RU2809257C2 - Heterocyclic compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to new heterocyclic compounds of general formula (I), where A, B, L, X, R¹, R², R³ and R⁴ are as indicated in the claims, as well as to a method for their preparation and pharmaceutical composition containing the indicated compounds.

EFFECT: compounds have inhibitory activity against monoacylglycerol lipase (MAGL).

34 cl, 2 tbl, 74 ex

Description

Field of invention

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

State of the art

Endocannabinoids (EC) are signaling lipids whose biological actions are exerted through interaction with cannabinoid receptors (CBRs) CB1 and CB2. They modulate many physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA, et al., Progress in lipid research 2016, 62, 107-28.). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacyglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase, MAGL. MAGL hydrolyzes 85% of 2-AG; the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK, et at, Science 2011, 334, 809.). MAGL is expressed throughout the brain and in most brain cells, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, R.K., et at, Molecular pharmacology 2010, 78, 996; Viader, A., et at, Cell reports 2015, 12, 798.). Hydrolysis of 2-AG results in the formation of arachidonic acid (AA), a precursor to prostaglandins (PG) and leukotrienes (LT). Oxidative metabolism of AA is increased in inflamed tissues. There are two main enzymatic pathways for the oxygenation of arachidonic acid involved in inflammatory processes: cyclooxygenase, whose product is PG, and 5-lipoxygenase, whose product is LT. One of the most important cyclooxygenase products produced during inflammation is PGE2. These products have been found in all sites of inflammation, such as the cerebrospinal fluid of patients suffering from neurodegenerative disorders, and are thought to be involved in the inflammatory response and disease progression. Mice lacking MAGL (Mg11-/-) exhibit severely reduced 2-AG hydrolase activity and increased levels of 2-AG in the nervous system, whereas other arachidonoyl-containing phospholipid species and neutral lipids, including anandamide (AEA), as well as others free fatty acids remain unchanged. Conversely, levels of AA and 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 implicated as a major source of AA, but cPLA ₂ -deficient mice have intact AA levels in the brain, suggesting a key role for MAGL in the brain for AA production and regulation of inflammatory processes in the brain.

Neuroinflammation is a common feature of pathological changes in brain diseases, including, but not limited to, neurodegenerative diseases (eg, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy and psychiatric disorders, such as anxiety and migraines). In the brain, the production of eicosanoids and prostaglandins regulates the process of neuroinflammation. The proinflammatory agent lipopolysaccharide (LPS) leads to a dramatic, time-dependent increase in brain eicosanoids, which are significantly reduced in Mg11-/- mice. LPS treatment also induces widespread increases in levels of proinflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor a (TNF-a), which are limited in Mg11-/- mice. .

Neuroinflammation is characterized by activation of central nervous system innate immune cells, microglia, and astrocytes. It has been reported that anti-inflammatory drugs can suppress glial cell activation and disease progression in preclinical models, including Alzheimer's disease and multiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403.). It is also important that 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.).

In addition, genetic and/or pharmacological disruption of MAGL activity has been shown to demonstrate protective properties in several animal models of neurodegeneration, including, but not limited to, Alzheimer's disease, Parkinson's disease and multiple sclerosis. For example, an irreversible MAGL inhibitor 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 reproduces the phenotype of Mg11-/- mice in the brain, including increased 2-AG levels, decreased AA levels and associated eicosanoid production, and prevention of cytokine production and microglial activation following LPS-induced neuroinflammation (Nomura, D.K., et al., Science 2011, 334, 809.), which together confirm that MAGL is a druggable target.

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

In addition, oligodendrocytes (OL), the myelinating cells of the central nervous system, and their progenitors (OPCs) express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand of the CB1 and CB2 receptors. Both cannabinoids and pharmacological inhibition of MAGL have been reported to attenuate the susceptibility of OL and OPC to excitotoxic stress and may therefore have neuroprotective properties (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 may promote differentiation of ORFs into myelinating OLs in vivo (Alpar, A., et al., Nature communications 2014, 5, 4421.) . MAGL inhibition 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, 57 (35), 8385.).

Finally, in recent years, the importance of metabolism in cancer research, especially lipid metabolism, has been highlighted. Researchers believe that de novo fatty acid synthesis plays an important role in tumor development. Many studies have demonstrated that endocannabinoids have anti-oncogenic effects, including antiproliferative, apoptosis-inducing, and antimetastatic effects. MAGL, as an important degrading enzyme for both lipid metabolism and the endocannabinoid system, and additionally as part of a gene expression signature, influences various aspects of tumorigenesis (Qin, N., 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).

Finally, inhibition of MAGL action and/or activation is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and psychiatric disorders. In addition, inhibition of MAGL action and/or activation is a promising new therapeutic strategy to provide neuroprotection and myelin repair. Accordingly, there is a significant unmet medical need for new MAGL inhibitors.

The essence of the invention

In a first aspect, the present invention provides a compound of formula (I)

where A, B, L, X, R ¹ , R ² , R ³ and R ⁴ are as described herein.

In one aspect, this invention provides a method for the production of urea compounds of formula (I) described herein, and pharmaceutically acceptable salts thereof, comprising:

(a) reacting the first amine of formula 1, wherein R ¹ and R ² are as described herein, preferably wherein R ¹ and R ² are hydrogen,

with a secondary amine 2, where A, B, L, X, R ³ and R ⁴ are as described herein,

in the presence of a base and a urea-forming reagent to form said compound of formula (I); and optional

(b) converting said compound of formula (I) into pharmaceutically acceptable salts thereof.

In a further aspect, this invention provides a compound of formula (I) described herein, manufactured in accordance with the method described herein.

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

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

In a further aspect, this invention provides a compound of formula (I) described herein, or a pharmaceutical composition described herein, for use in a method of inhibiting monoacylglycerol lipase in a mammal.

In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutical composition described herein, for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.

In a further aspect, this invention provides a compound of formula (I) described herein, or a pharmaceutical composition 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-related spasticity in a mammal.

Detailed description of the invention

Definitions

The features, integers, characteristics, compounds, chemical moieties or groups described in connection 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 they are incompatible with them. All features disclosed in this specification (including the accompanying claims, abstract and drawings), and/or all steps of any method or process disclosed herein, can be combined in any combination, except combinations in which at least some of such features and/or stages are mutually exclusive. The present invention is not limited to the details of any of the above embodiments. This invention covers any new feature or any new combination of features disclosed in this specification (including the accompanying claims, abstract and drawings), and/or 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, e.g. mono- or di-valent, linear or branched saturated hydrocarbon group of 16 carbon atoms ("C ₁ -C ₆ -alkyl"), for example 1, 2, 3, 4, 5 or 6 carbon atoms. In some embodiments, the alkyl group contains 1-3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyls include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, t-butyl and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of alkyl is methyl.

The term "alkoxy" refers to an alkyl group as defined above, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, an alkoxy group contains 1-6 carbon atoms (“C ₁ -C ₆ -alkoxy”). In some preferred embodiments, the alkoxy group contains 14 carbon atoms. In other embodiments, the alkoxy group contains 13 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

The term "halogen" or "halo" 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 but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).

The term "bicyclic spirocycle" refers to a chemical compound consisting of two heterocyclyl or two cycloalkyl moieties as defined herein, or a combination of one heterocyclyl and one cycloalkyl moiety sharing a common ring atom, i.e. the two rings are connected through one common ring atom. Some preferred but non-limiting examples of bicyclic spiro rings include 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 1-oxa- 8-azaspiro[4.5]decane, 2,7-diazaspiro[4.4]nonane and 2,7-diazaspiro[3.4]octane.

The terms “heterocyclyl” refers to a saturated or partially unsaturated monocyclic ring system of 3-14 ring atoms, preferably 3-10 ring atoms, preferably 3-8 ring atoms, where 1, 2 or 3 of said ring atoms are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Preferably, 12 of said ring atoms are selected from N and O, and the remaining ring atoms are carbon. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin- 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, morpholin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl.

As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic hydrocarbon group of 3-10 ring carbon atoms (“C _3-10 -cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3-8 ring carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, for example 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred but non-limiting example of cycloalkyl is cyclopropyl.

The term "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having a total of 6-14 ring members ("C ₆ - ₁₄ -aryl"), preferably 6-12 ring members and more preferably 6-10 ring members, and wherein at least one ring in the system is aromatic. A particularly preferred but non-limiting example of aryl is phenyl.

The term "heteroaryl" refers to a mono- or multivalent, monocyclic or bicyclic, preferably bicyclic ring system having a total of 5-14 ring members, preferably 5-12 ring members, and more preferably 5-10 ring members, with at least one the ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1-2 heteroatom independently selected from O and N. Some non-limiting examples of heteroaryls include 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 but non-limiting example of heteroaryl is indolyl, in particular 1H-indol-3-yl.

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

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

The term "carbonyl" refers to the C(O) group.

The term "oxo" refers to an oxygen atom linked to the parent molecule by a double bond (=O).

The term "alkoxycarbonyl" refers to a -C(O)-O-alkyl group (ie, an alkyl ester). A particularly preferred but non-limiting example of an alkoxycarbonyl is tert-butoxycarbonyl.

The term "aryloxycarbonyl" refers to a C(O)-O-aryl group (ie, aryl ester). A particularly preferred but non-limiting example of an alkoxycarbonyl is phenoxycarbonyl.

The term “heteroaryloxycarbonyl” refers to a C(O)-O-heteroaryl group (ie, heteroaryl ester). A particularly preferred but non-limiting example of alkoxycarbonyl is pyridyloxycarbonyl.

The term "haloalkyl" refers to any alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, preferably fluorine. A particularly preferred but non-limiting example of haloalkyl is trifluoromethyl (CF ₃ ).

The term "haloalkoxy" refers to any 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, “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, preferably fluorine. A particularly preferred but non-limiting example of haloalkoxy is trifluoromethoxy (-OCF ₃ ).

The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of free bases or free acids that are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid , oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. .P. Additionally, these salts can be prepared 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 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 resins , tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine, etc. Specific pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride salts.

The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site as traditionally associated with it in the field of synthetic chemistry. Protecting groups can be removed at appropriate times. Typical protecting groups are amino protecting groups, carboxy protecting groups or hydroxy protecting groups. Specific protecting groups are tert-butoxycarbonyl (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). Typical 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 reagent" refers to a chemical compound that is capable of donating a first amine, which will react with a second amine to thereby form a urea derivative. Non-limiting examples of urea-forming reagents include bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (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 in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. In a preferred embodiment, the compound of formula (I) according to this invention is a cis-enantiomer of formula (Ia) or (Ib), respectively, as described herein.

In accordance with the Cahn-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 throughout this document.

As used herein, the term “treatment” includes: (1) inhibiting a condition, disorder, or pathological condition (eg, stopping, reducing, or slowing the progression of a disease or, in the case of maintenance treatment, the reappearance of at least one clinical or subclinical symptom thereof); and/or (2) alleviation of the pathological condition (ie, achieving regression of the condition, disorder or pathological condition or at least one clinical or subclinical symptom thereof). The benefit to the patient being treated is statistically significant or at least tangible to the patient or clinician. However, it should be understood that when a drug is administered to a patient to treat a disease, the result may not always be an effective treatment.

As used herein, the term "prevention" includes: preventing or delaying the onset of clinical symptoms of a condition, disorder or condition developing in a mammal and, in particular, a human who may be susceptible to or predisposed to the condition, disorder or condition, but has not yet feels or does not exhibit clinical or subclinical symptoms of a condition, disorder, or pathological condition.

As used herein, the term "neuroinflammation" refers to acute and chronic inflammation of the nervous tissue, which is the major tissue component of the 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 typically follows immediately after injury to the central nervous system, such as traumatic brain injury (TBI).

The term traumatic brain injury (“TBI,” also known as “intracranial injury”) refers to damage to the brain resulting from an external mechanical force, such as sudden acceleration or deceleration, impact, shock waves, or bullet penetration.

The term "neurodegenerative diseases" refers to diseases associated with the 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 called mental illness or psychiatric disorders) refers to behavioral or mental patterns that may result in distress or disability. Such signs may be constant, come and go, or appear as a single episode. Examples of mental illnesses include, but are not limited to, anxiety and depression.

The term "pain" refers to the unpleasant sensory and emotional sensations 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, caused by injury or disease affecting any part of the nervous system involved in the function of sensation (ie, the somatosensory system). In one embodiment, the “pain” is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the “pain” is chemotherapy-induced neuropathy.

The term "neurotoxicity" refers to toxicity in the nervous system. It occurs when exposure to natural or man-made toxic substances (neurotoxins) alters the normal activity of the nervous system in a way that damages the nervous system. Examples of neurotoxicity include, but are not limited to, neurotoxicity resulting from exposure to substances used in chemotherapy, radiation therapy, drug therapy, drug addiction and organ transplantation, as well as exposure to heavy metals, certain foods and dietary supplements, pesticides, industrial and /or cleaning solvents, cosmetics and some substances of natural origin.

The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor resulting from abnormal, uncontrolled cell growth (such cells are called "cancer cells"). As used herein, the term cancer specifically includes, but is not limited to, hepatocellular carcinoma, colon carcinogenesis, and ovarian cancer.

As used herein, the term “mammal” includes both humans and non-human animals, and includes, but is not limited to, humans, non-human primates, canines, felines, mice, bovines, equines and porciniformes. In a particularly preferred embodiment, the term "mammal" refers to humans.

Compounds of this invention

In a first aspect, the present invention provides a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

(i)X represents CR ⁵ ;

L represents a covalent bond, -(CH ₂ ) _n -N(C _1-6 -alkyl)-, -(CH ₂ ) _n -NH-, -N(C _1-6 -alkyl)-(CH ₂ ) _p -, -NH-(CH ₂ ) _p -, -(CH ₂ ) _n -O-, -O-(CH ₂ ) _p -, -SO ₂ -N(C _1-6 -alkyl)-, -SO ₂ -NH-, -N(C _1-6 -alkyl)-SO ₂ -, -NH-SO ₂ -, carbonyl, -(CH ₂ ) _n -, -CHR ⁶ -, -CF ₂ -(CH ₂ ) _n -, -(CH ₂ ) _p -CF ₂ - -(CH ₂ ) _n -S-, -S-(CH ₂ ) _p -, -SO ₂ -, -C(O)-NH-, -C(O )-N(C _1-6 -alkyl)-, -NH-C(O)- or -N(C _1-6 -alkyl)-C(O)-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X is N;

L represents a covalent bond, -(CH ₂ ) _n -, -CHR ⁶ -, -SO ₂ -, carbonyl, -N(C _1-6 -alkyl)-(CH ₂ ) _p -, -NH-(CH ₂ ) _p -, -O-(CH ₂ ) _p -, -CF ₂ -CH ₂ -, -N(C _1-6 -alkyl)-SO ₂ , NH-SO ₂ , NH-C(O) or -N (C _1-6 -alkyl)-C(O)-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(iii)X represents N;

L represents C _1-6 -alkoxycarbonyl, C _6-14 -aryloxycarbonyl or 5-14 membered heteroaryloxycarbonyl; And

A is missing;

B represents a bicyclic spirocycle;

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, hydroxy, C _1-6 alkyl or halo-C _1-6 alkyl;

R ⁶ represents C _6-14 -aryl or 5-14 membered heteroaryl;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, hydroxy, C _1-6 alkyl, halo-C _1-6 alkyl, halogen, C _{1- 6} -alkoxy, halogen-C _1-6 -alkoxy, SF ₅ , C _1-6 -alkylsulfonyl, cyano or group

C is 5-14 membered heteroaryl, 3-14 membered heterocyclyl or C _3-10 cycloalkyl;

each of ^RC1 , ^RC2 and ^RC3 independently represents hydrogen, _C1-6 -alkyl, halogen- _C1-6 -alkyl, oxo, halogen, hydroxy, _C1-6- alkoxy or halogen- _C1-6 -alkoxy;

n in each case is independently equal to 0, 1, 2 or 3;

p in each case is independently equal to 1, 2 or 3; And

q is 0, 1 or 2.

In one embodiment, this invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

(i) X is CR ⁵ ;

L represents -(CH ₂ ) _n -N(C _1-6 -alkyl)-, -(CH ₂ ) _n -NH-, -N(C _1-6 -alkyl)-(CH ₂ ) _p -, - NH-(CH ₂ ) _p -, -(CH ₂ ) _n -O-, -O-(CH ₂ ) _p -, -SO ₂ -N(C _1-6 -alkyl)-, -SO ₂ -NH- , -N(C _1-6 -alkyl)-SO ₂ - -NH-SO ₂ -, carbonyl, -(CH ₂ ) _n -, -CHR ⁶ -, -CF ₂ -(CH ₂ ) _n -, -( CH ₂ ) _p -CF ₂ -, -(CH ₂ ) _n -S-, -S-(CH ₂ ) _p -, -SO ₂ -, -C(O)-NH-, -C(O)-N (C _1-6 -alkyl)-, -NH-C(O)- or -N(C _1-6 -alkyl)-C(O)-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X is N;

L represents -(CH ₂ ) _n -, -CHR ⁶ -, SO ₂ , carbonyl, -N(C _1-6 -alkyl)-(CH ₂ ) _p -, -NH-(CH ₂ ) _p -, O -(CH ₂ ) _p , -CF ₂ -CH ₂ -, -N(C _1-6 alkyl)-SO ₂ -, -NH-SO ₂ -, -NH-C(O)- or -N(C _{1 -6} -alkyl)-C(O)-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(iii)X represents N;

L represents C _1-6 -alkoxycarbonyl, C _6-14 -aryloxycarbonyl or 5-14 membered heteroaryloxycarbonyl; And

A is missing;

B represents a bicyclic spirocycle;

R ¹ represents hydrogen or C _1-6 -alkyl;

R ² represents hydrogen or C _1-6 -alkyl;

R ³ is hydrogen, C _1-6 alkyl, halogen-C _1-6 alkyl, halogen or hydroxy;

R ⁴ is hydrogen, C _1-6 alkyl, halogen-C _1-6 alkyl, halogen or hydroxy;

R ⁵ is hydrogen, C _1-6 alkyl, halogen-C _1-6 alkyl, halogen or hydroxy;

R ⁶ represents C _6-14 -aryl or 5-14 membered heteroaryl; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 - alkoxy, halogen-C _1-6 -alkoxy, SF ₅ , SO ₂ CH ₃ , cyano, group group group or group

R ¹³ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, hydroxy or C _1-6 -alkoxy; And

R ¹⁴ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, hydroxy, C _1-6 -alkoxy; or

R ¹³ and R ¹⁴ , taken together with the carbon atom to which they are attached, form a 4-6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen and NR ¹⁸ ;

R ¹⁵ represents hydrogen, C _1-6 alkyl and halogen-C _1-6 alkyl;

R ¹⁶ is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy or cyano;

R ¹⁷ represents hydrogen, hydroxy, cyano, halogen-C _1-6 -alkyl or C _1-6 -alkyl;

R ¹⁸ represents hydrogen or C _1-6 -alkyl;

n in each case is independently equal to 0, 1, 2 or 3;

p in each case is independently equal to 1, 2 or 3; And

q is 0, 1 or 2.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ represents hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ² represents hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or its pharmaceutical

an acceptable salt wherein R ¹ and R ² are both hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are both hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are all hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen or C _1-6 alkyl.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is C _6-14 -aryl.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen, hydroxy, C _1-6 alkyl, halo-C _1-6 alkyl, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy, SF ₅ or group Where

C is 5-14 membered heteroaryl or 3-14 membered heterocyclyl;

R ^C1 is C _1-6 alkyl, halogenated C _1-6 alkyl or oxo; And

R ^C2 and R ^C3 are both hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen, C _1-6 alkyl, halogen - C _1-6 alkyl, halogen , C _1-6 -alkoxy, halogen-C _1-6 -alkoxy or SF ₅ .

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen, fluorine, chlorine, CF ₃ , methyl, methoxy, trifluoromethoxy and SF ₅ .

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen, C _1-6 alkyl, halogen, C _1-6 alkyl, halogen, C _1-6 -alkoxy or halogen-C _1-6 -alkoxy.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen, fluorine, chlorine, CF ₃ , methyl, methoxy or trifluoromethoxy.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen, C _1-6 alkoxy, halogen-C _1-6 alkyl, or halogen .

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen, halogen-C _1-6 -alkyl or halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen or CF ₃ , chlorine or fluorine.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ⁷ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy or halogen-C _1-6 -alkoxy;

R ⁸ represents hydrogen or halogen-C _1-6 -alkyl or halogen; And

R ⁹ represents hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is halogen or C _1-6 alkyl.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a halogen-C _1-6 -alkyl.

In a particularly preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is CF ₃ .

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen or C _1-6 alkyl.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen or CF ₃ .

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹² is hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ¹⁰ represents halogen-C _1-6 -alkyl;

R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl; And

R ¹² represents hydrogen.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or pyridyl.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents a covalent bond, -(CH ₂ ) _n -N(C _1-6 -alkyl)-, -(CH ₂ ) _n -NH, -(CH ₂ ) _n -O-, -OCH ₂ -, -CH ₂ -, -SO ₂ -, -SO ₂ -N(C _1-6 -alkyl)- or -SO ₂ -NH-;

n is 0 or 1; And

R ⁵ is as defined herein.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents a covalent bond, -CH ₂ O-, O, -OCH ₂ -, CH ₂ or -SO ₂ -N(C _1-6 -alkyl)-; And

R ⁵ is as defined herein.

In a particularly preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents a covalent bond, -CH ₂ O-, -O-, -OCH ₂ -, -CH ₂ - or -SO ₂ -N(methyl)-; And

R ⁵ is as defined herein.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents -CH ₂ -N(C _1-6 -alkyl)-, -CH ₂ -NH-, -(CH ₂ ) _n -O-, -O-CH ₂ -, -SO ₂ -N(C _{1 -6} -alkyl)- or -SO ₂ -NH-;

n is 0 or 1; And

R ⁵ is as defined herein.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents -CH ₂ -N(C _1-6 -alkyl)-, -CH ₂ -NH-, -(CH ₂ ) _n -O-, -O-CH ₂ -, -SO ₂ -N(C _{1 -6} -alkyl)- or -SO ₂ -NH-;

n is 0 or 1; And

R ⁵ represents hydrogen.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents -(CH ₂ ) _n -O-, -O-CH ₂ - or -SO ₂ -N(C _1-6 -alkyl)-;

n is 0 or 1; And

R ⁵ represents hydrogen.

In a particularly preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents CR ⁵ ;

L represents -(CH ₂ ) _n -O-, -O-CH ₂ - or -SO ₂ -N(methyl)-;

n is 0 or 1; And

R ⁵ represents hydrogen.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents N;

L represents a covalent bond, -CH ₂ -, -CHR ⁶ - or -SO ₂ -; And

R ⁶ is as defined herein.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents N; And

L represents -CH ₂ - or -SO ₂ -.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents N;

L represents -(CH ₂ ) _n -, -CHR ⁶ - or SO ₂ ; And

n represents 1; And

R ⁶ is as defined herein.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents N;

L represents -(CH ₂ ) _n -, -CHR ⁶ - or -SO ₂ -; And

n represents 1; And

R ⁶ represents C _6-14 -aryl.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

X represents N;

L represents -(CH ₂ ) _n - or -SO ₂ -; And

n is 1.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle having formula (II):

Where:

X is as defined herein;

each of Y ¹ , Y ² , Y ³ and Y ⁴ independently represents -(CH ₂ ) _m -, -(CH ₂ ) _m O-, -O(CH ₂ ) _m - -(CH ₂ ) _m NH- or -NH(CH ₂ ) _m -;

m in each case is independently equal to 1, 2 or 3;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I).

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle having formula (II):

Where:

X is as defined herein;

Y ¹ represents -(CH ₂ ) _m - or -(CH ₂ ) _m O-, where m is 1 or 2;

Y ² represents CH ₂ or CH ₂ O;

Y ³ and Y ⁴ are each independently (CH ₂ ) _m , where m is 1 or 2;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I).

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle having formula (II):

Where:

X is as defined herein;

Y ¹ represents -CH ₂ -;

Y ² represents CH ₂ or CH ₂ O;

Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I).

In a further preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle selected from the group consisting of:

Where:

(i) the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I); or

(ii) a wavy line, the point of attachment of the bicyclic spirocycle B to the rest of formula (I); And

the asterisk indicates the point of attachment of the bicyclic spirocycle B to L in formula (I).

In a particularly preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle selected from the group consisting of:

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I).

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

(i)X represents CR ⁵ ;

L represents a covalent bond, -CH ₂ -N(C _1-6 -alkyl)-, -CH ₂ -NH-, -O-, -CH ₂ O-, -OCH ₂ -, -CH ₂ -, -SO ₂ -, -SO ₂ -N(C _1-6 -alkyl)- or -SO ₂ -NH-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X is N;

L represents a covalent bond, -CH ₂ -, -CHR ⁶ - or -SO ₂ -; And

A is C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(iii) X is N;

L represents C _1-6 -alkoxycarbonyl; And

A is missing;

B is a bicyclic spirocycle having formula (II):

Where:

Y ¹ represents -(CH ₂ ) _m - or -(CH ₂ ) _m O-, where m is 1 or 2;

Y ² represents –CH ₂ - or -CH ₂ O-;

Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I);

R ¹ , R ² , R ³ , R ⁴ , R ⁹ and R ¹² are each hydrogen;

R ⁵ represents hydrogen or C _1-6 -alkyl;

R ⁶ represents C _6-14 -aryl;

R ⁷ represents hydrogen, hydroxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy or halogen-C _1-6 -alkoxy, SF ₅ or group

R ⁸ represents hydrogen, C _1-6 alkoxy, halogen-C _1-6 alkyl or halogen;

R ¹⁰ represents halogen or C _1-6 -alkyl;

R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl;

R ^C1 is C _1-6 alkyl, halogen-C _1-6 alkyl or oxo;

^RC2 and ^RC3 are both hydrogen; And

C is 5-14 membered heteroaryl or 3-14 membered heterocyclyl.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

(i) X is CR ⁵ ;

L represents -CH ₂ O-, -OCH ₂ -, -O-, -CH ₂ - or -SO ₂ -N(C _1-6 -alkyl)-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X is N;

L represents -CH ₂ - or -SO ₂ -; And

A is C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

B is a bicyclic spirocycle having formula (II):

Where:

Y ¹ represents -CH ₂ -;

Y ² represents -CH ₂ - or -CH ₂ O-;

Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I);

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen;

R ⁷ is hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy or SF ₅ ;

R ⁸ represents hydrogen, halogen-C _1-6 -alkyl or halogen;

R ¹⁰ represents halogen-C _1-6 -alkyl; And

R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl.

In a particularly preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

(i) X is CR ⁵ ;

L represents -CH ₂ O-, -OCH ₂ -, -O-, -CH ₂ - or -SO ₂ -N-(methyl)-; And

A represents:

(i) phenyl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) pyridyl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X is N;

L represents -CH ₂ - or -SO ₂ -; And

A is phenyl substituted with R ⁷ , R ⁸ and R ⁹ ; or

B is a bicyclic spirocycle selected from the group consisting of:

, Where

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I);

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen;

R ⁷ is hydrogen, fluorine, chlorine, CF ₃ , methyl, methoxy, trifluoromethoxy or SF ₅ ;

R is hydrogen, CF ₃ , chlorine or fluorine;

R ¹⁰ is CF ₃ ; And

R ¹¹ represents hydrogen or CF ₃ .

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

(i) X is CR ⁵ ;

L represents CH ₂ -N(C _1-6 -alkyl), -CH ₂ -NH-, -(CH ₂ ) _n -O-, -O-CH ₂ -, -SO ₂ -N(C _1-6 -alkyl)- or -SO ₂ -NH-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X is N;

L represents -CH ₂ -, CHR ⁶ or -SO ₂ -; And

A is C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(iii)X represents N;

L represents C _1-6 -alkoxycarbonyl; And

A is missing;

B is a bicyclic spirocycle having formula (II):

Where:

Y ¹ represents -(CH ₂ ) _m - or -(CH ₂ ) _m O-, where m is 1 or 2;

Y represents -CH ₂ - or -CH ₂ O-;

Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I);

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen;

R ⁶ represents C _6-14 -aryl;

R ⁷ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 koxy or halogen-C _1-6 koxy;

R ⁸ represents hydrogen, halogen-C _1-6 kil or halogen;

R ¹⁰ represents halogen-C _1-6 kl;

R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl; And

n is 0 or 1.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

(i) X is CR ⁵ ;

L represents -(CH ₂ ) _n -O-, -O-CH ₂ - or -SO ₂ -N(C _1-6 -alkyl)-; And

A represents:

(i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) 5-14 membered heteroaryl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X represents N;

L represents CH ₂ or SO ₂ ; And

A is C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or

B is a bicyclic spirocycle having formula (II):

Where:

Y ¹ represents -CH ₂ -;

Y represents CH ₂ or CH ₂ O;

Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2;

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I);

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen;

R ⁷ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy or halogen-C _1-6 -alkoxy;

R ⁸ represents hydrogen, halogen-C _1-6 -alkyl or halogen;

R ¹⁰ represents halogen-C _1-6 -alkyl;

R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl; And

n is 0 or 1.

In a particularly preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein:

(i) X is CR ⁵ ;

L represents -(CH ₂ ) _n -O-, -O-CH ₂ - or -SO ₂ -N(methyl)-; And

A represents:

7 8 9

(i) phenyl substituted with R ⁷ , R ⁸ and R ⁹ ; or

(ii) pyridyl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or

(ii) X represents N;

L represents -CH ₂ - or -SO ₂ -; And

A is phenyl substituted with R ⁷ , R ⁸ and R ⁹ ; or

B is a bicyclic spirocycle selected from the group consisting of:

Where

the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And

the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I);

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen;

R ⁷ is hydrogen, fluorine, chlorine, CF ₃ , methyl, methoxy or trifluoromethoxy;

R ⁸ is hydrogen, CF ₃ , chlorine or fluorine;

R ¹⁰ is CF ₃ ;

R ¹¹ Represents hydrogen or CF ₃ ; And

n is 0 or 1.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of:

(4aR,8aS)-6-(6-(2-Chloro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Methoxy-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(Trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-she;

(4aR,8aS)-6-(6-(4-Chloro-2-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,4-Difluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(3-Fluoro-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Chloro-4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1, 4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-Chloro-4-fluorophenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(7-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-Fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

rac-(4aR,8aS)-N-((R)-8-(3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide;

rac-(4aR,8aS)-N-((S)-8-(3-Oxooctahydro-2H-pyrido[4,3-b][l,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide;

rac-(4aR,8aS)-6-(2-Benzhydryl-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she;

rac-(4aR,8aS)-6-(4-((4-Fluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((5,6-Bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

2-Chloro-4-fluoro-N-methyl-N-((R)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6 -carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide;

(4aR,8aS)-6-(6-((5-(Trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((4-Methyl-3-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-((2-Chloro-4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

N-((S)-8-((4aR,8aS)-3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)-4-(trifluoromethyl)benzenesulfonamide;

N-Methyl-N-((R)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa- 8-azaspiro[4.5]decan-3-yl)benzenesulfonamide;

2-Chloro-4-fluoro-N-((S)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide;

N-((S)-8-((4aR,8aS)-3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-((4-(Trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one;

rac-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(Phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she;

rac-tert-butyl 6-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][l,4]oxazin-6-carbonyl)-2,6-diazaspiro[3.4]octane- 2-carboxylate;

(4aR,8aS)-6-(6-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-fluoro-6-hydroxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-hydroxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she;

(4aR,8aS)-6-(2-(4-(2-oxopyrrolidin-l-yl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-fluoro-6-methoxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(pentafluoro-16-sulfanyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(2-methoxy-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2 carbonyl)hexahydro-2H-pyrido[4,3-b] [1, 4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-chloro-4-fluorophenoxy)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-fluoro-6-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4 ]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(4-isopropoxyphenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(4-isopropoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(2-(4-methoxy-3-methylphenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1, 4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(4-chloro-3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-fluoropyridin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1, 4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,5-bis(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [ 1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[33]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-chloro-4-fluorophenyl)sulfonyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((3-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[33]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,6-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; And

(4aR, 8a8)-6-(6-(2-methoxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of:

(4aR,8aS)-6-(6-(2-Chloro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Methoxy-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(Trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-she;

(4aR,8aS)-6-(6-(4-Chloro-2-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,4-Difluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(pentafluoro-16-sulfanyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(2-methoxy-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one; And

(4aR,8aS)-6-(6-((2-chloro-4-fluorophenoxy)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of:

(4aR,8aS)-6-(6-(2-Chloro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Methoxy-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(Trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-she;

(4aR,8aS)-6-(6-(4-Chloro-2-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,4-Difluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(3-Fluoro-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Chloro-4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1, 4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-Chloro-4-fluorophenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(7-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-Fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

rac-(4aR,8aS)-N-((R)-8-(3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide;

rac-(4aR,8aS)-N-((S)-8-(3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide;

rac-(4aR,8aS)-6-(2-Benzhydryl-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she;

rac-(4aR,8aS)-6-(4-((4-Fluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((4,5-Bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((5,6-Bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

2-Chloro-4-fluoro-N-methyl-N-((R)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6 -carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide;

(4aR,8aS)-6-(6-((5-(Trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((4-Methyl-3-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-((2-Chloro-4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one;

N-((S)-8-((4aR,8aS)-3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)-4-(trifluoromethyl)benzenesulfonamide;

N-Methyl-N-((R)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa- 8-azaspiro[4.5]decan-3-yl)benzenesulfonamide;

2-Chloro-4-fluoro-N-((S)-8-((4aH,8a8)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide;

N-((S)-8-((4aR,8aS)-3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4,3- b] [1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-((4-(Trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one;

rac-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(Phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she; And

rac-tert-Butyl 6-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-2,6-diazaspiro[3.4]octane- 2-carboxylate.

In a preferred embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of:

(4aR,8aS)-6-(6-(2-Chloro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(2-(2-Fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Methoxy-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2-Chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4] oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(4-(Trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-she;

(4aR,8aS)-6-(6-(4-Chloro-2-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1 ,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(6-(2,4-Difluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona;

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; And

(4aR,8aS)-6-(6-((4,5-Bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one.

In one embodiment, this invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein: said compound of formula (I) is not (4aR,8aS)-6-(6-(2- fluoro-6-methoxybenzyl)-2-azaspiro[3.3]heptan-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

In a specific embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) described herein, particularly the hydrochloride salts. In a further specific embodiment, this invention provides compounds of formula (I) described herein.

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

Substitution with heavier isotopes such as deuterium, i.e. H may provide certain therapeutic benefits as a result of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies to study substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described in the examples below, using an appropriate isotopically labeled reagent in place of the previously used unlabeled reagent.

Production methods

The preparation of the compounds of formula (I) according to this invention can be carried out by sequential or convergent synthesis. The synthesis methods of the invention are illustrated in the following general diagrams. The skills required to carry out the reaction and purify the resulting products are known to one of ordinary skill in the art. Substituents and subscripts used in the following description of methods have the meaning specified herein unless otherwise indicated.

If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups can be introduced prior to the key 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.), using methods well known in the art. 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, chiral SLC or chiral crystallization. Racemic compounds can, for example, be separated into antipodes using diastereomeric salts by crystallization with optically pure acids or by separating the antipodes by special chromatographic methods using a chiral adsorbent or 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) typically results in the corresponding diastereomeric/enantiomerically enriched compounds of formula (I).

One skilled in the art will appreciate that the synthesis of compounds of formula (I), unless otherwise required, will employ an "orthogonal protecting group strategy" which allows removal of multiple protecting groups at a time without affecting others. protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in the literature (eg, Barany and R. B. Merrifield, J. Am. C hem. 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 can be varied depending on the reactivity and nature of the intermediates.

More specifically, the compounds of formula (I) can be prepared by the methods given below, the methods given in the examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to one skilled in the art. Also, information regarding reaction conditions described in the literature relating to the described reactions can be found, for example, in: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). Carrying out reactions in the presence or absence of a solvent has been found convenient. There is no particular limitation on the nature of the intended solvent, provided that it does not adversely affect the reaction or the reactants involved and that it can dissolve the reactants to at least some extent. The described reactions can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in the temperature range from -78°C to boiling. The time required for a reaction can also vary greatly depending on many factors, namely the reaction temperature and the nature of the reagents. In this case, a period from 0.5 hour to several days is usually sufficient to obtain the described intermediates and compounds. The reaction sequence is not limited to that shown in the diagrams, however, depending on the starting materials and their respective reactivity, the 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, Bn = benzyl, Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts number), Cbz = benzyloxycarbonyl, Cs ₂ CO ₃ = cesium carbonate, CO = monoxide carbon, CuCl = copper(I) chloride, CuCN = copper(I) cyanide, CuI = copper(I) iodide, DAST = (diethylamino)sulfur trifluoride, DBU = 1,8-diazabicyclo[5,4,0]undec- 7-ene, DEAD = diethylazodicarboxylate, DIAD = diisopropyl azodicarboxylate, 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, EC = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour(s), FA = formic acid, H ₂ O = water, H ₂ SO ₄ = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3 -hexafluorophosphate oxide, HBTU = O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-N-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropyl magnesium chloride, 12 = iodine, IPA = 2-propanol, PIR = positive ion sputter, OIR = negative ion sputter, 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, m-CPBA = meta-chloroperoxybenzoic acid, MgSO ₄ = magnesium sulfate, min = minute(s), ml = milliliter, LCSD = medium pressure liquid chromatography, MS = mass spectrum, MTBE = methyl tert-butyl ether nBuLi = n-butyllithium, NaBH3CN = sodium cyanoborohydride, NaH = sodium hydride, NaHC ₃ = sodium bicarbonate, NaNO ₂ = sodium nitrite, NaBH(OAc) ₃ = sodium triacetoxyborohydride, 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-butyllithium, NEt ₃ = triethylamine (TEA), NH ₄ Cl = ammonium chloride, NMP = M-methyl-2-pyrrolidone, OAc = acetoxy, T ₃ P = propylphosphonic anhydride, PE = petroleum ether, PG = protecting group, Pd-C = palladium on activated carbon, PdCl ₂ (dppf)-CH ₂ Cl ₂ = 1,1'-bis(diphenylphosphino) dichloride complex ferrocene-palladium(II) with 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, SLC = supercritical liquid chromatography, S-PHOS = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl , TBAI = tetra-butylammonium iodine, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMEDA = N,N,N',N'-tetramethylethylenediamine, ZnCl ₂ = zinc chloride, Hal = halogen.

Compounds of formula I, wherein A, L, X, R ¹ , R ² , R ³ and R ⁴ are as described herein, can be synthesized by analogy with procedures described in the literature and/or as illustrated, for example, in Scheme 1a.

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

Compounds of formula (I) wherein R ¹ , R ² , R ³ and R ⁴ are as defined herein and where R ⁷ is C1 or Br may be further modified according to the general procedure described in Scheme 1b.

Treatment of compounds of formula I containing bromo- or chloroaryl as A under typical Suzuki-Miyaura reaction conditions, Buchwald-Hartwig reaction or other organometallic C-C or CN cross-links known in the art leads to substituted compounds of formula I, where bromine is replaced by an alkyl, heterocyclyl, cycloalkyl or heteroaryl moiety. This usually requires a suitable reaction partner such as boronic acid, potassium trifluoroborate, pinacolboronate, amine or organozinc compound, a suitable catalyst such as tetrakis(triphenylphosphine) palladium (0), PdCl ₂ (DPPF)-CH ₂ Cl ₂ , Pd2 (dba )3 + Xantphos, cataCXiurn A, Pd G-2, RuPhos Pd G2, an organic or inorganic base such as sodium carbonate, TEA, TMEDA or cesium carbonate, in a solvent system such as dioceanic/water, DMF or toluene/water. The reactions are usually carried out at elevated temperatures from 100 to 120°C in an inert atmosphere (argon).

Intermediates 1 can be synthesized as illustrated in Scheme 2 and/or by analogy with methods described in the literature.

Thus, 3-aminopiperidin-4-ol derivatives 3 in which "PG" represents a suitable protecting group such as a Cbz or Boc protecting group and R ² is as defined herein can be acylated with, for example, acyl chlorides 4 wherein R ¹ is as described herein and "LG" represents a suitable leaving group (eg Cl or Br) using a suitable base such as sodium or potassium carbonate, sodium hydroxide or sodium acetate, in an appropriate solvent such as THF, water, acetone or mixtures thereof to obtain intermediates 5 (step a). Intermediates 4 are commercially available or can be prepared according to methods described in the literature in achiral (R ¹ = H), racemic (R ¹ is not H) or enantiomerically pure form (R ¹ is not H).

Intermediates 5 can be cyclized to intermediate 6 using methods well known in the art, for example by treating 5 with sodium hydride in THF or potassium tert-butoxide in IPA and water (step b). Reactions of this type are described in the literature (eg, Z. Rafinski et al., J. Org. Chem. 2015, 80, 7468; S. Dugar et al., Synthesis 2015, 47(5), 712; WO2005/066187).

Removal of the protecting group from intermediates 6 using methods known in the art (e.g. Boe group using TFA in DCM at temperatures from 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 "Wilts, 4th Ed., 2006 , Wiley NY), provides intermediates 1 (step c).

Intermediates 1 can be obtained in the form of mixtures of diastereomers and enantiomers, respectively, or in the form of individual stereoisomers, depending on whether racemic mixtures or enantiomerically pure forms of cis- or trans-3-aminopiperidin-4-ol a derivatives 3 and acid chlorides4 (when R ¹ is not H). If racemization occurs at the stereocenter bearing R ¹ during conversion 3 to 5 (step a) and/or 5 to 6 (step 6), the resulting diastereoisomers can be separated by chromatography (e.g. HPLC, chiral HPLC) or other methods known in the art. Intermediates 3 are commercially available and their synthesis is also described in the literature (eg WO 2005/066187; WO 2011/0059118; WO 2016/185279). Optically pure intermediates 1 B and 1 C in the cis configuration can be obtained, for example, in accordance with Scheme 3 by chiral resolution of the commercially available rac-(4aR,8aS)-4a,5,b,7,8,8a-hexahydro-4H -pyrido[4,3-b][1,4]oxazin-3-one (1A) (optionally in salt form, such as, for example, the hydrochloride salt), using methods known in the art, e.g. crystallization of the diastereomeric salt or by chiral chromatography (step a).

In some embodiments, intermediates 2 are Type A intermediates. Type A intermediates in which A, B, R ³ and R ⁴ are as described herein and R ⁵ is hydrogen, C _1-6 - alkyl and halo-C _1-6 -alkyl can be prepared by methods well known in the art and exemplified by the general synthetic methods outlined in Scheme 4.

Spirocyclic compounds 7 in which PG represents a suitable protecting group such as the Boc, Cbz or VP protecting group (either commercially available or prepared as described in the literature, e.g. Eur. J. Org. Chem. 2017, 36, 5316 ; Topics in Het. Ckem. 2014, 35, 189; World Journal of Pharmacy and Pharmaceutical Sciences 2014, 3 (12), 536; Chem. Rev. 2014, 114(16), 8257-8322) may undergo Mitsunobu reaction with derivatives alcohol 8 using a suitable phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD in a suitable solvent such as THF to give intermediates 9 (step a). Mitsunobu reactions of this type are widely described in the literature (e.g. Org. Chem. Pront. 2015, 2, 739; Chem. Rev. 2009, 109 (6), 2551).

Removal of the protecting group from intermediates 9 using methods known in the art, for example, the Boe group using TFA in DCM or 4 M HCl in dioxane at temperatures from 0°C to room temperature, the Bn or 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), allows you to obtain intermediate compounds A (step b).

Intermediates 9 can be prepared by alkylation of compounds 8 with spirocyclic derivatives 10 (either commercially available or prepared by methods known in the art) in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO halkyl (e.g. mesylate (methanesulfonate), OSO ₂ fluoroalkyl (e.g. triphthalate (trifluoromethanesulfonate) or OSO ₂ aryl (e.g. tosylate (p-toluenesulfonate), using a suitable base in a suitable solvent (e.g. sodium hydride in DMF) at temperatures between 0°C and boiling point of the solvent (step c).

In some embodiments, intermediates 2 are type B intermediates. Type B intermediates in which A, B, R ³ and R ⁴ are as described herein can be prepared by methods well known to one skilled in the art, and illustrated by the general synthesis procedure shown in Scheme 5.

Compounds of type 11 are either commercially available or prepared by methods known in the art, and in which PG represents a suitable protecting group, such as, for example, a Boc, Cbz or Bn protecting group, can be subjected to a reductive amination reaction with type 12 aldehydes using a suitable reducing agent and solvent such as NaBH ₃ CN in MeOH, AcOH or mixtures thereof, or NaBH(OAc) ₃ in DCE, DCM or THF to give intermediates 13 (step a).

Removal of the protecting group from intermediates 13 using methods known in the art or described under Scheme 4, step 6, provides intermediates B (step b).

Intermediates 13 can alternatively be prepared by alkylation of compounds 11 with compounds 15 (either commercially available or prepared by methods known in the art) in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO ₂ alkyl (eg , methanesulfonate), OSO ₂ fluoroalkyl (eg trifluoromethanesulfonate) or OSO ₂ aryl (eg p-toluenesulfonate), using a suitable base in a suitable solvent (eg Nbt ₃ or DIPEA in ANN) at temperatures between 0°C and boiling point solvent (step c). Reactions of this type are known in the art and are widely described in the literature (eg ARKIVOC 2005 (vi) 287-292).

In some embodiments, intermediates 2 are type C, D, or E intermediates. Type C, D, or E intermediates, in which A, B R ³ and R ⁴ are as described herein, can be prepared by methods such as well known to one skilled in the art, and illustrated by the general synthesis procedure shown in Scheme 6.

Compounds of type 11 are either commercially available or prepared by methods known in the art, and in which PG represents a suitable protecting group, such as, for example, a Boc, Cbz or Bn protecting group, can be acylated with carboxylic acids 16 to form intermediates 17 ( stage a). Amide couplings of this type are widely described in the literature and can be performed using coupling reagents such as CDI, DCC, HATU, HBTU, HOBT, TBTU, T3R or Mukayama reagent (e.g. Angew. C hem., Int. Ed. Engl. 1979, 18, 707) in a suitable solvent such as DMF, DMA, DCM or dioxane, optionally in the presence of a base such as NEt ₃ , DIPEA (Hunig's base) or DMAP.

Alternatively, the carboxylic acids 16 can be converted to their acid chlorides by treatment with, for example, thionyl chloride or oxalyl chloride alone or optionally in a solvent such as DCM. Reaction of the acid chloride with intermediates 11 in a suitable solvent such as DCM or DMF and a base such as NEt ₃ , Huenig's base, pyridine, DMAP or lithium bis(trimethylsilyl)amide at temperatures from 0°C to the boiling point of the solvent or mixture of solvents gives intermediates 17 (step a).

Removal of the protecting group from intermediates 17 using methods known in the art or described under Scheme 4, step 6, provides intermediates C (step b).

Compounds of type 11 can be sulfonylated, for example, by treatment with sulfonyl chlorides 18 (either commercially available or prepared by methods known in the art or described in the literature) using a suitable base and solvent such as NEt3 or pyridine in DCM to give intermediates 19 (stage c).

Removal of the protecting group from intermediates 19 using methods known in the art or described under Scheme 4, step 6, provides intermediates D (step d).

Compounds of type 11 can be converted to the corresponding carbamates 20, for example, by first reacting 11 with an activating and carbonylating reagent such as bis(trichloromethyl) carbonate using a suitable base and solvent such as, for example, sodium bicarbonate in DCM followed by the reaction the intermediate carbamoyl chloride formed with type 8 alcohols in the presence of a suitable base such as pyridine or NEt3, optionally at elevated temperatures (step e). Additional activating agents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, or 1,1'-carbonyldiimidazole. The synthesis of carbamates is well known in the art and widely described in the literature (eg, J. Med. Chem. 2015, 58(7), 2895).

Removal of the protecting group from intermediates 20 using methods known in the art or described under Scheme 4, step 6, provides intermediates E (step e).

In some embodiments, intermediates 2 are intermediates of type F, G, and H. Intermediates of type F, G, and H, in which A, B, R ³ and R ⁴ are as defined herein and R ⁵ is hydrogen, Ci-6-alkyl, halo-C _1-6 -alkyl can be prepared by methods well known in the art and exemplified by the general synthetic methods outlined in Scheme 7.

Intermediates 21, commercially available or prepared by methods described in the literature, can be converted into intermediates 22, for example, by reductive amination using aldehydes 12 and using the conditions described in Scheme 5, step a (step a).

Removal of the protecting group from intermediates 22 using methods known in the art or described under Scheme 4, step 6, provides intermediates B (step 6).

Intermediates 21 can be reacted with carboxylic acids 16 using, for example, the conditions described in Scheme 6, step a, to obtain intermediates 23 (step c).

Removal of the protecting group from intermediate 23 using methods known in the art or described under Scheme 4, step b, provides intermediates G (step d).

Intermediates 21 can be sulfonylated, for example, by treatment with sulfonyl chlorides 18 (either commercially available or prepared by methods known in the art or described in the literature), using, for example, the reaction conditions described in Scheme 6, step c, to obtain intermediates compounds 24 (step e).

Removal of the protecting group from intermediates 24 using methods known in the art or described under Scheme 4, step b, provides intermediates H (step e).

In some embodiments, intermediates 2 are type J, K, and L intermediates. Type J, K, and L intermediates in which A, B, R ³ and R ⁴ are as described herein, R ⁵ is hydrogen, C _1-6 -alkyl or halo-C _1-6 -alkyl, and R ¹⁹ is hydrogen or halo-C _1-6 -alkyl can be prepared by methods well known in the art and exemplified by the general synthetic methods set forth in Scheme 8.

Intermediates 22 can be converted to intermediates 27, for example, by reductive amination using aldehydes 26 and using the conditions described in Scheme 5, step a (step a).

Alternatively, intermediates 22 can be alkylated with compounds 25 of the R ²⁰ LG type, in which LG represents a suitable leaving group such as chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate, using, for example, the conditions described in Scheme 4. step c to obtain intermediates 27 (step a).

Removal of the protecting group from intermediate 27 using methods known in the art or described under Scheme 4, step b, provides intermediates J (step b).

Intermediates 22 can be alkylated with compounds 25 of type R ²⁰ LG, in which LG represents a suitable leaving group such as chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate, using, for example, the conditions described in Scheme 4, step c to obtain intermediates 28 (step c).

Removal of the protecting group from intermediates 28 using methods known in the art or described under Scheme 4, step b, provides intermediates K (step d).

Intermediates 24 can be alkylated with compounds 25 of the R ²⁰ LG type, in which LG represents a suitable leaving group such as chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate, using, for example, the conditions described in Scheme 4, step c to obtain intermediates 29 (step e).

Removal of the protecting group from intermediates 29 using methods known in the art or described under Scheme 4, step b, provides intermediates L (step d).

In some embodiments, intermediates 2 are type M intermediates. Type M intermediates in which A, B, R ³ and R ⁴ are as described herein and R ⁵ is hydrogen, C _1-6 - alkyl and halo-C _1-6 -alkyl can be prepared by methods well known in the art and exemplified by the general synthetic methods outlined in Scheme 9.

Spirocyclic compounds 7, in which PG represents a suitable protecting group, can be alkylated with compounds 15, in which LG represents a suitable leaving group, such as chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate (prepared using those described in the literature methods, for example from compounds 30) using, for example, the conditions described in Scheme 4, step c, to obtain intermediates 31 (step a).

Removal of the protecting group from intermediates 31 using methods known in the art or described under Scheme 4, step b, provides intermediates M (step b).

Alternatively, intermediates 31 can be prepared from intermediates 7 and compounds 30 via the Mitsunobu reaction, using, for example, the conditions described in Scheme 4, step a (step c).

In addition, intermediates 31 can also be prepared by alkylation of compounds 7 with compounds 10 and using, for example, the conditions described in Scheme 4, step c (step d).

Intermediates 10 can in turn be synthesized from compounds 7 by converting the hydroxy group to a leaving group such as an alkyl halide (e.g. bromine using PBr ₃ , chlorine using SOCl ₂ ) or an alkyl or arylsulfonate such as methanesulfonate ( using mesyl chloride) or p-toluenesulfonate (using toeyl chloride). Reactions of this type are widely described in the literature and are well known in the art.

In some embodiments, intermediates 2 are type N intermediates. Type N intermediates in which A, B, R ³ , R ⁴ and R ⁵ are as described herein can be prepared by methods well known in the art field, and with examples of general synthetic methods outlined in Scheme 10.

Compounds of type 32, commercially available or prepared by methods known in the art, can be subjected to the Mitsunobu reaction with compounds 8, using, for example, the conditions described in Scheme 4, step a, to obtain intermediate compounds 34 (step a).

Removal of the protecting group from intermediates 34 using methods known in the art or described under Scheme 4, step b, provides intermediates N (step b).

Alternatively, intermediates 34 can be prepared by alkylation of compounds 32 with compounds 33 in which LG is a suitable leaving group, under the conditions described, for example, in Scheme 4, step c (step c).

Intermediates N can be alternatively prepared as illustrated by the general synthetic routes outlined in Scheme 11.

Compounds 8 can be subjected to a Mitsunobu reaction with compounds 32 under the conditions described in Scheme 4, step a, to yield intermediates 34 (step a).

Removal of the protecting group from intermediates 34 using methods known in the art or described under Scheme 4, step b, provides intermediates N (step b).

Alternatively, compounds 8 can be alkylated with compounds 35, in which LG is a suitable leaving group such as chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate, using, for example, the conditions described in Scheme 4, step c to give intermediates 34 (stage c).

In some embodiments, intermediates 2 are type P intermediates. Type P intermediates in which A, B, R ³ and R ⁴ are as described herein and R ⁵ is hydrogen, C _1-6 - alkyl and halo-C _1-6 -alkyl can be prepared by methods well known in the art and exemplified by the general synthetic methods outlined in Scheme 12.

Spirocyclic compounds 38 in which PG is a suitable protecting group such as a Boc, Cbz or Bn protecting group (either commercially available or prepared as described in the literature, e.g. Eur. J. Org. Chem. 2017, 36, 5316 , Topics in Het. Chem. 2014, 35, 189; World Journal of Pharmacy and Pharmaceutical Sciences 2014, 3(12), 536; Chem. Rev. 2014 114(16), 8257-8322) can be prepared by alkylation of thiol 37 with spirocyclic derivatives 36 (either commercially available or prepared by methods known in the art) in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO ₂ alkyl (eg, mesylate (methanesulfonate), OSO ₂ fluoroalkyl ( for example, triphthalate (trifluoromethanesulfonate) or OSO ₂ aryl (for example, tosylate (p-toluenesulfonate), using a suitable base in a suitable solvent (for example, K ₂ CO ₃ in DMF) at temperatures between 0 C and the boiling point of the solvent (step a).

Intermediates 38 can be oxidized to intermediates 39 using a suitable oxidizing reagent such as mCPBA in a suitable solvent (eg DCM) at temperatures from 0° C. to the boiling point of the solvent (step b).

Removal of the protecting group from intermediates 39 using methods known in the art, e.g. Boc group using TFA in DCM or 4 M HCl in dioxane at temperatures between 0°C to room temperature, Bn or 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), allows you to obtain intermediate compounds P (step c).

In some embodiments, intermediates 2 are type Q intermediates. Type Q intermediates in which A, B, R ³ and R ⁴ are as described herein and R ⁵ is hydrogen, C _1-6 - alkyl and halo-C _1-6 -alkyl can be prepared by methods well known in the art and exemplified by the general synthetic methods outlined in Scheme 13.

Alternatively, bromide-functionalized compounds 40 can be subjected to electrophilic cross-coupling with aryl or heteroaryl bromides 41 under irradiation with 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'-bipyridin-N1, N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C]iridium(III) hexafluorophosphate), nickel catalyst such as glyme NiCl ₂ (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).

Removal of the protecting group from intermediates 42 using methods well known in the art or described under Scheme 12, step c, provides intermediates Q (step b).

In some embodiments, intermediates 2 are intermediates of type R and S. Intermediates of type R and R, in which A, B, R ³ and R ⁴ are as described herein and R ⁵ is hydrogen, can be prepared by methods well known to one skilled in the art and illustrated by the general synthesis procedure shown in Scheme 14.

Ketones 43, either commercially available or prepared by methods known in the art, can be subjected to, for example, a Wittig reaction with alkylidenetriphenylphosphoranes type 44a in a suitable solvent such as, for example, THF, Methyl-THF or DMSO to obtain intermediates 45 (stage a). Phosphoranes 44a can be formed by treating the corresponding phosphonium salts with a suitable base, such as BuLi, NaH or KOtBu, in a suitable solvent such as THF, dioxane or Methyl-THF, and can be isolated or used in situ. Phosphonium salts, in turn, are readily available from aryl/hetero aryl/heterocyclic substituted alkyl halide (the halide of which is Cl, Br and iodine) and triphenylphosphine in a suitable solvent such as toluene. Heat can be used to speed up the reaction or to bring the reaction to completion (for example, N.J. Cristau, F. in PATAI'S Chemistry of Functional Groups, Editor(s): Frank R. Hartley, 07th August 2006, Series Editor(s): Prof. Saul Patai).

Alternatively, intermediates 45 can be prepared by the Horner-Wadsworth-Emmons (HWE) reaction using ketones 43 and phosphonates 44b, where R ^a is alkyl, such as methyl or ethyl. Phosphonates 44b are α-metalated in situ using a suitable base and solvent such as NaH, nBuLi or KOtBu in THF (step a). Phosphonates 44b are readily prepared using, for example, the Arbuzov reaction by alkylation of an aryl/heteroaryl/heterocyclic halide (the halide of which is Cl, Br and iodine) with a commercially available trialkyl phosphite (eg Chem. Rev. 1984, 84, 577).

Both types of olefination reactions are widely described in the literature (e.g. Current Org. Chem. 2015, 19(9), page 744; Chem. Rev. 1989, 89(4), 863; Org. React. 1977, 25, 73; Liebigs Ann./Recueil 1997, 1283; Acc. Chem. Res. 1983, 16, 411).

Reduction of the double bond in intermediates 45 using, for example, hydrogen in the presence of a suitable catalyst such as palladium on carbon, in a suitable solvent or mixture of solvents such as EtOAc, MeOH or AcOH, gives compounds 46 (step b).

Removal of the protecting group from intermediates 45 using methods known in the art (e.g., Boc group using TFA in DCM or 4 M HCl in dioxane at temperatures between 0 C and 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 T.W. Greene and P.G.M. Wuts, 4th Ed ., 2006, Wiley NY), allows you to obtain intermediate compounds R (step c).

If methoxy is among the A substituents ( ^R7 , ^R8 or ^R9 ), demethylation can lead to hydroxy-substituted intermediates S. This requires a reagent such as BBr3 in a suitable solvent such as DCM at temperatures between 0°C and boiling point of the solvent. The Boc protecting group will also be cleaved under the reaction conditions, leading directly to intermediate S (step d).

In some embodiments, intermediates 2 are type T intermediates. Type T intermediates in which A, B, R ³ and R ⁴ are as described herein and X is nitrogen can be prepared by methods well known in the art. one skilled in the art, and illustrated by the general synthesis procedure shown in Scheme 15.

Treatment of amines 47 with bromo-aryl or bromo-heteroaryl 41 under typical Buchwald-Hartwig reaction conditions or other organometallic CN cross-links known in the art results in intermediates 48. This usually requires a suitable catalyst system, such as PdCl ₂ ( DPPF)-CH ₂ Cl ₂ , Pd ₂ (dba) ₃ + Xantphos, cataCXium A Pd G2, RuPhos Pd G2, organic or inorganic base such as cesium carbonate or sodium t-butoxide in a solvent such as Dioxane or toluene. The reactions are usually carried out at elevated temperatures from 70 to 120°C in an inert atmosphere (step a).

Removal of the protecting group from intermediates 48 using methods well known in the art or described under Scheme 12, step c, provides intermediates T (step b).

In one aspect, this invention provides a method for the production of urea compounds of formula (I) described herein, and pharmaceutically acceptable salts thereof, comprising:

(c) reacting the first amine of formula 1, wherein R ¹ and R ² are as described herein, preferably wherein R ¹ and R ² are hydrogen,

with a second amine 2, where A, B, L, X, R ³ and R ⁴ are as described herein,

in the presence of a base and a urea-forming reagent to form said compound of formula (I); and optional

(d) converting said compound of formula (I) into pharmaceutically acceptable salts thereof.

In one embodiment, a method according to the invention is provided, wherein said base is sodium bicarbonate.

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

In one aspect, this invention provides a compound of formula (I) described herein produced in accordance with any of the methods described herein.

MAGL inhibitory activity

The compounds of this invention are MAGL inhibitors. Thus, in one aspect, this invention provides the use of the compounds of formula (I) described herein for the inhibition of MAGL in a mammal.

In a further aspect, this invention provides compounds of formula (I) described herein for use in a method of inhibiting MAGL in a mammal.

In a further aspect, this invention provides the use of the compounds of formula (I) described herein for the manufacture of a medicament for inhibiting MAGL in a mammal.

In a further aspect, the present invention provides a method of inhibiting MAGL in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (I) described herein.

Compound profiles for MAGL inhibitory activity were obtained by measuring MAGL enzymatic activity following hydrolysis of 4-nitrophenylacetate to produce 4-nitrophenol, which absorbs at 405-412 nm (G.G. Muccioli, G. Labar, D.M. Lambert, Chem. Bio. Chem. 2008, 9, 2704-2710). In the following, this assay is abbreviated as the “4-NPA assay.”

The 4-NPA assay was performed in 384-well assay plates (black with clear bottom, non-binding surface treatment, 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 with 3-fold dilution steps to obtain a final assay concentration range of 25 μM to 1.7 nM. 1 µl dilution of compounds (100% DMSO) was added to 19 µl MAGL (recombinant, wild type) in assay buffer (50 mM Tris (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml)). The plate was shaken for 1 min at 2000 rpm (Variomag Teleshake) and then incubated for 15 min at RT. To initiate the reaction, 20 μl of 4-nitrophenylacetate (Sigma N-8130) in assay buffer with 6% EtOH was added. The final concentrations in the assay were 1 nM MAGL and 300 μM 4-nitrophenylacetate. After shaking (1 min, 2000 rpm) and 5 min incubation at RT, absorbance was first measured at 405 nm (Molecular Devices, SpectraMax Paradigm). The second measurement was performed after incubation for 80 min at RT. From two measurements, the slope was calculated by subtracting the first measurement from the second.

Alternatively, compound profiles for MAGL inhibitory activity were obtained by determining enzymatic activity by monitoring the hydrolysis of the natural substrate 2-arachidonoylglycerol to produce arachidonic acid, which can be monitored using mass spectrometry. In the following, this assay is abbreviated as the “2-AG assay.”

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 with 3-fold dilution steps to obtain a final assay concentration range of 12.5 μM to 0.8 pM. 0.25 μl of compound dilution (100% DMSO) was added to 9 μl of MAGL in assay buffer (50 mM Tris (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml), 0.01% (vol. /vol.) Tween. After shaking, the plate was incubated for 15 min at RT. To initiate the reaction, 10 μl of 2-arachidonoylglycerol in assay buffer was added. Final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglycerol. After shaking and 30 min After incubation at RT, the reaction was quenched by adding 40 μl of acetonitrile containing 4 μM d8-arachidonic acid.The amount of arachidonic acid was monitored using an online SPE system (Agilent Rapidfire) in combination with a triple quadrupole mass spectrometer (Agilent 6460). C18 SPE cartridge (G9205A) used with acetonitrile/water liquid settings. The mass spectrometer was operated in negative electrospray mode with mass transfer tracking 303.1 259.1 for arachidonic acid and 311.1 267.0 for d8-arachidonic acid. The activity of the compounds was calculated based on the intensity ratio [arachidonic acid/d8-arachidonic acid].

In one aspect, this invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters described herein, wherein said compounds of formula (I) and their pharmaceutically acceptable salts or esters have an IC of 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 assays described herein.

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

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

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

b) obtaining a solution of MAGL (recombinant, wild type) in analytical 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 the mixture for 1 minute at 2000 rpm;

e) incubation for 15 min at RT;

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

g) shaking the mixture for 1 minute at 2000 rpm;

h) incubation for 5 min at RT;

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

j) incubation for an additional 80 min at RT;

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

m) subtracting the absorbance measured in i) from the absorbance measured in l) and calculating the absorption slope; Where:

i) the concentration of the compound of formula (I) or its pharmaceutically acceptable salt or ester after step e) is in the range of 25 μM to 1.7 nM;

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

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

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

Use of the compounds according to the invention

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

In a further aspect, this invention provides the use of the compounds of formula (I) 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 the compounds of formula (I) 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 the compounds of formula (I) described herein for the treatment or prevention of neurodegenerative diseases in a mammal.

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

In one aspect, this invention provides the use of compounds of formula (I) 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-related spasticity in a mammal.

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

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

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

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

In one aspect, this invention provides compounds of formula (I) 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-related spasticity in a mammal.

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

In one aspect, this invention provides the use of the compounds of formula (I) 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, this invention provides the use of the compounds of formula (I) described herein for the manufacture 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 the compounds of formula (I) 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 the compounds of formula (I) described herein for the manufacture of a medicament for the treatment or prevention of cancer in a mammal.

In a further aspect, this invention provides the use of compounds of formula (I) 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 carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain-related spasticity in a mammal.

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

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

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

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

In one aspect, this invention provides a method of 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 includes administering to a mammal an effective amount of a compound of formula (I) described herein.

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

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

Pharmaceutical compositions and administration

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

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as drugs (eg, in the form of pharmaceuticals). Pharmaceuticals may be administered orally, for example, orally (eg, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (eg, in the form of nasal sprays) or rectally (eg, in suppository form). In this case, administration can also be carried out parenterally, for example, intramuscularly or intravenously (for example, in the form of injection solutions).

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

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

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

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils, etc.

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

In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, wetting agents, emulsifiers, sweeteners, colors, flavors, osmotic salts, buffers, masking agents, or antioxidants. They may also contain other substances of therapeutic value.

The dosage can vary over a wide range and, of course, will be tailored to individual requirements in each specific case. In general, for oral administration, a suitable daily dosage would be from about 0.1 mg to 20 mg per kg body weight, preferably from 0.5 mg to 4 mg per kg body weight (for example, about 300 mg per person), preferably divided into 1-3 separate doses, which may be, for example, the same amount. It should be understood that the upper limit given herein may be exceeded if indicated.

Examples

The present invention will be better understood with reference to the following examples. However, the claims should not be understood as limiting the scope of examples.

In the case where the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to one skilled in the art, such as, for example, chiral chromatography (eg, chiral SLC) or crystallization.

All reaction samples and intermediates were prepared under argon unless otherwise noted.

Method Α1

Example 4

(4aR,8aS)-6-(6-(2-Fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one

DIPEA (110 mg, 149 μL, 851 μmol) and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[ 4,3-b][1,4]oxazine-6(5H)-carboxylate (91.1 mg, 284 µmol, BB2a). The reaction vessel was stirred at 80°C for 4 hours. The crude material was purified by reverse phase HPLC to give the title compound (66.8 mg, 134 μmol, 47.3%) as a white solid. MS (PER): m/z=474.3 [M+H] ⁺ .

Method A2

Example 1

(4aR,8aS)-6-(6-(2-Chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] Oxazin-3(4H)-one

DIPEA (895 mg, 1.21 ml, 6.92 mmol) and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (816 mg, 2. 54 mmol, BB2a). The reaction vessel was stirred at 80°C for 2.5 hours. The solution was evaporated. The residue was dissolved in a saturated aqueous solution of NaHCO ₃ (30 ml) and EtOAc (30 ml) and the layers were separated. The organic layer was washed once with saturated aqueous NaHCO ₃ solution (30 ml). The combined aqueous layers were extracted once with EtOAc (100 ml). The organic layers were washed once with saturated aqueous NaHCO ₃ (100 ml) and brine, 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 HPLC system, eluting with a gradient of n-heptane: EtOAc/EtOH 3/1 (70:30 to 0:100) and evaporated to give the title compound as white foam (841.2 mg, 1.94 mmol, 84.3%). MS (IER): m/z=424.4 [M+H] ⁺ .

Method A3

Example 18

rac-(4aR,8aS)-N-((R)-8-(3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide

(R ₎ -N-(1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (89.6 mg, 218 µmol, prepared as described in US 20170029390) in one portion and the mixture was stirred at RT overnight. Cool in an ice bath and add rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (50 mg, 218 µmol, BB1) and DIPEA (113 mg, 152 µl, 873 µmol). The suspension was stirred at RT for 4 hours. The reaction mixture was poured into 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 product was purified by preparative HPLC (Gemini NX column) using an ACN:water (containing 0.1% formic acid) gradient (20:80 to 98:2) to give the desired compound as a colorless gum (0.025 g; 23. 9%). MS (IER): m/z=479.2 [M+H] ⁺ .

Method A4

Example 22

The round bottom flask was dried using a heat gun under HV, refilled with argon and charged with bis(trichloromethyl) carbonate (39.9 mg, 134 µmol) and sodium bicarbonate (64.5 mg, 768 µmol). DCM (2 ml) was added to obtain a suspension. (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (30 mg, 192 μmol) was added to the suspension at 0°C. The mixture was stirred at 0 °C for 5 minutes at RT for 20 hours. BB22 (84.6 mg, 192 µmol) and DIPEA (99.3 mg, 134 µl, 768 µmol) were added. The resulting off-white suspension was stirred at RT for 1 hour. The reaction mixture was poured into 5 ml H ₂ O and extracted with DCM (2×10 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, 10 g, 0% to 10% MeOH in DCM). The fractions were combined and evaporated to give the product as a white foam, 69 mg, 70% yield.

Method A5

Chiral separation of stereoisomers on an NR column

Two stereoisomers rac-(4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H -pyrido[4,3-b][1,4]oxazin-3(4H)-one (Examples 33 and 34) were separated by preparative chiral HPLC (Reprosil Chiral NR column) using isocratic EtOH mixture (containing 0.05% NH ₄ OAc): n-heptane (40:60). The absolute stereochemistry of the isomers has not been determined.

Method A6

Chiral separation of stereoisomers on an OD column

Two stereoisomers rac-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)amino)-1-oxa-8-azaepyro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one (Example 38) was separated by preparative chiral HPLC (Reprosil Chiral OD column) using isocratic EtOH mixture (containing 0.05% NH ₄ OAC): n -heptane (40: 60). The absolute stereochemistry of the isomers has not been determined.

Method A7

Preparative HPLC: Column Gemini NX, 12 nm, 5 µm, 100 × 30 mm, travel time 15 min, gradient 25-45-60-100% ACN in water +0.1% HCOOH

Method A8

Preparative HPLC: Column YMC-Triart C18, 12 nm, 5 µm, 100×30 mm, travel time 11 min, gradient 30-50-60-100% ACN in water +0.1% HCOOH

Method A9

Preparative HPLC: Column Gemini NX, 12 nm, 5 µm, 100×30 mm, ACN gradient in water +0.1% TEA

Method A10

Preparative HPLC: Column YMC-Triart C18, 12 nm, 5 µm, 100×30 mm, travel time 11 min, gradient 20-40-60-100% ACN in water +0.1% TEA

Method Α11

Preparative HPLC: Column YMC-Triart C18, 12 nm, 5 µm, 100×30 mm, travel time 11 min, gradient 15-35-50-100% ACN in water +0.1% HCOOH

The following examples were prepared from the corresponding building blocks and methods outlined in Table 2.

Example 47

(4aR,8aS)-6-(6-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one

To a suspension of (4aR, 8aS)-6-(6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-one (0.050 g, 115 µmol) and 2-(trifluoromethyl)pyrrolidine (16 mg, 115 µmol) in tert-Butanol (1 ml) under argon was added XPhos (4.94 mg, 10.4 µmol , eq: 0.09), Pd2 (dba) 3 CHCl ₃ (3.57 mg, 3.45 µmol) and cesium carbonate (150 mg, 460 µmol), and the mixture was heated in a microwave oven to 100°C for 30 minutes. The mixture was filtered, and the filtrate was evaporated. The product was purified by preparative HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm, acetonitrile/water +0.1% TEA gradient) to give the desired product as 2.1 mg of a yellow oil. MS (IER): m/z=493.4 [M+H] ⁺ .

Step a) 6-(4-bromophenyl)-2-azaspiro[3.3]heptane trifluoroacetate was prepared by analogy with BB41 from tert-butyl 6-bromo-2-azaspiro[3.3]heptane-2-carboxylate (1 equiv.) and 1 ,4-dibromobenzene (2 eq.). MS (IER): m/z=298.1 [M-56-N] ⁺ .

Step b) (4aR, 8aS-6-(6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-one was synthesized similarly to the general method A4 from 6-(4-bromophenyl)-2-azaspiro[3.3]heptane trifluoroacetate and BB1a, purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM). MS (IER): m/z=434.2 [M+H] ⁺ .

Example 48

(4aR, 8aS)-6-(6-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one

(4aR,8aS)-6-(6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-one (0.050 g, 115 µmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (14.5 mg, 115 µmol), potassium carbonate (79.5 mg, 576 µmol) and tetrakis (triphenylphosphine)palladium(0) (6.65 mg, 5.76 μmol) was dissolved in THF (1.5 ml)/water (0.150 ml) under argon, and stirred at 80°C for 2 days. The reaction mixture was poured into 10 ml H ₂ O and extracted with EtOAc (2 x 20 ml). The organic layers were combined, washed with brine, dried over Na2SO ₄ and concentrated in vacuo. The crude material was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 µm, 100 x 30 mm, run time 15 minutes, gradient 15-35-50-100 ACN in water + 0.1% HCOOH). The product was obtained as a white lyophilized powder (15.6 mg, 31%). MS (IER): m/z=436.4 [M+H] ⁺ .

Synthesis of building blocks BB1a and BB1b

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

(ВВ1а)

And

(-)-(4aS,8aR)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

(BB1b)

Enantiomers of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (BB1, 500 mg, 2.18 mmol, ChemBridge Corporation) were separated by preparative chiral HPLC (ReprosilChiral NR column) using an isocratic mixture of EtOH (containing 0.05% NH ₄ OAc): n-heptane (30:70).

The first enantiomer to elute: (+)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (BB1a). Yellow solid (0.150 g; 44.0%). MS (IER): m/z=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. (BB1b). Yellow solid (0.152 g; 44.6%). MS (IER): m/z=157.1 [M+H] ⁺ .

BB2a and BB2b

(+)-4-Nitrophenyl (4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB2a)

And

(-)-4-nitrophenyl (4aS,8aR)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazin-

6(5H)-carboxylate (BB2b)

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) at 0°C, DIPEA (6.35 g, 8.58 ml, 49.1 mmol) was added, and then 4- nitrophenyl carbonochloridate (4.35 g, 21.6 mmol). The reaction mixture was stirred at 0°C for 10 min and at RT for 2 h. The crude reaction was diluted with DCM and transferred to a separatory funnel for saturated extraction. 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 SO4 and evaporated to dryness to obtain 6.62 g of crude racemic product (BB2) as a yellow solid. The crude material was directly subjected to chiral SLC separation to yield enantiomer BB2b (2.72 g, second eluting enantiomer) as a yellow solid and enantiomer BB2a (3.25 g, first eluting enantiomer) as a light beige solid, but with BB2b impurities. Additional chiral SLC separation was carried out to obtain 2.71 g of BB2a. MS (ESI): m/z=322.2 [M+H] ⁺ for both enantiomers.

BB3

(2R,4aR,8aS)-2-Methyl-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

In a solution of 6-benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (isomer A, 1,10 g, 4.26 mmol) in EtOAc (16 ml) and MeOH (16 ml) under argon, Pd-C (227 mg, 213 µmol) was added and the suspension was stirred in a hydrogen atmosphere (balloon) at 1 bar for 24 hours. The suspension was filtered through a fine glass filter and washed with 20 ml EtOAc under an inert gas atmosphere. The filtrate was evaporated to give BB4 as a colorless solid (715 mg). MS (IER): m/z=170.8 [M+H] ⁺ . Note: Only one enantiomer was formed during reduction. The relative conformation was confirmed by proton NMR.

Step a) 2-methyl-4H-pyrido[4,3-b][1,4]oxazin-3-one

To a solution of 3-aminopyridin-4-ol (2.5 g, 22.7 mmol) in DMF (100 ml), 2-chloropropanoyl chloride (3.03 g, 2.31 ml, 23.8 mmol) was added dropwise and stirred mixture at RT for 30 min. After adding K ₂ CO ₃ (7.84 g, 56.8 mmol), the suspension was heated to 100 ° C (oil bath) for 20 hours. DMF was removed in vacuum, then 100 ml of ESO Ac was added and stirred at RT for 10 min, washed with 50 ml H ₂ O, extracted 3 times with EtOAc. The organic phases were combined, dried with MgSO ₄ and concentrated in vacuo to obtain 3.72 g of 2-methyl-4H-pyrido[4,3-b][1,4]oxazin-3-one, which was used in the next step without further cleaning.

Step b) 6-Benzyl,-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[4,3-

b][1,4]oxazine-6-bromide

A suspension of 2-methyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (3.72 g, 22.7 mmol) in DCM (32 ml) and MeOH (8 ml ) were treated with (bromomethyl)benzene (4.65 g, 3.23 ml, 27.2 mmol) and the mixture was stirred at RT for 60 hours. 20 ml of n-hexane was added to the resulting suspension, which was cooled to 0°C, after which the precipitate was filtered. The residue was washed with 15 ml of cold DCM/n-hexane to give the compound as an off-white solid (5.2 g). MS (IER): m/z=255 [M+H] ⁺ .

Step c) (rac)-6-Benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one

To a suspension of 6-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium bromide (5.2 g, 15.5 mmol) in EtOH (38 ml) NaBH ₄ (763 mg, 20.2 mmol) was added portionwise (exothermic, 22°C to 30°C, yellow suspension). After completion of the exothermic reaction, the mixture was stirred at room temperature for 3 hours, then at 60°C for 1 hour and at 22°C for 1 hour. The reaction mixture was evaporated, partitioned between H ₂ O and EtOAc and the layers were separated. The aqueous layer was extracted once with EtOAc. The organic layers were washed twice 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 120 g column using an HPLC system, eluting with a gradient of n-heptane: EtOAc (50 to 100 over 30 min) to give the compound as a light yellow solid (2.48 g) , which could be used in the next step without further purification.

Step d) 6-Benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-

b][1,4]oxazin-3(4H)-one

Enantiomers were separated by preparative chiral HPLC (Chiralcel OD column) using an isocratic mixture of EtOH (containing 0.05% XH ₄ OAc):n-heptane (10:90). The fractions were evaporated to give the desired compounds as light yellow solids (isomer A, 1.17 g; isomer B, 1.10 g).

BB4

rac-(4aS,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-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 ). The reaction solution was degassed in vacuum and again filled with argon. Pd-C (20 mg, 188 μmol) was added under argon. Argon was removed from the reaction mixture and again filled with hydrogen. The reaction mixture was stirred at RT for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered through a syringe filter and concentrated in vacuo to give the desired product as a colorless solid (62 mg, 92.2%). MS (IER): m/z=157.098 [M+H] ⁺ .

Step a) 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 in accordance with US patent 2011/59118 A1) and sodium acetate (208 mg , 2.53 mmol, CAS RN 127-09-3) in a mixture of acetone (4 ml)/H ₂ O (0.5 ml) a solution of chloroacetyl chloride (150 mg, 107 μl, 1.33 mmol, CAS RN) was added dropwise 79-04-9) in acetone (3 ml) between 0-5°C. After addition, the reaction mixture was stirred at RT for 1 hour and then evaporated to dryness to obtain a yellow gum. The crude product was purified by silica gel chromatography to provide the desired product as a yellow solid (385 mg, 93%). MS (IER): m/z=325.2 [M-N] ^- .

Step b) Benzyl rac-(4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b] [1,4] oxazine-6(5H)-carboxylate

To a stirred solution of rac-benzyl (3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate (385 mg, 1.18 mmol) in dry THF (4 ml) was added NaH (67.9 mg , 1.7 mmol) at 0°C. The mixture was allowed to reach RT and then stirred for 90 min under argon. H ₂ O (5 ml) was added and stirring was continued for 10 min at RT. THF was removed from the reaction mixture under vacuum. The residue was treated with DCM and the organic phase was washed with _H2O and brine, dried over Na2SO4, filtered and then concentrated in vacuo. The residue was purified by flash chromatography (12 g reverse phase column, 0-100% ACN gradient in H ₂ O (containing 0.1% LA) to give the desired product as a colorless solid (133 mg, 38.9% MS (IER): m/z=291.3 [M+H] ⁺ .

BB5

6-(2-Chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane; trifluoroacetate salt

TFA (4, 02 g; 2.72 mL, 35.3 mmol) and stirred the reaction mixture at RT for 3.5 hours. The reaction mixture was concentrated to give the title compound as a yellow oil (2.015 g, 4.42 mmol, 100% ), which was used in the next step without further purification. MS (IER): m/z=242.2 [M+H] ⁺ .

Step a) tert-Butyl 6-(2-chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of 2-chloro-4-fluorophenol (756 mg, 562 µl, 5.16 mmol, CAS RN 1996-41-4), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1000 mg, 4.69 mmol, CAS RN 1147557-97-8) and triphenylphosphine (1.48 g, 5.63 mmol, CAS RN 603-35-0) in THF (23.4 ml) was added DIAD (1.14 g, 1.09 ml, 5.63 mmol, CAS RN 2446-83-5) dropwise at 0°C, and the reaction mixture was stirred at RT for 18 hours. Triphenylphosphine (738 mg, 2.81 mmol) was added followed by DIAD (569 mg, 547 μL, 2.81 mmol) and the reaction mixture was stirred at RT for 6 hours. The reaction mixture was poured into sat. aq. NaHCO ₃ solution (50 ml) and EtOAc (30 ml) was added. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give an orange oil. The crude product was immobilized on Isolute and purified by column chromatography (40 g, 0 to 30% EtOAc in heptane) to give the title compound as a yellow solid (1.51 g, 4.19 mmol, 89.3% ). MS (IER): m/z=286.2 [M-56+N] ⁺ .

By analogy with BB5 and BB5 of step a), intermediates BB6 BB13 from the following table were prepared from commercially available phenols.

BB14

2-(2-Fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane; trifluoroacetate salt

To a solution of tert-butyl 2-(2-fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3,5]nonane-7-carboxylate (21.3 mg, 52.8 µmol) in DCM (520 µl) trifluoroacetic acid (48.2 mg, 32.5 μl, 422 μmol) was added and the reaction mixture was stirred at RT for 19 hours. The reaction mixture was concentrated to give the title compound as an off-white solid (23.2 mg, 52.8 μmol, 100%), which was used in the next step without further purification. MS (IER): m/z=304.2 [M+H] ⁺ .

Step a) tert-butyl 2-(2-fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]ponan-7-carboxylate

To a solution of 2-fluoro-4-(trifluoromethyl)phenol (41 mg, 28.7 µl, 228 µmol, CAS RN 77227-78-2), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7- carboxylate (50 mg, 207 µmol, CAS RN 240401-28-9) and triphenylphosphine (59.8 mg, 228 µmol, CAS RN 603-35-0) in THF (1.04 ml) was added DIAD (46.1 mg , 44.3 µl, 228 µmol, CAS RN 2446-83-5) dropwise, and the reaction mixture was stirred at RT for 23 hours. The reaction mixture was quenched by adding sat. aq. NaHCO ₃ solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a colorless oil. The crude product was immobilized on Isolute and purified by column chromatography (12 g, 0 to 30% EtOAc in n-heptane) to give the title compound as a yellow colorless oil (21.3 mg, 50.2 µmol, 24. 2%). MS (IER): m/z=348.2 [M-56+N] ⁺ .

BB15

2-(2-Chloro-4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane; trifluoroacetate salt

To a solution of tert-butyl 6-(2-chloro-4-trifluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (65.5 mg, 192 µmol) in DCM (961 µl) was added TFA (175 mg ; 118 µl, 1.54 mmol) and stirred the reaction mixture at RT for 7 hours. The reaction mixture was concentrated to give the title compound as a yellow oil which crystallized on standing (116.8 mg, 191 µmol, 99.4 %), which was used in the next step without additional purification. MS (IER): m/z=241.1 [M+H] ⁺ .

Step a) tert-Butyl 6-(2-chloro-4-fluorobenzyl)-2,b-diazaspiro[3.3]heptane-2-carboxylate

To a suspension of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (50 mg, 204 µmol, CAS RN 1041026-71-4) and 2-chloro-4-fluorobenzaldehyde (32.4 mg, 204 µmol , CAS RN 84194-36-5) in DCE (1.02 ml) was added sodium triacetoxyborohydride (64.9 mg, 306 µmol, CAS RN 56553-60-7) and the mixture was stirred at RT for 2.5 hours. The solution was diluted with EtOAc. The combined organic layers were washed with aq. sat. NaHCO ₃ solution. The phases were separated and aq. The layer was extracted with EtOAc, washed with brine, filtered over MgSO ₄ and evaporated to dryness to give the title compound as a light yellow oil (65.5 mg, 84.7%), which was used in the next step without further purification. MS (IER): m/z=341.1 [M+H] ⁺ .

BB16

2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-azaspiro[3.3]heptane; trifluoroacetate salt

To a solution of tert-butyl 6-(2-fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (71.0 mg, 190 µmol) in DCM (948 µl) trifluoroacetic acid (173 mg, 117 μL, 1.52 mmol) was added and the reaction mixture was stirred at RT for 17 hours. The reaction mixture was concentrated to give the title compound as a yellow oil (119.5 mg, 188 μmol, 99% ), which was used in the next step without further purification. MS (IER): m/z=275.2 [M+H] ⁺ .

Step a) tert-Butyl 2-(2-fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a suspension of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (50 mg, 204 µmol, CAS RN 1041026-71-4) and 2-fluoro-4-(trifluoromethyl)benzaldehyde (39.2 mg , 27.8 μl, 204 μmol, CAS RN 89763-93-9) to DCE (1.0 ml) was added sodium triacetoxyborohydride (64.9 mg, 306 μmol, CAS RN 56553-60-7) and the mixture was stirred at CT scan within 19 hours. The solution was diluted with EtOAc and washed with aq. sat. NaHCO ₃ solution The phases were separated, and aq. the layer was extracted with EtOAc. The combined organic layers were washed with brine, filtered over MgSO ₄ and evaporated to dryness. The residue was immobilized on Isolute and purified by column chromatography (4 g, 0 to 40% 3:1 EtOAc/EtOH in n-heptane) to give the title compound as a light yellow oil (71.0 mg, 180 μmol , 88.2%). MS (IER): m/z=375.3 [M+H] ⁺ .

BB17

2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane

Trifluoroacetic acid ( 179 mg, 121 μl, 1.57 mmol) and the reaction mixture was stirred at RT for 7 hours. The reaction mixture was concentrated and the resulting residue was dissolved in EtOAc, washed with sat. aq. NaHCO ₃ solution and the aqueous phase was again extracted with EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a yellow oil (57.3 mg, 91.7%), which was used in the next step without further purification. MS (IER): m/z=303.3 [M+H] ⁺ .

Step a) tert-Butyl 2-(2-fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a suspension of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (50 mg, 221 µmol, CAS RN 896464-16-7) and 2-fluoro-4-(trifluoromethyl)benzaldehyde (42.4 mg, 30.1 µl, 221 µmol, CAS RN 89763-93-9) to DCE (1.1 ml) sodium triacetoxyborohydride (70.2 mg, 331 µmol, CAS RN 56553-60-7) was added and the mixture was stirred at RT within 4 hours. The solution was diluted with EtOAc and washed with aq. sat. NaHCO ₃ solution. The phases were separated, and aq. the layer was extracted with EtOAc. The combined organic layers were washed with brine, filtered over MgSO ₄ and evaporated to dryness to give the title compound as an off-white oil (79.0 mg, 80%), which was used without further purification in the next step. MS (IER): m/z=403.4 [M+H] ⁺ .

BB18

2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane

Trifluoroacetic acid was added to a solution of tert-butyl 7-(2-fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (123 mg, 275 µmol) in DCM (1.38 µl). acid (251 mg, 170 μl, 2.2 mmol) and the reaction mixture was stirred at RT for 7 hours. The reaction mixture was concentrated and the resulting residue was dissolved in EtOAc, washed with sat. aq. NaHCO ₃ solution and the aqueous phase was again extracted with EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a yellow oil (107.7 mg, 99.7%), which was used in the next step without further purification. MS (IER): m/z=303.3 [M+H] ⁺ .

Step a) tert-Butyl 7-(2-fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]ponap-2-carboxylate

To a suspension of tert-butyl tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (83.1 mg, 367 µmol, CAS RN 236406-49-8) and 2-fluoro-4-(trifluoromethyl)benzaldehyde ( 70.5 mg, 0.05 µl, 367 µmol, CAS RN 89763-93-9) to DCE (1.1 ml) was added sodium triacetoxyborohydride (117 mg, 550 µmol, C AS RN 56553-60-7) and the mixture stirred at RT for 1 hour. The solution was diluted with EtOAc and washed with aq. sat. NaHCO ₃ solution. The phases were separated, and aq. the layer was extracted with EtOAc. The combined organic layers were washed with brine, filtered over MgSO ₄ and evaporated to dryness to give the title compound as a light yellow oil (123.0 mg, 75%), which was used without further purification in the next step. MS (IER): m/z=403.4 [M+H] ⁺ .

BB19

2-(2-Fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane

To a solution of tert-butyl 2-(2-fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (147.6 mg, 361 µmol) in DCM (1.8 ml) trifluoroacetic acid (329 mg, 223 μL, 2.89 mmol) was added and the reaction mixture was stirred at RT for 7 hours. The reaction mixture was concentrated and the resulting residue was dissolved in EtOAc, washed with sat. aq. NaHCO ₃ solution and the aqueous phase was again extracted with EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a yellow oil (84.7 mg, 77.3%), which was used in the next step without further purification. MS (IER): m/z=289.2 [M+H] ⁺ .

Step a) tert-Butyl 2-(2-fluoro-4-(trifluoromethyl)benzyl)-2,b-diazaspiro[3.4]octane-6-carboxylate

To a suspension of tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (85.6 mg, 403 µmol, CAS RN 885270-86-0) and 2-fluoro-4-(trifluoromethyl)benzaldehyde (77.5 mg, 55 µl, 403 µmol, CAS RN 89763-93-9) to DCE (2.0 ml) was added sodium triacetoxyborohydride (128 mg, 605 µmol, CAS RN 56553-60-7) and the mixture was stirred at RT for 1 hour. The solution was diluted with EtOAc and washed with aq. sat. NaHCO ₃ solution. The phases were separated, and aq. the layer was extracted with EtOAc. The combined organic layers were washed with brine, filtered over MgSO ₄ and evaporated to dryness to give the title compound as a light yellow oil (147.6 mg, 361 µmol, 89.5% yield), which was used without further purification as follows. stages. MS (IER): m/z=389.3 [M+H] ⁺ .

BB20

2-((2-Chloro-4-fluorophenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane; trifluoroacetate salt

To a solution of tert-butyl 6-((2-chloro-4-fluorophenyl)sulfonyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (54.7 mg, 140 µmol) in DCM (700 µl) trifluoroacetic acid (128 mg, 86.3 μL, 1.12 mmol) was added and the reaction mixture was stirred at RT for 22 hours. The reaction mixture was concentrated to give the title compound as an off-yellow oil (75.7 mg, 140 μmol, 100%), which was used in the next step without further purification. MS (IER): m/z=291.2 [M+H] ⁺ .

Step a) tert-Butyl 6-((2-chloro-4-fluorophenyl)sulfonyl)-2,b-diazaspiro[3.3]heptane-2-carboxylate

To a suspension of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (50 mg, 204 µmol, CAS RN 885270-86-0) was added TEA (31 mg, 43 µl, 306 µmol), then 2- chloro-4-fluorobenzenesulfonyl chloride (58.5 mg, 37 µl, 255 µmol, CAS RN 85958-57-2) and the resulting clear solution were stirred at RT for 17.5 hours. The reaction mixture was diluted with DCM and quenched with water. The phases were separated, and aq. phase was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (54.7 mg, 65.1%), which was used in the next step without further purification. MS (IER): m/z=335.1 [M+H] ⁺ .

BB21

2-((2-Fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane; trifluoroacetate salt

To a solution of tert-butyl 6-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (67.6 mg, 159 µmol) in DCM (796 µl ) TFA (145 mg; 98.2 μL, 1.27 mmol) was added and the reaction mixture was stirred at RT for 20 hours. The reaction mixture was concentrated to give the title compound as a yellow oil (90 mg, 99.3%) , which was used in the next step without further purification. MS (IER): m/z=325.2 [M+H] ⁺ .

Step a) tert-Butyl 6-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

TEA (31 mg, 42.7 µl, 306 µmol) was added to a suspension of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (50 mg, 204 µmol, CAS RN 885270-86-0) in DCM. , then 2-fluoro-4-(trifluoromethyl)benzenesulfonyl chloride (59 mg, 225 µmol, CAS 1177009-38-9) and the resulting clear solution was stirred at RT for 18 hours. The reaction mixture was diluted with DCM and quenched with water. The phases were separated, and aq. phase was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (67.6 mg, 74.1%), which was used in the next step without further purification. MS (IER): m/z=369.2 [M+H] ⁺ .

BB22

6-[[4,5-bis(Trifluoromethyl)-2-pyridyl]oxy]-2-azaspiro[3.3]heptane; trifluoroacetate salt

To a solution of tert-butyl 6-((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (0.334 g, 783 µmol) in CH ₂ Cl ₂ ( 5 mL) TFA (893 mg, 604 μL, 7.83 mmol) was added. The resulting reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under high vacuum to obtain 366 mg of the desired product as a light yellow oil. MS (IER): m/z=327.2 [M+H] ⁺ .

Step a) tert-Butyl 6-((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]' heptane-2-carboxylate

A 1 M solution of potassium tert-butoxide in THF (985 μL, 985 µmol), and the cloudy reaction mixture was stirred at RT for 15 minutes followed by the addition of 2-chloro-4,5-bis(trifluoromethyl)pyridine (234 mg, 938 µmol). The reaction mixture was then stirred at RT for 19 hours. The crude reaction mixture was diluted with EtOAc and extracted with water, the organic phase was collected, and the aqueous phase was again extracted with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane). The required product was obtained as a white solid, 334 mg. MS (ESI): m/z=371.2 [M 56+H] ⁺

6-[[5,6-bis(trifluoromethyl)-2-pyridyl]oxy]-2-azaspiro[3.3]heptane; trifluoroacetate salt

To a solution of tert-butyl 6-((5,6-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (0.376 g, 882 µmol) in CH ₂ Cl ₂ ( 5 mL) TFA (1.01 g, 679 μL, 8.82 mmol) was added. The resulting reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under high vacuum to obtain 398 mg of the desired product as a light yellow oil. MS (IER): m/z=327.2 [M+H] ⁺ .

Step a) tert-Butyl 6-((5,b-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (0.2 g, 938 µmol) in dry THF (3 ml) was added a 1 M solution of potassium tert-butoxide in THF (985 µl, 985 µmol), and the cloudy reaction mixture was stirred at RT for 15 minutes followed by the addition of 6-chloro-2,3-bis(trifluoromethyl)pyridine (234 mg, 938 µmol). The reaction mixture was then stirred at RT for 19 hours. The crude reaction mixture was diluted with EtOAc and extracted with water, the organic phase was collected, and the aqueous phase was again extracted with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane). The desired product was obtained as a white solid, 376 mg. MS (IER): m/z=371.2 [M-56+N] ⁺ .

BB24

2-Chloro-4-fluoro-N-methyl-N-[(311)-1-oxa-8-azaspiro[4.5]decan-3-yl]benzenesulfonamide; hydrochloride salt

In a 10 ml test tube, tert-butyl (11)-3-((2-chloro-4-fluoro-N-methylphenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (87 mg, 188 µmol) was dissolved in DCM (3.61 ml) and HCl in 2M diethyl ether (752 µl, 1.5 mmol) was added. The reaction mixture was stirred at RT for 6 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=363.1 [M+H] ⁺ .

Step a) tert-Butyl (R)-3-((2-chloro-4-fluorophenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

In a 20 ml test tube purged with argon, dissolve tert-butyl (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (80 mg, 312 µmol) in DCM (2.67 ml ). TEA (69.5 mg, 687 μmol) and 2-chloro-4-fluorobenzenesulfonyl chloride (75.1 mg, 328 μmol) were added and the reaction mixture was stirred for 2 hours at RT. The reaction mixture was extracted with DCM/water, dried over Na2SO4, the solvent was removed in vacuo and the residue was purified by preparative HPLC (Gemini NX column, ACN/water + 0.1% TEA gradient). The product was obtained as a white solid (83 mg). MS (IER): m/z=448.9 [M-N] ⁺

Step b) tert-Butyl (R)-3-((2-chloro-4-fluoro-N-methylphenyl)sulfopamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl (R)-3-((2-chloro-4-fluorophenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (110 mg, 245 µmol) in DMF (2 ml) at 0°C, 60% NaH in mineral oil (14.7 mg, 368 µmol) was added. The reaction mixture was stirred at RT for 30 minutes, after which iodomethane (104 mg, 46 μl, 735 μmol) was added and stirring was continued for 1 hour.

Saturated aqueous ammonium chloride was added and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC HPLC (Gemini NX column, ACN/water+0.1% HCOOH gradient). 87 mg of product was obtained as a white solid. MS (IER): m/z=407.2 [M-56+N] ⁺ .

BB25

6-[[5-(Trifluoromethyl)-2-pyridyl]oxy]-2-azaspiro[3.3]heptane; trifluoroacetate salt

tert-butyl 6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (0.314 g, 876 μmol) was dissolved in CH ₂ Cl ₂ (3 ml) and TFA (799 mg, 540 μL, 7.01 mmol) was added. The reaction mixture was stirred at RT for 2 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=259.2 [M+H] ⁺ .

Step a) tert-Butyl 6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (0.200 g, 938 µmol) in dry THF (3 ml) was added a 1 M solution of potassium tert-butoxide in THF (985 µl, 985 µmol) , and the cloudy reaction mixture was stirred at RT for 15 minutes followed by the addition of 2-bromo-5-(trifluoromethyl)pyridine (212 mg, 938 μmol). The reaction mixture was then stirred at RT for 19 hours. The crude reaction mixture was diluted with EtOAc and extracted with water, the organic phase was collected, and the aqueous phase was again extracted with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated to dryness. Purification: The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane). The product was obtained as a light yellow solid (314 mg). MS (IER): m/z=303.2 [M-56+N] ⁺ .

BB26

6-[[4-Methyl-3-(trifluoromethyl)phenyl]methoxy]-2-azaspiro[3.3]heptane tert-Butyl 6-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2-azaspiro[ 3.3]heptane-2-carboxylate (170 mg, 441 µmol) was dissolved in DCM (2 ml) and TFA (302 mg, 204 µl, 2.65 mmol) was added. The reaction mixture was stirred at RT for 8 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=286.3 [M+H] ⁺ .

Step a) tert-Butyl 6-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]' heptane-2-carboxylate

In a 20 ml test tube under argon, tert-butyl 6-hydroxy-2-azaspiro[3,3]heptane-2-carboxylate (142 mg, 664 µmol) was dissolved in DMF (2.5 ml) and cooled to 2-4 °C. NaH (31.9 mg, 797 µmol) was added and the mixture was stirred for 20 minutes. The cooling bath was removed and 4-(bromomethyl)-1-methyl-2-(trifluoromethyl)benzene (168 mg, 664 μmol) was added, then stirred at 22°C for 3 hours. Added 3 ml sat. NH4C1 solution, extracted with water/EtOAc/saturated. NaCl, dried over MgSO ₄ . The solvent was removed and the crude product was purified by flash chromatography (20 g silica with heptane/EtOAc 0 to 40% for 30 min at UV 265 nm). MS (IER): m/z=330.2 [M-56+N] ⁺ .

BB27

2-((2-Chloro-4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride

In a 10 ml tube, tert-butyl 2-((2-chloro-4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (140 mg, 334 µmol) was dissolved in DCM (4 ml) and HCl in 2M diethyl ether (1 ml, 2 mmol) was added. The reaction mixture was stirred at RT for 6 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=319.1 [M+H] ⁺ .

Step a) tert-Butyl 2-((2-chloro-4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

In a 20 mL tube purged with argon, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (80 mg, 353 μmol) was dissolved in DCM (3.3 mL). TEA (78.7 mg, 108 μL, 778 μmol) and 2-chloro-4-fluorobenzenesulfonyl chloride (89.1 mg, 389 μmol) were added and the mixture was stirred for 2 hours at RT. The reaction mixture was extracted with DCM/water, the organic fractions were combined and dried over Na2S04, the solvent was removed in vacuo, the residue was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 µm, 100 × 30 mm, 9 min gradient ACN/water+0 .1% TEA). The product was obtained in the form of a white foam. MS (IER): m/z=363.1 [M-56+N] ⁺ .

BB28

6-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate

tert-Butyl 6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (235 mg, 604 µmol) was dissolved in DCM (3 ml) and TFA was added ( 344 mg, 232 µl, 3.02 mmol). The reaction mixture was stirred at RT for 8 hours and concentrated in vacuo (azeotrope with toluene, EE+Hep). Used directly for the next stage. MS (IER): m/z=290.2 [M+H] ⁺ .

Step a) tert-Butyl 6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]-heptane-2-carboxylate

To an ice-cold solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.17 mmol) in DMF (3 mL) was added 60% NaH in mineral oil (51.6 mg, 1 .29 mmol) in portions, and the mixture was stirred at ice bath temperature for 5 minutes followed by stirring at RT for 40 minutes. A solution of 2-fluoro-4-(trifluoromethyl)benzylmethanesulfonate (383 mg, 1.41 mmol) was dissolved in DMF (1 ml) and added dropwise to the mixture at RT. Stirring of the suspension was continued at RT for 16 hours. The reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl (10 ml) and EtOAc (20 ml) and the layers were separated. The aqueous layer was extracted once with EtOAc (50 ml). The organic layers were washed twice with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an HPLC system, eluting with a gradient of n-heptane: EtOAc (100:0 to 50:40) to give the desired compound as a light yellow solid (235 mg ). MS (IER): m/z=334.2 [M-56+N] ⁺ .

BB29

(11)-N-(1-oxa-8-azaspiro[4.5]decan-3-yl)-4-(trifluoromethyl)benzenesulfonamide hydrochloride

In a 10 ml test tube, tert-butyl (R)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (63 mg, 136 µmol) was dissolved in DCM (1 ml) and HCl in 2M diethyl ether (678 µl, 1.36 mmol) was added. The reaction mixture was stirred at RT for 4 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=365.1 [M+H] ⁺ .

Step a) tert-Butyl (R)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

In a 20 mL tube purged with argon, tert-butyl (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (60 mg, 234 μmol) was dissolved in DCM (2 mL). TEA (52.1 mg, 515 µmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (68.7 mg, 281 µmol) were added and the mixture was stirred for 2 hours at RT. The reaction mixture was extracted with DCM/water, the organic fractions were combined and dried over Na ₂ SO ₄ , the solvent was removed in vacuo, the residue was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100 × 30 mm, gradient ACN/water + 0.1 % TEA). The product was obtained as a white solid (63 mg). MS (IER): m/z=463.3 [M-N] ⁺

BB30

(R)-N-methyl-N-(1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide hydrochloride

In a 10 ml test tube, tert-butyl (R)-3-(N-methylphenylsulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (96 mg, 234 µmol) was dissolved in DCM (1 ml) and HCl in 2M diethyl ether (1.75 mL, 3.51 mmol) was added. The reaction mixture was stirred at RT for 4 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=311.2 [M+H] ⁺ .

Step a) tert-Butyl (R)-3-(phenylsulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

In a 20 mL tube purged with argon, tert-butyl (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (60 mg, 234 μmol) was dissolved in DCM (2 mL). TEA (52.1 mg, 515 µmol) and benzenesulfonyl chloride (49.6 mg, 281 µmol) were added and the mixture was stirred for 2 hours at RT. The reaction mixture was extracted with DCM/water, the organic fractions were combined and dried over Na2S04, the solvent was removed in vacuo, the residue was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100 × 30 mm, gradient ACN/water + 0.1% TEA) . The product was obtained as a white solid (63 mg). MS (IER): m/z=395.3 [M-H] ⁺

Step b) tert-Butyl (R)-3-(N-methylphenylsulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl (11)-3-(phenylsulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (110 mg, 277 μmol) in DMF (1.2 ml) at 0°C was added NaH in mineral oil 60% (16.6 mg, 416 µmol). The reaction mixture was stirred at RT for 30 minutes, after which iodomethane (118 mg, 52 μl, 832 μmol) was added and stirring was continued for 1 hour. A saturated aqueous solution of NH ₄ C1 was added and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC. (Gemini NX, 12 nm, 5 µm, 100 × 30 mm column, ACN/water+0.1% TEA gradient). The product was obtained as a colorless oil (96 mg). MS (IER): m/z=355.1 [M-56+N] ⁺ .

BB31

(11)-2-Chloro-4-fluoro-N-(1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide hydrochloride

In a 10 ml test tube, tert-butyl (N)-3-((2-chloro-4-fluorophenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (64 mg, 143 µmol) was dissolved in DCM (2 ml) and added 2M HCl in diethyl ether (1070 µl, 2.14 mmol). The reaction mixture was stirred at RT for 6 hours. The solvent was removed in vacuo and the product was used in the next step without purification. MS (IER): m/z=349.1 [M+H] ⁺ .

Step a) tert-butyl (R)-3-((2-chloro-4-fluorophenyl)sulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

The synthesis is described in BB24.

BB32

(R)-N-(1-oxa-8-azaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)benzenesulfonamide hydrochloride

Synthesized as described for BB29, starting with tert-butyl(N)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (60 mg, 234 µmol) and 3-(trifluoromethyl)benzenesulfonyl chloride ( 68.7 mg, 281 µmol). 53 mg of product was obtained as a light yellow oil. MS (IER): m/z=365.1 [M+H] ⁺ .

BB33

N-(2-chloro-4-fluorobenzyl)-N-methyl-1-oxa-8-azaspiro[4.5]decane-3-amine trifluoroacetate

To a solution of tert-butyl-3-((2-chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.107 g, 259 µmol) in DCM (2 ml) trifluoroacetic acid (236 mg, 160 μl, 2.07 mmol) was added and the reaction mixture was stirred at RT for 19 hours. The reaction mixture was concentrated to give the title compound as a light yellow oil (111 mg), which was used in the next step without further purification. MS (IER): m/z=313.2 [M+H] ⁺ .

Step a) tert-Butyl 3-((2-chloro-4-fluorobepzyl)amipo)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.5 g, 1.95 mmol) and 2-chloro-4-fluorobenzaldehyde (309 mg, 1. 95 mmol) to MeOH (12 ml) was added sodium cyanoborohydride (613 mg, 9.75 mmol). The reaction mixture was stirred at RT for 2 hours. For processing, the reaction mixture was poured into sat. NaHCO ₃ solution and extracted with EtOAc. 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 100% EtOAc in heptane) to give 231 mg of product as a colorless oil. MS (IER): m/z=399.2 [M+H] ⁺ .

Step b) tert-Butyl 3-((2-chloro-4-fluorobepzyl)(methyl)amipo)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl 3-((2-chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.100 g, 251 µmol) in DMF (1.5 ml) at 0°C, 60% NaH in mineral oil (15 mg, 376 μmol) was added. The reaction mixture was stirred at RT for 30 minutes, then iodomethane (107 mg, 47 μl, 752 μmol) was added and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a yellow oil (104 mg), which was used directly in the next step. MS (IER): m/z=413.4 [M+H] ⁺ .

N-(2-chloro-4-fluorobenzyl)-1-oxa-8-azaspiro[4.5]decane-3-amine trifluoroacetate

To a solution of tert-butyl 3-((2-chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.088 g, 221 μmol) in DCM (1 ml) was added trifluoroacetic acid. acid (201 mg, 136 μl, 1.76 mmol) and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated to give the title compound as a colorless oil (91 mg), which was used in the next step without further purification.

Step a) tert-Butyl 3-((2-chloro-4-fluorobepzyl)amipo)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

tert-Butyl 3-((2-chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was synthesized as described for BB33.

BB35

2-((4-(Trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride

In a 10 ml test tube, tert-butyl 2-((4-(trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (124 mg, 285 µmol) was dissolved in DCM (4 ml) and added HCl in diethyl ether 2M (856 µl, 1.71 mmol). The reaction mixture was stirred at RT for 3 hours. The solvent was removed in vacuo and the product was obtained as a white solid (105 mg) and used in the next step without purification. MS (IER): m/z=335.1 [M+H] ⁺ .

Step a) tert-Butyl 2-((4-(trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

In a 20 mL tube purged with argon, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (80 mg, 353 μmol, Eq: 1) was dissolved in DCM (3.3 mL). TEA (78.7 mg, 108 μL, 778 μmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (95.1 mg, 389 μmol) were added and the mixture was stirred for 2 hours at RT. The reaction mixture was extracted with DCM/water, the organic fractions were combined and dried over Na ₂ SO ₄ , the solvent was removed in vacuo, the residue was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, 9 min gradient ACN/ water+0.1% TEA). The product was obtained in the form of a white foam. MS (IER): m/z=379.1 [M-56+N] ⁺ .

BB36

2-(Phenylsulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride

BB36 was prepared from tert-butyl 2,7-diazaspiro[3,5]nonane-7-carboxylate (80 mg, 353 μmol) and benzenesulfonyl chloride (74.9 mg, 424 μmol) as described for BB35. MS (IER): m/z=267.2 [M+H] ⁺ .

BB37

2-(2,4-Difluorophenoxy)-7-azaspiro[3.5]nonane trifluoroacetate

Trifluoroacetic acid (823 mg, 556 µl, 7.22 mmol), and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated to give the title compound as a white solid (510 mg), which was used in the next step without further purification. MS (IER): m/z=254.2 [M+H] ⁺

Step a) tert-butyl 2-(2,4-difluorophepoxy)-7-azaspiro[3.5]ponan-7-carboxylate

In a 25 ml four-neck sulfonation flask under argon, tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (401 mg, 1.66 mmol, C AS RN 240401-28-9) was dissolved in THF ( 6 ml), 2,4-difluorophenol (216 mg, 159 μl, 1.66 mmol) and triphenylphosphine (479 mg, 1.83 mmol) were added. The clear solution was stirred at RT for 5, then cooled to 0-2°C and DEAD (318 mg, 289 μl, 1.83 mmol) was added slowly over 10 minutes, stirring was continued for 1 hour at 2-4°C , then the cooling bath was removed and stirred overnight at RT. 20 ml of diethyl ether was added and the mixture was washed with water, 1 M NaOH and brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to give 511 mg of product as a colorless oil. MS (IER): m/z=298.3 [M-56+N] ⁺ .

BB38

2-(2-Chloro-4-fluorophenoxy)-7-azaspiro[3.5]nonane trifluoroacetate

8838 was prepared from tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (412 mg, 1.71 mmol) and 2-chloro-4-fluorophenol (250 mMrg, 1.71 mmol) as described for BB37. MS (IER): m/z=270.2 [M+H] ⁺ .

BB39

6-[[2-Fluoro-4-(trifluoromethyl)phenoxy]methyl]-2-azaspiro[3.3]heptane trifluoroacetate

8839 was prepared by analogy with BB37 from tert-butyl-6-[[2-fluoro-4-(trifluoromethyl)phenoxy]methyl]-2-azaspiro[3.3]heptane-2-carboxylate and was used in the next step without further purification. MS (IER): m/z=290.2 [M+H] ⁺ .

Step a) tert-Butyl 6-[[2-fluoro-4-(trifluoromethyl)fepoxy]methyl]-2-azaspiro[3.3]heptane-2-carboxylate. The compound was prepared analogously to example 37, step a, from tert-butyl 6 -(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (CAS RN 1363381-93-4) and 2-fluoro-4-(trifluoromethyl)phenol (CAS RN 77227-78-2). The colorless oil was used in the next step without further purification. MS (IER): m/z=334.1 [M-56-N] ⁺ .

6-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)-6-(trifluoromethyl)-2-azaspiro[3.3]heptane trifluoroacetate

BB40 was prepared by analogy with BB25 from tert-butyl 6-hydroxy-6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carboxylate (CAS 1251923-04-2) and 1-(bromomethyl)-2-fluoro-4 -(trifluoromethyl)benzene. MS (IER): m/z=358.1 [M-56-N] ⁺ .

BB41

6-(2-fluoro-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane trifluoroacetate

TFA (240 mg, 162 µl, 2.1 mmol). The resulting reaction mixture was stirred at RT for 1 hour and then concentrated in vacuo (toluene azeotrope) to give 143 mg of a colorless oil, which was used in the next step without further purification. MS (IER): m/z=260.2 [M+H] ⁺ .

Step a) tert-butyl 6-(2-fluoro-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate Photocatalyst (Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ (6.09 mg, 5.43 µmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (198 mg, 137 µl, 815 µmol), tert-butyl 6-bromo-2-azaspiro[3.3]heptane-2-carboxylate (0.150 g, 543 µmol), tris(trimethylsilyl)silane (135 mg, 168 µl, 543 µmol) and anhydrous sodium carbonate (115 mg, 1.09 mmol ). The vessel was sealed and placed under argon before adding DME (3 ml). A complex of nickel (II) chloride with ethylene glycol dimethyl ether (1.19 mg, 5.43 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.46 mg, 5 .43 µmol). The vial with the precatalyst was hermetically sealed, purged with argon, and then DME (2 ml) was added to it. The vial with the precatalyst was treated with ultrasound for 5 min, after which 1 ml (0.5 mol.% catalyst, 0.005 eq.) was injected into the reaction vessel with a syringe. The solution was degassed by bubbling argon.

The reaction mixture was stirred and irradiated with a 420 nm lamp for 5 hours. The reaction was quenched by exposure to air and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 20% EtOAc in heptane) to give 151 mg (77% yield, not pure by NMR) of a colorless liquid, which was used in the next step. MS (IER): m/z=304.2 [M-56-N] ⁺ .

BB42

6-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane trifluoroacetate

TFA (156 mg, 105 µl, 1.37 mmol). The resulting reaction mixture was stirred at RT for 2 hours and then concentrated in vacuo (toluene azeotrope) to give 108 mg of a colorless oil, which was used in the next step without further purification. MS (IER): m/z=274.2 [M+H] ⁺ .

Step a) (2-fluoro-4-(trifluoromethyl)benzyl)triphenylphosphonium bromide under argon, triphenylphosphine (1.02 g, 3.89 mmol) was dissolved in acetonitrile (10 ml) and 1-(bromomethyl)-2-fluoro was added -4-(trifluoromethyl)benzene (1 g, 3.89 mmol). The mixture was stirred at 80°C for 3 hours. The suspension was allowed to cool to RT. 100 ml of MTBE was added and stirred at RT for 30 minutes. The solid was filtered and washed with MTBE. The solid was dried under HV and the product was used directly in the next step. White solid, 2.02 g (98%). MS (IER): m/z=439.2 [M+H] ⁺ .

Stage b) tert-butyl 6-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-azaspiro[3.3]heptap-2-carboxylate In an argon atmosphere at -78°C (2-fluoro-4-(trifluoromethyl) benzyl)triphenylphosphonium bromide (0.5 g, 963 µmol) was dissolved in dry THF (5 ml) and LiHMDS (1.93 ml, 1.93 mmol) was added. The reaction mixture was stirred at -78°C for 2 hours. Tert-butyl 6-oxo-2-azaspiro[3,3]heptane-2-carboxylate (407 mg, 1.93 mmol) was then added at room temperature and the mixture was stirred at 85° C. overnight. MTBE was added and the precipitate was filtered off (Triphenylphosphine oxide). The filtrate was concentrated and purified directly. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 80% EtOAc in heptane) to give the product as a yellow solid (119 mg, 33%). MS (IER): m/z=316.2 [M-56+N] ⁺ .

Step c) tert-butyl 6-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl 6-(2-fluoro-4-(trifluoromethyl)benzylidene)- 2-azaspiro[3.3]heptane-2-carboxylate (0.119 g, 320 µmol) was dissolved in ethyl acetate (2.5 ml). The flask was purged and filled again with argon (3x). Pd-C (34.1 mg, 32 µmol) was added and the reaction mixture was stirred under Hg (balloon) for 2 hours. The reaction mixture was filtered through a pad of celite, washed with EtOAc and dried in vacuo to give the product as a colorless oil (108 mg, 90%). MS (IER): m/z=318.2 [M-56+N] ⁺ .

BB43

6-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptane trifluoroacetate

BB43 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2-chloro-4-fluorobenzene. MS (IER): m/z=240.1 [M+H] ⁺ .

BB44

6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane trifluoroacetate

BB44 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2,4-difluorobenzene. MS (IER): m/z=224.1 [M+H] ⁺ .

BB45

6-(2-methoxy-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane trifluoroacetate

BB45 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2-methoxy-4-(trifluoromethyl)benzene. MS (IER): m/z=286.2 [M+H] ⁺ .

BB46

6-(2-fluoro-6-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane trifluoroacetate

BB46 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene. MS (IER): m/z=274.2 [M+H] ⁺ .

BB47

6-((2-chloro-4-fluorophenoxy)methyl)-2-azaspiro[3.3]heptane trifluoroacetate

BB47 was prepared from tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.32 mmol) and 2-chloro-4-fluorophenol (193 mg, 1.32 mmol), as described for BB37. MS (IER): m/z=256.1 [M+H] ⁺ .

2-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate

To a solution of tert-butyl 6-(3-(trifluoromethyl)phenyl)-2,6-

Diazaspiro[3.3]heptane-2-carboxylate (230 mg, 672 µmol) in DCM (2 ml) was added with TFA (306 mg, 207 µl, 2.69 mmol). The resulting reaction mixture was stirred at RT overnight and then concentrated in vacuo (toluene azeotrope) to give 245 mg of a colorless oil, which was used in the next step without further purification. MS (IER): m/z=243.2 [M+H] ⁺ .

Step a) tert-butyl 6-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptap-2-carboxylate Added to the flask: 1-bromo-3-(trifluoromethyl)benzene (170 mg, 104 µl , 756 µmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (165 mg, 831 µmol), Cs ₂ CO ₃ (492 mg, 1.51 mmol) and 1,4-dioxane (4 ml), the suspension was bubbled with N2 for 5 minutes and Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] was added. palladium(II) (RuPhos Pd G2, 29.3 mg, 37.8 µmol). The mixture was heated to 100°C for 2 hours. The mixture was diluted with 10 ml EA and filtered through celite, the filtrate was concentrated to give a yellow oil. It was then purified over 20 g of silica with heptane/EA 0-40% and product fractions were concentrated to give the desired product as a yellow solid (233 mg, 90%). MS (IER): m/z=343.2 [M+H] ⁺ .

BB49

2-(4-isopropoxyphenyl)-2,6-diazaspiro[3.3]heptane 2,2,2-trifluoroacetate

BB49 was prepared similarly to BB48, starting with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate and 1-bromo-4-isopropoxybenzene.

The reaction mixture was heated to 120°C for 4 hours. MS (IER): m/z=233.2 [M+H] ⁺ .

BB50

1-(4-(2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrrolidin-2-one 2,2,2-trifluoroacetate

8850 was prepared similarly to BB48, starting with tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate and 1-(4-bromophenyl)pyrrolidin-2-one. The reaction mixture was heated to 125°C for 18 hours. MS (IER): m/z=272.3 [M+H] ⁺ .

BB51

2-(4-methoxy-3-methylphenyl)-2,6-diazaspiro[3.4]octane trifluoroacetate

8851 was prepared similarly to BB48, starting with tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate and 4-bromo-1-methoxy-2-methylbenzene. The reaction mixture was heated to 125°C for 18 hours. MS (IER): m/z=233.2 [M+H] ⁺ .

BB52

2-(4-chloro-3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane trifluoroacetate

8852 was prepared similarly to BB48, starting with tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate and 4-bromo-1-chloro-2-(trifluoromethyl)benzene. The reaction mixture was heated to 125°C for 18 hours. MS (IER): m/z=291.1 [M+H] ⁺ .

BB53

2-(2-fluoropyridin-4-yl)-2,6-diazaspiro[3.4]octane dihydrochloride

8853 was prepared similarly to BB48, starting with tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate and 4-bromo-2-fluoropyridine. The reaction mixture was heated to 125°C for 18 hours. Deprotection was achieved using 2M HCl in diethyl ether (16 hours, RT). MS (IER): m/z=208.2 [M+H] ⁺ .

BB54

2-(2,5-bis(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate

8854 was prepared similarly to BB48, starting with tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate and 4-bromo-2-fluoropyridine. The reaction mixture was heated to 120°C for 4 hours. MS (IER): m/z=311.4 [M+H] ⁺ .

BB55

2-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane 2,2,2-trifluoroacetate

To a solution of tert-butyl 6-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (269 mg, 634 µmol) in DCM (2 ml) was added TFA (434 mg, 293 µl, 3.8 mmol). The resulting reaction mixture was stirred at RT for 4 hours and then concentrated in vacuo (toluene azeotrope) to obtain 264 mg of a white solid, which was used in the next step without further purification. MS (IER): m/z=325.1 [M+H] ⁺ .

Step a) tert-butyl 6-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate In a 20 ml glass test tube, tert-butyl 2 was stirred in an argon atmosphere ,6-diazaspiro[3.3]heptane-2-carboxylate (190 mg, 958 µmol) in DCM (3 ml) and TEA (145 mg, 200 µl, 1.44 mmol) for 5 minutes at RT, then add 4- fluoro-2-(trifluoromethyl)benzenesulfonyl chloride (315 mg, 1.2 mmol) (slightly exothermic) and stirred overnight at RT. 10 ml DCM and silica gel were added, the solvent was removed in vacuo and chromatography was performed on 20 g silica with heptane/EA (0 to 50% in 35 minutes) to give the desired product as a white solid (269 mg, 66%). MS (IER): m/z=369.1 [M-56+N] ⁺ .

BB56

6-((2-chloro-4-fluorophenyl)sulfonyl)-2-azaspiro[3.3]heptane trifluoroacetate

TFA (306 mg, 207 µl, 2.68 mmol). The resulting reaction mixture was stirred at RT for 16 hours and then concentrated in vacuo (azeotrope with toluene), 5 ml of diethyl ether was added and the suspension was placed in an ultrasonic bath, filtration gave the desired product as a white solid (195 mg, 100%) , which was used in the next step without further purification. MS (IER): m/z=290.1 [M+H] ⁺ .

Stage a) tert-butyl 6-((2-chloro-4-fluorophenyl)sulfopyl)-2-azaspiro[3.3]heptane-2-carboxylate In a 20 ml glass tube tert-butyl 6-((methylsulfonyl)oxy)- 2-azaspiro[3.3]heptane-2-carboxylate (538 mg, 1.84 mmol), 2-chloro-4-fluorobenzenethiol (250 mg, 1.54 mmol) and K ₂ CO ₃ (425 mg, 3.07 mmol ) was dissolved in DMF (7 ml) under argon atmosphere. The suspension was heated at 80°C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 ml), washed twice with water (40 ml), then with brine (40 ml). The organic layer was dried over MgSO ₄ , filtered, and the solvent was removed under reduced pressure. The crude product was purified over 50 g of silica with heptane/EA from 0 to 40% in 40 minutes, removing the solvent in vacuo to give the product as a colorless viscous oil (218 mg, 38%). MS (IER): m/z=302.1 [M-56+N] ⁺ .

Step b) tert-butyl 6-((2-chloro-4-fluorophenyl)sulfonyl)-2-azaspiro[3.3]heptane-2-carboxylate

In a 25 ml glass test tube under argon, tert-butyl 6-((2-chloro-4-fluorophenyl)thio)-2-azaspiro[3.3]heptane-2-carboxylate (218 mg, 609 µmol) was dissolved in DCM (8 ml ), mCPBA (315 mg, 1.28 mmol) was added in portions at 10-12°C and stirred at room temperature for 3 hours. 10 ml DCM was added, the organic phase was washed with 5% NaHCO ₂ , water and brine, dried with MgSO ₄ and the solvent was removed under vacuum. Chromatography on 20 g of silica with heptane/EA (0 to 50%) provided 209 mg (88%) of product as a white solid. MS (IER): m/z=334.1 [M-56+N] ⁺ .

BB57

2-((3-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate

BB57 was prepared similarly to BB55, starting with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate and 3-chloro-4-(trifluoromethyl)benzenesulfonyl chloride. MS (IER): m/z=341.0 [M+H] ⁺ .

BB58

2-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate

8858 was prepared similarly to BB55, starting with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate and 2,4-bis(trifluoromethyl)benzenesulfonyl chloride. MS (IER): m/z=419.1 [M+H] ⁺ .

BB59

6-(2,6-difluorobenzyl)-2-azaspiro[3.3]heptane trifluoroacetate

8859 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2,6-difluorobenzene. MS (IER): m/z=224.1 [M+H] ⁺ .

BB60

6-(2-fluoro-6-methoxybenzyl)-2-azaspiro[3.3]heptane trifluoroacetate

8860 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2-fluoro-6-methoxybenzene. MS (IER): m/z=236.2 [M+H] ⁺ .

BB61

6-(2-methoxybenzyl)-2-azaspiro[3.3]heptane trifluoroacetate

8861 was prepared similarly to BB42, starting with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and 1-(bromomethyl)-2-methoxybenzene. MS (IER): m/z=218.2 [M+H] ⁺ .

BB62

2-((2-azaspiro[3.3]heptan-6-yl)methyl)-3-fluorophenol

In a 10 mL round bottom flask, combine tert-butyl 6-(2-fluoro-6-methoxybenzyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.050 g, 149 μmol) with DCM (1 mL) to obtain a colorless solution . BBr ₃ (37.3 mg, 14.1 μl, 149 μmol) was added at 0°C. The reaction mixture was stirred at RT for 3 hours. BBr ₃ (37.3 mg, 14.1 μl, 149 μmol) was added again and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched by adding saturated NaHCO ₃ solution and extracted with EtOAc/THF. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. MS (IER): m/z=222.2 [M+H] ⁺ .

BB63

2-((2-azaspiro[3.3]heptan-6-yl)methyl)phenol

BB61 was prepared similarly to BB62, starting with tert-butyl 6-(2-methoxybenzyl)-2-azaspiro[3.3]heptane-2-carboxylate. MS (IER): m/z=204.2 [M+H] ⁺ .

Claims (247)

1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, where: (i) X is CR ⁵ ; L represents a covalent bond, -(CH ₂ ) _n -N(C _1-6 -alkyl)-, -(CH ₂ ) _n -NH-, -(CH ₂ ) _n -O-, -O-(CH ₂ )p-, -SO ₂ -N(C _1-6 -alkyl)-, -SO ₂ NH-, -(CH ₂ ) _n -, -SO ₂ -; And A represents: (i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or (ii) 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, substituted with R ¹⁰ , R ¹¹ and R ¹² ; or (ii) X is N; L represents a covalent bond, -(CH ₂ ) _n -, -CHR ⁶ -, -SO ₂ -; And A represents: (i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or (ii) 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, substituted with R ¹⁰ , R ¹¹ and R ¹² ; or (iii) X is N; L represents C _1-6 -alkoxycarbonyl; And A is missing; B is a bicyclic spirocycle having formula (II): , Where: X is as defined above; Y ¹ represents -CH ₂ -; Y ² represents -CH ₂ - or -CH ₂ O-; Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2; the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I); R ¹ , R ² , R ³ , R ⁴ and R ⁵ independently represent hydrogen or halogen-C _1-6 -alkyl; R ⁶ represents C _6-14 -aryl; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, hydroxy, C _1-6 alkyl, halo-C _1-6 alkyl, halogen, C _{1- 6} -alkoxy, halogen-C ^1-6 -alkoxy, SF ₅ or group ; C is a 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, or a 3-14 membered heterocyclyl wherein 1 or 2 ring atoms are N; ^RC1 , ^RC2 and ^RC3 are each independently hydrogen, _C1-6alkyl , halo- _C1-6alkyl , oxo; n in each case is independently equal to 0 or 1; p in each case is independently equal to 1 or 2. 2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ represents hydrogen. 3. A compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ² represents hydrogen. 4. A compound of formula (I) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein R ³ represents hydrogen. 5. A compound of formula (I) according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, wherein R ⁴ represents hydrogen. 6. A compound of formula (I) according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof, wherein R ⁵ represents hydrogen. 7. A compound of formula (I) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, where R ⁷ represents hydrogen, hydroxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy, halogen-C _1-6 - alkoxy, SF ₅ or group ; Where: C is a 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, or a 3-14 membered heterocyclyl wherein 1 or 2 ring atoms are N; R ^C1 is C _1-6 alkyl, halogen-C _1-6 alkyl or oxo; R ^C2 and R ^C3 are both hydrogen. 8. A compound of formula (I) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, wherein R ⁷ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy or _SF5 . 9. A compound of formula (I) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen, fluorine, chlorine, CF ₃ , methyl, methoxy, trifluoromethoxy or SF ₅ . 10. A compound of formula (I) according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen, C _1-6 alkoxy, halogen-C _1-6 alkyl or halogen. 11. A compound of formula (I) according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R ⁸ represents hydrogen, halogen-C _1-6 -alkyl or halogen. 12. A compound of formula (I) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, where R ⁸ represents hydrogen, CF ₃ , chlorine or fluorine. 13. A compound of formula (I) according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt thereof, wherein R ⁹ represents hydrogen. 14. A compound of formula (I) according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ represents halogen or halogen-C _1-6 -alkyl. 15. A compound of formula (I) according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ represents halogen-C _1-6 -alkyl. 16. A compound of formula (I) according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ represents CF ₃ . 17. A compound of formula (I) according to any one of paragraphs. 1-16 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl. 18. A compound of formula (I) according to any one of paragraphs. 1-16 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ represents hydrogen or CF ₃ . 19. A compound of formula (I) according to any one of paragraphs. 1-18 or a pharmaceutically acceptable salt thereof, wherein R ¹² represents hydrogen. 20. A compound of formula (I) according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof, wherein A is phenyl or pyridyl. 21. A compound of formula (I) according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt thereof, where: X represents CR ⁵ ; L represents a covalent bond, -(CH ₂ ) _n -N(C _1-6 -alkyl)-, -(CH ₂ ) _n -NH-, -(CH ₂ ) _n -O-, -OSH ₂ -, - CH ₂ -, SO ₂ -, -SO ₂ -N(C _1-6 -alkyl)- or -SO ₂ -NH-; n is 0 or 1; And R ⁵ is as defined in paragraph 1. 22. A compound of formula (I) according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt thereof, where: X represents CR ⁵ ; L represents a covalent bond, -CH ₂ O-, -O-, -OCH ₂ -, -CH ₂ - or -SO ₂ -n(C _1-6 -alkyl)-; And R ⁵ is as defined in paragraph 1. 23. A compound of formula (I) according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt thereof, where: X represents CR ⁵ ; L represents a covalent bond, -CH ₂ O-, -O-, -OCH ₂ -, -CH ₂ - or -SO ₂ -N(methyl)-; And R ⁵ is as defined in paragraph 1. 24. A compound of formula (I) according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt thereof, where: X represents N; L represents a covalent bond, -CH ₂ -, -CHR ⁶ - or -SO ₂ -; And R ⁶ is as defined in paragraph 1. 25. A compound of formula (I) according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt thereof, where: X represents N; And L represents -CH ₂ - or -SO ₂ -. 26. A compound of formula (I) according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle selected from the group consisting of: ; Where: the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I). 27. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, where: (i) X is CR ⁵ ; L represents a covalent bond, -CH ₂ -N(C _1-6 -alkyl)-, -CH ₂ -NH-, -O-, -CH ₂ O-, -OCH ₂ -, -CH ₂ -, -SO ₂ -, -SO ₂ -N(C _1-6 -alkyl)- or -SO ₂ -NH-; And A represents: (i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or (ii) 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, substituted with R ¹⁰ , R ¹¹ and R ¹² ; or (ii) X is N; L represents a covalent bond, -CH ₂ -, -CHR ⁶ - or -SO ₂ -; And A is C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or (iii) X is N; L represents C _1-6 -alkoxycarbonyl; And A is missing; B is a bicyclic spirocycle having formula (II): Where: Y ¹ represents -CH ₂ -; Y ² represents -CH ₂ - or -CH ₂ O-; Y ³ and Y ⁴ are each independently -(CH ₂ ) _m -, where m is 1 or 2; the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I); R ¹ , R ² , R ³ , R ⁴ , R ⁹ and R ¹² are each hydrogen; R ⁵ represents hydrogen; R ⁶ represents C _6-14 -aryl; R ⁷ represents hydrogen, hydroxy, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy or halogen-C _1-6 -alkoxy, SF ₅ or group ; R ⁸ represents hydrogen, C _1-6 alkoxy, halogen-C _1-6 alkyl or halogen; R ¹⁰ represents halogen or C _1-6 -alkyl; R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl; R ^C1 is C _1-6 alkyl, halogenated C _1-6 alkyl or oxo; ^RC2 and ^RC3 are both hydrogen; And C is a 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, or a 3-14 membered heterocyclyl where 1 or 2 ring atoms are N. 28. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, where: (i) X is CR ⁵ ; L represents -CH ₂ O-, -OCH ₂ -, -O-, -CH ₂ - or -SO ₂ -N(C _1-6 -alkyl)-; And A represents: (i) C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or (ii) 5-14 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, substituted with R ¹⁰ , R ¹¹ and R ¹² ; or (ii) X is N; L represents -CH ₂ - or -SO ₂ -; And A is C _6-14 -aryl substituted with R ⁷ , R ⁸ and R ⁹ ; or B is a bicyclic spirocycle having formula (II): Where: Y ¹ represents -CH ₂ -; Y ² represents -CH ₂ - or -CH ₂ O-; each of Y ³ and Y ⁴ independently represents -(CH ₂ ) _m -, where m represents 1 or 2; the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I); R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen; R ⁷ represents hydrogen, C _1-6 -alkyl, halogen-C _1-6 -alkyl, halogen, C _1-6 -alkoxy, halogen-C _1-6 -alkoxy or SF ₅ ; R ⁸ represents hydrogen, halogen-C _1-6 -alkyl or halogen; R ¹⁰ represents halogen-C _1-6 -alkyl; And R ¹¹ represents hydrogen or halogen-C _1-6 -alkyl. 29. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, where: (i) X is CR ⁵ ; L represents -CH ₂ O-, -OCH ₂ -, -O-, -CH ₂ - or -SO ₂ -N(methyl)-; And A represents: (i) phenyl substituted with R ⁷ , R ⁸ and R ⁹ ; or (ii) pyridyl substituted with R ¹⁰ , R ¹¹ and R ¹² ; or (ii) X is N; L represents -CH ₂ - or -SO ₂ -; And A is phenyl substituted with R ⁷ , R ⁸ and R ⁹ ; or B is a bicyclic spirocycle selected from the group consisting of: , Where: the wavy line indicates the point of attachment of the bicyclic spirocycle B to L in formula (I); And the asterisk indicates the point of attachment of bicyclic spirocycle B to the rest of formula (I); R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹² are each hydrogen; R ⁷ is hydrogen, fluorine, chlorine, CF ₃ , methyl, methoxy, trifluoromethoxy or SF ₅ ; R ⁸ is hydrogen, CF ₃ , chlorine or fluorine; R ¹⁰ represents CF ₃ ; And R ¹¹ represents hydrogen or CF ₃ . 30. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: (4aR,8aS)-6-(6-(2-chloro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(2-fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-methoxy-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(6-(4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-she; (4aR,8aS)-6-(6-(4-chloro-2-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2,4-difluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; (4aR,8aS)-6-(6-(3-fluoro-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-chloro-4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(2-fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-chloro-4-fluorophenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(7-(2-fluoro-4-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(2-fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-N-((R)-8-(3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide; rac-(4aR,8aS)-N-((S)-8-(3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)benzenesulfonamide; rac-(4aR,8aS)-6-(2-benzhydryl-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she; rac-(4aR,8aS)-6-(4-((4-fluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((5,6-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; 2-chloro-4-fluoro-N-methyl-N-((R)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6 -carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide; (4aR,8aS)-6-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-((2-chloro-4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; N-((S)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)-4-(trifluoromethyl)benzenesulfonamide; N-methyl-N-((R)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa- 8-azaspiro[4.5]decan-3-yl)benzenesulfonamide; 2-chloro-4-fluoro-N-((S)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)benzenesulfonamide; N-((S)-8-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)-3-(trifluoromethyl)benzenesulfonamide; (4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)(methyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-((4-(trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she; rac-tert-butyl-6-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazin-6-carbonyl)-2,6-diazaspiro[3.4]octane -2-carboxylate; (4aR,8aS)-6-(6-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-6-hydroxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-hydroxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she; (4aR,8aS)-6-(2-(4-(2-oxopyrrolidin-1-yl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-6-methoxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(6-(4-(pentafluoro-I6-sulfanyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; (4aR,8aS)-6-(6-(2-methoxy-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-chloro-4-fluorophenoxy)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-6-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(4-isopropoxyphenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; (4aR,8aS)-6-(6-(4-isopropoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; (4aR,8aS)-6-(2-(4-methoxy-3-methylphenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(4-chloro-3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(2-fluoropyridin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2,5-bis(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2-chloro-4-fluorophenyl)sulfonyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((3-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2,6-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; And (4aR,8aS)-6-(6-(2-methoxybenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3( 4H)-she. 31. A compound of formula (I) according to any one of paragraphs. 1-29 or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: (4aR,8aS)-6-(6-(2-chloro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(2-(2-fluoro-4-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-methoxy-5-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethoxy)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4] oxazin-3(4H)-one; (4aR,8aS)-6-(6-(4-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-she; (4aR,8aS)-6-(6-(4-chloro-2-(trifluoromethyl)phenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2,4-difluorophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(4-(pentafluoro-I6-sulfanyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; (4aR,8aS)-6-(6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin- 3(4H)-ona; (4aR,8aS)-6-(6-(2-methoxy-4-(trifluoromethyl)benzyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one; And (4aR,8aS)-6-(6-((2-chloro-4-fluorophenoxy)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazin-3(4H)-one. 32. A method for producing compounds of formula (I) according to any one of paragraphs. 1-31 or pharmaceutically acceptable salts thereof, including: (a) reacting the first amine of formula 1, wherein R ¹ and R ² are as described in any one of paragraphs. 1-31, with a second amine 2, where A, B, L, X, R ³ and R ⁴ are as described in any of paragraphs. 1-31 in the presence of a base and a urea-forming reagent to form said compound of formula (I); and optional (b) converting said compound of formula (I) into pharmaceutically acceptable salts thereof. 33. A compound of formula (I) according to any one of paragraphs. 1-31, and the specified compound of formula (I) has an IC ₅₀ in relation to monoacylglycerol lipase below 10 μM. 34. A pharmaceutical composition having inhibitory activity against monoacylglycerol lipase, containing an effective amount of a compound of formula (I) according to any one of paragraphs. 1-31 and 33 and a therapeutically inert carrier.