" refers to esters that are hydrolysable in vivo and include esters that are easily broken down in the human body to give the parent compound or a salt thereof. Suitable ester groups include, for example, groups derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic acid, alkenoic acid, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Representative examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates. Examples of types of pharmaceutically acceptable prodrugs are described in Higuchi and Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

The term "protecting group" (PG) means a group that selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be selectively carried out at another unprotected reactive site in the sense traditionally associated with it in synthetic chemistry. The protecting groups can be removed at an appropriate point. Typical protecting groups are amino protecting groups, carboxy protecting groups or hydroxy protecting groups. Specific protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Additional specific protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry" by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

The term "urea-forming agent" refers to a chemical compound that is capable of converting a first amine to a compound that will react with a second amine, thereby forming a urea derivative. Non-limiting examples of a urea-forming reagent include bis(trichloromethyl)carbonate, phosgene, trichloromethylchloroformate, (4-nitrophenyl)carbonate, and 1,1'-carbonyldiimidazole. The urea forming reagents described in G. Sartori et al., Green Chemistry 2000, 2, 140, are incorporated herein by reference.

The compounds of formula (I) may contain several asymmetric centers and may be present as optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

According to the Kahn-Ingold-Prelog rule, an asymmetric carbon atom can be in the "R" or "S" configuration.

The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

The term "treatment" as used herein includes: (1) inhibition of a disorder or condition (e.g., stopping, reducing, or delaying the development of a disease or its recurrence, in the case of supportive treatment, of at least one of its clinical or subclinical symptom); and/or (2) alleviating the condition (ie causing regression of the disorder or condition, or at least one of its clinical or subclinical symptoms). The benefit to the patient being treated is either statistically significant or at least tangible to the patient or to the attending physician. However, it will be understood that when a drug is administered to a patient to treat a disease, an effective treatment may not always result.

The term "prophylaxis" as used herein includes: preventing or delaying the onset of clinical symptoms of a disorder or condition occurring in a mammal, and especially in a human, that may be affected or predisposed to the disorder or condition, but not yet experiencing or not demonstrating clinical or subclinical symptoms of the disorder or condition.

The term "neuroinflammation" as it is used to refer to bruising and chronic inflammation of the nervous tissue, which is the main tissue component of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branched peripheral nerves of the peripheral nervous system (PNS) . Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. Acute neuroinflammation usually follows immediately after injury to the central nervous system, such as from traumatic brain injury (TBI).

The term "traumatic brain injury" ("TBI", also known as "intracranial injury") refers to brain injury resulting from an external mechanical force such as rapid acceleration or deceleration, impact, blast waves, or the penetration of a flying fragment.

The term "neurodegenerative diseases" refers to diseases that are associated with a progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

The term "mental disorders" (also referred to as mental illness or psychiatric disorders) refers to behavioral or mental patterns that can cause suffering or poor ability to function in life. Such characteristics may be persistent, recurrent, and temporarily subsiding, or occur as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

The term "pain" refers to an unpleasant sensory or emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain, including chemotherapy-induced neuropathy, phantom pain, and psychogenic pain. A specific example of pain is neuropathic pain, which is caused by an injury or disease that affects any part of the nervous system involved in bodily sensations (ie, the somatosensory system). In one embodiment, "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, "pain" is chemotherapy-induced neuropathy.

The term "neurotoxicity" refers to toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances (neurotoxins) alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. Examples of neurotoxicity include neurotoxicity resulting from exposure to substances used in chemotherapy, radiation therapy, drug therapies, drug addiction and organ transplantation, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics. and some naturally occurring substances.

The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor arising from abnormal, uncontrolled growth of cells (where such cells are "cancer cells"). The term "cancer" as used herein expressly includes, but is not limited to, hepatocellular carcinoma, colon oncogenesis, and ovarian cancer.

The term "mammal" as used herein includes both humans and non-human mammals, and includes humans, non-human primates, canines, felines, mice, cattle, horses, and pigs, but not limited to them. In a particularly preferred embodiment, the term "mammal" refers to a human.

Compounds of the invention

In a first aspect, the present invention provides compounds of Formula (I)

wherein:

L is selected from -CR ¹ R ² -(CH ₂ ) _p - -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and a covalent bond;

m is 1, n is 1 or 2, and X is CH; or

m is 2, n is 2 or 3, and X is CH or N;

p is 0, 1 or 2;

A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

R ¹ is selected from alkoxy, substituted or unsubstituted alkyl, cyano, halogen, substituted or unsubstituted cycloalkyl, (substituted or unsubstituted cycloalkyl)alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R ² is hydrogen or halogen;

or R ¹ and R ² taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclyl group;

R ³ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl;

R ⁴ is hydrogen;

or R ³ and R ⁴ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclyl group;

Where:

each substituted alkyl is independently substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, arylalkoxy, trialkylsilyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, and substituted or unsubstituted heterocyclyl;

each substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkoxy, and substituted heterocyclyl is independently substituted with one or more substituents independently selected from halogen, cyano, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, cycloalkyl substituted with R ⁵ , R ⁶ and R ⁷ , cycloalkoxy substituted with R ^5a , R ^6a and R ^7a , cycloalkylalkoxy substituted with R ^5b , R ^6b and R ^7b , heterocyclyl substituted with R ⁸ , R ⁹ and R ¹⁰ , heterocyclyloxy substituted with R ^8a , R ^9a and R ^10a and aryl substituted with R ¹¹ , R ¹² and R ¹³ ; And

each of R ⁵ , R ⁶ , R ⁷ , R ^5a , R ^6a , R ^7a , R ^5b , R ^6b , R ^7b , R ⁸ , R ⁹ , R ¹⁰ , R ^{8a , R 9a ,} R ^10a , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, halogen, alkoxy, haloalkoxy, alkoxycarbonyl, and substituted or unsubstituted alkyl;

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein the compound of formula (I) is a compound of formula (Ia):

in which A, L, X, m and n are as described in this document.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein the compound of formula (I) is a compound of formula (Ib):

in which A, L, X, m and n are as described in this document.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and a covalent bond;

m is 1, n is 1 or 2, and X is CH; or

m is 2, n is 2 or 3, and X is CH or N;

p is 0, 1 or 2;

A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; Where:

substituted aryl is substituted with one or more, preferably 1-3, more preferably 1-2 substituents, in particular 1 substituent selected from halogen (particularly fluorine) and haloalkyl (particularly trifluoromethyl);

substituted heteroaryl is substituted with one or more, preferably 1-3, more preferably 1-2 substituents, in particular 2 substituents selected from halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl and heterocyclyl substituted with alkoxycarbonyl; Where:

substituted alkyl is substituted with one or more substituents selected from hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy, halogen, and heterocyclyl substituted with alkoxycarbonyl;

substituted cycloalkyl is substituted with one or more, preferably 1-3, more preferably 1-2 substituents, in particular 1 substituent selected from haloaryl and haloalkylaryl; And

substituted heterocyclyl is substituted with one or more, preferably 1-3, more preferably 1-2 substituents selected from substituted or unsubstituted alkyl, halogen and alkoxy; Where:

substituted alkyl is substituted with one or more, preferably 1-3 substituents selected from hydroxy, halo, alkoxy, arylalkoxy and cycloalkyl;

R ¹ is selected from alkoxy, alkoxyalkyl, hydroxyalkyl, alkyl, cyano, halogen, cycloalkyl, cycloalkylalkoxy, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Where:

said substituted aryl is substituted with one or more, preferably 1-3, more preferably 1-2 substituents, in particular 1 substituent selected from halogen; And

said substituted heteroaryl is substituted with one or more, preferably 1-3, more preferably 1-2 substituents, in particular 1 substituent selected from alkyl;

R ² is hydrogen or halogen;

or R ¹ and R ² taken together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group;

R ³ is selected from alkyl, cycloalkyl and aryl; And

R ⁴ is hydrogen;

or R ³ and R ⁴ taken together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group.

In one embodiment, the present invention provides compounds of formula (I) as described herein, wherein:

L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and a covalent bond;

m is 1, n is 1 or 2, and X is CH; or

m is 2, n is 2 or 3, and X is CH or N;

p is 0, 1 or 2;

A is selected from substituted or unsubstituted C _6-10 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C _3-8 cycloalkyl, or substituted or unsubstituted heterocyclyl;

R ¹ is selected from C _1-6 -alkoxy, substituted or unsubstituted C _1-6 -alkyl, cyano, halogen, substituted or unsubstituted C _3-8 -cycloalkyl, (substituted or unsubstituted C _3-8 -cycloalkyl)C _1-6 alkoxy, substituted or unsubstituted C _6-10 aryl, and substituted or unsubstituted heteroaryl;

R ² is hydrogen or halogen;

or R ¹ and R ² taken together with the carbon atom to which they are attached form a substituted or unsubstituted C _3-8 cycloalkyl group, or a substituted or unsubstituted heterocyclyl group;

R ³ is selected from substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-8 cycloalkyl, and substituted or unsubstituted C _6-10 aryl; And

R ⁴ is hydrogen;

or R ³ and R ⁴ taken together with the carbon atom to which they are attached form a substituted or unsubstituted C _3-8 cycloalkyl group, or a substituted or unsubstituted heterocyclyl group;

Where:

each substituted C _1-6 alkyl is independently substituted with one or more substituents independently selected from halo, hydroxy, C _1-6 alkoxy, C _6-10 aryl-C _1-6 alkoxy, tri(C _{1- 6} -alkyl)silyloxy, substituted or unsubstituted C _3-8 -cycloalkyl and substituted or unsubstituted heterocyclyl; And

each substituted C _6-10 aryl, substituted heteroaryl, substituted C _3-8 cycloalkyl, and substituted heterocyclyl is independently substituted with one or more substituents independently selected from halo, C _1-6 alkoxy, substituted or unsubstituted C _1-6 -alkyl, C _3-8 -cycloalkyl substituted with R ⁵ , R ⁶ and R ⁷ , cycloalkoxy substituted with R ^5a , R ^6a and R ^7a , cycloalkylalkoxy substituted with R ^5b , R ^6b and R ^7b , heterocyclyl substituted with R ⁸ , R ⁹ and R ¹⁰ , heterocyclyloxy substituted with R ^8a , R ^9a and R ^10a , and aryl substituted with R ¹¹ , R ¹² and R ¹³ ; And

each of R ⁵ , R ⁶ , R ⁷ , R ^5a , R ^6a , R ^7a , R ^5b , R 6b , R ^7b , R ⁸ , R ⁹ , R ¹⁰ , R ^8a , R ^9a , ^{R 10a ,} R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, halogen, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkoxycarbonyl, and substituted or unsubstituted C _1-6 alkyl;

each "heteroaryl" means a monocyclic or bicyclic ring system having a total of 5 to 10 ring members, at least one ring in the system is aromatic, and at least one ring in the system contains 1-2 heteroatoms independently selected from O and N; And

each "heterocyclyl" means a saturated or partially unsaturated mono- or bicyclic ring system of 3-8 ring atoms, said 1-2 ring atoms being heteroatoms selected from O and N, with the remaining ring atoms being carbon atoms;

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is a covalent bond; And

A is selected from aryl, substituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted cycoalkyl; Where

substituted heteroaryl is substituted with 1-2 substituents independently selected from substituted or unsubstituted alkyl, halogen and cycloalkyl, wherein said substituted heterocyclyl is substituted with one substituent selected from substituted alkyl; and wherein each substituted alkyl is independently substituted with 1-3 substituents independently selected from cycloalkyl, heterocycloalkyl, hydroxy, and trialkylsilyloxy.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is a covalent bond; And

A is selected from aryl and substituted heteroaryl; Where

said substituted heteroaryl is substituted with 1-2 substituents independently selected from substituted or unsubstituted alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; and wherein each substituted alkyl is independently substituted with 1-3 substituents independently selected from cycloalkyl, heterocyclyl, hydroxy, halo, and trialkylsilyloxy.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is a covalent bond; And

A is heteroaryl substituted with 2 substituents independently selected from halo, alkyl, cycloalkyl, cycloalkylalkyl and heterocyclyl.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is a covalent bond; And

A is heteroaryl substituted with 2 substituents independently selected from chlorine, methyl, cyclopropyl, cyclopropylmethyl and oxethanyl.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is a covalent bond; And

A is indolyl substituted with 2 substituents independently selected from chlorine, methyl, cyclopropyl, cyclopropylmethyl and oxethanyl.

In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is a covalent bond; And

A is selected from 5-chloro-1-(cyclopropylmethyl)indol-3-yl, 5-chloro-1-methyl-indol-3-yl, 5-chloro-1-cyclopropyl-indol-3-yl and 5-chloro- 1-(oxetan-3-yl)indol-3-yl.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is -CHR ¹ -;

R ¹ is as defined herein; And

A is selected from substituted or unsubstituted aryl, heteroaryl substituted with one haloalkyl, heterocyclyl and cycloalkyl, where the substituted aryl is substituted with 1-2 substituents selected from halo and haloalkyl.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is -CHR ¹ -;

R ¹ is as defined herein; And

A is selected from aryl and aryl substituted with 1-2 substituents selected from halo and haloalkyl.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is -CHR ¹ -;

R ¹ is as defined herein; And

A is selected from aryl and aryl substituted with 1-2 substituents selected from fluorine, chlorine and trifluoromethyl (CF ₃ ).

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is -CHR ¹ -;

R ¹ is as defined herein; And

A is selected from phenyl and phenyl substituted with 1-2 substituents selected from fluorine, chlorine and trifluoromethyl (CF ₃ ).

In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L is -CHR ¹ -;

R ¹ is as defined herein; And

A is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-chloro-4-fluorophenyl and 4-(trifluoromethyl)phenyl.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ - or a covalent bond;

p is 0 or 1;

R ¹ is selected from alkoxy, alkoxyalkyl, hydroxyalkyl, alkyl, cyano, hydrogen, aryl and haloaryl;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

R ¹ is selected from alkoxyalkyl, hydroxyalkyl, aryl, haloaryl and halogen;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

R ¹ is selected from methoxyethyl, hydroxyethyl, phenyl, fluorophenyl and fluorine;

R ² is selected from hydrogen and fluorine; And

R ³ is methyl.

In another particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

R ¹ is selected from 2-methoxyethyl, 2-hydroxyethyl, phenyl, 4-fluorophenyl and fluorine;

R ² is selected from hydrogen and fluorine; And

R ³ is methyl.

In yet another particularly preferred embodiment, L is -CF ₂ -.

In one embodiment, L is -CHR ¹ - or a covalent bond, where R ¹ is as defined herein.

In one embodiment, R ¹ is selected from aryl, halogen, alkoxyalkyl, alkoxy, haloaryl, alkyl, and hydroxyalkyl.

In one embodiment, R ¹ is selected from phenyl, fluorine, 2-methoxyethyl, methoxy, methyl, 4-fluorophenyl and 2-hydroxyethyl.

In one embodiment, R ² is hydrogen or halogen.

In one embodiment, R ² is hydrogen or fluoro.

In one embodiment, R ³ is alkyl.

In one embodiment, R ³ is methyl.

In one embodiment, R ⁴ is hydrogen.

In one embodiment, p is 0 or 1.

In one embodiment, p is 0.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

A is selected from substituted or unsubstituted aryl and substituted heteroaryl;

where said substituted aryl is substituted with one or more substituents selected from halo and haloalkyl; and where said substituted heteroaryl is substituted with one or more substituents selected from halo, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl; And

wherein said substituted alkyl is substituted with one or more substituents selected from hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy, and halo.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

A is selected from substituted aryl and substituted heteroaryl; where said substituted heteroaryl is substituted with one or more substituents, preferably 2 substituents selected from halogen, alkyl, cycloalkyl, cycloalkylalkyl and heterocyclyl; and wherein said substituted aryl is substituted with one or more substituents, preferably 1-2 substituents selected from halo and haloalkyl.

In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

A is selected from substituted aryl and substituted indolyl; where said substituted indolyl is substituted with one or more substituents, preferably 2 substituents selected from cyclopropyl, chlorine, methyl, cyclopropylmethyl and oxethanil; and wherein said substituted phenyl is substituted with one or more substituents, preferably 1-2 substituents selected from chlorine, fluorine and trifluoromethyl (CF ₃ ).

In another particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

A is selected from 5-chloro-1-(cyclopropylmethyl)indol-3-or, 5-chloro-1-methyl-indol-3-yl, 5-chloro-1-cyclopropyl-indol-3-yl, 5-chloro- 1-(oxethan-3-yl)indol-3-yl, 4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-(trifluoromethyl)phenyl and 4-chlorophenyl.

In yet another particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

A is selected from 5-chloro-1-(cyclopropylmethyl)indol-3-yl; 5-chloro-1-methyl-indol-3-yl; 9H-fluoren-9-yl; 6-fluoro-1H-indol-3-yl; 5-fluoro-1,2-benzoxazol-3-yl; 5-chloro-1H-indol-3-yl; 1-methylindazol-5-yl; 5-chloro-1-cyclopropyl-indol-3-yl; 5-chloro-1-[1-(chloromethyl)-2-hydroxyethyl]indol-3-yl; 5-chloro-1-(oxethan-3-yl)indol-3-yl; 5-chloro-1-(oxethan-3-ylmethyl)indol-3-yl; 1-[2-[t-butyl(dimethyl)silyl]oxyethyl]-5-chloro-indol-3-yl; 5-chloro-1-(2-hydroxyethyl)indol-3-yl; 5-(trifluoromethyl)-3-pyridyl; 5-methoxy-3-pyridyl; 5-(trifluoromethoxy)-2-pyridyl; 5-ethyl-3-pyridyl; 5-(1,1-difluoroethyl)-2-pyridyl; 6-chloro-1-methyl-indazol-3-yl; phenyl; 4-fluoromenyl; 4-chlorophenyl; cyano(phenyl)methyl; 4-(trifluoromethyl)phenyl and 2-chloro-4-fluorophenyl.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

both m and n are 2; And

X is CH or N.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ - or a covalent bond;

both m and n are 2;

p is 0 or 1;

X is CH or N;

A is selected from substituted or unsubstituted aryl and substituted heteroaryl;

where said substituted aryl is substituted with one or more substituents, preferably 1-2 substituents selected from halogen and haloalkyl; and where said substituted heteroaryl is substituted with one or more substituents, preferably 2 substituents selected from halogen, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl; where said substituted alkyl is substituted with one or more substituents, preferably 1-3 substituents selected from hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy and halogen;

R ¹ is selected from alkoxy, alkoxyalkyl, hydroxyalkyl, alkyl, cyano, halogen, aryl and haloaryl;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

both m and n are 2;

X is CH or N;

A is selected from substituted aryl and substituted heteroaryl; where said substituted heteroaryl is substituted with one or more substituents, preferably 2 substituents selected from halogen, alkyl, cycloalkyl, cycloalkylalkyl and heterocyclyl; and wherein said substituted aryl is substituted with one or more substituents, preferably 1-2 substituents selected from halo and haloalkyl;

R ¹ is selected from alkoxyalkyl, hydroxyalkyl, aryl, haloaryl and halogen;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

both m and n are 2;

X is CH or N;

A is selected from substituted phenyl and substituted indolyl; where said substituted indolyl is substituted with one or more substituents, preferably 2 substituents selected from cyclopropyl, chlorine, methyl, cyclopropylmethyl and oxethanil; and where said substituted phenyl is substituted with one or more substituents, preferably 1-2 substituents selected from fluorine, chlorine and trifluoromethyl (CF ₃ );

R ¹ is selected from methoxyethyl, hydroxyethyl, phenyl, fluorophenyl and fluorine;

R ² is selected from hydrogen and fluorine; And

R ³ is methyl.

In another particularly preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

both m and n are 2;

X is CH or N;

A is selected from 5-chloro-1-(cyclopropylmethyl)indol-3-yl, 5-chloro-1-methyl-indol-3-yl, 4-fluorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 2-chloro -4-fluorophenyl, 5-chloro-1-cyclopropyl-indol-3-yl, 5-chloro-1-oxethanyl-indol-3-yl;

R ¹ is selected from 2-methoxyethyl, 2-hydroxyethyl, phenyl, 4-fluorophenyl and fluorine;

R ² is selected from hydrogen and fluorine; And

R ³ is methyl.

The present invention also provides the following listed embodiments (E):

E1: compound of formula (I)

in which:

L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and a covalent bond;

m is 1, n is 1 or 2, and X is CH; or

m is 2, n is 2 or 3, and X is CH or N;

p is 0, 1 or 2;

A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

R ¹ is selected from alkoxy, substituted or unsubstituted alkyl, cyano, halogen, substituted or unsubstituted cycloalkyl, (substituted or unsubstituted cycloalkyl)alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R ² is hydrogen or halogen;

or R ¹ and R ² taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclyl group;

R ³ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl; And

R ⁴ is hydrogen;

or R ³ and R ⁴ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclyl group;

Where:

each substituted alkyl is independently substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, arylalkoxy, trialkylsilyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, and substituted or unsubstituted heterocyclyl;

each substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkyloxy and substituted heterocyclyl is independently substituted with one or more substituents independently selected from halogen, cyano, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, cycloalkyl substituted with R ⁵ , R ⁶ and R ⁷ , cycloalkyloxy substituted with R ^5a , R ^6a and R ^7a , cycloalkylalkoxy substituted with R ^5b , R ^6b and R ^7b , heterocyclyl substituted with R ⁸ , R ⁹ and R ¹⁰ , heterocyclyloxy substituted with R ^8a , R ^9a and R ^10a , and aryl substituted with R ¹¹ , R ¹² and R ¹³ ; And

each of R ⁵ , R ⁶ , R ⁷ , R ^5a , R ^6a , R ^7a , R ^5b , R ^6b , R ^7b , R ⁸ , R ⁹ , R ¹⁰ , R ^{8a , R 9a ,} R ^10a , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, halogen, alkoxy, haloalkoxy, alkoxycarbonyl, and substituted or unsubstituted alkyl;

or a pharmaceutically acceptable salt or ester thereof.

E2: a compound of formula (I) according to E1, where the compound of formula (I) is a compound of formula (Ia):

in which A, L, X, m and n are as defined in clause 1.

E3: a compound of formula (I) according to E1, where the compound of formula (I) is a compound of formula (Ib):

in which A, L, X, m and n are as defined in clause 1.

E4: a compound of formula (I) according to any one of E1-E3, wherein:

L represents -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ - or a covalent bond;

p is 0 or 1;

R ¹ is selected from alkoxy, alkyl, alkoxyalkyl, hydroxyalkyl, cyano, halogen, aryl and haloaryl;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

E5: a compound of formula (I) according to any one of E1-E3, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

R ¹ is selected from alkoxyalkyl, hydroxyalkyl, aryl, haloaryl and halogen;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

E6: a compound of formula (I) according to any one of E1-E3, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

R ¹ is selected from methoxyethyl, hydroxyethyl, phenyl, fluorophenyl and fluorine;

R ² is selected from hydrogen and fluorine; And

R ³ is methyl.

E7: a compound of formula (I) according to any one of E1-E6, wherein:

A is selected from substituted or unsubstituted aryl and substituted heteroaryl;

Where:

said substituted aryl is substituted with one or more substituents selected from halo and haloalkyl; And

said substituted heteroaryl is substituted with one or more substituents selected from halo, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl; Where:

said substituted alkyl is substituted with one or more substituents selected from hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy and halogen.

E8: a compound of formula (I) according to any one of E1-E6, wherein:

A is selected from haloaryl and substituted heteroaryl; Where:

said substituted heteroaryl is substituted with one or more substituents selected from halo, alkyl, cycloalkyl, cycloalkylalkyl, and heterocyclyl.

E9: a compound of formula (I) according to any one of E1-E6, wherein:

A is selected from fluorophenyl, chlorophenyl and substituted indolyl, where:

said substituted indolyl is substituted with one or more substituents selected from cyclopropyl, chlorine, methyl, cyclopropylmethyl and oxethanyl.

E10: A compound of formula (I) according to any one of E1-E9, wherein m and n are both 2 and X is CH or N.

E11: a compound of formula (I) according to any one of E1-E3, wherein:

L represents -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ - or a covalent bond;

m and n are both 2;

p is 0 or 1;

X is CH or N;

A is selected from substituted or unsubstituted aryl and substituted heteroaryl;

Where:

said substituted aryl is substituted with one or more substituents selected from halo and haloalkyl; And

said substituted heteroaryl is substituted with one or more substituents selected from halogen, substituted or unsubstituted alkyl, alkoxy, halogenalkoxy, cycloalkyl, and heterocyclyl; where said substituted alkyl is substituted with one or more substituents selected from hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy, and halogen;

R ¹ is selected from alkoxy, alkoxyalkyl, alkyl, hydroxyalkyl, cyano, halogen, aryl and haloaryl;

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

E12: a compound of formula (I) according to any one of E1-E3, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

m and n are both 2;

X is CH or N;

A is selected from haloaryl or substituted heteroaryl; Where:

said substituted heteroaryl is substituted with one or more substituents selected from halo, alkyl, cycloalkyl, cycloalkylalkyl, and heterocyclyl;

R ¹ is selected from alkoxyalkyl, hydroxyalkyl, aryl, halogen and haloaryl.

R ² is selected from hydrogen and halogen; And

R ³ is alkyl.

E13: a compound of formula (I) according to any one of E1-E3, wherein:

L represents -CR ¹ R ² -, -OCHR ³ - or a covalent bond;

m and n are both 2;

X is CH or N;

A is selected from fluorophenyl, chlorophenyl and substituted indolyl, where:

said substituted indolyl is substituted with one or more substituents selected from cyclopropyl, chlorine, methyl, cyclopropylmethyl, and oxethanyl; And

R ¹ is selected from methoxyethyl, hydroxyethyl, phenyl, fluorine and fluorophenyl.

R ² is selected from hydrogen and fluorine; And

R ³ is methyl.

In one aspect, the present invention provides a compound of formula (Ic)

or a pharmaceutically acceptable salt thereof, wherein:

L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and a covalent bond;

m is 0, n is 0 or 1, and X is CR ²⁴ ; or

m is 1, n is 1 or 2, and X is CR ²⁴ or N;

p is 0, 1 or 2;

; и R² выбран из водорода, галогена и гидрокси; илиR ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 - alkyl-, halogen-C _1-6 -alkoxy, halogen-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

; and R ² is selected from hydrogen, halogen and hydroxy; or

R ¹ and R ² taken together with the carbon atom to which they are attached form C _3-12 cycloalkyl or C _2-9 heterocyclyl;

R ³ is selected from C _1-6 alkyl, halo-C _1-6 alkyl, C _3-12 cycloalkyl and C _6-14 aryl; and R ⁴ is hydrogen; or

R ³ and R ⁴ taken together with the carbon atom to which they are attached form C _3-12 cycloalkyl or C _2-9 heterocyclyl;

R ²⁰ is hydrogen or C _1-6 alkyl;

и группы

R ²¹ , R ²² and R ²³ are independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl , hydroxy-C _1-6 -alkyl, (halo-C _1-6 -alkyl) -hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 - alkoxycarbonyl-NH-C _1-6 -alkoxy-, C _1-6 -alkoxycarbonyl-NH-(C _1-6 -alkoxy) ₂ -C _1-6 -alkyl-C (O) -NH-C _1-6 - alkoxy-, C _1-6 -alkoxycarbonyl-NH-C _1-6 -alkoxy-C _1-6 -alkyl-C (O) -NH-C _1-6 -alkoxy-, SF ₅ , (C _1-6 - alkyl) ₃ Si-O-C _1-6 -alkyl-, groups

and groups

R ²⁴ is selected from hydrogen, halogen, hydroxy, halo-C _1-6 alkyl and C _1-6 alkyl;

R ²⁵ and R ²⁶ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, C _1-6 alkyl -SO ₂ - and C _3-12 -cycloalkyl;

R ²⁷ and R ²⁸ are independently selected from hydrogen, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, halogen, hydroxy, C _1-6 -alkylsulfonyl, carbamoyl, cyano, cycloalkyl-C _1-6 -alkoxy-, C _1-6 -alkyl-NH-C(O)- and cycloalkyl;

A and B are independently selected from C _6-14 aryl, C _1-13 heteroaryl, C _3-12 cycloalkyl, and C _2-9 heterocyclyl;

C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl;

C ² is C _6-14 aryl;

L ² is selected from a covalent bond, -O-, -CH ₂ O-, -CH ₂ OCH ₂ - and -CH ₂ - and;

L ³ is selected from a covalent bond, -O-, -CH ₂ O, -OCH ₂ -, -CH ₂ OCH ₂ - and -CH ₂ - and;

L ^3a is selected from a covalent bond, -CH ₂ O-, -OCH ₂ -, -CH ₂ OCH ₂ - and -CH ₂ -.

In a preferred embodiment, the compound of formula (Ic) is a compound of formula (I) as defined herein above:

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Ic) is a compound of formula (Id):

in which A, L, X, m, n and R ²⁰ -R ²³ are as defined in paragraph 1.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Ic) is a compound of formula (Ie):

where A, L, X, m, n and R ²⁰ -R ²³ are as defined in paragraph 1. In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof where the compound of formula (Ic) is a compound of formula (If):

where A, L, X, m, n and R ²⁰ -R ²³ are as defined in paragraph 1.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Ic) is a compound of formula (Ig):

where A, L, X, m, n and R ²⁰ -R ²³ are as defined in paragraph 1.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

m is 0, n is 0 or 1, and X is CR ²⁴ ; or

m is 1, n is 1, and X is CR ²⁴ or N.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 0.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

; и R² выбран из водорода, галогена и гидрокси; илиR ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 - alkyl-, halogen-C _1-6 -alkoxy, gelogen-C _1-6 -alkoxy-C _1-6 -alkyl-cyano and groups

; and R ² is selected from hydrogen, halogen and hydroxy; or

R ¹ and R ² taken together with the carbon atom to which they are attached form C _3-12 -cycloalkyl.

и R² представляет собой водород или галоген.In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 -alkoxy-C _1-6 -alkyl- halogen-C _1-6 -alkoxy and groups

and R ² is hydrogen or halogen.

и R² представляет собой водород или фтор.In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and groups

and R ² is hydrogen or fluorine.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is C _1-6 alkyl; and R ⁴ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is C _1-6 alkyl; and R ⁴ is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl; and R ⁴ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁰ is hydrogen.

и группы

где R²⁷, R²⁸, С¹, С², L³ and L^3a являются такими, как определено в данном документе.In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C ^1-6 -alkyl, (halo-C _1-6 -alkyl) -hydroxy-C _1-6 -alkyl, C _{1 -6} -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _1-6 -alkoxy-, C _1-6 -alkoxycarbonyl-NH- (C _1-6 -alkoxy) ₂ -C _1-6 -alkyl-C (O) -NH-C _1-6 -alkoxy-, C _1-6 -alkoxycarbonyl-NH-C _1-6 -alkoxy-C _1-6 -alkyl-C (O) -NH -C _1-6 -alkoxy-, SF ₅ , (C _1-6 -alkyl) ₃ Si-O-C _1-6 -alkyl-, groups

and groups

where R ²⁷ , R ²⁸ , C ¹ , C ² , L ³ and L ^3a are as defined herein.

где R²⁷, R²⁸, С¹ и L³ являются такими, как определено в данном документе.In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and groups

where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein.

где R²⁷, R²⁸, С¹ и L³ являются такими, как определено в данном документе.In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, t-butyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl and group

where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy , C _1-6 -alkyl and cyano.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy .

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²³ is hydrogen or halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²³ is hydrogen or fluorine.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁴ is hydrogen.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogen -C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ - and C _3-12 -cycloalkyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 alkoxy and C _3-12 cycloalkyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁶ is selected from hydrogen, C _1-6 alkyl, and C _1-6 alkoxy.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁶ is hydrogen or C _1-6 -alkoxy.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁶ is hydrogen or methoxy.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁷ is selected from hydrogen, halo-C _1-6 alkoxy, C _1-6 alkyl, halogen -C _1-6 -alkyl and halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methyl- ethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy, fluorine and chlorine.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁸ is selected from hydrogen, C _1-6 alkyl and halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is C _6-14 aryl or C _1-13 heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pyridyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is C _6-14 aryl or C _1-13 heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is phenyl or 1,2,4-oxadiazol-5-yl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C ¹ is selected from azetidin-1-yl, pyrrolidin-1-yl, cyclopropyl, and oxethan-3-yl .

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C ² is phenyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bonds; in which from R ¹ to R ⁴ and R are as defined in this document.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein L ² is selected from a covalent bond, -O- and -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein L ² is a covalent bond.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from a covalent bond, -CH ₂ O- and -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L ³ is a covalent bond or -CH ₂ -.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L ³ is a covalent bond or -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L ^3a is a covalent bond.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

m is 0, n is 0 or 1, and X is CR ²⁴ ; or

m is 1, n is 1, and X is CR ²⁴ or N;

L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -, -CHR ³ O- and a covalent bond;

p is 0 or 1;

и R² выбран из водорода, галогена и гидрокси; илиR ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 - alkyl-halogen-C _1-6 -alkoxy, halogen-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

and R ² is selected from hydrogen, halogen and hydroxy; or

R ¹ and R ² taken together with the carbon atom to which they are attached form C _3-12 -cycloalkyl;

R ³ is C _1-6 alkyl or halo-C _1-6 alkyl;

R ²⁰ is hydrogen or C _1-6 alkyl;

и группы

R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl , (halo-C _1-6 -alkyl) -hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-C _1-6 -alkoxycarbonyl-NH-C _1-6 -alkoxy -, SF ₅ , (C _1-6 -alkyl) ₃ Si-O-C _1-6 -alkyl-, groups

and groups

R ²² is selected from hydrogen, halogen, C _1-6 alkoxy, halo-C _1-6 alkoxy, C _1-6 alkyl and cyano;

R ²³ is hydrogen or halogen;

R ²⁴ is selected from hydrogen, halogen, hydroxy and C _1-6 alkyl;

R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ - and C _3-12 cycloalkyl;

R ²⁶ is selected from hydrogen, C _1-6 alkyl and C _1-6 alkoxy;

R ²⁷ is selected from hydrogen, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, halogen , hydroxy, C _1-6 -alkylsulfonyl, carbamoyl, cyano, cycloalkyl-C _1-6 -alkoxy and cycloalkyl;

R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen;

A represents C _6-14 aryl or C _1-13 heteroaryl;

B is C _6-14 aryl or C _1-13 heteroaryl;

C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl;

C ² is C _6-14 -aryl;

L ² is selected from a covalent bond, -O- and -CH ₂ -;

L ³ is selected from a covalent bond, -CH ₂ O- and -CH ₂ -; And

L ^3a is a covalent bond or -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

m is 0, n is 0 or 1, and X is CH; or

m is 1, n is 1, and X is CH or N;

L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and a covalent bond;

R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halogen-C _1-6 -alkoxy and groups

R ² is hydrogen or halogen;

R ³ is C _1-6 alkyl;

R ²⁰ is hydrogen;

R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and the group

R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy;

R ²³ is hydrogen or halogen;

R ²⁵ is selected from hydrogen, halogen, C _1-6 alkoxy and C _3-12 cycloalkyl;

R ²⁶ is hydrogen or C _1-6 alkoxy;

R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl and halogen;

R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen;

A represents C _6-14 aryl or C _1-13 heteroaryl;

B is C _6-14 aryl or C _1-13 heteroaryl;

C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl;

L ³ is a covalent bond or -CH ₂ -.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

m is 0, n is 0 or 1, and X is CH; or

m is 1, n is 1, and X is CH or N;

L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and a covalent bond;

R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and the group

R ² is hydrogen or fluorine;

R ³ is methyl;

R ²⁰ is hydrogen;

R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, t-butyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl and group

R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl;

R ²³ represents hydrogen or fluorine;

R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl;

R ²⁶ is hydrogen or methoxy;

R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methyl-ethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy, fluoro and chlorine;

R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine;

A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pyridyl;

B is phenyl or 1,2,4-oxadiazol-5-yl;

C ¹ is selected from azetidin-1-yl, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl; And

L ³ is a covalent bond or -CH ₂ -.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

m is 0, n is 0 or 1, and X is CR ²⁴ ; or

m is 1, n is 1, and X is CR ²⁴ or N; And

R ²⁴ is selected from hydrogen, halogen, hydroxy and C _1-6 alkyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

m is 0, n is 0 or 1, and X is CH; or

m is 1, n is 1, and X is CH or N.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -, -CHR ³ O- and a covalent bond;

p is 0 or 1;

и R² выбран из водорода, галогена и гидрокси; илиR ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 - alkyl-, halogen-C _1-6 -alkoxy, halogen-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

and R ² is selected from hydrogen, halogen and hydroxy; or

R ¹ and R ² taken together with the carbon atom to which they are attached form C _3-12 -cycloalkyl;

R ³ is C _1-6 alkyl or halo-C _1-6 alkyl;

R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ - and C _3-12 cycloalkyl;

R ²⁶ is selected from hydrogen, C _1-6 alkyl and C _1-6 alkoxy;

B is C _6-14 aryl or C _1-13 heteroaryl; And

L ² is selected from a covalent bond, -O- and -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and a covalent bond;

R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halogen-C _1-6 -alkoxy and groups

R ² is hydrogen or halogen;

R ³ is C _1-6 alkyl;

R ²⁵ is selected from hydrogen, halogen, C _1-6 alkoxy and C _3-12 cycloalkyl;

R ²⁶ is hydrogen or C _1-6 alkoxy; And

B is C _6-14 aryl or C _1-13 heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and a covalent bond;

R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and the group

R ² is hydrogen or fluorine;

R ³ is methyl;

R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl;

R ²⁶ is hydrogen or methoxy; And

B is 1,2,4-oxadiazol-5-yl.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

и группы

R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl , (halo-C _1-6 -alkyl) -hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _1-6 - alkoxy-, SF ₅ , (C _1-6 -alkyl) ₃ Si-O-C _1-6 -alkyl-, groups

and groups

R ²² is selected from hydrogen, halogen, C _1-6 alkoxy, halo-C _1-6 alkoxy, C _1-6 alkyl and cyano;

R ²³ is hydrogen or halogen;

R ²⁷ is selected from hydrogen, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, halogen , hydroxy, C _1-6 -alkylsulfonyl, carbamoyl, cyano, cycloalkyl-C _1-6 -alkoxy and cycloalkyl;

R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen;

A is C _6-14 aryl or C _1-13 heteroaryl;

C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl;

C ² is C _6-14 aryl;

L ³ is selected from a covalent bond, -CH ₂ O- and -CH ₂ -; And

L ^3a is a covalent bond or -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and the group

R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy;

R ²³ is hydrogen or halogen;

R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl and halogen;

R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen;

A is C _6-14 aryl or C _1-13 heteroaryl;

C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl; And

L ³ is a covalent bond or -CH ₂ -.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, t-butyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl and group

R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl;

R ²³ represents hydrogen or fluorine;

R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methylethoxy, 2,2,2-trifluoro-1,1-dimethylethoxy, 2,2,2-trifluoroethoxy, fluoro and chlorine;

R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine;

A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pridyl;

C ¹ is selected from azetidin-1-yl, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl; And

L ³ is a covalent bond or -CH ₂ -.

In one embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, selected from the compounds shown in Table 1 and Table 3.

In a preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, selected from the compounds shown in Table 1.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Ic) is selected from the following:

rac-cis-6-(4-(5-chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one;

rac-cis-6-(4-(5-chloro-1-methyl-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one;

rac-cis-6-(4-(1-(4-fluorophenyl)-3-methoxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-He;

rac-cis-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He;

(+)-cis-6-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He;

(+)- or (-)-cis-6-(4-(5-chloro-1-cyclopropyl-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(+)- or (-)-cis-6-(4-(5-chloro-1-(oxethan-3-yl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one;

rac-cis-6-(4-(1-(4-fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-He;

(4aR,8aS)-6-(4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(+) or (-)-cis-6-(4-((R or S)-1-(2-chloro-4-fluorophenoxy)ethyl)piperidine-1-cabonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(+) or (-)-cis-6-(4-((4-chlorophenyl)difluoromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(+) or (-)-cis-6-(4-((2-chloro-4-fluorophenyl)difluoromethyl)pipeidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((R or S)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carbonyl)hexahydro-2H-piido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-[4-[(S or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(3-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((S or R)-(3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(4-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((S or R)-(3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(4-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(4-((S or R)-(4-(2-fluoroethoxy)phenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-[3-[4-(trifluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4 ]oxazin-3-one;

(4aR,8aS)-6-(3-(2'-trifluoromethoxy)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-bromo-3-chlorophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He;

(4aR,8aS)-6-[3-[4-(4-chloro-2-fluorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-[4-(2-chloro-4-fluorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one;

(4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H -pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(tert-butyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H) -He;

(4aR,8aS)-6-(3-(4-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ;

(4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl )hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(4aR,8aS)-6-(3-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(3-(trifluoromethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(6-(2,4-dichlorophenyl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-[4-[3-[(1S or 1R)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl]phenyl]azetidin-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-[4-[3-[(1R or 1S)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl]phenyl]azetidin-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-(3-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(pentafluoro-16-sulfaneyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-[4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7, 8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-(3-(5-(2,4-dichlorophenyl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-((R or S)-2-(Trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-((S or R)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(4aR,8aS)-6-(3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(4aR,8aS)-6-(3-(3,5-difluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-one;

(4aR,8aS)-6-(3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he;

(4aR,8aS)-6-((R or S)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-((S or R)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(tert-butyl)-3-methoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he;

(4aR,8aS)-6-(3-(4-propylphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he;

(4aR,8aS)-6-(3-(5-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-(5-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-[3-[6-[3-(R or S)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-[6-[3-(S or R)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

(4aR,8aS)-6-[3-(4-tetrahydropyran-3-ylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one;

(4aR,8aS)-6-[3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one and

(4aR,8aS)-6-(3-(4-(neopentyloxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one .

In one embodiment, the present invention provides pharmaceutically acceptable salts or esters of compounds of formula (I) as described herein. In a specific embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) as described herein, especially the hydrochloride salts. In another specific embodiment, the present invention provides pharmaceutically acceptable esters of the compounds of formula (I) as described herein. In yet another specific embodiment, the present invention provides compounds according to formula (I) as described herein.

Manufacturing methods

The preparation of compounds of formula (I) according to the present invention may be carried out by sequential or convergent synthetic routes. The syntheses of the invention are shown in the following general schemes. The skills required to carry out the reaction and purify the resulting products are known to those skilled in the art. Substituents and suffixes used in the following description of these methods have the meaning given herein unless otherwise indicated.

If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more of the reaction steps, suitable protecting groups may be introduced before the critical step ( as described, for example, in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.). Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

If the starting materials or intermediates contain stereogenic centers, the compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, for example, chiral HPLC (high performance liquid chromatography), SFC (supercritical fluid chromatography) or chiral crystallization. Racemic compounds, for example, can be resolved to their antipodes via diastereomeric salts by crystallization with optically pure acids, or by separation of the antipodes by specific chromatographic techniques using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to obtain diastereomeric/enantiomerically enriched starting materials and intermediates. The use of such diastereomeric/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically result in the corresponding diastereomerically/enantiomerically enriched compounds of formula (I).

The person skilled in the art will appreciate that the synthesis of compounds of formula (I) - to the extent that it is not otherwise desirable - will use an "orthogonal protecting group strategy" to ensure that several protecting groups each are cleaved at the same time without effects on other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in the literature (e.g., Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

One skilled in the art will appreciate that the sequence of reactions may vary depending on the reactivity and nature of the intermediates.

In more detail, the compounds of formula (I) can be produced by the methods below, the methods given in the examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Also regarding reaction conditions described in the literature affecting the described reactions, 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 convenient to carry out these reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be used, provided that it does not adversely affect the reaction or the reagents involved, and that it can dissolve these reagents, at least to some extent. The reactions described can take place over a wide range of temperatures, and the exact reaction temperature is critical to the present invention. It is convenient to carry out the described reactions in the temperature range from -78°C to the reflux temperature. The time required for the reaction can also vary widely, depending on many factors, notably 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 sequence of reactions is not limited to the sequence shown in the schemes, however, depending on the starting materials and their respective reactivity, this sequence of reaction steps can be freely changed.

If the starting materials or intermediates are not commercially available, or their synthesis is not described in the literature, they can be prepared by analogy with existing procedures for close analogues or as described in the experimental section.

The following abbreviations are used in this text:

AcOH - acetic acid, ACN - acetonitrile, Boc - tert-butyloxycarbonyl, CAS RN - registration number of chemical abstracts, Cbz - benzyloxycarbonyl, Cs ₂ CO ₃ - cesium carbonate, CO - carbon monoxide, CuCl - copper (I) chloride, CuCN - copper(I) cyanide, CuI - copper(I) iodide, DMAP - 4-dimethylaminopyridine, DME - dimethoxyethane, DMEDA - N,N'-dimethylethylenediamine, DMF - N,N-dimethylformamide, DIPEA - N,N-diisopropylethylamine, dppf - 1,1 bis(diphenylphosphino)ferrocene, EDC.HCl - N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EI - electron impact, ESI - electrospray ionization, EtOAc - ethyl acetate, EtOH - ethanol, h - h ( sy), FA - formic acid, H ₂ O - water, H ₂ SO ₄ - sulfuric acid, Hal - halogen, HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4, 5-b]pyridinium-3-oxide hexafluorophosphate, HBTU - O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, HCl - hydrochloric acid, HOBt - 1-hydroxy-1H-benzotriazole; HPLC - high performance liquid chromatography, iPrMgCl - isopropylmagnesium chloride, I ₂ - iodine, IPA - 2-propanol, (Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ -[4,4'-bis(1, 1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate, ISP - ion spray positive (mode), ISN - ion spray negative (mode), K ₂ CO ₃ - potassium carbonate, KHCO ₃ - potassium bicarbonate, KI - potassium iodide, KOH - potassium hydroxide, K ₃ PO ₄ - tribasic potassium phosphate, LiAlH ₄ or LAH - lithium aluminum hydride, LiHMDS - lithium bis (trimethylsilyl) amide, LiOH - lithium hydroxide, MgSO ₄ - magnesium sulfate, min - minute (you), ml - milliliter, MPLC - medium pressure liquid chromatography, MS - mass spectrum, NaH - sodium hydride, NaHCO ₃ - sodium bicarbonate, NaNO ₂ - sodium nitrite, NaOH - sodium hydroxide, Na ₂ CO ₃ - sodium carbonate, Na ₂ SO ₄ - sodium sulfate, Na ₂ S ₂ O ₃ - sodium thiosulfate, NBS - N-bromosuccinimide, nBuLi - n-butyl lithium, NEt ₃ - triethylamine (TEA), NH ₄ Cl - ammonium chloride, glyme NiCl ₂ - nickel (II) chloride complex of ethylene glycol dimethyl ether, NMP - N-methyl-2-pyrrolidone , OAc -acetoxy, T ₃ P - propylphosphonic anhydride, P ₂ O ₅ - phosphorus pentoxide, PE - petroleum ether, PG - protective group, Pd-C - palladium on activated carbon, PdCl ₂ (dppf) -CH ₂ Cl ₂ - complex of 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane, Pd ₂ (dba) ₃ - tris (dibenzylideneacetone) dipalladium (0), Pd (OAc) ₂ - palladium (II) acetate, Pd (OH) ) ₂ - palladium hydroxide, Pd (PPh ₃ ) ₄ - tetrakis (triphenylphosphine) palladium (0), PTSA - p-toluenesulfonic acid, R - any group, RT - room temperature, SFC - supercritical fluid chromatography, S-PHOS - 2 -dichlorophenylphosphino-2',6'-dimethoxybiphenyl, ТЗР - propylphosphonic anhydride, TBAI - tetrabutylammonium iodide, TEA - triethylamine, TFA - trifluoroacetic acid, THF - tetrahydrofuran, TMEDA - N,N,N',N'-tetramethylethylenediamine, ZnCl ₂ - zinc chloride, Xantphos - 4,5-bis(diphenylphosphino)-9,9-dimethylxatene.

Compounds of formula I in which A, L, X, n and m are as described herein can be synthesized by analogy with literature procedures and/or as shown, for example, in Scheme 1.

Accordingly, 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-ones 1 react with intermediates 2 in the presence of a urea-forming reagent such as as bis(trichloromethyl)carbonate using a suitable base and solvent such as, for example, sodium bicarbonate in DCM to give compounds of formula I (step a). Other urea-forming reagents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, or 1,1'-carbonyldiimidazole. Reactions of this type and the use of these reagents are widely described in the literature (eg G. Sartori et al., Green Chemistry 2000, 2, 140). One skilled in the art will recognize that the order of addition of the reactants can be important for this type of reaction due to the reactivity and stability of the intermediate carbamoyl chlorides formed, as well as avoiding the formation of unwanted symmetrical urea by-products.

Compounds of formula (Ic) described herein can be prepared in analogy to compounds of formula (I) as described herein in Schemes 1-18. For example, by analogy with the procedure described in Scheme 1 above, 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-ones 1 are reacted with intermediates 2a to give compounds of formula (Ic) (Scheme 1A, step a).

Intermediate compounds 1 can be synthesized as described, for example, in Scheme 2 and/or by analogy with the methods described in the literature.

Thus, 3-aminopiperidin-4-ol derivatives 3, in which "PG" denotes a suitable protecting group, such as a Cbz or Boe protecting group, can be acylated, for example, with chloro- or bromoacetyl chloride 4, in which "LG" denotes a suitable leaving group (e.g. Cl or Br) using a suitable base such as sodium or potassium carbonate, sodium hydroxide or sodium acetate in a suitable solvent such as THF, water, acetone or mixtures thereof to give intermediates 5 (step A).

Intermediates 5 can be cyclized to intermediates 6 using methods well known in the art, for example by treating 5 with sodium hydride in THF or potassium t-butoxide in IPA and water (step b). Reactions of this type are described in the literature (e.g. Z. Rafinski et al., J, Org, Chem. 2015, 80, 7468; S. Dugar et al., Synthesis 2015, 47(5), 712; WO 2005/066187) .

Deprotection of intermediates 6 using methods known in the art (e.g. Boe group using TFA in DCM at 0°C to room temperature, Cbz group using hydrogen in the presence of a suitable catalyst such as Pd or Pd (OH) ₂ on carbon in a suitable solvent such as MeOH, EtOH, EtOAc or mixtures thereof, and as described, for example, in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 4th Ed., 2006, Wiley NY) yields intermediate 1 (step c).

Intermediates 1 can be obtained as mixtures of diastereomers and enantiomers, respectively, or as single stereoisomers, depending on whether racemic mixtures or enantiomerically pure forms of cis- or trans-3-aminopiperidin-4-ol derivatives are used in their synthesis 3. Intermediates 3 are commercially available and their synthesis has also been described in the literature (eg WO 2005/066187; WO 2011/0059118; WO 2016/185279).

Optically pure cis-configured intermediates 1B and 1C can be prepared, for example, according to Scheme 3 by chiral resolution of commercially available (cis-rac)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4 ,3-b][1,4]oxazin-3-one (1A) (possibly in the form of a salt, such as, for example, the hydrochloride salt) using methods known in the art, for example, by crystallization of a diastereomeric salt or by a chiral chromatography (step a).

In some embodiments, intermediates 2 are type B, C, D, or E type intermediates. Type B, C, D, or E type intermediates can be prepared, for example, by the synthetic procedures described in Schemes 4, 5, 6, and 7.

Type B intermediates in which R1 is as defined herein can be prepared through a variety of conditions, which can be exemplified by the general synthetic procedure described in Scheme 4.

Starting with aryl or heteroaryl halides 7 in which X ¹ is selected from Cl, Br or I and A is as defined herein, a lithium halide exchange reaction can be carried out using a solution of LiHMDS or n-BuLi, preferably n- BuLi, in a solvent like THF, diethyl ether, n-pentane, n-hexane or mixtures thereof, preferably THF, and in the temperature range from -20°C to -78°C, preferably at -78°C, to obtain the corresponding lithiated aryl or heteroaryl intermediate. Nucleophilic addition of an in situ-produced lithiated aryl or heteroaryl intermediate to type 8 ketones, where R ¹ , m and n are as defined herein, in a solvent such as THF and preferably at -78° C., gives the corresponding tertiary alcohols 9 (step a).

Subsequent elimination of the tertiary hydroxyl group, with concomitant removal of the Boe protecting group, using acidic conditions such as 4 M HCl in dioxane, in a solvent like MeOH, or preferably TFAb DCM, gives the corresponding olefins 10 (step b).

Heterogeneous catalytic hydrogenation of olefins 10 using a catalyst such as Pd(OH) ₂ or Pd/C in a solvent like THF, MeOH, EtOH, EtOAc or mixtures thereof, preferably Pd/C in THF, e.g. at atmospheric hydrogen pressure, gives type B intermediates (step c).

Intermediates 8 are commercially available and/or can be prepared in analogy to methods described in the literature, eg Bioorg. Med. Chem. Lett. 2011, 27(18), 5191, WO 2012/155199, WO 2016/180536, Bioorg. Med. Chem. Lett. 2008, 78(18), 5087, WO 2007/117557, J. Am. Chem. soc. 2017, 739(33), 11353, J. Med. Chem. 2017, 60(13), 5507.

Type C intermediates in which A is as defined herein and n is 1, 2, or 3 can be prepared through a variety of conditions, which can be exemplified by the general synthetic procedures described in Scheme 5.

Treatment of a mixture of aryl or heteroaryl compounds 11 wherein A is as defined herein, preferably wherein A is substituted heteroaryl as defined herein, most preferably substituted indolyl as defined herein, and ketones 12 , in which n is as defined herein, a base such as NaOH or KOH, in a solvent like EHH or MeOH, and in the temperature range from room temperature to 80°C, preferably around the reflux temperature of the mixture, gives olefins 13 (stage a).

Subsequent heterogeneous catalytic hydrogenation using a transition metal catalyst such as PtO ₂ in a polar solvent like MeOH, EtOH, AcOEt, AcOH or a mixture thereof, preferably an EtOH/AcOH mixture, at about room temperature, low to high pressure, preferably hydrogen gas pressure of about 5 kPa gives intermediate compounds 14 (step b).

Removal of the Boc protecting group using acidic conditions such as treatment with TFA in DCM or preferably 4 M HCl in dioxane, in a solvent like MeOH, affords the corresponding type C intermediates (step c).

In some embodiments, intermediate 14 is an intermediate of formula 14a wherein ring A is a heteroaryl containing a secondary amino group (i.e. "-NH-" such as indolyl) and m and n are as defined in this document. Intermediates 14a can be converted to type D intermediates wherein A is a heteroaryl containing at least one nitrogen atom, the type is as defined herein, and R ¹⁴ is selected from alkyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, preferably methyl, cyclopropyl, cyclopropylmethyl, hydroxyethyl, oxethan-3-yl and oxethan-3-ylmethyl, for example as described in Scheme 6.

Thus, intermediates 14a can be N-functionalized by treatment with a suitable base such as NaH, KH, NaHMDS, LiHMDS, LDA, preferably NaH, in a suitable solvent like DMF, THF, dioxane, or a mixture thereof, preferably DMF, and at temperature range from -78°C to room temperature, preferably at 0°C, followed by the addition of compounds R ¹⁴ -LG, in which LG denotes a suitable leaving group, such as chlorine, bromine, iodine, OSO ₂ alkyl (for example, mesylate (methanesulfonate ), OSO ₂ fluoroalkyl (e.g. triflate (trifluoromethanesulfonate) or OSO ₂ aryl (e.g. tosylate (p-toluenesulfonate)) to give the corresponding N-functionalized compounds 15 in which R ¹⁴ is as defined above for Intermediate D The person skilled in the art will appreciate that, depending on the nature of R ¹⁴ , additional or different reagents may be used, such as using cyclopropylboronic acid in the presence of copper(II) acetate and a base such as DMAP with NaHMDS, in a solvent such as toluene at temperatures up to the boiling point of the solvent in cases where R ¹⁴ is a cyclopropyl group (step a).

Deprotection of compounds 15 using the same conditions as described above for compounds 14 (see Scheme 5, step c) gives type D intermediates (step b).

In one embodiment, intermediate D is an indazole derivative of type E, wherein m, n, and R ¹⁴ are as defined herein. In addition to the procedure described in Scheme 6, type E intermediates can be prepared through a variety of conditions, in particular the general synthetic procedure described in Scheme 7.

Accordingly, the condensation of intermediates 16 in which PG is a protecting group such as Boc, Cbz or Bn and m and n are as described herein with a hydrazine derivative of type R ¹⁴ NHNH ₂ in which R ¹⁴ is as described herein in a solvent like n-BuOH, DMA, DMF, DMSO, or mixtures thereof, preferably n-BuOH, in a sealed reaction vessel at elevated temperature, e.g. 120° C., gives the imidazole compounds 17 ( stage a).

Then removal of the protecting group, in the case of the Boe group using, for example, acidic conditions such as treatment with HCl in dioxane or TFA in DCM, preferably using 4 M HCl in dioxane, in a solvent like MeOH, preferably at about room temperature, gives type E intermediates (step b).

In some embodiments, intermediates 2 are type F, G, H, J, K, L, and M type intermediates. F, G, H, J, K, L, and M type intermediates wherein A, m, and n are R ¹⁵ and R ¹⁶ are each independently selected from alkyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, preferably methyl, cyclopropyl, cyclopropylmethyl, hydroxyethyl, oxethan-3-yl and oxethane-3 -ylmethyl; and R ¹⁷ selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkyl may be prepared by methods well known to one of skill in the art and as illustrated by the examples of general synthetic methods described in Scheme 8.

The carbonyl group in intermediates 18 wherein A, m and n are as described herein and PG is a suitable protecting group such as a Boe, Cbz or Bn group, either commercially available or prepared according to methods described in the literature (e.g., J. Am. Chem. Soc. 2017, 739(33), 11353, J. Med. Chem. 2017, 60(13), 5507, RSC Advances 2015, 5(61), 40964), can be reduced by methods well known in the art, eg using NaBH ₄ in MeOH, to give intermediates 19 (step a).

Deprotection of intermediates 19 using methods known in the art (e.g., Boc group using TFA in DCM or 4 M HCl in dioxane, at temperatures from 0°C to room temperature, Cbz group using hydrogen in the presence of a suitable a catalyst such as Pd or Pd(OH) ₂ on carbon in a suitable solvent such as MeOH, EtOH, EtOAc or mixtures thereof, and as described, for example, in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 4th Ed., 2006, Wiley NY) yields G intermediates (step b).

Alkylation of the hydroxy group of intermediates 19 using an R ¹⁵ LG type alkylating agent wherein LG is a suitable leaving group such as chlorine, bromine, iodine, OSO ₂ alkyl (e.g. mesylate (methanesulfonate), OSO ₂ fluoroalkyl (e.g. triflate ( trifluoromethanesulfonate) or OSO ₂ aryl (e.g. tosylate (p-toluenesulfonate) and R ¹⁵ is as described herein using a suitable base in a suitable solvent (e.g. sodium hydride in DMF) at temperatures between 0°C and to the boiling point of the solvent, gives intermediate compounds 20 (stage c).

Deprotection of intermediates 20 using methods well known in the art and as described above (step b) gives intermediates F (step d).

Intermediates 18 can be converted to intermediates 21 in which R ^a is alkyl, preferably methyl or ethyl, using an olefination reaction such as the widely described Wittig or Horner Emmons reaction, for example using ethyl-2-(diethoxyphosphoryl) acetate and LiHMDS in dioxane, at temperatures ranging from 0° C. to the melting point of the solvent (step e).

The double bond in intermediates 21 can be reduced, for example, by hydrogenation in the presence of a suitable catalyst such as Pd-C in a suitable solvent such as MeOH, EtOH or EtOAc, or mixtures thereof, to give intermediates 22 (step f).

Reduction of the ester functional group in intermediates 22 using, for example, LiBH ₄ in THF, at temperatures ranging from 0° C. to the reflux temperature of the solvent, gives intermediates 23 (step g).

Deprotection of intermediates 23 using methods well known in the art and as described above (step b) gives intermediates G (step h).

Alkylation of the hydroxy group of intermediates 23 with an alkylating agent such as R ¹⁶ LG, in which LG is a suitable leaving group and R ¹⁶ is as described herein, using the conditions as described above (step c), gives intermediates 24 (stage i).

Deprotection of intermediates 24 using methods well known in the art and as described above (step b) gives intermediates H (step i).

Addition of an organometallic compound of type R ¹⁷ M, in which M is, for example, MgCl, MgCl, or Li and R ¹⁷ , as described herein, to intermediates 18 gives intermediates 25 (step k). Reactions of this type are well known in the art and are described in the literature (J, Med. Chem. 1989, 32(1), 105, J, Med. Chem, 2014, 57(4), 1543, Bioorg. Med. Chem Lett. 2015, 25(13), 2720).

Deprotection of intermediates 25 using methods well known in the art and as described above (step b) gives intermediates J (step I).

Alkylation of the hydroxyl group of intermediates 25 with an alkylating agent of the R ¹⁵ LG type, in which LG is a suitable leaving group and R ¹⁵ is as described herein, using the conditions as described above (step c), gives intermediates 26 (stage m).

Deprotection of intermediates 26 using methods well known in the art and as described above (step b) gives intermediates K (step n).

Intermediates 18 can be converted to intermediates 27 using methods known in the art and described in the literature (e.g. J. Med. Chem. 2003, 46(25), 5445; WO 2016/205590), e.g. Wittig olefination using, for example, methyltriphenylphosphonium bromide and potassium tert-butoxide in toluene or LiHMDS in THF (step o).

Reduction of the double bond of intermediates 27 using, for example, hydrogenation conditions (eg, hydrogen in the presence of a suitable catalyst such as Pd-C or PtO ₂ ), or using 9-borabicyclo(3.3.1)nonane in THF (by analogy with the literature methods, eg WO 2007/002057) gives intermediate compounds 28 (step p).

Deprotection of intermediates 28 using methods well known in the art and as described above (step b) gives intermediates L (step q).

Conversion of the ketone of intermediates 18 using, for example, fluorination conditions using aminosulfurans such as DAST gives intermediates 29 (step d).

Deprotection of intermediates 29 using methods well known in the art and as described above (step b) gives intermediates M (step s).

In some embodiment, intermediates 2 are N and O type intermediates wherein A, m, n and R ¹⁵ are as described herein and can be prepared by methods well known to one of skill in the art and as illustrated by the general synthetic procedures described in Scheme 9.

Scheme 9

Accordingly, intermediates 30a in which A, m and n are as defined herein, PG is a suitable protecting group such as Boc, Cbz or Bn, and Y is a formyl group (commercially available or obtained by literary methods , e.g., Bioorg. Med. Chem. Lett. 2006, 76(14), 3668; WO 2013/179024) can be treated with a reducing agent such as NaBH ₄ in MeOH to give intermediates 31. Reactions of this type are also described in the literature (eg WO 2013/179024) (step a).

Alternatively, intermediates 31 can be prepared from intermediates 30b in which Y is a carboxyl group (commercially available or prepared by analogy with methods described in the literature, e.g. Bioorg, Med. Chem, 2013, 27(15 ), 4600; WO 2016/109501), by using a suitable reducing agent such as a tetrahydrofuran borane complex in a solvent such as THF. Reactions of this type are also widely described in the literature, for example, Bioorg. Med. Chem. 2013, 27(15), 4600) (stage a).

Deprotection of intermediates 31 using methods well known in the art and as described above gives intermediates N (step b).

Alkylation of the hydroxyl group of intermediates 31 with an alkylating agent such as R ¹⁵ LG, in which LG is a suitable leaving group and R ¹⁵ is as described herein, using the conditions as described above, gives intermediates 32 (step c) .

Deprotection of intermediates 32 using methods well known in the art and as described in Scheme 8, step b, gives intermediates O (step d).

In another embodiment, intermediates 2 are type P intermediates wherein A is as defined herein, m is 1 or 2, Ar is an aryl group, and HET is a heterocyclyl or heteroaryl group. Intermediates of this type can be prepared by analogy with literature methods (e.g., Bioorg. Med. Chem. 2013, 27(7), 1756) or as illustrated by an example of the synthetic method described in Scheme 10.

Scheme 10

The carbonyl group in intermediates 33 in which Ar is aryl and HET is heteroaryl or heterocyclyl can be reduced by methods well known in the art, e.g. using NaBH ₄ in MeOH, to give intermediates 34 (step a) .

The hydroxyl group of intermediates 34 can be converted to a suitable leaving group such as chlorine, bromine, OSO ₂ alkyl (e.g. mesylate (methanesulfonate), OSO ₂ fluoroalkyl (e.g. triflate (trifluoromethanesulfonate) or OSO ₂ aryl (e.g. tosylate (p -toluenesulfonate)), for example a chlorine group, by reaction with thionyl chloride in toluene to give intermediates 34 (step b).

Intermediates 35 can be reacted with commercially available mono-protected piperazines (m is 1) or homopiperazines (m is 2) 36 where PG is a protecting group such as Boc, Cbz or Bn, optionally in the presence of KI, using an appropriate base and solvent such as TEA or Hunig's base in AcCN to give intermediates 37 (step c).

Deprotection of intermediates 37 using methods well known in the art and as described above gives intermediates P (step d).

In another embodiment, intermediates 2 are Q-type intermediates wherein A is as defined herein, m is 1 or 2, Ar is an aryl group, and HET is a heteroaryl group. Intermediates of this type can be prepared by analogy with literature methods (e.g. Bioorg. Med. Chem. Lett. 2006, 76(16), 4349; Bioorg. Med. Chem. Lett. 2010, 20(12), 3788) and as illustrated by an example of the synthesis procedure described in Scheme 11.

Scheme 11

Condensation of aryl or heteroarylaldehydes 38 with monoprotected piperazines (m is 1) or homopiperazines (m is 2) 36 in which PG is a suitable protecting group such as a Boc group and a benzotriazole, for example in toluene at reflux, at azeotropic removal of H ₂ O gives intermediate compounds 39 (step a).

Intermediates 39 are reacted in situ with a benzyl Grignard reagent or zinc reagent 40 of the Ar/NETCH ₂ MX type with MX representing a group such as MgCl, MgBr, ZnCl or ZnBr to give intermediates 41 (step b).

Deprotection of intermediates 41 using methods well known in the art and as described above gives intermediates Q (step c).

In another embodiment, intermediates 2 wherein X is N are R and S type intermediates wherein m and R ¹⁴ are as defined herein and R ¹⁸ and R ¹⁸ are each independently selected from hydrogen , substituted or unsubstituted alkyl, cyano, alkoxy and halogen, where substituted alkyl is as defined herein. Intermediates of this type can be prepared in analogy to literature methods (e.g. WO 2007/098418) and as illustrated by the example of the synthetic procedure described in Scheme 12.

Scheme 12

Indole intermediates 42 can be reacted with monoprotected piperazines (m is 1) or homopiperazines (m is 2) 36 wherein PG is a suitable protecting group such as a Boc, Cbz or Bn group and LG is a suitable leaving group, such as -OAc or iodine to give intermediates 43 (step a). Reactions of this type are described in the literature (eg WO 2007/098418).

Concurrent or sequential deprotection of intermediates 43 using methods well known in the art and as described above gives intermediates R (step b)-

Selective removal of the indole protecting group from intermediates 43 by methods well known in the art yields intermediates 44 (step c). Intermediates 44 can be converted to intermediates 45 using R ¹⁴ LG type compounds by methods known in the art and as described in Scheme 6, step a (step d). Deprotection of intermediates 45 using methods well known in the art and as described above gives intermediates S (step e).

In another embodiment, intermediates 2 are type T intermediates wherein A is as defined herein, m is 1 or 2, and R ¹ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl. Intermediates of this type can be prepared by analogy with literature methods (e.g. Tetrahedron Letters 1990, 31(39), 5547) or as illustrated by the example of the synthetic procedure described in Scheme 13.

The carbonyl group in intermediates 46 can be reacted via reductive amination with amine 36 in ways well known in the art, for example catalyzed by an acid such as TiCl ₄ , to give an imine which is then directly reduced in situ to the corresponding amine intermediate 47 with a reducing agent, such as sodium cyanoborohydride (step a).

Deprotection of intermediates 47 using methods well known in the art and as previously described yields intermediates T (step b).

Scheme 13

In another embodiment, intermediates 2 are U-type intermediates wherein A is pyrazole substituted with aryl and m is as described herein. Intermediates of this type can be prepared by analogy with literature methods (e.g., J, Med. Chem. 2018, 61(7), 3008) or as illustrated by the synthetic method example described in Scheme 14.

Scheme 14

The ketone in intermediates 48 is reacted with N,N-dimethylformamidadimethyl acetal and hydrazine dihydrochloride to give pyrazole intermediate 49 (step a).

The aryl-boronic acid is then reacted, using copper(II) acetate and pyridine reagents to facilitate the reaction, to form intermediate 50 (step b). Deprotection of intermediates 50 using methods well known in the art and as described above gives intermediates U (step c).

In some embodiments, intermediates 2 are type V intermediates wherein m, n are as described herein, A is an optionally optionally substituted aryl or heteroaryl ring, and R ²¹ -R ²³ are each independently selected from hydrogen, substituted or unsubstituted (cyclo)alkyl, (cyclo)alkoxy, substituted or unsubstituted aryl, R ^b R ^c N, cyano, heterocycle, methylsulfonyl and halogen, where substituted alkyl, aryl and heteroaryl are as defined herein. Intermediates of this type can be prepared by methods well known in the art and as exemplified by the general synthetic procedures described in Scheme 15.

Scheme 15

Commercially available intermediates 51 in which PG is a suitable protecting group and X is bromide or iodide can be subjected to cross-coupling reactions such as Negishi, Heck, Stille, Suzuki, Sonogashier or Buchwald-Hartwig coupling reactions with compounds 52, either commercially available or prepared by methods known in the art, wherein FG is a suitable functional group such as chloro-, bromo-, iodo-, OSO ₂ alkyl (e.g. mesylate (methanesulfonate), OSO ₂ fluoroalkyl (e.g. triflate (trifluoromethanesulfonate) or OSO ₂ aryl (eg tosylate (p-toluenesulfonate)) (step a) Reactions of this type are widely described in the literature and are well known to those skilled in the art.

For example, intermediates 51 can be reacted with aryl- or heteroarylboronic acids 52a (FG - B(OH) ₂ ) or boronic esters 52b (FG - for example, 4,4,5,5-tetramethyl-2-phenyl-1 ,3,2-dioxaborolane (pinacol) ester) either commercially available or prepared using literature methods as described, for example, in "Boronic Acids - Preparation and Applications in Organic Synthesis and Medicine" by Dennis G. Hall (ed. ) 1st Ed., 2005, John Wiley & Sons, New York) using a suitable catalyst (e.g., dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane, tetrakis(triphenylphosphine)palladium(0 ) or palladium(II) acetate with triphenylphosphine) in a suitable solvent (eg dioxane, dimethoxyethane, water, toluene, DMF or mixtures thereof) and a suitable base (eg Na ₂ CO ₃ , NaHCO ₃ , KF, K ₂ CO ₃ or TEA) at temperatures from room temperature to the boiling point of the solvent or mixture of solvents, to obtain intermediate compounds 53 (step a). Suzuki reactions of this type are widely described in the literature (e.g., A. Suzuki, Pure Appl. Chem. 1991, 63, 419-422; A. Suzuki, N. Miyaura, Chem. Rev. 1995, 95, 2457-2483; A. Suzuki, J. Organomet. Chem. 1999, 576, 147-168; V. Polshettiwar et al., Chem. Sus. Chem. 2010, 3, 502-522) and are well known to those skilled in the art. Alternatively, aryl- or heteroaryl-trifluoroborates 52 c (FG-BF ₃ ) can be used in the cross-coupling reaction using a palladium catalyst such as, for example, tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate or an adduct dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane in the presence of a suitable base such as cesium carbonate or potassium phosphate in solvents such as toluene, THF, dioxane, water, or mixtures thereof, at temperatures from room temperature to the boiling point of the solvent or mixture of solvents.

Alternatively, intermediates 51 may be reacted with aryl or heteroaryl stannanes 52d in which FG is Sn(alkyl) ₃ and alkyl is preferably n-butyl or methyl using a suitable catalyst and solvent such as, for example , tetrakis(triphenylphosphine)palladium(0) in DMF, at temperatures from room temperature to the boiling point of the solvent or mixture of solvents to obtain intermediate compounds 53 (step a). Stiele reactions of this type are well known in the art and are described in the literature, for example, Org. React. 1997, 50, 1-652, ACS Catal. 2015, 5, 3040-3053.

In addition, intermediates 51 can be reacted with aryl- or heteroaryl zinc halides 52e, in which FG is ZnHal and Hal is preferably bromide or iodide, either commercially available or prepared by literature methods using a suitable catalyst and system solvents such as, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and copper(I) iodide in DMA or tetrakis(triphenylphosphine)palladium(0) in THF or DMF at temperatures from room temperature to the boiling point of the solvent to obtain intermediate compounds 53 (step a). Negishi reactions of this type are well known in the art and are also described in the literature, for example, Org. Lett., 2005, 7, 4871, ACS Catal. 2016, 6(3), 1540-1552. Asya. Chem. Res. 1982, 15(11), pp. 340-348. Alternatively, intermediates 53 can be prepared by converting intermediates 51 in which X is, for example, iodide, to the corresponding zinc compound using literature methods (for example, reaction 51 with Zn powder in the presence of chlorotrimethylsilane and 1,2-dibromoethane in a suitable solvent such as DMA) and combinations of zinc compounds with aryl or heteroaryl bromides or iodides under the conditions mentioned previously.

Alternatively, intermediates 51 in which X is preferably bromide can be electrophilically cross-coupled with aryl or heteroaryl bromides 52f in which FG is bromide under a 420 nm blue light lamp using a suitable photocatalyst, such as [Ir{dF(CF ₃ )ppy}2(dtbpy)]PF ₆ ([4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3 ,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate), nickel catalyst similar to NiCl ₂ glyme (dichloro(dimethoxyethane)nickel), 4,4'-di-tert-butyl-2,2'-dipyridyl and tris(trimethylsilyl)silane in the presence of a suitable base such as anhydrous sodium carbonate in a solvent like DME. Reactions of this type are described in the literature, for example, J. Am. Chem. soc. 2016, 138, 8084. (stage a).

Deprotection of intermediates 53 using methods well known in the art and as described, for example, in Scheme 2, step c, yields intermediates V (step b).

Intermediates 53 can alternatively be prepared from intermediates 51 and aryl or heteroaryl bromides 54, either commercially available or prepared by methods known in the art using the transformations described above under step a to give intermediates 55 (stage c).

Intermediates 55 may further be reacted with compounds 56 using the same synthetic strategies as previously described under step a to give intermediates 53 (step d).

Intermediates 53 in which R ²³ is an amino group of the R ^b R ^c N type, in which R ^b is hydrogen, alkyl or aryl, and R ^c is alkyl or aryl, or in which R ^b and R ^c taken together with nitrogen atom to which they are attached, form a possibly additionally substituted 4-11-membered mono- or bicyclic heterocyclic ring, can be synthesized, for example, as a result of the reaction 55 with primary or secondary amines R ^b R ^c NH and using, for example, suitable catalyst (eg Pd(OAc) ₂ , Pd ₂ (dba) ₃ ), ligand (eg BINAP, Xphos, BrettPhos, RuPhos), base (eg Cs ₂ CO ₃ , K ₂ CO ₃ , KOt-Bu, LiHMDS, K ₃ PO ₄ ) and a solvent (eg toluene, THF, dioxane). Buchwald-Hartwig reactions of this type are known in the art and are described in the literature (e.g. Angew. Chem. Int. Ed. 2008, 47, 6338; Chem. Rev. 2008, 108, 3054, J. Organomet. Chem. 2018, 861 , 17) (step d).

In some embodiment, the compounds of Formula (I) are compounds Id and Ie, in which m and n are as described herein, R ²¹ and R ²² are each independently selected from hydrogen, substituted or unsubstituted (cyclo)alkyl, haloalkyl, (cyclo)alkoxy, substituted or unsubstituted aryl, R ^b R ^c N, cyano, heterocycle, methylsulfonyl and halo, X is Hal, A is optionally substituted aryl or optionally substituted heteroaryl, C is optionally substituted aryl or 4-7 -membered heterocycle containing at least one nitrogen atom by which it is bonded to ring A. Intermediates of this type can be prepared by methods well known in the art, and as exemplified by the general synthetic procedures described in Scheme 16.

Scheme 16

The protective group of intermediates 55 can be removed using methods well known in the art, and as described, for example, in Scheme 2, step c, to give intermediates 57 (step a).

Intermediates 50 may be coupled to intermediates 1 under the conditions described in Scheme 1, step a, to give compounds 1d (step b).

The bromine or iodine substituent in compounds 1d can be converted to boronic acid or boronic ester (e.g. pinacol ester) according to methods described in the literature or as described in Scheme 15, step a, to give intermediates 58 (step With).

Intermediates 58 may be reacted with compounds 59, either commercially available or prepared in the literature, and in which FG is a suitable functional group such as chloride, bromide, OSO ₂ alkyl (e.g. mesylate (methanesulfonate), -OSO ₂ fluoroalkyl (e.g., triflate (trifluoromethanesulfonate) or -OSO ₂ aryl (e.g., tosylate (p-toluenesulfonate), in Suzuki coupling using, for example, the reaction conditions described in Scheme 15, step a, to give compounds 1e (step d).

Compounds 1e in which ring C is a 4-7 membered heterocycle bonded through its nitrogen to ring A can be prepared, for example, by the Buchwald-Hartwig coupling reaction of compounds 1d with compounds 60 using, for example, the conditions described on Scheme 15, step d (step e).

In an embodiment, intermediates 2 are W, X, and Y type intermediates wherein m, n are as described herein, L is a covalent bond, and A is a 5-membered heteroaryl ring optionally substituted another substituted aryl ring. Compounds of this type can be prepared by methods well known in the art or by the methods exemplified in Schemes 17, 18 and 19 below.

W-type intermediates wherein each Y is independently CH or a heteroatom, e.g., a heteroatom selected from N, O, and S, can be prepared through a variety of conditions, which can be exemplified by the general synthetic procedure described in Scheme 17. For example , if the 5-membered heteroaryl ring in compounds 62 is a bromo-substituted 1H-pyrrole, 1H-imidazole, 1H-pyrazole or 1H-triazole, it can be subjected to a Suzuki coupling reaction with optionally substituted phenylboronic acids 61a (B(OR ^a ) ₂ - B (OH) ₂ ) or boronic esters 61b (for example, B (OR ^a ) ₂ - complex 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (pinacol) ether)), in which each R ²⁷ and R ²⁸ is independently selected from hydrogen, substituted or unsubstituted (cyclo)alkyl, haloalkyl, (cyclo)alkoxy, substituted or unsubstituted aryl, R ^b R ^c N, cyano, substituted or unsubstituted heteroaryl, heterocycle, methylsulfonyl and halogen using methods known in the art, and as described in Scheme 15, step a, to obtain intermediate compounds 63 (step a).

Intermediates 63 may be reacted with compounds 64 either commercially available or prepared by analogy with literature methods, for example, using photoredox conditions as described in Scheme 15, step a, to give intermediates 65 (step b).

Deprotection of intermediates 65 using methods well known in the art and as described, for example, in Scheme 2, step c, yields intermediates W (step c).

Scheme 17

Type X intermediates in which the 5-membered heteroaryl ring is 1,2,4-oxadiazole further substituted in position 3 with an optionally further substituted phenyl ring can be prepared, for example, by the general synthetic procedure described in Scheme 18.

Scheme 18

Benzonitriles 66, commercially available or synthesized by methods known in the art, can be reacted with hydroxylamine, for example, using hydroxylamine hydrochloride, and K ₂ CO ₃ in EtOH at temperatures ranging from RT to the boiling point of the solvent, to obtain amidoximes 67 ( stage a).

Coupling of intermediates 67 with activated carboxylic acids 68a (X-H) or carboxylic acid chlorides 68b (X-Cl) in which PG is a suitable protecting group, followed by cyclodehydration, gives intermediates 69 (step b). Amide couplings of this type are widely described in the literature and can be carried out using coupling reagents such as CDI, DCC, HATU, HBTU, HOBT, TBTU, T3R, or Mukaiyama's reagent (Mukaiyama T. Angew. Chem., Int. Ed. Engl 1979, 18, 707) in a suitable solvent, eg DMF, DMA, DCM or dioxane, optionally in the presence of a base (eg NEt ₃ , DIPEA (Hünig's base) or DMAP). Alternatively, the carboxylic acids 68a can be converted to their acid chlorides 68b by treatment with, for example, thionyl chloride or oxalyl chloride, neat or optionally in a solvent such as DCM. Reaction of the acid chloride with intermediates 68 in a suitable solvent such as DCM or DMF and a base such as NEt ₃ , Hunig's base, pyridine, DMAP or lithium bis(trimethylsilyl)amide at temperatures ranging from 0°C to the reflux temperature of the solvent or solvent mixtures, gives the acylated form of intermediates 67, which can be dehydrated, eg at elevated temperatures, to give intermediates 69 (step b).

Deprotection of intermediates 69 using methods well known in the art and as described, for example, in Scheme 2, step c, yields intermediates X (step c).

Y-type intermediates in which the 5-membered heteroaryl ring is 1,3,4-oxadiazole further substituted in position 5 with a possibly further substituted phenyl ring can be prepared by methods described in the literature or, for example, by the general synthetic procedure, described in Figure 19.

Scheme 19

Acylation of acyl hydrazides 70, either commercially available or prepared by methods well known in the art, with activated carboxylic acids 68a (X - H) or carboxylic acid chlorides 68b (X - Cl) using the conditions described in Scheme 18, step b, gives intermediates 71 (step a).

Subsequent cyclodehydration of intermediates 71, for example by heating, gives intermediates 72 (step b).

Deprotection of intermediates 72 using methods well known in the art and as described, for example, in Scheme 2, step c, yields intermediates Y (step c).

In one aspect, the present invention provides a process for the manufacture of compounds of formula (I) as described herein, comprising:

implementation of the interaction of 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (1),

with heterocyclic amine 2, in which A, L, X, m and n are as defined in this document,

in the presence of a base and a urea-forming reagent,

to form said compounds of formula (I).

In another aspect, the present invention provides a process for the manufacture of compounds of formula (Ic) as described herein, comprising:

implementation of the interaction of 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (1),

with heterocyclic amine 2a, in which A, L, X, m, n and R ²⁰ -R ²³ are as defined in this document

in the presence of a base and a urea-forming reagent,

to form said compounds of formula (Ic).

In one embodiment, the method of the invention is provided wherein said base is sodium bicarbonate.

In one embodiment, a process according to the invention is provided wherein said urea forming agent is selected from bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate and 1,1'-carbonyldiimidazole, preferably wherein said urea forming agent is , is bis(trichloromethyl)carbonate.

In one aspect, the present invention provides a compound of formula (I) as described herein, manufactured according to any of the methods described herein.

MAGL inhibitory activity

The compounds of the present invention are MAGL inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) and (Ic), as described herein, to inhibit MAGL in a mammal.

In another aspect, the present invention provides compounds of formulas (I) and (Ic) as described herein for use in a method for inhibiting MAGL in a mammal.

In another aspect, the present invention provides the use of compounds of formulas (I) and (Ic) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

In another aspect, the present invention provides a method for inhibiting MAGL in a mammal, which comprises administering an effective amount of a compound of formulas (I) and (Ic) as described herein to the mammal.

Compounds were profiled for MAGL inhibitory activity by measuring MAGL enzymatic activity, monitoring the hydrolysis of 4-nitrophenyl acetate resulting in 4-nitrophenol which absorbs at 405-412 nm (G. G. Muccioli, G. Labar, D. M. Lambert, Chem. Bio. Chem 2008, 9, 2704-2710). This assay is further abbreviated "4-NPA assay".

This assay was performed in 384-well assay plates (black with clear bottom, non-binding surface treated, Corning, Ref. 3655) in a total volume of 40 μl. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-fold stepwise dilutions to give a final assay concentration range of 25 μM to 1.7 nM. 1 μl compound dilutions (100% DMSO) were added to 19 μl MAGL (recombinant, wild type) in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100mL)). This plate was shaken for 1 min at 2000 rpm (Variomag Teleshake) and then incubated for 15 min at RT. To start the reaction, 20 μl of 4-nitrophenylacetate (Sigma N-8130) in assay buffer with 6% EtOH was added. Final concentrations in this assay were 1 nM MAGL and 300 μM 4-nitrophenylacetate. After shaking (1 min, 2000 rpm) and 5 min incubation at RT, absorbance at 405 nm was measured for the first time (Molecular Devices, SpectraMax Paradigm). A second measurement was then taken after incubation for 80 minutes at RT. From the two measurement data, the slope was calculated by subtracting the first from the second measurement.

Alternatively, compounds were profiled for MAGL inhibitory activity by enzymatic activity monitoring hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG) resulting in arachidonic acid, which can be monitored by mass spectrometry. This assay is further abbreviated "assay 2-AG".

The 2-AG assay was performed in 384-well assay plates (PP, Greiner Cat. No. 784201) in a total volume of 20 μl. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in a three-fold stepwise dilution to give a final concentration range in this assay of 12.5 μM to 0.8 pM. 0.25 µl compound dilutions (100% DMSO) were added to 9 µl MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 mL), 0.01% (v/v) ./v) Tween After shaking, this plate was incubated for 15 min at RT To start the reaction, 10 µl of 2-arachidonoylglycerol in assay buffer was added.Final concentrations in this assay were 50 pM MAGL and 8 µM 2-arachidonoylglycerol. shaking and 30 min incubation at RT, this reaction was quenched by the addition of 40 µl of ACN containing 4 µM d8-arachidonic acid.The amount of arachidonic acid was monitored by an online SPE system (Agilent Rapidfire) linked to a triple quadrupole mass spectrometer (Agilent 6460). C18 SPE (G9205A) in ACN/Water Liquid System This mass spectrometer was operated in negative electrospray mode following mass transitions 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. of these compounds was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid].

In one aspect, the present invention provides compounds of formula (I) and (Ic) and their pharmaceutically acceptable salts or esters as described herein, wherein said compounds of formula (I) and (Ic) and their pharmaceutically acceptable salts or esters have an IC ₅₀ for MAGL inhibition of less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM, as measured in the MAGL assay as described herein.

In one embodiment, the compounds of formula (I) and (Ic), and their pharmaceutically acceptable salts or esters, as described herein, have IC ₅₀ values (MAGL inhibition) from 0.000001 μM to 25 μM, specific compounds have IC values ₅₀ from 0.000005 μM to 10 μM, other specific compounds have IC ₅₀ values from 0.00005 μM to 5 μM as measured in the MAGL assay described herein.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) and their pharmaceutically acceptable salts or esters as described herein, wherein said compounds of formula (I) and (Ic) and their pharmaceutically acceptable salts or esters have an IC ₅₀ with respect to MAGL less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM, when measured in an assay comprising the following steps:

a) providing a solution of a compound of formula (I) or (Ic), or a pharmaceutically acceptable salt or ester thereof, in DMSO;

b) providing a solution of MAGL (recombinant wild type) in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid);

c) adding 1 µl of the compound solution from step a) to 19 µl of the MAGL solution from step b);

d) shaking this mixture for 1 minute at 2000 rpm;

e) incubation for 15 min at RT;

f) adding 20 μl of a solution of 4-nitrophenylacetate in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid, 6% EtOH);

e) shaking this mixture for 1 min at 2000 rpm;

e) incubation for 5 min at RT;

i) measuring the absorbance of this mixture for the first time at 405 nm;

j) Incubation an additional 80 min at RT;

k) measuring the absorbance of this mixture a second time at 405 nm;

l) subtracting the absorbance measured according to i) from the absorbance measured according to k) and calculating the absorbance slope;

Where:

i) the concentration of a compound of formula (I) or (Ic) and a pharmaceutically acceptable salt or ester thereof in the assay after step f) is between 25 μM and 1.7 nM;

ii) the concentration of MAGL in the assay after step f) is 1 nM;

iii) the concentration of 4-nitrophenylacetate in the assay after step f) is 300 μM;

And

(iv) steps a) - l) are repeated at least 3 times, each time with a different concentration of a compound of formula (I) or (Ic), or a pharmaceutically acceptable salt or ester thereof.

Use of the Compounds of the Invention

In one aspect, the present invention provides compounds of formula (I) and (Ic) as described herein for use as a therapeutically active agent.

In another aspect, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of cancer in a mammal.

In one aspect, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy , anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-associated spasticity in a mammal.

In a preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of multiple sclerosis in a mammal.

In one aspect, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of cancer in a mammal.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of neurodegenerative diseases in a mammal.

In one aspect, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain associated spasticity in a mammal.

In a preferred embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of multiple sclerosis in a mammal.

In one aspect, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the manufacture of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the preparation of a medicament for the treatment or prevention of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the manufacture of a medicament for the treatment or prevention of neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the manufacture of a medicament for the treatment or prevention of cancer in a mammal.

In another aspect, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity , stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-associated spasticity in a mammal.

In a preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.

In a particularly preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the preparation of a medicament for the treatment or prevention of multiple sclerosis in a mammal.

In one aspect, the present invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal, comprising administering an effective amount of a compound of formulas (I) and (Ic) as described herein to the mammal.

In one embodiment, the present invention provides a method for treating or preventing neuroinflammation and/or neurodegenerative diseases in a mammal, which comprises administering an effective amount of a compound of formula (I) or (Ic) as described herein to the mammal.

In one embodiment, the present invention provides a method for treating or preventing neurodegenerative diseases in a mammal, which comprises administering an effective amount of a compound of formula (I) or (Ic) as described herein to the mammal.

In one aspect, the present invention provides a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, and/or pain in a mammal, which comprises administering an effective an amount of a compound of formula (I) or (Ic) as described herein to a mammal.

In a preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal, which comprises administering an effective amount of a compound of formula (I) or (Ic) as described herein to the mammal.

In a particularly preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis in a mammal, which comprises administering an effective amount of a compound of formula (I) or (Ic) as described herein to the mammal.

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.

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as drugs (for example, in the form of pharmaceutical preparations). These pharmaceutical preparations can be administered internally, such as orally (eg, as tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (eg, as nasal sprays) or rectally (eg. , in the form of suppositories). However, the administration can also be carried out parenterally, such as intramuscularly or intravenously (eg, in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert inorganic or organic adjuvants to obtain tablets, coated tablets, dragees and hard gelatin capsules. As such adjuvants for tablets, dragees and hard gelatin capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols, and the like.

Suitable adjuvants for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable adjuvants for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable suppository adjuvants 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, viscosifiers, stabilizers, humectants, emulsifiers, sweeteners, coloring agents, flavoring agents, osmotic salts, buffers, masking agents, or antioxidants. In addition, they may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will naturally be adapted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of from about 0.1 mg to 20 mg per kg of body weight, preferably from about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person) should be appropriate. preferably divided into 1-3 individual doses, which may consist, for example, of equal amounts. However, it will be apparent that the upper limit given herein may be exceeded in demonstrating that this is shown.

According to this invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prevention of microvascular complications associated with type 2 diabetes (such as, but not limited to, diabetic retinopathy, diabetic neuropathy and diabetic nephropathy), coronary diseases arteries, obesity and underlying inflammatory diseases, chronic inflammatory and autoimmune/inflammatory diseases.

EXAMPLES

The present invention will be better understood by referring to the following examples. The claims, however, should not be construed as being limited by the scope of these examples.

In the case where the preparations are prepared as a mixture of enantiomers, the pure enantiomers may be separated by the methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography (eg, chiral SFC) or crystallization.

All examples of reactions and intermediates were prepared under argon, unless otherwise specified.

Method A1

Example 1

rac-(4aR,8aS)-6-(4-Benzhydrylpiperidin-1-carbonyl)-4,4а,5,7,8,8а-hexahydropyrido[4,3-b][1,4]oxazin-3-one

Rac-cis- hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (15 mg, 96 µmol, ChemBridge Corporation), and the resulting reaction mixture was heated at 80°C for 18 hours, leading to the completion of the reaction. This reaction mixture was diluted with H ₂ O and NaHCO ₃ and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using an ACN : H ₂ O gradient (containing 0.1% FA) (20:80 to 98:2) to give the desired compound as a colorless solid (0.015 g; 36. 5%). MS (ESI): m/z is 434.2 [M+H] ⁺ .

Method A2

Example 2

rac-(4aR,8aS)-6-(4-(5-Chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4Н)-one

To an ice-cold suspension of bis(trichloromethyl) carbonate (45.3 mg, 153 µmol, CAS RN 32315-10-9) and NaHCO ₃ (73.3 mg, 873 µmol) in DCM (1 ml) was added 5-chloro- 1-(cyclopropylmethyl)-3-(piperidin-4-yl)-1H-indole acetate formate (76.1 mg, 218 µmol, BB2) and this mixture was stirred overnight at RT. After cooling in an ice bath, rac-cis-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (50 mg, 218 µmol, ChemBridge Corporation) and DIPEA (112 mg, 152 µl, 870 µmol). This suspension was stirred at RT for 6 hours. This reaction mixture was poured onto H ₂ O and DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a DCM:MeOH (100:0 to 90:10) gradient to give the desired compound as a colorless gum (0.070 g; 68.1%). MS (ESI): m/z is 471.2 [M+H] ⁺ .

Method A3

Example 22

(+)- or (-)-cis-6-(4-(5-Chloro-1-(oxethan-3-yl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4Н)-one

NaHCO ₃ (32.3 mg, 384 µmol) and rac-cis-hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one (20 mg, 128 µmol, ChemBridge Corporation) and this mixture was stirred at RT overnight. This suspension was cooled to 0°C before adding 5-chloro-1-(oxethan-3-yl)-3-(piperidin-4-yl)-1H-indole (37.2 mg, 128 μmol, BB10) and DIPEA ( 49.7 mg, 67.1 µl, 384 µmol). This mixture was stirred at RT for 1 hour. This reaction mixture was poured onto water and DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a DCM:MeOH gradient (100:0 to 90:10) to give the desired compound as a colorless solid (0.025 g; 41.3%). MS (ESI): m/z is 473.2 [M+H] ⁺ .

Method A4

Example 67

(4aR,8aS)-6-(4-((3-Cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one

To a suspension of 4-nitrophenyl-(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (50 mg, 156 µmol, BB15a) and DIPEA (50.3 mg, 68 µl, 389 µmol) in ACN (0.7 ml) was added a solution of 3-cyclopropyl-5-((4-fluorophenyl)(piperidin-4-yl)methyl)-1,2,4- oxadiazole hydrochloride (55.2 mg, 163 μmol, BB39) in ACN (0.7 ml) and this solution was stirred at RT overnight. The light yellow solution was stirred at reflux for 23 hours and then evaporated. The residue was dissolved in 2 M aqueous Na ₂ CO ₃ and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc/EtOH 3/1 (70:30 to 90:10) to give the desired compound as a light brown solid (0.022 g; 29.2%). MS (ESI): m/z is 484.2 [M+H] ⁺ .

Method A5

Example 111

(4aR,8aS)-6-(3-(4'-Chloro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazine-3(4Н)-one

Suspension of (4-chlorophenyl)boronic acid (15.9 mg, 101 µmol, CAS RN 1679-18-1), (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (40 mg, 101 µmol, Example 110), potassium carbonate (70.1 mg, 507 µmol), water (100 ml ) and tetrakis(triphenylphosphine)palladium (0) (5.86 mg, 5.07 µmol, CAS RN 14221-01-3) in THF (1 mL) was stirred at 80°C for 3 h. This reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc/EtOH (3/1 v/v) (70:30 to 90:10) to give the desired compound as colorless solid (0.020 g; 46.3%). MS (ESI): m/z is 426.16 [M+H] ⁺ .

Method A6

Example 128

(4aR,8aS)-6-(3-(4-(3-Methoxyazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4Н)-one

Into a solution of (4aR,8a8)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ( 50 mg, 127 µmol, example 110) in tert-butanol (1 ml) under argon was added XPhos (5.44 mg, 11.4 µmol, CAS RN 564483-18-7), tris(dibenzylideneacetone) dipalladium adduct (0 ) with chloroform (3.94 mg, 3.8 µmol, CAS RN 52522-40-4), 3-methoxyazetidine hydrochloride (23.5 mg, 190 µmol, CAS RN 148644-09-1) and cesium carbonate (165 mg , 507 µmol) and this mixture was heated to 85° C. for 21 hours. This mixture was filtered and the filtrate was evaporated. The product was purified on preparative HPLC (Gemini NX column) using an ACN:water gradient (containing 0.1% formic acid) (20:80 to 98:2) to give the desired compound as a colorless solid (0.006 g; 11 ,8%). MS (ESI): m/z is 401.2 [M+H] ⁺ . Alternatively, this reaction can also be carried out in a microwave oven at 100°C.

Method A7

Example 225

(4aR,8aS)-6-[3-[4-(Oxethan-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b] [1,4]oxazin-3-one

(Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ (1.42 mg, 1.27 µmol, CAS RN 870987-63-6), 3- Bromoxethane (17.4 mg, 127 µmol, CAS RN 39267-79-3), (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one (50 mg, 127 µmol, example 110), tris(trimethylsilyl)silane (31.5 mg, 39.1 µl, 127 µmol, CAS RN 1873- 77-4) and anhydrous sodium carbonate (26.9 mg, 254 µmol). This vial was sealed and placed under argon before adding DME (1 ml). In a separate vial was added ethylene glycol dimethyl ether nickel(II) chloride complex (2.79 mg, 12.7 µmol, CAS RN 29046-78-4) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.4 mg, 12.7 µmol, CAS RN 72914-19-3). The pre-catalyst vial was sealed, purged with argon, and then DME (0.4 ml) was added. The pre-catalyst vial was sonicated for 5 min, after which 0.4 ml (0.5 mol. % catalyst, 0.01 equiv.) was withdrawn from it with a syringe into the reaction vessel. This reaction mixture was degassed with argon. The reaction mixture was stirred and irradiated with a 420 nm lamp for 4 hours. The reaction was quenched by exposure to air, filtered and washed with a small volume of EtOAc. The filtrate was treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system (ISCO) eluting with a gradient of n-heptane: EtOAc/EtOH 3/1 (v/v) (70:30 to 10:90) to give the desired compound as a light yellow solid (0.010 g; 21.2%). MS (ESI): m/z is 372.3 [M+H] ⁺ .

Method A8

Example 159

2-[4-[1-[(4aR,8aS)-3-Oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl] azetidin-3-yl]phenyl]-5-chloro-benzonitrile

In a solution of [4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl] azetidin-3-yl]phenyl]boronic acid (100.0 mg, 0.280 mmol, BB38) and 2-bromo-5-chlorobenzonitrile (120.5 mg, 0.560 mmol, CAS RN 57381-37-0) and CsF (127 mg, 0.840 mmol) in DMF (5 ml) was added Pd(dppf)Cl ₂ (40.8 mg, 0.060 mmol), this mixture was stirred at 90° C. under N ₂ for 12 h. The mixture was filtered and the filtrate was diluted water (20 ml) and extracted with EtOAc (10 ml, three times), the combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated, the residue was purified by preparative HPLC (FA) and lyophilized to obtain the desired compound as a white solid (38.8 mg, 30.7%). MS (ESI): m/z is 451.1 [M+H] ⁺ .

Method A9

Examples 75 and 76

(4aR,8aS)-6-(3-(R or S)-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one and

(4aR,8aS)-6-(3-(S or R)-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one

To a solution of 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-2,2,2-trifluoroacetate (BB94) (133.5 mg, 207 µmol) in CH ₃ CN (517 µl ) and 2-propanol (517 µl) were added DIPEA (66.8 mg, 90.3 µl, 517 µmol) and 4-nitrophenyl-(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b] [1,4]oxazine-6(5H)-carboxylate (66.5 mg, 207 µmol, BB15a). The reaction vial was stirred at 90° C. for 21 hours. An additional portion of 4-nitrophenyl-(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H) was added -carboxylate (19.9 mg, 62.1 µmol, BB15a) and DIPEA (8.02 mg, 10.8 µl, 62.1 µmol) and this mixture was heated to 95° C. for 23 hours. purification by non-chiral reverse phase HPLC to give (4aR,8aS)-6-(3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one (88 mg, 92.1%) as a white solid. The epimers were separated by chiral HPLC to give Example 75 (33.6 mg) and Example 76 (43.2 mg) as yellow solids. MS (ESI): m/z is 462.2 [M+H] ⁺ for both compounds.

Method A10

Examples 91, 96 and 97

(4aR,8aS)-6-(3-(1-(2-Fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4Н)-one,

(4aR,8aS)-6-(3-((R or S)-1-(2-Fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one and

(4aR,8aS)-6-(3-((S or R)-1-(2-Fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one

To a solution of 3-(1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-2,2,2-trifluoroacetate, BB97 (51.4 mg, 136 µmol) in CH ₃ CN (681 µl) was added DIPEA (52.8 mg, 71.4 µl, 409 µmol) and 4-nitrophenyl-(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H )-carboxylate (43.8 mg, 136 µmol, BB15a). The reaction vial was stirred at 95° C. for 3 hours. The crude material was subjected to reverse phase HPLC purification to give (4aR,8aS)-6-(3-(1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl) Azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 91; 31 mg, 51%) as an off-white solid. MS (ESI): m/z is 446.3 [M+H] ⁺ . This racemic product was resolved by chiral SFC to give (4aR,8aS)-6-(3-((R or S)-1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl) hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (15.9 mg, Example 96) and (4aR,8aS)-6-(3-((S or R)-1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (15.2 mg, Example 97) as white solids. MS (ESI): m/z is 446.2 [M+H] ⁺ for both compounds.

Method A11

Example 55

(4aR,8aS)-6-(3-(Fluorobis(4-fluorophenyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- she

To an ice-cold solution of triethylamine trihydrofluoride (31.8 mg, 32.1 µl, 197 µmol) in DCM (493 µl) under argon was added (diethylamino)difluorosulfonium tetrafluoroborate (33.9 mg, 148 µmol, CAS RN 63517-29-3 ), followed by the addition of (4aR,8aS)-6-(3-(bis(4-fluorophenyl)(hydroxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one (Example 54) (45.1 mg, 98.6 µmol) in DCM (493 µl) and this mixture was stirred for 70 min at 0°C and then at RT for 25 min. This reaction mixture was quenched at 0°C with saturated aqueous NaHCO ₃ and stored in the refrigerator overnight. The phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a clear oil. The crude material was purified by reverse phase HPLC to give the desired compound as a white solid (20 mg, 41.5%). MS (ESI): m/z is 504.18 [M+HCOO] ^- .

Method A12

Example 224

(4aR,8aS)-6-(3-(3-Chloro-4-(3-methylazetidin-1-yl)phenyl)azetidine-1-cabonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4Н)-one

In a solution of (4aR,8aS)-6-(3-(4-bromo-3-chlorophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-one (example 132, 0.020 g, 0.047 mmol) in dioxane (0.5 ml) were added Pd ₂ (dba) ₃ (0.004 g, 0.0047 mmol), Xantphos (0.003 g, 0.0047 mmol) and carbonate cesium (0.030 g, 0.093 mmol). This mixture was degassed with argon, then 3-methylazetidine hydrochloride (CAS RN 1375472-05-1, 0.010 g, 0.093 mmol) was added and this reaction mixture was heated to 100° C. for 16 h. After this time, 3-methylazetidine hydrochloride ( 0.005 g, 0.047 mmol), Pd ₂ (dba) ₃ (0.004 g, 0.0047 mmol), Xantphos (0.003 g, 0.0047 mmol) and cesium carbonate (0.015 g, 0.047 mmol), and this reaction mixture was heated to 100°C for another 2 hours This mixture was diluted with EtOAc and washed with H ₂ O and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (0.007 g, 36%) as a yellow solid. MS (ESI): m/z is 419.3 [M+H] ⁺ .

Method B1

Example 5

(+)-cis-6-[4-(6-Fluoro-1H-indol-3-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one

The racemate (product of Example 7) was separated by preparative chiral HPLC (Reprosil Chiral NR column) using isocratic EtOH (containing 0.05% NH ₄ OAc) : n-heptane (60:40). Fractions were evaporated to give the desired compound as a light yellow solid (0.009 mg). MS (ESI): m/z is 401.2 [M+H] ⁺ .

Method B2

Example 11

(+)-cis-6-(4-(bis(4-Fluorophenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He

The enantiomers of Example 12 were separated by preparative chiral HPLC (Chiralcel OD column) using isocratic EtOH (containing 0.05% NH ₄ OAc) : n-heptane (80:20). Fractions were evaporated to give the desired compound as a colorless solid (0.014 g). MS (ESI): m/z is 471.3 [M+H] ⁺ .

Method B3

Examples 31 and 32

(+)-cis-6-(4-((R or S)-1-(4-Fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazine-3(4Н)-one

And

(-)-cis-6-(4-((S or R)-1-(4-Fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazine-3(4Н)-one

The enantiomers of racemic example 26 were separated by preparative chiral HPLC (Chiralpak AD column) using isocratic EtOH (containing 0.05% NH ₄ OAc) : n-heptane (40:60). Fractions were evaporated. The residue was taken up in EtOH, DCM and n-heptane and again evaporated to remove excess AcOH. Compounds were purified by silica gel chromatography on a 4 g column using an MPLC system (ISCO) eluting with a DCM:MeOH gradient (100:0 to 80:20) to give the desired products as colorless gums (0.004 g; 7.7% and 0.010 g, 19%). MS (ESI): m/z is 420.2 [M+H] ⁺ for each stereoisomer.

Method B4

Example 94

(4aR,8aS)-6-(4-((R or 3)-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro- 2Н-pyrido[4,3-b][1,4]oxazin-3(4Н)-one

The racemate of Example 68 was separated by preparative chiral SFC (IA, 12 nm, 5 μm, column 250×4.6 mm) using isocratic MeOH:carbon dioxide (25:75). Fractions containing were evaporated to give the desired product as a light brown solid (0.016 g, 40.0%). MS (ESI): m/z is 484.2 [M+H] ⁺ .

Method B5

Examples 114 and 115

(4aR,8aS)-6-[3-[(1R)-1-[4-(Trifluoromethyl)phenyl]ethoxy]azetidine-1-carbonyl]-4,4a, 5,7,8,8a-hexahydropyrido[4 ,3-b][1,4]oxazin-3-one and (4aR,8aS)-6-[3-[(1S)-[4-(Trifluoromethyl)phenyl]ethoxy]azetidine-1-carbonyl]-4 ,4а,5,7,8,8а-hexahydropyrido[4,3-b][1,4]oxazin-3-one

The enantiomers of Example 90 were separated by preparative chiral SFC (column OZ-H, 220 nm, 250×10 mm) using isocratic MeOH:carbon dioxide (20:80). Fractions were evaporated to give the title products as colorless amorphous solids (0.005 g). MS (ESI): m/z is 428.4 [M+H] ⁺ for both enantiomers.

Example 25

(+)- or (-)-cis-6-(4-(5-Chloro-1-(2-hydroxyethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one

In a solution of (+)- or (-)-cis-6-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-1H-indol-3-yl)piperidin-1 -carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (39 mg, 67.8 µmol, Example 24) in DCM (0.5 ml) TFA was added (77.3 mg, 52.2 µl, 678 µmol) and this solution was stirred at RT for 1.5 hours. THF (0.1 ml) and H ₂ O (0.1 ml) were added to this light yellow solution, and stirring was continued at RT for 96 hours. The reaction mixture was evaporated. The residue was poured into saturated aqueous NaHCO ₃ and DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a DCM:MeOH gradient (100:0 to 90:10) to give the desired compound as a colorless solid (0.014 g, 44.8%). MS (ESI): m/z is 461.2 [M+H] ⁺ .

Example 173

(4aR,8aS)-6-(3-(4'-Chloro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one

A solution of (4aR,8aS)-6-(3-(4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one (27 mg, 60.8 µmol, Example 133) in DMSO (0.5 mL) was treated with sodium methanethiolate (4.26 mg, 60.8 µmol ) and stirred at 100° C. overnight. Another batch of sodium methanethiolate (4.26 mg, 60.8 µmol) was added and stirring continued at 100° C. for 2 hours. After cooling, this mixture was poured into water and the layers were separated. The organic layers were extracted twice with EtOAc. These organic layers were dried over MgSO ₄ , filtered and evaporated. The resulting crude intermediate (112 mg, light yellow oil) was dissolved in DCM (0.7 mL) and m-chloroperbenzoic acid (98.2 mg, 195 µmol) was added at RT. This mixture was stirred at RT, and stirring was continued at RT for 1 h. This reaction mixture was poured onto saturated aqueous NaHCO ₃ and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a DCM:MeOH gradient (100:0 to 90:10) to give the desired sulfoxide intermediate as a colorless gum (0.014 g). This was dissolved in DCM (0.7 ml) and m-chloroperbenzoic acid (43.6 mg, 195 µmol) was added. Stirring was continued at RT for 3 hours. The reaction mixture was poured onto saturated aqueous NaHCO ₃ and DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a DCM:MeOH gradient (100:0 to 90:10) to give the desired compound as a colorless solid (0.004 g; 13.0%). MS (ESI): m/z is 504.1 [M+H] ⁺ .

Example 193

(4aR,8aS)-6-(3-(5-(2,4-Dichlorophenyl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one

In a solution of (4aR,8aS)-6-(3-(5-chloropyridin-2-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4]oxazin-3(4Н )-one (63 mg, 180 µmol, example 181) in dioxane (0.5 ml) tricyclohexylphosphine (4.03 mg, 14.4 µmol, CAS RN 2622-14-2), tris(dibenzylideneacetone) adduct was added under argon dipalladium (0) with chloroform (7.44 mg, 7.18 µmol), (2,4-dichlorophenyl)boronic acid (36 mg, 189 µmol, CAS RN 68716-47-2) and Cs2C03 (70.2 mg, 216 μmol) and this mixture was stirred at 100° C. overnight. This reaction mixture was poured onto water and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using an ACN:water gradient (containing 0.1% TEA) (20:80 to 98:2) to give the desired compound as a light brown solid (0.0038 g; 4.6%). MS (ESI): m/z is 461.1 [M+H] ⁺ .

Example 218

(4aR,8aS)-6-[4-[Phenyl(pyridazin-3-yl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one

Solution of 3-[phenyl(4-piperidyl)methyl]pyridazine (70 mg, 0.28 mmol, BB86) and (4-nitrophenyl)-(4aR,8aS)-3-oxo-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (106 mg, 0.330 mmol) in pyridine (3 mL) was stirred at 80°C for 16 h. the solution was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (basic conditions) to give (4aR,8aS)-6-[4-[phenyl(pyridazin-3-yl)methyl]piperidine-1-carbonyl]-4 ,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (5.9 mg, 5%) as a gray solid. MS (ESI): m/z is 436.2 [M+H] ⁺ .

Example 247

(4aR,8aS)-6-[3-[4-(3-Fluoropropyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1 ,4]oxazin-3-one

To a stirred solution of 3-[4-(3-fluorophenyl)phenyl]azetidine (40 mg, 0.21 mmol, BB87) and DIPEA (0.07 ml, 0.41 mmol) in MeCN (0.9 ml) at 20 °С (4-nitrophenyl)-(4aR,8aS)-3-oxo-4,4а,5,7,8,8а-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate ( 66 mg, 0.210 mmol; BB15a). The resulting mixture was stirred at 80° C. for 16 h. This solution was concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[3-[4-(3-fluoropropyl )phenyl]azetidine-1-carbonyl]-4,4а,5,7,8,8а-hexahydropyrido[4,3-b][1,4]oxazin-3-one (16 mg, 17%, 84% purity ) as a white solid. This material was combined with the product from the second reaction on a similar scale (0.23 mmol 3-[4-(3-fluoropropyl)phenyl]azetidine) and purified a second time by preparative HPLC (TFA conditions) to give the compound indicated in the title, as a white solid. MS (ESI): m/z is 376.3 [M+H] ⁺ .

Example 252

(4aR,8aS)-6-[4-[[3-(2-Aminoethoxy)phenyl]-phenyl-methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one

In a solution of tert-butyl-(2-(3-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidine- 4-yl)(phenyl)methyl)phenoxy)ethyl)carbamate (Example 237; 178 mg, 300 µmol) in DCM (2.5 mL) TFA (274 mg, 185 µL, 2.4 mmol) was added and this reaction the mixture was stirred at ambient temperature for 3 hours. Added EtOAc and an aqueous solution of KHCO ₃ . The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (148 mg, quantitatively) as a light yellow foam. MS (ESI): m/z is 493.3 [M+H] ⁺ .

Example 255

tert-Butyl-N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3 -b][1,4]oxazine-6-carbonyl]-4-piperidyl]-phenyl-methyl]phenoxy]ethylamino]-3-oxopropoxy]ethyl]carbamate

DIPEA (52.5 mg, 70.9 µl, 406 µmol) was added to the mixture of (4aR,8aS)-6-(4-((3-(2-aminoethoxy)phenyl)(phenyl)methyl)piperidine-1-carbonyl )hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 252; 50 mg, 101 µmol), 3-(2-m-boc-aminoethoxy)propanoic acid (CAS RN 1260092-44-1; 23.7 mg, 101 µmol) and HATU (42.5 mg, 112 µmol) in DMF (203 µl). This mixture was stirred at ambient temperature for 18 hours. Ethyl acetate and aqueous KHC03 were added. The layers were separated and the organic phase was washed twice with water. The organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (71 mg, quantitatively) as a colorless oil, MS (ESI): m/z=708.4 [M+H] ⁺ .

Example 256

tert-butyl-N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazine-6-carbonyl]-4-piperidine]-phenyl-methyl]phenoxy]ethylamino]-3-oxo-propoxy]ethoxy]ethyl]carbamate

DIPEA (52.5 mg, 70.9 µl, 406 µmol) was added to the mixture of (4aR,8aS)-6-(4-((3-(2-aminoethoxy)phenyl)(phenyl)methyl)piperidine-1-carbonyl )hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 252; 50 mg, 101 µmol), 13,13-dimethyl-11-oxo-4-7 ,12-thioxa-10-azatetradecanoic acid (CAS RN 1365655-91-9; 28.1 mg, 101 µmol) and HATU (42.5 mg, 112 µmol) in DMF (135 µl). This mixture was stirred at ambient temperature for 18 hours Added ethyl acetate and aqueous solution of KHCO ₃ . The layers were separated and the organic phase was washed twice with water. The organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (76 mg, quantitatively) as a colorless oil, MS (ESI): m/z=774.4 [M+Na] ⁺ .

Example 258

(4aR,8aS)-6-[3-(4-Propoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine- 3rd

Into a suspension of (4aR,8aS)-6-(3-(4-hydroxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ( 0.032 g, 96.6 µmol, BB145) and potassium carbonate (16 mg, 116 µmol) in DMF (0.4 ml) was added 1-iodopropane (19.7 mg, 11.3 µl, 116 µmol) and this mixture stirred at 50° C. in a sealed tube overnight. The mixture was filtered and the filter cake washed with a few drops of DMF. The product was purified on preparative HPLC (YMC Triart C18 column) using an ACN:water gradient (containing 0.1% TEA) (20:80 to 100:0) to give the desired compound as a colorless solid (0.013 g; 36 .0%). MS (ESI): m/z is 374.3 [M+H] ⁺ .

Example 260

2-14-11-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidine- 3-yl]phenyl]-N-ethyl-5-methyl-benzamide

In a solution of (4aR,8aS)-6-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidine-1-carbonyl]-4, 4a,5,7,8,8a-hexahydropyrdo[4,3-b][1,4]oxazin-3-one (100.0 mg, 0.230 mmol, BB91), Na ₂ CO ₃ (48.03 mg, 0.450 mmol) and 2-bromo-N-ethyl-5-methyl-benzamide (54.86 mg, 0.230 mmol, BB92) in 1,4-dioxane (4 ml) and water (1 ml) were added Pd(dppf)Cl ₂ (16.58 mg, 0.020 mmol) and this mixture was stirred at 100° C. under N ₂ . After stirring at this temperature for 12 h, the mixture was poured into water (20 ml) and extracted three times with EtOAc (10 ml). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , concentrated, the residue was purified by reverse phase flash chromatography (0.1% v/v FA), followed by preparative HPLC (0.225% v/v FA) , to give the desired product (13.8 mg, 12.5%) as a white solid. MS (ESI): m/z is 477.3 [M+H] ⁺ .

Unless otherwise indicated, the following examples of Table 2 were synthesized from the appropriate building block(s) in analogy to the reaction methods described herein.

Syntheses of building blocks

BBI

4-Nitrophenyl-4-benzhydrylpiperidine-1-carboxylate

To a solution of 4-benzhydrylpiperidine (50 mg, 199 µmol, CAS RN 19841-73-7) in DCM (1.2 ml) was added TEA (40.3 mg, 55.4 µl, 398 µmol). While cooling to 0°, 4-nitrophenylcarbonochloridate (44.1 mg, 219 µmol, CAS RN 7693-46-1) was added and the reaction mixture was allowed to warm to RT and stirred for 18 hours. This reaction mixture was diluted with DCM and then washed with N ₂ O and sat. aqueous NaHCO ₃ , the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel 10 g, eluting with EtOAc/n-heptane 0-50%) to give the title compound as a light yellow solid (75 mg, 90.5%). MS (ESI): m/z is 417.4 [M+H] ⁺ .

BB2

5-Chloro-1-(cyclopropylmethyl)-3-(piperidin-4-yl)-1H-indole (FA salt)

A mixture of tert-butyl 4-[5-chloro-1-(cyclopropylmethyl)indol-3-yl]piperidine-1-carboxylate (400.0 mg, 1.03 mmol) in HCl/EtOAc (4 M, 15.0 ml) was stirred at 20°C for 15 hours. This mixture was concentrated in vacuo and the residue taken up in H ₂ O (5 ml). The pH was adjusted to pH 7 using ammonia, then purified by prep HPLC (0.1% FA in H ₂ O and ACN) to give the title compound as a white solid (215.9 mg, 62.6%) . MS (ESI): m/z is 289.1 [M+H] ⁺ .

Intermediate: tert-Butyl-4-(5-chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)piperidine-1-carboxylate

A mixture of (bromomethyl) cyclopropane (0.17 mL, 1.79 mmol; CAS RN 7051-34-5), tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate ( 500.0 mg, 1.49 mmol, BB9, intermediate step b), 15-crown-5 (0.06 ml, 0.300 mmol; CAS RN 33100-27-5) and sodium tert-butoxide (287.01 mg, 2.99 mmol; CAS RN 865-48-5) in anhydrous EtOH (5 ml) was stirred at 25° C. for 12 hours. This mixture was diluted with H ₂ O (20 ml), extracted three times with EtOAc (40 ml each) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (100-200 mesh) using a PE:EtOAc gradient (50:1 to 20:1) to give the title compound as a light yellow solid (400 mg, 68 ,8%). MS (ESI): m/z is 411.1 [M+Na] ⁺ .

BB3

5-Chloro-1-methyl-3-(piperidin-4-yl)-1H-indole

Mixture of tert-butyl 4-(5-chloro-1-methyl-indol-3-yl)piperidine-1-carboxylate (480.0 mg, 1.38 mmol) in HCl/EtOAc (20.0 mL, 6M) stirred at 20°C for 15 hours. This mixture was concentrated in vacuo, adjusted to pH 7 using aqueous ammonia and then concentrated to give a residue which was purified by preparative HPLC to give the title compound as a colorless powder (172.3 mg, 49.3%) . MS (ESI): m/z is 249.2 [M+H] ⁺ .

Intermediate: tert-butyl-4-(5-chloro-1-methyl-indol-3-yl)piperidine-1-carboxylate

To a mixture of 60% NaH in mineral oil (119.46 mg, 2.99 mmol) in THF (20 mL) was added a solution of tert-butyl-4-(5-chloro-1H-indol-3-yl)piperidin-1- carboxylate (500.0 mg, 1.49 mmol, BB9, intermediate step b) in THF (5 ml) at 0°C. This mixture was stirred at 0° C. for 0.5 hours, then Mel (211.95 mg, 1.49 mmol) was added. This mixture was stirred at 0°C for 1 hour, poured into H ₂ O (5 ml) and was extracted with EtOAc (20 ml × 3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a light yellow solid (480 mg, 92.1%). MS (ESI): m/z is 349.1 [M-Boc+H] ⁺ .

BB4

4-(9H-Fluoren-9-yl)piperidine

Platinum(IV) oxide (10 mg, 44 µmol) was added to a solution of 4-(9H-fluoren-9-yl)pyridine (70 mg, 288 µmol) in AcOH (1 ml). This reaction mixture was stirred over night in a nitrogen atmosphere of 2000 kPa at 40°C. This reaction mixture was filtered and the filtrate was washed with AcOH. The solution thus obtained was concentrated under vacuum. The residue was dissolved in DCM, and the DCM was washed three times with saturated aqueous NaHCO ₃ . The organic layer was dried over MgSO ₄ , filtered and concentrated to give the desired product. (0.060 g; 83%). MS (ESI): m/z is 250.2 [M+H] ⁺ .

Intermediates:

a) 4-(9H-Fluoren-9-yl)pyridine

Sulfuric acid (0.8 ml) was added dropwise to a solution of diphenyl(4-pyridyl)methanol (135 mg, 517 μmol) in FA (2 ml). This mixture was heated to 100°C for 15 minutes, cooled to RT and poured into 20 ml of an aqueous solution of 5N. NaOH, which caused precipitation of the product. This product was collected by filtration to give the product as a light yellow solid (75 mg, 60%). MS (ESI): m/z is 244.2 [M+H] ⁺ .

b) Diphenyl(4-pyridyl)methanol

To a solution of phenyl(pyridin-4-yl)methanone (0.52 g, 2.84 mmol, CAS RN 14548-46-0) in THF (10 ml) was added dropwise a 1 M solution of phenylmagnesium bromide in THF (9 ml, 9 mmol, CAS RN 100-58-3) at RT for 2 hours. This reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a DCM:MeOH gradient (100:0 to 90:10) to give the desired compound as a colorless solid (0.290 g; 39.0%), MS (ESI): m/z is equal to 262.2 [M+H] ⁺ .

BB5

4-[1-(4-Fluorophenyl)-3-methoxypropyl]piperidine

4 M HCl in dioxane ( 338 µl, 1.35 mmol) and this mixture was stirred at RT for 2 h. The light yellow solution was completely evaporated. The residue was taken up in saturated aqueous NaHCO ₃ and DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were dried over MgSO ₄ , filtered and evaporated to give the desired compound as a light yellow oil (0.057 g; 83.9%). MS (ESI): m/z is 252.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[1-(4-fluorophenyl)-3-methoxypropyl]piperidine-1-carboxylate

55% NaH in mineral oil ( 13.5 mg, 310 µmol) and this mixture was stirred at this temperature for 30 minutes before adding iodomethane (47.9 mg, 21.1 µl, 337 µmol). After stirring at this temperature for 30 minutes, the cloudy solution was allowed to warm up to RT. After stirring at RT for 4 hours, the reaction mixture was poured onto N ₂ O and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO ₄ , filtered and evaporated to give the desired compound as a light yellow oil (0.097 g; 98%). MS (ESI): m/z is 252 [M-Boc+H] ⁺ .

b) tert-Butyl-4-[1-(4-fluorophenyl)-3-hydroxypropyl]piperidine-1-carboxylate

To a solution of tert-butyl 4-[3-ethoxy-1-(4-fluorophenyl)-3-oxo-propyl]piperidine-1-carboxylate (148 mg, 390 µmol) in THF (1.5 ml) at 0° Lithium borohydride (21.2 mg, 975 µmol) was added in one portion and the mixture was stirred in an ice bath for 1.25 hours. The ice bath was removed and stirring continued at RT for 20 hours. The reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) to give the desired compound as a colorless oil (0.097 g, 73.7%). MS (ESI): m/z is 282.3 [M-C ₄ H ₈ +H] ⁺ .

c) tert-Butyl-4-[3-ethoxy-1-(4-fluorophenyl)-3-oxo-propyl]piperidine-1-carboxylate

Into a solution of tert-butyl-(E) and (Z)-4-(3-ethoxy-1-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate (1.74 g, 4.63 mmol) in EtOAc (17.1 ml) was added Pd/C 10% (175 mg) and this suspension was stirred at RT under a hydrogen atmosphere at 150 kPa for 4 hours. This reaction mixture was filtered through a microfilter. The compound was purified by silica gel chromatography on a 24 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a colorless liquid (1.23 g, 69.8%) . MS (ESI): m/z is 280 [M-Boc+H] ⁺ .

d) tert-Butyl-4-[(E) and (Z)-3-ethoxy-1-(4-fluorophenyl)-3-oxo-prop-1-enyl]piperidine-1-carboxylate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (2.1 g, 1.86 ml, 9.36 mmol, CAS RN 867-13-0) in 1,4-dioxane (9.73 ml) was added dropwise LiHMDS 1.0 M in hexanes (15 ml, 15 mmol) and this solution was stirred for 15 minutes. To this mixture was added dropwise a solution of tert-butyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (2.878 g, 9.36 mmol, CAS RN 160296-40-2) in 1,4-dioxane (9.73 ml) and stirring was continued at reflux temperature for two days. This reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with H ₂ O, dried over MgSO 4 , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 40 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a colorless liquid (1.74 g; 49.4% ). MS (ESI): m/z is 278.2 [M-Boc+H] ⁺ .

BB6

4-[(4-Fluorophenyl)-methoxymethyl]piperidine

To a solution of tert-butyl 4-[(4-fluorophenyl)-methoxymethyl]piperidine-1-carboxylate (57 mg, 176 µmol) in dioxane (200 µl) was added 4 M HCl in dioxane (220 µl, 880 µmol) , and the mixture was stirred at RT for 2 hours. This light yellow solution was completely evaporated. The residue was taken up in saturated aqueous NaHCO ₃ and DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to give the desired compound as a light yellow oil (0.036 g; 91.5%). MS (ESI): m/z is 224.2 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[(4-fluorophenyl)-methoxy-methyl]piperidine-1-carboxylate

55% NaH in mineral oil (9.31 mg, 213 µmol) and this mixture was stirred at this temperature for 30 minutes before adding iodomethane (33.1 mg, 14.6 µl, 233 µmol). After stirring at this temperature for 30 minutes, this cloudy solution was allowed to warm up to RT. After stirring for 2 hours at RT, another batch of iodomethane (33 mg, 14.6 µl, 233 µmol) was added. After 4.5 hours this reaction mixture was poured onto H ₂ O and EtOAc and the layers separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to give the desired compound as a light yellow oil (0.057 g; 90.9%). MS (ESI): m/z is 268.2 [M-C ₄ H ₈ +H] ⁺ .

BB7

1-Methyl-5-(4-piperidyl)indazole hydrochloride

To a solution of tert-butyl 4-(1-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (155 mg, 491 µmol) in dioxane (0.5 ml) was added 4 M HCl in dioxane (614 µl , 2.46 mmol). This colorless suspension was stirred at RT for 3.5 hours. Ether (4 ml) was added and the suspension was filtered. The filter cake was washed with ether to give the desired product as a light yellow solid (0.107 g; 86.5%). MS (ESI): m/z is 216.2 [M+-HCl+H] ⁺ .

Intermediates:

a) tert-Butyl-4-(1-methylindazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(1-methyl-1H-indazol-5-yl)-3,6-dichloropyridine-1(2H)-carboxylate (160 mg, 511 µmol) in MeOH (3 ml) and EtOAc ( 1 ml) was added under argon Pd-C 10% (16.3 mg, 15.3 µmol) and this suspension was stirred under a hydrogen atmosphere at 170 kPa for 2.5 hours. The solids were filtered off and the filtrate was evaporated to give the desired compound as a colorless oil (0.156 g; 96.9%). MS (ESI): m/z is 316.3 [M+H] ⁺ .

b) tert-Butyl-4-(1-methyl-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

To a mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 604 µmol, CAS RN 138647-49-1) in DME (3 ml ) and 2M aqueous Na ₂ CO ₃ (770 μl, 1.54 mmol) were added palladium(II) acetate (2.71 mg, 12.1 μmol), triphenylphosphine (7.92 mg, 30.2 μmol) and 1- methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (171 mg, 664 µmol, CAS RN 1235469-00-7), and this clear the two-layer mixture was heated at 90° C. for 2 hours. This reaction mixture was poured onto H ₂ O and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) to give the desired compound as a colorless solid (0.163 g; 86.2%) . MS (ESI): m/z is 314.3 [M+H] ⁺ .

BB8

(E or Z)-2-Phenyl-3-piperazin-1-yl-prop-2-ennitrile hydrochloride

(E or Z)-tert-Butyl-4-[2-cyano-2-phenyl-vinyl]piperazine-1-carboxylate (300 mg, 951 µmol) was treated with 4 M HCl in dioxane (3.6 g, 3 ml , 98.7 mmol). This reaction mixture was stirred at RT for 15 h, then concentrated in vacuo to give a light yellow solid (240 mg, 100%); MS (ESI): m/z is 214.2 [M+H] ⁺ .

Intermediate: (E or Z)-tert-butyl-4-[2-cyano-2-phenyl-vinyl]piperazine-1-carboxylate

tert-Butyl-piperazine-1-carboxylate (200 mg, 1.07 mmol, CAS RN 57260-71-6), 3-oxo-2-phenylpropanenitrile (156 mg, 1.07 mmol, CAS RN 5841-70-3 ) and sodium triacetoxyborohydride (228 mg, 1.07 mmol, CAS RN 56553-60-7) were dissolved in DCM (5 ml). This reaction mixture was stirred at RT for 48 hours. This reaction mixture was washed with H ₂ O, NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give a brown solid (300 mg). MS (ESI); m/z is 314.2 [M+H] ⁺ .

BB9

5-Chloro-1-cyclopropyl-3-(4-piperidinyl)indole hydrochloride

HCl/EtOAc ( 4 M, 4 ml), and this mixture was stirred at 20°C for 3 hours. This mixture was concentrated and the residue was diluted with H ₂ O (30 ml), washed with EtOAc (10 ml × 2). The aqueous layer was lyophilized to give the title compound as a light yellow solid (189.4 mg, 81.3%). ¹ H NMR (Nuclear Magnetic Resonance) (400 MHz, DMSO-d6) δ 9.29-8.87 (m, 2H), 7.76 (d, J=1.9 Hz, 1H), 7.53 (d, J=8.7 Hz , 1Н), 7.23-7.10 (m, 2H), 3.38-3.27 (m, 3H), 3.08-2.90 (m, 3H), 2.07-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.09 -1.00 (m, 2H), 0.96-0.88 (m, 2H). MS (ESI): m/z is 275.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-(5-chloro-1-cyclopropyl-1H-indol-3-yl)piperidine-1-carboxylate

Mixture of tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate (500mg, 1.49mmol), cyclopropylboronic acid (153.92mg, 1.79mmol; CAS RN 411235-57-9), 1 M NaHMDS in THF (3 mL, 2.99 mmol; CAS RN 1070-89-9), DMAP (0.22 mL, 1.79 mmol) and copper(II) acetate ( 270.22 mg, 1.49 mmol; CAS RN 142-71-2) in toluene (25 ml) was stirred at 95° C. for 12 hours (carrying an oxygen balloon). This mixture was poured into H ₂ O (20 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (100-200 mesh) using a PE:EtOAc gradient (50:1 to 20:1) to give the title compound as a light yellow oil (275 mg, 0.730 mmol, 49.1%). MS (ESI): m/z is 275.1 [M-Boc+H] ⁺ .

b) tert-Butyl-4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.003 g, 3.01 mmol) and platinum(IV) oxide ( 100.0 mg, 0.350 mmol; CAS RN 1314-15-4) in AcOH (10.0 ml) and EtOH (20 ml) was stirred at 40°C for 15 h under H ₂ (1520 mmHg) . This mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with PE (50 ml) and filtered. The filter cake was collected and dried under vacuum to give the title compound as a light gray solid (780 mg, 77.3%). MS (ESI): m/z is 235.1 [M-Boc+H] ⁺ .

c) tert-Butyl-4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

To a mixture of 5-chloroindole (1 g, 6.6 mmol; CAS RN 17422-32-1) in MeOH (20 ml) was added tert-butyl-4-oxo-piperidine-1-carboxylate (1.97 g, 9.9 mmol ; CAS RN 79099-07-3). This mixture was stirred at 20° C. for 1 hour and then potassium hydroxide (1.48 g, 26.39 mmol) was added. This mixture was stirred at 70° C. for 15 hours. This mixture was concentrated in vacuo. The residue was triturated with a mixture of PE and EtOAc (5:1, 50 ml) and filtered. The filter cake was collected and dried under vacuum to give the title compound as a light yellow solid (2 g, 91.3%). MS (ESI): m/z is 227.1 [M-C ₄ H ₈ +H] ⁺ .

BB10

5-Chloro-1-(oxetan-3-yl)-3-(4-piperidyl)indole

To a mixture of tert-butyl 4-[5-chloro-1-(oxethan-3-yl)-1H-indol-3-yl]piperidine-1-carboxylate (1 g, 2.56 mmol) in DCM (20 ml ) was added TFA (5.0 ml). This mixture was stirred at 20°C for 12 hours. This mixture was concentrated in vacuo, purified by prep HPLC (0.1% FA in N ₂ O and ACN) to give the title compound as a light yellow solid (311.3 mg, 37.3%). ¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=1.8 Hz, 1H), 7.65 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.17 (dd , J=1.9, 8.7 Hz, 1H), 5.73 (quin (quintet), J=7.0 Hz, 1H), 5.01 (t, J=7.2 Hz, 2H), 4.90 (t, J=6.5 Hz, 2H), 3.38 (br d (wide doublet), J=12.2 Hz, 2H), 3.14-3.00 (m, 3H), 2.07 (br d, J=13.2 Hz, 2H), 1.96-1.78 (m, 2H). MS (ESI): m/z is 291.1 [M+H] ⁺ .

Intermediate: tert-Butyl-4-(5-chloro-1-(oxethan-3-yl)-1H-indol-3-yl)piperidine-1-carboxylate

60% NaH in mineral oil (143.35 mg, 3.58 mmol) at 0°C. This mixture was stirred at 20° C. for 1 hour, then oxethan-3-yl-4-methylbenzenesulfonate (1022.55 mg, 4.48 mmol; CAS RN 26156-48-9) was added and the mixture was stirred at 85° C within 12 hours. This mixture was poured into H ₂ O (60 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a light yellow solid (1.1 g, 2.81 mmol, 94.2% ). MS (ESI): m/z is 291.1 [M-Boc+H] ⁺ .

BB11

Formic acid salt of 4-(bis)(4-fluorophenyl)methyl)piperidine

To a solution of 4-[bis(4-fluorophenyl)methylene]piperidine (700.0 mg, 1.75 mmol) in AcOH (50.0 ml) was added Pd/C (1.0 g), the reaction mixture was purged with hydrogen for three times and stirred at 90°C (under a balloon with hydrogen) for 48 hours. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (0.1% FA in water and MeCN) to give the title compound as a light gray solid (263.5 mg, 32.1%). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.39 (s, 1H), 7.45-7.37 (m, 4H), 7.15-7.07 (m, 4H), 3.68 (d, J=11.2 Hz, 1H) , 3.17 (br d, J=12.3 Hz, 2H), 2.80-2.68 (m, 1H), 2.46 (br d, J=11.2 Hz, 1H), 1.54-1.32 (m, 2H), 1.27 -1.09 (m, 2H). MS (ESI): m/z is 288.1 [M+H] ⁺ .

Intermediates:

a) 4-[bis(4-Fluorophenyl)methylene]piperidine

To a solution of bis(4-fluorophenyl)(piperidin-4-yl)methanol (900.0 mg, 2.59 mmol) in DCM (30 ml) was added TFA (10.0 ml) and the reaction mixture was stirred at 20° C within 12 hours. This reaction mixture was concentrated in vacuo to give the crude title compound, which was used in the next step without further purification. MS (ESI): m/z is 286.1 [M+H] ⁺ .

b) bis(4-Fluorophenyl)(piperidin-4-yl)methanol

A mixture of Mg (1.4 g, 58.29 mmol) and I ₂ (20.0 mg, 0.080 mmol) was suspended in THF (40 ml) at 10°C. To the above yellow solution was added 1-bromo-4-fluorobenzene (1.0 g, 5.75 mmol, CAS RN 460-00-4) and the reaction mixture was heated to 45° C. until the solution became clear. Another batch of 1-bromo-4-fluorobenzene (9.14 g, 52.54 mmol, CAS RN 460-00-4) (dissolved in 10 ml THF) was added thereto. This reaction mixture was stirred at 45° C. for 30 minutes. Ethyl-N-BOC-piperidine-4-carboxylate (1.5 g, 5.83 mmol, CAS RN 142851-03-4) was added and the reaction mixture was stirred at 80° C. for 12 hours. The mixture was poured into sat. aq. NH ₄ Cl solution (50 ml), this mixture was extracted twice with EtOAc (each time 50 ml), the combined organic layer was washed with water (30 ml × 2) and brine (30 ml), dried over Na ₂ SO ₄ and concentrated in vacuo with yielding the title compound (900 mg, 38.2%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (br s, 1H), 7.57-7.47 (m, 4H), 7.12 (t, J=8.8 Hz, 4H), 5.73 (s, 1H), 3.23 (br d, J=12.3 Hz, 2H), 2.92-2.79 (m, 3H), 1.68-1.54 (m, 2H), 1.39 (br d, J=13.6 Hz, 2H). MS (ESI): m/z is 304.1 [M+H] ⁺ .

BB12

5-Chloro-1-(oxethan-3-ylmethyl)-3-(4-piperidyl)indole

To a solution of tert-butyl 4-[5-chloro-1-(oxethan-3-ylmethyl)indol-3-yl]piperidine-1-carboxylate (700.0 mg, 1.73 mmol) in DCM (20 mL) TFA (3.38 ml) was added. This mixture was stirred at 20° C. for 12 h. This mixture was concentrated in vacuo, purified by preparative HPLC (0.1% FA in H ₂ O and ACN) to give the title compound as a light yellow solid ( 154.57 mg, 29.0%). ¹ H NMR (400 MHz, DMSO-d6) δ 8.60 (br s, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.33 ( s, 1H), 7.13 (dd, J=1.8, 8.7 Hz, 1H), 4.59 (dd, J=6.2, 7.6 Hz, 2H), 4.47-4.33 (m, 4H), 3.43-3.37 (m, 3H), 3.08-2.99 (m, 3H), 2.04 (d, J=13.0 Hz, 2H), 1.89-1.76 (m, 2H). MS (ESI): m/z is 305.2 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[5-chloro-1-(oxethan-3-ylmethyl)indol-3-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate (400.0 mg, 1.19 mol, BB9, intermediate step b) in DMF (8 mL) was added 60% NaH in mineral oil (57.34 mg, 2.39 mmol) at 0°C. This mixture was stirred at 20°C for 1 hour. Then, oxethan-3-ylmethyl-4-methylbenzenesulfonate (434.16 mg, 1.79 mmol) was added and the mixture was stirred at 85° C. for 12 hours. This mixture was poured into H ₂ O (60 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a yellow oil (629 mg, crude). MS (ESI): m/z is 305.0 [M-Boc+H] ⁺ .

b) Oxetan-3-ylmethyl 4-methylbenzenesulfonate

TEA (1.19 ml, 8.51 mmol), DMAP (69.33 mg , 0.570 mmol) and 4-methylbenzene-1-sulfonyl chloride (1293.77 mg, 6.81 mmol; CAS RN 98-59-9). This mixture was stirred at 20°C for 6 hours. The mixture was diluted with a mixture of EtOAc and saturated aqueous NH ₄ Cl (1:1, 20 ml). This mixture was extracted with EtOAc (40 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a brown solid (1.25 g, 5.16 mmol, 78.7%). MS (ESI): m/z is 243.1 [M+H] ⁺ .

BB13

1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5-chloro-3-(piperidin-4-yl)-1H-indole

To a solution of 2-[5-chloro-3-(4-piperidyl)indol-1-yl]ethanol (600.0 mg, 1.39 mmol) in pyridine (5 ml) 1.67 mmol; CAS RN 18162-48-6), and this mixture was stirred at 20° C. for 12 hours. This mixture was poured into H ₂ O (10 ml) and extracted with EtOAc (20 ml × 3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with PE (10 ml) and filtered. The filter cake was washed with PE (5 mL x 2), the solid was collected and dried in vacuo to give the title compound as a light yellow solid (164.7 mg, 29.8%). ¹ H NMR (400 MHz, DMSO-d6) δ 8.97 (br s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.20 ( s, 1H), 7.10 (dd, J=1.8, 8.7 Hz, 1H), 4.22 (br t, J=4.8 Hz, 2H), 3.84 (t, J=4.9 Hz, 2H ), 3.44-3.32 (m, 2H), 3.12-2.94 (m, 3H), 2.08-1.96 (m, 2H), 1.95-1.81 (m, 2H), 0.73 (s, 9H), -0.24 (s, 6H). MS (ESI): m/z is 393.1 [M+H] ⁺ .

Intermediates:

a) 2-[5-Chloro-3-(4-piperidyl)indol-1-yl]ethanol

To a mixture of tert-butyl 4-[5-chloro-1-(2-hydroxyethyl)indol-3-yl]piperidine-1-carboxylate (1.1 g, 2.9 mmol) in EtOAc (10 ml) was added HCl /EtOAc (4 M, 0.73 ml). This mixture was stirred at 20°C for 3 hours and then concentrated in vacuo. The residue was diluted with DCM (20 ml) and washed with saturated aqueous NaHCO ₃ (10 ml). The aqueous layer was extracted with DCM:MeOH (5:1 v/v; 20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a light yellow oil (750 mg, 59.8%). MS (ESI): m/z is 279.1 [M+H] ⁺ .

b) tert-Butyl-4-[5-chloro-1-(2-hydroxyethyl)indol-3-yl]piperidine-1-carboxylate

A mixture of tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate (1 g, 2.99 mmol, intermediate BB9, step b), 2-bromoethanol (0.32 ml , 4.48 mmol; CAS RN 540-51-2) and potassium hydroxide (335.12 mg, 5.97 mmol) in DMF (10 ml) were stirred at 100° C. for 12 hours. This mixture was purified by preparative HPLC (0.1% ammonia in H ₂ O and ACN) to give the title compound as a light yellow oil (1.1 g, 97.2%). MS (ESI): m/z is 323.1 [M-C ₄ H ₈ +H] ⁺ .

BB14a and BB14b

(+)-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

And

(-)-cis-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

The enantiomers of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (500 mg, 2.18 mmol, ChemBridge Corporation) were separated by preparative chiral HPLC (ReprosilChiral NR column) using isocratic EtOH (containing 0.05% NH ₄ OAc : n-heptane (30:70).

First eluting enantiomer: (+)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one. Yellow solid (0.150 g; 44.0%). MS (ESI): m/z is 157.1 [M+H] ⁺ .

Second eluting enantiomer: (-)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one. Yellow solid (0.152 g; 44.6%). MS (ESI): m/z is 157.1 [M+H] ⁺ .

BB15a and BB15b

4-Nitrophenyl-(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB15a)

And

4-Nitrophenyl-(4aS,8aR)-3-oxohexahydro-2Н-pyrido[4,3-b][1,4]oxazine-6(5Н)-carboxylate (BB15b)

Into a suspension of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; dihydrochloride salt (4.5 g, 19.6 mmol, BB1) in dry DCM (125 ml) DIPEA (6.35 g, 8.58 ml, 49.1 mmol) was added at 0°C, followed by the addition of 4- nitrophenyl carbonochloridate (4.35 g, 21.6 mmol). This reaction mixture was stirred at 0° C. for 10 min and at RT for 2 h. The crude reaction mixture was diluted with DCM and transferred to a separating funnel to extract sat. aq. Na ₂ CO ₃ solution. The organic phase was collected and the aqueous phase was back extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ and evaporated to dryness to give 6.62 g of crude racemic product (BB7) as a yellow solid. This crude material was directly subjected to resolution with chiral SFC to give the BB15b enantiomer (2.72 g, second eluting enantiomer) as a yellow solid and the BB15a enantiomer (3.25 g, first eluting enantiomer) as a light beige solid, but contaminated BB15b. Additional separation of chiral SFC was carried out to obtain 2.71 g of BB15a. MS (ESI): m/z is 322.2 [M+H] ⁺ for both enantiomers.

BB16

3-(4-Fluorophenyl)-3-(piperidin-4-yl)propan-1-ol hydrochloride

Solution of tert-butyl 4-(1-(4-fluorophenyl)-3-hydroxypropyl)piperidine-1-carboxylate (119 mg, 353 µmol, BB5, intermediate b) in 2 M HCl in diethyl ether (1.76 ml , 3.52 mmol) was stirred at RT for 4.5 h before adding another batch of 2 M HCl in diethyl ether (1.76 ml, 3.53 mmol). Stirring was continued at RT overnight. The suspension was homogenized in an ultrasonic ice bath and filtered. The filter cake was washed with a small volume of diethyl ether to give the desired compound as a colorless solid (0.067 g; 69.4%). MS (ESI): m/z is 238.2 [M+H] ⁺ .

BB17

4-[1-[4-(Trifluoromethyl)phenyl]ethyl]piperidine formate

A solution of tert-butyl 4-[1-[4-(trifluoromethyl)phenyl]ethyl]piperidine-1-carboxylate (1.5 g, 4.2 mmol) in HCl/dioxane (50.0 ml, 1/1 v/v) was stirred at 20° C. for 2 h. This mixture was concentrated and the residue was purified by preparative HPLC (FA) and lyophilized to give the desired compound as a light yellow oil (838.4 mg, 77.1% ). MS (ESI): m/z is 258.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[1-[4-(trifluoromethyl)phenip]ethyl]piperidine-1-carboxylate

Pd/C (1, 0 g, 5.63 mmol), this mixture was stirred at 20° C. under H ₂ (balloon) for 12 h. The mixture was filtered and the filtrate was concentrated to give the desired compound as a colorless oil (1.8 g, 89. 5%). MS (ESI): m/z is 302.2 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-4-[1-[4-(trifluoromethyl)phenyl]vinyl]piperidine-1-carboxylate

To a solution of methyltriphenylphosphonium bromide (10.0 g, 27.98 mmol, CAS RN 1779-49-3) in THF (250 ml) was added dropwise at 0°C lithium bis(trimethylsilyl)amide in THF (41.97 ml, 41.97 mmol) and this mixture was stirred at 0°C for 1 hour. 98 mmol, CAS RN 725229-27-6) in THF (50 ml) and this mixture was allowed to warm to 20° C. for 2 hours. The mixture was poured into aq. NH ₄ Cl solution (500 ml) and extracted three times with EtOAc (each time 200 ml). The organic phase was washed with brine and dried over Na ₂ SO ₄ , filtered, and the filtrate was purified through a silica gel column (PE : EtOAc = 20:1) to give the desired compound as a light yellow oil. (5.1 g, 51.3%). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.61 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 5.25 (s, 1H), 5.13 (s , 1Н), 4.27-4.14 (m, 2H), 2.77 (br t, J=12.3 Hz, 2H), 2.58 (br t, J=11.6 Hz, 1Н), 1.78 (br d, J= 13.0 Hz, 2H), 1.48 (s, 9H), 1.43-1.32 (m, 2H).

BB18

6-Chloro-1-methyl-3-(4-piperidyl)indazole

A mixture of 1-[4-(6-chloro-1-methyl-indazol-3-yl)-1-piperidyl]ethanone (3.95 g, 14 mmol) was refluxed in an aqueous solution of 25% HCl (25.75 ml) for 4 h. After cooling to RT, this mixture was basified using concentrated aqueous NaOH. The aqueous layer was extracted twice with DCM. The organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired compound as a light red oil (3.6 g, 98.2%). MS (ESI): m/z is 250.2 [M+H] ⁺ . This compound was used in the next step without further purification.

Intermediate connection:

1-[4-(6-Chloro-1-methyl-indazol-3-yl)-1-piperidyl]ethanone

In a sealed tube, 1-[4-(4-chloro-2-fluorobenzoyl)-1-piperidyl]ethanone (3.9 g, 14 mmol; Novel Chemical Solutions) and methylhydrazine (0.94 ml, 18 mmol) were mixed, and this mixture was heated at 120° C. for 16 hours. After cooling, this mixture was basified using concentrated aqueous NaHCO ₃ solution. The aqueous layer was extracted twice with DCM. The organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired compound as a yellow oil (3.97 g, 100%). MS (ESI): m/z is 292.3 [M+H] ⁺ . This compound was used in the next step without further purification.

BB19

2-(4-Fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride

This product was obtained by analogy with BB16 from tert-butyl 4-(cyano(4-fluorophenyl)methyl)piperidine-1-carboxylate (MFCD28112711, A Chemtek) as a light yellow solid. (0.101 g; 87.1%). MS (ESI): m/z is 219.1 [M+H] ⁺ .

BB20

4-((4-Fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine hydrochloride

This product was obtained by analogy with BB16 from tert-butyl 4-((4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carboxylate as a colorless foam (0.151 g, 100.0%). MS (ESI): m/z is 292.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-((4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carboxylate

tert-Butyl-4-((4-fluorophenyl )(hydroxy)methyl)piperidine-1-carboxylate (200 mg, 646 µmol, CAS RN 160296-41-3) and this mixture was stirred at RT for 10 min. Addition of 2,2,2-trifluoroethanol (711 mg, 514 μl, 7.11 mmol) gave a suspension. After heating at reflux temperature for 20 hours, the reaction mixture was cooled to RT. Silica gel was added and the mixture was evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system (ISCO) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a colorless oil (0.180 g; 71.1 %). MS (ESI): m/z is 391.1 [M+H] ⁺ .

BB21

5-(2-(4-Fluorophenyl)-2-(piperidin-4-yl)ethyl)-3-methyl-1,2,4-oxadiazole hydrochloride

This product was obtained by analogy with BB16 from tert-butyl-4-(1-(4-fluorophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)piperidine-1-carboxylate in as a colorless solid (0.051 g; 98.3%). MS (ESI): m/z is 290.2 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-(1-(4-fluorophenip)-2-(3-methyl-1,2,4-oxadiazol-6-yl)ethyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-(3-ethoxy-1-(4-fluorophenyl)-3-oxopropyl)piperidine-1-carboxylate (100 mg, 264 µmol) and (Z)-N'-hydroxyacetimidamide (39 mg, 527 μmol) in toluene (2.5 ml) was added K ₂ CO ₃ (72.8 mg, 527 μmol) and the reaction mixture was stirred at 130°C for 14 days. The reaction was not complete, so (Z)-N'-hydroxyacetimidamide (39 mg, 527 µmol) and K ₂ CO ₃ (72.8 mg, 527 µmol) were added and the RM (reaction mixture) was stirred over the weekend at 130°C. This reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. This compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) to give the desired compound as a colorless solid. MS (ESI): m/z is 290.3 [M-Boc+H] ⁺ .

b) tert-Butyl-4-(3-ethoxy-1-(4-fluorophenyl)-3-oxopropyl)piperidine-1-carboxylate

In a 25 ml round bottom flask, tert-butyl-(E)-4-(3-ethoxy-1-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate (1.747 g, 4 .63 mmol) was combined with EtOAc (17.1 ml) to give a colorless solution. Pd/C 10% (175 mg, 4.63 mmol) was added under argon. This suspension was stirred under a hydrogen atmosphere at 150 kPa for 4 hours. This reaction mixture was filtered and the filtrate was concentrated in vacuo. The compound was purified by silica gel chromatography on a 24 g column using an MPLC system (ISCO) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a colorless oil (1.22 g; 69 ,8%). MS (ESI): m/z is 280 [M-Boc+H] ⁺ .

c) tert-Butyl-(E)-4-(3-ethoxy-1-(4-fluorophenyl)-3-oxoprop-1-en-1-yl) piperidine-1-carboxylate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (2.1 g, 1.86 ml, 9.36 mmol) in 1,4-dioxane (9.73 ml) was added dropwise 1.0 M LiHMDS in hexanes (15 ml, 15 mmol) and this solution was stirred for 15 min. To this mixture was added dropwise tert-butyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (2.878 g, 9.36 mmol, CAS RN 160296-40-2) dissolved in 1,4-dioxane (9. 73 ml) and stirring was continued at reflux temperature for two days. This reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. This compound was purified by silica gel chromatography on a 40 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a colorless liquid (1.74 g; 49.4 %). MS (ESI): m/z is 278.2 [M-Boc+H] ⁺ .

BB22

4-(1-(4-(Trifluoromethyl)phenyl)cyclopropyl)piperidine formate

TFA (1.0 ml, 0.680 mmol) and this mixture was stirred at 20° C. for 16 h. This mixture was concentrated and the residue was purified by preparative HPLC (FA) to give the desired compound as a yellow oil (181 mg, 81.5%). MS (ESI): m/z is 270.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[1-[4-(trifluoromethyl)phenyl]cyclopropyl]piperidine-1-carboxylate

Into a solution of tert-butyl 4-[2,2-dibromo-1-[4-(trifluoromethyl)phenyl]cyclopropyl]piperidine-1-carboxylate (800.0 mg, 1.52 mmol) and titanium (IV) isopropoxide ( 862.56 mg, 3.03 mmol) in THF (30 ml) was added 3 M solution of EtMgBr in THF (5.06 ml, 15.17 mmol) dropwise at 0°C. This mixture was heated to 20° C. for 16 hours. This mixture was poured into NH ₄ Cl (aq. 100 ml) and extracted three times with EtOAc (each time 30 ml). The organic phase was washed with brine and dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The residue was purified by reverse phase (FA) flash chromatography to give the desired compound as a light yellow oil (250 mg, 44.6%). MS (ESI): m/z is 314.1 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-4-[2,2-dibromo-1-[4-(trifluoromethyl)phenyl]cyclopropyl]piperidine-1-carboxylate

To a vigorously stirred mixture of tert-butyl 4-[1-[4-(trifluoromethyl)phenyl]vinyl]piperidine-1-carboxylate (1.2 g, 3.38 mmol, BB17, intermediate b), bromoform (2, 56 g, 10.13 mmol, CAS RN 75-25-2) and cetrimide (0.37 g, 1.01 mmol, CAS RN 57-09-0) in DCM (10 ml) were added dropwise 50% aq. NaOH (1.35 ml, 16.88 mmol). This reaction mixture was vigorously stirred at 50°C for 16 h and then added H ₂ O (20 ml). The organic phase was separated, the aqueous phase was extracted three times with DCM (each time 10 ml). The combined organic phases were washed with H ₂ O, 2% HCl and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by preparative TLC (Thin Layer Chromatography) (PE : EtOAc - 20:1) to give the desired compound as a colorless oil (900 mg, 50.5%). MS (ESI): m/z is 471.9 [M-C ₄ H ₈ +H] ⁺ .

BB23

4-(1-(4-Fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)piperidine hydrochloride

The product was obtained by analogy with BB16 from tert-butyl 4-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)piperidine-1-carboxylate as a colorless foam (0.173 g; 97. 7%). MS (ESI): m/z is 306.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)piperidine-1-carboxylate

To a yellow solution of tri-n-butylphosphine (273 mg, 333 mcp, 1.35 mmol) and azodicarboxylic dipiperidide (340 mg, 1.35 mmol) in toluene (11.1 ml) was added tert-butyl-4-(1- (4-fluorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (218 mg, 674 µmol, BB5, intermediate b), and this mixture was stirred at RT for 10 minutes. Addition of 2,2,2-trifluoroethanol (742 mg, 536 μl, 7.42 mmol) gave a suspension. Upon heating to 65°C, a yellow solution re-formed. After heating at reflux temperature for 17 hours, the reaction mixture was cooled to RT. Silica gel was added and the mixture was evaporated. The compound was purified by chromatography on silica gel on a 12 g column using an MPLC system (ISCO) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a colorless oil (0.211 g; 77.2 %). MS (ESI): m/z is 350.1 [M-C ₄ H ₈ +H] ⁺ .

BB24

3-(1-(4-(Trifluoromethyl)phenyl)ethyl)azetidine formate

This product was obtained by analogy with BB22 from tert-butyl 3-[1-[4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate as a light yellow oil (151.5 mg, 27.4%). MS (ESI): m/z is 230.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-[1-[4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

This product was obtained by analogy with BB17 - intermediate compound a - from tert-butyl-3-[1-[4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate as a colorless oil (1 g, 99.4%) . MS (ESI): m/z is 274.0 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-3-[1-[4-(trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylate

Lithium bis(trimethylsilyl)amide/THF (9.11 ml, 9.11 mmol ) at 0°C, this mixture was stirred at 0°C for 1 h, then tert-butyl 3-[4-(trifluoromethyl)benzoyl]azetidine-1-carboxylate (1500.0 mg, 4.55 mmol, MFCD24368873, group FCH) in THF (5 ml), this mixture was heated to 20°C for 2 h. The mixture was poured into aq. NH ₄ Cl solution (100 ml) and extracted three times with EtOAc (each time 50 ml), the organic phase was washed with brine and dried over Na ₂ SO ₄ , filtered, and the filtrate was purified through a silica gel column (PE : EtOAc - 20:1) to give the desired compound as a light yellow oil (1000 mg, 67.0%). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.61 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 5.61 (s, 1H), 5.32 (s , 1H), 4.20 (t, J=8.4 Hz, 2H), 3.89 (br s, 2H), 3.83-3.73 (m, 1H), 1.46 (s, 9H).

BB25

5-((4-Fluorophenyl)(piperidin-4-yl)methyl)-3-(trifluoromethyl)-1,2,4-oxadiazole hydrochloride

This product was obtained by analogy with BB16 from tert-butyl 4-((4-fluorophenyl)(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carboxylate as a colorless solid substances (0.119 g; 90.1%). MS (ESI): m/z is 330.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-((4-fluorophenyl)(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carboxylate

CDI (120 mg, 741 µmol) and this mixture was stirred at RT for 30 minutes. To this clear solution was added a solution of (Z)-2,2,2-trifluoro-N'-hydroxyacetimidamide (94.9 mg, 741 μmol) in DMF (0.5 ml) and stirring was continued at RT for 1 hour. This reaction mixture was heated in a microwave oven at 120°C for 30 minutes, followed by heating at 150°C for 30 minutes. This reaction mixture was poured onto water and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed twice with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. This compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) to give the desired compound as a colorless foam (0.155 g, 48.7%) . MS (ESI): m/z is 428.3 [M-H] ^- .

BB26

(4aR,8aS)-6-[3-[(4-Fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazi-3-one

This product was prepared in analogy to Method A4 using 3-[(4-fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-2,2,2-trifluoroacetate to give the desired product as a white solid. MS (ESI): m/z is 446.2 [MC ₄ H ₈ +H] ⁺ . This product was used in the next step without further purification.

Intermediates:

a) 3-[(4-Fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine 2,2,2-trifluoroacetate

TFA was added to a solution of tert-butyl 3-[(4-fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-1-carboxylate (1000.0 mg, 2.75 mmol) in DCM (20 mL). (2.0 ml, 2.75 mmol), this mixture was stirred at 20°C for 12 hours. This mixture was concentrated, the residue was purified by preparative HPLC (TFA) to obtain the desired product as an off-white solid (608.8 mg, 57.6%). MS (ESI): m/z is 264.1 [M+H] ⁺ .

b) tert-Butyl-3-[(4-fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-1-carboxylate

In a solution of tert-butyl 3-[(4-fluorophenyl)-hydroxy-methyl]azetidine-1-carboxylate (3000.0 mg, 10.66 mmol), 2,2,2-trifluoroethanol (1.55 ml, 21 .33 mmol) and triphenylphosphine (4195.52 mg, 16 mmol) in THF (50 ml) was added diisopropyl azodicarboxylate (3.15 ml, 16 mmol) and the mixture was stirred at 80°C for 12 h. This mixture was concentrated, and the residue was purified by reverse phase (FA) flash chromatography to give the desired product as a yellow oil (1 g, 25.8%). MS (ESI): m/z is 308.1 [M-C ₄ H ₈ +H] ⁺ .

c) tert-Butyl-3-[(4-fluorophenyl)-hydroxy-methyl]azetidine-1-carboxylate

NaBH ₄ (541.33 mg, 14.32 mmol), and this mixture was stirred at 20°C for 1 h. This mixture was concentrated and dissolved in EtOAc (100 ml), washed with aq. NH ₄ Cl and brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a light yellow oil (2 mg, 99.3%). This compound was used in the next step without any further purification.

BB27

(4aR,8aS)-6-[3-[1-(2-Chloro-4-fluoro-phenyl)ethoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one

This product was prepared in analogy to Method A4 using 3-[1-(2-chloro-4-fluoro-phenyl)ethoxy]azetidine 2,2,2-trifluoroacetate to give the desired product as an off-white solid (230 mg, 59 ,8%). MS (ESI): m/z is 412.2 [M+H] ⁺ .

Intermediates:

a) 3-[1-(2-Chloro-4-fluoro-phenyl)ethoxy]azetidine 2,2,2-trifluoroacetate

This product was prepared in analogy to BB26 - intermediate a - using tert-butyl 3-[1-(2-chloro-4-fluorophenyl)ethoxy]azetidine-1-carboxylate to give the desired product as a light yellow gums (1.4 g, 67.2%). MS (ESI): m/z is 230.1 [M+H] ⁺ .

b) tert-butyl-3-[1-(2-chloro-4-fluoro-phenip)ethoxy]azetidine-1-carboxylate

Sodium hydride (1.54 g, 38.53 mmol) at 0°С. This mixture was stirred at 20° C. for 1 h. this mixture was stirred at 20° C. for 12 hours. This mixture was poured into ice water (200 ml) and extracted three times with EtOAc (each time 100 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (FA) and concentrated in vacuo to give the desired product as a light yellow oil (2 g, 23.6%). MS (ESI): m/z is 230 [M+H-Bos] ⁺ .

BB28

3-(2-Chloro-[1,1'-biphenyl]-4-yl)azetidine 4-methylbenzenesulfonate

4-methylbenzenesulfonic acid hydrate (39.8 mg, 209 µmol) and this mixture was heated at reflux temperature for 1 hour. The clear colorless solution was evaporated to give the desired product as a colorless solid (0.10 g; 100%). MS (ESI): m/z is 244.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(2-chloro-[1,1'-biphenyl]-4-yl)azetidine-1-carboxylate

This product was prepared in analogy to Method A5 from phenylboronic acid (CAS RN 98-80-6) and tert-butyl 3-(4-bromo-3-chlorophenyl)azetidine-1-carboxylate (CAS RN 2222937-56-4) as a colorless solid. MS (ESI): m/z is 288.2 [M-C ₄ H ₈ +H] ⁺ .

BB29

3-(4-Bromo-3-chlorophenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(4-bromo-3-chlorophenyl)azetidine-1-carboxylate (CAS RN 2222937-56-4) as a colorless solid. MS (ESI): 248.1 [M+H] ⁺ .

BB30

3-(3-Bromophenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(3-bromophenyl)azetidine-1-carboxylate (CAS RN 1203681-54-2) as a colorless solid. MS (ESI): 212.1 [M+H] ⁺ .

BB31

3-(4-tert-Butylphenyl)azetidine; 4-methylbenzenesulfonic acid

This product was obtained by analogy with BB28 from tert-butyl 3-(4-(tert-butyl)phenyl)azetidine-1-carboxylate (CAS RN 1629889-13-9) as a colorless solid. MS (ESI): 190.2 [M+H] ⁺ .

BB32

5-(Azetidin-3-yl)-2-chloropyridine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(6-chloropyridin-3-yl)azetidine-1-carboxylate (CAS RN 870689-19-3) as a colorless solid. MS (ESI): 169.1 [M+H] ⁺ .

BB33

3-(4-(Trifluoromethyl)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate (CAS RN 1638255-66-9) as a colorless solid. MS (ESI): 202.2 [M+H] ⁺ .

BB34

3-((1,1,1-Trifluoro-2-methylpropan-2-yl)oxy)azetidine hydrochloride

To a solution of 1-benzhydryl-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidine (114 mg, 326 µmol) in ethanol (0.5 ml) and EtOAc (0.5 ml) was added 1 M HCl in H ₂ O (326 μl, 326 μmol) and 10% Pd/C (20 mg, 326 μmol) and this mixture was stirred in a hydrogen atmosphere at 170 kPa for 5 h. This suspension was filtered through microfilter, and the filtrate was evaporated to give the desired compound as a colorless amorphous solid (0.105 g). MS (ESI): m/z is 184.2 [M+H] ⁺ . Used in the next step without further purification.

Intermediate connection:

Benzhydryl-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidine

To a solution of 1,1,1-trifluoro-2-methyl-propan-2-ol (807 mg, 690 μl, 6.3 mmol, CAS RN 507-52-8) in DMF (5 ml) was added under argon 60% sodium hydride in mineral oil (252 mg, 6.3 mmol) and this mixture was stirred at RT for 30 minutes. After adding (1-benzhydrylazetidin-3-yl)methanesulfonate (1 g, 3.15 mmol, CAS RN 33301-41-6), this reaction mixture was heated in a microwave oven at 130° C. for 60 minutes. The reaction mixture was poured onto water and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. This compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) to give the desired compound as a yellow solid (0.324 g; 29.4% ). MS (ESI): m/z is 350.3 [M+H] ⁺ .

BB35

3-(4-(1,1-Difluoroethyl)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carboxylate as a colorless solid (0.050 g, 35.9%). MS (ESI): m/z is 198.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carboxylate

To a stirred suspension of 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (568 mg, 2.12 mmol, CAS RN 1000994-94- 4) in 2-propanol (1.5 ml) was added a solution of tert-butyl-3-iodazetidine-1-carboxylate (300 mg, 1.06 mmol, CAS RN 254454-54-1) in 2-propanol (1.5 ml) at RT to give a solution. To this mixture was added rac-(1R,2R)-2-aminocyclohexan-1-ol (7.32 mg, 63.6 µmol, CAS RN 13374-31-7), nickel(II) iodide (19.9 mg, 63.6 µmol) and sodium bis(trimethylsilyl)amide (1.06 ml, 2.12 mmol) under argon. This mixture was heated in a microwave oven for 30 minutes at 100°C. This reaction mixture was poured onto water and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. This compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc (100:0 to 70:30) to give the desired compound as a colorless oil (0.0112 g; 35.5 %). MS (ESI): m/z is 242.2 [M-C ₄ H ₈ +H] ⁺ .

BB36

5-(4-(Azetidin-3-yl)phenyl)-1-methyl-1H-pyrazole 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)azetidine-1-carboxylate as a light brown gum, which was used in. MS (ESI): m/z is 214.1 [M+H] ⁺ . This product was used in the next step without further purification.

Intermediate connection:

tert-Butyl-3-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)azetidine-1-carboxylate

This product was prepared analogously to BB35, an intermediate, from (4-(1-methyl-1H-pyrazol-5-yl)phenyl)boronic acid (CAS RN 1487353-57-0) as a light brown gum. MS (ESI): m/z is 314.3 [M+H] ⁺ . This product was used in the next step without further purification.

BB37

3-[4-(2,2,2- Trifluoroethoxy)phenyl]azetidine trifluoroacetate

This product was obtained by analogy with BB26 - intermediate compound a - from tert-butyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]azetidine-1-carboxylate as a light yellow oil. MS (ESI): m/z is 232.1 [M+H] ⁺ . This product was used in the next step without further purification.

Intermediate connection:

tert-Butyl-3-[4-(2,2,2-trifluoroethoxy)srenyl]azetidine-1-carboxylate

To a solution of 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (0.45 g, 1.77 mmol, CAS RN 106854-77-7), 1-BOC-3-iodazetidine (0.5 g , 1.77 mmol, CAS RN 254454-54-1), 1,10-phenanthroline (63.65 mg, 0.350 mmol, CAS RN 5144-89-8), NaBF4 (96.95 mg, 0.880 mmol, CAS RN 13755-29-8), glyme NiCl ₂ (38.8 mg, 0.180 mmol, CAS RN 29046-78-4) and Mn powder (194.06 mg, 3.53 mmol) in MeOH (10 ml) was added 4- ethylpyridine (94.62 mg, 0.880 mmol, CAS RN 536-75-4). This mixture was stirred at 60° C. under N ₂ atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated, the residue was purified by reverse phase (FA) flash chromatography to give the desired product as a light yellow foam (60 mg, 10 .2%). MS (ESI): m/z is 276.0 [M-C ₄ H ₈ +H] ⁺ .

BB38

[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidine- 3-yl]phenyl]boronic acid

In a solution of (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4] oxazin-3-one (300.0 mg, 0.760 mmol, Example 110) and PdCl ₂ (dppf)⋅CH ₂ Cl ₂ (53.34 mg, 0.080 mmol) were added potassium acetate (224.04 mg, 2.28 mmol ) and bis(pinacolato)diboron (289.84 mg, 1.14 mmol, CAS RN 73183-34-3), this reaction mixture was purged with nitrogen and stirred at 90° C. for 12 h. This reaction mixture was diluted with water and three extracted twice with EtOAc, the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a yellow residue which was purified by reverse phase (FA) chromatography to give the desired product as a light yellow solid (230 mg, 84 ,1%). MS (ESI): m/z is 360.5 [M+H] ⁺ .

BB39

3-Cyclopropyl-5-((4-fluorophenyl)(piperidin-4-yl)methyl)-1,2,4-oxadiazole hydrochloride

This product was obtained by analogy with BB16 from tert-butyl 4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carboxylate as a colorless foam (0.170 g; 84.7%). MS (ESI): m/z is 302.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carboxylate

This product was prepared by analogy with BB25, an intermediate, from 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-fluorophenyl)acetic acid and N'-hydroxycyclopropanecarboxamidine as a colorless foam (0.240 g ; 80.7%). MS (ESI): m/z is 346.2 [M-C ₄ H ₈ +H] ⁺ .

b) 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2-(4-fluorophenyl)acetic acid

To a cloudy solution of 2-(4-fluorophenyl)-2-(piperidin-4-yl)acetic acid hydrobromide (535 mg, 1.55 mmol) in 1 M NaOH in H ₂ O (3.09 ml, 3.09 mmol ) was added dropwise to a solution of di-tert-butyl dicarbonate (368 mg, 391 μl, 1.68 mmol) in DME (5 ml) and the mixture was stirred at RT for 3 h. DME was evaporated. The remainder was taken up in approx. 1.2 ml 10% citric acid in water (pH approx. 4) and EtOAc, and the layers were separated. The aqueous layer was extracted once with EtOAc. The organic layers were dried over MgSO ₄ , filtered and evaporated to give the desired compound as a light brown solid (0.520 g; 99.6%). MS (ESI): m/z is 336.3 [M-H] ^- .

c) 2-(4-Fluorophenyl)-2-(piperidin-4-yl)acetic acid hydrobromide

A solution of tert-butyl 4-(cyano(4-fluorophenyl)methyl)piperidine-1-carboxylate (555 mg, 1.74 mmol, CAS RN 1824014-64-3) in 48% HBr in water (8.27 g, 5.55 ml, 49.1 mmol) was stirred at reflux temperature for 4.5 hours. This mixture was evaporated. The light brown solid was suspended in 2-propanol (2 ml), homogenized and filtered. The filter cake was washed three times with 2-propanol (each time 1 ml). The mother liquor was completely evaporated and dried for 2 hours under high vacuum in the presence of P ₂ O ₅ to give the desired product as a light brown solid (0.535 g; 96.5%). MS (ESI): m/z is 238.2 [M-HBr+H] ⁺ .

BB40

3-(3-(Trifluoromethoxy)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(3-(trifluoromethoxy)phenyl)azetidine-1-carboxylate (CAS RN 2222044-21-3) as a colorless solid. MS (ESI): 218.1 [M+H] ⁺ .

BB41

[4-(Azetidin-3-yl)phenyl]-pentafluoro-lambda6-sulfan 4-methylbenzenesulfonate

This product was obtained in analogy to BB28 from tert-butyl 3-(4-(pernafluoro-16-sulfaneyl)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): 260.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(4-(pentafluoro-I6-sulfaneyl)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with BB35, an intermediate, from (4-(pentafluoro-16-sulfaneyl)phenyl)boronic acid (CAS RN 871507-70-9) as a colorless oil. MS (ESI): m/z is 304.1 [M-C ₄ H ₈ +H] ⁺ .

BB42

2-(Azetidin-3-yl)-5-chloropyridine bis(4-methylbenzenesulfonate)

This product was obtained by analogy with BB28 from tert-butyl-3-(5-chloropyridin-2-yl)azetidine-1-carboxylate and twice the amount of p-TsOH as a colorless solid. MS (ESI): m/z is 169.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(5-chloropyridin-2-yl)azetidine-1-carboxylate

This product was obtained by analogy with BB37 - an intermediate compound - from (5-chloropyridin-2-yl)boronic acid and tert-butyl-3-iodazetidine-1-carboxylate as a colorless oil (0.045 g; 11.2%). MS (ESI): m/z is 213.1 [M-C ₄ H ₈ +H] ⁺ .

BB43

3-(2-Ftr-4-(trifluoromethoxy)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 236.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with BB35, an intermediate, from (2-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (CAS RN 503309-10-2) as a colorless oil. MS (ESI): m/z is 280.1 [M-C ₄ H ₈ +H] ⁺ .

BB44

3-[4-(2,2,2-Trifluoroethyl)phenyl]azetidine trifluoroacetate

This product was prepared in analogy to BB26, an intermediate, from tert-butyl 3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carboxylate as a yellow oil. MS (ESI): m/z is 216.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carboxylate

This product was obtained by analogy with BB37, an intermediate, from 1-bromo-4-(2,2,2-trifluoroethyl)benzene (CAS RN 155820-88-5) as a yellow oil. MS (ESI): m/z is 260.0 [M-C ₄ H ₈ +H] ⁺ .

BB45

3-[4-[1-(Trifluoromethyl)cyclopropyl]phenyl]azetidine trifluoroacetate

This product was prepared by analogy with BB26, an intermediate, from tert-butyl 3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carboxylate as a yellow oil. MS (ESI): m/z is 242.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carboxylate

This product was prepared analogously to BB37, an intermediate, from 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene (CAS RN 1227160-18-0) as a yellow oil. MS (ESI): m/z is 286.0 [M-C ₄ H ₈ +H] ⁺ .

BB46

3-(3-Fluoro-4-(trifluoromethoxy)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained in analogy to BB28 from tert-butyl 3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 236.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with BB37, an intermediate, from 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (CAS RN 105529-58-6) as a colorless oil. MS (ESI): m/z is 280.1 [M-C ₄ H ₈ +H] ⁺ .

BB47

3-(3-Methyl-4-(trifluoromethoxy)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 232.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with BB37, an intermediate, from 4-bromo-2-methyl-1-(trifluoromethoxy)benzene (CAS RN 887268-26-0) as a colorless oil. MS (ESI): m/z is 276.2 [M-C ₄ H ₈ +H] ⁺ .

BB48

3-(3,5-Difluoro-4-(trifluoromethoxy)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(3,5-difluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 254.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3,5-Difluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

This product was prepared in analogy to BB37, an intermediate, from 5-bromo-1,3-difluoro-2-(trifluoromethoxy)benzene (CAS RN 115467-07-7) as a colorless solid. MS (ESI): m/z is 298.1 [M-C ₄ H ₈ +H] ⁺ .

BB49

3-(2-Chloro-4-(trifluoromethoxy)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(2-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 252.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(2-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with BB37, an intermediate, from 1-bromo-2-chloro-4-(trifluoromethoxy)benzene (CAS RN 892845-59-9) as a colorless oil. MS (ESI): m/z is 296.1 [M-C ₄ H ₈ +H] ⁺ .

BB50

3-(4-(Bicyclo[1.1.1]pentan-1-yl)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(4-(bicyclo[1.1.1]pentan-1-yl)phenyl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 200.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(4-(bicyclo[1.1.1]pentan-1-yl)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with BB37, an intermediate, from 1-(4-bromophenyl)bicyclo[1.1.1]pentane (CAS RN 1823935-76-7) as a colorless oil. MS (ESI): m/z is 244.2 [M-C ₄ H ₈ +H] ⁺ .

BB51

5-(Azetidin-3-yl)-2-(trifluoromethoxy)benzonitrile 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(3-cyano-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a light brown gum. MS (ESI): m/z is 243.1 [M+H] ⁺ . This compound was used in the next step without further purification.

Intermediate connection:

tert-Butyl-3-(3-cyano-4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

This product was prepared in analogy to BB37, an intermediate, from 5-bromo-2-(trifluoromethoxy)benzonitrile (CAS RN 1210906-15-2) as a light yellow oil. MS (ESI): m/z is 287.1 [M-C ₄ H ₈ +H] ⁺ .

BB52

(1-(4-(Azetidin-3-yl)phenyl)cyclopropyl)methanol hydrochloride

HCl in 4 M dioxane (330 µl , 1.32 mmol) and this mixture was stirred at RT for 3 hours. Diethyl ether (2 ml) was added to the light yellow suspension and this oily mixture was evaporated to give the desired compound as a light yellow oil. MS (ESI): m/z is 204.2 [M+H] ⁺ . This compound was used in the next step without further purification.

Intermediates:

a) tert-Butyl-3-(4-(1-(hydroxymethyl) cyclopropyl) phenyl) azetidine-1-carboxylate

To an ice-cold solution of tert-butyl 3-(4-(1-(methoxycarbonyl)cyclopropyl)phenyl)azetidine-1-carboxylate (238 mg, 718 µmol) in THF (2 ml) was added dropwise a solution of 1 M LAH in THF ( 718 µl, 718 µmol). This solution was stirred at 0°C for 1.25 hours and then poured into a half-saturated aqueous solution of NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated.

The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc (100:0 to 50:50) to give the desired compound as a colorless oil (0.151 g; 69.3%). MS (ESI): m/z is 248.2 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-3-(4-(1-(methoxycarbonyl)cyclopropyl)phenyl)azetidine-1-carboxylate

This product was prepared in analogy to Method A7 from methyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (CAS RN 638220-35-6) and tert-butyl 3-bromomazetidine-1-carboxylate (CAS RN 1064194-10 -0) as a colorless solid. MS (ESI): m/z is 276.2 [M-C ₄ H ₈ +H] ⁺ .

BB53

4-(Azetidin-3-yl)-1-methyl-1H-indazole hydrochloride

This product was obtained by analogy with BB52 from tert-butyl-3-(1-methyl-1H-indazol-4-yl)azetidine-1-carboxylate as a light yellow solid. MS (ESI): m/z is 188.2 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-(1-methyl-1H-indazol-4-yl)azetidine-1-carboxylate

This product was prepared in analogy to Method A7 from 4-bromo-1-methyl-1H-indazole (CAS RN 365427-30-1) and tert-butyl-3-bromazetidine-1-carboxylate (CAS RN 1064194-10-0) as a light brown oil. MS (ESI): m/z is 232.1 [M-C ₄ H ₈ +H] ⁺ .

BB54

3-[4-(Trifluoromethoxy)phenyl]pyrrolidine trifluoroacetate

This product was prepared by analogy with BB26, an intermediate, from tert-butyl 3-[4-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate as a light brown solid. MS (ESI): m/z is 232.6 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-[4-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate

This product was prepared by analogy with BB17, an intermediate, from tert-butyl 3-[4-(trifluoromethoxy)phenyl]-2,5-dihydropyrrole-1-carboxylate as a light yellow oil (200 mg, 66.3% ). MS (ESI): m/z is 276.5 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-3-[4-(trifluoromethoxy)phenyl]-2,5-dihydropyrrole-1-carboxylate

To a solution of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 3.15 mmol, CAS RN 630121-86-7) and 4 -(trifluoromethoxy)phenylboronic acid (973.57 mg, 4.73 mmol, CAS RN 139301-27-2), Na ₂ CO ₃ (668.1 mg, 6.3 mmol) in 1,4-dioxane (20 ml ) and water (5 ml) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (461.24 mg, 0.630 mmol) and the mixture was stirred at 100°C under N ₂ atmosphere for 12 h This reaction mixture was concentrated and purified by silica gel chromatography (PE:EtOAc - 20:1) to give the desired product as a light yellow oil (320 mg, 30.8%). MS (ESI): m/z is 274.5 [M-C ₄ H ₈ +H] ⁺ .

BB55

Tributyl-(3-chloro-2-pyridyl)stannan

To a solution of 2-bromo-3-chloropyridine (576.0 mg, 2.99 mmol, CAS RN 96424-68-9) in toluene (20 ml) under N2 was added dropwise 2.5 M n-BuLi in hexane (1 .32 ml, 3.29 mmol) at -78°C. This reaction mixture was stirred for 2 h followed by the addition of tributyltin chloride (1071.73 mg, 3.29 mmol, CAS RN 1461-22-9). This reaction mixture was stirred 2 h at -78°C, heated to RT, stirred for another 12 h and then extinguished with a saturated solution of NH ₄ Cl (50 ml). This reaction mixture was extracted with EtOAc (30 ml three times) and the combined organic layers were washed with brine (15 ml), dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated in vacuo to the desired product as a light yellow oil (1.1 g, 91.3%). MS (ESI): m/z is 404.1 [M+H] ⁺ .

BB56

6-(Azetidin-3-yl)-1-methyl-1H-indazole hydrochloride

This product was obtained by analogy with BB52 from tert-butyl-3-(1-methyl-1H-indazol-6-yl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 188.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-(1-methyl-1H-indazol-6-yl)azetidine-1-carboxylate

This product was prepared in analogy to Method A7 from 6-bromo-1-methyl-1H-indazole (CAS RN 365427-30-1) and tert-butyl-3-bromazetidine-1-carboxylate (CAS RN 1064194-10-0) as a light yellow oil. MS (ESI): m/z is 288.2 [M+H] ⁺ .

BB57

(4aR,8aS)-6-[3-[3-(Trifluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4 ]oxazin-3-one

This product was prepared in analogy to Method A4 using 3-[3-(trifluoromethoxy)phenyl]pyrrolidine-2,2,2-trifluoroacetate to give the desired product as a light yellow solid. MS (ESI): m/z is 414.3 [M+H] ⁺ .

Intermediates:

a) 3-[3-(Trifluoromethoxy)phenyl]pyrrolidine trifluoroacetate

This product was prepared by analogy with BB26, an intermediate, from tert-butyl 3-[3-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate as a light brown oil. MS (ESI): m/z is 232.6 [M+H] ⁺ .

b) tert-Butyl-3-[3-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate

This product was prepared in analogy to BB54, an intermediate, from tert-butyl 3-[3-(trifluoromethoxy)phenyl]-2,5-dihydropyrrole-1-carboxylate to give the desired product as a light yellow oil. MS (ESI): m/z is 276.5 [M-C ₄ H ₈ +H] ⁺ .

c) tert-Butyl-3-[3-(trifluoromethoxy)phenyl]-2,5-dihydropyrrole-1-carboxylate

This product was prepared analogously to BB54, an intermediate, from 3-(trifluoromethoxy)phenylboronic acid (CAS RN 179113-90-7) to give the desired product as a light brown oil. MS (ESI): m/z is 274.5 [M-C ₄ H ₈ +H] ⁺ .

BB58

2-Methyl-3-(4-(trifluoromethoxy)phenyl)azetidine 2,2,2-trifluoroacetate

This product was prepared by analogy with BB26, an intermediate, from tert-butyl 2-methyl-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a crude material. MS (ESI): m/z is 232.2 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-2-methyl-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

A solution of tert-butyl-(Z)-3-(2-((4-methoxyphenyl)sulfonyl)hydrazinelidene)-2-methylazetidine-1-carboxylate (265.5 mg, 719 µmol) and (4 -(trifluoromethoxy)phenyl)boronic acid (222 mg, 1.08 mmol, CAS RN 139301-27-2) in dioxane (2.87 ml). Cesium carbonate (351 mg, 1.08 mmol) was added to this solution. The RM was degassed with argon, the flask was sealed and heated with stirring to 110° C. for 18 hours. The RM was cooled to RT before quenching with 2 ml saturated aqueous NaHCO ₃ and extracted three times with DCM. The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the desired product as a yellow oil (71.1 mg; 29.9%). MS (ESI): m/z is 276.2 [M-C ₄ H ₈ +H] ⁺ .

b) tert-butyl-(Z)-3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)-2-methylazetidine-1-carboxylate

A solution of 4-methoxybenzenesulfonohydrazide (180 mg, 890 µmol, CAS RN 1950-68-1) and tert-butyl 2-methyl-3-oxoazetidine-1-carboxylate (165 mg, 890 µmol, CAS RN 1408076-36-7) in DMSO d6 (593 μl) was heated to 60° C. with stirring for 1 h. This reaction mixture was cooled to RT and poured onto stirred H ₂ O, releasing a white precipitate. The precipitate was filtered and redissolved in MeOH. The solvent was removed in vacuo to give the desired product as a yellow oil (265.5 mg; 80.7%). MS (ESI): m/z is 368.3 [M-H] ^- .

BB59

3-(3,3-Dimethyl-2,3-digibrobenzofuran-6-yl)azetidine4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)azetidine-1-carboxylate as a colorless solid. MS (ESI): m/z is 204.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)azetidine-1-carboxylate

This product was obtained by analogy with Method A7 from 6-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (CAS RN 140896-85-1) as a colorless solid. MS (ESI): m/z is 248.2 [M-C ₄ H ₈ +H] ⁺ .

BB60

3-(3-Chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carboxylate as a colorless oil. MS (ESI): m/z is 280.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carboxylate

This product was obtained by analogy with Method A7 from 1-bromo-3-chloro-5-(2,2,2-trifluoroethoxy)benzene as a colorless oil. MS (ESI): m/z is 324.1 [M-C ₄ H ₈ +H] ⁺ .

b) 1-Bromo-3-chloro-5-(2,2,2-trifluoroethoxy)benzene

To a solution of 3-bromo-5-chlorophenol (330 mg, 1.59 mmol, CAS RN 56962-04-0) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (554 mg, 2.39 mmol) in DMF (3 mL) was added potassium carbonate (440 mg, 3.18 mmol) and this mixture was stirred at 50° C. over the weekend. After cooling, this reaction mixture was poured into water and EtOAc, and these layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed twice with water, dried over MgSO ₄ , filtered and evaporated to give the desired compound as a colorless oil (0.484 g; 100%). The compound was used in the next step without further purification.

BB61

Methyl 2-(4-(azetidin-3-yl)phenyl)-2-methylpropanoate 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(4-(1-methoxy-2-methyl-1-oxopropan-2-yl)phenyl)azetidine-1-carboxylate as a colorless gum. MS (ESI): m/z is 234.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)azetidine-1-carboxylate

This product was prepared analogously to Method A7 from methyl 2-(4-bromophenyl)-2-methylpropanoate (CAS RN 154825-97-5) as a light yellow oil. MS (ESI): m/z is 278.2 [M-C ₄ H ₈ +H] ⁺ .

BB62

3-(3,5-Dichlorophenyl)pyrrolidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(3,5-dichlorophenyl)pyrrolidine-1-carboxylate as a brown oil. MS (ESI): m/z is 216.0 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3,5-dichlorophenyl)pyrrolidine-1-carboxylate

This product was obtained by analogy with method A7 from 1-bromo-3,5-dichlorobenzene (CAS RN 19752-55-7) as a colorless oil. MS (ESI): m/z is 260.1 [M-C ₄ H ₈ +H] ⁺ .

BB63

2-[4-(Azetidin-3-yl)phenyl]-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole-2,2,2-trifluoroacetate

This product was obtained by analogy with BB26 - an intermediate compound - from tert-butyl-3-[4-[5-(2,2-dimethyl propyl)-1,3,4-oxadiazol-2-yl]phenyl]azetidine-1 -carboxylate as a light brown oil. MS (ESI): m/z is 272.6 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl]phenyl]azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 2-(4-bromophenyl)-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole as a light brown oil. MS (ESI): m/z is 372.5 [M+H] ⁺ .

b) 2-(4-Bromophenyl)-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole

To a solution of 4-bromo-N'-(3,3-dimethylbutanoyl)benzohydrazide (5 g, 15.96 mmol) in toluene (102 ml) was added p-toluenesulfonic acid (5.5 g, 31.93 mmol), then stirred at 110° C. for 12 hours. LCMS indicated that the reaction was complete, this mixture was concentrated and the residue was purified by silica gel chromatography eluting with PE:EtOAc - 10:1 to give the desired product as a light yellow solid (1 g, 21.2%). MS (ESI): m/z is 295.4 [M+H] ⁺ .

c) 4-Bromo-N'-(3,3-dimethylbutanoyl)benzohydrazide

3,3-Dimethylbutyryl chloride ( 3.76 g, 27.9 mmol, CAS RN 7065-46-5) at 0°C, this mixture was stirred at 20°C for 12 hours. The aqueous layer was extracted with EtOAc (200 ml, 3 times) and water (100 ml, 3 times). The separated organic layer was washed with water, dried over Na ₂ SO ₄ and evaporated to give the desired product as a light yellow solid (7 g, 96.1%). MS (ESI): m/z is 315.4 [M+H] ⁺ .

BB64

3-(4-(tert-Butyl)-3-methoxyphenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(4-(tert-butyl)-3-methoxyphenyl)azetidine-1-carboxylate as a crude material.

MS (ESI): m/z is 220.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(4-(tert-butyl)-3-methoxyphenyl)azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 4-bromo-1-(tert-butyl)-2-methoxybenzene (CAS RN 30788-02-4) as a light yellow oil. MS (ESI): m/z is 264.2 [M-C ₄ H ₈ +H] ⁺ .

BB65

3-(Azeidin-3-yl)-1-methyl-1H-indazole 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(1-methyl-1H-indazol-5-yl)azetidine-1-carboxylate as a crude material. MS (ESI): m/z is 188.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(1-methyl-1H-indazol-5-yl)azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 5-bromo-1-methyl-1H-indazole (CAS RN 465529-57-1) as a yellow oil. MS (ESI): m/z is 288.2 [M+H] ⁺ .

BB66

3-(4-Propylphenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl 3-(4-propylphenyl)azetidine-1-carboxylate as a crude material. MS (ESI): m/z is 176.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(4-propylphenyl)azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 1-bromo-4-propylbenzene (CAS RN 588-93-2) as a light yellow oil. MS (ESI): m/z is 220.2 [M-C ₄ H ₈ +H] ⁺ .

BB67

3-(4-(Trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carboxylate as a crude material. MS (ESI): m/z is 286.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 4-bromo-1-(trifluoromethoxy)-2-(trifluoromethyl)benzene (CAS RN 933674-89-6) as a light yellow oil. MS (ESI): m/z is 330.1 [M-C ₄ H ₈ +H] ⁺ .

BB68

3-[4-[[1-(Trifluoromethyl) cyclopropyl]methoxy]phenyl]azetidine 4-2,2,2-trifluoroacetate

This product was prepared in analogy to BB26, an intermediate, from tert-butyl 3-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]azetidine-1-carboxylate as a yellow oil. MS (ESI): m/z is 272.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]azetidine-1-carboxylate

This product was obtained in analogy with method A7 from 1-bromo-4-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzene (CAS RN 1594130-28-5) as a light yellow oil. MS (ESI): m/z is 316.1 [M-C ₄ H ₈ +H] ⁺ .

BB69

3-[4-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)phenyl]azetidine 2,2,2-trifluoroacetate

This product was prepared by analogy with BB26, an intermediate, from tert-butyl 3-[4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)phenyl]azetidine-1-carboxylate as a yellow oil. MS (ESI): m/z is 244.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)phenyl]azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 1-bromo-4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)benzene (CAS RN 1225380-05-1) as a light yellow oil. MS (ESI): m/z is 288.1 [M-C ₄ H ₈ +H] ⁺ .

BB70

3-[4-(Azetidin-3-yl)phenyl]-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole 2,2,2-trifluoroacetate

This product was obtained by analogy with BB26 - an intermediate compound - from tert-butyl-3-[4-[5-(2,2-dimethyl propyl)-1,2,4-oxadiazol-3-yl]phenyl]azetidine-1 -carboxylate in the form of a light yellow oil. MS (ESI): m/z is equal to 272.6 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]phenyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-[4-(N-hydroxycarbomimidail)phenyl]azetidine-1-carboxylate (770.0 mg, 2.64 mmol) and DIPEA (1.41 ml, 7.93 mmol) in toluene ( 6 ml) was added 3,3-dimethylbutyryl chloride (426.88 mg, 3.17 mmol, CAS RN 7065-46-5) at 0°C, this mixture was stirred at 25°C for 10 min, then the temperature was increased to 80 °C and stirred for 12 hours. This mixture was evaporated and the residue was purified by chromatography on silica gel (PE : EtOAc - 10:1) to obtain the desired product as a light brown oil (620 mg, 63.2%). MS (ESI): m/z is 316.5 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-3-[4-(N-hydroxycarbamimidoyl)phenyl]azetidine-1-carboxylate

To a solution of hydroxylamine hydrochloride (349.71 mg, 5.03 mmol) in ethanol (8 ml) was added sodium carbonate (266.69 mg, 2.52 mmol) in water (2 ml) and stirred at 20°C for 25 min. Then tert-butyl 3-(4-cyanophenyl)azetidine-1-carboxylate (1000.0 mg, 3.87 mmol, CAS RN 206446-41-5) was added, the mixture was stirred at 95°C for 12 hours.

This mixture was diluted with water, concentrated in vacuo to remove EHN, the residue was partitioned between EtOAc (100 ml) with water (100 ml × 3), then saturated sodium chloride (50 ml), dried over sodium sulfate and evaporated to obtain the desired product as light yellow oil (773 mg, 68.5%). MS (ESI): m/z is 292.5 [M+H] ⁺ .

BB71

(4aR,8aS)-6-[3-[4-(2,2,2-Trifluoro-1-methyl-ethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one

This product was obtained by analogy with method A4 from 3-[4-(2,2,2-trifluoro-1-methyl-ethoxy)phenyl]azetidine 2,2,2-trifluoroacetate as a light yellow solid. MS (ESI): m/z is 428.3 [M+H] ⁺ .

Intermediates:

a) 3-[4-(2,2,2-Trifluoro-1-methyl-ethoxy)phenyl]azetidine 2,2,2-trifluoroacetate

This product was prepared by analogy with BB26, an intermediate, from tert-butyl 3-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-azetidine-1-carboxylate as a light yellow oil. MS (ESI): m/z is 246.1 [M+H] ⁺ .

b) tert-Butyl-3-[4-(2,2,2-trifluoro-1-methyl-ethoxy)phenyl]azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 1-bromo-4-(2,2,2-trifluoro-1-methyl-ethoxy)benzene (CAS RN 1239611-43-8) as a colorless solid. MS (ESI): m/z is 290.1 [M-C ₄ H ₈ +H] ⁺ .

BB72

3-(3-Methoxy-4-methylphenyl)azetidine 4-methylbenzenesulfonate

This product was obtained by analogy with BB28 from tert-butyl-3-(3-methoxy-4-methylphenyl)azetidine-1-carboxylate as a colorless solid.

MS (ESI): m/z is 178.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(3-methoxy-4-methylphenyl)azetidine-1-carboxylate

This product was obtained by analogy with method A7 from 4-bromo-2-methoxy-1-methylbenzene (CAS RN 67868-73-9) as a light brown oil. MS (ESI): m/z is 222.1 [M-C ₄ H ₈ +H] ⁺ .

BB73

4-((4-Fluorophenyl)((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)piperidine hydrochloride

This product was obtained by analogy with BB16 from tert-butyl-4-((4-fluorophenyl)((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)piperidine-1-carboxylate in as a colorless foam (0.194 g; 98.0%). MS (ESI): m/z is 358.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-((4-fluorophenyl)((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)piperidine-1-carboxylate

To a yellow solution of tri-n-butylphosphine (327 mg, 399 μl, 1.62 mmol) and azodicarboxylic dipiperidide (408 mg, 1.62 mmol) in toluene (12.5 ml) was added tert-butyl-4-((4 -fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (250 mg, 808 µmol, CAS RN 160296-41-3), and this mixture was stirred at RT for 20 min. This resulted in a pale yellow solution. Addition of 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol (268 mg, 1.62 mmol, CAS RN 119022-51-4) gave a suspension. After stirring at RT for 75 minutes, heat was set. After stirring at 65° C. for 19 hours, the reaction mixture was cooled to RT. Silica gel was added and the mixture was evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system (ISCO) eluting with a gradient of n-heptane: EtOAc (100:0 to 50:50) to give the desired compound as a colorless gum (0.230 g; 62.2 %). MS (ESI): m/z is 358.2 [M-Boc+H] ⁺ .

BB74

3-[1-[4-Trifluoromethyl)phenyl]ethoxy]azetidine

TFA (0.178 ml, 2 .32 mmol) and the reaction mixture was stirred at RT for 30 min. The solvent was removed under reduced pressure and the residue was taken up in EtOAc, poured into sat. aq. Na ₂ CO ₃ solution (5 ml) and the aqueous layer was extracted twice with EtOAc (each time 10 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude title compound (0.025 g, 88%) as a colorless gum; MS (ESI): m/z is 246.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[1-[4-(trifluoromethyl)phenyl]ethoxy]azetidine-1-carboxylate

NaH (60% in mineral oil; 0.023 g, 0.577 mmol) and this reaction mixture was stirred at this temperature for 15 minutes. Then 1-(1-bromoethyl)-4-(trifluoromethyl)benzene (0.161 g, 0.635 mmol, CAS RN 68120-42-3) was added and the mixture was allowed to warm to RT and stirring continued overnight. This mixture was poured into sat. aq. ammonium chloride solution (15 ml) and extracted twice with EtOAc (each time 20 ml). The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a gradient of EtOAc in n-heptane (0% to 70%) to give the title compound (0.045 g, 22.6%) as a colorless amorphous solid. MS (ESI): m/z is 290.2 [M-C ₄ H ₈ +H] ⁺ .

BB75

4-[1-[4-(Trifluoromethyl)phenyl]ethoxy]piperidine hydrochloride

This product was prepared in analogy to BH1 using tert-butyl 4-hydroxypiperidine-1-carboxylate (CAS RN 109384-19-2) in an intermediate step and then a solution of 4 M HCl/dioxane in MeOH instead of TFA/DCM for the deprotection step . Colorless solid; MS (ESI): 274.1 [M+H] ⁺ .

BB76

5-(Azetidin-3-yl)-2-methoxy-pyridine 4-methylbenzenesulfone

This product was prepared in analogy to BB28 using tert-butyl 3-(6-methoxypyridin-3-yl)azetidine-1-carboxylate. Colorless solid. MS (ESI) is equal to 165.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-(6-methoxypyridin-3-yl)azetidine-1-carboxylate

This product was prepared in analogy to BB35, an intermediate, using (6-methoxypyridin-3-yl)boric acid (CAS RN 163105-89-3) as a colorless oil. MS (ESI) is equal to 265.2 [M+H] ⁺ .

BB77

3-[3-Chloro-4-(trifluoromethoxy)phenyl]azetidine 4-methylbenzenesulfonate

This product was prepared in analogy to BB28 using tert-butyl 3-[3-chloro-4-(trifluoromethoxy)phenyl]azetidine-1-carboxylate as a colorless solid; MS (ESI) is equal to 252.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[3-chloro-4-(trifluoromethoxy)phenyl]azetidine-1-carboxylate

This product was prepared in analogy to BB35, an intermediate, using (3-chloro-4-(trifluoromethoxy)phenyl)boronic acid (CAS RN 870822-79-0) as a colorless liquid. MS (ESI) is equal to 296.1 [M-C ₄ H ₈ +H] ⁺ .

BB78

(4aR,8aS)-6-[3-[3-Bromo-4-(trifluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4а,5,7,8,8а-hexahydropyrido[4,3-b] [1,4]oxazin-3-one

This product was prepared in analogy to Example 132 using 3-[3-bromo-4-(trifluoromethoxy)phenyl]azetidine 4-methylbenzenesulfonate as a light yellow solid. MS (ESI) is equal to 480.1 [M+H] ⁺ .

Intermediates:

a) 3-[3-Bromo-4-(trifluoromethoxy)phenyl]azetidine 4-methylbenzenesulfonate

This product was prepared in analogy to BB28 using tert-butyl 3-[3-bromo-4-(trifluoromethoxy)phenyl]azetidine-1-carboxylate as a colorless solid. MS (ESI) is equal to 296.0 [M+H] ⁺ .

b) tert-Butyl-3-[3-bromo-4-(trifluoromethoxy)phenyl]azeidin-1-carboxylate

This product was prepared in analogy to BB35, an intermediate, using (3-bromo-4-(trifluoromethoxy)phenyl)boronic acid (MFCD22580724; Apollo Scientific) as a colorless viscous oil. MS (ESI) is equal to 342.0 [M-C ₄ H ₈ +H] ⁺ .

BB79

3-[3-Fluoro-4-(trifluoromethyl)phenyl]azetidine 4-methylbenzenesulfonate

This product was prepared in analogy to BB28 using tert-butyl 3-[3-fluoro-4-(trifluoromethyl)phenyl]azetidine-1-carboxylate. Colorless solid. MS (ESI): 220.1 [M+H] ⁺ .

Intermediate connection:

tert-butyl-3-[3-fluoro-4-(trifluoromethyl)phenyl]azetidine-1-carboxylate

This product was obtained by analogy with BB37 - intermediate - using 4-bromo-2-fluoro-1-(trifluoromethyl)benzene, as a colorless viscous oil. MS (ESI): 264.1 [M-C ₄ H ₈ +H] ⁺ .

BB80

(4aR,8aS)-6-[4-[(3,4-Dimethoxyphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one

A solution of 2-[(3,4-dimethoxyphenyl)-(4-piperidyl)methyl]pyridine (101 mg, 0.320 mmol), cesium carbonate (97 mg, 0.30 mmol) and (4-nitrophenyl)(4aR,8aS) -3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (80 mg, 0.25 mmol) in DMF (5 ml) was stirred at 25°C for 16 hours This solution was poured into brine (10 ml) and was extracted twice with EtOAc (each time 10 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[4-[(3,4-dimethoxyphenyl)-(2-pyridyl)methyl]piperidine -1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (60 mg, 49%) as a white solid. MS (ESI): m/z is 495.3 [M+H] ⁺ .

Intermediate connections.

a) tert-Butyl-4-(3,4-dimethoxybenzoyl)piperidine-1-carboxylate

To a solution of 4-bromoveratrol (12.4 g, 57.3 mmol) in THF (200 ml) at -78°C was added a solution of butyllithium (28.6 ml, 71.6 mmol) and this solution was stirred at -78° C for 1 h. Then tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (CAS Nr. 139290-70-3) (13.0 g, 47.7 mmol) was added at -78 °C, and stirring was continued at -78°C for 5 hours This solution was poured into brine (20 ml) and was extracted with EtOAc (2×10 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by flash column chromatography (PE : EtOAc - 2:1) to give the title compound as a white solid. MS (ESI): m/z is 372.1 [M+Na] ⁺ .

b) tert-Butyl-4-[C-(3,4-dimethoxyphenyl)-N-(p-tolylsulfonylamino)carbonimidoyl]piperidine-1-carboxylate

Solution of 4-methylbenzenesulfonhydrazide (6.40 g, 34.3 mmol) and tert-butyl 4-(3,4-dimethoxybenzoyl)piperidine-1-carboxylate (10.0 g, 28.6 mmol) in 1,4-dioxane (200 ml) was stirred at 80° C. for 24 hours. This reaction solution was concentrated in vacuo to give a residue, which was purified by flash column chromatography (petroleum ether: EtOAc - 2:1) to give the compound indicated in title (8, 0 g, 54%), as a light yellow solid. MS (ESI): m/z is 540.2 [M+Na] ⁺ .

c) tert-Butyl-4-[(3,4-dimethoxyphenyl)-(2-pyridyl)methylene]piperidine-1-carboxylate

A mixture of 2-bromopyridine (1.11 ml, 11.6 mmol), tert-butyl-4-[C-(3,4-dimethoxyphenyl)-N-(p-tolylsulfonylamino)carbonimidoyl]piperidine-1-carboxy (3, 00 g, 5.8 mmol), lithium tert-butoxide (557 mg, 6.95 mmol) and bis(triphenylphosphine)palladium(II) chloride (407 mg, 0.580 mmol) in 1,4-dioxane (37 ml) were stirred at 90°C for 16 h under N2. The solids were filtered off and this solution was poured into brine (30 ml) and then extracted with EtOAc (2×20 ml). The combined organic layers were concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether:EtOAc - 1:1) to give the desired compound as a colorless oil (280 mg, 12%). MS (ESI): m/z is 411.3 [M+H] ⁺ .

d) 2-[(3,4-Dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine

A solution of tert-butyl 4-[(3,4-dimethoxyphenyl)-(2-pyridyl)methylene]piperidine-1-carboxylate (280 mg, 0.680 mmol) and trifluoroacetic acid (0.53 ml, 6.82 mmol) in DCM (10 ml) was stirred at 25° C. for 4 hours. This solution was concentrated in vacuo to give the title compound as a colorless oil (200 mg, 94%). MS (ESI): m/z is 311.1 [M+H] ⁺ .

e) 2-[(3,4-Dimethoxyphenyl)-(4-piperidyl)methyl]pyridine

A solution of 2-[(3,4-dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine (200 mg, 0.640 mmol) and Pd/C (69 mg, 0.060 mmol) in DMF (5 mo) was stirred at 25°C for for 6 hours under H ₂ (760 mm Hg). This solution was concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give the compound as a colorless oil (150 mg, 71%). MS (ESI): m/z is 313.3 [M+H] ⁺ .

BB81

d) (4aR,8aS)-6-[4-[(3,4-Dimethoxyphenyl)-(3-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one

Solution of 3-[(3,4-dimethoxyphenyl)-(4-piperidyl)methyl]pyridine (126 mg, 0.400 mmol), cesium carbonate (122 mg, 0.370 mmol) and (4-nitrophenyl)(4aR,8aS)-3 -ox-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (100 mg, 0.310 mmol) in DMF (5 ml ) was stirred at 25° C. for 16 hours. This solution was poured into brine (10 ml) and extracted with EtOAc (2×10 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give the desired compound as a white solid (80 mg, 52%). MS (ESI): m/z is 495.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[(3,4-dimethoxyphenyl)-(3-pyridyl)methylene]piperidine-1-carboxylate

t-Butyl 4-[C-(3,4-dimethoxyphenyl)-N-(p-tolylsulfonylamino)carbonimidoyl]piperidine-1-carboxylate mixture (intermediate b, examples 118/119) (2.00 g, 3. 86 mmol), 3-bromopyridine (0.56 ml, 5.8 mmol), lithium tert-butoxide (464 mg, 5.8 mmol) and bis(triphenylphosphine)palladium (I) chloride (271 mg, 0.390 mmol) in DMF (30 ml) was stirred at 90°C for 16 h under N ₂ . This mixture was filtered and the filtrate was poured into brine (50 ml) and then extracted with EtOAc (2×40 ml).

The combined organic layers were concentrated in vacuo to give a residue which was purified by flash column chromatography (petroleum ether: EtOAc - 2:1). tert-Butyl 4-[(3,4-dimethoxyphenyl)-(3-pyridyl)methylene]piperidine-1-carboxylate was obtained as a colorless oil (600 mg, 38%). MS (ESI): m/z is 411.2 [M+H] ⁺ .

b) 3-[(3,4-Dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine trifluoroacetate

A solution of tert-butyl 4-[(3,4-dimethoxyphenyl)-(3-pyridyl)methylene]piperidine-1-carboxylate (600 mg, 1.46 mmol) and trifluoroacetic acid (1.13 ml, 15 mmol) in DCM (10 ml) was stirred at 25° C. for 4 h. This solution was concentrated in vacuo to give crude 3-[(3,4-dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine (450 mg, 49% as TFA salts) as a brown oil, which was used directly in the next step. MS (ESI): m/z is 311.1 [M+H] ⁺ .

c) 3-[(3,4-Dimethoxyphenyl)-(4-piperidyl)methyl]pyridine

A mixture of 3-[(3,4-dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine (450 mg, 0.710 mmol) and Pd/C (38 mg, 0.040 mmol) in DMF (10 mL) was stirred at 25°C for for 16 hours under H ₂ (760 mm Hg). This mixture was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA condition) to give the desired compound as a colorless oil (220 mg, 99%). MS (ESI): m/z is 313.2 [M+H] ⁺ .

BB82

(4aR,8aS)-6-[4-[(3,4-Dimethoxyphenyl)-(4-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one

Solution of 4-[(3,4-dimethoxyphenyl)-(4-piperidyl)methyl]pyridine (100 mg, 0.320 mmol), cesium carbonate (97 mg, 0.30 mmol) and (4-nitrophenyl)(4aR,8aS) -3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (80 mg, 0.25 mmol) in DMF (4 ml) was stirred at 25° C. for 16 h. This solution was poured into brine (10 ml) and extracted twice with EtOAc (each time 10 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give the title compound as a white solid (60 mg, 49%). MS (ESI): m/z is 495.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[(3,4-dimethoxyphenyl)-(4-pyridyl)methylene]piperidine-1-carboxylate

A mixture of 4-bromopyridine (0.56 ml, 5.8 mmol), tert-butyl-4-[C-(3,4-dimethoxyphenyl)-N-(p-tolylsulfonylamino)carbonimidoyl]piperidine-1-carboxylate (intermediate b, examples 118/119) (2.00 g, 3.86 mmol), lithium tert-butoxide (464 mg, 5.8 mmol) and bis(triphenylphosphine)palladium(II) chloride (271 mg, 0.390 mmol) in DMF (30 ml) was stirred under N ₂ at 90°C for 16 hours This mixture was filtered and the filtrate was poured into brine (30 ml) and then was extracted with EtOAc (2×20 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by flash column chromatography (petroleum ether: EtOAc - 2:1). tert-Butyl 4-[(3,4-dimethoxyphenyl)-(4-pyridyl)methylene]piperidine-1-carboxylate (400 mg, 25%) was obtained as a colorless oil. MS (ESI): m/z is 411.3 [M+H] ⁺ .

b) 4-[(3,4-Dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine

A solution of tert-butyl 4-[(3,4-dimethoxyphenyl)-(4-pyridyl)methylene]piperidine-1-carboxylate (400 mg, 0.970 mmol) and trifluoroacetic acid (0.75 ml, 9.7 mmol) in DCM (15 ml) was stirred at 25° C. for 4 h. This solution was concentrated in vacuo to give crude 4-[(3,4-dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine (as TFA salt; 250 mg , 83%) as a brown oil, which was used directly in the next step. MS (ESI): m/z is 311.2 [M+H] ⁺ .

f) 4-[(3,4-Dimethoxyphenyl)-(4-piperidyl)methyl]pyridine

A mixture of 4-[(3,4-dimethoxyphenyl)-(4-piperidylidene)methyl]pyridine (250 mg, 0.810 mmol) and Pd/C (43 mg, 0.040 mmol) in DMF (6 mL) was stirred at 25°C for for 16 hours under H ₂ (760 mm Hg). This mixture was filtered and concentrated in vacuo to give a residue which was purified by prep HPLC (TFA conditions) to give 4-[(3,4-dimethoxyphenyl)-(4-piperidyl)methyl]pyridine (200 mg, 79%) as colorless oil. MS (ESI): m/z is 313.2 [M+H] ⁺ .

BB83

(4aR,8aS)-6-[4-[(3-Methylsulphunylphenyl)-(3-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one

Solution of 3-[(3-methylsulfonylphenyl)-(4-piperidyl)methyl]pyridine (110 mg, 0.330 mmol) and (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (160 mg, 0.500 mmol) in pyridine (5.5 ml) was stirred at 90°C for 16 h This solution was concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[4-[(3-methylsulfonylphenyl)-(3-pyridyl)methyl]piperidine-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (95 mg, 61%) as a white solid. MS (ESI): m/z is 513.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[N-(p-tolylsulfonylamino)-C-(3-pyridyl)carbonimidoyl]piperidine-1-carboxylate

A solution of 4-methylbenzenesulfonhydrazide (1.54 g, 8.27 mmol) and tert-butyl 4-(pyridine-3-carbonyl)piperidine-1-carboxyate (CAS Nr. 148148-35-0) (2.00 g, 689 mmol) in 1,4-dioxane (200 ml) was stirred at 80° C. for 16 h. This reaction mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography (petroleum ether: EtOAc - 2:1), to give 7-butyl-4-[N-(p-tolylsulfonylamino)-C-(3-pyridyl)carbonimidoyl]piperidine-1-carboxylate (2.0 g, 63%) as a yellow solid. MS (ESI): m/z is 403.1 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-4-[(3-methylsulfonylphenyl)-(3-pyridyl)methylene]piperidine-1-carboxylate

A solution of 3-bromophenylmethyl sulfone (1.54 g, 6.54 mmol), tert-butyl-4-[N-(p-tolylsupfonylamino)-C-(3-pyridyl)carbonimidoyl]piperidine-1-carboxylate (2.00 g , 4.36 mmol), lithium tert-butoxide (524 mg, 6.54 mmol) and bis(triphenylphosphine)palladium(II) chloride (918 mg, 1.31 mmol) in 1,4-dioxane (30 ml) were stirred at 90°C for 16 hours This reaction mixture was diluted with EtOAc (20 ml) and then filtered through celite. The filtrate was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: EtOAc - 20:1 to 1:1) to give tert-butyl 4-[(3-methylsulfonylphenyl)-(3-pyridyl)methylene]piperidine-1-carboxylate (400 mg , 21%) as a light yellow oil. MS (ESI): m/z is 429.2 [M+H] ⁺ .

c) tert-Butyl-4-[(3-methylsulfonylphenyl)-(3-pyridyl)methyl]piperidine-1-carboxylate

Mixture of tert-butyl 4-[(3-methylsulfonylphenyl)-(3-pyridyl)methylene]piperidine-1-carboxylate (350 mg, 0.820 mmol) and Pd/C (43 mg, 0.410 mmol) in DMF (10 mL) stirred at 25°C for 16 h under H2 (760 mm Hg). This mixture was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (basic conditions) to give tert-butyl 4-[(3-methylsulfonylphenyl)-(3-pyridyl)methyl]piperidine-1-carboxylate (80 mg, 23%) as a colorless oil, and isolation of the starting material (300 mg). The isolated starting material was hydrogenated again using the same conditions as above to give a second batch of product (110 mg, 31%) as a colorless oil. Total yield 190 mg (54%). MS (ESI): m/z is 375.0 [M-C ₄ H ₈ +H] ⁺ .

d) 3-[(3-Methylsulfonylphenyl)-(4-piperidyl)methyl]pyridine

A solution of tert-butyl 4-[(3-methylsulfonylphenyl)-(3-pyridyl)methyl]piperidine-1-carboxylate (220.0 mg, 0.510 mmol) and trifluoroacetic acid (0.2 ml, 2.55 mmol) in DCM (4.4 ml) was stirred at 25° C. for 4 h. This solution was concentrated in vacuo to give 3-[(3-methylsulfonylphenyl)-(4-piperidyl)methyl]pyridine (as TFA salt; 160 mg, quantities) as a colorless oil, which was used in the next step without further purification.

BB84

(4aR,8aS)-6-[4-[(3-Methylsulphunylphenyl)-(4-lyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one

Solution of 4-[(3-methylsulfonylphenyl)-(4-piperidyl)methyl]pyridine (150 mg, 0.450 mmol) and (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (219 mg, 0.680 mmol) in pyridine (6 mL) was stirred at 90°C for 16 h. the solution was concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[4-[(3-methylsulfonylphenyl)-(4-pyridyl)methyl]piperidine-1-carbonyl] -4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (60 mg, 26%) as a colorless oil. MS (ESI): m/z is 513.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[N-(p-tolylsulfonylamino)-C-(4-pyridyl)carbonimidoyl]piperidine-1-carboxylate

Solution of 4-methylbenzenesulfonhydrazide (1.31 g, 7.03 mmol) and tert-butyl 4-(pyridine-4-carbonyl)piperidine-1-carboxylate (CAS Nr. 1334415-27-8) (1.70 g, 5.5 85 mmol) in 1,4-dioxane (170 ml) was stirred at 80° C. for 16 h. obtaining tert-butyl 4-[N-(p-tolylsulfonylamino)-C-(4-pyridyl)carbonimidoyl]piperidine-1-carboxylate (1.60 g, 60%) as a light yellow solid. MS (ESI): m/z is 459.2 [M+H] ⁺ .

b) tert-Butyl-4-[(3-methylsulfonylphenyl)-(4-pyridyl)methylene]piperidine-1-carboxylate

A solution of 3-bromophenylmethylsulfone (1.23 g, 5.23 mmol), tert-butyl-4-[N-(p-tolylsulfonylamino)-C-(4-pyridyl)carbonimidoyl]piperidine-1-carboxylate (1.60 g , 3.49 mmol), lithium tert-butoxide (419 mg, 5.23 mmol) and bis(triphenylphosphine)palladium(II) chloride (735 mg, 1.05 mmol) in 1,4-dioxane (32 ml) were stirred at 90°C for 16 hours This reaction mixture was diluted with EtOAc (5 ml), then filtered through celite. The filtrate was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: EtOAc - 20:1 to 1:1) to give tert-butyl 4-[(3-methylsulfonylphenyl)-(4-pyridyl)methylene]piperidine-1-carboxylate (420 mg , 28%) as a colorless oil. MS (ESI): m/z is 429.2 [M+H] ⁺ .

c) tert-Butyl-4-[(3-methylsulfonylphenyl)-(4-pyridyl)methyl]piperidine-1-carboxylate

Mixture of tert-butyl 4-[(3-methylsulfonylphenyl)-(4-pyridyl)methylene]piperidine-1-carboxylate (320 mg, 0.750 mmol) and Pd/C (795 mg, 0.750 mmol) in DMF (6.4 ml) was stirred at 25°C for 16 h at H ₂ (760 mm Hg). This mixture was filtered and concentrated in vacuo to give t-butyl 4-[(3-methylsulfonylphenyl)-(4-pyridyl)methyl]piperidine-1-carboxylate (280 mg, 87%) as a colorless oil. MS (ESI): m/z is 431.2 [M+H] ⁺ .

d) 4-[(3-Methylsulfonylphenyl)-(4-piperidyl)methyl]pyridine

A solution of tert-butyl 4-[(3-methylsulfonylphenyl)-(4-pyridyl)methyl]piperidine-1-carboxylate (280 mg, 0.650 mmol) and trifluoroacetic acid (0.25 ml, 3.2 mmol) in DCM ( 6 ml) was stirred at 25° C. for 4 h. This solution was concentrated in vacuo to give a residue which was purified by preparative HPLC (basic conditions) to give 4-[(3-methylsulfonylphenyl)-(4-piperidyl)methyl]pyridine (150 mg, 61%) as a colorless oil. MS (ESI): m/z is 331.2 [M+H] ⁺ .

BB85

(4aR,8aS)-6-[4-[(3-Methylsulphunylphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one

A solution of oxone (256 mg, 0.420 mmol) and (4aR,8aS)-6-[4-[(3-methylsulfonylphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7, 8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (100 mg, 0.210 mmol) in water (5 ml) and MeCN (5 ml) were stirred at 25°C for 16 h This solution was poured into sat. aq. Na ₂ CO ₃ (10 ml) and was extracted with EtOAc (2×20 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[4-[(3-methylsulfonylphenyl)-(2-pyridyl)methyl]piperidine-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (60 mg, 56%) as a colorless oil. MS (ESI): m/z is 513.3 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-[hydroxy-(3-methylsulfanylphenyl)-(2-pyridyl)methyl]piperidine-1-carboxylate

To a solution of 3-bromothioanisole (1.00 mg, 4.92 mmol) in THF (30 ml) at -78°C was added a solution of butyllithium (2.36 ml, 5.91 mmol) over a period of 0.5 h. Then tert-butyl 4-(pyridine-2-carbonyl)piperidine-1-carboxylate (CAS Nr. 416852-19-2) (1.43 g, 4.92 mmol) was added and stirring continued at -78°C within 4.5 hours This solution was quenched with sat. aq. NH ₄ Cl (50 ml) and extracted with EtOAc (2×30 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by prep HPLC (TFA conditions) to give t-butyl 4-[hydroxy-(3-methylsulfanylphenyl)-(2-pyridyl)methyl]piperidine-1-carboxylate (1 .40 g, 69%) as a colorless oil. MS (ESI): m/z is 415.2 [M+H] ⁺ .

b) 2-[Chloro-(3-methylsulfanylphenyl)-(4-piperidyl)methyl]pyridine

A mixture of tert-butyl 4-[hydroxy-(3-methylsulfanylphenyl)-(2-pyridyl)methyl]piperidine-1-carboxylate (300 mg, 0.720 mmol), sulfur dichloride (86 mg, 0.72 mmol) in Tol ( 5 ml) was stirred at 25°C for 6 h under N ₂ . This mixture was concentrated in vacuo to give 2-[chloro-(3-methylsulfanylphenyl)-(4-piperidyl)methyl]pyridine (220 mg, 91%) as a yellow solid, which was used as the crude in the next step. MS (ESI): m/z is 333.1 [M+H] ⁺ .

f) 2-[(3-Methylsulfanylphenyl)-(4-piperidyl)methyl]pyridine

A mixture of 2-[chloro-(3-methylsulfanylphenyl)-(4-piperidyl)methyl]pyridine (220 mg, 0.660 mmol), ammonium chloride (35 mg, 0.66 mmol) and zinc (238 mg, 3.64 mmol) in MeOH (6 ml) was stirred at 25° C. for 0.5 h. -piperidyl)methyl]pyridine (160 mg, 81%) as a colorless oil. MS (ESI): m/z is 299.1 [M+H] ⁺ .

d) (4aR,8aS)-6-[4-[(3-Methylsulfanylphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one

Solution of 2-[(3-methylsulfanylphenyl)-(4-piperidyl)methyl]pyridine (160 mg, 0.540 mmol) and (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (intermediate BB15a) (207 mg, 0.640 mmol) in pyridine (10 ml) was stirred at 90°C for 16 h. the solution was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[4-[(3-methylsulfanylphenyl)-(2-pyridyl)methyl]piperidine-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (200 mg, 78%) as a white solid. MS (ESI): m/z is 481.2 [M+H] ⁺ .

BB86

3-[Phenyl(4-piperidyl)methyl]pyridazine hydrochloride Solution of tert-butyl 4-[phenyl(pyridazin-3-yl)methyl]pipeidine-1-carboxylate (150 mg, 0.420 mmol) and trifluoroacetic acid (0.1 ml, 1.3 mmol) in DCM (3 ml) was stirred at 25° C. for 4 h. This solution was concentrated in vacuo to give a residue which was purified by preparative HPLC (HCl conditions) to give 3-[phenyl(4- piperidyl)methyl]pyridazine (as HCl salt, 70 mg, quant.) as a gray solid. MS (ESI): m/z is 254.2 [M+H] ⁺ .

Intermediates:

tert-Butyl-4-(chloro-phenyl-pyridazin-3-yl-methyl)piperidine-1-carboxylate

A solution of tert-butyl 4-(pyridazine-3-carbonyl)piperidine-1-carboxylate (CAS Nr. 2044281-15-2) (250 mg, 0.860 mmol) and phenyl magnesium bromide (3 M, 0.34 ml, 1, 03 mmol) in THF (6 ml) was stirred at 0°C for 3 h under N ₂ . This solution was poured into brine (20 ml) and extracted with EtOAc (20 ml). The organic layer was concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give tert-butyl 4-(hydroxy-phenyl-pyridazin-3-yl-methyl)-piperidine-1-carboxylate (200 mg, 63% ) as a gray solid. MS (ESI): m/z is 314.1 [M-C ₄ H ₈ +H] ⁺ .

tert-Butyl-4-(chloro-phenyl-pyridazin-3-yl-methyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(hydroxy-phenyl-pyridazin-3-yl-methyl)piperidine-1-carboxylate (200 mg, 0.520 mmol) and sulfur dichloride (306 mg, 2.59 mmol) in Tol (10 ml) stirred at 25°C for 6 hours. This mixture was filtered and concentrated under vacuum to obtain tert-butyl 4-(chloro-phenyl-pyridazin-3-yl-methyl)piperidine-1-carboxylate (200 mg, 99%) as a yellow solid, which was used as a crude substance in the next step. MS (ESI): m/z is 410.2 [M+Na] ⁺ .

tert-Butyl-4-[phenyl(pyridazin-3-yl)methyl]piperidine-1-carboxylate

A solution of tert-butyl 4-(chloro-phenyl-pyridazin-3-yl-methyl)piperidine-1-carboxylate (200 mg, 0.52 mmol), ammonium chloride (28 mg, 0.52 mmol) and zinc (185 mg, 2.84 mmol) in MeOH (4.7 ml) was stirred at 25° C. for 0.5 h. This mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give t-butyl -4-[phenyl(pyridazin-3-yl)methyl]piperidine-1-carboxylate (150 mg, 82%) as a yellow solid. MS (ESI): m/z is 298.1 [M-C ₄ H ₈ +H] ⁺ .

BB87

3-[4-(3-Fluoroppyl)phenyl]azetidine

Solution of tert-butyl 3-[4-(3-fluoropropyl)phenyl]azetidine-1-carboxylate (80 mg, 0.27 mmol) and trifluoroacetic acid (0.07 ml, 0.85 mmol) in DCM (2 ml ) was stirred at 25° C. for 4 hours. This mixture was concentrated in vacuo to give 3-[4-(3-fluoropropyl)phenyl]azetidine (40 mg, 76%) as a colorless oil, which was used as such in the next step. . MS (ESI): m/z is 194.1 [M+H] ⁺ .

Intermediates:

a) 2-[4-(3-Fluoropropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Solution of 1-bromo-4-(3-fluoropropyl)benzene (CAS Nr. 168104-62-9) (1.00 g, 4.61 mmol), bis(pinacolato)diboron (2.34 g, 9.21 mmol ), [Pd(dppf)Cl ₂ ]⋅CH ₂ Cl ₂ (376 mg, 0.460 mmol) and KOAc (1.35 g, 13.8 mmol) in 1,4-dioxane (40 ml) were stirred at 100°C within 16 h under N ₂ . This mixture was filtered and concentrated to give a residue which was purified by flash column chromatography (petroleum ether: EtOAc - 10:1) to give 2-[4-(3-fluoropropyl)phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1.2 g, 99%) as a colorless oil. MS (ESI): m/z is 265.1 [M+H] ⁺ .

b) [4-(3-Fluoropropyl)phenyl]boronic acid

To a solution of 2-[4-(3-fluoropropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, 2.27 mmol) in H ₂ O (12 ml) and acetone (60 ml) was added HCl (1M, 1 ml). This solution was stirred at 25° C. for 16 hours. This solution was poured into brine (40 ml) and extracted with EtOAc (2×20 ml). The combined organic layers were concentrated in vacuo to give [4-(3-fluoropropyl)phenyl]boronic acid (300 mg, 73%) as a light yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.19 (d, J=7.9 Hz, 2H), 7.37 (d, J=7.8 Hz, 2H), 4.52 (dt, J=47.2 , 5.9 Hz, 2H), 2.87 (t, J=7.1 Hz, 2H), 2.16 - 2.02 (m, 2H).

c) tert-Butyl-3-[4-(3-fluoropropyl)phenyl]azetidine-1-carboxylate

Solution of [4-(3-fluoropropyl)phenyl]boronic acid (145 mg, 0.790 mmol), tert-butyl-3-iodazetidine-1-carboxylate (CAS Nr. 254454-54-1) (150 mg, 0.530 mmol), nickel(II) iodide (99 mg, 0.32 mmol), (1S,2S)-2-aminocyclohexanol (37 mg, 0.32 mmol) and sodium bis(trimethylsilyl)amide (1.06 ml, 1.06 mmol ) in 2-propanol (4 ml) was stirred at 80°C for 1 h in a sealed tube. This mixture was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give tert-butyl 3-[4-(3-fluoropropyl)phenyl]azetidine-1-carboxylate (82 mg, 46%) as a colorless oil. MS (ESI): m/z is 238.1 [M-C ₄ H ₈ +H] ⁺ .

BB88

2-(Azetidin-3-yl)-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole

The compound tert-butyl-3-[[(2,4-dichlorobenzoyl)amino]carbamoyl]azetidine-1-carboxylate (800.0 mg, 2.06 mmol) was suspended in polyphosphoric acid (5 ml), this mixture was stirred at 180 °C for 2 h. This mixture was poured into ice-cold ammonia (100 ml), stirred for 10 min, then extracted three times with EtOAc (each time 100 ml), the combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated . The residue was purified by flash column chromatography (0.1% v/v FA) to give the desired product (130 mg, 17%) as a light brown oil. MS (ESI): m/z is 270.4 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-3-[[(2,4-dichlorobenzoyl)amino]carbamoyl]azetidine-1-carboxylate

To a solution of 1-Boc-azetidine-3-carboxylic acid (490.68 mg, 2.44 mmol, CAS RN 142253-55-2) and 2,4-dichlorobenzhydrazide (500.0 mg, 2.44 mmol, CAS RN 5814-06-2), DIPEA (1.27 ml, 7.32 mmol) in DMF (20 ml) was added T ₃ P (1122.42 mg, 4.88 mmol, 50% in EtOAc), this mixture was stirred at 80°C for 12 hours This mixture was diluted with EtOAc (50 ml), washed with NaHCO ₃ (100 ml) and brine, then dried over Na ₂ SO ₄ and evaporated to obtain the crude product (800 mg, 84.5%) in light brown oil. MS (ESI): m/z is 332.4 [M-C ₄ H ₈ +H] ⁺ .

BB89

3-(Azetidin-3-yl)-1-(2,4-dichlorophenyl)pyrazole, trifluoroacetic acid salt

TFA (1.0 ml, 0.950 mmol) and this mixture was stirred at 20° C. for 12 hours. This mixture was concentrated to give the desired product as a yellow oil (350 mg, 96.4%). MS (ESI): m/z is 268.1 [M+H] ⁺ .

Intermediates:

a) tert-But yl-3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate

To a solution of 1-BOC-azetidine-3-carboxylic acid (10.0 g, 49.7 mmol, CAS RN 142253-55-2) in DCM (200 ml) was added CDI (8.06 g, 49.7 mmol) , this mixture was stirred at 20°C for 1 h, then TEA (13.85 ml, 99.39 mmol) and HCl salt of O,N-dimethylhydroxylamine (5.82 g, 59.64 mmol, CAS RN 6638- 79-5), this mixture was stirred at 20°C for 15 h, then this mixture was washed with aqueous Na ₂ CO ₃ and brine, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to obtain the crude product as a light yellow oil (12 g) which was used in the next step without further purification.

b) tert-Butyl-3-acetyl-azetidine-1-carboxylate

MeMgBr/THF (1.77 ml, 3 M) was added to a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (1000.0 mg, 4.09 mmol) in THF (30 ml) at 0° C., this mixture was stirred at 20° C. for 2 h, then the mixture was then poured into sat. NH ₄ Cl solution (100 ml) and extracted with EtOAc (three times 30 ml), the combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a light yellow oil (810 mg, 99.3 %). ¹ H NMR (400 MHz, CHLOROFORM-d) δ=4.05 (br d, J=7.4 Hz, 4H), 3.48 - 3.34 (m, 1H), 2.18 (d, J=2.0 Hz, 2H) , 1.44 (d, J=2.0 Hz, 9H).

c) tert-Butyl-3-[(E)-3-(dimethylamino)prop-2-enoyl]azetidine-1-carboxylate

A solution of tert-butyl-3-acetylazetidine-1-carboxylate (500.0 mg, 2.51 mmol) in N,N-dimethylformamidadimethyl acetal (10.0 ml) was stirred at 110°C for 12 h, this mixture was concentrated to obtain title compound as a yellow oil (640 mg, 2.52 mmol). MS (ESI): m/z is 199.2 [M-C ₄ H ₈ +H] ⁺ .

d) tert-Butyl-3-[1-(2,4-dichlorophenyl)pyrazol-3-yl]azetidine-1-carboxylate

A solution of tert-butyl 3-[(E)-3-(dimethylamino)prop-2-enoyl]azetidine-1-carboxylate (500.0 mg, 1.97 mmol) and 2,4-dichlorobenzohydrazide hydrochloride (474.78 mg, 1.97 mmol) in EtOH (30 ml) was stirred at 80°C for 12 h, this mixture was concentrated, the residue was purified by a column of silica gel (PE : EtOAc - from 20:1 to 3:1) to obtain the desired product (450 mg, 62.2%) as a yellow oil. MS (ESI): m/z is 368.1 [M+H] ⁺ .

BB90

3-[4-(2,2-Dimethylpropyl)phenyl]azetidine, trifluoroacetic acid salt

TFA (2.0 ml) was added to a solution of tert-butyl 3-[4-(2,2-dimethylpropyl)phenyl]azetidine-1-carboxylate (500.0 mg, 1.65 mmol) in DCM (10 ml) , and the mixture was stirred at 20° C. for 12 hours. This mixture was concentrated to give the crude product as a light yellow oil (520 mg). MS (ESI): m/z is 204.2 [M+H] ⁺ .

Intermediates:

a) 1-Bromo-4-(2,2-dimethylpropyl)benzene

To a solution of 2,2-dimethylpropylbenzene (500.0 mg, 3.37 mmol, CAS RN 1007-26-7) in acetic acid (10 ml) was added bromine (0.17 ml, 3.37 mmol). This mixture was stirred at 20°C in the dark for 12 h, and then this mixture was poured into sat. aq. Na ₂ SO ₃ (30 ml) and extracted three times with EtOAc (each time 10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude product as a light yellow oil (600 mg, 78.3%) which was used in the next step without further purification.

b) tert-Butyl-3-[4-(2,2-dimethylpropyl)phenyl]azetidine-1-carboxylate

To a 40 ml vial equipped with a stirring bar was added tert-butyl-3-bromazetidine-1-carboxylate (519.75 mg, 2.2 mmol, CAS RN 1064194-10-0), 1-bromo-4-(2, 2-dimethylpropyl)benzene (500.0 mg, 2.2 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (24.68 mg, 0.020 mmol, CAS RN 870987-63-6), NiCl ₂ glyme (2.42 mg, 0.010 mmol, CAS RN 29046-78-4), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (3.54 mg, 0.010 mmol, CAS RN 69641-93-6), bis(trimethylsilyl)silyl-trimethyl-silane (547.37 mg, 2.2 mmol, CAS RN 1873-77-4) and Na ₂ CO ₃ (466.63 mg, 4, 4 mmol), then DME (20 ml). This vial was sealed and placed under nitrogen. This reaction mixture was stirred and irradiated with a 34 W blue LED lamp (7 cm distance), with a cooling fan to maintain the reaction temperature at 25° C. for 14 hours. This mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography (0.1% v/v FA) to give the desired product (500 mg, 74.8%) as a light yellow oil. MS (ESI): m/z is 248.2 [M-C ₄ H ₈ +H] ⁺ .

BB91

(4aR,8aS)-6-[3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidine-1-carbonyl]-4,4a, 5,7,8,8а-hexahydropyrido[4,3-b][1,4]oxazin-3-one

In a solution of (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4] oxazin-3-one (200.0 mg, 0.510 mmol, Example 110) and PdCl ₂ (dppf)⋅DCM (35.56 mg, 0.050 mmol) were added potassium acetate (149.36 mg, 1.52 mmol) and bis (pinacolato)diboron (193.23 mg, 0.760 mmol), this reaction mixture was purged with nitrogen and stirred at 90° C. for 12 hours. This reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a yellow residue which was purified by reverse phase flash chromatography (0.1% v/v FA) to give the desired product (140 mg, 0.320 mmol, 62.5%) as a light yellow solid. MS (ESI): m/z is 442.3 [M+H] ⁺ .

BB92

2- Bromo-N-ethyl-5-methyl-benzamide

To a solution of 2-bromo-5-methylbenzoic acid (500.0 mg, 2.33 mmol, CAS RN 6967-82-4) and HOBT (534.11 mg, 3.49 mmol), EDCl (541.43 mg, 3.49 mmol) and DIPEA (1.21 ml, 6.98 mmol) in DMF (10 ml) was added ethylamine hydrochloride (227.51 mg, 2.79 mmol) and the mixture was stirred at 20°C for 12 h This mixture was then poured into sat. aq. Na ₂ CO ₃ solution (50 ml) and extracted three times with EtOAc (each time 20 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a light yellow solid (450 mg, 79.9%). MS (ESI): m/z is 242.0 [M+H] ⁺ .

BB93

Azetidin-3-ylbis(4-fluorophenyl)methanol

A dried 100 ml two-necked round bottom flask equipped with a reflux condenser under argon was charged with THF (18.6 ml) and 1-(tert-butyl)-3-methyl-azetidine-1,3-dicarboxylate (800 mg, 746 μl, 3. 72 mmol, CAS RN 610791-05-4). This mixture was purged with argon for 5 min and cooled to 0°C. Then (4-fluorophenyl)magnesium bromide, 0.8 M solution in THF (18.6 ml, 14.9 mmol) was added over 10 minutes. After complete addition, the reaction mixture was heated to 85° C. (oil bath) for 17 hours. The reaction was quenched with water (5 ml), diluted with EtOAc (10 ml) and the resulting suspension stirred for 15 minutes. Water was added and the mixture was acidified with 2 M HCl (20 ml) until aq. the phase did not become a colorless solution. These phases were separated and the aqueous phase was extracted with EtOAc (100 ml). The pH was adjusted to 7 and the aqueous phase was extracted four times with EtOAc. The combined organic layers were concentrated to about 50 ml. A precipitate formed and the flask was cooled to 4°C. The precipitate was filtered off and the white solid was washed with small portions of EtOAc to give the title compound (317 mg, 31%). MS (ESI): m/z is 276.2 [M+H] ⁺ .

BB94

3-(1-(2-Chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine 2,2,2-trifluoroacetate

Trifluoroacetic acid (400 mg, 270 µl, 3.51 mmol) was added to a solution of tert-butyl 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (78.4mg , 206 µmol) in DCM (1.03 mL) and this solution was stirred at RT for 2 h. The solvent was removed under reduced pressure to give the compound as a light yellow oil (134 mg, 100%). The crude product was used in the next step without further purification. MS (ESI): m/z is 280.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate

In a solution of 2-chloro-4-(trifluoromethyl)phenol (500 mg, 340 µl, 2.54 mmol), tert-butyl-3-(1-hydroxyethyl)azetidine-1-carboxylate (512 mg, 2.54 mmol, CAS RN 1138331-90-4) and triphenylphosphine (734 mg, 2.8 mmol) in DCM (12.7 ml) was added DIAD (566 mg, 544 μl, 2.8 mmol) dropwise at 0°C, and this the reaction mixture was stirred at 0° C. for 10 min and at RT for 6 h. This reaction mixture was quenched by adding sat. aq. NaHCO ₃ solution (20 ml). The phases were separated, and aq. the phase was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and stored at 4°C for four days. The crude product was concentrated to dryness, immobilized on Isolute® and purified by flash column chromatography (eluting with a gradient of 0 to 30% EtOAc in n-heptane) to give the title compound as a pale oil (497 mg, 48.9%) . MS (ESI): m/z is 324.1 [M-C ₄ H ₈ +H] ⁺ .

BB95

4-(1-(2-Chloro-4-fluorophenoxy)-2,2,2-trifluoroethyl)piperidine hydrochloride

Hydrochloric acid (4 M in dioxane) (174 µl, 695 µmol) was added to a solution of tert-butyl 4-(1-(2-chloro-4-fluorophenoxy)-2,2,2-trifluoroethyl)piperidine-1-carboxylate (17.9 mg, 43.5 µmol) in dioxane (435 µl) and this solution was stirred for 2 h at RT. This solvent was removed under reduced pressure to give the desired compound as a light yellow oil (15 mg, 95%). The crude product was used in the next step without further purification. MS (ESI): m/z is 312.1 [M+H] ⁺ .

Intermediates

a) tert-Butyl-4-(1-(2-chloro-4-fluorophenoxy)-2,2,2-trifluoroethyl)piperidine-1-carboxylate

tert-Butyl-4-(2,2,2-trifluoro-1-(((trifluoromethyl)sulfonyl)oxy)ethyl)piperidine-1-carboxylate (126 mg, 303 µmol), 2-chloro-4-fluorophenol (48 .9 mg, 36.4 µl, 334 µmol) and cesium carbonate (109 mg, 334 µmol) were suspended in DMF (1.52 ml) and stirred at RT for 20 h. This reaction mixture was then quenched with water and extracted twice EtOAc. The combined organic phases were washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was immobilized on Isolute® and purified by flash column chromatography (gradient 0 to 30% EtOAc in n-heptane) to give the title compound as a colorless oil (20 mg, 15%). MS (ESI): m/z is 356.1 [M-C ₄ H ₈ +H] ⁺ .

b) Tert-butyl-4-(2,2,2-trifluoro-1-(((trifluoromethyl)sulphunyl)oxy)ethyl)piperidine-1-carboxylate

A microwave vessel was charged with tert-butyl 4-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (100 mg, 353 μmol, CAS RN 184042-83-9). This vessel was placed under argon, DCM (1.76 ml) was added and cooled to 0°C. Pyridine (33.5 mg, 34.3 µl, 424 µmol) was added, followed by triflate anhydride (110 mg, 65.6 µl, 388 µmol). This reaction mixture was stirred at 0° C. for 1 h and then quenched with water. This mixture was separated, the organic phase was washed with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the desired compound as a yellow oil (126 mg, 85.9%). This compound was used in the next step without further purification.

VV96

3-(bis(4-Fluorophenyl)methyl)azetidine

A solution of 3-(bis(4-fluorophenyl)methylene)azetidine (20 mg, 77.7 µmol) in MeOH (777 µl) was evacuated and refilled with argon five times. Under an argon atmosphere, Pd-C (4.14 mg, 3.89 µmol) was added and this atmosphere was replaced with hydrogen three times. This reaction mixture was stirred under a hydrogen atmosphere (balloon) at 100 kPa for 19 hours. This atmosphere was replaced with argon and the reaction mixture was filtered through a pad of dicalite. The filter cake was washed with MeOH. The filtrate was concentrated to give the desired compound as a yellow solid (20.1 mg, 94.7%) which was used in the next step without further purification. MS (ESI): m/z is 260.2 [M+H] ⁺ .

intermediate connection

3-(bis(4-Fluorophenyl)methylene)azetidine

To a suspension of azetidin-3-ylbis(4-fluorophenyl)methanol (244 mg, 886 µmol, BB93) in DCM (2.22 ml) was added TFA (2.22 ml) and the mixture was stirred for 3.5 hours. This gave a homogeneous solution. This reaction mixture was evaporated to dryness, the resulting residue was diluted with EtOAc, washed twice with saturated aqueous sodium bicarbonate, then with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was triturated with EtOAc/n-heptane and filtered. This gave the title compound as a white solid (20 mg, 8.3%). MS (ESI): m/z is 258.2 [M+H] ⁺ .

VV97

3-(1-(2-Fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-2,2,2-trifluoroacetate

In a solution of tert-butyl-3-(1-(2-fluoro-4-

(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (93 mg, 256 µmol) in DCM (1 ml) was added 2,2,2-trifluoroacetic acid (467 mg, 316 µl, 4.1 mmol) and this reaction the mixture was stirred at RT for 20 hours. This reaction mixture was concentrated to give the desired compound as a colorless oil (112.8 mg, 99%), which was used in the next step without further purification. MS (ESI): m/z is 264.1 [M+H] ⁺ .

intermediate connection

a) tert-Butyl-3-(1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-caroxylate

To a solution of 2-fluoro-4-(trifluoromethyl)phenol (100 mg, 69.9 µl, CAS RN 77227-78-2), tert-butyl 3-(1-hydroxyethyl)azetidine-1-carboxylate (112 mg, 555 µmol, CAS RN 1138331-90-4) and triphenylphosphine (160 mg, 611 µmol) in DCM (2.8 ml) were added dropwise with DIAD (124 mg, 119 µl, 611 µmol) and the reaction mixture was stirred at RT within 1.5 hours This reaction mixture was extinguished by adding feast upon. aq. NaHCO ₃ solution. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was immobilized on Isolute and purified by flash column chromatography (gradient 0 to 20% EtOAc in n-heptane) to give the desired compound as a colorless oil (93 mg, 43.8%). MS (ESI): m/z is 308.1 [M-C ₄ H ₈ +H] ⁺ .

VV98

3-(1-(4-Trifluoromethyl)phenoxy)ethyl)azetide on 2,2,2-trifluoroacetate

By analogy with BB97, BB98 was obtained from 4-(trifluoromethyl)phenol and tert-butyl-3-(1-hydroxyethyl)azetidine-1-carboxylate. This compound was used in the next step without further purification.

BB99

(S or R)-4-((4-Fluorophenyl)(3-methoxyphenyl)methyl)piperidine

A solution of 4-[(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine (760 mg, 2.54 mmol) in MeOH (5 mL) was purified by SFC separation to give 4-[(S or R)-(4 -fluorophenyl)-(3-methoxyphenyl)methyl]piperidine (128 mg, 0.43 mmol, 17%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ ; and 4-[(R or S)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine (170 mg, 0.57 mmol, 22%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ .

Intermediates

a) tert-Butyl-4-[(4-fluorophenyl)(hydroxy)(3-methoxyphenyl)methyl]piperidine-1-carboxylate

To a solution of 3-bromoanisole (487 mg, 2.6 mmol) in THF (40 ml) was added butyllithium (1.5 ml, 3.75 mmol, 2.5 M) at -78°C. After stirring for 1 hour, tert-butyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (CAS RN 160296-40-2; 800 mg, 2.6 mmol) was added to this mixture and stirring continued at -78 °C for 1 h. Then this reaction was heated to 25°C and stirred for another 13 h. The reaction was quenched with NH ₄ Cl (sat. aq., 50 ml) and was extracted with EtOAc (100 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired compound (1100 mg, 63%) as a yellow oil. MS (ESI): m/z is 438.1 [M+Na] ⁺ .

b) 4-[(4-Fluorophenyl) (3-methoxyphenyl)methylene]piperidine trifluoroacetate

A solution of tert-butyl 4-[(4-fluorophenyl)(hydroxy)(3-methoxyphenyl)methyl]piperidine-1-carboxylate (1.1 g, 1.64 mmol) and trifluoroacetic acid (5.0 ml, 65 mmol ) in DCM (10 ml) was stirred at 25° for 5 h. This reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc (50 ml) and washed with Na ₂ CO ₃ (aq., 10%, 50 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting oil was purified by preparative HPLC (TFA as additive) to give 4-[(4-fluorophenyl)(3-methoxyphenyl)methylene]pyeridine (TFA salt, 430 mg, 39%) as a white solid. MS (ESI): m/z is 298.1 [M+H] ⁺ .

c) 4-[(4-Fluorophenyl)(3-methoxyphenyl)methyl]piperidine trifluoroacetate

A solution of 4-[(4-fluorophenyl)(3-methoxyphenyl)methylene]piperidine (410 mg, 1.38 mmol) and Pd/C (100 mg, 1.38 mmol) in THF (10 ml) was stirred at 25°C within 16 hours under H ₂ (760 mm Hg). This reaction mixture was filtered through Celite then concentrated in vacuo to give 4-[(4-fluorophenyl)(3-methoxyphenyl)methyl]piperidine (TFA salt, 260 mg, 59%) as a yellow oil. MS (ESI): m/z is 300.1 [M+H] ⁺ .

BB100

(R or S)-4-((4-Fluorophenyl)(3-methoxyphenyl)methyl)piperidine

A solution of 4-[(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine (BB99, intermediate c, 760 mg, 2.54 mmol) in MeOH (5 ml) was purified by separation of SFC to give 4-[(S or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine (128 mg, 17%) as a light yellow semi-solid; LCMS: 300.1 [M+H] ⁺ ; and 4-[(R or S)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine or 4-[(5)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine (170 mg, 22%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ .

BB101

(S or R)-4-((3-Methoxyphenyl)(phenyl)methyl)piperidine

A solution of 4-[(3-methoxyphenyl)-phenyl-methyl]piperidine (960 mg, 3.41 mmol) in MeOH (5 ml) was purified by preparative HPLC using TFA as an additive to give 4-[-(3-methoxyphenyl) -phenyl-methyl]piperidine as its TFA salt (1260 mg). TFA salt 4-[-(3-methoxyphenyl)-phenyl-methyl]piperidine (1260 mg) was purified by SFC separation to give (S or R)-4-((3-methoxyphenyl)(phenyl)methyl)piperidine (443 mg , 45%) as a light yellow solid; MS (ESI): m/z is 282.2 [M+H] ⁺ ; and (R or S)-4-((3-methoxyphenyl)(phenyl)methyl)piperidine (383 mg, 39%) as a yellow solid; MS (ESI): m/z is 282.2 [M+H] ⁺ .

intermediate connection

4-((3-Methoxydienyl)(phenyl)methyl)piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting with 3-bromoanisole and tert-butyl-4-benzoylpiperidine- 1-carboxylate (CAS RN 922504-27-6) to give the title compound as a light yellow semi-solid. MS (ESI): m/z is 282.1 [M+H] ⁺ .

BB102

(R or S)-4-((3-Methoxyphenyl)(phenyl)methyl)piperidine

A solution of 4-[(3-methoxyphenyl)-phenyl-methyl]piperidine (BB101, intermediate, 960 mg, 3.41 mmol) in MeOH (5 ml) was purified by prep HPLC using TFA as an additive to give 4-[- (3-methoxyphenyl)-phenyl-methyl]piperidine as its TFA salt (1260 mg). 4-[-(3-Methoxyphenyl)-phenyl-methyl]piperidine TFA salt (1260 mg) was purified by SFC resolution to give (S or R)-4-((3-methoxyphenyl)(phenyl)methyl)piperidine (443 mg , 45%) as a light yellow solid; MS (ESI): m/z is 282.2 [M+H] ⁺ ; and (R or S)-4-((3-methoxyphenyl)(phenyl)methyl)piperidine (383 mg, 39%) as a yellow solid; MS (ESI): m/z is 282.2 [M+H] ⁺ .

BB103

(S or R)-4-((3-(2-Fluoroethoxy)phenyl)(phenyl)methyl)piperidine

A solution of 4-[[3-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (800 mg, 2.55 mmol) in MeOH (5 ml) was purified by separation of SFC to give (S or R)-4-(( 3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine (214 mg, 27%) as a white solid; MS (ESI): m/z is 314.1 [M+H] ⁺ ; and (R or S)-4-((3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine (305 mg, 38%) as a white solid; MS (ESI): m/z is 314.1 [M+H] ⁺ .

intermediate connection

4-((3-(2-Fluoroethoxy)phenyl)(phenyl)methyl)piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting from 1-bromo-3-(2-fluoroethoxy)benzene (CAS RN 132837-02-6) and tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6) to give the title compound as a colorless oil. MS (ESI): m/z is 314.1 [M+H] ⁺ .

BB104

(S or R)-4-((4-Fluorophenyl)(phenyl)methyl)piperidine

A solution of TFA salt 4-[(4-fluorophenyl)-phenyl-methyl]piperidine (690 mg, 1.8 mmol) in MeOH (10 ml) was purified by separation of SFC to give (S or R)-4-((4-fluorophenyl )(phenyl)methyl)piperidine (172 mg, 35%) as a light yellow solid; MS (ESI): m/z is 270.1 [M+H] ⁺ ; and (R or S)-4-((4-fluorophenyl)(phenyl)methyl)piperidine. (R or S)-4-((4-fluorophenyl)(phenyl)methyl)piperidine was dissolved in EtOAc (15 ml) and washed with Na ₂ CO ₃ (5 ml, aq., 30%) and water (5 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was lyophilized to give (R or S)-4-((4-fluorophenyl)(phenyl)methyl)piperidine (227 mg, 46%) as a light yellow solid. MS (ESI): m/z is 270.1 [M+H] ⁺ .

Intermediates

a) tert-Butyl-4-[(4-fluorophenyl)-hydroxy-phenyl-methyl]piperidine-1-carboxylate

To a solution of 4-bromofluorobenzene (2 g, 11.4 mmol) in THF (20 ml) cooled to -78°C was added dropwise n-butyllithium (5.81 ml, 14.51 mmol) and this reaction mixture stirred for 30 min. A solution of tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6; 3 g, 10.37 mmol) in THF (15 ml) was then added to this mixture, which was stirred at -78° for 2 hours. This mixture was allowed to warm up to RT, poured into sat. aqueous solution of NH ₄ Cl (50 ml) and was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini NX column) to give the title compound (1.18 g, 29%) as a colorless solid. MS: 312.1 [M-C ₄ H ₈ -H ₂ O+H] ⁺ .

b) 4-H4-Fluorophenyl)-phenyl-methylene]piperidine

Trifluoroacetic acid (1.4 mL, 18.16 mmol) and this reaction mixture was stirred at RT for 8 h. This mixture was concentrated in vacuo to give the crude title compound (0.3 g, 62%) as a light yellow solid . MS: 268.0 [M+H] ⁺ .

c) 4-[(4-Fluorophenyl)-phenyl-methyl]piperidine trifluoroacetate

A solution of 4-[(4-fluorophenyl)-phenyl-methylene]piperidine (1600 mg, 5.98 mmol) and Pd/C (300 mg, 5.98 mmol) in THF (100 mL) was stirred at RT for 16 h under the atmosphere of H ₂ (760 mm Hg). This suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC using TFA as additive to give the title compound as 2,2,2-trifluoroacetic acid salt (700 mg, 29%) as a white solid. MS (ESI): m/z is 270.1 [M+H] ⁺ .

VV 105

(S or R)-4-((4-Fluorophenyl)(p-tolyl)methyl)piperidine

A solution of 4-[(4-fluorophenyl)-(p-tolyl)methyl]piperidine (870 mg, 3.07 mmol) was separated by SFC (Method: DAICEL CHIRALPAK AD column 250 mm * 30 mm, 5 µm, conditions: 0.1 % NH ₃ •H ₂ O IPA, start B 35, end B 35, gradient time (min) 4.9 min, 110 min, hold time 100% B (min) 0, flow rate (ml/min) 60) s obtaining (R or S)-4-[(4-fluorophenyl)(p-tolyl)methyl]piperidine (253 mg, 28%; MS (ESI): m/z equal to 284.1 [M+H] ⁺ ) and (S or R)-4-[(4-fluorophenyl)(p-tolyl)methyl]piperidine (356 mg, 40% yield; MS (ESI): m/z equal to 284.1 [M+H] ⁺ ).

Intermediates

a) tert-Butyl-4-((4-fluorophenyl)(hydroxy)(p-tolyl)methyl)piperidine-1-carboxylate

To a stirred at -78° C. solution of 4-bromotoluene (1.70 g, 9.94 mmol) in THF (40 ml) was added a solution of butyllithium (5.57 ml, 13.9 mmol). After stirring for 1 hour, tert-butyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (CAS RN 160296-40-2; 3.05 g, 9.94 mmol) was added to this mixture and stirring continued. at -78°C for 1 h. Then this reaction mixture was heated to 25°C and stirred for another 13 h. This reaction was quenched with NH ₄ Cl (sat. aq., 50 ml) and was extracted with EtOAc (100 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired compound as a light yellow oil (2.85 g, 71%). MS (ESI): m/z is 422.1 [M+Na] ⁺ .

b) 4-[(4-Fluorophenyl)-(p-tolyl)methylene]piperidine

A solution of tert-butyl 4-[(4-fluorophenyl)-hydroxy-(p-tolyl)methyl]piperidine-1-carboxylate (2.83 g, 7.08 mmol) and trifluoroacetic acid (11 ml, 142 mmol) in DCM (20 ml) was stirred at 25°C for 3 hours This reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (TFA as additive) to give the title compound as a light yellow semi-solid (1.36 mg, 67%). MS (ESI): m/z is 282.1 [M+H] ⁺ .

c) 4-[(4-Fluorophenyl)-(p-tolyl)methyl]piperidine trifluoroacetate

A solution of 4-[(4-fluorophenyl)-(p-tolyl)methylene]piperidine (1.36 g, 4.83 mmol) and Pd/C (300 mg) in DMF (50 mL) was stirred at 25°C for 16 h under H ₂ (2280 mm Hg). This reaction solution was filtered through Celite and concentrated in vacuo. The residue was purified by preparative HPLC (TFA as additive) to give the desired compound as a white semi-solid (TFA salt, 870 mg, 45%). MS (ESI): m/z is 284.1 [M+H] ⁺ .

BB106

(R or S)-4-((4-(2-Fluoroethoxy)phenyl)(phenyl)methyl)piperidine

A solution of 4-[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (800 mg, 2.55 mmol) in MeOH (5 mL) was purified and the enantiomers separated with SFC to give (S or R)-4 -[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (279 mg, 0.89 mmol, 35%) as a white solid; MS (ESI): m/z is 314.2 [M+H] ⁺ ; and (R or S)-4-[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (373 mg, 47%) as a white solid. MS (ESI): m/z is 314.1 [M+H] ⁺ .

intermediate connection

4-((4-(2-Fluoroethoxy)phenyl)(phenyl)methyl)piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting from 1-bromo-4-(2-fluoroethoxy)benzene (CAS RN 332-47-8) and tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6) to give the title compound as a colorless oil. MS (ESI): m/z is 314.1 [M+H] ⁺ .

BB107

(S or R)-4-[(4-Fluorophenyl)-(4-methoxyphenyl)methyl]piperidine

A solution of 4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]piperidine (930 mg, 3.11 mmol) in MeOH (5 mL) was purified by SFC separation to give (S or R)-4-[(4 -fluorophenyl)-(4-methoxyphenyl)methyl]piperidine (277 mg, 0.93 mmol, 27%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ ; and (R or S)-4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]piperidine (291 mg, 30%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ .

intermediate connection

4-[(4-Fluorophenyl)-(4-methoxyphenyl)methyl]piperidine The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89- 7) starting with 1-bromo-4-methoxy-benzene (CAS RN 104-92-7) and tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6) to give the compound indicated in the title, as a colorless semi-solid. MS (ESI): m/z is 300.1 [M+H] ⁺ .

BB108

(R or S)-4-((4-Fluorophenyl)(p-tolyl)methyl)piperidine

A solution of 4-[(4-fluorophenyl)-(p-tolyl)methyl]piperidine (870 mg, 3.07 mmol, BB105, intermediate c) was separated by SFC (method: DAICEL CHIRALPAK AD column 250 mm * 30 mm, 5 µm , conditions 0.1% NH ₃ •H ₂ O IPA, start B 35, end B 35, gradient time (min) 4.9 min, 110 min, retention time 100% B (min) 0, flow rate (ml/ min) 60) to give (R or S)-4-[(4-fluorophenyl)(p-tolyl)methyl]piperidine (253 mg, 28%); MS (ESI): m/z is 284.1 [M+H] ⁺ ; and (S or R)-4-[(4-fluorophenyl)(p-tolyl)methyl]piperidine (356 mg, 40%). MS (ESI): m/z is 284.1 [M+H] ⁺ .

BB109

(S or R)-4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine

4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (900 mg) was separated by SFC (method: DAICEL CHIRALPAK AD column (250 mm * 50 mm, 10 µm), conditions 0.1% NH ₃ • H ₂ O MeOH, start B 25, end B 25, gradient time (min) 5.5 min: 900 min, retention time 100% B (min) 0; flow rate (ml/min) 50 g/min) to obtain (S or R)-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (278mg, 29%d). MS (ESI): m/z is 330.3 [M+H] ⁺ and (R or S)-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (426 mg, 44%; MS (ESI): m/z is 330.1 [M+H] ⁺ ) as whitish solids.

Intermediates

a) tert-Butyl-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

Butyllithium (3.28 ml, 8.2 mmol) was added dropwise to a solution of 4-bromoveratrol (CAS RN 2859-78-1; 1.27 g, 5.86 mmol) in THF (30 ml) with stirring at -78 °C. Stirring was continued at -78°C for 1 hour. Then tert-butyl-4-(4-fluorobenzoyl)piperidine-1-carboxylate (CAS RN 160296-40-2; 1.80 g, 5.86 mmol) was added, and this mixture was stirred at -78°C for 5 hours This mixture was poured into brine (50 ml) and was extracted twice with EtOAc (each time 30 ml). The combined organic layers were concentrated in vacuo to give the desired compound as a colorless oil (2.4 g, 91%). MS (ESI): m/z is 468.4 [M+Na] ⁺ .

b) 4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methylene)piperidine trifluoroacetate

Mixture of tert-butyl 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (2.4 g, 5.4 mmol) and trifluoroacetic acid (4.15 mL, 53 87 mmol) in DCM (20 ml) was stirred at 25°C for 4 h. This reaction mixture was concentrated in vacuo to give 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methylene)piperidine (TFA salt, 1 .7 g, 96%) as a brown oil. MS (ESI): m/z is 328.3 [M+H] ⁺ .

c) 4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine

Mixture of 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methylene)piperidine (1.7 g, 5.2 mmol, BB109, intermediate b) and Pd/C (276 mg, 0.260 mmol) in THF ( 10 ml) was stirred at 25°C for 16 h under H ₂ (760 mm Hg). This mixture was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (900 mg, 52%) as white solid. MS (ESI): m/z is 330.3 [M+H] ⁺ .

BB110

(R or S)-4-((3,4-Dimethoxyphenyl)(phenyl)methyl)piperidine

A solution of 4-[(3,4-dimethoxyphenyl)-phenyl-methyl]piperidine (900 mg, 2.89 mmol) in MeOH (5 mL) was purified by separation of SFC to give (S or R)-(3,4-dimethoxyphenyl) -phenyl-methyl]piperidine (326 mg, 36%) as a white solid; MS (ESI): m/z is 312.3 [M+H] ⁺ ; and (R or S)-(3,4-dimethoxyphenyl)-phenyl-methyl]piperidine (222 mg, 24%) as a white solid; MS (ESI): m/z is 312.3 [M+H] ⁺ .

intermediate connection

4-[(3,4-Dimethoxyphenyl)-phenyl-methyl]piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting from 4-bromo-1,2-dimethoxy-benzene ( CAS RN 2859-78-1) and tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6) to give the title compound as a white solid. MS (ESI): m/z is 312.3 [M+H] ⁺ .

BB111

(R or S)-4-((4-Fluorophenyl)(phenyl)methyl)piperidine

A solution of TFA salt 4-[(4-fluorophenyl)-phenyl1-methyl]piperidine (690 mg, 1.8 mmol) in MeOH (10 ml) was purified by SFC separation to give (S or R)-4-((4- fluorophenyl)(phenyl)methyl)piperidine (172 mg, 35%) as a light yellow solid. MS (ESI): m/z is 270.1 [M+H] ⁺ ; and (R or S)-4-((4-fluorophenyl)(phenyl)methyl)piperidine. (R or S)-4-((4-Fluorophenyl)(phenyl)methyl)piperidium was dissolved in EtOAc (15 ml) and washed with aqueous Na ₂ CO ₃ (5 ml, 30%) and water (5 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was lyophilized to give (R or S)-4-((4-fluorophenyl(phenyl)methyl)piperidine (227 mg, 0.84 mmol, 46%) as a yellow solid; MS (ESI): m/z = 270.1 [M+H] ⁺ .

BB112

(S or R)-4-(Phenyl(m-tolyl)methyl)piperidine

A solution of 4-(phenyl(m-tolyl)methyl)piperidine (730mg, 2.75mmol) in MeOH (5mL) was purified by SFC separation to give (S or R)-4-(phenyl(m-tolyl)methyl )piperidine (221 mg, 0.83 mmol, 30%) as a yellow semi-solid. MS (ESI): m/z is 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl(m-tolyl)methyl)piperidine (228 mg, 31%) as a yellow semi-solid. MS (ESI): m/z is 266.2 [M+H] ⁺ .

intermediate connection

4-(Phenyl(m-tolyl)methyl)piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting from 1-bromo-3-methyl-benzene (CAS RN 591-17-3) and tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6) to give the title compound as a light yellow solid. MS (ESI): m/z is 266.1 [M+H] ⁺ .

BB113

(S or R)-4-((4-(2-Fluoroethoxy)phenyl)(phenyl)methyl)piperidine

A solution of 4-[[4-(2-fluoroethoxy)-phenyl]-phenyl-methyl]-piperidine (BB106, intermediate; 800 mg, 2.55 mmol) in MeOH (5 mL) was purified and the enantiomers separated by SFC separation to give (S or R)-4-[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (279 mg, 35%) as white solid, MS (ESI): m/z = 314.2 [M+H] ⁺ ; and (R or S)-4-[(S)-[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (373 mg, 47%) as a white solid; MS (ESI): m/z is 314.1 [M+H] ⁺ .

BB114

(R or S)-4-(Phenyl(m-tolyl)methyl)piperidine

A solution of 4-(phenyl(m-tolyl)methyl)piperidine (BB112, intermediate, 730 mg, 2.75 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give (S or R)-4 -(phenyl(m-tolyl)methyl)piperidine (221 mg, 30%) as a yellow semi-solid; MS (ESI): m/z is 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl(m-tolyl)methyl)piperidine (228 mg, 31%) as a yellow semi-solid. MS (ESI): m/z is 266.2 [M+H] ⁺ .

BB115

(S or R)-4-(Phenyl(p-tolyl)methyl)piperidine

A solution of 4-(phenyl(p-tolyl)methyl)piperidine (720 mg, 2.71 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give ((S or R)-4-(phenyl( p-tolyl)methyl)piperidine (277 mg, 35%) as an off-white solid, MS (ESI): m/z = 266.2 [M+H] ⁺ , and (R or S)-4-(phenyl (p-tolyl)methyl)piperidine (313 mg, 43%) as an off-white solid MS (ESI): m/z = 266.2 [M+H] ⁺ .

intermediate connection

4-(Phenyl(p-tolyl)methyl)piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting from 1-bromo-4-methyl-benzene (CAS RN 106-38-7) and tert-butyl 4-benzoylpiperidine-1-carboxylate (CAS RN 922504-27-6) to give the title compound as a white solid, MS (ESI): m/z equals 266.2 [M+H] ⁺ .

BB116

(R or S)-4-(Phenyl(p-tolyl)methyl)piperidine

A solution of 4-(phenyl(p-tolyl)methyl)piperidine (BB117, intermediate, 720 mg, 2.71 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give ((S or R)- 4-(phenyl(p-tolyl)methyl)piperidine (277 mg, 1.04 mmol, 35%) as an off-white solid MS (ESI): m/z = 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl(p-tolyl)methyl)piperidine (313 mg, 1.18 mmol, 43%) as off-white solid MS (ESI): m/z = 266.2 [M +H] ⁺ .

BB117

3-Benzilazetidine

A solution of 3-(diphenylmethylene)azetidine (800 mg, 3.62 mmol) and Pd/C (1923 mg) in THF (20 ml) was stirred at 25° C. under an atmosphere of H ₂ (760 mmHg) for 5 h. This solution was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (TFA conditions) to give 3-benzhydrylazetidine (315 mg, 37%) as a white solid. MS (ESI): m/z is 224.1 [M+H] ⁺ .

Intermediates

a) tert-Butyl-3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate

1-boc-azetidine-3-carboxylic acid mixture (CAS RN 142253-55-2; 50 g, 248 mmol), triethylamino (69.3 ml, 497 mmol), 1-hydroxybenzotriazole (33.5 g, 248 mmol) , EDCI (47.6 g, 248 mmol) and O,N-dimethylhydroxylamine hydrochloride (24.24 g, 248.5 mmol) in DMF (1000 ml) were stirred at 25° C. for 16 h. This mixture was concentrated in vacuo to give a residue which was neutralized with HCl (1M) for pH 7 and extracted three times with EtOAc (each time 200 ml). The combined organic layers were washed twice with 200 ml aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated in vacuo to give tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (55 g, 72%) in the form of a colorless oil. MS (ESI): m/z is 189.1 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-3-benzoylazetidine-1-carboxylate

To a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (55 g, 225 mmol) in THF (600 ml) was added phenyl magnesium bromide (82 ml, 248 mmol) with stirring at 0°C , and then this solution was stirred at 0°C for 3 hours This solution was poured into sat. aq. NH ₄ Cl solution (300 ml) and extracted twice with EtOAc (each time 150 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by column chromatography (petroleum ether: EtOAc 10:1) to give the desired compound as a light yellow solid (28 g, 46% ). MS (ESI): m/z is 206.1 [M-C ₄ H ₈ +H] ⁺ .

c) tert-Butyl-3-(hydroxydiphenylmethyl)azetidine-1-carboxylate

A solution of phenylmagnesium bromide (3.06 ml, 9.18 mmol) and tert-butyl 3-benzoylazetidine-1-carboxylate (2.0 g, 7.65 mmol) in THF (20 ml) was stirred at 0°C for 2 h. This solution was quenched by adding sat. aq. NH ₄ Cl solution (50 ml) and extracted twice with EtOAc (each time 20 ml). The combined organic layers were concentrated in vacuo to give a residue which was purified by flash column chromatography (PE:EtOAc 5:1) to give the desired compound as a white solid (1.03 g, 39%). MS (ESI): m/z is 362.2 [M+Na] ⁺ .

d) 3-(Diphenylmethylene)azetidine trifluoroacetate

A solution of tert-butyl 3-(hydroxydiphenylmethyl)azetidine-1-carboxylate (1.00 g, 2.95 mmol) and TFA (2.27 ml, 29.5 mmol) in DCM (15 ml) was stirred at 25°C over 4 h. This solution was concentrated in vacuo to give the title compound as a brown oil (TFA salt, 650 mg, 99%). MS (ESI): m/z is 222.1 [M+H] ⁺ .

BB118

(S or R)-4-((3,4-Dimethoxyphenyl)(phenyl)methyl)piperidine

A solution of 4-[(3,4-dimethoxyphenyl)-phenyl-methyl]piperidine (BB110, intermediate; 900 mg, 2.89 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give (S or R)-(3,4-dimethoxyphenyl)-phenyl-methyl]piperidine (326 mg, 1.05 mmol, 36%) as a white solid; MS (ESI): m/z is 312.3 [M+H] ⁺ ; and (R or S)-(3,4-dimethoxyphenyl)-phenyl-methyl]piperidine (222 mg, 0.71 mmol, 24%) as a white solid. MS (ESI): m/z is 312.3 [M+H] ⁺ .

BB119

(R or S)-4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine

4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (BB109, intermediate c; 900 mg) was separated by SFC (method: DAICEL CHIRALPAK AD column (250 mm * 50 mm, 10 µm), conditions 0 1% NH ₃ •H ₂ O MeOH, start B 25, end B 25, gradient time (min) 5.5 min: 900 min, retention time 100% B (min) 0, flow rate (ml/min) 50 g/min)) to give (S or R)-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (278 mg, 29%; MS (ESI): m/z=330.3 [M+H] ⁺ ) and (R or S)-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine (426 mg, 44%; MS (ESI): m/z is 330, 1 [M+H] ⁺ ) as whitish solids.

BB120

(R or S)-4-[(4-Fluorophenyl)-(4-methoxyphenyl)methyl]piperidine

A solution of 4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]piperidine (BB107, intermediate; 930 mg, 3.11 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give (S or R)-4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]piperidine (277 mg, 27%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ ; and (R or S)-4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]piperidine (291 mg, 30%) as a light yellow semi-solid; MS (ESI): m/z is 300.1 [M+H] ⁺ .

BB121

(R or S)-4-((4-(2-Fluoroethoxy)phenyl)(4-fluorophenyl)methyl)piperidine

A solution of 4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine (700 mg, 2.11 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give (R or S)-4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine (203 mg, 29%) as a colorless oil; MS (ESI): m/z is 332.2 [M+H] ⁺ ; and (S or R)-4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine (160 mg, 23%) as a colorless oil; MS (ESI): m/z is 332.2 [M+H] ⁺ .

intermediate connection

4-[[4-(2-Fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine

The title compound was prepared by analogy with the intermediate 1-[(4-fluorophenyl)-phenyl-methyl]piperazine (CAS RN 27064-89-7) starting from 1-bromo-4-(2-fluoroethoxy)benzene (CAS RN 332-47-8) and tert-butyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (CAS RN 160296-40-2) to give the title compound as a colorless oil. MS (ESI): m/z is 332.1 [M+H] ⁺ .

BB122

(R or S)-4-((3-(2-Fluoroethoxy)phenyl)(phenyl)methyl)piperidine

A solution of 4-[[3-(2-fluoroethoxy)phenyl]-phenyl-methyl]piperidine (BB103, intermediate; 800 mg, 2.55 mmol) in MeOH (5 mL) was purified and the enantiomers separated using SFC to give (S or R)-4-((3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine (214 mg, 27%) as a white solid; MS (ESI): m/z is 314.1 [M+H] ⁺ ; and (R or S)-4-((3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine (305 mg, 38%) as a white solid. MS (ESI): m/z is 314.1 [M+H] ⁺ .

BB123

(S or R)-4-((4-(2-Fluoroethoxy)phenyl)(4-fluorophenyl)methyl)piperidine

A solution of 4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine (BB121, intermediate; 700 mg, 2.11 mmol) in MeOH (5 ml) was purified and the enantiomers were separated by SFC with obtaining (R or S)-4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine (203 mg, 29%) as a colorless oil; MS (ESI): m/z is 332.2 [M+H] ⁺ ; and (S or R)-4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]piperidine (160 mg, 23%) as a colorless oil. MS (ESI): m/z is 332.2 [M+H] ⁺ .

BB124

tert-Butyl-(2-(3-(phenyl(piperidin-4-yl)methyl)phenoxy)ethyl)carbamate

Into a mixture of benzyl 4-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)(menyl)methylene)piperidine-1-carboxylate (60 mg, 111 µmol), methanol (3 ml) and AcOH (60 μl) was loaded with Pt-Pd/C (60 mg, 2.5% plus 2.5%, 63% H ₂ O) and placed in an atmosphere of hydrogen gas (50 kPa). This mixture was shaken at 50°C for 2 h, diluted with EtOAc and filtered. The filtrate was washed with KHCO ₃ and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the crude title compound (33 mg, 68%) as a white foam, which was used in the next reaction step without further purification. MS (ESI): m/z is 411.3 [M+H] ⁺ .

Intermediates

a) Benzyl-(Z)-4-(phenyl(2-tosylhydrazinylidene)methyl)piperidine-1-carboxylate

Solution of 4-methylbenzenesulfonhydrazide (1.54 g, 8.29 mmol, CAS RN 1576-35-8;) and tert-butyl 4-benzoylpiperidine-1-carboxylate (2 g, 6.91 mmol, CAS RN 922504-27 -6) in 1,4-dioxane (150 ml) was stirred at 100° C. for 16 hours. EtOAc and water were added. The layers were separated and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography (25 g silica gel; gradient EtOAc (0-30%) in n-heptane) to give the title compound (3.55 g, 82%) as light - brown butter. MS (ESI): m/z is 492.2 [M+H] ⁺ .

b) 4-((3-(2-((tert-Butoxycarbonyl)amino)ethoxy)phenyl)(phenyl)methylene)piperidine-1-carboxylate

A mixture of benzyl-(Z)-4-(phenyl(2-tosylhydrazinylidene)methyl)piperidine-1-carboxylate (1 g, 2.03 mmol), bis(triphenylphosphine)palladium(II) chloride (143 mg, 203 µmol), lithium tert-butoxide (246 mg, 3.05 mmol) and N-boc-2-(3-bromophenoxy)ethylamine (CAS RN 1098107-26-6; 772 mg, 2.44 µmol) in 1,4-dioxane ( 65 ml) was stirred at 80° C. for 12 hours. EtOAc and water were added. These layers were separated and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography (80 g silica gel; gradient EtOAc in n-heptane 0-30%) to give the title compound (280 mg, 22%) as a light yellow foam. MS (ESI): m/z is 443.2 [M-Boc+H] ⁺ .

BB125

5-Chloro-2-(piperidin-4-yl)isoindoline hydrochloride

This compound was prepared in analogy to BB52 from tert-butyl 4-(5-chloroisoindolin-2-yl)piperidine-1-carboxylate to give the desired compound as a light yellow solid. MS (ESI): m/z is 237.2 [M+H] ⁺ .

intermediate connection

tert-Butyl 4-(5-chloroisoindolin-2-yl)piperidine-1-carboxylate as a light brown solid. MS (ESI): m/z is 337.3 [M+H] ⁺ .

BB126

(4aS,8aS)-Hexahydro-2Н-pyrido[4,3-b][1,4]oxazin-3(4Н)-one hydrochloride

White suspension of tert-butyl-(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-caboxylate (330 mg, 1.29 mmol) in 2 M hydrochloric acid in ether (6.44 ml, 12.9 mmol) was stirred at RT for 22 hours. This colorless suspension was filtered and washed with diethyl ether to give the desired product as a colorless solid (0.172 g; 69.3%). MS (ESI): m/z is 157.0990 [M+H] ⁺ .

Intermediates

a) tert-Butyl-(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate

To an ice-cold solution of tert-butyl-(3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate (436 mg, 1.49 mmol) in DCM (7 ml) was added dropwise a solution of tert-butoxide potassium (668 mg, 5.96 mmol) in 2-propanol (18 ml). The ice bath was removed and the mixture was stirred at RT for 24 hours to give a white suspension. This mixture was evaporated. The residue was taken up in ethyl acetate and water and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried over MgSO ₄ , filtered, treated with silica gel and evaporated. This compound was purified by silica gel chromatography on a 40 g column using an MPLC system eluting with a DCM:MeOH gradient (100:0 to 90:10) to give the desired compound as a colorless foam (330 mg; 86.5% yield). MS (ESI): m/z is 201.1 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-(3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate

To a suspension of tert-butyl-(3S,4S)-3-amino-4-hydroxypiperidine-1-carboxylate (500 mg, 2.31 mmol, CAS RN 1312812-78-4) and sodium acetate trihydrate (629 mg, 4, 62 mmol) in acetone (4 ml) and water (300 μl) was added dropwise a solution of 2-chloroacetyl chloride (261 mg, 184 μl, 2.31 mmol) in acetone (500 μl). This mixture was stirred at RT for 3 hours before adding the silica gel. This suspension was evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system (ISCO) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to give the desired compound as a colorless foam (436 mg; 64.4% ). MS (ESI): m/z is 291.3 [M-H] ^- .

BB127

4-[1-[4-(Trifluoromethyl)phenyl]ethyl]piperidine formate

A solution of tert-butyl 4-[1-[4-(trifluoromethyl)phenyl]ethyl]piperidine-1-carboxylate (1500.0 mg, 4.2 mmol) in HCl in dioxane (50.0 ml, 200 mmol) was stirred at 20° C. for 2 hours. This mixture was concentrated and the residue was purified by preparative HPLC (FA) and lyophilized to give the desired compound as a light yellow oil (838.4 mg, 77.1%). MS (ESI): m/z is 258.1 [M+H] ⁺ .

Intermediates

a) tert-Butyl-4-[1-[4-(trifluoromethyl)phenyl]eynyl]piperidine-1-carboxylate

To a solution of methyltriphenylphosphonium bromide (499.8 mg, 1.4 mmol, CAS RN 1779-49-3) in THF (10 mL) was added potassium tert-butoxide (235.5 mg, 2.1 mmol) in portions at 0°C , and the mixture was stirred at 0° C. for 30 minutes. tert-Butyl-4-[4-(trifluoromethyl)benzoyl]piperidine-1-carboxylate (500.0 mg, 1.4 mmol, CAS RN 725229-27-6) in THF (5 mL) was added dropwise, and this the mixture was heated to 20° C. and stirred at RT for 12 h. This mixture was poured into saturated aq. NH ₄ Cl solution (50 ml) and extracted twice with EtOAc (each time 20 ml). The layers were separated, the organic phase was washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was purified on a silica gel column (PE:EtOAc - 20:1) to give the desired compound as a light yellow oil (200 mg, 40.2%). MS: MS (ESI): m/z is 300.0 [MC ₄ H ₈ +H] ⁺ .

b) tert-Butyl-4-[1-[4-(trifluoromethyl)phenyl]ethyl]piperidine-1-carboxylate

Pd/C (1, 0 g, 5.63 mmol) and this mixture was stirred at 20° C. under hydrogen atmosphere for 12 hours. This mixture was filtered and the filtrate was concentrated to give the crude product (1.8 g, 89.5%) as a colorless oil which was used in the next step without further purification. MS (ESI): m/z is 302.2 [M-C ₄ H ₈ +H] ⁺ .

BB128

3-(Piperidin-4-yl)-5-(trifluoromethyl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (110 mg, 333 µmol) was dissolved in DCM (1 ml) and HCl in 2 M ether ( 2 ml, 4 mmol). This reaction mixture was stirred for 5 hours at RT. The solvent was removed in vacuo to give the crude product as a white foam, 100 mg (99%). Used without further purification. MS (ESI): m/z is 231.1 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-(5-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate

In a dried 25 ml three-necked flask, zinc powder (172 mg, 2.63 mmol) was combined with 1 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorothymethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl-4-iodopiperidine-1-carboxylate (688 mg, 2.21 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-necked flask, 3-bromo-5-(trifluoromethyl)pyridine (250 mg, 1.11 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(1) iodide (21.1 mg, 111 µmol) was added ) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) - complex with dichloromethane (45.2 mg, 55.3 µmol). This reaction mixture was degassed with argon, a freshly prepared zinc reagent solution was added, again degassed with argon, and this reaction mixture was stirred overnight at 80°C. This reaction mixture was quenched with 10 ml sat. an aqueous solution of NH ₄ Cl and was extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 80% over 35 minutes gave the desired product as a light yellow oil (112 mg, 31%). MS (ESI): m/z is 331.2 [M+H] ⁺ .

BB129

4-(Difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine hydrochloride

tert-Butyl 4-(difluoro(4-(trifluoromethyl)phenyl)methyl)pipeidine-1-carboxylate (0.338 g, 891 µmol) was dissolved in DCM (1 ml) and HCl in 2 M ether (4.45 ml, 8.91 mmol). This reaction mixture was stirred 16 hours at RT. The solvent was removed in vacuo to give the crude product as an off-white solid, 246 mg (82%). Used without further purification. MS (ESI): m/z is 280.11 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-(4-(trifluoromethyl)benzoyl)piperidine-1-carboxylate

To a solution of piperidin-4-yl(4-(trifluoromethyl)phenyl)methanone hydrochloride (0.500 g, 1.7 mmol), triethylamine (345 mg, 475 µl, 3.4 mmol) and DMAP (62.4 mg, 511 µmol ) in acetonitrile (10 ml) was added Boc20 (446 mg, 2.04 mmol) at 0° C. under argon. This reaction mixture was stirred at RT for 4 hours. This reaction mixture was poured into 15 ml sat. NaHCO ₃ and extracted twice with EtOAc (each time 25 ml). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was triturated with n-heptane to give the desired product as an off-white solid (354 mg, 58%), which was used directly for the next step. MS (ESI): m/z is 302.1 [M-C ₄ H ₈ +H] ⁺ .

b) tert-Butyl-4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperidine-1-carboxylate (0.350 g, 979 µmol) in DCM (3 ml) was added DAST (5.53 g, 34.3 mmol). This reaction mixture was stirred at 45°C for three days. This reaction mixture was poured into 15 ml H ₂ O and ice and extracted twice with DCM (each time 20 ml). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% EtOAc in n-heptane) to give the desired compound as a yellow oil (341 mg, 92%). MS (ESI): m/z is 379.1 [M+H] ⁺ .

BB130

3-Methoxy-5-(piperidin-4-yl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-methoxypyridin-3-yl)piperidine-1-carboxylate (150 mg, 513 µmol) was dissolved in DCM (1 ml) and HCl in 2 M ether (2.57 ml, 5.13 mmol). This reaction mixture was stirred 3 hours at RT. The solvent was removed in vacuo to give the crude product as a light yellow foam, 136 mg (100%). Used without further purification. MS (ESI): m/z is 193.1 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-(5-methoxypyridin-3-yl)piperidine-1-carboxyl obtaining a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl 4-iodopiperidine-1-carboxylate (927 mg, 2.98 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-neck flask, 3-bromo-5-methoxypyridine (280 mg, 1.49 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(I) iodide (28.4 mg, 149 µmol) was added and [ 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) - complex with dichloromethane (60.8 mg, 74.5 µmol). This reaction mixture was degassed with argon, a freshly prepared solution of zinc reagent was added, again degassed with argon, and this reaction mixture was stirred for 6 h at 80°C. This reaction mixture was quenched with 10 ml sat. NH ₄ Cl and extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 100% over 35 minutes gave the desired product as a light yellow oil (150 mg, 34.5%). MS (ESI): m/z is 293.2 [M+H] ⁺ .

BB131

4-((4-Chporphenyl)difluoromethyl)piperidine hydrochloride

tert-Butyl 4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate (440mg, 1.27mmol) was dissolved in DCM (2mL) and HCl in 2M ether (6, 36 ml, 12.7 mmol). This reaction mixture was stirred for 64 hours at RT. The solvent was removed in vacuo to give the crude product as an off-white solid, 323 mg (90%). Used without further purification. MS (ESI): m/z is 246.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (0.500 g, 1.54 mmol) in DCM (3 mL) was added DAST (8.71 g, 54 mmol). This reaction mixture was stirred at 45°C for eight days. This reaction mixture was poured into 15 ml H ₂ O and ice and extracted twice with DCM (each time 20 ml). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% EtOAc in n-heptane) to give the desired product as a yellow oil (440 mg, 82%). MS (ESI): m/z is 345.1 [M+H] ⁺ .

BB132

2-(Piperidin-4-yl)-5-(trifluoromethoxy)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-(trifluoromethoxy)pyridin-2-yl)piperidine-1-carboxylate (380 mg, 1.1 mmol) was dissolved in DCM (2 ml) and HCl in 2 M ether was added (3.29 ml, 6.58 mmol). The reaction mixture was stirred at RT for 4 hours. The solvent was removed in vacuo to give the crude product as a light yellow foam (349 mg, 99%) which was used in the next step without further purification. MS (ESI): m/z is 246.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-(5-(trifluoromethoxy)pyridin-2-yl)piperidine-1-carboxylate

In a dried 25 ml three-neck flask, zinc powder (193 mg, 2.38 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl 4-iodopiperidine-1-carboxylate (771 mg, 2.48 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-necked flask, 2-bromo-5-(trifluoromethoxy)pyridine (300 mg, 172 μl, 1.24 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(I) iodide (23.6 mg , 124 µmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (50.6 mg, 62 µmol). This reaction mixture was degassed with argon, a freshly prepared solution of zinc reagent was added, again degassed with argon, and this reaction mixture was stirred for 6 h at 80°C. This reaction mixture was quenched with 10 ml sat. NH ₄ Cl and extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 50% over 35 minutes gave the desired product as a light yellow oil (387 mg, 90.1%). MS (ESI): m/z is 347.1 [M+H] ⁺ .

BB133

4-((2-Chloro-4-fluorophenyl)difluoromethyl)piperidine hydrochloride

In a 25 ml tube, tert-butyl 4-((2-chloro-4-fluorophenyl)difluoromethyl)piperidine-1-carboxylate (0.363 g, 998 µmol) was dissolved in DCM (2 ml) and HCl in 2 M ether (4 .99 ml, 9.98 mmol). This reaction mixture was stirred at RT overnight. The solvent was removed in vacuo to give the crude product as a light brown solid, 296 mg (99%). Used without further purification. MS (ESI): m/z is 264.08 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-((2-chloro-4-fluorophenyl)difluoromethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(2-chloro-4-fluorobenzoyl)piperidine-1-carboxylate (0.48 g, 1.4 mmol) in DCM (4 mL) was added DAST (7.92 g, 49. 2 mmol). This reaction mixture was stirred at 45°C for ten days. This reaction mixture was poured into 15 ml H20 plus ice and extracted with DCM (2×20 ml). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% EtOAc in n-heptane): 363 mg (71%), light brown oil, desired product. MS (ESI): m/z is 363.1 [M+H] ⁺ .

BB134

3-Ethyl-5-(piperidin-4-yl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-ethylpyridin-3-yl)piperidine-1-carboxylate (295 mg, 1.02 mmol) was dissolved in DCM (3 ml) and HCl in 2 M ether (3 .05 ml, 6.09 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a yellow solid, 266 mg (99%). Used without further purification. MS (ESI): m/z is 191.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(5-ethylpyridin-3-yl)piperidine-1-carboxylate

In a dried 25 ml three-necked flask, zinc powder (234 mg, 3.58 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-necked flask, 3-bromo-5-ethylpyridine (280 mg, 1.5 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(1) iodide (28.7 mg, 150 µmol) was added and [ 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) - complex with dichloromethane (61.5 mg, 75.2 µmol). This reaction mixture was degassed with argon, a freshly prepared zinc reagent solution was added, again degassed with argon, and this reaction mixture was stirred for 2.5 h at 80°C. This reaction mixture was quenched with 10 ml sat. aqueous solution of NH ₄ Cl and was extracted with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 60% over 40 minutes gave the desired product as a light yellow oil (299 mg, 68.4%). MS (ESI): m/z is 291.2 [M+H] ⁺ .

BB135

5-(1,1-Difluoroethyl)-2-(piperidin-4-yl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-(1,1-difluoroethyl)pyridin-2-yl)piperidine-1-carboxylate (416 mg, 1.27 mmol) was dissolved in DCM (3 ml) and added HCl in 2 M ether (3.82 ml, 7.65 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a yellow solid, 381 mg (99%). Used without further purification. MS (ESI): m/z is 227.2 [M+H] ⁺ .

Intermediate connection:

tert-Butyl-4-(5-(1,1-difluoroethyl)pyridin-2-yl)piperidine-1-carboxylate

In a dried 25 ml three-necked flask, zinc powder (210 mg, 3.22 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl-4-iodopiperidine-1-carboxylate (841 mg, 2.7 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-neck flask, 2-bromo-5-(1,1-difluoroethyl)pyridine (300 mg, 1.35 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(I) iodide (25.7 mg, 135 µmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (55.2 mg, 67.6 µmol). This reaction mixture was degassed with argon, a freshly prepared zinc reagent solution was added, again degassed with argon, and this reaction mixture was stirred for 2.5 h at 80°C. This reaction mixture was quenched with 10 ml sat. NH ₄ Cl and extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 50% over 40 minutes gave the desired product as a yellow oil (419 mg, 85%). MS (ESI): m/z is 327.2 [M+H] ⁺ .

BB136

(4aR,8aS)-6-(4-(5-(1,1-Difluoroethyl)pyridin-2-yl)-3-methylpiperidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1 ,4]oxazine-3(4Н)-one

The title compound was prepared by analogy with Method A2 from BB14a and 5-(1,1-difluoroethyl)-2-(3-methyl-4-piperidyl)pyridine dihydrochloride. MS (ESI): m/z is 423.4 [M+H] ⁺ .

Intermediates:

a) 5-(1,1-Difluoroethyl)-2-(3-methyl-4-piperidyl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-(1,1-difluoroethyl)pyridin-2-yl)piperidine-1-carboxylate (265 mg, 778 µmol) was dissolved in DCM (3 ml) and HCl was added in 2 M ether (3.11 ml, 6.23 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a light yellow solid (242 mg, 99%). Used without further purification. MS (ESI): m/z is 241.2 [M+H] ⁺ .

b) tert-Butyl-4-[5-(1,1-difluoroethyl)-2-pyridyl]-3-methyl-piperidine-1-carboxylate

In a dried 25 ml three-necked flask, zinc powder (140 mg, 2.14 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl-4-iodo-3-methylpiperidine-1-carboxylate (586 mg, 1.8 mmol) in 2 ml of DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-necked flask, 2-bromo-5-(1,1-difluoroethyl)pyridine (200 mg, 901 µmol, CAS RN 1211521-60-6) was combined with 1.5 ml DMA to give a colorless solution, copper iodide ( I) (17.2 mg, 90.1 µmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (36.8 mg, 45 µmol). This reaction mixture was degassed with argon, a freshly prepared zinc reagent solution was added, again degassed with argon, and this reaction mixture was stirred for 3 h at 80°C. This reaction mixture was quenched with 10 ml sat. NH ₄ Cl and extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc (0 to 50% in 35 min) gave the desired product as a yellow oil (266 mg, 87%). MS (ESI): m/z is 341.2 [M+H] ⁺ .

BB137

1-(2,2,2-Trifluoro-1-phenyl-ethyl)piperazine hydrochloride

In a 25 ml tube, tert-butyl 4-(2,2,2-trifluoro-1-phenylethyl)piperazine-1-carboxylate (155 mg, 450 µmol) was dissolved in DCM (2 ml) and HCl in 2 M ether was added (1.8 ml, 3.6 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a light brown solid, 127 mg (100%). Used without further purification. MS (ESI): m/z is 245.3 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(2,2,2-trifluoro-1-phenyl-ethyl)piperazine-1-carboxylate

To a dry 100 ml baffled flask with N ₂ sparger was added tert-butyl piperazine-1-carboxylate (1000 mg, 5.37 mmol), triethylamine (1.63 g, 2.25 ml, 16.1 mmol), 2 ,2,2-trifluoro-1-phenylethan-1-one (935 mg, 754 µl, 5.37 mmol) and DCM (33 ml). 1 M titanium tetrachloride in DCM (2.68 mL, 2.68 mmol) was added via syringe. This reaction mixture was stirred for 18 h, carefully quenched with a methanolic solution of NaCNBH ₃ (sodium cyanoborohydride (1.01 g, 16.1 mmol) in methanol (12.8 ml, 316 mmol) and stirred for 15 min. This reaction mixture basified to pH 13 with 5 M NaOH (0.5 ml), extracted with DCM (2×60 ml), dried (Na ₂ SO ₄ ) and evaporated to give a yellow oil (2 g).

Purification by flash chromatography on SiO ₂ using a gradient of EtOAc in n-heptane (0 to 30% over 40 min) gave the desired product as a light yellow oil (156 mg, 8.4%). MS (ESI): m/z is 345.2 [M+H] ⁺ .

BB138

1-[1-(2,4-Difluoromethyl)-2,2,2-trifluoro-ethyl]piperazine hydrochloride

In a 25 ml tube, tert-butyl 4-(2,2,2-trifluoro-1-phenylethyl)piperazine-1-carboxylate (330 mg, 868 µmol) was dissolved in DCM (2 ml) and HCl in 2 M ether was added (2.6 ml, 5.1 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a brown viscous oil, 266 mg (97%). Used without further purification. MS (ESI): m/z is 282.3 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-[1-(2,4-difluorophenyl)-2,2,2-trifluoro-ethyl]piperazine-1-carboxylate

To a dry 100 ml baffled flask with N ₂ sparger was added tert-butyl piperazine-1-carboxylate (1000 mg, 5.37 mmol), triethylamine (1.63 g, 2.25 ml, 16.1 mmol), 1 -(2,4-difluorophenyl)-2,2,2-trifluoroethan-1-one (1.13 g, 5.37 mmol) and DCM (33 ml). 1 M titanium tetrachloride in DCM (2.68 mL, 2.68 mmol) was added via syringe. This reaction mixture was stirred for 18 h, quenched thoroughly with a methanolic solution of NaCNBH ₃ (sodium cyanoborohydride (1.01 g, 16.1 mmol) in methanol (4.3 ml, 107 mmol) and stirred for 6 h. This reaction mixture basified with sat.NaHCO ₃ (10 ml) The resulting insoluble matter was filtered through celite, the filtrate was extracted with DCM (2×60 ml), dried (Na ₂ SO ₄ ) and evaporated to give a yellow oil (2.1 g).

Purification by flash chromatography on SiO ₂ using a n-heptane/EtOAc gradient of 0 to 20% over 40 minutes gave the desired product as a yellow oil (340 mg, 13.3%). MS (ESI): m/z is 381.1 [M+H] ⁺ .

BB139

2-Cyclopropyl-4-(4-piperidyl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(2-cyclopropylpyridin-4-yl)piperidine-1-carboxylate (278 mg, 919 µmol) was dissolved in DCM (2 ml) and HCl in 2 M ether (2.76 ml, 5.52 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a light yellow solid, 250 mg (99%). Used without further purification. MS (ESI): m/z is 202.4 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(2-cyclopropyl-4-pyridyl)piperidine-1-carboxylate

In a dried 25 ml three-neck flask, zinc powder (196 mg, 3 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl 4-iodopiperidine-1-carboxylate (786 mg, 2.52 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-necked flask, 4-bromo-2-cyclopropylpyridine (250 mg, 1.26 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(I) iodide (24 mg, 126 µmol) was added and [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) - complex with dichloromethane (51.1 mg, 63.1 µmol). This reaction mixture was degassed with argon, a freshly prepared zinc reagent solution was added, again degassed with argon, and this reaction mixture was stirred for 3 h at 80°C. This reaction mixture was quenched with 10 ml sat. aqueous solution of NH ₄ Cl and was extracted with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 60% over 45 minutes gave the desired product as a light yellow oil (278 mg, 73%). MS (ESI): m/z is 303.2 [M+H] ⁺ .

BB140

3-Methyl-5-(4-piperidyl)-2-(trifluoromethyl)pyridine dihydrochloride

In a 25 ml tube, tert-butyl 4-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (360 mg, 1.05 mmol) was dissolved in DCM (3 ml) and added HCl in 2 M ether (2.61 ml, 5.23 mmol). This reaction mixture was stirred 4 h at RT. The solvent was removed in vacuo to give the crude product as a white solid, 314 mg (95%). Used without further purification. MS (ESI): m/z is 245.2 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-[5-methyl-6-(trifluoromethyl)-3-pyridyl]piperidine-1-carboxylate

In a dried 25 ml three-necked flask, zinc powder (182 mg, 2.78 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl-4-iodopiperidine-1-carboxylate (726 mg, 2.33 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-neck flask, 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (280 mg, 1.17 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(I) iodide (22.2 mg, 117 µmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (48 mg, 58 µmol). This reaction mixture was degassed with argon, a freshly prepared zinc reagent solution was added, again degassed with argon, and this reaction mixture was stirred for 2.5 h at 70°C. This reaction mixture was quenched with 10 ml sat. NH ₄ Cl and extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using n-heptane/EtOAc 0 to 50% over 40 min gave the desired product as a white crystalline solid (360 mg, 90%). MS (ESI): m/z is 345.2 [M+H] ⁺ .

BB141

4-(4-Piperidyl)-5,6,7,8-tetrahydroquinoline dihydrochloride

In a 25 ml tube, tert-butyl 4-(5,6,7,8-tetrahydroquinolin-4-yl)piperidine-1-carboxylate (255 mg, 806 µmol) was dissolved in DCM (3 ml) and HCl was added in 2 M ether (2.01 ml, 4.03 mmol). This reaction mixture was stirred 8 hours at RT. The solvent was removed in vacuo to give the crude product as a light yellow solid, 230 mg (99%). Used without further purification. MS (ESI): m/z is 217.4 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(5,6,7,8-tetrahydroquinolin-4-yl)piperidine-1-carboxylate

In a dried 25 ml three-neck flask, zinc powder (177 mg, 2.71 mmol) was combined with 1.5 ml DMA (through a molecular sieve) to give a gray suspension. This mixture was stirred at RT while adding a mixture of 7:5 v/v. chlorotrimethylsilane (32 μl) and 1,2-dibromoethane (22 μl) as a solution in DMA (1 ml) at such a rate as to maintain the temperature below 65°C (slightly exothermic conditions). The resulting suspension was stirred for 20 minutes. To this mixture was slowly added a solution of tert-butyl-4-iodopiperidine-1-carboxylate (734 mg, 2.36 mmol) in 2 ml DMA. The resulting reaction mixture was then stirred for 30 minutes at RT. This reaction mixture was allowed to stand for 15 min without stirring for decantation.

In a 25 ml three-neck flask, 4-bromo-5,6,7,8-tetrahydroquinoline (250 mg, 1.18 mmol) was combined with 1.5 ml DMA to give a colorless solution, copper(I) iodide (22.4 mg , 118 µmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (48 mg, 58 µmol). This reaction mixture was degassed with argon, a freshly prepared solution of zinc reagent was added, degassed with argon again, and this reaction mixture was stirred for 2.5 h at 75°C. This reaction mixture was quenched with 10 ml sat. NH ₄ Cl and extracted twice with EtOAc (each time 40 ml). The organic layers were washed with brine. These organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by flash chromatography on SiO ₂ using a gradient of EtOAc in n-heptane (0 to 70% over 40 min) gave the desired product as a colorless viscous oil (255 mg, 68.4%). MS (ESI): m/z is 317.3 [M+H] ⁺ .

BB142

3-[2-Fluoro-4-(trifluoromethyl)phenyl]azetidine trifluoroacetate

TFA (94.1 µl, 1.22 mmol ). The resulting reaction mixture was stirred at RT for 1 hour. This reaction mixture was concentrated in vacuo (co-evaporated with toluene) to give the desired product as a colorless oil (85 mg, 100%). MS (ESI): m/z is 220.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-3-[2-fluoro-4-(trifluoromethyl)phenyl]azetidine-1-carboxylate

To a 20 ml vessel equipped with a stirring bar was added photocatalyst (Ir[dF(CF3)ppy]2(dtbpy))PF6 (6.93 mg, 6.17 µmol), 1-bromo-2-fluoro-4-(trifluoromethyl )benzene (150 mg, 88.5 µl, 617 µmol), tert-butyl-3-bromazetidine-1-carboxylate (219 mg, 152 µl, 926 µmol), Tris(trimethylsilyl)silane (153 mg, 617 µmol) and anhydrous sodium carbonate (131 mg, 1.23 mmol). This vessel was sealed and placed under argon before adding DME (5 ml). Glim NiCl ₂ (1.36 mg, 6.17 µmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (1.66 mg, 6.17 µmol) were added to a separate vessel. The vessel with the catalyst was sealed, purged with argon, then DME (2 ml) was added to it. The vessel with the precatalyst was sonicated for 5 min, after which 1 ml (0.5 mol. % catalyst, 0.005 eq.) was injected into the reaction vessel with a syringe. This solution was degassed by sparging with argon. This reaction mixture was stirred and irradiated with a lamp with a wavelength of 420 nm for 5 hours. This reaction was quenched by exposure to air and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, gradient 0% to 50% EtOAc in n-heptane) and a second flash chromatography (silica gel, 50 g, 0% to 20% EtOAc in n-heptane). The product was obtained as a colorless liquid (197 mg, 44%). MS (ESI): m/z is 264.2 [M-C ₄ H ₈ +H] ⁺ .

BB143

4-(1-(4-Fluorophenyl)-1H-pyrazol-3-yl)piperidine hydrochloride

In a 25 ml tube, tert-butyl 4-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (100 mg, 290 µmol) was dissolved in DCM (3 ml) and HCl was added in 2 M ether (1.16 ml, 2.23 mmol). This reaction mixture was stirred for 6 hours at RT. The solvent was removed in vacuo to give the crude product as a light yellow solid (81 mg, 99%). This compound was used without further purification. MS (ESI): m/z is 246.2 [M+H] ⁺ .

Intermediates:

a) tert-Butyl-4-(1H-pyrazol-3-yl)piperidine-1-carboxylate

tert-Butyl 4-acetylpiperidine-1-carboxylate (620 mg, 2.73 mmol) was combined with N,N-dimethylformamide dimethylacetal (6.7 g, 54.6 mmol) and heated at 100°C for 15 h. LCMS indicated completion of the reaction. This reaction mixture was directly concentrated in vacuo and the residue combined with EtOH (8 ml) and hydrazine dihydrochloride (344 mg, 3.27 mmol). This mixture was stirred at reflux temperature for 1.5 hours. LCMS again indicated completion of the reaction. This reaction mixture was concentrated to give the crude product as a light yellow solid (650 mg, 95%). Used in the next step without further purification.

b) tert-Butyl-4-[1-(4-fluorophenyl)pyrazol-3-yl]piperidine-1-carboxylate

In a 100 ml flask purged with argon, tert-butyl-4-(1H-pyrazol-3-yl)piperidine-1-carboxylate (300 mg, 1.19 mmol) was suspended in DMF (8 ml), pyridine (386 μl) was added , 4.77 mmol), (4-fluorophenyl)boronic acid (217 mg, 1.55 mmol) and copper(II) acetate (325 mg, 1.79 mmol). The resulting green solution was stirred for 60 hours at RT. The solvent was removed in vacuo, the residue was extracted with ethyl acetate/water/sat. NaCl, dried over MgSO ₄ , filtered and the solvent was removed in vacuo. The crude material was purified by flash chromatography (silica gel, gradient from 0% to 40% EtOAc in n-heptane over 40 minutes). The product was obtained as a colorless viscous oil (290 mg, 70%). MS (ESI): m/z is 290.2 [M-C ₄ H ₈ +H] ⁺ .

BB144

4-(4-Piperidyl)-3-(trifluoromethyl)pyridazine hydrochloride

In a 25 ml tube, tert-butyl 4-(3-(trifluoromethyl)pyridazin-4-yl)piperidine-1-carboxylate (180 mg, 543 µmol) was dissolved in DCM (1 ml) and HCl in 2 M ether ( 2.72 ml, 5.43 mmol). This reaction mixture was stirred 6 h at RT. The solvent was removed in vacuo to give the crude product as a yellow solid, 145 mg (100%). Used without further purification. MS (ESI): m/z is 232.2 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(3-(trifluoromethyl)pyridazin-4-yl)piperidine-1-carboxylate

Potassium (1-(tert-butoxycarbonyl)piperidin-4-yl)trifluoroborate (649 mg, 2.23 mmol), silver nitrate (68.8 mg, 405 µmol) and potassium persulfate ( 2.74 g, 10.1 mmol). 1,2-dichloroethane (2 ml), water (2 ml), 3-(trifluoromethyl)pyridazine (300 mg, 2.03 mmol) and TFA (462 mg, 312 μl, 4.05 mmol) were added successively, and this the tube was sealed. This reaction mixture was vigorously stirred at RT for 24 h.

This reaction mixture was then poured into 20 ml of a 1/1 v/v mixture. sat. aq. NaHCO ₃ and 5% aq. NaS ₂ O ₃ and the resulting solution was extracted three times with DCM. The combined organic layers were dried (MgSO ₄ ) and evaporated to give the crude product.

Purification by flash chromatography on SiO ₂ with a n-heptane/EtOAc gradient of 0 to 80% over 35 min gave the desired product as a yellow viscous oil (180 mg, 80% pure, 21.5%). The regioisomer was confirmed by NMR. MS (ESI): m/z is 332.2 [M+H] ⁺ .

BB145

(4aR,8aS)-6-(3-(4-Hydroxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

This compound was prepared by analogy with method A4 from 3-(4-hydroxyphenyl)azetidine-4-methylbenzenesulfonate. Light brown solid. MS (ESI): m/z is 332.2 [M+H] ⁺ .

Intermediates

a) 3-(4-Hydroxyphenyl)azetidine-4-methylbenzenesulfonate

Mixture of tert-butyl 3-(4-(tert-butoxy)phenyl)azetidine-1-carboxylate (70 mg, 229 µmol) and 4-methylbenzenesulfonic acid hydrate (52.3 mg, 275 µmol) in EtOAc (1 ml) stirred at reflux for 30 min. This mixture was evaporated to give the desired product, which was used in the next step without further purification.

b) tert-Butyl-3-(4-(tert-butoxy)phenyl)azetidine-1-carboxylate

This compound was prepared analogously to Method A7 from 1-bromo-4-(tert-butoxy)benzene (CAS RN 60876-70-2) to give the desired compound as a colorless solid. MS (ESI): m/z is 250.2 [M-C ₄ H ₈ +H] ⁺ .

BB146

3-(3,4-Dimethylphenyl)azetidine 4-methylbenzenesulfonate This compound was prepared by analogy with BB28 from tert-butyl-3-(3,4-dimethylphenyl)azetidine-1-carboxylate to give the desired compound as a colorless solid. MS (ESI): m/z is 162.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-3-(3,4-dimethylphenyl)azetidine-1-carboxylate

This compound was prepared in analogy to BB35, an intermediate, from (3,4-dimethylphenyl)boronic acid to give the desired compound as a colorless oil. MS (ESI): m/z is 206.1 [M-C ₄ H ₈ +H] ⁺ .

BB147

3-(4-tert-Butoxyphenyl)azetidine 4-methylbenzenesulfonate

This compound was obtained by analogy with BB28 from tert-butyl 3-(4-tert-butoxyphenyl)azetidine-1-carboxylate (BB145, intermediate b) at RT as a colorless solid. MS (ESI): m/z is 206.2 [M+H] ⁺ .

BB148

5-Chloro-1-(4-piperidyl)indoline

This compound was prepared in analogy to BB26 intermediate a from tert-butyl 4-(5-chloroindolin-1-yl)piperidine-1-carboxylate to give the desired compound as a gray solid. MS (ESI): m/z is 237.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(5-chloroindolin-1-yl)piperidine-1-carboxylate

AcOH (605.43 mg, 9.76 mmol), 5- chlorindoline (500.0 mg, 3.25 mmol, CAS RN 25658-80-4) and NaBH ₃ (CN) (613.63 mg, 9.76 mmol) at 25°C and the reaction mixture was stirred for 2 am This reaction mixture was poured into sat. aqueous solution of NH ₄ Cl (20 ml) and was extracted three times with EtOAc (each time 20 ml). The combined organic layers were washed three times with water (20 ml each) and brine (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the product as a white solid (1 g, 118.3%). MS (ESI): m/z is 337.1 [M+H] ⁺ . The crude product was directly used in the next step without further purification.

BB149

4-Chloro-2-(piperidin-4-yl)isoindoline hydrochloride

This compound was prepared in analogy to BB52 from tert-butyl 4-(4-chloroisoindolin-2-yl)piperidine-1-carboxylate to give the desired compound. MS (ESI): m/z is 237.2 [M+H] ⁺ . Used in the next step without further purification.

Intermediates

tert-Butyl-4-(4-chloroisoindolin-2-yl)piperidine-1-carboxylate

This compound was prepared in analogy to BB148, an intermediate, from 4-chloroisoindoline (CAS RN 123594-04-7) to give the desired compound as a gray oil. MS (ESI): m/z is 337.3 [M+H] ⁺ .

BB150

5'-Chloro-1'-(4-piperidyl)spiro[cyclopropane-1,3'-indoline]

This compound was prepared by analogy with BB26, an intermediate, from tert-butyl 4-(5'-chlorospiro[cyclopropan-1,3'-indoline]-1'-yl)piperidine-1-carboxylate to give the desired compound as yellow solid. MS (ESI): m/z is 263.1 [M+H] ⁺ .

intermediate connection

tert-Butyl-4-(5'-chlorospiro[cyclopropan-1,3'-indoline]-1'-yl)piperidine-1-carboxylate

This compound was prepared in analogy to BB148, an intermediate, from 5'-chlorospiro[cyclopropane-1,3'-indoline] (CAS RN 1538359-43-1) to give the desired compound as a pink solid. MS (ESI): m/z is 307.1 [M-C ₄ H ₈ +H] ⁺ .

BB151

2-(Azetidin-3-yl)-4-chloroisoindoline hydrochloride

This compound was prepared in analogy to BB52 from tert-butyl 3-(4-chloroisoindolin-2-yl)azetidine-1-carboxylate to give the desired compound as a light green solid. MS (ESI): m/z is 209.2 [M+H] ⁺ .

intermediate connection

tert-Butyl-3-(4-chloroisoindolin-2-yl)azetidine-1-carboxylate

This compound was prepared in analogy to BB148, an intermediate, from 4-chloroisoindoline hydrochloride (CAS RN 924304-73-4) to give the desired compound as a colorless amorphous solid. MS (ESI): m/z is 309.2 [M+H] ⁺ .

BB152

3-[2-Methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine 2,2,2-trifluoroacetate

This compound was prepared in analogy to BB26, an intermediate, from tert-butyl 3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carboxylate to give the desired compound as a yellow oil. MS (ESI): m/z is 246.1 [M+H] ⁺ .

Intermediates

a) tert-Butyl-3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-[2-methoxy-4-[2,2,2-trifluoro-1-(p-tolylsulfonyloxy)ethyl]phenyl]azetidine-1-carboxylate (480.0 mg, 0.930 mmol) in EtOH (24 mL) was added with Pd/C (120.0 mg, 0.930 mmol) and the mixture was stirred at 20° C. under H ₂ (balloon) for 24 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (30 ml) and washed with aqueous Na ₂ CO ₃ (20 ml), followed by brine, dried over Na ₂ SO ₄ and concentrated to obtain the desired product as a light yellow foam. (300 mg, 93.3%). MS (ESI): m/z is 290.1 [MC ₄ H ₈ +H] ⁺ .

b) tert-Butyl-3-[2-methoxy-4-[2,2,2-trifluoro-1-(p-tolylsulfonyloxy)ethyl]phenyl]azetidine-1-carboxylate

This compound was prepared in analogy to Method A7 from [1-(4-bromo-3-methoxy-phenyl)-2,2,2-trifluoro-ethyl]-4-methylbenzenesulfonate to give the desired compound as a light yellow oil. MS (ESI): m/z is 460.1 [M-C ₄ H ₈ +H] ⁺ .

c) [1-(4-Bromo-3-methoxy-phenyl)-2,2,2-trifluoro-ethyl]-4-methylbenzenesulfonate

To a solution of 1-(4-bromo-3-methoxy-phenyl)-2,2,2-trifluoro-ethanol (1000.0 mg, 3.51 mmol), p-toluenesulfonyl chloride (668.81 mg, 3.51 mmol ) and DMAP (20.0 mg, 0.180 mmol) in DCM (20 ml) was added TEA (708.62 mg, 7.02 mmol) at 0°C. This mixture was stirred at 20° C. for 12 hours. This mixture was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a light yellow oil (1.5 g, 97.4%). This compound was used in the next step without further purification.

d) 1-(4-Bromo-3-methoxy-phenyl)-2,2,2-trifluoro-ethanol

To a solution of 4-bromo-3-methoxy-benzaldehyde (2.0 g, 9.3 mmol, CAS RN 43192-34-3) and trifluoromethyltrimethylsilane (1586.94 mg, 11.16 mmol) in THF (30 ml) was added TBAF/THF (0.09 ml, 0.090 mmol) at 0° C., this mixture was stirred at 20° C. for 12 h, then 1 M aq. HCl (18.6 ml, 18.6 mmol). This mixture was stirred at 20° C. for another 2 hours. This mixture was poured into water (50 ml) and extracted three times with EtOAc (each time 30 ml). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a light yellow oil (2.5 g, 94.3%). 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.57 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 5.01 (q , J=6.5 Hz, 1H), 3.93 (s, 3H).

BB153

3-[4-(2,2-Dimethylpropoxy)phenyl]azetidine 4-methylbenzenesulfonate

This compound was prepared in analogy to BB28 at RT for 5 from t-butyl 3-[4-(2,2-dimethylpropoxy)phenyl]azetidine-1-carboxylate to give the desired compound as a white solid. Used in this form for the next stage.

intermediate connection

tert-Butyl-3-[4-(2,2-dimethylpropoxy)phenyl]azetidine-1-carboxylate

This compound was prepared analogously to Method A7 from 1-bromo-4-(neopentyloxy)benzene (CAS RN 528528-58-7) to give the desired compound as a colorless solid. MS (ESI): m/z is 264.2 [M-C ₄ H ₈ +H] ⁺ .

BB154

rac-(4aS,8aS)-Hexahydro-2Н-pyrido[4,3-b][1,4]oxazin-3(4Н)-one

rac-Benzyl-(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (125 mg, 431 µmol) was dissolved in MeOH (5 ml ). This reaction solution was degassed in vacuo and refilled with argon. Pd-C (20 mg, 188 µmol) was added under argon. Argon was removed from the reaction mixture and the reaction flask was refilled with hydrogen. This reaction mixture was stirred at RT for 15 hours under a hydrogen atmosphere. This reaction mixture was filtered through a syringe filter and concentrated in vacuo to give the desired product as a white solid (62 mg, 92.2%). MS (ESI): m/z is 157.098 [M+H] ⁺ .

Intermediates

a) rac-Benzyl-(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate

NaH (67.9 mg, 1.7 mmol) at 0°C. This mixture was allowed to reach RT and then stirred for 90 minutes under argon. N ₂ O (5 ml) was added and stirring was continued at RT for 10 minutes. THF was removed from the reaction mixture in vacuo. The residue was treated with DCM and the organic phase was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The residue was purified by flash chromatography (12 g reverse phase column, gradient 0-100% ACN (0.1% FA) in water (0.1% FA) to give the desired product as a white solid (133 mg, 38. 9%) MS (ESI): m/z is 291.3 [M+H] ⁺ .

b) rac-Benzyl-(3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate

Into a stirred suspension of rac-benzyl-(3S,4S)-3-amino-4-hydroxypiperidine-1-carboxylate (317 mg, 1.27 mmol, synthesized according to US 2011/59118 A1) and sodium acetate (208 mg, 2 .53 mmol, CAS RN 127-09-3) in acetone (4 ml)/H ₂ O (0.5 ml) was added dropwise a solution of chloroacetyl chloride (150 mg, 107 μl, 1.33 mmol, CAS RN 79- 04-9) in acetone (3 ml) at 0-5°C. After the addition, the reaction mixture was stirred at RT for 1 hour and then evaporated to dryness to give a yellow gum. The crude product was purified by silica gel chromatography to give the desired product as a yellow solid (385 mg, 93%). MS (ESI): m/z is 325.2 [M-H] ^- .

Example A

The compound of formula (I) can be used in a manner known per se as an active ingredient for the production of tablets of the following composition:

Per pill

Active Ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropyl methylcellulose 20 mg

425 mg

Example B

The compound of formula (I) can be used in a manner known per se as an active ingredient for the production of capsules of the following composition:

per capsule

Active Ingredient 100.00 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg magnesium stearate 0.5 mg

220.0 mg

Claims (459)

1. Compound of formula (Ic)

or a pharmaceutically acceptable salt thereof, wherein: m is 0, n is 0 or 1, and X is CR ²⁴ ; or m is 1, n is 1, and X is CR ²⁴ or N; L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -, -CHR ³ O- and a covalent bond; p is 0 or 1; R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 - alkyl-, halogen-C _1-6 -alkoxy, halogen-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

and R ² is selected from hydrogen, halogen and hydroxy; or R ¹ and R ² taken together with the carbon atom to which they are attached form C _3-12 -cycloalkyl; R ³ is C _1-6 alkyl or halo-C _1-6 alkyl; R ²⁰ is hydrogen or C _1-6 alkyl; R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl , (halo-C _1-6 -alkyl) -hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _1-6 - alkoxy-, SF ₅ , (C _1-6 -alkyl) ₃ Si-O-C _1-6 -alkyl-, groups

and groups

R ²² is selected from hydrogen, halogen, C _1-6 alkoxy, halo-C _1-6 alkoxy, C _1-6 alkyl and cyano; R ²³ is hydrogen or halogen; R ²⁴ is selected from hydrogen, halogen, hydroxy and C _1-6 alkyl; R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ - and C _3-12 cycloalkyl; R ²⁶ is selected from hydrogen, C _1-6 alkyl and C _1-6 alkoxy; R ²⁷ is selected from hydrogen, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, halogen , hydroxy, C _1-6 -alkylsulfonyl, carbamoyl, cyano, cycloalkyl-C _1-6 -alkoxy and cycloalkyl; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 aryl or C _1-13 heteroaryl; B is C _6-14 aryl or C _1-13 heteroaryl; C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl; C ² is C _6-14 aryl; L ² is selected from a covalent bond, -O- and -CH ₂ -; L ³ is selected from a covalent bond, -CH ₂ O- and -CH ₂ -; And L ^3a is a covalent bond or -CH ₂ -; where each C _1-13 -heteroaryl and each C _2-9 -heterocyclyl contains from 1 to 3 heteroatoms independently selected from O, S and N. 2. The compound of formula (Ic) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Ic) is a compound of formula (Id):

in which A, L, X, m, n and R ²⁰ -R ²³ are as defined in paragraph 1. 3. The compound of formula (Ic) according to claim 1 or a pharmaceutically acceptable salt thereof, where the compound of formula (Ic) is a compound of formula (le):

where A, L, X, m, n and R ²⁰ -R ²³ are as defined in paragraph 1. 4. The compound of formula (Ic) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein p is 0. 5. The compound of formula (Ic) according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, in which R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halogen- C _1-6 -alkoxy and groups

and R ² is hydrogen or halogen. 6. The compound of formula (Ic) according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and the group

and R ² is hydrogen or fluorine. 7. The compound of formula (Ic) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, wherein R ³ is C _1-6 alkyl. 8. The compound of formula (Ic) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl. 9. The compound of formula (Ic) according to any one of paragraphs. 1-8 or a pharmaceutically acceptable salt thereof, wherein R ²⁰ is hydrogen. 10. The compound of formula (Ic) according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R ²¹ is selected from halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and groups

where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein. 11. The compound of formula (Ic) according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, in which R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, tert-butyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2 ,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl and group

where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein. 12. The compound of formula (Ic) according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, and halo-C _1-6 -alkoxy. 13. The compound of formula (Ic) according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof, wherein R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl, and trifluoromethyl. 14. The compound of formula (Ic) according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt thereof, wherein R ²³ is hydrogen or fluorine. 15. The compound of formula (Ic) according to any one of paragraphs. 1-14 or a pharmaceutically acceptable salt thereof, wherein R ²⁴ is hydrogen. 16. The compound of formula (Ic) according to any one of paragraphs. 1-15 or a pharmaceutically acceptable salt thereof, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 alkoxy and C _3-12 cycloalkyl. 17. The compound of formula (Ic) according to any one of paragraphs. 1-15 or a pharmaceutically acceptable salt thereof, wherein R ²⁵ is selected from hydrogen, methoxy, fluorine, and cyclopropyl. 18. The compound of formula (Ic) according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt thereof, wherein R ²⁶ is hydrogen or C _1-6 -alkoxy. 19. The compound of formula (Ic) according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt thereof, wherein R ²⁶ is hydrogen or methoxy. 20. The compound of formula (Ic) according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof, in which R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _1-6 -alkyl-NH -C(O)- and halogen. 21. The compound of formula (Ic) according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof, wherein R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methyl-ethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy , 2,2,2-trifluoroethoxy, fluorine and chlorine. 22. The compound of formula (Ic) according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof, wherein R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine. 23. The compound of formula (Ic) according to any one of paragraphs. 1-22 or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pyridyl. 24. The compound of formula (Ic) according to any one of paragraphs. 1-23 or a pharmaceutically acceptable salt thereof, wherein B is phenyl or 1,2,4-oxadiazol-5-yl. 25. The compound of formula (Ic) according to any one of paragraphs. 1-24 or a pharmaceutically acceptable salt thereof, wherein C ¹ is selected from azetidin-1-yl, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl. 26. The compound of formula (Ic) according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof, wherein C ² is phenyl. 27. The compound of formula (Ic) according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt thereof, wherein L ² is a covalent bond. 28. The compound of formula (Ic) according to any one of paragraphs. 1-27 or a pharmaceutically acceptable salt thereof, wherein L ³ is a covalent bond or -CH ₂ -. 29. The compound of formula (Ic) according to any one of paragraphs. 1-28 or a pharmaceutically acceptable salt thereof, wherein L ^3a is a covalent bond. 30. The compound of formula (Ic) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein: m is 0, n is 0 or 1, and X is CH; or m is 1, n is 1, and X is CH or N; L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and a covalent bond; R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-halo-C _1-6 -alkoxy and groups

R ² is hydrogen or halogen; R ³ is C _1-6 alkyl; R ²⁰ is hydrogen; R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and the group

R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy; R ²³ is hydrogen or halogen; R ²⁵ is selected from hydrogen, halogen, C _1-6 alkoxy and C _3-12 cycloalkyl; R ²⁶ is hydrogen or C _1-6 alkoxy; R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl and halogen; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 aryl or C _1-13 heteroaryl; B is C _6-14 aryl or C _1-13 heteroaryl; C ¹ is C _3-12 cycloalkyl or C _2-9 heterocyclyl; And L ³ is a covalent bond or -CH ₂ - 31. The compound of formula (Ic) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein: m is 0, n is 0 or 1, and X is CH; or m is 1, n is 1, and X is CH or N; L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and a covalent bond; R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and the group

R ² is hydrogen or fluorine; R ³ is methyl; R ²⁰ is hydrogen; R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, t-butyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl and group

R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl; R ²³ represents hydrogen or fluorine; R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl; R ²⁶ is hydrogen or methoxy; R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methylethoxy, 2,2,2-trifluoro-1,1-dimethylethoxy, 2,2,2-trifluoroethoxy, fluoro and chlorine; R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine; A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pyridyl; B is phenyl or 1,2,4-oxadiazol-5-yl; C ¹ is selected from azetidin-1-yl, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl; And L ³ is a covalent bond or -CH ₂ -. 32. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof, selected from the following: rac-(4aR,8aS)-6-(4-benzhydrylpiperidin-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one ; rac-(4aR,8aS)-6-(4-(5-chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(5-chloro-1-methyl-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(9H-fluoren-9-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4Н )-He; (+)-cis-6-[4-(6-fluoro-1H-indol-3-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-(4-(1-(4-fluorophenyl)-3-methoxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]ocazine-3 (4H)-he; rac-(4aR,8aS)-6-[4-(6-fluoro-1H-indol-3-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3 -b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((4-fluorophenyl)(methoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-He; rac-(4aR,8aS)-6-(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; cis-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-cis-6-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; rac-(4aR,8aS)-6-[4-[bis(4-fluorophenyl)methyl]piperazine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one; (-)-cis-6-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; rac-(4aR,8aS)-6-(4-(5-chloro-1H-indol-3-yl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; rac-(4aR,8aS)-6-(4-(1-phenylethyl)piperazin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(1-methyl-1H-indazol-5-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; rac-(4aR,8aS)-6-[4-[(4-fluorophenyl)-phenylmethyl]piperazine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one; (E/Z)-3-[4-[rac-(4aS,8aR)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine -6-carbonyl]piperazin-1-yl]-2-phenylprop-2-ennitrile; (+)- or (-)-cis-6-(4-(5-chloro-1-cyclopropyl-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(5-chloro-1-(1-chloro-3-hydroxypropan-2-yl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(bis(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)piperidine-1-cabonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-(oxetan-3-ylmethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-1H-indol-3-yl)piperidine-1-carbonyl )hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-(2-hydroxyethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; rac-cis-6-(4-(1-(4-fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-He; rac-(4aR,8aS)-6-(4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; rac-(4aR,8aS)-6-(4-(1-(2-chloro-4-fluorophenoxy)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(4-(5-(trifluoromethyl)pyridin-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (+)-(4aR,8aS)-6-(4-((R or S)-1-(4-fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (-)-(4aR,8aS)-6-(4-((S or R)-1-(4-fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((S or R)-1-(2-chloro-4-fluorophenoxy)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((R or S)-1-(2-;lor-4-fluorophenoxy)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (+) yl and (-)-cis-6-(4-(5-methoxypyridin-3-yl)piperidine-1-carbonyl)hexahydro-2Η-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (+) or (-)-cis-6-(4-(bis(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (+) or (-)-cis-6-(4-((4-chlorophenyl)difluoromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (+) or (-)-cis-6-(4-(5-(trifluoromethoxy)pyridin-2-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((2-chloro-4-fluorophenyl)difluoromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (+) or (-)-cis-6-(4-(5-ethylpyridin-3-yl1)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (+) or (-)-cis-6-(4-(5-(1,1-difluoroethyl)pyridin-2-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-(6-chloro-1-methyl-1H-indazol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((3R or SS)-4-(5-(1,1-difluoroethyl)pyridin-2-yl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((3S or 3R)-4-(5-(1,1-difluoroethyl)pyridin-2-yl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((4R or 4S)-(5-(1,1-difluoroethyl)pyridin-2-yl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; 2-(4-fluorophenyl)-2-(1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl )acetonitrile; (4aR,8aS)-6-(4-(2,2,2-trifluoro-1-phenylethyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(4-((4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(1-(4-fluorophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)piperidine-1-carbonyl)hexahydro-2Н -pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(4-(1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(bis(4-fluorophenyl)(hydroxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(fluorobis(4-fluorophenyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (4aR,8aS)-6-(4-(1-(4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-1-(4-fluorophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)piperidine-1 -carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-1-(4-fluorophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)piperidine-1 -carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(2-cyclopropylpyridin-4-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)- He; (4aR,8aS)-6-[4-[(S or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(3-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3-methoxyphenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(3-methoxyphenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S)-(4-fluorophenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[(S or R)-(4-fluorophenyl)-(4-methylphenyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(R or S)-[4-(2-fluoroethoxy)phenyl]-phenylmethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(4-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(p-tolyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(3,4-dimethoxyphenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-phenyl(m-tolyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; (4aR,8aS)-6-[4-[(S or R)-[4-(2-fluoroethoxy)phenyl]-phenylmethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((S or R)-((S)-3-methylcyclohexa-2,4-dien-1-yl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(1-(2-chloro-4-fluorophenoxy)-2,2,2-trifluoroethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(bis(4-fluorophenyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (4aR,8aS)-6-[3-[1-[4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-phenyl(p-tolyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3 -b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((R or S)-phenyl(p-tolyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; (4aR,8aS)-6-(3-benzhydrylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3,4-dimethoxyphenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(4-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[1-[4-(trifluoromethyl)phenyl]ethoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(1-(4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-[4-[1-[4-(trifluoromethyl)phenyl]ethoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((R or S)-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((R or S)-1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((S or R)-1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((R or S)-1-(4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((S or R)-1-(4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-(2-fluoroethoxy)phenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(4-((4-fluorophenyl)(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((S or R)-1-(4-(trifluoromethyl)phenyl)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((R or S)-1-(4-(trifluoromethyl)phenyl)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-(S or R)-[(4-fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-1-carbonyl]-4,4a,5,7, 8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(R or S)-[(4-fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-1-carbonyl]-4,4a,5,7, 8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-(5,6,7,8-tetrahydroquinolin-4-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-(2-fluoroethoxy)phenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4'-chloro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2'-chloro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(1-(R or S)-(4-(trifluoromethyl)phenyl)ethoxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(1-(S or R)-(4-(trifluoromethyl)phenyl)ethoxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-(S or R)-[1-(2-chloro-4-fluorophenyl)ethoxy]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(R or S)-[1-(2-chloro-4-fluorophenyl)ethoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(R or S)-(3,4-dimethoxyphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-(3,4-dimethoxyphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(trifluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4 ]oxazin-3-one; (4aR,8aS)-6-(3-(2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-bromophenyl)-3-fluoroazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ; (4aR,8aS)-6-(3-(4-bromophenyl)-3-hydroxyazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ; (4aR,8aS)-6-(3-(4-bromophenyl)-3-methylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ; (4aR,8aS)-6-(3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; 4'-(1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)azetidine-3-yl)-[1,1' -biphenyl]-2-carbonitrile; (4aR,8aS)-6-(3-(4-(3-methoxyazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl] azetidin-3-yl]phenyl]benzamide; (4aR,8aS)-6-(3-(2-chloro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-bromo-3-chlorophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (4aR,8aS)-6-[3-[4-(4-chloro-2-fluorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-chloro-4-fluorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(R or S)-(3,4-dimethoxyphenyl)-(3-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-(3,4-dimethoxyphenyl)-(3-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(2'-methyl-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H -pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(tert-butyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H) -He; (4aR,8aS)-6-[3-(4-phenylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine- 3-he; (4aR,8aS)-6-[3-[4-[2-(difluoromethyl)phenyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(3'-methyl-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-chloropyridin-3-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4]oxazin-3(4Н)- He; (4aR,8aS)-6-(3-(4-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl )hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-[4-[(R or S)-(3,4-dimethoxyphenyl)-(4-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-(3,4-dimethoxyphenyl)-(4-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(3-methylazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-(3-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2,4-dichlorophenyl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2'-chloro-4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3,3-difluoroazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(4-(4-bromophenyl)piperdine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl] azetidin-3-yl]phenyl]-5-chloro-benzonitrile; (4aR,8aS)-6-[3-[4-[3-[(1S or 1R)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl]phenyl]azetidin-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1R or 1S)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl]phenyl]azetidin-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-bromophenyl)pyrrolidin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2-ethylpyrrolidin-1-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl] azetidin-3-yl]phenyl]-3-chloro-benzonitrile; (4aR,8aS)-6-(3-(4-(2-cyclopropylpyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-(4-(4-bromophenyl)piperazin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ; (4aR,8aS)-6-(3-(4-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4'-chloro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[(R or S)-(3-methylsulfonylphenyl)-(3-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-(3-methylsulfonylphenyl)-(3-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(R or S)-(3-methylsulfonylphenyl)-(4-pyridyl)methyl]pipeidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-(3-methylsulfonylphenyl)-(4-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(5-azaspiro[2.4]heptan-5-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(pentafluoro-l6-sulfaneyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(5-chloropyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)- He; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-[3-(6-methoxypyridin-3-yl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-(3-(4-bromophenyl)pyrrolidin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aE)-6-(3-phenylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aE)-6-(4-phenylpiperidin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(R or S)-(3-methylsulfonylphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(S or R)-(3-methylsulfonylphenyl)-(2-pyridyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7, 8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-(2,4-dichlorophenyl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(1-piperidyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydro[4,3-b][1 ,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(3-hydroxy-3-methylazetidin-1-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-Fluoro-3-methylazetidin-1-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(3-fluoroazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(3,5-difluoro-4-(trifluoromeoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-(3-(2-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(4-(bicyclo[1.1.1]pentan-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-fluoro-1H-indol-3-yl)pyrrolidin-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(3-(1-benzyl-5-chloro-1H-indol-3-yl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-[3-[4-[3-(cyclopropylmethoxy)azetidin-1-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4 ,3-b][1,4]oxazin-3-one; 5-(1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)azetidine-3-yl)-2-(trifluoromethoxy)benzonitrile ; (4aR,8aS)-6-(3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(3-(1-methyl-1H-indazol-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(3-(4-(3-fluoropyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-(3-(4-(2-methylazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-[4-[phenyl(pyridazin-3-yl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(trifluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4 ]oxazin-3-one; (4aR,8aS)-6-(3-(1-methyl-1H-indazol-6-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-[3-(S or R)-[3-(trifluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(R or S)-[3-(trifluoromethoxy)phenyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aE)-6-(3-(3-chloro-4-hydroxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (4aR,8aS)-6-(3-(3-chloro-4-(3-methylazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(oxetan-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b] [1,4]oxazin-3-one; (4aR,8aS)-6-(3-(3-chloro-4-(3,3-difluoroazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-(3-methylazetidin-1-yl)-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[(3S or R)-3-(3-bromophenyl)pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one; (4aR,8aS)-6-[(3R or S)-3-(3-bromophenyl)pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-azabicyclo[3.1.1]heptan-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(2-methyl-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; methyl-2-methyl-2-(4-(1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)azetidine-3- yl)phenyl)propanoate; (4aR,8aS)-6-(3-(3,5-dichlorophenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-methoxy-3-methylazetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; tert-butyl-(2-(3-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidine-4- yl)(phenyl)methyl)phenoxy)ethyl)carbamate; (4aR,8aS)-6-((R or S)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((S or R)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(tert-butyl)-3-methoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(3-(1-methyl-1H-indazol-5-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(3-(4-propylphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-he; (4aR,8aS)-6-[3-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(R or S)-[4-(2,2,2-trifluoro-1-methyl-ethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydro[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-fluoropropyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1 ,4]oxazin-3-one; (4aR,8aS)-6-[3-(S or R)-[4-(2,2,2-trifluoro-1-methyl-ethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-cyclobutylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine- 3-he; (4aR,8aS)-6-[3-(3-methoxy-4-methyl-phenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4]oxazin-3-one; (4aR,8aS)-6-(4-((4-fluorophenyl)((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H -pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[[3-(2-aminoethoxy)phenyl]-phenyl-methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]azetidine-1-carbonyl]-4,4а,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[3-fluoro-4-(trifluoromethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b] [1,4]oxazin-3-one; tert-Butyl-N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3 -b][1,4]oxazine-6-carbonyl]-4-piperidyl]-phenylmethyl]phenoxy]ethylamino]-3-oxopropoxy]ethyl]carbamate; tert-Butyl-N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazine-6-carbonyl]-4-piperidyl]phenylmethyl]phenoxy]ethylamino]-3-oxopropoxy]ethoxy]ethyl]carbamate; (4aR,8aS)-6-[3-[1-(2,4-dichlorophenyl)pyrazol-3-yl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-propoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine- 3-he; (4aR,8aS)-6-[3-(3,4-dimethylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4] oxazin-3-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl] azetidin-3-yl]phenyl]-N-ethyl-5-methyl-benzamide; (4aR,8aS)-6-[3-[4-(2,2-dimethylpropyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b] [1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-tert-butoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4] oxazin-3-one; (4aR,8aS)-6-[4-(5-chloroindolin-1-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-[4-(4-chloroisoindolin-2-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-[4-(5'-chlorospiro[cyclopropan-1,3'-indoline]-1'-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a -hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-chloroisoindolin-2-yl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-[4-(5-chloro-2-yl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-[4-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-indol-3-yl]piperidine-1-carbonyl]-4,4a, 5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[5-Chloro-1-(2-hydroxyethyl)indol-3-yl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(5-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[6-[3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-[3-(R or S)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-[3S- or 3R-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-tetrahydropyran-3-ylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-[3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one and (4aR,8aS)-6-(3-(4-(neopentyloxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one . 33. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof, selected from the following: rac-cis-6-(4-(5-chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; rac-cis-6-(4-(5-chloro-1-methyl-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; rac-cis-6-(4-(1-(4-fluorophenyl)-3-methoxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-He; rac-cis-6-(4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (+)-cis-6-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (+)- or (-)-cis-6-(4-(5-chloro-1-cyclopropyl-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)piperidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; rac-cis-6-(4-(1-(4-fluorophenyl)-3-hydroxypropyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-He; (4aR,8aS)-6-(4-(difluoro(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (+) or (-)-cis-6-(4-((R or S)-1-(2-chloro-4-fluorophenoxy)ethyl)piperidine-1-cabonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((4-chlorophenyl)difluoromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (+) or (-)-cis-6-(4-((2-chloro-4-fluorophenyl)difluoromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[(S or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a- hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(3-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3-(2-fluoroethoxy)phenyl)(phenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(4-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(4-methoxyphenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-(2-fluoroethoxy)phenyl)(4-fluorophenyl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(trifluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4 ]oxazin-3-one; (4aR,8aS)-6-(3-(2'-trifluoromethoxy)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-bromo-3-chlorophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)- He; (4aR,8aS)-6-[3-[4-(4-chloro-2-fluorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-chloro-4-fluorophenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H -pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(tert-butyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H) -He; (4aR,8aS)-6-(3-(4-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl )hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2,4-dichlorophenyl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1S or 1R)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl]phenyl]azetidin-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1R or 1S)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl]phenyl]azetidin-1- carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(pentafluoro-I6-sulfaneyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b ][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7, 8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(5-(2,4-dichlorophenyl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2Н-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-(3-(3,5-difluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-one; (4aR,8aS)-6-(3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-he; (4aR,8aS)-6-((R or S)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((S or R)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(tert-butyl)-3-methoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-he; (4aR,8aS)-6-(3-(4-propylphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine- 3(4H)-one; (4aR,8aS)-6-(3-(5-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[6-[3-(R or S)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-[3-(S or R)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1-carbonyl]-4,4a,5, 7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-tetrahydropyran-3-ylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1, 4]oxazin-3-one; (4aR,8aS)-6-[3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[ 4,3-b][1,4]oxazin-3-one and (4aR,8aS)-6-(3-(4-(neopentyloxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one . 34. The compound of formula (Ic) according to any one of paragraphs. 1-33, wherein said compound of formula (Ic) has an IC ₅₀ for monoacylglycerol lipase of less than 10 μM. 35. The compound of formula (Ic) according to any one of paragraphs. 1-34 for use as a therapeutically active substance. 36. Pharmaceutical composition for inhibiting the activity of monoacylglycerol lipase (MAGL), containing an effective amount of a compound of formula (Ic) according to any one of paragraphs. 1-34 and a therapeutically inert carrier. 37. The use of compounds of formula (Ic) according to any one of paragraphs. 1-34 for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders mediated by inhibition of MAGL activity in a mammal. 38. The use of compounds of formula (Ic) according to any one of paragraphs. 1-34 for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatic cell carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain-associated spasticity mediated by inhibition of MAGL activity in a mammal. 39. The compound of formula (Ic) according to any one of paragraphs. 1-34 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders in a mammal. 40. The compound of formula (Ic) according to any one of paragraphs. 1-34 for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer , neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain associated spasticity in a mammal. 41. The use of compounds of formula (Ic) according to any one of paragraphs. 1-34 for the manufacture of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or psychiatric disorders mediated by inhibition of MAGL activity in a mammal. 42. The use of compounds of formula (Ic) according to any one of paragraphs. 1-34 for the manufacture of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain-associated spasticity mediated by inhibition of MAGL activity in a mammal. 43. A method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders mediated by inhibition of MAGL activity in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (Ic) according to any one of paragraphs. 1-34. 44. A method for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatic cell carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain-associated spasticity mediated by inhibition of MAGL activity in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (Ic) according to any one of claims. 1-34.