MPTP inhibitors

Abstract

The present invention relates to compounds of formula (I) and related aspects. # imgabs0 #

Description

Field of the Invention

[0001] The present invention relates to novel compounds which are inhibitors of the mitochondrial permeability transition pore (mPTP). The invention also particularly relates to such compounds for use as medicaments, in particular for the treatment or prevention of degenerative diseases, neurodegenerative diseases or mitochondrial diseases, or other diseases or disorders in which inhibition of the mPTP provides a therapeutic or preventive effect. Background of the Invention

[0003] The mitochondrial permeability transition pore (mPTP) is a high-conductance channel located in the inner mitochondrial membrane that is activated by certain cellular stress conditions, especially Ca 2+ It is activated under conditions of overload and oxidative stress. It is permeable to solutes with a molecular weight of <1.5 kDa and is a potential 2+ mitochondrial membrane potential and disrupted mitochondrial metabolism. In addition, solutes enter the mitochondrial matrix, leading to swelling and eventual rupture of the outer membrane, followed by the release of apoptotic factors and sequestered Ca. 2+ , ultimately leading to cell death through apoptosis or necrosis, depending on the cell type and physiology. Therefore, it is considered a key pathological event in multiple degenerative and metabolic diseases.

[0004] Under normal physiological conditions, mitochondria play a crucial role in regulating cellular Ca 2+ Ca plays a key role in homeostasis. 2+ Entering cells through cell surface channels is a common mechanism of cell signaling. 2+ Rapidly sequestered by mitochondria, thereby preventing excessive and toxic Ca in the cytoplasm 2+ Accumulation. 2+ In cell types with high Ca flux, such as neurons, skeletal muscle fibers, and cardiomyocytes, mitochondria 2+ This buffering effect is crucial for maintaining cellular health. However, mitochondria sequester C a2+ The capacity is limited if mitochondrial Ca 2+ When the level reaches a certain threshold, Ca 2+ Sensitive mPTP is activated, leading to mitochondrial collapse and triggering cell death. Activation of mPTP in degenerative diseases may occur in various ways, depending on the disease, such as: 1) Excessive Ca 2+ Ca entering cells and mitochondria 2+ Overload, 2) mitochondrial Ca 2+ Dysfunction of efflux mechanisms, particularly Ca2+ The activity of the efflux transporter NCLX is reduced, leading to the 2+ Overload, 3) Ca in mitochondria 2+ Overactivity or upregulation of the uptake mechanism, 4) oxidative stress, 5) mPTP sensitization due to impaired mitochondrial function, i.e., lower intramitochondrial Ca 2+ mPTP activation at concentrations of 6) occurs when excess Ca is transported from the endoplasmic reticulum to the mitochondria at the contact point between the two organelles (called the mitochondria-associated membrane). 2+ transfer.

[0005] Although the properties and function of the mPTP can be studied in isolated mitochondria using simple in vitro assays, the molecular identity of the mPTP remains unclear. Several proteins have been proposed to constitute the pore-forming complex, including ATP synthase and the adenine nucleotide transporter (ANT) protein family, but no single protein is widely accepted to be responsible for pore formation. However, peptidylprolyl cis-trans isomerase F (Ppif-Uniprot ID P30405, also known as cyclophilin D) is recognized as a key regulator of the pore, but it does not itself form a transmembrane channel. In response to Ca 2+ Genetic or pharmacological inhibition of Ppif significantly reduces the sensitivity of pore opening to phospholipids and other mPTP activators. Therefore, genetic ablation or pharmacological inhibition of Ppif has been used to evaluate the involvement of mPTP in pathological pathways in cell and animal disease models. In this way, inhibition of mPTP has been shown to have protective effects in many disease models, especially those with known Ca2+ deficiency. 2+ Disease models in which dysregulation and oxidative stress lead to cellular degeneration. Notably, genetic knockout of Ppif has shown protective effects in various preclinical in vivo transgenic models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and motor neuron disease, also known as amyotrophic lateral sclerosis (ALS), demonstrating the therapeutic potential of mPTP inhibition. In each of these diseases, genetic mutations in specific proteins (amyloid precursor protein, α-synuclein, and superoxide dismutase 1, respectively) that cause the inherited disease and are expressed in mouse models have been shown to result in decreased mitochondrial Ca 2+ Overload or mPTP sensitization. Recent evidence suggests that this may occur through the same mechanism in Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. In each case, mitochondrial Ca 2+ was reported to be elevated in cells expressing mutant disease-associated proteins (amyloid precursor protein, PINK1, and frataxin, respectively). 2+ Reduced activity or expression of the efflux transporter NCLX leads to mitochondrial Ca 2+In the case of Parkinson's disease, pathological aggregated forms of α-synuclein, a misfolded protein commonly found in sporadic and hereditary Parkinson's diseases, have also been shown to sensitize and activate the mPTP.

[0006] Genetic ablation of Ppif has been shown to be beneficial in a variety of other preclinical models of degenerative diseases, thus demonstrating the potential of mPTP inhibitors in Duchenne muscular dystrophy and congenital muscular dystrophy, ischemia-reperfusion injury, bone repair, pancreatitis, and other related diseases.

[0007] In addition to the benefits of Ppif inhibition demonstrated in preclinical models, dysregulation of mPTP function has been demonstrated in a variety of other disease indications. In particular, in many diseases, responses to Ca 2+ The threshold for mPTP activation appears to be sensitized in response to overload, suggesting that mPTP activation may occur abnormally under physiological conditions and drive tissue degeneration. For example, the threshold for mPTP activation is reduced in muscle mitochondria from muscle biopsies of elderly individuals compared with healthy controls. Such sensitization of mPTP activity is an additional rationale for the therapeutic potential of mPTP inhibitors in these diseases.

[0008] mPTP inhibitors may also have therapeutic potential in other diseases where mitochondrial dysfunction, oxidative stress, inflammatory stress, or Ca2+ are involved in the pathogenesis of these diseases. 2+ Disharmony.

[0009] The discovery and development of mPTP inhibitors has largely focused on the identification of Ppif inhibitors. Cyclosporin A (CsA), initially identified as an immunosuppressant due to its inhibitory activity against calcineurin, has also been found to inhibit Ppif and other members of the peptidylprolyl cis-trans isomerase (Ppi) enzyme family. Several cyclosporin A derivatives, such as Debio-25 and NIM811, that retain broad activity against the Ppi enzyme family but do not inhibit calcineurin have subsequently been developed, but none have reached the market. To date, no potent, brain-penetrant, and selective Ppif inhibitors have been reported. Other, more recent approaches to the discovery of mPTP inhibitors have employed phenotypic screening in isolated mitochondria. These approaches have successfully identified potent small-molecule mPTP inhibitors with a Ppif-independent mode of action.

[0010] Yu et al. (2020, Cell, 183, 1-14) are involved in the connection between the mechanism of mPTP activation and TDP-43 proteinopathy (e.g., neurodegeneration associated with TAR DNA binding protein 43 (TDP-43)). The accumulation of normal nuclear protein TDP-43 in the cytoplasm of neurons is a disease hallmark of almost all ALS cases and 40-50% of frontotemporal lobar degeneration (FTLD) cases, and some familial cases are caused by mutant forms of the protein. Both diseases are associated with a neuroinflammatory cytokine profile that is associated with upregulation of NF-κB and type I IFN pathways, directly indicating the role of TDP-43 in neuroinflammation. Mutated or overexpressed WT TDP-43 in neurons is mislocalized to mitochondria and induces mitochondrial DNA (mtDNA) to be released into the cytoplasm. The mtDNA then activates the immune sensor cGAS-STING, triggering the induction of innate immune genes (e.g., IL-6, TNFα, and interferon β). Inhibition of the mPTP with cyclosporine A or by Ppif knockdown prevented TDP-43-induced mtDNA release and subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING prolonged the survival of mutant mice expressing mutant TDP-43. These data suggest that mPTP activation mediates the toxic effects of TDP-43 in ALS and other diseases in which mutations in the TDP-43 gene cause disease or in which TDP-43 proteinopathies are observed.

[0011] Jang et al. (2021American Journal of Physiology:Renal physiology, 2021321:4, F431-F442) highlight the potential therapeutic benefits of mPTP inhibition (by Ppif knockout) in a mouse model of renal fibrosis. In WT and Ppif knockout mice, unilateral ureteral obstruction was used to induce renal fibrosis. Compared with the wild type, inflammation, proximal tubule atrophy and fibrosis markers in Ppif knockout mice were reduced. Fibrosis measurements included collagen deposition, α-SMA and TGFβ expression and interstitial cell proliferation. This highlights the potential role of mPTP in cell damage / death-mediated tissue remodeling and fibrosis generation. Therefore, mPTP inhibitors may be beneficial for diseases such as chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic fatty liver disease, primary biliary cholangitis and systemic sclerosis, in which fibrosis is a key pathological mechanism.

[0012] WO2010 / 049768 relates to acrylamide derivatives and their use as therapeutic agents, in particular for preventing and / or treating diseases associated with mPTP activity (see also Plyte et al., J. Med Chem. 2014, 57, 5333-47). Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455) relate to phenotypic screening of mPTP modulators using platelets and disclose additional acrylamide derivatives. CA2884607A1 relates to acrylamide and maleimide compounds, which are said to be useful for treating mitochondrial diseases. WO2022 / 049376, WO2022 / 049377 and WO2023 / 166303 disclose cinnamamide compounds that are mPTP inhibitors.

[0013] There remains a need to discover additional compounds that act as mPTP inhibitors. SUMMARY OF THE INVENTION

[0015] In a first aspect, the present invention provides a compound of formula (I):

[0016]

[0017] in,

[0018] R 1a Is H or C 1-4 alkyl;

[0019] R 1b Is H or C 1-4 alkyl;

[0020] R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0021] R 3a is H, halogen or C 1-4 alkyl;

[0022] R 4a Is H or C 1-4 alkyl;

[0023] R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen;

[0024] R 6a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0025] x is 0, 1, or 2;

[0026] AA is phenyl or with C 5-6 Cycloalkyl-fused phenyl, wherein the phenyl or C 5-6 The cycloalkyl-fused phenyl group may optionally be replaced by one or more AA 1 replace;

[0027] AA 1 Halogen, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 ring

[0028] Alkyl, CN, OH, NR q R r or NHSO2R t ;

[0029] R q Is H or C 1-4 alkyl;

[0030] R r Is H or C 1-4 alkyl;

[0031] R t It is C 1-4 alkyl;

[0032] BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl may be optionally replaced by one or more B 1A replace; and

[0033] B 1A Halogen, C 1-6 Alkyl, C 1-6Haloalkyl, oxo (=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH);

[0034] or a salt and / or solvate thereof, with the proviso that the compound of formula (I) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

[0035]

[0036] In one embodiment, the compound of formula (I) is in the form of a salt. In one embodiment, the compound of formula (I) is in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) is in the form of a solvate. In one embodiment, the compound of formula (I) is in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of formula (I) is in the form of a pharmaceutically acceptable salt and solvate (i.e., a pharmaceutically acceptable salt of a pharmaceutically acceptable solvate). In one embodiment, a compound of formula (I) is provided.

[0037] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient, wherein the prerequisites of formula (I) do not apply.

[0038] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, wherein the premise of formula (I) does not apply.

[0039] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, wherein the premise of formula (I) does not apply.

[0040] The present invention also provides a method for treating or preventing a disorder in an individual in which mPTP inhibition provides a therapeutic or preventive effect, the method comprising administering to the individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0041] Suitably, the disease or disorder is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, ischemia-reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a geriatric disease, and a renal disease.

[0042] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for treating or preventing mitochondrial diseases, wherein the aforementioned prerequisites of formula (I) do not apply.

[0043] The present invention also provides use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing mitochondrial disease, wherein the prerequisite of formula (I) is not applicable.

[0044] The present invention also provides a method for treating or preventing mitochondrial disease in an individual, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0045] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, wherein the precondition of formula (I) does not apply.

[0046] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, wherein the prerequisites of formula (I) do not apply.

[0047] The present invention also provides a method for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0048] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease or disorder associated with fibrosis, wherein the precondition of formula (I) does not apply.

[0049] The present invention also provides use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing diseases or disorders associated with fibrosis, wherein the prerequisites of formula (I) do not apply.

[0050] The present invention also provides a method for treating or preventing a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply. Detailed Description of the Invention

[0052] As used herein, the term "alkyl" whether used alone or forming part of a larger group, such as C 1-4 An alkyl group is a straight or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. References to "propyl" include n-propyl and isopropyl. References to "butyl" include n-butyl, isobutyl, tert-butyl, and sec-butyl.

[0053] Whether used alone or to form a larger group such as C 1-4 Alkylene (OH), C 1-6 Alkylene (OH) or C 1-6 Alkylene (C 3-6 As used herein, the term "alkylene" is a moiety such as C 1-4 Alkylene or C 1-6 Alkylene is a difunctional straight or branched fully saturated hydrocarbon radical containing the specified number of carbon atoms. 1-6 Examples of alkylene groups include methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), n-propylene (i.e., (-CH2)3-), n-butylene (i.e., (-CH2)4-), n-pentylene (i.e., (-CH2)5-), and n-hexylene (i.e., (-CH2)6-). 1-6 An example of a branched chain of an alkylene group is isopropylidene (ie, -CH(Me)CH2-). References to C0 alkylene will be understood to mean that the alkylene chain is absent, for example, C0 alkylene(OH) represents OH.

[0054] The term C used in this article 1-4 Alkylene (OH) such as C 1-4 Alkylene (OH) refers to a C 1-4 References to C0 alkylene will be understood as meaning that the alkylene chain is absent, for example C0 alkylene(OH) represents OH.

[0055] The term "alkoxy" as used herein, for example, C 1-4 Alkoxy or C 1-6 Alkoxy refers to an alkyl group as defined above (e.g., C 1-4 C 1-6 Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy and 3-butoxy, especially methoxy.

[0056] The term "halo" or "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. Specific examples of halo are bromine, fluorine and chlorine, especially fluorine.

[0057] The term "haloalkyl" as used herein, for example, C 1-4 Haloalkyl or C 1-6 A haloalkyl group is a straight or branched alkyl group containing the specified number of carbon atoms substituted by one or more halogen atoms, for example, fluoromethyl (CH2F), difluoromethyl (CHF2), trifluoromethyl (CF3), 1-fluoroethyl (CH2FCH2) and 2-fluoroethyl (CH2CH2F).

[0058] Whether used alone or forming part of a larger group such as C 0-6 Alkylene (C 3-6 Cycloalkyl), the term "cycloalkyl" as used herein is, for example, C 3-6 Cycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular cyclopropyl. Optionally, the cycloalkyl group may be substituted as defined herein.

[0059] The term 'alkenyl' as used herein, for example, C 2-6 Alkenyl refers to a straight or branched hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon double bond, for example, one or two double bonds. The term includes CH=CH2, CH2CH=CH2, CH=CHCH3, CH2CH2CH=CH2, CH=CHCH2CH3, CH2CH=CHCH3, CH2CH2CH2CH=CH2, CH=CHCH2CH2CH3, CH2CH=CHCH2CH3, CH2CH=CHCH2CH3, CH2CH2CH=CHCH3, CH=CHCH=CHCH3, and CH2CH=CHCH=CH2. Straight-chain variants such as CH(CH3)CH=CH2 and CH=C(CH3)2 are also included.

[0060] The term 'haloalkenyl' as used herein, for example C 2-6 Haloalkenyl is a straight or branched alkenyl chain containing the specified number of carbon atoms and at least one halogen atom such as fluorine or chlorine, e.g. fluorine.

[0061] As used herein, the term 'aryl' refers to a monocyclic ring system (i.e., phenyl) or a polycyclic ring system containing at least one benzene ring (e.g., comprising one or two additional rings, such as one additional ring), suitably, the aryl group contains 6-10 ring members. The additional rings in the polycyclic ring system may be saturated (e.g., forming indane or tetralin) or partially unsaturated (e.g., forming indene) or fully saturated (e.g., forming naphthalene) hydrocarbon rings, or the additional rings may be saturated or partially unsaturated heterocycles (e.g., forming chromanes). Suitably, aryl refers to a monocyclic ring system (i.e., phenyl) or a bicyclic ring system containing at least one benzene ring (and no heteroaromatic rings).

[0062] As used herein, the term 'heteroaromatic ring' refers to a monocyclic or polycyclic ring system (e.g., a bicyclic ring system) containing at least one ring having aromatic characteristics and containing at least one heteroatom (e.g., N) selected from N, O, and S. Suitably, the heteroaromatic ring contains 5-10 ring members. If the heteroaromatic ring contains more than one ring, not all rings must contain heteroatoms, nor must all rings have aromatic characteristics. In some instances, the heteroaromatic ring is a monocyclic ring, such as a 5- or 6-membered heteroaromatic ring (e.g., containing one or two heteroatoms selected from N, S, and O). In other instances, the heteroaromatic ring is a bicyclic ring, such as a 5,5-, 5,6-, or 6,6-bicyclic ring system (e.g., containing one, two, or three heteroatoms selected from N, S, and O). The heteroaromatic ring may contain one heteroatom selected from N, S, and O, such as N and O, especially N. In other instances, the heteroaromatic ring may contain two heteroatoms selected from N, S, and O. In other embodiments, the heteroaromatic ring may contain three heteroatoms selected from N, S, and O, such as N and O. Examples of 6-membered heteroaromatic groups include one nitrogen atom (pyridyl), two nitrogen atoms (pyridazinyl, pyrimidinyl, or pyrazinyl), and three nitrogen atoms (triazinyl). Additional examples of heteroaromatic rings include triazolyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, quinolyl, isoquinolyl, and quinazolinyl.

[0063] The term heterocycle as used herein means a non-aromatic cyclic group of carbon atoms, wherein 1 to 4 carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen (N), oxygen (O) or sulphur (S). A heterocyclic group can be, for example, a monocyclic or bicyclic ring. In a bicyclic heterocyclic group, one or more heteroatoms can be present in each ring or only in one of the rings. If a heterocyclic group contains more than one ring, not all rings must contain a heteroatom. The heteroatom can be S, O or N, and suitably O or N. Suitably, the heterocyclic group contains 5-10 ring members.

[0064] The heterocycle may contain one heteroatom selected from N, S and O, such as N and O, especially N. In other examples, the heterocycle may contain two heteroatoms selected from N, S and O. In yet other examples, the heterocycle may contain three heteroatoms selected from N, S and O, such as N and O. In some examples, the heterocycle is a monocyclic ring, such as a 5- or 6-membered heterocycle. Examples of heterocycles include morpholinyl, tetrahydrofuran and tetrahydropyran.

[0065] When in the embodiments and preferences listed below, when the substituent in formula (I) or (IB) is indicated as being optionally substituted, the optional substituent can be connected to an available carbon atom, wherein the available carbon atom refers to a carbon atom connected to a hydrogen atom, i.e., a CH group, or the optional substituent can be connected to an available nitrogen-atoms, wherein the available nitrogen-atoms refers to a nitrogen-atoms connected to a hydrogen atom, i.e., an NH group. The optional substituent replaces the hydrogen atom connected to the carbon atom or the hydrogen atom connected to the nitrogen-atoms.

[0066] The present invention provides a compound of formula (I):

[0067]

[0068] in,

[0069] R 1a Is H or C 1-4 alkyl;

[0070] R 1b Is H or C 1-4 alkyl;

[0071] R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0072] R 3a is H, halogen or C 1-4 alkyl;

[0073] R 4a Is H or C 1-4 alkyl;

[0074] R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen;

[0075] R 6a It is H, halogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0076] x is 0, 1, or 2;

[0077] AA is phenyl or with C 5-6 Cycloalkyl-fused phenyl, wherein the phenyl or C 5-6 The cycloalkyl-fused phenyl group may optionally be replaced by one or more AA 1 replace;

[0078] AA 1 Halogen, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 ring

[0079] Alkyl, CN, OH, NR q R r or NHSO2R t ;

[0080] R q Is H or C 1-4 alkyl;

[0081] R r Is H or C 1-4 alkyl;

[0082] R t It is C 1-4 alkyl;

[0083] BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl may be optionally replaced by one or more B 1A replace; and

[0084] B 1A Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo (=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH);

[0085] or a salt and / or solvate thereof, with the proviso that the compound of formula (I) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

[0086]

[0087] In one embodiment, the present invention provides a compound of formula (IB):

[0088]

[0089] in,

[0090] R 1a Is H or C 1-4 alkyl;

[0091] R 1b Is H or C 1-4 alkyl;

[0092] R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0093] R 3a is H, halogen or C 1-4 alkyl;

[0094] R 4a Is H or C 1-4 alkyl;

[0095] R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen;

[0096] R 6a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0097] x is 0, 1, or 2;

[0098] AA is phenyl or with C 5-6Cycloalkyl-fused phenyl, optionally substituted with one or more AA 1 replace;

[0099] AA 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r or NHSO2R t ;

[0100] R q Is H or C 1-4 alkyl;

[0101] R r Is H or C 1-4 alkyl;

[0102] R t It is C 1-4 alkyl;

[0103] BA is a monocyclic or bicyclic heterocyclic ring or a monocyclic or bicyclic heteroaryl ring, which may be optionally replaced by one or more B 1A replace; and

[0104] B 1A Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH); or a salt and / or solvate thereof, with the proviso that Formula (IB) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

[0105]

[0106] The compound of formula (IB) or its salt and / or solvate is a subclass of the compound of formula (I) or its salt and / or solvate. The compound of formula (IB') or its salt and / or solvate described below is a subclass of the compound of formula (IB) or its salt and / or solvate. The following embodiments are also applicable to the compound of formula (I), (IB) and / or (IB') or its salt and / or solvate.

[0107] In one embodiment, R 1a is H. In a second embodiment, R 1a It is C 1-4 Alkyl groups, such as methyl.

[0108] In one embodiment, R 1b is H. In a second embodiment, R 1b It is C 1-4 Alkyl groups, such as methyl.

[0109] In one embodiment, R 1a and R 1b Each is H.

[0110] In one embodiment, R 2a is H. In a second embodiment, R 2a In a third embodiment, R 2a It is C 1-4 In a fourth embodiment, R 2a It is C 1-4 Halogenated alkyl.

[0111] In one embodiment, R 3a is H. In a second embodiment, R 3a In a third embodiment, R 3a It is C 1-4 alkyl.

[0112] In one embodiment, R 2a and R 3a Each is H.

[0113] In one embodiment, R 4a is H. In a second embodiment, R 4a It is C 1-4 Alkyl groups, such as methyl.

[0114] In one embodiment, R 5a is H. In a second embodiment, R 5a It is C 1-6 In a third embodiment, R 5a It is C 1-6 In a fourth embodiment, R 5a It is C 1-6 In a fifth embodiment, R 5a It is C 1-6 In a sixth embodiment, R 5a It is C 2-6 In a seventh embodiment, R 5a It is C 2-6 In an eighth embodiment, R 5a It is C 0-6 Alkylene (C 3-6 In a ninth embodiment, R5a It is C 0-6 Alkylene (OH).

[0115] In one embodiment, R 4a and R 5a Each is a methyl group.

[0116] In one embodiment, R 4a and R 5a Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl. Within such embodiments, the C 3-6 The cycloalkyl group may be selected from C 1-4 Alkyl, C 1-4 Suitable C 3-6 The cycloalkyl group is replaced by a 1-4 Alkyl, C 1-4 Suitable, the C 3-6 Cycloalkyl is unsubstituted. In one embodiment, R 4a and R 5a Together with the atoms to which they are attached they form a cyclobutyl group.

[0117] In one embodiment, R 6a is H. In a second embodiment, R 6a In a third embodiment, R 6a It is C 1-4 In a fourth embodiment, R 6a It is C 1-4 In a fifth embodiment, R 6a It is C 1-4 In a sixth embodiment, R 6a It is C 1-4 Halogenated alkoxy.

[0118] In one embodiment, x is 0. In a second embodiment, x is 1. In a third embodiment, x is 2.

[0119] In one embodiment, AA is phenyl. In a second embodiment, AA is C 5-6 Cycloalkyl-fused phenyl.

[0120] In one embodiment, AA is replaced by one or more (eg one, two or three, such as one or two, in particular one) AA 1 replace.

[0121] In one embodiment, at least one AA 1is halogen, such as F. In a second embodiment, at least one AA 1 It is C 1-6 In a third embodiment, at least one AA 1 It is C 1-6 In a fourth embodiment, at least one AA 1 It is C 1-6 In a fifth embodiment, at least one AA 1 It is C 1-6 In a sixth embodiment, at least one AA 1 It is C 3-6 In a seventh embodiment, at least one AA 1 In an eighth embodiment, at least one AA 1 In a ninth embodiment, at least one AA 1 It is C 2-6 In a tenth embodiment, at least one AA 1 It is NR q R r . Appropriately, R q is H. Appropriately, R q It is C 1-4 Suitably, R r is H. Appropriately, R r It is C 1-4 In an eleventh embodiment, at least one AA 1 It is NHSO2R t .

[0122] In one embodiment, AA is replaced by one, two or three AA 1 Substitution, where AA 1 It's a halogen.

[0123] In one embodiment, AA is unsubstituted.

[0124] In one embodiment, BA is a monocyclic heterocycle. Suitably, BA is a 5-membered monocyclic heterocycle. In a second embodiment, BA is a bicyclic heterocycle. In a third embodiment, BA is a monocyclic heteroaromatic ring. Suitably, BA is a 6-membered monocyclic heteroaromatic ring. In a fourth embodiment, BA is a bicyclic heteroaromatic ring.

[0125] In one embodiment, BA is replaced by one or more (eg one, two or three, such as one or two, in particular one) B 1A replace.

[0126] In one embodiment, at least one B 1AIn a second embodiment, at least one B 1A It is C 1-6 In a third embodiment, at least one B 1A It is C 1-6 In a fourth embodiment, at least one B 1A It is C 1-6 In a fifth embodiment, at least one B 1A It is C 1-6 In a sixth embodiment, at least one B 1A It is C 0-6 In a seventh embodiment, at least one B 1A It is oxo (=O).

[0127] In one embodiment, BA is unsubstituted.

[0128] In one embodiment, BA is selected from:

[0129]

[0130] in,

[0131] B 1B Is H or C 1-6 Alkyl groups, such as methyl;

[0132] B 2B Is H or C 1-6 an alkyl group, such as a methyl group; and

[0133] B 2B It is C 0-6 Alkylene (OH), such as OH.

[0134] In one embodiment, BA is selected from:

[0135]

[0136] in,

[0137] B 1B Is H or C 1-6 Alkyl groups, such as methyl;

[0138] B 2B Is H or C 1-6 an alkyl group, such as a methyl group; and

[0139] B 2B It is C 0-6 Alkylene (OH), such as OH.

[0140] In one embodiment, BA is

[0141] In one embodiment, BA is

[0142] In one embodiment, B 1B is H. In a second embodiment, B 1B It is C 1-6 Alkyl groups, such as methyl.

[0143] In one embodiment, B 2B is H. In a second embodiment, B 2B It is C 1-6 Alkyl groups, such as methyl.

[0144] In one embodiment, the present invention provides a compound of formula (IB'):

[0145]

[0146] in

[0147] R 4a’ It is C 1-4 alkyl;

[0148] R 5a’ It is C 1-4 Alkyl; or R 4a’ and R 5a’ Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0149] B 1A’ is a halogen, such as F; and

[0150] BA' selected or a salt and / or solvate thereof.

[0151] In one embodiment, R 4a’ In one embodiment, R 5a’ In one embodiment, R 4a’ and R 5a’ Together with the atoms to which they are attached they form a cyclobutyl ring.

[0152] In one embodiment, BA' is In a second embodiment, BA' is

[0153] In the following paragraphs, references and preferences with respect to the compounds of formula (I) or their salts and / or solvates, salts, isomers, methods, pharmaceutical compositions, compounds for use, uses and methods, etc., also apply to the compounds or their salts and / or solvates of formula (IB) and / or compounds of formula (IB′) or their salts and / or solvates.

[0154] In one embodiment, the compound of formula (I) is selected from:

[0155] (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0156] (4-Hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0157] (3,3-Dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone;

[0158] 2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0159] (S)-(6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0160] 6-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0161] 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0162] 6-(3,3-Dimethyl-4-phenylpiperidin-1-carbonyl)pyrazin-2(1H)-one;

[0163] (R)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0164] (S)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0165] 5-(8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; and 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0166] or a salt and / or solvate thereof.

[0167] In another embodiment, the compound of formula (I) is selected from:

[0168] (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0169] (4-Hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0170] (3,3-Dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone;

[0171] 2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0172] (S)-2-Methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (R)-2-Methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (S)-(6-hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octane-6-yl)methanone;

[0173] (R)-(6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0174] 6-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0175] 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0176] 6-(3,3-Dimethyl-4-phenylpiperidin-1-carbonyl)pyrazin-2(1H)-one;

[0177] (S)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0178] (R)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0179] 5-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0180] (S)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane;

[0181] (R)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane;

[0182] (R),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0183] (S),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0184] (R),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0185] (S),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0186] (S)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0187] (R)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0188] (S)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one;

[0189] (R)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one;

[0190] rac-2-{8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-3H-pyrimidin-4-one;

[0191] (S)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0192] (R)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0193] (S)-4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile;

[0194] (R)-4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile;

[0195] (S)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one;

[0196] (R)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one;

[0197] (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0198] (S)-(3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0199] (R)-(3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0200] 3-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-oxadiazol-5-one;

[0201] (R),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0202] (S),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0203] (R),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0204] (S),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0205] (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one;

[0206] (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one;

[0207] (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one;

[0208] (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one;

[0209] (S)-6-(8-(4-methoxyphenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0210] (R)-6-(8-(4-methoxyphenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0211] (S)-6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0212] (R)-6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0213] (S)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0214] (R)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0215] (S)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0216] (R)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0217] (S)-6-8-(5-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0218] (R)-6-8-(5-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0219] (S)-6-(8-(3-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0220] (R)-6-(8-(3-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0221] (S)-3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0222] (R)-3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0223] (S)-6-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0224] (R)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0225] (S)-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0226] (R)-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0227] (S)-6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0228] (R)-6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0229] (S)-(8-(3-Fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0230] (R)-(8-(3-Fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0231] (S)-(8-(2,3-Difluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(2,3-Difluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0232] (R)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0233] (S)-3-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0234] (R)-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0235] (S)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0236] (R)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0237] (S)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0238] (R)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0239] (S)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0240] (R)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0241] (S)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0242] (R)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0243] (S)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0244] (R)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0245] (S)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0246] (R)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0247] (S)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; and

[0248] (R)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0249] or a salt and / or solvate thereof.

[0250] The definition of compounds of formula (I) includes all tautomers of said compounds.

[0251] The compounds of the present invention may be provided in the form of pharmaceutically acceptable salts and / or solvates. In particular, the compounds of formula (I) may be provided in the form of pharmaceutically acceptable salts and / or solvates, for example pharmaceutically acceptable salts. In one embodiment, a compound of formula (I) is provided.

[0252] It should be understood that for use in medicine, the salt of the compound of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compound of formula (I) can be used in other situations, such as in the preparation process of the compound of formula (I). Suitable pharmaceutically acceptable salts are obvious to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid. Other salts such as oxalates or formates can be used for the separation of compounds of formula (I), for example, and are included within the scope of the present invention.

[0253] Certain compounds of formula (I) may form acid or base addition salts with one or more equivalents of acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0254] The compound of formula (I) can be prepared in crystalline or non-crystalline form and, if crystalline, can optionally be solvated, for example, be a hydrate. The present invention includes within its scope stoichiometric solvates (for example hydrates) and compounds containing variable amounts of solvent (for example water).

[0255] It should be understood that the present invention includes all stereoisomers of formula (I) and pharmaceutically acceptable derivatives thereof, including all geometric isomers, tautomers and optical isomers, and mixtures thereof (e.g., racemic mixtures). When there is another chiral center in the compound of formula (I), the present invention includes all possible diastereomers within its scope, including mixtures thereof. Different isomeric forms can be separated or split from each other by conventional methods, or any given isomer can be obtained by conventional synthesis methods or by stereospecific or asymmetric synthesis.

[0256] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether (i) in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (referred to herein as a "natural isotopic form") or (ii) in which one or more atoms are replaced by atoms having the same atomic number but a mass number different from the mass number of atoms that predominates in nature (referred to herein as a "non-natural variant isotopic form"). It should be understood that atoms can exist in nature as a mixture of different mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number having a mass number that is less common in nature (referred to herein as an "uncommon isotope") is increased relative to the naturally occurring isotopic proportion, for example to a level of >20%, >50%, >75%, >90%, >95% or >99% of the number of atoms of that atomic number (the latter embodiments are referred to as "isotopically enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments in which the ratio of the uncommon isotope is reduced relative to the ratio of the isotope occurring in nature. Isotopic forms can include radioactive forms (i.e., they have incorporated a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0257] Thus, non-naturally occurring isotopic forms of a compound may contain one or more artificial or unusual isotopes, such as deuterium, at one or more atoms. 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 (15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35( 35 S), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), fluorine-18 ( 18 F), iodine-123 ( 123 I), iodine-125( 125 I), or may contain in one or more atoms said isotope in an increased proportion compared to the proportion predominant in nature.

[0258] Non-natural variant isotopic forms containing radioactive isotopes are useful, for example, in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly suitable for this purpose due to their ease of incorporation and readily available detection methods. 2 Unnatural variant isotopic forms of H or D may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. In addition, it is possible to prepare isotopes incorporating positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 In one embodiment, the compounds of the present invention are provided in natural isotopic forms. In one embodiment, the compounds of the present invention are provided in non-natural isotopic forms. In a specific embodiment, if hydrogen is specified in the chemical structure of one or more atoms of the compounds of the present invention, the non-natural isotopic form is one in which deuterium (i.e., 2 In one embodiment, the atoms of the compounds of the invention are in non-radioactive isotopic forms. In one embodiment, one or more atoms of the compounds of the invention are in radioactive isotopic forms. Suitably, the radioisotope is a stable isotope. Suitably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0259] In one embodiment, compounds of the present invention are provided wherein individual atoms of the compound exist in non-natural variant isotopic forms. In another embodiment, compounds of the present invention are provided wherein two or more atoms exist in non-natural variant isotopic forms.

[0260] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by methods described herein, for example, methods analogous to those described in the accompanying examples for preparing natural isotopic forms. Thus, non-natural isotopic variant forms can be prepared by using appropriate isotopic variant (or labeled) reagents in place of the conventional reagents used in the examples. Since the compounds of formula (I) are used in pharmaceutical compositions, it will be readily understood that each of them is preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, preferably at least 85%, and especially at least 98% pure (% is based on weight / weight). Impure formulations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0261] Typically, compounds of formula (I) can be prepared according to organic synthesis techniques known to those skilled in the art and by the representative methods listed below, those methods in the examples, and modifications thereof. In the following schemes, reactive groups can be protected and deprotected with protecting groups according to established techniques well known to those skilled in the art.

[0262] General Route

[0263] The general routes by which examples of the compounds of the present invention can be conveniently prepared are summarized below. In the following description, unless otherwise indicated, the group R 1a 、R 1b 、R 2a 、R 3a 、R 4a 、R 5a 、R 6a , BA, AA and x are as defined above for the compounds of formula (I) and (IB).

[0264] Solution 1

[0265]

[0266] Compounds of formula (I) or (IB) may be prepared by reacting a compound of formula (IIB) with a compound of formula (IIIB) under amide coupling conditions using a species such as EDC.HCl (N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as dimethylformamide at room temperature. Alternative conditions known to those skilled in the art may be used, for example, HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) or PyBOP (benzotriazol-1-yloxytripyrrolidinium phosphonium hexafluorophosphate) in the presence of a base such as N,N′-diisopropylethylamine and a solvent such as dimethylformamide; or T3P (1-propanephosphonic anhydride) in the presence of a base such as triethylamine and a solvent such as dimethylformamide.

[0267] Compounds of formula (IIB) and (IIIB) are commercially available or can be prepared according to methods known to the skilled person.

[0268] Option 2

[0269]

[0270] The following method can be used to prepare R 1a 、R 1b 、R 2a and R 3a Compounds of formula (IIB) wherein x is H and 1: reacting a compound of formula (IVB) under metal-mediated cyclization conditions using a metal such as zinc in a solvent such as a mixture of acetic acid and water. Compounds of formula (IVB) can be obtained by reacting a compound of formula (VB) with a compound of formula (VIB) using an organic catalyst such as L-proline in a solvent such as ethanol.

[0271] Compounds of formula (VB) and (VIB) are commercially available or can be prepared according to methods known to the skilled person.

[0272] Option 3

[0273]

[0274] Alternatively, R 1a 、R 1b 、R 2a and R 3aCompounds of formula (IIB) wherein X is H and 1: reacting a compound of formula (VIIB) under reducing conditions, for example, using lithium aluminum hydride, in a solvent such as tetrahydrofuran. Compounds of formula (VIIB) can be obtained by reacting a compound of formula (VIIIB) under reducing conditions, for example, using Raney nickel and hydrogen, and a solvent such as methanol. Compounds of formula (VIIIB) can be obtained by reacting a compound of formula (IXB) with a compound of formula (XB) using a base such as sodium hydride in a solvent such as dimethyl sulfoxide.

[0275] Compounds of formula (IXB) and (XB) are commercially available or can be prepared according to methods known to the skilled person.

[0276] Option 4

[0277]

[0278] Compounds of formula (IIB) wherein x is 2 can be prepared by reacting a compound of formula (XIB) under hydrogenation conditions, for example, using palladium on carbon and hydrogen. Compounds of formula (XIB) can be prepared by elimination of a compound of formula (XIIB) using an acid, for example, p-toluenesulfonic acid, in a solvent, for example, toluene. Compounds of formula (XIIB) can be prepared by reacting a compound of formula (XIVB) wherein P is a nitrogen protecting group, for example, BOC (tert-butoxycarbonyl), under deprotection conditions, for example, using hydrochloric acid, in a solvent, for example, methanol. Compounds of formula (XIVB) can be prepared by reacting a compound of formula (XVB) using a commercially available reagent, for example, bromobenzene, using a base, for example, N-butyllithium, and a solvent, for example, tetrahydrofuran.

[0279] Compounds of formula (XVB) are commercially available or can be prepared according to methods known to the skilled person.

[0280] Those skilled in the art will appreciate that protecting groups can be used throughout the synthetic schemes described herein to provide protected derivatives of any of the above compounds or formulas. Protecting groups and methods for their removal are described in: "Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons Inc, 4th revised edition, 2006, ISBN-10: 0471697540. Examples of nitrogen protecting groups include trityl (Tr), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzyl (Bn), and p-methoxybenzyl (PMB). Examples of oxygen protecting groups include acetyl (Ac), methoxymethyl (MOM), p-methoxybenzyl (PMB), benzyl, tert-butyl, methyl, ethyl, tetrahydropyranyl (THP), and silyl ethers and esters (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers and esters). Specific examples of carboxylic acid protecting groups include alkyl esters (e.g., C 1-6 Alkyl and C 1-6 Haloalkyl, such as C 1-4 Alkyl esters and C 1-4 haloalkyl esters), benzyl esters (including substituted benzyl esters such as p-methoxybenzyl ester), and silyl esters.

[0281] method

[0282] The present invention also provides a method for preparing a compound of formula (I) or a salt and / or solvate thereof, which comprises:

[0283]

[0284] where R 1a 、R 1b 、R 2a 、R 3a 、R 4a 、R 5a 、R 6a , AA and x are as defined for the compound of formula (I) or a salt thereof, reacted with a compound of formula (IIIB),

[0285]

[0286] wherein BA is as defined for the compound of formula (I) or a salt thereof.

[0287] intermediates

[0288] The present invention also provides novel intermediates for preparing compounds of formula (I). Particularly interesting intermediates are those of the following general formula, wherein the variable groups and associated preferences are as previously defined for compounds of formula (I) or salts thereof. Thus, in one embodiment, the present invention provides a compound selected from the group consisting of:

[0289] Compounds of formula (IIB):

[0290]

[0291] where R 1a 、R 1b 、R 2a 、R 3a 、R 4a 、R 5a 、R 6a , x and AA are as defined for the compound of formula (I);

[0292] - Compounds of formula (IIIB):

[0293]

[0294] wherein BA is as defined for the compound of formula (I);

[0295] - Compound of formula (IVB):

[0296]

[0297] where R 4a 、R 5a 、R 6a and AA are as defined for the compound of formula (I);

[0298] - Compounds of formula (VIIB):

[0299]

[0300] where R 4a 、R 5a 、R 6a and AA are as defined for the compound of formula (I);

[0301] - Compound of formula (VIIIB):

[0302]

[0303] where R 4a 、R 5a 、R 6a and AA are as defined for the compound of formula (I);

[0304] - Compounds of formula (XIB):

[0305]

[0306] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA are as defined for the compound of formula (I);

[0307] - Compounds of formula (XIIB):

[0308]

[0309] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA are as defined for the compound of formula (I);

[0310] - Compounds of formula (XIIIB):

[0311]

[0312] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA are as defined for the compound of formula (I); and

[0313] - Compounds of formula (XIVB):

[0314]

[0315] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA are as defined for compounds of formula (I), and P is a nitrogen protecting group, such as BOC (tert-butoxycarbonyl),

[0316] or a salt of any one thereof, such as a pharmaceutically acceptable salt.

[0317] Treatment

[0318] The compounds of formula (I) of the present invention have use as mPTP inhibitors.

[0319] In the context of the methods of treatment and prevention described below, references to compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof are understood to exclude the antecedent of formula (I), i.e., (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

[0320]

[0321] These compounds are commercially available and to date no uses (eg therapeutic uses) of these compounds have been described.

[0322] The present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, in particular for the treatment or prevention of diseases or disorders in which mPTP inhibition provides a therapeutic or preventive effect, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0323] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, in particular for use in the treatment of diseases or disorders in which mPTP inhibition provides a therapeutic effect, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0324] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, in particular for use in the prevention of diseases or disorders in which mPTP inhibition provides a preventive effect, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0325] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament, in particular a medicament for the treatment or prevention of diseases or disorders in which mPTP inhibition provides a therapeutic or preventive effect, such as those diseases and disorders mentioned below, wherein the premise of formula (I) does not apply.

[0326] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament, in particular for the treatment of diseases or disorders in which mPTP inhibition provides a therapeutic effect, such as those diseases and disorders mentioned below, wherein the premise of formula (I) does not apply.

[0327] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament, in particular for the prevention of diseases or disorders in which mPTP inhibition provides a preventive effect, such as those diseases and disorders mentioned below, wherein the premise of formula (I) does not apply.

[0328] The present invention also provides a method for preventing or treating a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect in an individual, such as those diseases and disorders mentioned below, which method comprises administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the preconditions of formula (I) do not apply.

[0329] The present invention also provides a method for treating a disease or disorder in which mPTP inhibition provides a therapeutic effect in an individual, such as those diseases and disorders mentioned below, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the preconditions of formula (I) do not apply.

[0330] The present invention also provides a method for preventing a disease or disorder in which mPTP inhibition provides a preventive effect in an individual, such as those diseases and disorders mentioned below, which method comprises administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the preconditions of formula (I) do not apply.

[0331] As used herein, the term "treating" includes controlling, alleviating, reducing or regulating the disease state or its symptoms.

[0332] As used herein, the term "prevent" or "preventing" refers to preventing symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an afflicted subject, and is not limited to complete prevention of affliciton.

[0333] In one embodiment, the disease or disorder is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, ischemia-reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a geriatric disease, and a renal disease.

[0334] In another embodiment, the disease or disorder is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, ischemia-reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a geriatric disease, a kidney disease, hearing loss, an eye disease or disorder, Charcot-Marie-Tooth disease (CMT1a), and Leigh syndrome disease.

[0335] In a specific embodiment, the disease or disorder is a degenerative or neurodegenerative disease, such as Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontal temporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury (e.g., concussion), and Friedreich's ataxia. In a preferred embodiment, the disease or disorder is Parkinson's disease. In a preferred embodiment, the disease or disorder is Alzheimer's disease. In a preferred embodiment, the disease or disorder is amyotrophic lateral sclerosis.

[0336] In another embodiment, the disease or disorder is a central nervous system disease, such as AIDS dementia syndrome, depression, schizophrenia, and epilepsy.

[0337] In another embodiment, the disease or disorder is ischemia-reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplantation.

[0338] In another embodiment, the disease or disorder is a metabolic disease, such as hepaticsteatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease.

[0339] In another embodiment, the disease or disorder is a complication associated with a metabolic disease, such as diabetic neuropathy.

[0340] In another embodiment, the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis.

[0341] In another embodiment, the disease or disorder is a disease of geriatrics, such as bone repair, bone weakness in aging in osteoporosis, and sarcopenia.

[0342] In another embodiment, the disease or disorder is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene variants.

[0343] In another embodiment, the disease or disorder is hearing loss, such as hearing loss caused by aging, noise, concussion, traumatic brain injury (TBI), drug-induced hearing loss, and / or hereditary hearing loss, including spinal muscular atrophy (SMA) syndrome (SMA1, SMA2, SMA3, and SMA4, also known as types I, II, III, and IV).

[0344] In another embodiment, the disease or disorder is an ocular disease or disorder, such as age-related macular degeneration.

[0345] In another embodiment, the disease or disorder is Charcot-Marie-Tooth disease (CMT1a).

[0346] In another embodiment, the disease or disorder is Leigh's syndrome.

[0347] The compounds of formula (I) are expected to be useful in the treatment and prevention of mitochondrial diseases.

[0348] Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a mitochondrial disease, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0349] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a mitochondrial disease, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0350] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in preventing mitochondrial diseases, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0351] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing mitochondrial diseases, such as those diseases and disorders mentioned below, wherein the prerequisites of formula (I) do not apply.

[0352] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating mitochondrial diseases, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0353] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for preventing mitochondrial diseases, such as those diseases and disorders mentioned below, wherein the prerequisites of formula (I) do not apply.

[0354] The present invention also provides a method for treating or preventing mitochondrial diseases, such as those diseases and disorders mentioned below, in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0355] The present invention also provides a method of treating a mitochondrial disease, such as those diseases and disorders mentioned below, in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0356] The present invention also provides a method for preventing mitochondrial diseases, such as those diseases and disorders mentioned below, in an individual, comprising administering to the individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the preconditions of formula (I) do not apply.

[0357] Suitably, the mitochondrial disease is selected from Reye's syndrome, Leber's hereditary optic neuropathy and related disorders and disorders such as those disclosed in CA2884607A1 (Stealth Peptides International Inc.).

[0358] The compounds of formula (I) are expected to be useful in treating and preventing diseases or disorders associated with TDP-43 proteinopathies, such as neurodegeneration associated with TDP-43 proteinopathies.

[0359] Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as neurodegeneration associated with a TDP-43 proteinopathy, such as those diseases and disorders mentioned below, wherein the precondition of formula (I) does not apply.

[0360] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a disease or disorder associated with a TDP-43 proteinopathy, such as neurodegeneration associated with a TDP-43 proteinopathy, such as those diseases and disorders mentioned below, wherein the precondition of formula (I) does not apply.

[0361] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in preventing a disease or disorder associated with a TDP-43 proteinopathy, such as neurodegeneration associated with a TDP-43 proteinopathy, such as those diseases and disorders mentioned below, wherein the precondition of formula (I) does not apply.

[0362] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, such as those diseases and disorders mentioned below, wherein the aforementioned preconditions of formula (I) do not apply.

[0363] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0364] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, such as those diseases and disorders mentioned below, wherein the preconditions of formula (I) do not apply.

[0365] The present invention also provides a method for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, such as those diseases and disorders mentioned below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0366] The present invention also provides a method for treating a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, such as those diseases and disorders mentioned below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0367] The present invention also provides a method for preventing a disease or disorder associated with a TDP-43 proteinopathy, such as neurodegeneration associated with a TDP-43 proteinopathy, such as those diseases and disorders mentioned below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0368] Suitably, the disease or disorder associated with a TDP-43 proteinopathy, e.g., neurodegeneration associated with a TDP-43 proteinopathy, is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensory and motor neuronopathy, primary lateral sclerosis, progressive muscular dystrophy, inclusion body myopathy associated with early-onset Paget disease of the bone and frontotemporal lobar degeneration dementia, Perry disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and cerebral age-related TDP-43 with sclerosis.

[0369] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease or disorder associated with fibrosis, wherein the precondition of formula (I) does not apply.

[0370] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a disease or disorder associated with fibrosis, wherein the precondition of formula (I) does not apply.

[0371] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in preventing a disease or disorder associated with fibrosis, wherein the precondition of formula (I) does not apply.

[0372] The present invention also provides use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating or preventing diseases or disorders associated with fibrosis, wherein the prerequisites of formula (I) do not apply.

[0373] The present invention also provides use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for treating a disease or disorder associated with fibrosis, wherein the prerequisites of formula (I) do not apply.

[0374] The present invention also provides use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for preventing diseases or disorders associated with fibrosis, wherein the prerequisites of formula (I) do not apply.

[0375] The present invention also provides a method for treating or preventing a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0376] The present invention also provides a method for treating a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0377] The present invention also provides a method for preventing a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the precondition of formula (I) does not apply.

[0378] Suitably, the disease or disorder associated with fibrosis is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis.

[0379] Suitably, the subject is a mammal, in particular, the subject is a human.

[0380] Pharmaceutical composition

[0381] For use in treatment, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, and a pharmaceutically acceptable carrier or excipient, wherein the aforementioned prerequisites of formula (I) are not applicable.

[0382] In one embodiment, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, for treating or preventing a disease or disorder as described herein, wherein the premise of formula (I) is not applicable. In one embodiment, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, for treating a disease or disorder as described herein, wherein the premise of formula (I) is not applicable. In one embodiment, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, for preventing a disease or disorder as described herein, wherein the premise of formula (I) is not applicable.

[0383] In another embodiment, there is provided a method for treating or preventing a disease or disorder as described herein, the method comprising administering an effective amount of a pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt), wherein the premise of formula (I) is not applicable. In another embodiment, there is provided a method for treating a disease or disorder as described herein, the method comprising administering an effective amount of a pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt), wherein the premise of formula (I) is not applicable. In another embodiment, there is provided a method for preventing a disease or disorder as described herein, the method comprising administering an effective amount of a pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt), wherein the premise of formula (I) is not applicable. The pharmaceutical composition of the present invention may take the form of a pharmaceutical preparation as described below.

[0384] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof for use in the preparation of a medicament for treating or preventing a disease or disorder described herein, wherein the premise of formula (I) is not applicable. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof for use in the preparation of a medicament for treating a disease or disorder described herein, wherein the premise of formula (I) is not applicable. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof for use in the preparation of a medicament for preventing a disease or disorder described herein, wherein the premise of formula (I) is not applicable.

[0385] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary with the specific compound, route of administration, the individual being treated or prevented (including the type, species, age, weight, sex and medical condition of the individual, as well as the renal and liver function of the individual), the specific disorder or disease being treated or prevented, and its severity. A physician, veterinarian or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0386] For adults, oral doses of the present invention are in the following range when used for specified effects: about 0.01mg / kg body weight / day (mg / kg / day) to about 100mg / kg / day, suitably 0.01mg / kg body weight / day (mg / kg / day) to 10mg / kg / day, most suitably 0.1 to 5.0mg / kg / day. For oral administration, compositions is suitable for providing in tablet form or in other forms provided in discrete units, and it contains 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active components, for symptomatic dose adjustment of patient to be treated. Medicament generally contains about 0.01mg to about 500mg active components, suitably about 1mg to about 100mg active components. During intravenous administration, during constant rate infusion, most suitable dosage range is about 0.1 to about 10mg / kg / minute. Advantageously, the compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times, or four times a day. In addition, the compounds of the present invention can be suitably administered in an intranasal form by topical use of a suitable intranasal carrier, or can be administered by a transdermal route using transdermal skin patches of the forms known to those of ordinary skill in the art. Of course, in order to be administered in the form of a transdermal delivery system, dosage administration is continuous rather than intermittent throughout the dosage regimen.

[0387] Pharmaceutical formulations of the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), intranasal (also known as nasal administration), inhalation (including fine particle powders or mists, which can be produced by various types of metered dose pressurized aerosols, nebulizers, or insufflators), insufflation, rectal, intraperitoneal, topical (including dermal, buccal, sublingual, and intraocular), and intrathecal administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient.

[0388] Suitable pharmaceutical formulations according to the present invention are those suitable for oral, intrathecal and parenteral administration; more suitably those suitable for oral or intrathecal administration.

[0389] In one suitable embodiment, the compound of formula (I) is administered by intrathecal administration. Such administration methods include injecting the compound of the invention into the spinal canal or subarachnoid space so that it reaches the cerebrospinal fluid. This is advantageous for compounds that may not be able to pass through the blood-brain barrier when administered by other routes of administration (such as oral administration).

[0390] Suitable pharmaceutical formulations can be administered intrathecally by continuous infusion, for example, using a catheter or pump, or by a single bolus or by intermittent bolus. For intrathecal administration, the pharmaceutical composition can be administered continuously or intermittently. Intermittent administration can be, for example, administered once every thirty minutes, every hour, every few hours, every 24 hours, every few days (e.g., every 48 or 72 hours), or any combination thereof.

[0391] When the pharmaceutical preparation of the present invention is administered continuously, an implantable delivery device, such as an implantable pump, can be used. Examples of such delivery devices include devices that can be implanted subcutaneously in the body or skull and provide access ports that can deliver the pharmaceutical preparation to nerves or the brain.

[0392] When administered as a single dose or intermittently to adults, the intrathecal dose of the present invention is typically less than 1 mg per kilogram of body weight, for example less than 500 μg, for example less than 250 μg, when used for the indicated effect. For adults, the intrathecal dose of the present invention is typically less than 250 μg / kg body weight / hour, for example less than 125 μg / kg body weight / hour when administered continuously.

[0393] In another suitable embodiment, the compound of formula (I) is administered by intranasal, inhalation (including fine particle dust or mist, which can be produced by various types of metered dose pressurized aerosols, nebulizers or insufflators) or insufflation administration. Such administration methods allow the administration of low doses of the compound of the invention, which can result in a reduction in side effects. For example, the compound of the invention can be used in a daily dose range of 10 to 0.01 μg, suitably 1 to 0.01 μg, more suitably as low as 0.1 μg (100 ng).

[0394] The preparation can be conveniently present in the form of unit dosage form and can be prepared by any method known in the pharmaceutical field. All methods include the step of combining the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally, the preparation is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired preparation.

[0395] Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, pills, or tablets, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid, such as an elixir, tincture, suspension, or syrup; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0396] Tablets can be prepared by compression or molding, optionally using one or more adjuvants. Compressed tablets can be prepared by compressing a free-flowing form such as a powder or granular active ingredient optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide a slow or controlled release of the active ingredient therein. The compound of formula (I) can, for example, be used in a form suitable for immediate release or extended release. By using a suitable pharmaceutical composition comprising the compound of the present invention, or particularly in the case of extended release, by using a device such as a subcutaneous implant or an osmotic pump, immediate release or extended release can be achieved. The compound of the present invention can also be used by liposomes.

[0397] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as suspending agents, methylcellulose as viscosity enhancers, and sweeteners or flavorings, such as those known in the art; and immediate release tablets, which may contain, for example, microcrystalline cellulose, calcium hydrogen phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants, such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compound of formula (I) may also be delivered orally by sublingual and / or oral administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that can be used. Exemplary compositions include those formulated with fast-dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. High molecular weight excipients, such as cellulose (avicel) or polyethylene glycol (PEG) can also be included in these preparations. Such preparations can also include excipients that contribute to mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (such as Gantrez), and controlled-release materials, such as polyacrylic acid copolymers (such as Carbopol 934). For ease of manufacture and use, lubricants, glidants, flavorings, colorants and stabilizers can also be added. Lubricants for these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carriers such as ethanol, glycerol, water, etc.

[0398] The compounds of formula (I) can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin) or phosphatidylcholine (lecithin).

[0399] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The preparation may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, just before use. Immediate injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic monoglycerides or diglycerides, and fatty acids, including oleic acid or Cremaphor.

[0400] Exemplary compositions for intranasal, aerosol, or inhalation administration include saline solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents, such as those known in the art.

[0401] Formulations for rectal administration may be presented as suppositories containing conventional carriers such as cocoa butter, synthetic glycerides, or polyethylene glycols. Such carriers are generally solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0402] Formulations for topical administration in the mouth, e.g., buccal or sublingual, include lozenges containing the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, as well as pastilles containing the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0403] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0404] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0405] Compounds of formula (I) are expected to have the following advantageous properties: mPTP inhibitory activity as demonstrated in the assays of Biological Example 1 (preferably, pIC 50 Values ​​of 6.0 and above and / or pIC in rat brain assay 50 value of 7.0 and above).

[0406] entry

[0407] The present invention is further defined by the following items.

[0408] Item 1. Compound of formula (I):

[0409]

[0410] in,

[0411] R 1a Is H or C 1-4 alkyl;

[0412] R 1b Is H or C 1-4 alkyl;

[0413] R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0414] R 3a is H, halogen or C 1-4 alkyl;

[0415] R 4a Is H or C 1-4 alkyl;

[0416] R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen;

[0417] R 6a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0418] x is 0, 1, or 2;

[0419] AA is phenyl or with C 5-6 Cycloalkyl-fused phenyl, optionally substituted with one or more AA 1 replace;

[0420] AA 1 Halogen, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r NHSO2R t ;

[0421] R q Is H or C 1-4 alkyl;

[0422] R r Is H or C 1-4 alkyl;

[0423] R t It is C 1-4 alkyl;

[0424] BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl may be optionally replaced by one or more B 1A replace; and

[0425] B 1A Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo (=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH);

[0426] or a salt and / or solvate thereof, with the proviso that the compound of formula (I) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

[0427]

[0428] Item 2. The compound of formula (IB) according to claim 1:

[0429]

[0430] in,

[0431] R 1a Is H or C1-4 alkyl;

[0432] R 1b Is H or C 1-4 alkyl;

[0433] R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0434] R 3a is H, halogen or C 1-4 alkyl;

[0435] R 4a Is H or C 1-4 alkyl;

[0436] R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen;

[0437] R 6a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0438] x is 0, 1, or 2;

[0439] AA is phenyl or with C 5-6 Cycloalkyl-fused phenyl, optionally substituted with one or more AA 1 replace;

[0440] AA 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6Cycloalkyl, CN, OH, NR q R r NHSO2R t ;

[0441] R q Is H or C 1-4 alkyl;

[0442] R r Is H or C 1-4 alkyl;

[0443] R t It is C 1-4 alkyl;

[0444] BA is a monocyclic or bicyclic heterocyclic ring or a monocyclic or bicyclic heteroaryl ring, which may be optionally replaced by one or more B 1A replace; and

[0445] and

[0446] B 1A Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 or a salt and / or solvate thereof, with the proviso that the compound of formula (IB) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

[0447]

[0448] Item 3. The compound or salt and / or solvate according to Item 1 or Item 2, which is the compound or a pharmaceutically acceptable salt and / or solvate thereof.

[0449] Item 4. The pharmaceutically acceptable salts and solvates according to Item 3.

[0450] Item 5. The pharmaceutically acceptable salt according to Item 3.

[0451] Item 6. The pharmaceutically acceptable solvate according to Item 3.

[0452] Item 7. The compound according to Item 1.

[0453] Item 8. The compound according to any one of Items 1 to 7, or a salt and / or solvate thereof, which is a compound of formula (IB):

[0454]

[0455] or a salt and / or solvate thereof.

[0456] Item 9. The compound according to any one of Items 1, 2, and 8, or a salt and / or solvate thereof, wherein R 1a It’s H.

[0457] Item 10. The compound according to any one of Items 1, 2 or 8, or a salt and / or solvate thereof, wherein R 1a It is C 1-4 Alkyl groups, such as methyl.

[0458] Item 11. The compound according to any one of Items 1, 2, or 8 to 10, or a salt and / or solvate thereof, wherein R 1b It’s H.

[0459] Item 12. The compound according to any one of Items 1, 2, or 8 to 10, or a salt and / or solvate thereof, wherein R 1b It is C 1-4 Alkyl groups, such as methyl.

[0460] Item 13. The compound according to any one of Items 1, 2, or 8 to 12, or a salt and / or solvate thereof, wherein R 2a It’s H.

[0461] Item 14. The compound according to any one of Items 1, 2, or 8 to 12, or a salt and / or solvate thereof, wherein R 2a It's a halogen.

[0462] Item 15. The compound according to any one of Items 1, 2, or 8 to 12, or a salt and / or solvate thereof, wherein R 2a It is C 1-4 alkyl.

[0463] Item 16. The compound according to any one of Items 1, 2, or 8 to 12, or a salt and / or solvate thereof, wherein R 2a It is C 1-4 Halogenated alkyl.

[0464] Item 17. The compound according to any one of Items 1, 2, or 8 to 16, or a salt and / or solvate thereof, wherein R 3a It’s H.

[0465] Item 18. The compound according to any one of Items 1, 2, or 8 to 16, or a salt and / or solvate thereof, wherein R 3a It's a halogen.

[0466] Item 19. The compound according to any one of Items 1, 2, or 8 to 16, or a salt and / or solvate thereof, wherein R 3a It is C 1-4 alkyl.

[0467] Item 20. The compound according to any one of Items 1, 2, or 8 to 19, or a salt and / or solvate thereof, wherein R 4a It’s H.

[0468] Item 21. The compound according to any one of Items 1, 2, or 8 to 19, or a salt and / or solvate thereof, wherein R 4a It is C 1-4 Alkyl groups, such as methyl.

[0469] Item 22. The compound according to any one of Items 1, 2, or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It’s H.

[0470] Item 23. The compound according to any one of Items 1, 2 or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 1-6 Alkyl groups, such as methyl.

[0471] Item 24. The compound according to any one of Items 1, 2, or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 1-6 Halogenated alkyl.

[0472] Item 25. The compound according to any one of Items 1, 2 or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 1-6 Alkoxy.

[0473] Item 26. The compound according to any one of Items 1, 2, or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 1-6 Halogenated alkoxy.

[0474] Item 27. The compound according to any one of Items 1, 2 or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 2-6 Alkenyl.

[0475] Item 28. The compound according to any one of Items 1, 2 or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 2-6 Halogenated alkenyl.

[0476] Item 29. The compound according to any one of Items 1, 2 or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 0-6 Alkylene (C 3-6 cycloalkyl).

[0477] Item 30. The compound according to any one of items 1, 2 or 8 to 21, or a salt and / or solvate thereof, wherein R 5a It is C 0-6 Alkylene (OH).

[0478] Item 31. The compound according to any one of Items 1, 2, or 8 to 19, or a salt and / or solvate thereof, wherein R 4a and R 5a Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, for example cyclobutyl.

[0479] Item 32. The compound according to any one of Items 1, 2 or 8 to 31, or a salt and / or solvate thereof, wherein R 6a It’s H.

[0480] Item 33. The compound according to any one of Items 1, 2 or 8 to 31, or a salt and / or solvate thereof, wherein R 6a It's a halogen.

[0481] Item 34. The compound according to any one of Items 1, 2, or 8 to 31, or a salt and / or solvate thereof, wherein R 6a It is C 1-4 alkyl.

[0482] Item 35. The compound according to any one of Items 1, 2 or 8 to 31, or a salt and / or solvate thereof, wherein R 6a It is C 1-4 Halogenated alkyl.

[0483] Item 36. The compound according to any one of Items 1, 2, or 8 to 31, or a salt and / or solvate thereof, wherein R 6a It is C 1-4 Alkoxy.

[0484] Item 37. The compound according to any one of Items 1, 2 or 8 to 31, or a salt and / or solvate thereof, wherein R 6a It is C 1-4 Halogenated alkoxy.

[0485] Item 38. The compound according to any one of items 1, 2, or 8 to 37, or a salt and / or solvate thereof, wherein x is 1.

[0486] Item 39. The compound according to any one of items 1, 2, or 8 to 37, or a salt and / or solvate thereof, wherein x is 2.

[0487] Item 40. The compound according to any one of items 1, 2 or 8 to 39, or a salt and / or solvate thereof, wherein AA is phenyl.

[0488] Item 41. The compound according to any one of Items 1, 2 or 8 to 39, or a salt and / or solvate thereof, wherein AA is 5-6 Cycloalkyl-fused phenyl.

[0489] Item 42. The compound according to item 40 or 41, or a salt and / or solvate thereof, wherein AA is replaced by one or more (eg 1, 2 or 3, such as 1 or 2, in particular 1) AA 1 replace.

[0490] Item 43. The compound according to Item 42, or a salt and / or solvate thereof, wherein at least one AA 1 It's a halogen.

[0491] Item 44. The compound according to Item 43, or a salt and / or solvate thereof, wherein at least one AA 1 It's F.

[0492] Item 45. The compound according to any one of Items 42 to 44, or a salt and / or solvate thereof, wherein at least one AA 1 It is C 2-6 Alkynyl.

[0493] Item 46. The compound according to any one of Items 42 to 45, or a salt and / or solvate thereof, wherein at least one AA 1 It is C 1-6 alkyl.

[0494] Item 47. The compound according to any one of Items 42 to 46, or a salt and / or solvate thereof, wherein at least one AA 1 It is C 1-6 Halogenated alkyl.

[0495] Item 48. The compound according to any one of Items 42 to 47, or a salt and / or solvate thereof, wherein at least one AA 1 It is C 1-6 Alkoxy.

[0496] Item 49. The compound according to any one of Items 42 to 48, or a salt and / or solvate thereof, wherein at least one AA 1 It is C 1-6 Halogenated alkoxy.

[0497] Item 50. The compound according to any one of Items 42 to 49, or a salt and / or solvate thereof, wherein at least one AA 1 It is C 3-6 Cycloalkyl.

[0498] Item 51. The compound according to any one of Items 42 to 50, or a salt and / or solvate thereof, wherein at least one AA 1 It is CN.

[0499] Item 52. The compound according to any one of Items 42 to 51, or a salt and / or solvate thereof, wherein at least one AA 1 It is NR q R r .

[0500] Item 53. The compound according to Item 52, or a salt and / or solvate thereof, wherein R q It’s H.

[0501] Item 54. The compound according to Item 52, or a salt and / or solvate thereof, wherein R q It is C 1-4 alkyl.

[0502] Item 55. The compound according to any one of Items 42 to 54, or a salt and / or solvate thereof, wherein at least one AA 1 It is NHSO2R t .

[0503] Item 56. The compound according to Item 40 or 41, or a salt and / or solvate thereof, wherein AA is unsubstituted.

[0504] Item 57. The compound according to any one of Items 1, 2 or 8 to 56, or a salt and / or solvate thereof, wherein BA is a monocyclic heterocycle.

[0505] Item 58. The compound according to Item 57, or a salt and / or solvate thereof, wherein BA is a 5-membered monocyclic heterocycle.

[0506] Item 59. The compound according to any one of Items 1, 2 or 8 to 56, or a salt and / or solvate thereof, wherein BA is a bicyclic heterocycle.

[0507] Item 60. The compound according to any one of Items 1, 2, or 8 to 56, or a salt and / or solvate thereof, wherein BA is a monocyclic heteroaryl.

[0508] Item 61. The compound according to Item 60, or a salt and / or solvate thereof, wherein BA is a 6-membered monocyclic heteroaryl group.

[0509] Item 62. The compound according to any one of items 1, 2 or 8 to 56, or a salt and / or solvate thereof, wherein BA is a bicyclic heteroaryl.

[0510] Item 63. The compound according to any one of Items 57 to 62, or a salt and / or solvate thereof, wherein BA is replaced by one or more (eg 1, 2 or 3, such as 1 or 2, in particular 1) B 1A replace.

[0511] Item 64. The compound according to Item 63, or a salt and / or solvate thereof, wherein at least one B 1A It's a halogen.

[0512] Item 65. The compound according to Item 63 or Item 64, or a salt and / or solvate thereof, wherein at least one B 1A It is C 1-6 alkyl.

[0513] Item 66. The compound according to Item 63 or Item 65, or a salt and / or solvate thereof, wherein at least one B 1A It's methyl.

[0514] Item 67. The compound according to any one of Items 63 to 66, or a salt and / or solvate thereof, wherein at least one B 1A It is C 1-6 Halogenated alkyl.

[0515] Item 68. The compound according to any one of Items 63 to 67, or a salt and / or solvate thereof, wherein at least one B 1A It is oxo (C=O).

[0516] Item 69. The compound according to any one of Items 63 to 68, or a salt and / or solvate thereof, wherein at least one B 1A It is C 1-6 Alkoxy.

[0517] Item 70. The compound according to any one of Items 63 to 69, or a salt and / or solvate thereof, wherein at least one B 1A It is C 1-6 Halogenated alkoxy.

[0518] Item 71. The compound according to any one of Items 63 to 70, or a salt and / or solvate thereof, wherein at least one B 1A It is C 0-6 Alkylene (OH), such as OH.

[0519] Item 72. The compound according to any one of Items 57 to 62, or a salt and / or solvate thereof, wherein BA is unsubstituted.

[0520] Item 73. The compound according to any one of items 1, 2 or 8 to 72, or a salt and / or solvate thereof, wherein BA is selected from:

[0521]

[0522] in,

[0523] B 1B Is H or C 1-6 Alkyl groups, such as methyl;

[0524] B 2B Is H or C 1-6 an alkyl group, such as a methyl group; and

[0525] B 2B It is C 0-6 Alkylene (OH), such as OH.

[0526] Item 74. The compound according to Item 73, or a salt and / or solvate thereof, wherein BA is:

[0527]

[0528] Item 75. The compound according to Item 73, or a salt and / or solvate thereof, wherein BA is:

[0529]

[0530] Item 76. The compound according to Item 73, or a salt and / or solvate thereof, wherein BA is:

[0531]

[0532] Item 77. The compound according to any one of Items 1, 2 or 8, or a salt and / or solvate thereof, which is a compound of formula (IB'):

[0533]

[0534] in

[0535] R 4a’ It is C 1-4 alkyl;

[0536] R 5a’ It is C 1-4 Alkyl; or R 4a’ and R 5a’ Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0537] B 1A’ is a halogen, such as F; and

[0538] BA' selected or a salt and / or solvate thereof.

[0539] Item 78. The compound according to Item 77, or a salt and / or solvate thereof, wherein R 4a’ and R 5a’ Together with the atoms to which they are attached they form a cyclobutyl ring.

[0540] Item 79. The compound according to Item 77 or Item 78, or a salt and / or solvate thereof, wherein BA' is

[0541] Item 80. The compound according to any one of Items 1, 2 or 8, or a salt and / or solvate thereof, selected from:

[0542] (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0543] (4-Hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0544] (3,3-Dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone;

[0545] 2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0546] (S)-(6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0547] 6-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0548] 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0549] 6-(3,3-Dimethyl-4-phenylpiperidin-1-carbonyl)pyrazin-2(1H)-one;

[0550] (R)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0551] (S)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0552] 5-(8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; and 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0553] or a salt and / or solvate thereof.

[0554] Item 81. The compound according to any one of Items 1, 2 or 8, or a salt and / or solvate thereof, which is selected from: (6-hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0555] (4-Hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0556] (3,3-Dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone;

[0557] 2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0558] (S)-2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0559] (R)-2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0560] (S)-(6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0561] (R)-(6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0562] 6-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0563] 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0564] 6-(3,3-Dimethyl-4-phenylpiperidin-1-carbonyl)pyrazin-2(1H)-one;

[0565] (S)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0566] (R)-6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0567] 5-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0568] 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0569] (S)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane;

[0570] (R)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane;

[0571] (R),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0572] (S),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0573] (R),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0574] (S),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one;

[0575] (S)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0576] (R)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0577] (S)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one;

[0578] (R)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one;

[0579] rac-2-{8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-3H-pyrimidin-4-one;

[0580] (S)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0581] (R)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one;

[0582] (S)-4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile;

[0583] (R)-4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile;

[0584] (S)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one;

[0585] (R)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one;

[0586] (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0587] (S)-(3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone;

[0588] (R)-(3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octane-6-yl)methanone; 3-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-oxadiazol-5-one;

[0589] (R),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0590] (S),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0591] (R),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0592] (S),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one;

[0593] (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one;

[0594] (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one;

[0595] (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one;

[0596] (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one;

[0597] (S)-6-(8-(4-methoxyphenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(4-methoxyphenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0598] (R)-6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0599] (S)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0600] (R)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0601] (S)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0602] (R)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0603] (S)-6-8-(5-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-8-(5-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-6-(8-(3-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0604] (R)-3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0605] (S)-6-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0606] (R)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0607] (S)-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0608] (R)-6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0609] (S)-(8-(2,3-Difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0610] (R)-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0611] (S)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0612] (R)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0613] (S)-3-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0614] (R)-3-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0615] (S)-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0616] (R)-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0617] (S)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0618] (R)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0619] (S)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0620] (R)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0621] (S)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0622] (R)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one;

[0623] (S)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0624] (R)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone;

[0625] (S)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0626] (R)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0627] (S)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0628] (R)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one;

[0629] (S)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; and

[0630] (R)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one,

[0631] or a salt and / or solvate thereof.

[0632] Item 82. A pharmaceutical composition comprising a compound according to any one of items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso to formula (I) does not apply.

[0633] Item 83. A compound according to any one of Items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, wherein the proviso to formula (I) does not apply.

[0634] Item 84. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of items 3 to 81 for use in treating or preventing a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, wherein the proviso to formula (I) does not apply.

[0635] Item 85. Use of a compound according to any one of Items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for the treatment or prevention of a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, wherein the proviso of formula (I) does not apply.

[0636] Item 86. A method for preventing or treating a disease or disorder in a subject in which mPTP inhibition provides a therapeutic or preventive effect, the method comprising administering to the subject in need thereof an effective amount of a compound according to any one of Items 3 to 81, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso to Formula (I) does not apply.

[0637] Item 87. A compound for use according to any one of items 3 to 86, or a pharmaceutically acceptable salt and / or solvate thereof, a use or a method, wherein the disease or disorder is selected from degenerative or neurodegenerative diseases, central nervous system disorders, ischemia-reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, geriatric diseases and renal diseases.

[0638] Item 88. A compound for use according to any one of items 3 to 86, or a pharmaceutically acceptable salt and / or solvate thereof, a use or a method, wherein the disease or disorder is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, ischemia-reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a geriatric disease, a kidney disease, hearing loss, an eye disease or disorder, Charcot-Marie-Tooth disease (CMT1a) and Leigh syndrome.

[0639] Item 89. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is a degenerative or neurodegenerative disease, such as Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury (e.g., concussion) and Friedreich's ataxia.

[0640] Item 90. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is a central nervous system disease, such as AIDS dementia syndrome, depression, schizophrenia and epilepsy.

[0641] Item 91. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is ischemia-reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury and organ damage during transplantation.

[0642] Item 92. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive impairment and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease.

[0643] Item 93. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive impairment and other diabetes-related conditions, obesity and eating behavior, diabetic neuropathy and non-alcoholic fatty liver disease.

[0644] Item 94. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis.

[0645] Item 95. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is a geriatric disease, such as bone repair, senile bone fragility in osteoporosis, and sarcopenia.

[0646] Item 96. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is a kidney disease, such as chronic kidney disease associated with APOL1 gene variants and chronic kidney disease.

[0647] Item 97. The compound for use according to Item 88, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method, wherein the disease or disorder is hearing loss, such as hearing loss caused by aging, noise, concussion, traumatic brain injury (TBI), drug-induced hearing loss, and / or hereditary hearing loss, including spinal muscular atrophy (SMA) syndrome (SMA1, SMA2, SMA3 and SMA4, also known as types I, II, III and IV).

[0648] Item 98. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Item 88, wherein the disease or disorder is an ocular disease or disorder, such as age-related macular degeneration.

[0649] Item 99. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method according to Item 88, wherein the disease or disorder is Charcot-Marie-Tooth disease (CMT1a).

[0650] Item 100. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method according to Item 88, wherein the disease or disorder is Leigh's syndrome.

[0651] Item 101. The compound according to any one of Items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a mitochondrial disease, wherein the proviso to Formula (I) does not apply.

[0652] Item 102. A compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of items 3 to 81 for use in treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, wherein the proviso of formula (I) does not apply.

[0653] Item 103. Use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to any one of items 3 to 81 for the preparation of a medicament for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as neurodegeneration associated with TDP-43 proteinopathy, wherein the precondition of formula (I) does not apply.

[0654] Item 104. A method for treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as neurodegeneration associated with a TDP-43 proteinopathy, comprising administering to a subject in need thereof an effective amount of a compound according to any one of Items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso to Formula (I) does not apply.

[0655] Item 105. The compound or pharmaceutically acceptable salt and / or solvate for use, use or method according to any one of items 102 to 104, wherein the disease or disorder is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial-onset sensory and motor neuron disease, primary lateral sclerosis, progressive muscular dystrophy, inclusion body myopathy associated with early-onset Paget's disease of bone and frontotemporal degeneration, Perry's disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy and age-related TDP-43 with sclerosis of the brain.

[0656] Item 106. A compound according to any one of Items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease or disorder associated with fibrosis, wherein the proviso to Formula (I) does not apply.

[0657] Item 107. Use of a compound according to any one of items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating or preventing a disease or disorder associated with fibrosis, wherein the proviso of formula (I) does not apply.

[0658] Item 108. A method for treating or preventing a disease or disorder associated with fibrosis, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of Items 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso to Formula (I) does not apply.

[0659] Item 109. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, the use or the method according to any one of items 106 to 108, wherein the disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis.

[0660] Item 110. A method for preparing a compound of formula (I) according to any one of items 1, 2 or items 8 to 76, the method comprising: reacting a compound of formula (IIB) or a salt thereof,

[0661]

[0662] where R 1a 、R 1b 、R 2a 、R 3a 、R 4a 、R 5a 、R 6a , AA and x are as defined for the compound of formula (I),

[0663] Reaction with a compound of formula (IIIB) or a salt thereof

[0664]

[0665] wherein BA is as defined for the compound of formula (I).

[0666] Item 111. A compound selected from the group consisting of:

[0667] - Compounds of formula (IIB):

[0668]

[0669] where R 1a 、R 1b 、R 2a 、R 3a 、R 4a 、R 5a 、R 6a , x and AA are as defined in any of the above items;

[0670] - Compounds of formula (IIIB):

[0671]

[0672] Where BA is defined in any of the above items;

[0673] - Compound of formula (IVB):

[0674]

[0675] where R 4a 、R 5a 、R 6a and AA as defined in any of the above items;

[0676] - Compounds of formula (VIIB):

[0677]

[0678] where R 4a 、R 5a 、R 6a and AA as defined in any of the above items;

[0679] - Compound of formula (VIIIB):

[0680]

[0681] where R 4a 、R 5a 、R 6a and AA as defined in any of the above items;

[0682] - Compounds of formula (XIB):

[0683]

[0684] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA as defined in any of the above items;

[0685] - Compounds of formula (XIIB):

[0686]

[0687] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA as defined in any of the above items;

[0688] - Compounds of formula (XIIIB):

[0689]

[0690] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA as defined in any of the above clauses; and

[0691] - Compounds of formula (XIVB):

[0692]

[0693] where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA is as defined in any of the above clauses, and P is a nitrogen protecting group, such as BOC (tert-butoxycarbonyl), or a salt thereof, such as a pharmaceutically acceptable salt.

[0694] The present invention is further illustrated by the following non-limiting examples. Example

[0695] The present invention is illustrated by the compounds described below. The following examples describe laboratory syntheses of specific compounds of the present invention and are not intended to limit the scope of the compounds or methods of the present invention in any way. It should be understood that although specific reagents, solvents, temperatures and times are used, there are many possible equivalent alternatives that can be used to produce similar results. The present invention is intended to include such equivalent schemes.

[0696] General experimental details

[0697] Unless otherwise stated, raw materials, reagents and solvents were obtained from commercial suppliers and used without further purification. Unless otherwise stated, all compounds with chiral centers are racemic. When a reaction is described as being carried out in a manner similar to the previously described reaction, the general reaction conditions used are essentially the same. The post-processing conditions used are standard types in the art, but can be adjusted between different reactions. The starting materials may not necessarily be prepared from the batches mentioned. The synthesized compounds can have various purities, for example 85%-99%. In some cases, the calculation of mole numbers and yields can be adjusted for this.

[0698] The purity of the final compounds was confirmed by HPLC / MS analysis and determined to be at least ≥90%, and in the vast majority of cases ≥95%. Analytical LCMS was performed using the instrumentation shown in Table 1 or Table 2. 1 H NMR was recorded at 300 K using a Bruker 300 MHz instrument (ADVANCE III and ADVANCE III HD) or a Bruker 400 MHz instrument (Avance Neo 400).

[0699] Table 1: Analytical LC-MS conditions

[0700]

[0701]

[0702] Table 2: Analytical LC-MS conditions

[0703]

[0704]

[0705] Synthesis of Example Compounds

[0706] Abbreviations

[0707] AcOH acetic acid

[0708] ADP adenosine 5'-diphosphate

[0709] Boc2O Di-tert-butyl dicarbonate

[0710] BOC tert-Butoxycarbonyl

[0711] BSA bovine serum albumin

[0712] CDI Carbonyldiimidazole

[0713] CH3CN acetonitrile

[0714] Cs2CO3 cesium carbonate

[0715] DAST Diethylaminosulfur trifluoride

[0716] DBU Diazabicyclo(5.4.0)undec-7-ene

[0717] DCM dichloromethane

[0718] DIPEA Diisopropylethylamine

[0719] DMF dimethylformamide

[0720] DMSO dimethyl sulfoxide

[0721] DPBS Dulbecco's Phosphate Buffered Saline

[0722] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0723] EDTA Ethylenediaminetetraacetic acid

[0724] EGTA Ethylene glycol tetraacetic acid

[0725] Et3N triethylamine

[0726] EtOAc

[0727] EtOH

[0728] ES electrospray

[0729] FA Formic acid

[0730] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0731] HCl

[0732] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[0733] HOBt Hydroxybenzotriazole

[0734] HPLC high-performance liquid chromatography

[0735] K2CO3 potassium carbonate

[0736] K3PO4 potassium phosphate

[0737] LAH lithium aluminum hydride

[0738] LC-MS liquid chromatography-mass spectrometry

[0739] LDA lithium diisopropylamide

[0740] LiHMDS Lithium Bis(trimethylsilyl)amide

[0741] m multiplet

[0742] m / z mass-to-charge ratio

[0743] M molar concentration

[0744] mg milligrams

[0745] MgSO4 magnesium sulfate

[0746] MeCN Acetonitrile

[0747] MeOH methanol

[0748] MHz Megahertz

[0749] mmol millimole

[0750] MOPS 3-(N-morpholino)propanesulfonic acid

[0751] MSA Methanesulfonic acid

[0752] NaHCO3 sodium bicarbonate

[0753] NaOAc sodium acetate

[0754] NaOH sodium hydroxide

[0755] Na2SO4 sodium sulfate

[0756] NBS N-bromosuccinimide

[0757] NCS N-chlorosuccinimide

[0758] NH4Cl ammonium chloride

[0759] nm nanometer

[0760] NMI N-Methylimidazole

[0761] NMR Nuclear Magnetic Resonance

[0762] PE petroleum ether

[0763] Pd(OAc)2 Palladium(II) acetate

[0764] Pd(dppf)Cl2.CH2Cl2 Bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane

[0765] Pd(dppf)Cl2 Bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0766] ppm parts per million

[0767] PTSA p-Toluenesulfonic acid

[0768] PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[0769] RT Room temperature

[0770] o / n overnight (16h)

[0771] SFC Supercritical Fluid Chromatography

[0772] TBAF Tetra-n-butylammonium fluoride

[0773] TBD Triazabicyclodecene

[0774] TCFH N′-Tetramethylformamidinium hexafluorophosphate

[0775] TEA triethylamine

[0776] TFA trifluoroacetic acid

[0777] THF Tetrahydrofuran

[0778] THP Tetrahydropyranyl

[0779] T3P Propanephosphonic Anhydride

[0780] TMSOTf trimethylsilyl trifluoromethanesulfonate

[0781] Intermediate 1: 1-Methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid

[0782]

[0783] To a 1 L round-bottom flask was added methylhydrazine (35 g, 759.66 mmol, 1.00 equiv), KCO (209.98 g, 1519.33 mmol, 2.00 equiv), EtOH (350 mL), and ethyl 2-amino-2-thioxoacetate (101.16 g, 759.66 mmol, 1.00 equiv) at room temperature. The mixture was stirred overnight, filtered, and the filter cake was washed with EtOH (3 x 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using PE / EtOAc (1:1) as the eluent to afford ethyl 2-imino-2-(2-methylhydrazinyl)acetate (7 g) as a yellow oil.

[0784]

[0785] To a 500 mL round-bottom flask was added ethyl 2-imino-2-(2-methylhydrazinyl)acetate (7 g, 48.22 mmol, 1.00 equiv), DCM (150 mL), and CDI (23.46 g, 144.67 mmol, 3.00 equiv) at room temperature. The mixture was stirred overnight and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This afforded ethyl 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylate (4.5 g, 54% yield) as a light yellow solid.

[0786]

[0787] To a 250 mL round-bottom flask was added ethyl 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylate (2.5 g, 14.61 mmol, 1.00 equiv), EtOH (100 mL) and NaOH (1.75 g, 43.82 mmol, 3.00 equiv) at room temperature. The mixture was stirred at room temperature overnight. The mixture was acidified to 5% with concentrated hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (1.7 g, 81% yield) as a white solid.

[0788] LC-MS (ES, m / z): [MH] - =142

[0789] Example 1(a): (5-Hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone

[0790]

[0791] Into an 8-mL sealed tube was placed 8-phenyl-6-azaspiro[3.4]octane (70.00 mg, 0.374 mmol, 1.00 equiv), 5-methoxypyridine-3-carboxylic acid (57.24 mg, 0.374 mmol, 1.00 equiv), DIPEA (120.62 mg, 0.935 mmol, 2.5 equiv), EDCI (107.48 mg, 0.561 mmol, 1.50 equiv), and DMF (2.00 mL). The resulting solution was stirred at room temperature for 6 hours. The mixture was purified by preparative HPLC. This afforded 13 mg of 6-(5-methoxypyridine-3-carbonyl)-8-phenyl-6-azaspiro[3.4]octane as a white solid. LC-MS (ES, m / z): [M+H] + =309;

[0792] 1 H-NMR (300MHz, DMSO-d6, ppm): 8.21-8.17(m,2H),7.41-7.20(m,6H),3.82-3.75(m,2H),3.73-3.56(m,2H),3.32-3.23(m,1H),2.02-1.53(m,6H).

[0793] Examples 1(b) and 1(c): (5-Hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer A and (5-Hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer B

[0794]

[0795] To a 25-mL round-bottom flask, place 5-hydroxypyridine-3-carboxylic acid (220.00 mg, 1.58 mmol, 1.00 equiv) and thionyl chloride (10 mL). Stir the resulting solution at 70°C for 12 h. Cool the reaction mixture to room temperature and concentrate the resulting mixture.

[0796] This gave 200 mg (80% yield) of 5-hydroxypyridine-3-carbonyl chloride as a light yellow solid.

[0797]

[0798] At 0 ° C, 8-phenyl-6-azaspiro [3.4] octane hydrochloride (227.22 mg, 1.02 mmol, 1.00 equivalent), DCM (10.00 mL), Et3N (205.53 mg, 2.03 mmol, 2.00 equivalent) were placed in a 25-mL 3-neck round-bottom flask purged with nitrogen and maintained under a nitrogen inert atmosphere. 5-hydroxypyridine-3-carbonyl chloride (160.00 mg, 1.02 mmol, 1.00 equivalent) was added thereto. The resulting solution was stirred at room temperature for 12 h. Then, the reaction was quenched by adding 10 mL of water. The resulting solution was extracted with 2x15 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column together with ethyl acetate / petroleum ether (1 / 3). The racemic product was purified by preparative SFC. This gave 30 mg of (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone enantiomer A as an off-white solid. This gave 33 mg of (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone enantiomer B as an off-white solid.

[0799] Enantiomer A

[0800] LC-MS (ES, m / z): [M+H] + =309;

[0801] H-NMR (300MHz, DMSO-d6, ppm): 10.20 (brs, 1H), 8.24-8.22 (m, 2H), 7.40-7.22 (m, 6H), 3.83-3.57 (m, 4H), 3.28-3.24 (m, 1H), 2.03-1.49 (m, 6H).

[0802] Enantiomer B

[0803] LC-MS (ES, m / z): [M+H]+ =309;

[0804] H-NMR (300MHz, DMSO-d6, ppm): 10.20 (brs, 1H), 8.24-8.22 (m, 2H), 7.40-7.22 (m, 6H), 3.83-3.57 (m, 4H), 3.28-3.24 (m, 1H), 2.03-1.49 (m, 6H).

[0805] One of the enantiomers A and B is (S)-(5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone, and the other is (R)-(5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone.

[0806] Example 2: (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone

[0807]

[0808] 8-Phenyl-6-azaspiro[3.4]octane hydrochloride (30.0 mg, 0.13 mmol, 1.00 eq), 6-hydroxypyrazine-2-carboxylic acid (20.66 mg, 0.15 mmol, 1.10 eq), EDC-HCl (38.56 mg, 0.20 mmol, 1.50 eq), DIPEA (41.93 mg, 0.325 mmol, 2.5 eq), and DMF (2.00 mL) were placed in an 8-mL sealed tube. The resulting solution was stirred at room temperature for 3 h. The mixture was purified by flash preparative HPLC. This yielded 14 mg of 6-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]pyrazin-2-ol as an off-white semisolid. LC-MS (ES, m / z): [M+H] + =310;

[0809] H-NMR (300MHz, DMSO-d6, ppm): 8.26-8.18(m,2H),7.40-7.21(m,5H),3.99-3.67(m,4H),3.30-3.24(m,1H),2.03-1.51(m,6H).

[0810] Example 3: (4-Hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone

[0811]

[0812] 8-Phenyl-6-azaspiro[3.4]octane hydrochloride (30.0 mg, 0.14 mmol, 1.00 eq), 4-hydroxypyridine-2-carboxylic acid (18.65 mg, 0.14 mmol, 1.00 eq), DMF (3.00 mL), EDC-HCl (38.56 mg, 0.20 mmol, 1.50 eq), and DIPEA (45.15 mg, 0.35 mmol, 2.5 eq) were placed in an 8-mL sealed tube. The resulting solution was stirred at room temperature for 2 h. The mixture was directly purified by flash preparative HPLC. This yielded 16 mg of 2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]pyridin-4-ol as an off-white semisolid. LC-MS (ES, m / z): [M+H] + =309;

[0813] H-NMR (300MHz, DMSO-d6, ppm): 8.59-8.53(m,1H),7.65(s,1H),7.44-7.25(m,6 H),3.92-3.65(m,4H),3.35-3.30(m,1H),2.04-1.92(m,2H),1.83-1.41(m,4H).

[0814] Example 4: (3,3-Dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone

[0815]

[0816] Into a 250-mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere of nitrogen was placed (E)-(2-nitrovinyl)benzene (0.70 g, 4.69 mmol, 1.00 equiv), isobutyraldehyde (1.02 g, 14.08 mmol, 3.00 equiv), EtOH (60 mL), and L-proline (0.11 g, 0.96 mmol, 0.20 equiv). The resulting solution was stirred at 60°C overnight. The reaction mixture was cooled to room temperature. The mixture was concentrated, and the crude product was purified by flash preparative HPLC. This afforded 800 mg (77% yield) of 2,2-dimethyl-4-nitro-3-phenylbutyraldehyde as an off-white solid.

[0817]

[0818] Into a 100-mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere of nitrogen were placed 2,2-dimethyl-4-nitro-3-phenylbutyraldehyde (420.00 mg, 1.90 mmol, 1.00 equiv), AcOH (20.00 mL), and H2O (20.00 mL). Zn (372.49 mg, 5.70 mmol, 3.00 equiv) was then added at 0°C. The resulting solution was stirred at room temperature overnight. The solid was filtered off. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This gave 150 mg (45% yield) of 3,3-dimethyl-4-phenylpyrrolidine as a light yellow oil.

[0819]

[0820] Into an 8-mL sealed tube was placed 3,3-dimethyl-4-phenylpyrrolidine (150.00 mg, 0.86 mmol, 1.00 equiv), 6-hydroxypyrazine-2-carboxylic acid (143.87 mg, 1.03 mmol, 1.20 equiv), EDC.HCl (246.09 mg, 1.28 mmol, 1.5 equiv), DIPEA (270.9 mg, 2.15 mmol, 2.50 equiv) and DMF (4 mL). The resulting solution was stirred at room temperature overnight. The mixture was purified by flash preparative HPLC. This afforded 17.9 mg of 6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2-ol as an off-white solid. LC-MS (ES, m / z): [M+H] + =297;

[0821] H-NMR (300MHz, DMSO-d6, ppm): δ10.21-10.16(m,1H),8.31-8.20(m,2H),7.39-7.22 (m,6H),4.06-3.70(m,2H),3.54-3.11(m,3H),1.07-0.98(m,3H),0.81-0.66(m,3H).

[0822] Example 5(a): 2-Methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0823]

[0824] To a 40-mL vial was placed 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (60.00 mg, 0.420 mmol, 1.00 equiv), DMF (3.00 mL), HATU (191.31 mg, 0.50 mmol, 1.20 equiv), DIPEA (108.38 mg, 0.84 mmol, 2.00 equiv), and 8-phenyl-6-azaspiro[3.4]octane hydrochloride (93.81 mg, 0.420 mmol, 1.00 equiv). The resulting solution was stirred at room temperature for 5 h. The mixture was purified by preparative HPLC. This afforded 40 mg of 2-methyl-5-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-triazol-3-one as an off-white solid. LC-MS (ES, m / z): [M+H] + =313; H-NMR (300MHz, DMSO-d6, ppm): 12.19 (s, 1H), 7.38-7.22 (m, 5H), 4.19-3.6 (m, 4H), 3.31 (s, 3H), 3.23-3.27 (m, 1H), 2.00-1.49 (m, 6H).

[0825] Example 5(b) and Example 5(c): 2-Methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one Enantiomer A and 2-Methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one Enantiomer B

[0826]

[0827] The enantiomers were separated by preparative HPLC using the following conditions: (column: CHIRALCEL OJ-3, 50*4.6 mm, 3 um OJ30CC-QK005; mobile phase: 70% EtOH (containing 0.2% MSA) / hexane; flow rate: 25 mL / min.; wavelength: 254 nm, to give:

[0828] Example 5(b) Enantiomer A was isolated (Rt 5.5 min) as an off-white solid and identified as 2-methyl-5-[(8S)-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-triazol-3-one (24 mg).

[0829] LCMS (ES, m / z): 313 [M+H] + , method LCMS2.

[0830] 1H NMR(400MHz,DMSO-d6,ppm)δ11.96(br,s,1H),7.40-7.35(m,2H),7.32-7.20(m,3H),4.24-4.05(m,1H),3.97(q,J=11.7Hz,1H),3.83- 3.79(m,1H),3.67(d,J=1.6Hz,1H),3.39-3.35(m,3H),3.30-3.26(m,1H),1.99(t,J=7.6Hz,2H),1.91-1.69(m,2H),1.71-1.44(m,2H).

[0831] Example 5(c) Enantiomer B was isolated (Rt 11.2 min) as an off-white solid and identified as 2-methyl-5-[(8R)-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-triazol-3-one (26 mg).

[0832] LCMS (ES, m / z): 313 [M+H] + , method LCMS2.

[0833] 1H NMR(400MHz,DMSO-d6,ppm)δ12.19(br,s,1H),7.42-7.33(m,2H),7.31-7.17(m,3H),4.20-4.06(m,1H),3.97(q,J=11.8Hz,1H),3.86 -3.71(m,1H),3.69-3.61(m,1H),3.39-3.35(m,3H),3.30-3.26(m,1H),1.99(t,J=7.6Hz,2H),1.87-1.72(m,2H),1.72-1.42(m,2H).

[0834] One of the enantiomers A and B is (S)-2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, and the other is (R)-2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0835] Examples 6a and 6b: (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer A and (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer B

[0836]

[0837] (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone (Example 65, 45 mg) was purified by preparative SFC to give (6-hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer A (13 mg) as an off-white solid.

[0838] LC-MS enantiomer A (ES, m / z): [M+H] + =310;

[0839] LC-MS enantiomer B (ES, m / z): [M+H] + =310.

[0840] H-NMR enantiomer A (300 MHz, DMSO-d6, ppm) δ 8.31-8.11 (m, 2H), 7.40-7.19 (m, 5H), 4.07-3.62 (m, 4H), 3.28-3.25 (m, 1H), 2.05-1.88 (m, 2H), 1.87-1.41 (m, 4H)

[0841] H-NMR enantiomer B (300 MHz, DMSO-d6, ppm) δ 8.31-8.11 (m, 2H), 7.40-7.19 (m, 5H), 4.07-3.62 (m, 4H), 3.28-3.25 (m, 1H), 2.05-1.88 (m, 2H), 1.87-1.41 (m, 4H)

[0842] One of the enantiomers A and B is (S)-(6-hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone, and the other is (R)-(6-hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone.

[0843] Example 7: 6-(8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one

[0844]

[0845] To a solution of 2-fluoro-phenylacetonitrile (3 g, 22.20 mmol, 1.00 equiv) in DMSO (30 mL) at 10°C was added sodium hydride (60% in oil, 1.33 g, 33.30 mmol, 1.50 equiv). The mixture was stirred for 15 min. 1-Bromocyclobutane-1-carboxylic acid ethyl ester (5.06 g, 24.42 mmol, 1.10 equiv) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched, extracted with EtOAc (2 x 50 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to afford 1-[cyano(2-fluorophenyl)methyl]cyclobutane-1-carboxylic acid ethyl ester (2.8 g, 48% yield) as a light yellow oil.

[0846]

[0847] In a pressure vessel, Raney nickel (0.25 g, 2.87 mmol, 0.30 equiv) was added to a solution of ethyl 1-[cyano(2-fluorophenyl)methyl]cyclobutane-1-carboxylate (2.50 g, 9.57 mmol, 1.00 equiv) in 20 mL of MeOH. The mixture was purged with nitrogen and then pressurized to 30 atm with hydrogen at 60 ° C for 18 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 8-(2-fluorophenyl)-6-azaspiro[3.4]octane-5-one (1 g, 48% yield) as a light yellow oil.

[0848]

[0849] To a stirred solution of 8-(2-fluorophenyl)-6-azaspiro[3.4]octan-5-one (400 mg, 1.82 mmol, 1.00 equiv) in THF (10 mL) at 0°C under a nitrogen atmosphere was added LAH (138.48 mg, 3.65 mmol, 2.00 equiv) portionwise. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 5 h. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of 15% NaOH (aq.) (0.1 mL) at 0°C. The resulting mixture was filtered; the filter cake was washed with THF (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to afford 8-(2-fluorophenyl)-6-azaspiro[3.4]octane (230 mg, 61% yield) as a light yellow oil.

[0850]

[0851] The product was prepared according to step 3 of Example 1 using 6-oxo-1H-pyrazine-2-carboxylic acid (50 mg, 0.357 mmol, 1.00 equiv) and 8-(2-fluorophenyl)-6-azaspiro[3.4]octane (73.26 mg, 0.357 mmol, 1.00 equiv) to give 6-[8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (15 mg) as an off-white solid. LC-MS (ES, m / z): [M+H] + =328;

[0852] H-NMR (400MHz, DMSO-d6, ppm): 8.02-7.95 (m, 2H), 7.32-7.18 (m, 4H), 3.98-3.88 (m, 1H), 3.84-3.53 (m, 4H), 2.00-1.57 (m, 6H).

[0853] Example 8: 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one

[0854]

[0855] To a 40 mL vial was added β-nitrostyrene (500 mg, 3.352 mmol, 1.00 equiv), EtOH (15 mL), isobutyraldehyde (483.46 mg, 6.704 mmol, 2.00 equiv), and L-proline (115.79 mg, 1.006 mmol, 0.30 equiv) at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 2,2-dimethyl-4-nitro-3-phenylbutyraldehyde (350 mg, 47% yield) as a light yellow oil.

[0856]

[0857] To a 50 mL round-bottom flask was added 2,2-dimethyl-4-nitro-3-phenylbutyraldehyde (350 mg, 1.582 mmol, 1.00 equiv), EtOH / AcOH (10 mL / 2 mL), and Zn (517.35 mg, 7.910 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOH 1×10 mL. The filtrate was concentrated under reduced pressure. The residue was basified to pH 10 with aqueous NaOH (15%). The resulting mixture was extracted with EtOAc (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 / MeOH (10:1) to give 3,3-dimethyl-4-phenylpyrrolidine (180 mg, 65% yield) as a colorless oil.

[0858]

[0859] The preparation was carried out according to Example 1 using 3,3-dimethyl-4-phenylpyrrolidine (70 mg, 0.399 mmol, 1.00 equiv) and 6-oxo-1H-pyrazine-2-carboxylic acid (55.95 mg, 0.399 mmol, 1.00 equiv) to give 6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)-1H-pyrazin-2-one (10.1 mg) as an off-white solid.

[0860] LC-MS (ES, m / z): [M+H] + =298

[0861] H-NMR (300MHz, DMSO-d6, ppm): 8.26-8.17(m,2H),7.39-7.23(m,5H),4.24-4.03(m,1H),3.9 9-3.90(m,1H),3.67-3.34(m,2H),3.19-3.14(m,1H),1.07-1.01(m,3H),0.77-0.68(m,3H).

[0862] Example 9: 6-(3,3-Dimethyl-4-phenylpiperidine-1-carbonyl)pyrazin-2(1H)-one

[0863]

[0864] To a solution of bromobenzene (0.46 g, 2.93 mmol, 1 eq) in THF (50 mL) at -78°C under an N2 atmosphere was added n-butyllithium solution (20.0 M in THF / hexane, 2.94 mL, 5.87 mmol) dropwise in a 50-mL round-bottom flask. The reaction mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (1 g, 4.40 mmol, 1.5 eq) in 50 mL of THF was then added dropwise, and the mixture was stirred for an additional 30 minutes. The reaction was quenched with water / saturated NH4Cl (20 mL), and the mixture was then extracted with ether / EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was directly purified by eluting with PE / EA (10:1) to give tert-butyl 4-hydroxy-3,3-dimethyl-4-phenylpiperidine-1-carboxylate (500 mg, 56%) as a light yellow solid.

[0865]

[0866] To a 50 mL 2-neck round-bottom flask was added tert-butyl 4-hydroxy-3,3-dimethyl-4-phenylpiperidine-1-carboxylate (400 mg, 1.31 mmol, 1 equivalent) and HCl (10 mL) in MeOH at room temperature. The mixture was basified to pH 7 with saturated NaHCO (aq.). The aqueous layer was extracted with EtOAc (2 x 20 mL). The resulting mixture was concentrated under reduced pressure to give 3,3-dimethyl-4-phenylpiperidin-4-ol (250 mg, 93%) as a light yellow oil.

[0867]

[0868] To a 50 mL 2-neck round-bottom flask at 90°C was added 3-methyl-4-phenylpiperidin-4-ol (230 mg, 1.20 mmol, 1 eq) in toluene (30 mL) and PTSA (310.60 mg, 1.80 mmol, 1.5 eq). The reaction was quenched with water (1 mL), and the mixture was extracted with ether / EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the crude product, which was directly purified by flash chromatography (PE / EA) to afford 3,3-dimethyl-4-phenyl-2,6-dihydro-1H-pyridine (200 mg, 89%) as an off-white oil.

[0869]

[0870] To a solution of 3,3-dimethyl-4-phenyl-2,6-dihydro-1H-pyridine (180 mg, 0.96 mmol, 1 equivalent) in 10 mL of MeOH in a pressure vessel was added Pd / C (50%, 85.23 mg). The mixture was hydrogenated under 15 atm of hydrogen pressure at room temperature overnight, filtered through a pad of Celite, and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to afford 3,3-dimethyl-4-phenylpiperidine (150 mg, 82%) as an off-white solid.

[0871]

[0872] To an 8 mL vial at room temperature was added 3,3-dimethyl-4-phenylpiperidine (40 mg, 0.21 mmol, 1 eq), 6-oxo-1H-pyrazine-2-carboxylic acid (32.56 mg, 0.23 mmol, 1.1 eq), HATU (88.38 mg, 0.23 mmol, 1.1 eq), and DIPEA (81.93 mg, 0.63 mmol, 3 eq) in DMF (4.00 mL). The desired product was detected by LCMS (254 nm, 24%). The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient over 10 min; detector, UV 254 nm, to afford 6-(3,3-dimethyl-4-phenylpiperidine-1-carbonyl)-1H-pyrazin-2-one (20 mg, 30%) as an off-white solid. LCMS (ES, m / z): [M+H] + =312

[0873] H-NMR (300MHz, DMSO-d6, ppm): 8.11(s,1H),7.97(s,1H),7.31-7.16(m,5H),3.97- 3.70(m,3H),2.71-2.65(m,1H),2.20-2.15(m,1H),1.56-1.51(m,1H),0.76(s,6H).

[0874] Examples 10(a) and 10(b): 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one Enantiomer A and 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one Enantiomer B

[0875]

[0876] 6-(-3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)-1H-pyrazin-2-one (Example 9, 15 mg) was purified by chiral HPLC using the following conditions: YMC cellulose-SB, 100x4.6 mm, 3 um 121AB00077, mobile phase A, n-hexane / DCM=3 / 1, mobile phase B ethanol (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm and 220 nm to give 6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one (enantiomer A) (5 mg, 33%) as an off-white solid, and 6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one (enantiomer B) (5 mg, 33%) as an off-white solid.

[0877] LCMS enantiomer A (ES, m / z): [M+H] + =298;

[0878] LCMS Enantiomer B (ES, m / z): [M+H] + =298

[0879] H-NMR (Enantiomer A) (300 MHz, CDCl3, ppm): δ 7.54 (s, 1H), 7.49–7.39 (m, 1H), 7.34–7.24 (m, 2H), 7.17–7.06 (m, 3H), 3.74–3.70 (m, 1H), 3.68 (d, 1H), 3.59–3.53 (m, 2H), 3.14–3.02 (m, 2H), 1.01 (s, 3H), 0.87 (s, 3H).

[0880] H-NMR (enantiomer B) (300 MHz, DMSO-d6, ppm): δ 8.40–8.02 (m, 2H), 7.48–7.13 (m, 5H), 4.19–3.83 (m, 2H), 3.70–3.47 (m, 2H), 3.22–3.11 (m, 1H), 1.03 (d, J = 20.4 Hz, 3H), 0.71 (d, J = 30.9 Hz, 3H).

[0881] One of the enantiomers A and B is (S)-6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one, and the other is (R)-6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one.

[0882] Example 11: 5-(8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0883]

[0884] The preparation was carried out according to Example 5A using 8-(2-fluorophenyl)-6-azaspiro[3.4]octane (50 mg, 0.244 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 34.86 mg, 0.244 mmol, 1.00 equiv) to give 5-[8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-2-methyl-4H-1,2,4-triazol-3-one (22 mg, 27% yield) as an off-white solid. LC-MS-PH (ES, m / z): [M+H] + =331

[0885] H-NMR (400MHz, DMSO-d6, ppm): 11.56 (br, 1H), 7.33-7.14 (m, 4H), 4.20-4.04 (m, 2H),3.90-3.50(m,3H),3.38-3.33(m,3H),2.00-1.99(m,2H),1.94-1.60(m,4H).

[0886] H-NMR(400MHz,DMSO-d6,ppm)δ12.33(s,1H),8.27-8.21(m,1H),7.22-7.20(m,2H),7.02 -7.00(m,1H),6.93-6.88(m,1H),3.83(s,3H),3.37(s,3H),3.18(d,J=6.4Hz,2H),2.72(s,2H),1.81-1.73(m,6H).

[0887] The following examples were prepared using similar methods disclosed in Examples 1 to 11:

[0888] Table 3: Synthesis of some example compounds

[0889]

[0890] Example 14(a): 8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane enantiomer A and 8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane enantiomer B

[0891]

[0892] To a solution of 8-phenyl-6-azaspiro[3.4]octane hydrochloride (150 mg, 0.7 mmol) in DMF (1.5 mL) were added 3H-1,2,3-triazole-4-carboxylic acid (99 mg, 0.9 mmol, 1.3 eq), EDC.HCl (0.21 g, 1.1 mmol, 1.6 eq) and DIPEA (0.22 g, 1.7 mmol, 2.5 eq). The mixture was stirred for 2 h and then quenched with H2O (0.5 mL). The resulting mixture was directly purified by preparative HPLC using the following conditions: (Xselect CSH C18 column, 30*150 mm, 5 μm, mobile phase: 25-75% ACN / 0.05% aqueous HCl over 8 minutes, 1.50 L / min) to give racemic 8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane (80 mg) as an off-white solid.

[0893] The enantiomers were separated by preparative HPLC using the following conditions: (column: CHIRALCEL OJ-H 2*25 cm, 5 μm; mobile phase: 50% EtOH (containing 0.2% MSA) / hexane; flow rate: 25 mL / min; wavelength: 254 nm) to give:

[0894] Example 14(a) Enantiomer A (Rt 12.6 min) was isolated as an off-white solid (24 mg, 32% yield).

[0895] LCMS (ES, m / z): 283 [M+H] + , method LCMS10.

[0896] 1 H NMR(300MHz,DMSO-d6,ppm)δ8.37(br,s,1H),7.40-7.33(m,2H),7.30-7.20(m,3H),4.24-4.10(m,1H),4.02(s,1 H),3.87-3.76(m,1H),3.69(s,1H),3.37-3.32(m,1H),2.09-1.93(m,2H),1.90-1.70(m,2H),1.68-1.45(m,2H).

[0897] Example 14(b) Enantiomer B (Rt 7.7 min) was isolated as an off-white solid (16 mg, 21% yield).

[0898] LCMS (ES, m / z): 283 [M+H] +, method LCMS10.

[0899] 1 H NMR(300MHz,DMSO-d6,ppm)δ8.37(br,s,1H),7.42-7.32(m,2H),7.30-7.20(m,3H),4.24-4.10(m,1H),4.02(s,1 H),3.86-3.78(m,1H),3.68(s,1H),3.32-3.22(m,1H),2.06-1.93(m,2H),1.91-1.72(m,2H),1.69-1.47(m,2H).

[0900] One of the enantiomers A and B is (S)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane, and the other is (R)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane.

[0901] Example 15(a)-(d): 6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one diastereomer A, 6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one diastereomer B, 6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one diastereomer C and 6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one diastereomer D

[0902]

[0903] To a stirred solution of β-nitrostyrene (5.0 g, 34 mmol) and butyraldehyde (3.6 g, 50 mmol, 1.5 eq) in THF (40 mL) was added L-proline (1.2 g, 10 mmol, 0.3 eq) and TEA (3.4 g, 34 mmol, 1.0 eq). The resulting mixture was stirred for 4 h and then concentrated. The residue was purified by silica gel column chromatography eluting with THF / n-hexane (1 / 3) to give 2-ethyl-4-nitro-3-phenylbutyraldehyde (3.8 g, 51% yield) as a light yellow oil.

[0904] LCMS (ES, m / z): 220 [MH] -

[0905]

[0906] Under a hydrogen atmosphere, 2-ethyl-4-nitro-3-phenylbutyraldehyde (3.0 g, 14 mmol), acetic acid (0.8 g, 14 mmol) and 10% Pd / C (1.5 g) in MeOH (30 mL) were stirred for 16 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 30 mL). The combined filtrate was concentrated and the residue was dissolved in EtOAc (5 mL). The mixture was acidified to pH 4 using a 2M HCl solution in EtOAc, and the precipitated solid was collected by filtration and washed with petroleum ether (3 × 10 mL) to give 3-ethyl-4-phenylpyrrolidine hydrochloride (2 g, 84% yield).

[0907] LCMS (ES, m / z): 176 [M+H] + .

[0908]

[0909] To 6-oxo-1H-pyrazine-2-carboxylic acid (0.53 g, 3.8 mmol) in DMF (10 mL) were added HOBT (1.3 g, 9.4 mmol, 2.5 eq) and EDCI (0.87 g, 4.5 mmol, 1.2 eq). 3-Ethyl-4-phenylpyrrolidine hydrochloride (1.6 g, 7.6 mmol, 2 eq) was added, and the mixture was stirred for 2 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 x 3 mL). The combined filtrates were concentrated and the residue was purified by preparative HPLC (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase: 15-60% MeCN / 0.05% aqueous ammonia over 10 minutes; flow rate: 90 mL / min; wavelength: 254 nm) to give 6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)-1H-pyrazin-2-one (350 mg, 31% yield) as an off-white solid.

[0910] LCMS (ES, m / z): 298 [M+H] +

[0911]

[0912] 6-(3-Ethyl-4-phenylpyrrolidine-1-carbonyl)-1H-pyrazin-2-one (250 mg, 0.8 mmol) was separated by preparative HPLC (column: CHIRALPAK AD-H, 2×25 cm, 5 μm; mobile phase: 20% EtOH / hexane (containing 0.1% TFA); flow rate: 25 mL / min; wavelength: 220 nm) to give:

[0913] Example 15(a) Diastereomer A (Rt 5.0 min) was isolated as a yellow solid (110 mg).

[0914] LCMS (ES, m / z): 298 [M+H] + , method LCMS2.

[0915] 1H NMR(400MHz,DMSO-d6,ppm)δ11.82(br,s,1H),8.32-8.08(m,2H),7.43-7.16(m,5H),4.11-3.84(m, 2H),3.77-3.12(m,2H),3.05-2.98(m,1H),2.40-2.20(m,1H),1.50-1.11(m,2H),0.94-0.62(m,3H).

[0916] Example 15(b) Diastereomer B (Rt 5.6 min) was isolated as a yellow solid (97 mg).

[0917] LCMS (ES, m / z): 298 [M+H] + , method LCMS2.

[0918] 1H NMR(400MHz,DMSO-d6,ppm)δ11.82(br,s,1H),8.36-8.07(m,2H),7.42-7.19(m,5H),4.12-3.89(m, 2H),3.75-3.10(m,2H),3.06-2.98(m,1H),2.36-2.18(m,1H),1.44-1.15(m,2H),0.93-0.65(m,3H).

[0919] Example 15(c) Diastereomer C (Rt 11.5 min) was isolated as a light brown solid (3.9 mg).

[0920] LCMS (ES, m / z): 298 [M+H] + , method LCMS2.

[0921] 1H NMR (400MHz, DMSO-d6, ppm) δ11.82(br,s,1H),8.48-8.10(m,2H),7.40-7.31(m,2H),7.28-7.17(m,2H),7.13(d,J=7.6Hz, 1H),4.10-3.66(m,3H),3.57-3.52(m,1H),3.47-3.27(m,1H),2.44-2.36(m,1H),1.06(t,J=7.0Hz,2H),0.88-0.68(m,3H).

[0922] Example 15(d) Diastereomer D (Rt 10.0 min) was isolated as a light brown solid (4.7 mg).

[0923] LCMS (ES, m / z): 298 [M+H] + , method LCMS2.

[0924] 1H NMR (400MHz, DMSO-d6, ppm) δ8.25 (s, 1H), 8.19 (d, J = 10.5Hz, 1H), 7.40-7.30 (m, 2H), 7.28-7.18 (m, 2H), 7.13 (d, J = 7.6Hz ,1H),4.12-3.69(m,3H),3.56-3.49(m,1H),3.47-3.25(m,1H),2.46-2.36(m,1H),1.08-0.86(m,2H),0.85-0.75(m,3H).

[0925] Diastereomers A to D are (stereochemistry not formally assigned):

[0926] (R), (R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one,

[0927] (S), (S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one,

[0928] (R),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one, and

[0929] (S),(R)-6-(3-Ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one.

[0930] Example 16(a) and Example 16(b): 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one Enantiomer A and 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one Enantiomer B

[0931]

[0932] To a stirred mixture of 4-chloroβ-nitrostyrene (5.0 g, 27 mmol) and cyclobutanecarbaldehyde (6.9 g, 82 mmol) in THF (50 mL) was added TEA (5.5 g, 54 mmol) and L-proline (0.94 g, 8.2 mmol). The resulting mixture was stirred for 8 h and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EA (5 / 1) to give 1-[1-(4-chlorophenyl)-2-nitroethyl]cyclobutane-1-carbaldehyde (3 g, 41% yield) as a light yellow oil.

[0933] LCMS (ES, m / z): 266 [MH] -

[0934]

[0935] To 1-(1-(4-chlorophenyl)-2-nitroethyl)cyclobutane-1-carbaldehyde (0.93 g, 3.5 mmol) in EtOH (18 mL) was added zinc powder (1.1 g, 18 mmol, 5 eq) and AcOH (1.7 g, 28 mmol, 8 eq). The reaction mixture was stirred at 60 °C for 2 h, then cooled and filtered, and the filter cake was washed with EtOAc (3 x 20 mL). The combined filtrates were concentrated, and the residue was taken up in a 2M HCl solution in EtOAc (30 mL). The resulting mixture was stirred for 2 h, then concentrated, and the residue was triturated with EtOAc and petroleum ether to give 8-(4-chlorophenyl)-6-azaspiro[3.4]octane hydrochloride (500 mg, 64% yield) as a white solid.

[0936] LCMS (ES, m / z): 222 [M+H] +

[0937]

[0938] To a stirred solution of 8-(4-chlorophenyl)-6-azaspiro[3.4]octane (100 mg, 0.4 mmol) and 6-oxo-1H-pyrazine-2-carboxylic acid (76 mg, 0.5 mmol, 1.2 eq) in DMF (1 mL) was added EDC-HCl (140 mg, 0.9 mmol, 2 eq) portionwise. The reaction mixture was stirred for 6 h and then quenched with water. The mixture was purified by preparative HPLC (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase: 20-75% MeCN / 0.05% ammonia over 10 min; flow rate: 80 mL / min) to afford 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (80 mg, 52% yield) as a white solid.

[0939] LCMS (ES, m / z): 344 [M+H] +

[0940]

[0941] 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (70 mg) was separated by SFC column: CHIRALPAK IH, 3×25 cm, 5 μm; mobile phase: 30% [2:1 MeOH:DCM (containing 0.1% 2M ammonia in MeOH solution)] / CO2; flow rate: 80 mL / min; wavelength: 220 nm, to obtain:

[0942] Example 16(a) Enantiomer A (Rt 4.4 min) was isolated as a yellow solid (16 mg, 23% yield).

[0943] LCMS (ES, m / z): 344 [M+H] + , method LCMS2.

[0944] 1 H NMR(400MHz,DMSO-d6,ppm)δ8.26-8.02(m,2H),7.42(t,J=8.0Hz,2H),7.33-7.24(m,2H), 4.08-3.79(m,2H),3.78-7.73(m,2H),3.66(s,1H),2.03-1.85(m,2H),1.82-1.43(m,4H).

[0945] Example 16(b) Enantiomer B (Rt 5.6 min) was isolated as a yellow solid (14 mg, 19% yield).

[0946] LCMS (ES, m / z): 344 [M+H] + , method LCMS2.

[0947] 1 H NMR(400MHz,DMSO-d6,ppm)δ8.24-8.05(m,2H),7.42(t,J=8.1Hz,2H),7.33-7.24(m,2H), 4.05-3.79(m,2H),3.79-3.72(m,2H),3.65(s,1H),2.07-1.85(m,2H),1.84-1.43(m,4H).

[0948] One of the enantiomers A and B is (S)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one, and the other is (R)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one.

[0949] Example 17(a) and Example 17(b): 6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one Enantiomer A and 6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one Enantiomer B

[0950]

[0951] A solution of (E)-(2-nitrovinyl)benzene (1.5 g, 10 mmol), L-proline (0.23 g, 2.0 mmol, 0.2 eq) and cyclopentanecarbaldehyde (3.0 g, 30 mmol, 3 eq) in EtOH (15 mL) was stirred overnight at 60° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5 / 1) to give 1-[1-(4-bromophenyl)-2-nitroethyl]cyclobutane-1-carbaldehyde (2 g, 80% yield) as a light yellow oil.

[0952] LCMS (ES, m / z): 246 [MH] -

[0953]

[0954] Under a nitrogen atmosphere, 10% Pd / C (500 mg) was added to a solution of 1-(2-nitro-1-phenylethyl)cyclopentane-1-carbaldehyde (0.90 g, 3.6 mmol) in MeOH (20 mL). The mixture was hydrogenated under a hydrogen atmosphere for 2 h, then filtered through a Celite pad, and the filtrate was concentrated. The residue was dissolved in MeOH (10 mL) and AcOH (210 uL, 3.6 mmol, 1 eq), and 10% Pd / C (400 mg) was added. The mixture was stirred overnight under a hydrogen atmosphere, then filtered through a Celite pad and concentrated under reduced pressure to obtain 4-phenyl-2-azaspiro[4.4]nonane (0.50 g, 68% yield) as a colorless oil.

[0955] LCMS (ES, m / z): 202 [M+H] +

[0956]

[0957] A solution of 4-phenyl-2-azaspiro[4.4]nonane (0.15 g, 0.7 mmol), EDCI (0.21 g, 1.1 mmol, 1.5 eq), HOBT (0.25 g, 1.8 mmol, 2.5 eq), DIPEA (0.27 g, 2.1 mmol, 3 eq) and 6-oxo-1H-pyrazine-2-carboxylic acid (0.12 g, 0.8 mmol, 1.2 eq) in DMF (2 mL) was stirred for 2 h and then concentrated. The mixture was purified by preparative HPLC (column: XBridge C18, 19*150 mm, 5 μm; mobile phase: 10-65% MeCN / 20 mM NH4HCO3 aqueous solution (containing 0.05% NH3·H2O) over 8 minutes; flow rate: 60 mL / min.) to give 6-(4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl)pyrazin-2(1H)-one (80 mg, 33% yield) as a white solid.

[0958] LCMS (ES, m / z): 324 [M+H] +

[0959]

[0960] 6-(4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl)pyrazin-2(1H)-one (80 mg) was separated by preparative HPLC using the following conditions: (column: CHIRALPAK AY-3, 100*4.6 mm, 3 um, AY30CC-AW003; mobile phase: 30% 1:1 EtOH / MeOH / n-hexane) to give:

[0961] Example 17(a) Enantiomer A (first eluting isomer) as a white solid (24 mg, 30% yield).

[0962] LCMS (ES, m / z): 324 [M+H] + , method LCMS2.

[0963] 1 H-NMR: (400MHz, DMSO-d6, ppm) δ8.27-8.01(m,2H),7.39-7.16(m,5H),4.10-3.78( m,2H),3.67-3.43(m,2H),3.26-3.21(m,1H),1.68-1.31(m,6H),1.29-1.05(m,2H).

[0964] Example 17(b) Enantiomer B (second eluting isomer) as a white solid (24 mg, 30% yield).

[0965] LCMS (ES, m / z): 324 [M+H] + , method LCMS2.

[0966] 1 H-NMR: (400MHz, DMSO-d6, ppm) δ8.24-8.03(m,2H),7.39-7.13(m,5H),4.11-3.76( m,2H),3.67-3.43(m,2H),3.26-3.22(m,1H),1.68-1.31(m,6H),1.27-1.04(m,2H).

[0967] One of the enantiomers A and B is (S)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one, and the other is (R)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one.

[0968] Example 18: Racemic-2-{8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-3H-pyrimidin-4-one

[0969]

[0970] A solution of 4-oxo-3H-pyrimidine-2-carboxylic acid (0.42 g, 3.0 mmol), TCFH (1.2 g, 4.5 mmol), and NMI (0.62 g, 7.5 mmol) in CHCN (3 mL) was stirred for 15 min. 8-Phenyl-6-azaspiro[3.4]octane hydrochloride (0.67 g, 3.6 mmol) was added portionwise over 5 min. The resulting mixture was stirred for 1 h. The resulting mixture was quenched with water and extracted with CHCl (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by reverse phase chromatography (column: C18 silica gel; mobile phase: 10-50% MeCN in 0.1% aqueous NH3 over 10 min; detector: UV 254 nm) to give racemic 2-{8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-3H-pyrimidin-4-one (12.5 mg, 1.4% yield) as a white solid.

[0971] LCMS (ES, m / z): 310 [M+H] + , method LCMS2.

[0972] 1 H NMR: (400MHz, DMSO-d6, ppm) δ12.74(br,s,1H),8.11-7.85(m,1H),7.42-7.33(m,2H),7.32-7.21(m,3H),6.46-6.34(m,1H),4.06 -3.86(m,1H),3.86-3.71(m,2H),3.70-3.59(m,1H),3.31-3.25(m,1H),2.07-1.91(m,2H),1.89-1.60(m,2H),1.60-1.47(m,2H).

[0973] Example 19(a) and Example 19(b): 6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one Enantiomer A and 6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one Enantiomer B

[0974]

[0975] A solution of 8-(4-bromophenyl)-6-azaspiro[3.4]octane (10 g, 38 mmol), TEA (11 g, 110 mmol), and Boc2O (16 g, 75 mmol) in DCM (100 mL) was stirred for 2 h. The resulting mixture was concentrated, and the residue was purified by silica gel chromatography using n-hexane / EtOAc (5 / 1) as the eluent to afford tert-butyl 8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carboxylate (8.0 g, 58% yield) as a reddish-brown oil.

[0976] LCMS (ES, m / z): 366,368 [M+H] +

[0977]

[0978] To a solution of tert-butyl 8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carboxylate (1.0 g, 2.7 mmol) in DMF (10 mL) was added trimethylsilylacetylene (1.1 g, 11 mmol), Pd(PPh3)2Cl2 (0.19 g, 0.3 mmol), CuI (0.05 g, 0.27 mmol), and TEA (0.83 g, 8.2 mmol). The resulting mixture was stirred at 75°C for 2 h. The mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (5 / 1) to give tert-butyl 8-{4-[2-(trimethylsilyl)ethynyl]phenyl}-6-azaspiro[3.4]octane-6-carboxylate (0.80 g, 76% yield) as a reddish brown oil.

[0979] LCMS (ES, m / z): 384 [M+H] +

[0980]

[0981] To a solution of tert-butyl 8-{4-[2-(trimethylsilyl)ethynyl]phenyl}-6-azaspiro[3.4]octane-6-carboxylate (0.33 g, 0.9 mmol) in DCM (3.3 mL) was added DIPEA (0.33 g, 2.6 mmol) and TMSOTf (0.57 g, 2.6 mmol). The resulting mixture was stirred for 1 h and then concentrated to give 8-{4-[2-(trimethylsilyl)ethynyl]phenyl}-6-azaspiro[3.4]octane (0.76 g, crude) as a brown solid. The crude product was used directly in the next step without further purification.

[0982] LCMS (ES, m / z): 284 [M+H] +

[0983]

[0984] A solution of 8-{4-[2-(trimethylsilyl)ethynyl]phenyl}-6-azaspiro[3.4]octane (0.76 g, 2.7 mmol), 6-oxo-1H-pyrazine-2-carboxylic acid (0.25 g, 1.8 mmol), TCFH (0.75 g, 2.7 mmol), and NMI (0.59 g, 7.1 mmol) in CH3CN (2.5 mL) was stirred for 1 h and then concentrated. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10 / 1) to give 6-(8-{4-[2-(trimethylsilyl)ethynyl]phenyl}-6-azaspiro[3.4]octane-6-carbonyl)-1H-pyrazin-2-one (0.46 g, 63% yield) as a dark red oil.

[0985] LCMS (ES, m / z): 406 [M+H] +

[0986]

[0987] To a solution of 6-(8-{4-[2-(trimethylsilyl)ethynyl]phenyl}-6-azaspiro[3.4]octane-6-carbonyl)-1H-pyrazin-2-one (390 mg, 1.0 mmol) in THF (4 mL) was added a 1 M solution of TBAF in THF (2.8 mL, 2.8 mmol). The resulting mixture was stirred for 1 h and then concentrated. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10 / 1) to afford 6-[8-(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (67 mg, 21% yield) as an off-white solid.

[0988] LCMS (ES, m / z): 334 [M+H] +

[0989]

[0990] 6-[8-(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (67 mg, 0.2 mmol) was separated by preparative HPLC using the following conditions: (column: XA CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase: 50% 1:1 EtOH:DCM / hexane (containing 0.2% FA); flow rate: 25 mL / min; wavelength: 254 nm) to give:

[0991] Example 19(a) Enantiomer A (Rt = 3.2 minutes) as an off-white solid (15 mg, 23% yield)

[0992] LCMS (ES, m / z): 334 [M+H] + 334, Method LCMS2

[0993] 1 H NMR: (400MHz, DMSO-d6, ppm) δ11.91(br,s,1H),8.31(br,s,1H),8.18(d,J=11 .4Hz,1H),7.48(t,J=8.1Hz,2H),7.31(d,J=8.0Hz,1H),7.25(d,J=8.1Hz,1H) ,4.17(s,1H),4.03-3.82(m,1H),3.82-3.70(m,1H),3.69-3.68(m,1H),3.67( s,1H),3.31(s,1H),2.06-1.88(m,2H),1.87-1.62(m,2H),1.61-1.46(m,2H).

[0994] Example 19(b) Enantiomer B (Rt = 4.2 min) as an off-white solid § (16 mg, 25% yield)

[0995] LCMS (ES, m / z): 334 [M+H] + , method LCMS2.

[0996] 1H NMR: (400MHz, DMSO-d6, ppm) δ11.91(br,s,1H),8.31(br,s,1H),8.20-8.16(m,1H),7.48(t,J=8.0Hz,2H),7.25-7.16(m,2H),4.17 (s,1H),4.10-3.89(m,2H),3.85-3.75(m,2H),3.67(s,1H),3.31(s,1H),2.06-1.87(m,2H),1.80-1.62(m,2H),1.60-1.46(m,2H).

[0997] One of the enantiomers A and B is (S)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one, and the other is (R)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one.

[0998] Example 20(a) and Example 20(b): 4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile Enantiomer A and 4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile Enantiomer B

[0999]

[1000] A mixture of tert-butyl 8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carboxylate (1.0 g, 2.7 mmol), zinc cyanide (1.6 g, 14 mmol), dppf (1.2 g, 2.2 mmol), and Pd(dba) (0.25 g, 0.3 mmol) in DMF (20 mL) was stirred at 120°C for 2 hours, then cooled and diluted with water (30 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (2 / 1) to give tert-butyl 8-(4-cyanophenyl)-6-azaspiro[3.4]octane-6-carboxylate (0.43 g, 50% yield) as a white solid.

[1001] LCMS (ES, m / z): 313 [M+H] +

[1002]

[1003] A solution of tert-butyl 8-(4-cyanophenyl)-6-azaspiro[3.4]octane-6-carboxylate (0.30 g, 1.0 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 2 h. The mixture was neutralized with NaHCO3 solution to pH 7 and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (8 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1 / 1) to give 4-(6-azaspiro[3.4]octan-8-ylbenzonitrile (200 mg, 98% yield) as a white solid.

[1004] LCMS (ES, m / z): 213 [M+H] +

[1005]

[1006] A mixture of 4-(6-azaspiro[3.4]octan-8-yl)benzonitrile (0.19 g, 0.9 mmol), 6-oxo-1H-pyrazine-2-carboxylic acid (0.15 g, 1.1 mmol), EDCI (0.34 g, 1.8 mmol) and HOBT (0.30 g, 2.2 mmol) in DMF (4 mL) was stirred for 2 h. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1 / 1) to give 4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile (80 mg, 26% yield) as a white solid.

[1007] LCMS (ES, m / z): 335 [M+H] +

[1008]

[1009] 4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile (40 mg, 0.1 mmol) was separated by preparative SFC (column: CHIRALPAK ID, 3×25 cm, 5 μm; mobile phase: 45% 2:1 MeOH:DCM / CO 2 ; flow rate: 80 mL / min; wavelength: 220 nm) to give:

[1010] Example 20(a) Enantiomer A (Rt = 7.8 min) as an off-white solid (13 mg, 34% yield)

[1011] LCMS (ES, m / z): 335 [M+H] + , method LCMS2

[1012] 1 H NMR (300MHz, DMSO-d6, ppm) δ12.05(br,s,1H),8.27(br,s,1H),8.18(d,J=8.6Hz,1H),7.84(dd,J=8.0,5.2H z,2H),7.51(d,J=8.1Hz,1H),7.45(d,J=8.0Hz,1H),4.12-3.57(m,4H),3.47-340(m,1H),2.06-1.35(m,6H).

[1013] Example 20(b) Enantiomer B (Rt=3.8 min) as an off-white solid (22 mg, 55% yield)

[1014] LCMS (ES, m / z): 335 [M+H] + , method LCMS2.

[1015] 1 H NMR (300MHz, DMSO-d6, ppm) δ12.05(br,s,1H),8.27(br,s,1H),8.18(d,J=8.6Hz,1H),7.84(dd,J=8.0,5.2Hz ,2H),7.51(d,J=8.1Hz,1H),7.45(d,J=8.0Hz,1H),4.12-3.57(m,4H),3.47-3.40(m,1H),2.06-1.35(m,6H).

[1016] One of the enantiomers A and B is (S)-4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile, and the other is (R)-4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile.

[1017] Example 21(a) and Example 21(b): 2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one enantiomer A and 2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one enantiomer B

[1018]

[1019] A solution of 8-phenyl-6-azaspiro[3.4]octane (0.80 g, 4.3 mmol), TEA (1.3 g, 13 mmol) and Boc2O (1.1 g, 5.1 mmol) in DCM (8 mL) was stirred for 4 h. The mixture was concentrated and purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10 / 1) to give tert-butyl 8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (640 mg, 52% yield) as an off-white solid.

[1020] LCMS (ES, m / z): 288 [M+H] +

[1021]

[1022] Tert-butyl 8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (390 mg, 1.4 mmol) was separated by preparative HPLC using the following conditions: (column: XA-CHIRALPAK IG, 3*25 cm, 5 μm; mobile phase: 30% EtOH (containing 0.2% IPA) / 3:1 hexane:DCM; flow rate: 35 mL / min; wavelength: 254 nm) to give:

[1023] Enantiomer A (Rt = 5.2 minutes) as a red oil (130 mg, 33% yield)

[1024] LCMS (ES, m / z): 288 [M+H] +

[1025] Enantiomer B (Rt = 7.0 min) as a red oil (150 mg, 37% yield)

[1026] LCMS (ES, m / z): 288 [M+H] +

[1027]

[1028] To a solution of tert-butyl 8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (enantiomer A) (145 mg, 0.5 mmol) in DCM (1.3 mL) was added 4 M HCl in 1,4-dioxane (1.3 mL). The resulting mixture was stirred for 2 h and concentrated. The precipitated solid was collected by filtration and washed with EtOAc (1 x 2.0 mL) to give 8-phenyl-6-azaspiro[3.4]octane hydrochloride enantiomer A (90 mg, 95%) as an off-white solid.

[1029] LCMS (ES, m / z): 188 [M+H] +

[1030]

[1031] A solution of 4-oxo-3H-pyrimidine-2-carboxylic acid (70 mg, 0.5 mmol), TCFH (210 mg, 0.8 mmol) and NMI (100 mg, 1.3 mmol) in CH3CN (0.7 mL) was stirred for 15 min. 8-phenyl-6-azaspiro[3.4]octane hydrochloride enantiomer A (90 mg, 0.5 mmol) was added portionwise over 5 min. The resulting mixture was stirred for 1 h and then concentrated. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, 10-50% MeCN in 0.1% NH3 aqueous solution; detector, UV 254 nm) to give:

[1032] Example 21(a) Enantiomer A as an off-white solid (30 mg, 19% yield).

[1033] LCMS (ES, m / z): 310 [M+H] + , method LCMS02

[1034] 1 H NMR: (400MHz, DMSO-d6, ppm) δ8.00(dd,J=17.9,6.7Hz,1H),7.40-7.33(m,2H),7.32-7.19(m,3H),6.42(dd,J=12.1,6.7Hz,1H),4.06 -3.87(m,1H),3.85-3.70(m,2H),3.69-3.59(m,1H),3.30(t,J=6.5Hz,1H),2.07-1.90(m,2H),1.90-1.70(m,2H),1.67-1.49(m,2H).

[1035]

[1036] Enantiomer B was synthesized using a similar method to give:

[1037] Example 21(b) Enantiomer B as an off-white solid (35 mg, 21% yield).

[1038] LCMS (ES, m / z): 310 [M+H] + , method LCMS02

[1039] 1H NMR: (400MHz, DMSO-d6, ppm) δ8.00(dd,J=17.9,6.7Hz,1H),7.40-7.33(m,2H),7.32-7.20(m,3H),6.42(dd,J=12.1,6.7Hz,1H),4.05 -3.83(m,1H),3.83-3.71(m,2H),3.68-3.57(m,1H),3.30(t,J=6.5Hz,1H),2.10-1.91(m,2H),1.87-1.67(m,2H),1.67-1.47(m,2H).

[1040] One of the enantiomers A and B is (S)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one, and the other is (R)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one.

[1041] Example 22: (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone

[1042]

[1043] To a solution of 8-phenyl-6-azaspiro[3.4]octane (0.2 g, 1.1 mmol) in MeOH (1 mL) was added methyl 3-oxo-2,3-dihydroisoxazole-5-carboxylate (0.2 g, 1.6 mmol) and TBD (0.4 g, 3.2 mmol). The solution was stirred at 80°C for 4 h and then concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase: 30-60% MeCN / 10 mmol / L NH4HCO3 aqueous solution (containing 0.1% NH3.H2O) over 7 min; flow rate: 30 mL / min) to afford (3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone (180 mg, 54% yield) as a white solid.

[1044] LCMS (ES, m / z): 299 [M+H] + , method LCMS11

[1045] 1H NMR(300MHz,DMSO-d6,ppm)δ11.80-11.62(m,1H),7.44-7.34(m,2H),7.31-7.18(m,3H),6.61(s,1H),4.12-3.92(m,1H),3.86(s,1H), 3.84-3.74(m,1H),3.74-3.58(m,1H),3.31-3.27(m,1H),2.06-1.93(m,2H),1.92-1.66(m,2H),1.66-1.51(m,1H),1.50-1.34(m,1H).

[1046] Example 23(a) and Example 23(b): (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer A and (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone Enantiomer B

[1047]

[1048] (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone (70 mg, 0.23 mmol) was separated by preparative HPLC (column: CSH-C18, 19×250 mm, 5 μm; mobile phase: 10-80% MeCN / 0.05% HCl aqueous solution; flow rate: 20 mL / min; wavelength: 254 nm / 220 nm) to give:

[1049] Example 23(a) Enantiomer A (first eluting isomer) as a white solid (22 mg, 31% yield).

[1050] LCMS (ES, m / z): 299 [M+H] + , method LCMS11

[1051] 1 H NMR (400MHz, DMSO-d6, ppm) δ11.87(br,s,1H),7.38-7.32(m,2H),7.29-7.21(m,3H),6.56(s,1H),4.09-3.95(m,1H),3.87-3. 73(m,2H),3.73-3.58(m,1H),3.27-3.23(m,1H),2.08-1.95(m,2H),1.87-1.67(m,2H),1.66-1.53(m,1H),1.53-1.39(m,1H).

[1052] Example 23(b) Enantiomer B (second eluting isomer) as a white solid (27 mg, 38% yield).

[1053] LCMS (ES, m / z): 299 [M+H] + , method LCMS11

[1054] 1 H NMR(400MHz,DMSO-d6,ppm)δ11.86(br,s,1H),7.37-7.34(m,2H),7.29-7.21(m,3H),6.56(s,1H),4.05-3.94(m,1H),3.79-3.75(m,1H ),3.73-3.65(m,1H),3.63-3.58(m,1H),3.7-3.23(m,1H),2.08-1.91(m,2H),1.85-1.74(m,2H),1.64-1.60(m,1H),1.46-1.44(m,1H).

[1055] One of the enantiomers A and B is (S)-(3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone, and the other is (R)-(3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone.

[1056] Example 24: 3-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-oxadiazol-5-one

[1057]

[1058] To a stirred solution of ethyl [(Z)-N'-hydroxycarbamimidoyl]carboxylate (2.5 g, 19 mmol) in 1,4-dioxane (25 mL) at 80°C was added CDI (3.7 g, 23 mmol) and DBU (3.5 g, 23 mmol) portionwise. The resulting mixture was stirred at 80°C for 2 h. The reaction was quenched with 1 M aqueous HCl at 0°C. The mixture was extracted with CHCl (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and then concentrated. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (5 / 1) to afford ethyl 5-oxo-4H-1,2,4-oxadiazole-3-carboxylate (1.2 g, 40% yield) as a yellow solid.

[1059] LCMS (ES, m / z): 157 [MH] -

[1060]

[1061] 5-Oxo-4H-1,2,4-oxadiazole-3-carboxylate (150 mg, 0.9 mmol), 8-phenyl-6-azaspiro[3.4]octane (270 mg, 1.4 mmol) and TBD (400 mg, 2.8 mmol) were stirred in EtOH (1.5 mL) at 80° C. for 2 h. The mixture was concentrated and the residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: 10-50% MeCN in 0.1% FA aqueous solution; wavelength: 254 nm) to give 3-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-oxadiazol-5-one (50 mg, 18% yield) as a white solid.

[1062] LCMS (ES, m / z): 300 [M+H] + , method LCMS12

[1063] 1 H NMR: (400MHz, DMSO-d6, ppm) δ13.07(s,1H),7.41-7.33(m,2H),7.33-7.22(m,3H),4.15-3.99(m,1H),3.96-3.87(m,1 H),3.86-3.73(m,1H),3.70-3.62(m,1H),3.31-3.24(m,1H),2.03-1.91(m,2H),1.88-1.71(m,2H),1.69-1.43(m,2H).

[1064] Example 25(a)-(d): 2-(2-Fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one Diastereomer A, Diastereomer B, Diastereomer C, and Diastereomer D

[1065]

[1066] To a solution of 3-(benzyloxy)cyclobutane-1-carboxylic acid (6.5 g, 32 mmol) in THF (65 mL) was added 2 mL of LAH in THF (26 mL, 52 mmol) at 0°C, and the resulting mixture was stirred overnight. The reaction was quenched by adding water / ice (25 mL) and 15% aqueous NaOH (7.2 ml) at 0°C. The mixture was extracted with EtOAc (3 × 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (3 / 1) to give [3-(benzyloxy)cyclobutyl]methanol (4.5 g, 74% yield) as a colorless oil.

[1067] LCMS (ES, m / z): 193 [M+H] +

[1068]

[1069] To a solution of [3-(benzyloxy)cyclobutyl]methanol (4.5 g, 23 mmol) in DCM (10 mL) at 0°C was added Dess-Martin periodinane (12 g, 28 mmol) portionwise. The resulting mixture was stirred for 1 h. The mixture was filtered, washed with Et2O (2 x 10 mL), and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (2 / 1) to afford 3-(benzyloxy)cyclobutane-1-carbaldehyde (3.2 g, 71% yield) as a light yellow oil.

[1070] LCMS (ES, m / z): 191 [M+H] +

[1071]

[1072] To a solution of β-nitrostyrene (860 mg, 5.7 mmol) and L-proline (0.20 g, 1.7 mmol) in THF (10 mL) was added 3-(benzyloxy)cyclobutane-1-carbaldehyde (3.3 g, 17 mmol) and Et3N (0.58 g, 5.7 mmol). The resulting mixture was stirred for 8 h and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (2 / 1) to give 3-(benzyloxy)-1-(2-nitro-1-phenylethyl)cyclobutane-1-carbaldehyde (1.7 g, 88% yield) as a white solid.

[1073] LCMS (ES, m / z): 338 [MH] -

[1074]

[1075] To a solution of 3-(benzyloxy)-1-(2-nitro-1-phenylethyl)cyclobutane-1-carbaldehyde (1.7 g, 5.0 mmol) in EtOH (16 mL) was added Zn (1.7 g, 25 mmol) and AcOH (2.5 g, 41 mmol). The resulting mixture was stirred at 60°C for 3 h, then filtered, washed with MeOH (3 x 6.0 mL), and concentrated. The residue was dissolved in 4 M HCl in dioxane (10 mL), stirred for 10 min, and then concentrated. The residue was triturated with hexanes (15 mL) to afford 2-(benzyloxy)-8-phenyl-6-azaspiro[3.4]octane hydrochloride (1.2 g, 80% yield) as a white solid.

[1076] LCMS (ES, m / z): 294 [M+H] +

[1077]

[1078] 2-(Benzyloxy)-8-phenyl-6-azaspiro[3.4]octane hydrochloride (1.2 g, 3.7 mmol), Et3N (1.2 g, 11 mmol) and Boc2O (890 mg, 4.4 mmol) were dissolved in MeOH (12 mL) and stirred for 3 h, then concentrated. The residue was purified by silica gel column chromatography using n-hexane / EtOAc (2 / 1) as the eluent to give tert-butyl 2-(benzyloxy)-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (1.5 g, 93% yield) as a light yellow oil.

[1079] LCMS (ES, m / z): 394 [M+H] +

[1080]

[1081] To a solution of tert-butyl 2-(benzyloxy)-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (1.5 g, 3.8 mmol) in MeOH (20 mL) was added 10% Pd / C (1.2 g). The mixture was stirred under a hydrogen atmosphere for 3 h, filtered through a Celite pad and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (1:1) to give tert-butyl 2-hydroxy-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (700 mg, 60% yield) as a colorless oil.

[1082] LCMS (ES, m / z): 304 [M+H] +

[1083]

[1084] A solution of tert-butyl 2-hydroxy-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (700 mg, 2.3 mmol) in DCM (10 mL) was cooled to -78°C and DAST (740 mg, 4.6 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight and then quenched with water / ice at 0°C. The mixture was extracted with DCM (3×10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated to afford tert-butyl 2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (340 mg, 48% yield) as a colorless oil.

[1085] LCMS (ES, m / z): 306 [M+H] +

[1086]

[1087] To a solution of tert-butyl 2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (340 mg, 1.1 mmol) in DCM (1.5 mL) was added dropwise 4M HCl in 1,4-dioxane (1.5 mL). The resulting mixture was stirred for 30 min and then concentrated to afford 2-fluoro-8-phenyl-6-azaspiro[3.4]octane hydrochloride (145 mg, 53% yield) as a white solid.

[1088] LCMS (ES, m / z): 206 [M+H] +

[1089]

[1090] A solution of 6-oxo-1H-pyrazine-2-carboxylic acid (98 mg, 0.7 mmol), TCFH (400 mg, 1.4 mmol), and NMI (120 mg, 1.4 mmol) in MeCN (2 mL) was stirred for 10 min, followed by the addition of 2-fluoro-8-phenyl-6-azaspiro[3.4]octane (150 mg, 0.7 mmol). The mixture was stirred for 1 h, then filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase: 30-90% MeCN / 0.05% NH3 aqueous solution; flow rate: 90 mL / min; wavelength: 254 nm) to afford 6-{2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-1H-pyrazin-2-one (95 mg, 41% yield) as a gray solid.

[1091] LCMS (ES, m / z): 328 [M+H] +

[1092]

[1093] 6-{2-Fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-1H-pyrazin-2-one (94 mg) was separated by preparative HPLC (column: CHIRALPAK IF-3, 50*4.6 mm, 3 um IF30CB-CM006; mobile phase: EtOH (containing 0.5% FA) / 3:1 n-hexane:DCM; flow rate: 1.0 mL / min) to give:

[1094] Example 25(a) Diastereomer A (first eluting diastereomer) was isolated as an off-white solid (21 mg, 38% yield)

[1095] LCMS (ES, m / z): 328 [M+H] + , method LCMS14

[1096] 1 H NMR(300MHz,DMSO-d6,ppm)δ12.05(br,s,1H),δ8.37-8.13(m,2H),7.48-7.06(m,5H),5.28 -4.75(m,1H),4.21-3.56(m,4H),3.47-3.32(m,1H),2.46-2.16(m,1H),2.19-1.63(m,3H).

[1097] Example 25(b) Diastereomer B (second eluting diastereomer) was isolated as an off-white solid (23 mg, 43% yield)

[1098] LCMS (ES, m / z): 328 [M+H] + , method LCMS14

[1099] 1 H NMR(300MHz,DMSO-d6,ppm)δ11.96(br,s,1H),δ8.31-8.07(m,2H),7.51-7.12(m,5H),5.25 -4.84(m,1H),4.09-3.53(m,4H),3.47-3.38(m,1H),2.46-2.22(m,1H),2.16-1.69(m,3H).

[1100] Example 25(c) Diastereomer C (the third eluting diastereomer) was isolated as an off-white solid (10 mg, 11% yield).

[1101] LCMS (ES, m / z): 328 [M+H] + , method LCMS14

[1102] 1 H NMR(300MHz,DMSO-d6,ppm)δ8.30-8.19(m,1H),8.19-8.08(m,1H),7.46-7.20(m,5H),4.72-4.24 (m,1H),4.13-3.90(m,1H),3.89-3.74(m,2H),3.68(s,1H),3.57-3.45(m,1H),2.34-1.84(m,4H).

[1103] Example 25(d) Diastereomer D (the fourth eluting diastereomer) was isolated as an off-white solid (10 mg, 11%).

[1104] LCMS (ES, m / z): 328 [M+H] + , method LCMS14

[1105] 1H NMR(300MHz,DMSO-d6,ppm)δ8.34-8.07(m,2H),7.54-7.18(m,5H),4.72-4.30(m,1H),4 .09-3.91(m,1H),3.90-3.76(m,2H),3.68(s,1H),3.53-3.38(m,1H),2.42-1.82(m,4H).

[1106] Diastereomers A to D are (stereochemistry not formally assigned):

[1107] (R), (R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one,

[1108] (S), (S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one,

[1109] (R),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one, and

[1110] (S),(R)-2-(2-Fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one.

[1111] The following compounds were synthesized in a similar manner using the appropriate acid or equivalent and amine. The synthesis of the amine was similar to the previous example. Enantiomer A corresponds to the eutomer.

[1112] Table 4:

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122] Example 35(a) 6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one Enantiomer A and Example 35(b) 6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one Enantiomer B

[1123] Step 1. Preparation of 1-[1-(4-fluorophenyl)-2-nitroethyl]cyclobutane-1-carbaldehyde

[1124]

[1125] To a stirred mixture of styrene, (E)-1-fluoro-4-(2-nitrovinyl)benzene (6.0 g, 36 mmol), and L-proline (4.1 g, 36 mmol, 1 eq) in THF (60 mL) was added cyclobutanecarbaldehyde (9.1 g, 110 mmol, 3 eq) and Et3N (1.1 g, 11 mmol, 0.3 eq). The resulting mixture was stirred for 4 h and then concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5 / 1) to give 1-[1-(4-fluorophenyl)-2-nitroethyl]cyclobutane-1-carbaldehyde (4.6 g, 50% yield) as a light yellow oil.

[1126] LCMS (ES, m / z): 250 [MH] -

[1127] Step 2. Preparation of 6-oxo-1H-pyrazine-2-carboxylic acid

[1128]

[1129] To 1-[1-(4-fluorophenyl)-2-nitroethyl]cyclobutane-1-carbaldehyde (0.85 g, 3.4 mmol) in EtOH (17 mL) was added zinc powder (1.1 g, 17 mmol, 5 eq) and acetic acid (1.6 g, 27 mmol, 8 eq). The reaction mixture was stirred at 60 ° C for 2 h, then cooled and filtered. The filtrate was concentrated and the residue was placed in a 4M HCl solution in MeOH (20 mL). It was stirred for 2 h and then concentrated. The residue was triturated with EtOAc and petroleum ether to give 6-[8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (0.6 g, 86% yield) as a white solid.

[1130] LCMS (ES, m / z): 206 [M+H] +

[1131] Step 3. Preparation of 6-[8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one

[1132]

[1133] To 6-oxo-1H-pyrazine-2-carboxylic acid (0.20 g, 1.4 mmol) in MeCN (2 mL) was added TCFH (0.6 g, 2.1 mmol, 1.5 eq) and NMI (0.29 g, 3.6 mmol, 2.5 eq). The reaction mixture was stirred for 15 min. 8-(4-fluorophenyl)-6-azaspiro[3.4]octane (0.35 g, 1.7 mmol, 1.2 eq) was then added. The resulting mixture was stirred for 1 h, then filtered, and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: (column, C18 silica gel; mobile phase: 10-50% MeOH / 0.1% NH3·H2O in water over 10 min; detector, UV 254 nm) to give 6-[8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (120 mg, 25% yield) as an off-white solid.

[1134] LCMS (ES, m / z): 328 [M+H] +

[1135] Step 4. Preparation of 6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one enantiomer A and 6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one enantiomer B

[1136]

[1137] 6-[8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (120 mg, 0.4 mmol) was separated by chromatography (column: XA-CHIRALPAK IG, 3×25 cm, 5 μm; mobile phase: 20% EtOH (containing 0.1% diethylamine) / hexane; flow rate: 35 mL / min; wavelength: 254 nm) to give:

[1138] Example 35(a) 6-[8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one enantiomer A (27 mg, 22% yield) was obtained as an off-white solid.

[1139] Rt = 10.3 minutes

[1140] LCMS (ES, m / z): 328 [M+H] +

[1141] 1 H NMR: (400MHz, DMSO-d6, ppm) δ12.01(br,s,1H),8.35-8.15(m,2H),7.37-7.25(m,2H),7.22 -7.16(m,2H),4.05-3.60(m,4H),3.30-3.27(m,1H),2.05-1.87(m,2H),1.86-1.44(m,4H).

[1142] Example 35(b) 6-[8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one enantiomer B (24 mg, 20% yield) was obtained as an off-white solid.

[1143] Rt=12.1 minutes

[1144] LC-MS (ES, m / z): 328 [M+H] +

[1145] 1H NMR: (400MHz, DMSO-d6, ppm) δ11.98(br,s,1H),8.32-8.17(m,2H),7.37-7.24(m,2H),7.22 -7.18(m,2H),4.04-3.62(m,4H),3.33-3.27(m,1H),2.05-1.88(m,2H),1.86-1.44(m,4H).

[1146] One of the enantiomers A and B is (S)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one, and the other is (R)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one.

[1147] The following compounds were synthesized in a similar manner using the appropriate acid or equivalent and amine. The synthesis of the amine was similar to the previous example. Enantiomer A corresponds to the eutantiomer.

[1148] Table 5:

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162] Biological Examples Biological Example 1 - Measurement of mPTP activity in isolated rat liver mitochondria and isolated rat brain mitochondria Rat liver mitochondrial assay

[1163] Pharmacological inhibition or modulation of the mPTP can be performed in isolated mitochondria using the well-characterized "Ca" 2+ In vitro, isolated mitochondria rapidly sequester exogenous Ca 2+ Until the mitochondrial Ca 2+ The concentration reaches the threshold for mPTP activation. Once the pore is activated, mitochondrial integrity is disrupted and stored Ca is released. 2+ . Membrane-impermeable Ca 2+ Real-time Ca measurement using sensitive fluorescent dyes 2+ Depending on the assay configuration, inhibition or modulation of the mPTP can delay pore opening or increase the Ca required to induce mPTP opening. 2+ concentration.

[1164] mPTP activity was measured in mitochondria freshly isolated from the livers of female Sprague Dawley rats (250-300 g) using the following method. Rats were subjected to cervical dislocation. The liver was then perfused in situ with approximately 40 ml of cold Dulbecco's phosphate-buffered saline (DPBS) and transferred to 30 ml of isolation buffer (250 mM sucrose, 10 mM KCl, 1 mM EGTA, 1 mM EDTA, 25 mM HEPES, adjusted to pH 7.5 with 1 M NaOH) prior to dissection. Each lobe of the liver was then removed from the buffer, minced into approximately 5 mm pieces using forceps and a scalpel, and then transferred to a 50 ml Potterton dounce homogenizer tube on ice containing 30 ml of ice-cold centrifugation buffer (300 mM trehalose, 25 mM HEPES, 1 mM EGTA, 1 mM EDTA, 10 mM KCl, adjusted to pH 7.5 with 1 M NaOH, and supplemented with 0.1% bovine serum albumin (BSA) and complete protease inhibitor cocktail (one inhibitor tablet per 50 ml of buffer). Homogenize with a pestle at 1800 rpm. Centrifuge the slurry at 800 g for 10 minutes at 4°C, and then centrifuge the supernatant at 10,000 g for 10 minutes. Wash the pellet once with FLIPR assay buffer (75 mM mannitol, 25 mM sucrose, 5 mM potassium dihydrogen phosphate, 20 mM Tris base, 100 mM KCl, 0.1% BSA, adjusted to pH 7.4 with 5 M HCl), centrifuge again, and resuspend in FLIPR assay buffer to a protein concentration of 8.8 mg / ml.

[1165] Test compounds (10 mM stock in DMSO) were serially diluted in DMSO in half-log steps to generate 10 test concentrations (final concentrations in the assay were 30 μM to 1 nM). 5 μl of the intermediate dilution of the DMSO sample was first diluted into 247 μl of FLIPR assay buffer, and then 5 μl was transferred to duplicate wells of a 384-well polypropylene assay plate. Control wells contained 0.5% (v / v) DMSO and 5 μM cyclosporin A.

[1166] Mitochondria / Fluo5N is measured in the 5.6ml FLIPR assay buffer (room temperature) being supplemented with disodium succinate (10mM), rotenone (1 μM), Fluo5N five potassium salts (2 μM) and 1ml mitochondria suspension, prepares stock solution, then its (15 μ l) is transferred in the assay plate containing test compound and is incubated at room temperature 10 minutes.Then assay plate is transferred to FLIPRTetra (Molecular Devices) or CLARIOstar (BMG) plate reader.For the kinetic fluorescence detection carried out on FLIPR, dye fluorescence is measured once every 3 seconds, measures 10 minutes altogether.After 12 seconds, from the source plate containing 675 μM CaCl2 in FLIPR assay buffer, add 2.5 μ l large doses (bolus) of CaCl2 (75 μ M).Or, use Viaflow384 to add 2.5 μ l CaCl2, plate is incubated at room temperature 10min, after 10min, dye fluorescence is measured on CLARIOstar plate reader. The pIC50 values ​​of the test compounds were calculated using the fluorescence values ​​collected on one of the two plate readers at the 10 min time point, with the % inhibition calculated using the DMSO control and cyclosporin A values ​​as 0 and 100%, respectively.

[1167] Rat brain mitochondrial assay

[1168] mPTP activity was measured in freshly isolated brain mitochondria from female Sprague Dawley rats (250-300 g). Anesthetized rats were perfused in situ with approximately 40 ml of cold Dulbecco's phosphate-buffered saline (DPBS), and the brains were dissected and transferred to 30 ml of isolation buffer (225 mM mannitol, 75 mM sucrose, 1 mM EGTA, adjusted to pH 7.4 with 1 M NaOH). The brains were minced into approximately 5 mm pieces using forceps and a scalpel and then transferred to 50 ml Potterton dounce homogenizer tubes on ice containing 10 ml of ice-cold isolation buffer (as described above, with the addition of complete protease inhibitors; 1 tablet per 50 ml of buffer). Homogenize with a pestle at 1800 rpm. Centrifuge the slurry at 2000 g for 10 minutes at 4°C, and then centrifuge the supernatant at 12,000 g for 9 minutes. Resuspend the pellet in the above isolation buffer using a Dounce homogenizer, but with 0.02% digitonin added, centrifuge at 12,000 g for 11 minutes, and finally resuspend in 5 ml of modified isolation buffer (as above, but with EGTA reduced to 0.1 mM).

[1169] As described above for the liver mitochondria assay method, test compounds are prepared in 384-well polypropylene assay plates. 5.6ml assay buffer (120mM mannitol, 40mMMOPS, 5mM KH being supplemented with Fluo5N five potassium salts (2 μ M) and 1ml mitochondria suspension PO , 60mM KCl, 10mM pyruvate, 2mM malate, 2mM MgCl , 20 μM ADP, 1.26 μM oligomycin A are adjusted to pH 7.4) in preparation mitochondria / Fluo5N and measure stock solution, then it (15 μ l) is transferred in the assay plate containing test compounds and at room temperature hatched 10 minutes. Then assay plate is transferred to FLIPR Tetra and reads on plate reader (Molecular Devices). Then per 3 seconds, dye fluorescence is measured once, measured 10 minutes altogether. After 12 seconds, from containing the 675 μ M CaCl in FLIPR assay buffer source plate adds 2.5 μ l large doses of Ca 2+ (75 μM) pIC50 values ​​for the test compounds were calculated using the fluorescence values ​​collected at the 10 minute time point, and the % inhibition calculated using the DMSO control and cyclosporin A values ​​as 100% and 0%, respectively.

[1170] General cytotoxicity was assessed using a standard cell survival method (Cell Titre Glo; Promega) in HEK293 and SHSY5Y cells, followed by incubation of test compounds for 24 to 96 hours.

[1171] Results: The mPTP pIC values ​​of certain example compounds in the rat liver and / or brain mPTP assay are provided in Table 6 below. 50 The results showed that the tested compounds of the present invention exhibited an inhibitory effect on mPTP, and many of the example compounds showed a pIC value of 6.0 or higher. 50 Example 35a showed the highest activity in the rat liver mitochondrial assay, and Example 36a showed the highest activity in the rat brain mitochondrial assay. Table 6 also provides the mPTP rat brain mitochondrial pIC values ​​for certain example compounds. 50 These results indicate that the tested compounds of the examples have activity against isolated rat liver mitochondria and isolated rat brain mitochondria.

[1172] Table 6: Summary of results of Biological Example 1

[1173]

[1174]

[1175]

[1176]

[1177] NT – Not tested

[1178] Conclusion: The results of Biological Example 1 demonstrate that a high proportion of the compounds of the invention tested (or at least one stereoisomeric form thereof) are mPTP inhibitors in the rat liver and / or brain mPTP assay. A large number of the compounds tested are potent, having pIC values ​​of 6.0 and above in the rat liver assay. 50 values ​​and / or a pIC value of 7.0 or above in the rat brain assay 50 The compounds of the present invention are therefore useful as medicaments, in particular for the treatment or prevention of diseases and disorders in which mPTP inhibition provides a therapeutic or preventive benefit.

[1179] Throughout the specification and claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer, step, group of integers or groups of steps but not the exclusion of any other integer, step, group of integers or groups of steps.

[1180] The present application, of which this specification and claims form a part, may serve as the basis for any subsequent application claiming priority. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, method, or use claims and may include, for example, but not limited to, subsequent claims.

[1181] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference in its entirety.

[1182] References

[1183] Berge S et al.Pharmaceutical Salts.J.Pharm.Sci.1977;66;1-19.

[1184] Greene et al.4th Rev Ed.,2006,ISBN-10:0471697540.“Protective Groupsin Organic Synthesis”.Yu et al.,TDP-43 Triggers Mitochondrial DNA Release viamPTP to Activate cGAS / STING in ALS,Cell,Volume 183,Issue 3,2020,pages 636-649.e18.

[1185] Jang et al.,Proximal tubule cyclophilin D mediates kidneyfibrogenesis in obstructive nephropathy,2021,American Journal of Physiology:Renal physiology,2021 321:4,F431-F442

[1186] Plyte et al.,Cinnamic Anilides as New Mitochondrial PermeabilityTransition Pore Inhibitors Endowed with Ischemia-Reperfusion InjuryProtective Effect in Vivo,J.Med Chem.2014,57,5333-47

[1187] Chen et al.,Probing Mitochondrial Permeability Transition PoreActivity in Nucleated Cells and Platelets by High-Throughput Screening AssaysSuggests Involvement of Protein Phosphatase 2B in Mitochondrial Dynamics,Assay and Drug Development Technologies,2018,16,445-45.

Claims

1. Compounds of formula (I): in, R 1a Is H or C 1-4 alkyl; R 1b Is H or C 1-4 alkyl; R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 3a is H, halogen or C 1-4 alkyl; R 4a Is H or C 1-4 alkyl; R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen; R 6a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or with C 5-6 Cycloalkyl-fused phenyl, wherein the phenyl or C 5-6 The cycloalkyl-fused phenyl group may optionally be replaced by one or more AA 1 replace; AA 1 Halogen, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r or NHSO2R t ; R q Is H or C 1-4 alkyl; R r Is H or C 1-4 alkyl; R t It is C 1-4 alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl may be optionally replaced by one or more B 1A replace; and B 1A Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo (=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH); or a salt and / or solvate thereof, Provided that the compound of formula (I) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

2. The compound of formula (IB) according to claim 1: in, R 1a Is H or C 1-4 alkyl; R 1b Is H or C 1-4 alkyl; R 2a It is H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 3a is H, halogen or C 1-4 alkyl; R 4a Is H or C 1-4 alkyl; R 5a It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl), C 0-6 Alkylene (OH); or R 4a and R 5a Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with one or more groups selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and halogen; R 6a It is H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or with C 5-6 Cycloalkyl-fused phenyl, optionally substituted with one or more AA 1 replace; AA 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r or NHSO2R t ; R q Is H or C 1-4 alkyl; R r Is H or C 1-4 alkyl; R t It is C 1-4 alkyl; BA is a monocyclic or bicyclic heterocyclic ring or a monocyclic or bicyclic heteroaryl ring, which may be optionally replaced by one or more B 1A replace; and and B 1A Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH); or its salt and / or solvate, Provided that the compound of formula (IB) is not (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone:

3. The compound according to claim 1 or claim 2, or a salt and / or solvate thereof, which is a compound of formula (IB): or a salt and / or solvate thereof. The compound or its salt and / or solvate according to claim 1 , which is the compound or its pharmaceutically acceptable salt and / or solvate.

5. The compound according to any one of claims 1 to 4, or a salt and / or solvate thereof, wherein R 1a and R 1b Each is H.

6. The compound according to any one of claims 1 to 5, or a salt and / or solvate thereof, wherein R 2a and R 3a Each is H.

7. The compound according to any one of claims 1 to 6, or a salt and / or solvate thereof, wherein R 4a and R 5a Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, for example cyclobutyl.

8. The compound according to any one of claims 1 to 6, or a salt and / or solvate thereof, wherein R 4a and R 5a Each is a methyl group.

9. The compound according to any one of claims 1 to 8, or a salt and / or solvate thereof, wherein R 6a It’s H. 10 . The compound according to claim 1 , or a salt and / or solvate thereof, wherein x is 1. The compound according to any one of claims 1 to 10, or a salt and / or solvate thereof, wherein AA is phenyl.

12. The compound according to any one of claims 1 to 11, or a salt and / or solvate thereof, wherein AA is replaced by one or more AA 1 substituted, and at least one AA 1 It's a halogen.

13. The compound according to any one of claims 1 to 12, or a salt and / or solvate thereof, wherein BA is selected from: For example in, B 1B Is H or C 1-6 Alkyl groups, such as methyl; B 2B Is H or C 1-6 an alkyl group, such as a methyl group; and B 2B It is C 0-6 Alkylene (OH), such as OH.

14. The compound according to claim 1 or its salt and / or solvate, which is selected from: (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; (4-Hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; (3,3-Dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone; 2-methyl-5-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; 6-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; 6-(3,3-Dimethyl-4-phenylpiperidin-1-carbonyl)pyrazin-2(1H)-one; 6-(3,3-Dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; 5-(8-(2-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; 8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane; 6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; 6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one; rac-2-{8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-3H-pyrimidin-4-one; 6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; 4-[6-(6-Oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile; 2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one; (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; (3-Hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; 3-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-oxadiazol-5-one; 2-(2-Fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; 6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one; 6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one; 6-(8-(4-methoxyphenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 6-8-(5-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 6-(8-(3-chloro-2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; 6-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (8-(4-Fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; 6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (8-(3-Fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (8-(2,3-Difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; 6-(8-(3-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 3-(8-(4-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (8-(2,4-Difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; 6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; 3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; 6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (8-(3,4-Difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; 3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; 3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; and 3-(8-(3-Fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; or a salt and / or solvate thereof. 15 . The compound according to claim 1 , or a salt and / or solvate thereof, which is a compound of formula (I). 16 . The compound or salt and / or solvate thereof according to claim 1 , which is a salt of the compound of formula (I).

17. A compound according to any one of claims 1 to 16 for use as a medicament.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

19. A compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, such as a disease or disorder selected from degenerative or neurodegenerative diseases, central nervous system disorders, ischemia-reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, geriatric diseases and renal diseases, wherein the premise of formula (I) does not apply.

20. A pharmaceutical composition according to claim 18 for use in the treatment or prevention of a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, such as a disease or disorder selected from degenerative or neurodegenerative diseases, central nervous system disorders, ischemia-reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, geriatric diseases and renal diseases, wherein the preconditions of formula (I) do not apply.

21. Use of a compound as claimed in any one of claims 4 to 16 or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition as claimed in claim 18, for the preparation of a medicament for treating or preventing a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, for example a disease or disorder selected from degenerative or neurodegenerative diseases, central nervous system disorders, ischemia-reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, geriatric diseases and renal diseases, wherein the premise of formula (I) does not apply.

22. A method for treating or preventing a disease or disorder in which mPTP inhibition provides a therapeutic or preventive effect, for example a disease or disorder selected from degenerative or neurodegenerative diseases, central nervous system disorders, ischemia-reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, geriatric diseases and renal diseases, wherein the premise of formula (I) does not apply, the method comprising administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition as described in claim 18.

23. A compound for use according to any one of claims 19 to 22, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use or a method for use, wherein the disease or disorder is selected from degenerative or neurodegenerative diseases (e.g. Parkinson's disease, Lewy body dementia, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury and Friedreich's ataxia, in particular Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis), central nervous system disorders (e.g. AIDS dementia syndrome, depression, schizophrenia and epilepsy), ischemia-reperfusion injury (e.g. acute myocardial infarction, stroke, renal ischemia-reperfusion injury and organ damage during transplantation), metabolic diseases (e.g. hepatic steatosis, diabetes, diabetic retinopathy, cognitive impairment and other diabetes-related conditions, obesity and eating behaviors, and nonalcoholic fatty liver disease), inflammatory or autoimmune diseases (e.g., acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis), geriatric diseases (e.g., bone repair, age-related bone frailty in osteoporosis, and sarcopenia), renal diseases (e.g., chronic kidney disease and chronic kidney disease associated with APOL1 gene variants), mitochondrial diseases (e.g., Reye's syndrome, Leber hereditary optic neuropathy, and related disorders), and TDP-43 diseases or disorders. For example, neurodegeneration associated with TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia, facial-onset sensory and motor neuron disease, primary lateral sclerosis, progressive muscular dystrophy, inclusion body myopathy associated with early-onset Paget's disease of bone and frontotemporal dementia, Perry disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and age-related TDP-43 with sclerosis of the brain).

24. The compound for use according to any one of claims 18 to 23, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use or a method thereof, wherein the compound is for administration to a human subject.

25. A compound for use according to any one of claims 18 to 24, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use or a method for use, for use in combination with an additional therapeutic agent.

26. Compounds of formula (IIB): where R 1a 、R 1b 、R 2a 、R 3a 、R 4a 、R 5a 、R 6a , x and AA are as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

27. Compounds of formula (IIIB): wherein BA is as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

28. Compounds of formula (IVB): where R 4a 、R 5a 、R 6a and AA as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

29. Compounds of formula (VIIB): where R 4a 、R 5a 、R 6a and AA as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

30. Compounds of formula (VIIIB): where R 4a 、R 5a 、R 6a and AA as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

31. Compounds of formula (XIB): where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA is as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

32. Compounds of formula (XIIB): where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA is as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

33. Compounds of formula (XIIIB): where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA is as defined in any preceding claim; or a salt thereof, such as a pharmaceutically acceptable salt.

34. Compounds of formula (XIVB): where R 1a 、R 2a 、R 1a / b 、R 2a 、R 3a 、R 4a 、R 5a and AA is as defined in any preceding claim, and P is a nitrogen protecting group, such as BOC (tert-butoxycarbonyl), or a salt thereof, such as a pharmaceutically acceptable salt.

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