mPTP inhibitors

Abstract

The present invention relates to compounds of formula (I) and related embodiments. [Formula 1] TIFF2026503519000218.tif30170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel compounds that are inhibitors of the mitochondrial permeability transition pore (mPTP). The present invention also relates to such compounds for use as medicaments, inter alia, for the treatment or prevention of degenerative, neurodegenerative, or mitochondrial diseases, or other diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect. [Background technology]

[0002] BACKGROUND OF THE INVENTION The mitochondrial permeability transition pore (mPTP) is a membrane-binding protein that acts as a barrier to certain cellular stress conditions, particularly excess Ca. 2+ It is a high-conductance channel present in the inner mitochondrial membrane that is activated under stress and oxidative stress. It is permeable to solutes with a molecular mass of less than 1.5 kDa and is sensitive to voltage and Ca. 2+ They are dependent on mitochondrial membrane potential (MMP) and exhibit a characteristically high conductance. Once activated, oxidative phosphorylation is released, resulting in loss of mitochondrial membrane potential and perturbation of mitochondrial metabolism. Furthermore, solutes penetrate the mitochondrial matrix, causing swelling and ultimately rupturing the outer membrane, resulting in the release of apoptotic factors and sequestered Ca. 2+ This is accompanied by the release of ATP, which, depending on the cell type and physiological state, leads to eventual cell death by apoptosis or necrosis, and has therefore been implicated as a key pathological event in several degenerative and metabolic diseases.

[0003] Under normal physiological conditions, mitochondria regulate cellular Ca 2+ It plays an important role in regulating homeostasis. Ca2+ enters cells through cell surface channels, a common mechanism of cell signaling. 2+ is rapidly sequestered by mitochondria and displaces excess and toxic Ca in the cell cytoplasm. 2+ Prevents accumulation of high levels of Ca 2+In cell types such as neurons, skeletal muscle fibers, and cardiomyocytes that undergo influx of this Ca into mitochondria 2+ The "buffering" effect is crucial for maintaining cellular health. However, mitochondria do not produce enough Ca 2+ Mitochondrial Ca sequestering capacity is limited. 2+ When levels reach a certain threshold, Ca 2+ The sensitive mPTP is activated, leading to mitochondrial breakdown and the initiation of cell death. Activation of mPTP in degenerative diseases can occur in a variety of ways depending on the disease, including, for example: 1) excessive Ca into the cell; 2+ Entry and Ca into mitochondria 2+ 2) mitochondrial Ca overload 2+ Dysfunction of efflux mechanisms, especially Ca 2+ Ca overload 2+ 3) decreased activity of the efflux transporter NCLX, and 3) Ca in mitochondria 2+ 4) overactivity or upregulation of the uptake mechanism, oxidative stress, and 5) sensitization of mPTP due to impaired mitochondrial function, i.e., low intramitochondrial Ca 2+ mPTP activation at high concentrations, 6) excess Ca transport from the endoplasmic reticulum to mitochondria at the contact point between the two organelles known as the mitochondrial-associated membrane 2+ There is a transition.

[0004] Although the properties and function of mPTP can be tested in simple in vitro assays in isolated mitochondria, the molecular identity of mPTP is unknown. Although multiple proteins, including ATP synthase and members of the adenine nucleotide translocator (ANT) protein family, have been proposed to comprise the pore-forming complex, no single protein is widely accepted as being involved in pore formation. However, peptidyl prolyl cis-trans isomerase F (Ppif - Uniprot ID P30405, also known as cyclophilin D), although not a transmembrane channel by itself, is widely accepted to be a key regulator of the pore. Genetic or pharmacological inhibition of Ppif results in Ca 2+ Ppif significantly reduces the sensitivity of pore opening in response to stress and other mPTP activators. Therefore, genetic ablation or pharmacological inhibition of Ppif has been utilized to assess the involvement of mPTP in pathological pathways in cellular and animal disease models. Thus, mPTP inhibition has been shown to be a valuable tool in numerous disease models, particularly in the treatment of Ca 2+ It has been shown to be protective in disease models in which dysregulation and oxidative stress are known to contribute to cellular degeneration. In particular, genetic knockout of Ppif has been shown to be protective 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 (i.e., amyloid precursor protein, alpha-synuclein, and superoxide dismutase 1, respectively) that cause inherited disease and are expressed in mouse models, result in the downregulation of mitochondrial Ca. 2+It has been shown that mitochondrial Ca2+ induces either overload or sensitization of the mPTP. Recent evidence suggests that this may occur through a mechanism shared by Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. In each case, mitochondrial Ca2+ is increased in cells expressing mutated disease-associated proteins (amyloid precursor protein, PINK1, and frataxin, respectively). 2+ The activity or expression of the efflux transporter NCLX is decreased, resulting in mitochondrial Ca 2+ In the case of Parkinson's disease, it has also been shown that pathological aggregated forms of the protein α-synuclein, a misfolded protein common in sporadic and inherited cases of Parkinson's disease, sensitize and activate the mPTP.

[0005] Genetic ablation of Ppif has been shown to be beneficial in numerous other preclinical models of degenerative disease, thus demonstrating the potential of mPTP inhibitors in Duchenne and congenital muscular dystrophy, ischemia-reperfusion injury, bone repair, pancreatitis, among other related disorders.

[0006] In addition to the proven benefits of Ppif inhibition in preclinical models, mPTP function has been shown to be dysregulated in multiple other disease indications. In particular, in several diseases, Ca 2+ The threshold for mPTP activation in response to stress appears to be sensitive, suggesting that mPTP activation occurs abnormally under physiological conditions and may promote tissue degeneration.For example, in muscle mitochondria from aged human muscle biopsies, the threshold for mPTP activation is reduced compared to healthy controls.In these diseases, this sensitization of mPTP activity provides further rationale for the therapeutic potential of mPTP inhibitors.

[0007] mPTP inhibitors are used to treat mitochondrial dysfunction, oxidative stress, inflammatory stress, or Ca 2+ It may also have therapeutic potential in other diseases in which dysregulation occurs during disease pathogenesis.

[0008] The discovery and development of mPTP inhibitors has primarily focused on identifying Ppif inhibitors. Cyclosporin A (CsA), originally identified as an immunosuppressant due to its inhibitory activity against calcineurin, was found to inhibit not only Ppif but also other members of the peptidyl prolyl cis-trans isomerase (Ppi) enzyme family. Several cyclosporin A derivatives, e.g., Debio-25 and NIM811, were subsequently developed that retain broad activity against the Ppi enzyme family without inhibiting calcineurin, but none of these have been marketed. To date, no potent, brain-penetrant, selective Ppif inhibitors have been reported. Another more recent approach to discovering mPTP inhibitors utilizes phenotypic screening in isolated mitochondria. This has successfully identified potent small-molecule mPTP inhibitors with a Ppif-independent mode of action.

[0009] Yu et al. (2020, Cell, 183, 1-14) reported a link between mPTP activation and the mechanisms of TDP-43 proteinopathies, such as TDP-43-associated neurodegeneration. Accumulation of the normally nuclear protein TDP-43 in the neuronal cytoplasm is a hallmark of nearly all cases of ALS and 40-50% of frontotemporal lobar degeneration (FTLD), with some familial cases caused by mutant forms of this protein. Both diseases are associated with a neuroinflammatory cytokine profile linked to upregulation of the NF-κB and type I IFN pathways, directly implicating a role for TDP-43 in neuroinflammation. Mutant or overexpressed wild-type TDP-43 in neurons mislocalizes to mitochondria and induces the release of mitochondrial DNA (mtDNA) from the mitochondria to the cytoplasm. This mtDNA then activates the immune sensor cGAS-STING, leading to the induction of innate immune genes such as IL-6, TNFα, and interferon-β. Inhibition of mPTP with cyclosporine A or by knockout of Ppif prevents TDP-43-induced mtDNA release and the subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING extends the survival of mutant mice expressing mutant TDP-43. These data implicate mPTP activation in mediating 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.

[0010] Jang et al. (2021 American Journal of Physiology: Renal physiology, 2021 321:4, F431-F442) highlighted the potential therapeutic benefit of mPTP inhibition (via Ppif knockout) in a mouse model of renal fibrosis. Renal fibrosis was induced in WT and Ppif KO mice using unilateral ureteral obstruction. Markers of inflammation, proximal tubular atrophy, and fibrosis were reduced in Ppif KO mice compared with WT mice. Measures of fibrosis included collagen deposition, α-SMA and TGFβ expression, and interstitial cell proliferation. This highlights the potential role of mPTP in tissue remodeling and fibrogenesis mediated by cell injury / cell death. Therefore, mPTP inhibitors may be beneficial in diseases in which fibrosis is an important pathological mechanism, such as chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[0011] WO 2010 / 049768 relates to acrylamide derivatives and their use as therapeutic agents, particularly for the prevention and / or treatment of 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) relates to phenotypic screening of mPTP modulators using platelets and discloses additional acrylamide derivatives. CA 2884607 A1 relates to acrylamide and maleimide compounds that are said to be useful in the treatment of mitochondrial diseases. WO 2022 / 049376, WO 2022 / 049377, and WO 2023 / 166303 disclose cinnamide compounds that are inhibitors of mPTP.

[0012] There remains a need to discover additional compounds that are inhibitors of the mPTP. Summary of the Invention

[0013] (Summary of the Invention) In a first aspect, the present invention provides a compound according to formula (I): or a salt and / or solvate thereof [ka] (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl, C 0-6 alkylene (OH); or R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or C 5-6 phenyl fused to a cycloalkyl, wherein the phenyl or C 5-6 The phenyl fused to the cycloalkyl may be one or more AA 1 may be optionally substituted by; AA 1 Ha, Halo, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r , or NHSO2R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo(=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); provided that the compound of formula (I) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: [ka] isn't it).

[0014] In one embodiment, the compound of formula (I) is provided in the form of a salt. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) is provided in the form of a solvate. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt and a solvate (i.e., a pharmaceutically acceptable salt of a pharmaceutically acceptable solvate). In one embodiment, the compound of formula (I) is provided.

[0015] The present invention further 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 provisos of formula (I) do not apply).

[0016] The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0017] The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0018] The present invention also provides a method for preventing or treating a disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect 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 provisos of formula (I) do not apply).

[0019] Preferably, the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease.

[0020] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the treatment or prevention of mitochondrial diseases.

[0021] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a mitochondrial disease.

[0022] The present invention also provides a method for preventing or treating a mitochondrial disease 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 provisos of formula (I) do not apply).

[0023] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use in the treatment or prevention of diseases or disorders associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration.

[0024] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration.

[0025] The present invention also provides a method for treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, 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 provisos of formula (I) do not apply).

[0026] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the treatment or prevention of a disease or disorder associated with fibrosis.

[0027] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis.

[0028] 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 provisos of formula (I) do not apply). DETAILED DESCRIPTION OF THE INVENTION

[0029] (Detailed Description of the Invention) As used herein, the term "alkyl" refers to alkyl groups, whether alone or forming part of a larger group, such as C 1-4 The term "alkyl" as used in alkyl refers to 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, iso-propyl, n-butyl, iso-butyl, tert-butyl, and sec-butyl. Reference to "propyl" includes n-propyl and iso-propyl. Reference to "butyl" includes n-butyl, iso-butyl, tert-butyl, and sec-butyl.

[0030] Either alone or in a larger group, e.g., C 1-4 Alkylene (OH), C 1-6 Alkylene (OH) or C 1-6 Alkylene (C 3-6 As used herein, "alkylene" refers to any group, whether or not it forms part of a cycloalkyl, such as C 1-4 Alkylene or C 1-6 The term alkylene refers to a difunctional straight-chain or branched, fully saturated hydrocarbon group 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 A branched example of an alkylene group is i-propylene (i.e., -CH(Me)CH-). It will be understood that reference to C alkylene means that the alkylene chain is absent, for example, C alkylene(OH) represents OH.

[0031] As used herein, C 1-4 Alkylene (OH), e.g., C 1-4 The term alkylene refers to a C substituted by OH. 1-4 It refers to an alkyl group, for example CHOH. It will be understood that reference to C alkylene means that the alkylene chain is absent, for example C alkylene(OH) represents OH.

[0032] In the present specification, for example, C 1-4 Alkoxy or C 1-6 The term "alkoxy" as used in alkoxy refers to an alkyl group, as defined above, singly bonded to an oxygen atom (e.g., C 1-4 C refers to alkyl groups. 1-6Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, and 3-butoxy, especially methoxy.

[0033] The term "halo" or "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine. Particular examples of halo are bromine, fluorine, and chlorine, especially fluorine.

[0034] In the present specification, for example, C 1-4 Haloalkyl or C 1-6 The term "haloalkyl" as used in haloalkyl refers to a straight-chain or branched alkyl group containing the specified number of carbon atoms substituted with one or more halo atoms, for example, fluoromethyl (CHF), di-fluoromethyl (CHF), tri-fluoromethyl (CF), 1-fluoroethyl (CHFCH), and 2-fluoroethyl (CHCHF).

[0035] Either alone or in a larger group, e.g., C 0-6 Alkylene (C 3-6 As used herein, the term "cycloalkyl" refers to any group, whether it forms part of a cycloalkyl group, such as C 3-6 The term "cycloalkyl" as used in cycloalkyl refers to a fully saturated hydrocarbon ring containing the specified number of carbon atoms. 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, especially cyclopropyl. Cycloalkyl may be optionally substituted as defined herein.

[0036] In the present specification, for example, C 2-6The term "alkenyl" as used in alkenyl refers to a straight-chain or branched hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon double bond, e.g., one or two double bonds. This term encompasses CH=CH2, CH2CH=CH2, CH=CHCH3, CH2CH2CH=CH2, CH=CHCH2CH3, CH2CH=CHCH3, CH2CH2CH2CH=CH2, CH=CHCH2CH2CH3, CH2CH=CHCH2CH3, CH2CH2CH=CHCH3, CH=CHCH=CHCH3, and CH2CH=CHCH=CH2. Branched variants such as CH(CH3)CH=CH2 and CH=C(CH3)2 are also included.

[0037] In the present specification, for example, C 2-6 The term "haloalkenyl" as used in haloalkenyl is a straight or branched alkenyl chain containing the specified number of carbon atoms and at least one halogen atom, eg, fluoro or chloro, eg, fluoro.

[0038] As used herein, the term "aryl" refers to a monocyclic (i.e., phenyl) or polycyclic ring system (e.g., containing one or two, e.g., one, additional ring) containing at least one phenyl ring; preferably, the aryl group contains 6 to 10 ring members. The additional ring in a polycyclic ring system may be a saturated (e.g., forming indane or tetralin), partially unsaturated (e.g., forming indene), or fully unsaturated (e.g., forming naphthalene) hydrocarbon ring, or the additional ring may be a saturated or partially unsaturated heterocycle (e.g., forming chromane). Preferably, aryl refers to a monocyclic (i.e., phenyl) or bicyclic ring system containing at least one phenyl ring (and no heteroaryl ring).

[0039] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic ring system (e.g., bicyclic) having aromatic character and at least one ring containing at least one heteroatom, e.g., N, selected from N, O, and S. Suitably, a heteroaryl group contains 5 to 10 ring members. When a heteroaryl group contains multiple rings, not all rings contain heteroatoms, and not all rings must be aromatic in nature. In some examples, a heteroaryl is monocyclic, e.g., a 5- or 6-membered heteroaryl ring (e.g., containing one or two heteroatoms selected from N, S, and O). In other examples, a heteroaryl is bicyclic, e.g., a 5,5-, 5,6-, or 6,6-bicyclic system (e.g., containing one, two, or three heteroatoms selected from N, S, and O). A heteroaryl may contain one heteroatom selected from N, S, and O, e.g., N and O, especially N. In other examples, heteroaryls may contain two heteroatoms selected from N, S, and O. In further examples, heteroaryls may contain three heteroatoms selected from N, S, and O, such as N and O. Examples of six-membered heteroaryls include one nitrogen atom (pyridinyl), two nitrogen atoms (pyridazinyl, pyrimidinyl, or pyrazinyl), and three nitrogen atoms (triazinyl). Further examples of heteroaryls include triazolyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzoxazolinyl, quinolinyl, isoquinolinyl, and quinazolinyl.

[0040] As used herein, the term heterocycle refers to a non-aromatic cyclic group of carbon atoms in which 1 to 4 carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The heterocyclic group may be, for example, monocyclic or bicyclic. In a bicyclic heterocyclic group, one or more heteroatoms may be in each ring or in only one of the rings. When a heterocyclic group contains multiple rings, not all rings must contain heteroatoms. The heteroatoms may be S, O, or N, and are preferably O or N. Preferably, the heterocyclic group contains 5 to 10 ring members.

[0041] The heterocycle may contain one heteroatom selected from N, S, and O, for example, N and O, especially N. In other examples, the heterocycle may contain two heteroatoms selected from N, S, and O. In further examples, the heterocycle may contain three heteroatoms selected from N, S, and O, for example, N and O. In some examples, the heterocycle is monocyclic, for example, a 5- or 6-membered heterocyclic ring. Examples of heterocycles include morpholinyl, tetrahydrofuran, and tetrahydropyran.

[0042] When a substituent is shown to be optionally substituted in formula (I) or (IB) in the embodiments and preferences presented below, the optional substituent may be attached to an available carbon atom (which means a carbon atom bonded to a hydrogen atom, i.e., a CH group), or the optional substituent may be attached to an available nitrogen atom (which means a nitrogen atom bonded to a hydrogen atom, i.e., an NH group). The optional substituent replaces a hydrogen atom bonded to a carbon atom or a hydrogen atom bonded to a nitrogen atom.

[0043] The present invention provides a compound according to formula (I): or a salt and / or solvate thereof [ka] (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl, C 0-6 alkylene (OH); or R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or C 5-6 phenyl fused to a cycloalkyl, wherein the phenyl or C 5-6 The phenyl fused to the cycloalkyl may be one or more AA 1 may be optionally substituted by; AA1 Ha, Halo, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r , or NHSO2R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo(=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); provided that the compound of formula (I) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: [ka] isn't it).

[0044] In certain embodiments, the present invention provides a compound according to formula (IB): or a salt and / or solvate thereof [ka] (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, 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, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or one or more AA 1 C optionally substituted by 5-6 is a phenyl fused to a cycloalkyl; AA 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6Cycloalkyl, CN, OH, NR q R r , or NHSO2R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, which may be substituted with one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); wherein formula (IB) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: [ka] isn't it).

[0045] The compounds according to formula (IB) or salts and / or solvates thereof are a subgenus of the compounds of formula (I) or salts and / or solvates thereof. The compounds according to formula (IB') below or salts and / or solvates thereof are a subgenus of the compounds of formula (IB) or salts and / or solvates thereof. The following embodiments apply equally to compounds of formula (I), (IB), and / or (IB') or salts and / or solvates thereof.

[0046] In one embodiment, R 1a is H. In a second embodiment, R 1a is C 1-4 Alkyl, for example, methyl.

[0047] In one embodiment, R 1b is H. In a second embodiment, R 1b is C 1-4 Alkyl, for example, methyl.

[0048] In one embodiment, R 1a and R 1b are H, respectively.

[0049] In one embodiment, R 2a is H. In a second embodiment, R 2a is halo. In a third embodiment, R 2a is C 1-4 In a fourth embodiment, R 2a is C 1-4 It is haloalkyl.

[0050] In one embodiment, R 3a is H. In a second embodiment, R 3a is halo. In a third embodiment, R 3a is C 1-4 It is alkyl.

[0051] In one embodiment, R 2a and R 3a are H, respectively.

[0052] In one embodiment, R 4a is H. In a second embodiment, R 4a is C 1-4 Alkyl, for example, methyl.

[0053] In one embodiment, R 5a is H. In a second embodiment, R 5a is C 1-6 alkyl, for example, methyl. In a third embodiment, R 5a is C 1-6 In a fourth embodiment, R 5a is C 1-6In a fifth embodiment, R 5a is C 1-6 In a sixth embodiment, R 5a is C 2-6 In a seventh embodiment, R 5a is C 2-6 In an eighth embodiment, R 5a is C 0-6 Alkylene (C 3-6 In a ninth embodiment, R 5a is C 0-6 It is alkylene (OH).

[0054] In one embodiment, R 4a and R 5a are each methyl.

[0055] In one embodiment, R 4a and R 5a together with the atoms to which they are attached, C 3-6 In such an embodiment, C 3-6 Cycloalkyl is C 1-4 Alkyl, C 1-4 It may be substituted by one or more (e.g., one, two, or three, e.g., one or two) groups selected from the group consisting of haloalkyl and halo. 3-6 Cycloalkyl is C 1-4 Alkyl, C 1-4 It is substituted by one group selected from the group consisting of haloalkyl and halo. 3-6 Cycloalkyl is unsubstituted. In one embodiment, R 4a and R 5a together with the atom to which they are attached form a cyclobutyl.

[0056] In one embodiment, R 6a is H. In a second embodiment, R 6a is halo. In a third embodiment, R 6a is C1-4 In a fourth embodiment, R 6a is C 1-4 In a fifth embodiment, R 6a is C 1-4 In a sixth embodiment, R 6a is C 1-4 It is haloalkoxy.

[0057] In one embodiment, x is 0. In a second embodiment, x is 1. In a third embodiment, x is 2.

[0058] In one embodiment, AA is phenyl. In a second embodiment, AA is C 5-6 It is a phenyl fused to a cycloalkyl.

[0059] In one embodiment, AA is one or more (e.g., one, two, or three, e.g., one or two, in particular one) AA 1 has been replaced by

[0060] In one embodiment, at least one AA 1 is halo, for example, F. In a second embodiment, at least one AA 1 is C 1-6 In a third embodiment, at least one AA is alkyl. 1 is C 1-6 In a fourth embodiment, at least one AA is haloalkyl. 1 is C 1-6 In a fifth embodiment, at least one AA is alkoxy. 1 is C 1-6 In a sixth embodiment, at least one AA is haloalkoxy. 1 is C 3-6 In a seventh embodiment, at least one AA is cycloalkyl. 1 is CN. In an eighth embodiment, at least one AA 1 is OH. In a ninth embodiment, at least one AA1 is C 2-6 In a tenth embodiment, at least one AA is alkynyl. 1 is NR q R r Preferably, R q is H. Preferably, R q is C 1-4 Preferably, R r is H. Preferably, R r is C 1-4 In an eleventh embodiment, at least one AA is alkyl. 1 is NHSO2R t is.

[0061] In one embodiment, AA is 1, 2, or 3 AA 1 where AA 1 is a halo.

[0062] In one embodiment, AA is unsubstituted.

[0063] In one embodiment, BA is a monocyclic heterocycle. Preferably, BA is a 5-membered monocyclic heterocycle. In a second embodiment, BA is a bicyclic heterocycle. In a third embodiment, BA is a monocyclic heteroaryl. Preferably, BA is a 6-membered monocyclic heteroaryl. In a fourth embodiment, BA is a bicyclic heteroaryl.

[0064] In one embodiment, BA is one or more (e.g., one, two, or three, e.g., one or two, particularly one) B 1A has been replaced by

[0065] In one embodiment, at least one B 1A is halo. In a second embodiment, at least one B 1A is C 1-6 In a third embodiment, at least one B 1A is C 1-6In a fourth embodiment, at least one B is haloalkyl. 1A is C 1-6 In a fifth embodiment, at least one B 1A is C 1-6 In a sixth embodiment, at least one B 1A is C 0-6 alkylene (OH), for example, OH. In a seventh embodiment, at least one B 1A is oxo (=O).

[0066] In one embodiment, BA is unsubstituted.

[0067] In one embodiment, BA is [ka] (In the formula: B 1B is H or C 1-6 alkyl, for example, methyl; B 2B is H or C 1-6 alkyl, for example, methyl; and B 2B is C 0-6 alkylene (OH), e.g., OH) : selected from the group consisting of:

[0068] In one embodiment, BA is [ka] (In the formula: B 1B is H or C 1-6 alkyl, for example, methyl; B 2B is H or C 1-6 alkyl, for example, methyl; and B 2B is C 0-6 alkylene (OH), e.g., OH) : selected from the group consisting of:

[0069] In one embodiment, BA is [ka] is.

[0070] In one embodiment, BA is [ka] is.

[0071] In one embodiment, B 1B is H. In a second embodiment, B 1B is C 1-6 Alkyl, for example, methyl.

[0072] In one embodiment, B 2B is H. In a second embodiment, B 2B is C 1-6 Alkyl, for example, methyl.

[0073] In one embodiment, the present invention provides a compound of formula (IB'): or a salt and / or solvate thereof [ka] (In the formula, R 4a' is C 1-4 is alkyl; R 5a' is C 1-4 alkyl; or R 4a' and R 5a' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; B 1A' is a halo, e.g., F; and BA' is [ka] (selected from).

[0074] In one embodiment, R 4a' is methyl. In one embodiment, R 5a' is methyl. In one embodiment, R 4a' and R 5a' together with the atoms to which they are attached form a cyclobutyl ring.

[0075] In one embodiment, BA′ is [ka] In a second embodiment, BA′ is [ka] is.

[0076] In the following paragraphs, the references and preferences given with respect to salts, isomers, processes, pharmaceutical compositions, compounds for use, uses and method aspects for compounds of formula (I) or salts and / or solvates thereof apply equally to compounds of formula (IB) or salts and / or solvates thereof and / or compounds of formula (IB') or salts and / or solvates thereof.

[0077] In one embodiment, the compound of formula (I) is (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; (S)-(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-phenylpiperidine-1-carbonyl)pyrazin-2(1H)-one; (R)-6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S)-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; and 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; or any one of salts and / or solvates thereof : selected from the group consisting of:

[0078] In another embodiment, the compound of formula (I) is (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; (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]octan-6-yl)methanone; (R)-(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-phenylpiperidine-1-carbonyl)pyrazin-2(1H)-one; (S)-6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (R)-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; (S)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane; (R)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane; (R),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (R),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (R)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (S)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one; (R)-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; (S)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (R)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (S)-4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile; (R)-4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile; (S)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one; (R)-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; (S)-(3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; (R)-(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; (R),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (S),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (R),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (S),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one; (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one; (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one; (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one; (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; (R)-6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (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; (R)-3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-(8-(4-fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(4-fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (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]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(3-fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (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]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one (S)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; and (R)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one or any one of salts and / or solvates thereof : selected from the group consisting of:

[0079] The definition of a compound of formula (I) is intended to include all tautomers of the compound.

[0080] The compound of the present invention may be provided in the form of its pharmaceutically acceptable salt and / or solvate.In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate, for example, a pharmaceutically acceptable salt.In one embodiment, the compound of formula (I) is provided:

[0081] It will be understood that for use in medicine, salts of compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of compounds of formula (I) may be useful in other contexts, for example, during the preparation of compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in 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, may be used, for example, in the isolation of compounds of formula (I), and are within the scope of the present invention.

[0082] Certain compounds of formula (I) can form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0083] The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).

[0084] It should be understood that the present invention encompasses all stereoisomers of formula (I) and pharmaceutically acceptable derivatives thereof, including all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). Where additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0085] The present disclosure includes all isotopic forms of the compounds of the present invention provided herein, whether they are (I) in a form in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as "natural isotopic forms"), or (ii) in a form in which one or more atoms are replaced by an atom having the same atomic number but a mass number different from the mass number of the atom predominant in nature (referred to herein as "unnatural variant isotopic forms"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "unnatural variant isotopic forms" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less commonly found in nature (referred to herein as "uncommon isotopes") is increased compared to the proportion occurring in nature, for example, by >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment is referred to as an "isotopically enriched variant form"). The term "non-naturally occurring variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope is reduced compared to the proportion occurring in nature. Isotopic forms can include radioactive forms (i.e., those incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are usually isotopically enriched variant forms.

[0086] Therefore, non-naturally occurring isotopic forms of the compounds are deuterium ( 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( 123I), iodine-125( 125 It may contain one or more artificial or uncommon isotopes, such as I), in one or more atoms, or may contain an increased proportion of such isotopes compared to the proportion that predominates in nature.

[0087] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, for drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Non-naturally occurring variant isotopic forms incorporating H or D can offer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms can be prepared incorporating positron emitting isotopes such as N, which are useful in positron emission topography (PET) studies to examine substrate receptor occupancy.

[0088] In one embodiment, the compounds of the invention are provided in natural isotopic form.

[0089] In one embodiment, the compounds of the present invention are provided in non-naturally occurring variant isotopic forms. In a specific embodiment, the non-naturally occurring variant isotopic forms contain deuterium (i.e., hydrogen) at the location where hydrogen is designated in the chemical structure of one or more atoms of the compounds of the present invention. 2 In one embodiment, the atoms of the compounds of the present invention are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the present invention are in a radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0090] In one embodiment, compounds of the present invention are provided in which a single atom of the compound exists in a non-naturally occurring variant isotopic form. In another embodiment, compounds of the present invention are provided in which two or more atoms exist in a non-naturally occurring variant isotopic form.

[0091] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, for example, those described in the accompanying Examples for preparing natural isotopic forms. Thus, non-natural isotopic variant forms can be prepared by substituting appropriate isotopic variant (or labeling) reagents for the conventional reagents utilized in the Examples. Because the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g., at least 60% pure, more suitably at least 75% pure, and preferably at least 85%, particularly at least 98% pure (percentages are on a weight-to-weight basis). Impure preparations of the compounds can be used to prepare more pure forms for use in pharmaceutical compositions.

[0092] In general, compounds of formula (I) can be made according to organic synthesis techniques known to those skilled in the art, as well as by the representative methods shown below, 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.

[0093] (General route) General routes by which example compounds of the invention can be conveniently prepared are outlined below. In the following description, unless otherwise specified, 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 compounds of formula (I) and (IB).

[0094] (Scheme 1) [ka] Compounds of formula (I) or (IB) can be prepared by reacting a compound of formula (IIB) with a compound of formula (IIIB) under amide coupling conditions using an agent 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 can be used, such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) or PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium 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.

[0095] Compounds of formula (IIB) and (IIIB) are commercially available or can be prepared according to methods known to those skilled in the art.

[0096] (Scheme 2) [ka] A compound of formula (IIB) 1a , R 1b , R 2a , and R 3awhere x is H and x is 1) can be prepared by reacting a compound of formula (IVB) with a metal such as zinc under metal mediated cyclization conditions 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.

[0097] Compounds of formula (VB) and (VIB) are commercially available or can be made according to methods known to those skilled in the art.

[0098] (Scheme 3) [ka] Alternatively, a compound of formula (IIB) 1a , R 1b , R 2a , and R 3a where x is H and x is 1) can be prepared by reacting a compound of formula (VIIB) under reducing conditions, for example, with lithium aluminum hydride in a solvent such as tetrahydrofuran. A compound of formula (VIIB) can be obtained by reacting a compound of formula (VIIIB) under reducing conditions, for example, with Raney nickel and hydrogen and a solvent such as methanol. A compound 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.

[0099] Compounds of formula (IXB) and (XB) are commercially available or can be made according to methods known to those skilled in the art.

[0100] Scheme 4 [ka] Compounds of formula (IIB) (wherein x is 2) can be prepared by reacting compounds of formula (XIB) under hydrogenation conditions, for example, using palladium on carbon and hydrogen. Compounds of formula (XIB) can be prepared by elimination reaction of compounds of formula (XIIB) using an acid such as p-toluenesulfonic acid in a solvent such as toluene. Compounds of formula (XIIB) can be prepared by reacting compounds of formula (XIVB) (wherein P is a nitrogen protecting group, for example, BOC (tert-butyloxycarbonyl)) under deprotection conditions, for example, using hydrochloric acid in a solvent such as methanol. Compounds of formula (XIVB) can be prepared by reacting compounds of formula (XVB) with a commercially available reagent, for example, bromobenzene, using a base such as n-butyllithium and a solvent such as tetrahydrofuran.

[0101] Compounds of formula (XVB) are commercially available or can be made according to methods known to those skilled in the art.

[0102] Those skilled in the art will understand that protecting groups can be used throughout the synthetic schemes described herein to obtain protected derivatives of any of the compounds described above or of the general formula. Protecting groups and procedures for their removal are described in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 4th Edition, 2006, ISBN-10: 0471697540. Examples of nitrogen protecting groups include trityl (Tr), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzyl (Bn), and para-methoxybenzyl (PMB). Examples of oxygen protecting groups include acetyl (Ac), methoxymethyl (MOM), para-methoxybenzyl (PMB), benzyl, tert-butyl, methyl, ethyl, tetrahydropyranyl (THP), and silyl ethers and esters (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (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, e.g., C 1-4 Alkyl esters and C 1-4 haloalkyl esters), benzyl esters (including substituted benzyl esters, for example, p-methoxybenzyl ester), and silyl esters.

[0103] (process) The present invention provides a process for preparing a compound of formula (I) or a salt and / or solvate thereof, comprising the step of: [ka] (In the formula, R 1a , R 1b , R 2a , R3a , R 4a , R 5a , R 6a , AA, and x are as defined for compounds of formula (I). or a salt thereof, a compound of formula (IIIB) [ka] wherein BA is as defined for compounds of formula (I). or a salt thereof.

[0104] (Intermediate) The present invention also provides novel intermediates for use in the preparation of compounds of formula (I). Particular intermediates of interest are of the following general formula: (wherein the variables and associated preferences are as defined above for compounds of formula (I)). Thus, in one embodiment, the present invention provides a novel intermediate for use in the preparation of compounds of formula (I): a compound of formula (IIB): [ka] (In the formula, R 1a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , x, and AA are as defined for compounds of formula (I); a compound of formula (IIIB): [ka] wherein BA is as defined for compounds of formula (I); a compound of formula (IVB): [ka] (In the formula, R 4a , R 5a , R 6a and AA are as defined for compounds of formula (I); a compound of formula (VIIB): [ka] (In the formula, R 4a , R 5a , R 6a and AA are as defined for compounds of formula (I): a compound of formula (VIIIB): [ka] (In the formula, R 4a , R 5a , R 6a and AA are as defined for compounds of formula (I): a compound of formula (XIB): [ka] (In the formula, 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); a compound of formula (XIIB): [ka] (In the formula, 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); a compound of formula (XIIIB): [ka] (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R5a and AA are as defined for compounds of formula (I); and a compound of formula (XIVB): [ka] (In the formula, 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-butyloxycarbonyl). or a salt, for example a pharmaceutically acceptable salt, of any one thereof, selected from the group consisting of:

[0105] (Treatment method) The compounds of formula (I) of the present invention have utility as inhibitors of mPTP.

[0106] References to compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof in the context of the methods of treatment and prevention below are to be understood as including the proviso to formula (I), i.e., (5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: [ka] It is understood that this does not include

[0107] These compounds are commercially available and to date, no utility (eg, therapeutic utility) has been described for these compounds.

[0108] The present invention therefore provides, in particular, compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use as a medicament in the treatment or prevention of diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned hereinafter.

[0109] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply), for use as a medicament in the treatment of diseases or disorders in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned hereinafter.

[0110] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use as medicaments, in particular in the prevention of diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned hereinafter.

[0111] The present invention also provides, in particular, the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned hereinafter.

[0112] The present invention also provides, in particular, the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned hereinafter.

[0113] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the prevention of diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned hereinafter.

[0114] The present invention also provides a method for preventing or treating a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, such as the diseases and disorders mentioned hereinbelow, 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 provisos of formula (I) do not apply).

[0115] The present invention also provides a method for treating a disease or disorder in which inhibition of mPTP provides a therapeutic effect in a subject, such as the diseases and disorders mentioned hereinbelow, 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 provisos of formula (I) do not apply).

[0116] The present invention also provides a method for preventing a disease or disorder in which inhibition of mPTP provides a preventive effect in a subject, such as the diseases and disorders mentioned hereinbelow, 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 provisos of formula (I) do not apply).

[0117] As used herein, the term "treatment" or "treating" includes controlling, alleviating, reducing, or modulating a disease state or its symptoms.

[0118] As used herein, the term "prevention" or "preventing" is used to mean preventing the symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an affected subject, and is not limited to complete prevention of the disease.

[0119] In one embodiment, the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia or reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease.

[0120] In another embodiment, the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia or reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, a kidney disease, hearing loss, a disease or disorder of the eye, Charcot-Marie-Tooth disease (CMT1a), and Leigh's syndrome disease.

[0121] In one particular embodiment, the disease or disorder is 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.In one preferred embodiment, the disease or disorder is Parkinson's disease.In one preferred embodiment, the disease or disorder is Alzheimer's disease.In one preferred embodiment, the disease or disorder is amyotrophic lateral sclerosis.

[0122] In another particular embodiment, the disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorders, schizophrenia, and epilepsy.

[0123] In another embodiment, the disease or disorder is ischemia or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplantation.

[0124] In another embodiment, the disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease.

[0125] In another embodiment, the disease or disorder is a complication associated with a metabolic disease, eg, diabetic neuropathy.

[0126] In another embodiment, the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus erythematosus, organ failure in sepsis, and hepatitis.

[0127] In another embodiment, the disease or disorder is an age-related disease, such as bone repair, weakening of bones with age in osteoporosis, and sarcopenia.

[0128] In another embodiment, the disease or disorder is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene mutations.

[0129] In another embodiment, the disease or disorder is hearing loss, for example, hearing loss due to aging, noise, concussion, traumatic brain injury (TBI), drug-induced and / or genetic hearing loss, including spinal muscular atrophy (SMA) syndromes (SMA1, SMA2, SMA3, and SMA4, also called types I, II, III, and IV).

[0130] In another embodiment, the disease or disorder is an ocular disease or disorder, such as age-related macular degeneration.

[0131] In another embodiment, the disease or disorder is Charcot-Marie-Tooth disease (CMT1a).

[0132] In another embodiment, the disease or disorder is Leigh's syndrome disease.

[0133] The compounds of formula (I) are believed to be useful in the treatment or prevention of mitochondrial diseases.

[0134] Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the treatment or prevention of mitochondrial diseases, such as the diseases and disorders mentioned hereinafter.

[0135] The present invention provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use in the treatment of mitochondrial diseases, such as the diseases and disorders mentioned hereinbelow.

[0136] The present invention provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use in the prevention of mitochondrial diseases, such as the diseases and disorders mentioned hereinafter.

[0137] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of mitochondrial diseases, such as the diseases and disorders mentioned hereinbelow.

[0138] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment of mitochondrial diseases, such as the diseases and disorders mentioned hereinafter.

[0139] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the prevention of mitochondrial diseases, such as the diseases and disorders mentioned hereinafter.

[0140] The present invention also provides a method for treating or preventing a mitochondrial disease in a subject, such as the diseases and disorders mentioned hereinbelow, 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 provisos of formula (I) do not apply).

[0141] The present invention also provides a method of treating a mitochondrial disease in a subject, such as the diseases and disorders mentioned hereinbelow, 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 provisos of formula (I) do not apply).

[0142] The present invention also provides a method for preventing mitochondrial diseases in a subject, such as the diseases and disorders mentioned hereinbelow, 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 provisos of formula (I) do not apply).

[0143] 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 Peptide International).

[0144] The compounds of formula (I) are believed to be useful in the treatment or prevention of diseases or disorders associated with TDP-43 proteinopathies, such as TDP-43-associated neurodegeneration.

[0145] Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned hereinbelow.

[0146] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use in the treatment of diseases or disorders associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned hereinbelow.

[0147] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (wherein the provisos of formula (I) do not apply) for use in the prevention of diseases or disorders associated with TDP-43 proteinopathies, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned hereinbelow.

[0148] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below.

[0149] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0150] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned hereinbelow.

[0151] The present invention also provides a method for treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein 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 provisos of formula (I) do not apply).

[0152] The present invention also provides a method for treating a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein 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 provisos of formula (I) do not apply).

[0153] The present invention also provides a method for preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein 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 provisos of formula (I) do not apply).

[0154] Suitably, the disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial-onset sensorimotor neuropathy, primary lateral sclerosis, progressive muscular atrophy, inclusion body myopathy associated with early-onset Paget's disease of bone and frontotemporal lobar degeneration dementia, Perry's disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and brain age-related TDP-43 with sclerosis.

[0155] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the treatment or prevention of a disease or disorder associated with fibrosis.

[0156] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the treatment of a disease or disorder associated with fibrosis.

[0157] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) for use in the prevention of a disease or disorder associated with fibrosis.

[0158] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis.

[0159] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the treatment of a disease or disorder associated with fibrosis.

[0160] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (wherein the provisos of formula (I) do not apply) in the manufacture of a medicament for the prevention of a disease or disorder associated with fibrosis.

[0161] 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 provisos of formula (I) do not apply).

[0162] 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 provisos of formula (I) do not apply).

[0163] 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 provisos of formula (I) do not apply).

[0164] Preferably, 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.

[0165] Preferably, the subject is a mammal, and in particular, the subject is a human.

[0166] (Pharmaceutical composition) For use in therapy, the compounds of the invention are usually administered as pharmaceutical compositions. The invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a salt) and a pharmaceutically acceptable carrier or excipient (wherein the provisos of formula (I) do not apply).

[0167] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof (wherein the provisos of Formula (I) do not apply), for use in the treatment or prevention of a disease or disorder described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof (wherein the provisos of Formula (I) do not apply), for use in the treatment of a disease or disorder described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof (wherein the provisos of Formula (I) do not apply), for use in the prevention of a disease or disorder described herein.

[0168] In a further embodiment, there is provided a method for treating or preventing a disease or disorder described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof (wherein the provisos of Formula (I) do not apply). In a further embodiment, there is provided a method for treating a disease or disorder described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof (wherein the provisos of Formula (I) do not apply). In a further embodiment, there is provided a method for preventing a disease or disorder described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof (wherein the provisos of Formula (I) do not apply). The pharmaceutical compositions of the present invention can be in the form of pharmaceutical formulations as described below.

[0169] The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder described herein (where the provisos of formula (I) do not apply). The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof in the manufacture of a medicament for the treatment of a disease or disorder described herein (where the provisos of formula (I) do not apply). The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof in the manufacture of a medicament for the prevention of a disease or disorder described herein (where the provisos of formula (I) do not apply).

[0170] The amount of active ingredient required to achieve a therapeutic effect will, of course, vary depending on the particular compound, the route of administration, the subject being treated or prevented (including the type, species, age, weight, sex, and medical condition of the subject), and the subject's renal and hepatic function, as well as the particular 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 disease.

[0171] Oral dosages of the present invention, when used for the indicated effects, range from about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day for adults, preferably 0.01 mg / kg body weight / day (mg / kg / day) to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets or other presentations provided in discrete units containing 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 ingredient for symptomatic adjustment of dosage to the patient being treated. Medicaments typically contain from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg. Intravenously, the most preferred dosage ranges from about 0.1 to about 10 mg / kg / minute during a constant rate infusion. Advantageously, compounds of the present invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, or four times daily. Furthermore, compounds of the present invention can be preferably administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patch formulations well known to those skilled in the art. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0172] Pharmaceutical formulations according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), intranasal (also known as intranasal administration), inhalation (including fine particle dusts or mists which may be generated by various types of pressurized metered dose aerosols, nebulizers, or inhalers), insufflation, rectal, intraperitoneal, topical (including cutaneous, buccal, sublingual, and intraocular), and intrathecal administration, although the most suitable route may depend, for example, on the disease and disorder of the recipient.

[0173] Preferred pharmaceutical formulations according to the present invention are those suitable for oral, intrathecal, and parenteral administration; and more preferably, those suitable for oral or intrathecal administration.

[0174] In one preferred embodiment, the compound according to formula (I) is administered by intrathecal administration.This administration method involves injecting the compound of the present invention into the spinal canal or into the subarachnoid space, so that it reaches cerebrospinal fluid.This is advantageous for administering compounds that may not be able to pass through the blood-brain barrier by other administration routes, such as oral administration.

[0175] Suitable pharmaceutical formulations can be administered intrathecally, for example, by continuous infusion using a catheter or pump, or by single bolus injection or intermittent bolus injection. For intrathecal administration, the pharmaceutical composition can be administered continuously or intermittently. Intermittent administration can be, for example, every 30 minutes, every hour, every few hours, every 24 hours, every 2-3 days (e.g., every 48 or 72 hours), or any combination thereof.

[0176] When the pharmaceutical formulations of the present invention are administered continuously, an implantable delivery device, such as an implantable pump, can be utilized. Examples of such delivery devices include devices that can be implanted subcutaneously within the body or within the skull and provide an access port through which the pharmaceutical formulation can be delivered to nerves or the brain.

[0177] Intrathecal dosages of the present invention when used for the indicated effects are typically less than 1 mg, e.g., less than 500 μg, e.g., less than 250 μg per kg body weight for adults when administered in a single dose or intermittently. When administered continuously, intrathecal dosages of the present invention are typically less than 250 μg per kg body weight per hour, e.g., less than 125 μg per kg body weight per hour for adults.

[0178] In another preferred embodiment, the compounds according to Formula (I) are administered intranasally, by inhalation (including fine particle dusts or mists that can be generated by various types of pressurized metered-dose aerosols, nebulizers, or inhalers), or by insufflation. Such administration methods allow for lower doses of the compounds of the invention to be administered, which may lead to fewer side effects. For example, daily doses of 10 to 0.01 μg, preferably 1 to 0.01 μg, and more preferably as little as 0.1 μg (100 ng) of the compounds of the invention can be used.

[0179] The formulations can be conveniently provided in unit dosage form and can be prepared by any method known in the art of pharmacy.All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0180] Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, pills, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid, for example, an elixir, tincture, suspension, or syrup; or as an oil-in-water or water-in-oil emulsion. The active ingredient can also be presented as a bolus, electuary, or paste.

[0181] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein. The compounds of formula (I) can be administered, for example, in a form suitable for immediate or sustained release. Immediate release or sustained release can be achieved by using a suitable pharmaceutical composition containing the compound of the present invention, or, particularly in the case of sustained release, by the use of devices such as subcutaneous implants or osmotic pumps. The compounds of the present invention can also be administered liposomally.

[0182] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to impart bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate-release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose, and / or lactose, and / or other excipients, binders, fillers, 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 syrup, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compound of formula (I) can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those in which the compound of the present invention is formulated with a fast-dissolving diluent such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also contain high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations may also contain excipients that aid in adhesion to the mucosa, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and release-controlling agents such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, glidants, flavors, colorants, and stabilizers may also be added for ease of manufacture and use.Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.

[0183] 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).

[0184] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above. 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 agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0185] Exemplary compositions for intranasal, aerosol, or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0186] Formulations for rectal administration can be presented as suppositories using conventional carriers such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are usually solid at room temperature but liquefy and / or melt in the rectal cavity to release the drug.

[0187] Formulations for topical administration in the mouth, e.g., buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base 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).

[0188] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0189] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0190] Compounds of formula (I) have a pIC of 6.0 or greater in the rat liver assay, as shown in the assays of Biological Example 1. 50 value and / or a pIC of 7.0 or greater in the rat brain assay 50 values), which are believed to exhibit advantageous properties of inhibitory activity of mPTP.

[0191] (Provisions) The invention is further defined by the following clauses. Clause 1. Compounds according to formula (I): or salts and / or solvates thereof [ka] (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, C 0-6 Alkylene (C 3-6 Cycloalkyl, C 0-6 alkylene (OH); or R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or one or more AA 1 C optionally substituted by 5-6 is a phenyl fused to a cycloalkyl; AA 1 Ha, Halo, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r , or NHSO2R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo(C=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); provided that the compound of formula (I) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: [ka] isn't it). Clause 2. A compound of formula (IB) according to claim 1: or a salt and / or solvate thereof [ka] (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, 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, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or one or more AA 1 C optionally substituted by 5-6 is a phenyl fused to a cycloalkyl; AA 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r , NHSO2R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, which may be substituted with one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); provided that the compound of formula (IB) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: [ka] isn't it). Clause 3. A compound according to Clause 1 or Clause 2, or a salt and / or solvate thereof, which is said compound or a pharmaceutically acceptable salt and / or solvate thereof. Clause 4. Pharmaceutically acceptable salts and solvates according to clause 3. Clause 5. A pharmaceutically acceptable salt according to clause 3. Clause 6. A pharmaceutically acceptable solvate according to clause 3. Clause 7. A compound according to clause 1. Clause 8. A compound according to any one of clauses 1 to 7, or a salt and / or solvate thereof, which is a compound according to formula (IB): or a salt and / or solvate thereof [ka] . Article 9.R 1a 9. The compound according to any one of clauses 1, 2 or 8, or a salt and / or solvate thereof, wherein is H. Article 10.R 1a C 1-4 9. The compound according to any one of clauses 1, 2 or 8, or a salt and / or solvate thereof, wherein alkyl, for example methyl. Article 11.R 1b 11. The compound according to any one of clauses 1, 2 or 8-10, or a salt and / or solvate thereof, wherein Article 12.R 1b C 1-4 11. The compound according to any one of clauses 1, 2, or 8-10, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl. Article 13.R 2a 13. The compound according to any one of clauses 1, 2 or 8-12, or a salt and / or solvate thereof, wherein Article 14.R 2a 13. The compound according to any one of clauses 1, 2 or 8-12, or a salt and / or solvate thereof, wherein is halo. Article 15.R 2a C 1-4 13. The compound according to any one of clauses 1, 2, or 8 to 12, or a salt and / or solvate thereof, wherein R is alkyl. Article 16.R 2a C 1-4 13. The compound according to any one of clauses 1, 2, or 8-12, or a salt and / or solvate thereof, which is haloalkyl. Article 17.R 3a 17. The compound according to any one of clauses 1, 2 or 8-16, or a salt and / or solvate thereof, wherein Article 18.R 3a 17. The compound according to any one of clauses 1, 2 or 8 to 16, or a salt and / or solvate thereof, wherein is halo. Article 19.R 3a C 1-417. The compound according to any one of clauses 1, 2, or 8 to 16, or a salt and / or solvate thereof, wherein R is alkyl. Article 20.R 4a 20. The compound according to any one of clauses 1, 2 or 8-19, or a salt and / or solvate thereof, wherein Article 21.R 4a C 1-4 20. The compound according to any one of clauses 1, 2 or 8-19, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl. Article 22.R 5a 22. The compound according to any one of clauses 1, 2 or 8-21, or a salt and / or solvate thereof, wherein Article 23.R 5a C 1-6 22. The compound according to any one of clauses 1, 2 or 8-21, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl. Article 24.R 5a C 1-6 22. The compound according to any one of clauses 1, 2, or 8 to 21, or a salt and / or solvate thereof, which is haloalkyl. Article 25.R 5a C 1-6 22. The compound according to any one of clauses 1, 2, or 8 to 21, or a salt and / or solvate thereof, which is alkoxy. Article 26.R 5a C 1-6 22. The compound according to any one of clauses 1, 2, or 8 to 21, or a salt and / or solvate thereof, which is haloalkoxy. Article 27.R 5a C 2-6 22. The compound according to any one of clauses 1, 2, or 8 to 21, or a salt and / or solvate thereof, which is alkenyl. Article 28.R 5a C 2-6 22. The compound according to any one of clauses 1, 2, or 8 to 21, or a salt and / or solvate thereof, which is haloalkenyl. Article 29.R 5a C 0-6 Alkylene (C 3-622. The compound according to any one of clauses 1, 2, or 8 to 21, or a salt and / or solvate thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 Article 30.R 5a C 0-6 22. The compound according to any one of clauses 1, 2, or 8-21, or a salt and / or solvate thereof, wherein is alkylene(OH). Article 31.R 4a and R 5a together with the atoms to which they are bonded, C 3-6 A compound according to any one of clauses 1, 2 or 8-19 or a salt and / or solvate thereof, which forms a cycloalkyl, for example cyclobutyl. Article 32.R 6a 32. The compound according to any one of clauses 1, 2 or 8-31, or a salt and / or solvate thereof, wherein Article 33.R 6a 32. The compound according to any one of clauses 1, 2 or 8 to 31, or a salt and / or solvate thereof, wherein is halo. Article 34.R 6a C 1-4 32. The compound according to any one of clauses 1, 2, or 8 to 31, or a salt and / or solvate thereof, wherein: Article 35.R 6a C 1-4 32. The compound according to any one of clauses 1, 2, or 8 to 31, or a salt and / or solvate thereof, which is haloalkyl. Article 36.R 6a C 1-4 32. The compound according to any one of clauses 1, 2, or 8 to 31, or a salt and / or solvate thereof, which is alkoxy. Article 37.R 6a C 1-4 32. The compound according to any one of clauses 1, 2, or 8 to 31, or a salt and / or solvate thereof, which is haloalkoxy. Clause 38. The compound according to any one of clauses 1, 2 or 8 to 37, or a salt and / or solvate thereof, wherein x is 1. Clause 39. The compound according to any one of clauses 1, 2 or 8 to 37, or a salt and / or solvate thereof, wherein x is 2. Clause 40. The compound according to any one of clauses 1, 2, or 8-39, or a salt and / or solvate thereof, wherein AA is phenyl. Article 41. AA is C 5-6 40. The compound according to any one of clauses 1, 2 or 8-39, or a salt and / or solvate thereof, wherein the compound is phenyl fused to a cycloalkyl. Article 42. AA is one or more (e.g., one, two, or three, e.g., one or two, in particular one) AA 1 42. The compound according to clause 40 or 41, or a salt and / or solvate thereof, substituted by: Article 43. At least one AA 1 43. The compound according to clause 42, or a salt and / or solvate thereof, wherein is halo. Article 44. At least one AA 1 44. The compound according to clause 43, or a salt and / or solvate thereof, wherein Article 45. At least one AA 1 C 2-6 45. The compound according to any one of clauses 42 to 44, or a salt and / or solvate thereof, which is alkynyl. Article 46. At least one AA 1 C 1-6 46. ​​The compound according to any one of clauses 42 to 45, or a salt and / or solvate thereof, wherein R is alkyl. Article 47. At least one AA 1 C 1-6 47. The compound according to any one of clauses 42 to 46, or a salt and / or solvate thereof, which is haloalkyl. Article 48. At least one AA 1 C 1-6 48. The compound according to any one of clauses 42 to 47, or a salt and / or solvate thereof, which is alkoxy. Article 49. At least one AA 1 C 1-649. The compound according to any one of clauses 42 to 48, or a salt and / or solvate thereof, which is haloalkoxy. Article 50. At least one AA 1 C 3-6 50. The compound according to any one of clauses 42 to 49, or a salt and / or solvate thereof, which is cycloalkyl. Article 51. At least one AA 1 51. The compound according to any one of clauses 42 to 50, or a salt and / or solvate thereof, wherein is CN. Article 52. At least one AA 1 NR q R r 52. The compound according to any one of clauses 42 to 51, or a salt and / or solvate thereof, wherein Article 53.R q 53. The compound according to clause 52, or a salt and / or solvate thereof, wherein is H. Article 54.R q C 1-4 53. The compound according to clause 52, or a salt and / or solvate thereof, wherein: Article 55. At least one AA 1 NHSO2R t 55. The compound according to any one of clauses 42 to 54, or a salt and / or solvate thereof, wherein Clause 56. A compound according to clause 40 or 41, or a salt and / or solvate thereof, wherein AA is unsubstituted. Clause 57. The compound according to any one of clauses 1, 2, or 8 to 56, or a salt and / or solvate thereof, wherein BA is a monocyclic heterocycle. Clause 58. The compound according to Clause 57, or a salt and / or solvate thereof, wherein BA is a 5-membered monocyclic heterocycle. Clause 59. The compound according to any one of clauses 1, 2, or 8 to 56, or a salt and / or solvate thereof, wherein BA is a bicyclic heterocycle. Clause 60. The compound according to any one of clauses 1, 2, or 8-56, or a salt and / or solvate thereof, wherein BA is monocyclic heteroaryl. Clause 61. The compound according to Clause 60, or a salt and / or solvate thereof, wherein BA is a 6-membered monocyclic heteroaryl. Clause 62. The compound according to any one of clauses 1, 2, or 8-56, or a salt and / or solvate thereof, wherein BA is bicyclic heteroaryl. Article 63. BA is one or more (e.g., one, two, or three, e.g., one or two, in particular, one) B 1A 63. The compound according to any one of clauses 57 to 62, or a salt and / or solvate thereof, substituted by: Article 64. At least one B 1A 64. The compound according to clause 63, or a salt and / or solvate thereof, wherein is halo. Article 65. At least one B 1A C 1-6 65. The compound according to clause 63 or 64, or a salt and / or solvate thereof, wherein R is alkyl. Article 66. At least one B 1A 66. The compound according to clause 63 or 65, or a salt and / or solvate thereof, wherein is methyl. Article 67. At least one B 1A C 1-6 67. The compound according to any one of clauses 63 to 66, or a salt and / or solvate thereof, which is haloalkyl. Article 68. At least one B 1A 68. The compound according to any one of clauses 63 to 67, or a salt and / or solvate thereof, wherein is oxo (C=O). Article 69. At least one B 1A C 1-6 69. The compound according to any one of clauses 63 to 68, or a salt and / or solvate thereof, which is alkoxy. Article 70. At least one B 1A C 1-6 70. The compound according to any one of clauses 63 to 69, or a salt and / or solvate thereof, which is haloalkoxy. Article 71. At least one B 1A C 0-671. The compound according to any one of clauses 63 to 70, or a salt and / or solvate thereof, which is alkylene (OH), such as OH. Clause 72. The compound according to any one of clauses 57 to 62, or a salt and / or solvate thereof, wherein BA is unsubstituted. Article 73. If BA: [ka] (In the formula: B 1B is H or C 1-6 alkyl, for example, methyl; B 2B is H or C 1-6 alkyl, for example, methyl; and B 2B is C 0-6 alkylene (OH), e.g., OH) 73. The compound according to any one of clauses 1, 2, or 8 to 72, or a salt and / or solvate thereof, selected from the group consisting of: Article 74. If BA: [ka] 74. A compound according to clause 73, or a salt and / or solvate thereof, which is: Article 75. If BA: [ka] 74. A compound according to clause 73, or a salt and / or solvate thereof, which is: Article 76. If BA: [ka] 74. A compound according to clause 73, or a salt and / or solvate thereof, which is: Article 77. Compounds of formula (IB'): or salts and / or solvates thereof [ka] (In the formula, R 4a' is C1-4 is alkyl; R 5a' is C 1-4 alkyl; or R 4a' and R 5a' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; B 1A' is a halo, e.g., F; and BA' is [ka] (selected from 9. The compound according to any one of clauses 1, 2 or 8, or a salt and / or solvate thereof, wherein Article 78.R 4a' and R 5a' together with the atom to which they are attached form a cyclobutyl ring or a salt and / or solvate thereof. Article 79. BA': [ka] 79. The compound according to clause 77 or 78, or a salt and / or solvate thereof, wherein Article 80. (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; (S)-(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-phenylpiperidine-1-carbonyl)pyrazin-2(1H)-one; (R)-6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S)-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; and 6-(3-methyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; or any one of salts and / or solvates thereof 9. The compound according to any one of clauses 1, 2 or 8, or a salt and / or solvate thereof, selected from the group consisting of: Article 81. (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; (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]octan-6-yl)methanone; (R)-(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-phenylpiperidine-1-carbonyl)pyrazin-2(1H)-one; (S)-6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (R)-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; (S)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane; (R)-8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane; (R),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (R),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one; (S)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (R)-6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (S)-6-[4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl]-1H-pyrazin-2-one; (R)-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; (S)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (R)-6-[(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one; (S)-4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile; (R)-4-[6-(6-oxo-1H-pyrazine-2-carbonyl)-6-azaspiro[3.4]octan-8-yl]benzonitrile; (S)-2-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-3H-pyrimidin-4-one; (R)-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; (S)-(3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone; (R)-(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; (R),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (S),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (R),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (S),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one; (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one; (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyridin-2(1H)-one; (S)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one; (R)-6-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-2(1H)-one; (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; (R)-6-(8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(2-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (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; (R)-3-(8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-(8-(4-fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(4-fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (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]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(3-fluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (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]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(2,3-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (R)-6-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one; (S)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (R)-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octan-6-yl)(3-hydroxyisoxazol-5-yl)methanone; (S)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(3,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one (S)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (R)-3-(8-(2,4-difluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; (S)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one; and (R)-3-(8-(3-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)-1,2,4-oxadiazol-5(4H)-one or any one of salts and / or solvates thereof 9. The compound according to any one of clauses 1, 2 or 8, its salt and / or solvate selected from the group consisting of: Clause 82. A pharmaceutical composition comprising a compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 83. A compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply) for use as a pharmaceutical. Clause 84. A compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply) for use in the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. Clause 85. Use of a compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect (wherein the proviso to formula (I) does not apply). Clause 86. A method for preventing or treating a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, comprising administering to a subject in need thereof an effective amount of a compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 87. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to any one of clauses 3 to 86, wherein said disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia and reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, age-related diseases, and renal diseases. Clause 88. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to any one of clauses 3 to 86, wherein said disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia and reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, age-related diseases, kidney diseases, hearing loss, diseases or disorders of the eye, Charcot-Marie-Tooth disease (CMT1a), and Leigh's syndrome diseases. Clause 89. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 88, wherein said 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. Article 90. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorders, schizophrenia, and epilepsy. Article 91. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is ischemia or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplantation. Article 92. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease. Article 93. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behaviour, diabetic neuropathy, and non-alcoholic fatty liver disease. Article 94. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is an inflammatory or autoimmune disease, for example, acute pancreatitis, systemic lupus erythematosus, organ failure in sepsis, and hepatitis. Article 95. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is an age-related disease, such as bone repair, weakening of bone with age in osteoporosis, and sarcopenia. Clause 96. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 88, wherein said disease or disorder is a renal disease, such as chronic renal disease and chronic renal disease associated with APOL1 gene mutations. Article 97. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 88, wherein said disease or disorder is hearing loss, for example hearing loss due to ageing, noise, concussion, traumatic brain injury (TBI), drug-induced and / or genetic hearing loss, including spinal muscular atrophy (SMA) syndromes (SMA1, SMA2, SMA3, and SMA4, also called types I, II, III, and IV). Clause 98. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 88, wherein said disease or disorder is an ocular disease or disorder, for example age-related macular degeneration. Clause 99. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 88, wherein said disease or disorder is Charcot-Marie-Tooth disease (CMT1a). Clause 100. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 88, wherein said disease or disorder is Leigh's syndrome disease. Clause 101. A compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply) for use in the treatment or prevention of mitochondrial diseases. Clause 102. A compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply) for use in the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration. Article 103. Use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to any one of Articles 3 to 81 in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, wherein the provisos of formula (I) do not apply. Clause 104. A method for treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, comprising administering to a subject in need thereof an effective amount of a compound according to any one of clauses 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 105. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use, or method according to any one of clauses 102 to 104, wherein said disease or disorder is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensorimotor neuropathy, primary lateral sclerosis, progressive muscular atrophy, inclusion body myopathy associated with early onset Paget's disease of bone, and frontotemporal lobar degeneration dementia, Perry's disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and brain age-related TDP-43 with sclerosis. Article 106. A compound according to any one of Articles 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply) for use in the treatment or prevention of a disease or disorder associated with fibrosis. Article 107. Use of a compound according to any one of Articles 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis (wherein the proviso to formula (I) does not apply). Article 108. 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 according to any one of Articles 3 to 81 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 109. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use, or method according to any one of clauses 106 to 108, wherein said disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis. Clause 110. A process for the preparation of a compound of formula (I) according to any one of clauses 1, 2 or 8 to 76, comprising the steps of: a compound of formula (IIB) or a salt thereof [ka] (In the formula, R 1a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , AA, and x are as defined for compounds of formula (I). a compound of formula (IIIB) or a salt thereof [ka] wherein BA is as defined for compounds of formula (I). The process comprising reacting Article 111. a compound of formula (IIB): [ka] (In the formula, R 1a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , x, and AA are as defined in any one of clauses 1 to 110. a compound of formula (IIIB): [ka] wherein BA is as described in any one of clauses 1 to 110; a compound of formula (IVB): [ka] (In the formula, R 4a , R 5a , R 6a , and AA is as set out in any one of clauses 1 to 110); a compound of formula (VIIB): [ka] (In the formula, R 4a , R 5a , R 6a , and AA is as set out in any one of clauses 1 to 110); a compound of formula (VIIIB): [ka] (In the formula, R 4a , R 5a , R 6a , and AA is as set out in any one of clauses 1 to 110); a compound of formula (XIB): [ka] (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a , and AA is as set out in any one of clauses 1 to 110); a compound of formula (XIIB): [ka] (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a , and AA is as set out in any one of clauses 1 to 110); a compound of formula (XIIIB): [ka] (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R5a and AA are as defined in any one of clauses 1 to 110); and a compound of formula (XIVB): [ka] (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a and AA is as defined in any one of clauses 1 to 110, and P is a nitrogen protecting group, for example, BOC (tert-butyloxycarbonyl). or a salt, for example a pharmaceutically acceptable salt, of any one of these.

[0192] The present invention is further illustrated by the following non-limiting examples. [Example]

[0193] (Example) The present invention is illustrated by the following compounds. The following examples describe experimental syntheses of specific compounds of the present invention and are not intended to limit the scope of the invention in any way with respect to the compounds or processes. Although specific reagents, solvents, temperatures, and time periods are used, it is understood that there are many possible equivalent alternatives that can be used to produce similar results. The present invention is intended to encompass such equivalents.

[0194] (General experimental details) Starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification unless otherwise specified. Unless otherwise specified, all compounds containing a chiral center are racemic. Where reactions are described as being carried out in a similar manner to earlier, more fully described reactions, the general reaction conditions used were essentially the same. Workup conditions used were of the type standard in the art but may have been adapted for each reaction. Starting materials were not necessarily prepared from the batch referred to. Synthesized compounds may have varying purities, ranging, for example, from 85% to 99%. Molar and yield calculations may be adjusted accordingly.

[0195] The purity of the final compounds was confirmed by HPLC / MS analysis and was determined to be at least 90%, and in the majority of cases, 95% or greater. Analytical LCMS was performed using the instrumentation shown in Table 1 or Table 2. 1 H NMR was recorded at 300 K on a Bruker 300 MHz instrument (ADVANCE III and ADVANCE III HD) or a Bruker 400 MHz (Avance Neo 400). Table 1: Analytical LC-MS conditions [Table 1] Table 2: Analytical LC-MS conditions [Table 2] TIFF2026503519000057.tif204170

[0196] (Synthesis of Example Compounds) (abbreviation) [Table 3] TIFF2026503519000059.tif247170TIFF2026503519000060.tif236170

[0197] (Intermediate 1: 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid) [ka] To a 1 L round-bottom flask were 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 × 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give ethyl 2-imino-2-(2-methylhydrazineyl)acetate (7 g) as a yellow oil.

[0198] [ka] To a 500 mL round-bottom flask was added ethyl 2-imino-2-(2-methylhydrazine)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 the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography. This afforded ethyl 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylate (4.5 g, 54% yield) as a pale yellow solid.

[0199] [ka] 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.). The mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 with concentrated HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (1.7 g, 81% yield) as a white solid. LC-MS (ES, m / z): [M−H] - =142

[0200] Example 1(a): (5-Hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone [ka] An 8-mL sealed tube was charged with 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 h. 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; [ka]

[0201] 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) [ka] A 25-mL round-bottom flask was charged with 5-hydroxypyridine-3-carboxylic acid (220.00 mg, 1.58 mmol, 1.00 equiv) and thionyl chloride (10 mL). The resulting solution was stirred at 70 °C for 12 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. This afforded 200 mg (80% yield) of 5-hydroxypyridine-3-carbonyl chloride as a pale yellow solid.

[0202] [ka] A 25-mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 8-phenyl-6-azaspiro[3.4]octane hydrochloride (227.22 mg, 1.02 mmol, 1.00 equiv.), DCM (10.00 mL), and EtN (205.53 mg, 2.03 mmol, 2.00 equiv.). Following this, 5-hydroxypyridine-3-carbonyl chloride (160.00 mg, 1.02 mmol, 1.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 12 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2 × 15 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column 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.

[0203] Enantiomer A LC-MS (ES, m / z): [M+H] + =309; [ka]

[0204] Enantiomer B LC-MS (ES, m / z): [M+H] + =309; [ka]

[0205] 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.

[0206] Example 2: (6-Hydroxypyrazin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone [ka] An 8-mL sealed tube was charged with 8-phenyl-6-azaspiro[3.4]octane hydrochloride (30.0 mg, 0.13 mmol, 1.00 equiv.), 6-hydroxypyrazine-2-carboxylic acid (20.66 mg, 0.15 mmol, 1.10 equiv.), EDC.HCl (38.56 mg, 0.20 mmol, 1.50 equiv.), DIPEA (41.93 mg, 0.325 mmol, 2.5 equiv.), and DMF (2.00 mL). The resulting solution was stirred at room temperature for 3 h. The mixture was purified by flash preparative HPLC. This afforded 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; [ka]

[0207] Example 3: (4-hydroxypyridin-2-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone [ka] An 8-mL sealed tube was charged with 8-phenyl-6-azaspiro[3.4]octane hydrochloride (30.0 mg, 0.14 mmol, 1.00 equiv.), 4-hydroxypyridine-2-carboxylic acid (18.65 mg, 0.14 mmol, 1.00 equiv.), DMF (3.00 mL), EDC.HCl (38.56 mg, 0.20 mmol, 1.50 equiv.), and DIPEA (45.15 mg, 0.35 mmol, 2.5 equiv.). The resulting solution was stirred at room temperature for 2 h. The mixture was directly purified by flash preparative HPLC. This afforded 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; [ka]

[0208] Example 4: (3,3-dimethyl-4-phenylpyrrolidin-1-yl)(5-hydroxypyridin-3-yl)methanone [ka] A 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (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-phenylbutanal as an off-white solid.

[0209] [ka] A 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,2-dimethyl-4-nitro-3-phenylbutanal (420.00 mg, 1.90 mmol, 1.00 equiv), AcOH (20.00 mL), and HO (20.00 mL). This was followed by the addition of Zn (372.49 mg, 5.70 mmol, 3.00 equiv) at 0 °C. The resulting solution was stirred overnight at room temperature. The solids were filtered off. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 150 mg (45% yield) of 3,3-dimethyl-4-phenylpyrrolidine as a pale yellow oil.

[0210] [ka] An 8-mL sealed tube was charged with 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; [ka]

[0211] 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 [ka] A 40-mL vial was charged with 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 gave 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; [ka]

[0212] (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)) [ka] The enantiomers were separated under the following conditions (column: CHIRALCEL OJ-3, 50 * Separation by preparative HPLC using 4.6 mm, 3 um OJ30CC-QK005; mobile phase: 70% EtOH (containing 0.2% MSA) / Hexane; flow rate: 25 mL / min; wavelength: 254 nm gave the following:

[0213] Enantiomer A of Example 5(b) (Rt 5.5 min) was isolated as an off-white solid and assigned as 2-methyl-5-[(8S)-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-triazol-3-one (24 mg). LCMS(ES, m / z): 313[M+H] + , Method LCMS2. [ka]

[0214] Enantiomer B of Example 5(c) (Rt 11.2 min) was isolated as an off-white solid and assigned as 2-methyl-5-[(8R)-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-triazol-3-one (26 mg). LCMS(ES, m / z): 313[M+H] + , Method LCMS2. [ka]

[0215] 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.

[0216] 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) [ka] (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. LC-MS Enantiomer A (ES, m / z): [M+H] + =310; LC-MS Enantiomer B (ES, m / z): [M+H] + =310 [ka]

[0217] 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.

[0218] Example 7: 6-(8-(2-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one [ka] To a solution of 2-fluoro-benzeneacetonitrile (3 g, 22.20 mmol, 1.00 equiv) in DMSO (30 mL) was added sodium hydride (60% in oil, 1.33 g, 33.30 mmol, 1.50 equiv) at 10 °C. The mixture was stirred for 15 min. Ethyl 1-bromocyclobutane-1-carboxylate (5.06 g, 24.42 mmol, 1.10 equiv) was added, and the mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with water, extracted with EtOAc (2 × 50 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash to give ethyl 1-[cyano(2-fluorophenyl)methyl]cyclobutane-1-carboxylate (2.8 g, 48% yield) as a pale yellow oil.

[0219] [ka] 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 was added Raney Ni (0.25 g, 2.87 mmol, 0.30 equiv.) in a pressure tank. The mixture was purged with nitrogen and then pressurized to 30 atmospheres with hydrogen at 60 °C for 18 hours. 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]octan-5-one (1 g, 48% yield) as a pale yellow oil.

[0220] [ka] 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) was added LAH (138.48 mg, 3.65 mmol, 2.00 equiv) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 5 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of 15% NaOH (aqueous) (0.1 mL) at 0° C. The resulting mixture was filtered; the filter cake was washed with THF (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash to give 8-(2-fluorophenyl)-6-azaspiro[3.4]octane (230 mg, 61% yield) as a pale yellow oil.

[0221] [ka] Prepared as in 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; [ka]

[0222] Example 8: 6-(3,3-dimethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one [ka] To a 40 mL vial, 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) were added at room temperature. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. 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-phenylbutanal (350 mg, 47% yield) as a pale yellow oil.

[0223] [ka] To a 50 mL round-bottom flask were added 2,2-dimethyl-4-nitro-3-phenylbutanal (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 under a nitrogen atmosphere for 12 hours. The resulting mixture was filtered, and the filter cake was washed with 1 × 10 mL of EtOH. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give 3,3-dimethyl-4-phenylpyrrolidine (180 mg, 65% yield) as a colorless oil.

[0224] [ka] Prepared as in 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. LC-MS (ES, m / z): [M+H] + =298 [ka]

[0225] Example 9: 6-(3,3-dimethyl-4-phenylpiperidine-1-carbonyl)pyrazin-2(1H)-one [ka] In a 50-mL round-bottom flask, n-butyllithium solution (20.0 M in THF / hexane, 2.94 mL, 5.87 mmol) was added dropwise to a solution of bromobenzene (0.46 g, 2.93 mmol, 1 equiv.) in THF (50 mL) under a N atmosphere at −78 °C. The reaction mixture was stirred at −78 °C for 30 min. Then, a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (1 g, 4.40 mmol, 1.5 equiv.) in 50 mL of THF was added dropwise, and the mixture was stirred for an additional 30 min. The reaction was quenched with water / saturated NH4Cl (20 mL), and the mixture was then extracted with ether / EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, which was directly purified by elution with PE / EA (10:1) to give tert-butyl 4-hydroxy-3,3-dimethyl-4-phenylpiperidine-1-carboxylate (500 mg, 56%) as a pale yellow solid.

[0226] [ka] To a 50 mL two-neck round-bottom flask was added tert-butyl 4-hydroxy-3,3-dimethyl-4-phenylpiperidine-1-carboxylate (400 mg, 1.31 mmol, 1 equiv.) and HCl in MeOH (10 mL) at room temperature. The mixture was basified with saturated NaHCO3 (aqueous) to pH 7. The aqueous layer was extracted with EtOAc (2 x 20 mL). The resulting mixture was concentrated under reduced pressure to afford 3,3-dimethyl-4-phenylpiperidin-4-ol (250 mg, 93%) as a pale yellow oil.

[0227] [ka] To a 50 mL two-neck round-bottom flask was added 3-methyl-4-phenylpiperidin-4-ol (230 mg, 1.20 mmol, 1 equiv.) and PTSA (310.60 mg, 1.80 mmol, 1.5 equiv.) in toluene (30 mL) at 90 °C. The reaction was quenched with water (1 mL), and then the mixture was extracted with ether / EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (PE / EA mixture) to give 3,3-dimethyl-4-phenyl-2,6-dihydro-1H-pyridine (200 mg, 89%) as an off-white oil.

[0228] [ka] To a solution of 3,3-dimethyl-4-phenyl-2,6-dihydro-1H-pyridine (180 mg, 0.96 mmol, 1 equiv.) in 10 mL of MeOH was added Pd / C (50%, 85.23 mg) in a pressure tank. The mixture was hydrogenated under 15 atmospheres of hydrogen pressure at room temperature overnight, filtered through a Celite pad, and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to give 3,3-dimethyl-4-phenylpiperidine (150 mg, 82%) as an off-white solid.

[0229] [ka] To an 8 mL vial, 3,3-dimethyl-4-phenylpiperidine (40 mg, 0.21 mmol, 1 equiv.), 6-oxo-1H-pyrazine-2-carboxylic acid (32.56 mg, 0.23 mmol, 1.1 equiv.), HATU (88.38 mg, 0.23 mmol, 1.1 equiv.), and DIPEA (81.93 mg, 0.63 mmol, 3 equiv.) in DMF (4.00 mL) were added at room temperature. The desired product could be detected by LCMS (254 nm, 24%). The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to give 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 [ka]

[0230] 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) [ka] 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, 100 x 4.6 mm, 3 μm 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. LCMS Enantiomer A (ES, m / z): [M+H] + =298; LCMS Enantiomer B (ES, m / z): [M+H] + =298 [ka]

[0231] 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.

[0232] 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 [ka] Prepared as in 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.), 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 [ka]

[0233] The following examples were prepared using methods similar to those disclosed for Examples 1-11: Table 3: Synthesis of certain example compounds [Table 4]

[0234] 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) [ka] To a solution of 8-phenyl-6-azaspiro[3.4]octane hydrochloride (150 mg, 0.7 mmol) in DMF (1.5 mL) was added 3H-1,2,3-triazole-4-carboxylic acid (99 mg, 0.9 mmol, 1.3 equiv.), EDC.HCl (0.21 g, 1.1 mmol, 1.6 equiv.), and DIPEA (0.22 g, 1.7 mmol, 2.5 equiv.). The mixture was stirred for 2 h, then quenched with HO (0.5 mL). The resulting mixture was purified under the following conditions: Xselect CSH C18 column, 30 * Direct purification by preparative HPLC using 150 mm, 5 μm, mobile phase: 25–75% ACN / 0.05% aqueous HCl over 8 min, 1.50 L / min) gave racemic 8-phenyl-6-(3H-1,2,3-triazole-4-carbonyl)-6-azaspiro[3.4]octane (80 mg) as an off-white solid.

[0235] The enantiomers were separated under the following conditions (column: CHIRALCEL OJ-H 2 * Separation by preparative HPLC using a 25 cm, 5 μm separator; mobile phase: 50% EtOH (containing 0.2% MSA) / hexane; flow rate: 25 mL / min; wavelength: 254 nm gave the following:

[0236] Enantiomer A of Example 14(a) (Rt 12.6 min) was isolated as an off-white solid (24 mg, 32% yield). LCMS(ES, m / z): 283[M+H] + , Method LCMS10. [ka]

[0237] Example 14(b) Enantiomer B (Rt 7.7 min) was isolated as an off-white solid (16 mg, 21% yield). LCMS(ES, m / z): 283[M+H] + , Method LCMS10. [ka]

[0238] 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.

[0239] (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)) [ka] To a stirred solution of β-nitrostyrene (5.0 g, 34 mmol) and butanal (3.6 g, 50 mmol, 1.5 equiv.) in THF (40 mL) was added L-proline (1.2 g, 10 mmol, 0.3 equiv.) and TEA (3.4 g, 34 mmol, 1.0 equiv.). 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-phenylbutanal (3.8 g, 51% yield) as a pale yellow oil. LCMS(ES, m / z): 220[MH] -

[0240] [ka] 2-Ethyl-4-nitro-3-phenylbutanal (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 under a hydrogen atmosphere for 16 hours. 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 with 2 M HCl 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). LCMS(ES, m / z): 176[M+H] + .

[0241] [ka] To 6-oxo-1H-pyrazine-2-carboxylic acid (0.53 g, 3.8 mmol) in DMF (10 mL) was added HOBT (1.3 g, 9.4 mmol, 2.5 equivalents) and EDCI (0.87 g, 4.5 mmol, 1.2 equivalents). 3-Ethyl-4-phenylpyrrolidine hydrochloride (1.6 g, 7.6 mmol, 2 equivalents) was added, and the mixture was stirred for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 3 mL). The combined filtrate was 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 min; 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. LCMS(ES, m / z): 298[M+H] +

[0242] [ka] 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 the following:

[0243] Diastereomer A of Example 15(a) (Rt 5.0 min) was isolated as a yellow solid (110 mg). LCMS(ES, m / z): 298[M+H] + , Method LCMS2. [ka]

[0244] Diastereomer B of Example 15(b) (Rt 5.6 min) was isolated as a yellow solid (97 mg). LCMS (ES, m / z): 298 [M+H] + , Method LCMS2. [ka]

[0245] Diastereomer C of Example 15(c) (Rt 11.5 min) was isolated as a light brown solid (3.9 mg). LCMS(ES, m / z): 298[M+H] + , Method LCMS2. [ka]

[0246] Diastereomer D of Example 15(d) (Rt 10.0 min) was isolated as a light brown solid (4.7 mg). LCMS(ES, m / z): 298[M+H] + , Method LCMS2. [ka]

[0247] Diastereomers A-D are as follows (stereochemistry not formally assigned): (R),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one, (S),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one, (R),(S)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one, and (S),(R)-6-(3-ethyl-4-phenylpyrrolidine-1-carbonyl)pyrazin-2(1H)-one.

[0248] (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)) [ka] To a stirred mixture of 4-chloro β-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 hours 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 pale yellow oil. LCMS(ES, m / z): 266[MH] -

[0249] [ka] 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 equiv.) and AcOH (1.7 g, 28 mmol, 8 equiv.). The reaction mixture was stirred at 60° C. for 2 h, then cooled, filtered, and the filter cake was washed with EtOAc (3×20 mL). The combined filtrate was concentrated, and the residue was dissolved in 2 M HCl in EtOAc (30 mL). The resulting mixture was stirred for 2 h and then concentrated. 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. LCMS(ES, m / z): 222[M+H] +

[0250] [ka] 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 equiv.) in DMF (1 mL) was added EDC.HCl (140 mg, 0.9 mmol, 2 equiv.) in portions. 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% aqueous ammonia over 10 min; flow rate: 80 mL / min) to give 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (80 mg, 52% yield) as a white solid. LCMS(ES, m / z): 344[M+H] +

[0251] [ka] 6-[8-(4-chlorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (70 mg) was separated on an SFC column: CHIRALPAK IH, 3×25 cm, 5 μm; mobile phase: 30% [2:1 MeOH:DCM in MeOH containing 0.1% 2 M ammonia] / CO; flow rate: 80 mL / min; wavelength: 220 nm to give the following:

[0252] Enantiomer A of Example 16(a) (Rt 4.4 min) was isolated as a yellow solid (16 mg, 23% yield). LCMS(ES, m / z): 344[M+H] + , Method LCMS2. [ka]

[0253] Enantiomer B of Example 16(b) (Rt 5.6 min) was isolated as a yellow solid (14 mg, 19% yield). LCMS(ES, m / z): 344[M+H] + , Method LCMS2. [ka]

[0254] 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.

[0255] (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)) [ka] A solution of (£)-(2-nitrovinyl)benzene (1.5 g, 10 mmol), L-proline (0.23 g, 2.0 mmol, 0.2 equiv), and cyclopentanecarbaldehyde (3.0 g, 30 mmol, 3 equiv) 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 pale yellow oil. LCMS(ES, m / z): 246[MH] -

[0256] [ka] To a solution of 1-(2-nitro-1-phenylethyl)cyclopentane-1-carbaldehyde (0.90 g, 3.6 mmol) in MeOH (20 mL) was added 10% Pd / C (500 mg) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere for 2 hours, then filtered through a Celite pad, and the filtrate was concentrated. The residue was dissolved in MeOH (10 mL), and AcOH (210 μL, 3.6 mmol, 1 equiv.) was added along with 10% Pd / C (400 mg). The mixture was stirred overnight under a hydrogen atmosphere, then filtered through a Celite pad and concentrated under reduced pressure to give 4-phenyl-2-azaspiro[4.4]nonane (0.50 g, 68% yield) as a colorless oil. LCMS(ES, m / z): 202[M+H] +

[0257] [ka] 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 equiv.), HOBT (0.25 g, 1.8 mmol, 2.5 equiv.), DIPEA (0.27 g, 2.1 mmol, 3 equiv.), and 6-oxo-1H-pyrazine-2-carboxylic acid (0.12 g, 0.8 mmol, 1.2 equiv.) in DMF (2 mL) was stirred for 2 h and then concentrated. The mixture was analyzed by preparative HPLC (column: XBridge C18, 19 * Separation on a 150 mm, 5 μm column (mobile phase: 10–65% MeCN / 20 mM aqueous NH4HCO3 solution (containing 0.05% NH3·H2O) over 8 min; flow rate: 60 mL / min) afforded 6-(4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl)pyrazin-2(1H)-one (80 mg, 33% yield) as a white solid. LCMS(ES, m / z): 324[M+H] +

[0258] [ka] 6-(4-phenyl-2-azaspiro[4.4]nonane-2-carbonyl)pyrazin-2(1H)-one (80 mg) was purified by HPLC under the following conditions (column: CHIRALPAKAY-3, 100 * Separation by preparative HPLC using 4.6 mm, 3 um, AY30CC-AW003; mobile phase: 30% 1:1 EtOH / MeOH / n-hexane) gave the following: Enantiomer A of Example 17(a) (first eluting isomer) as a white solid (24 mg, 30% yield) LCMS(ES, m / z): 324[M+H] + , Method LCMS2. [ka] Enantiomer B (second eluting isomer) of Example 17(b) as a white solid (24 mg, 30% yield) LCMS(ES, m / z): 324[M+H] +, Method LCMS2. [ka]

[0259] 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.

[0260] Example 18: rac-2-{8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-3H-pyrimidin-4-one [ka] 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 × 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 aqueous 0.1% 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. LCMS(ES, m / z): 310[M+H] + , Method LCMS2. [ka]

[0261] (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)) [ka] A solution of 8-(4-bromophenyl)-6-azaspiro[3.4]octane (10 g, 38 mmol), TEA (11 g, 110 mmol), and BocO (16 g, 75 mmol) in DCM (100 mL) was stirred for 2 h. The mixture was concentrated, and the residue was purified by silica gel chromatography eluting with n-hexane / EtOAc (5 / 1) to give tert-butyl 8-(4-bromophenyl)-6-azaspiro[3.4]octane-6-carboxylate (8.0 g, 58% yield) as a reddish-brown oil. LCMS(ES, m / z): 366, 368[M+H] +

[0262] [ka] 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(PPh)Cl (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 CHCl (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, 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. LCMS(ES, m / z): 384[M+H] +

[0263] [ka] 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) were added DIPEA (0.33 g, 2.6 mmol) and TMSOTf (0.57 g, 2.6 mmol). The resulting mixture was stirred for 1 hour 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 in the next step without further purification. LCMS(ES, m / z): 284[M+H] +

[0264] [ka] 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 CHCN (2.5 mL) was stirred for 1 h and then concentrated. The residue was purified by silica gel column chromatography eluting with CHCl / 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. LCMS(ES, m / z): 406[M+H] +

[0265] [ka] 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 1 M TBAF in THF (2.8 mL, 2.8 mmol). The resulting mixture was stirred for 1 hour and then concentrated. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10 / 1) to give 6-[8-(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (67 mg, 21% yield) as an off-white solid. LCMS(ES, m / z): 334[M+H] +

[0266] [ka] 6-[8-(4-ethynylphenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (67 mg, 0.2 mmol) was purified using the following conditions (column: XA CHIRALPAK IA, 2 * Separation by preparative HPLC using 25 cm, 5 μm; mobile phase: 50% 1:1 EtOH:DCM / hexane (containing 0.2% FA); flow rate: 25 mL / min; wavelength: 254 nm gave the following: Enantiomer A of Example 19(a) (Rt=3.2 min) as an off-white solid (15 mg, 23% yield) LCMS(ES, m / z): 334[M+H] + 334, Method LCMS2 [ka] Enantiomer B of Example 19(b) (Rt=4.2 min) as an off-white solid (16 mg, 25% yield) LCMS(ES, m / z): 334[M+H] + , Method LCMS2. [ka]

[0267] 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.

[0268] (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)) [ka] 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 h, 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. LCMS(ES, m / z): 313[M+H] +

[0269] [ka] 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 to pH 7 with NaHCO solution and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (8 mL), dried over anhydrous NaSO, 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. LCMS(ES, m / z): 213[M+H] +

[0270] [ka] A mixture of 4-(6-azaspiro[3.4]octan-8-ylbenzonitrile (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 NaSO, 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. LCMS(ES, m / z): 335[M+H] +

[0271] [ka] 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 x 25 cm, 5 μm; Mobile phase: 45% 2:1 MeOH:DCM / CO; Flow rate: 80 mL / min; Wavelength: 220 nm) to give: Enantiomer A of Example 20(a) (Rt=7.8 min) as an off-white solid (13 mg, 34% yield) LCMS(ES, m / z): 335[M+H] + , Method LCMS2 [ka] Enantiomer B of Example 20(b) (Rt=3.8 min) as an off-white solid (22 mg, 55% yield) LCMS(ES, m / z): 335[M+H] + , Method LCMS2. [ka]

[0272] 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.

[0273] (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)) [ka] A solution of 8-phenyl-6-azaspiro[3.4]octane (0.80 g, 4.3 mmol), TEA (1.3 g, 13 mmol), and BocO (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 CHCl / 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. LCMS(ES, m / z): 288[M+H] +

[0274] [ka] tert-Butyl 8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (390 mg, 1.4 mmol) was purified using the following conditions (column: XA-CHIRALPAK IG, 3 *Separation by preparative HPLC using 25 cm, 5 μm; mobile phase: 30% EtOH (containing 0.2% IPA) / 3:1 hexane:DCM; flow rate: 35 mL / min; wavelength: 254 nm) gave the following: Enantiomer A (Rt=5.2 min) as a reddish oil (130 mg, 33% yield) LCMS(ES, m / z): 288[M+H] + Enantiomer B (Rt=7.0 min) as a reddish oil (150 mg, 37% yield) LCMS(ES, m / z): 288[M+H] +

[0275] [ka] 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 × 2.0 mL) to give 8-phenyl-6-azaspiro[3.4]octane hydrochloride (enantiomer A) (90 mg, 95%) as an off-white solid. LCMS(ES, m / z): 188[M+H] +

[0276] [ka] 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 CHCN (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% aqueous NH; detector, UV 254 nm) to give the following: Enantiomer A of Example 21(a) as an off-white solid (30 mg, 19% yield) LCMS(ES, m / z): 310[M+H] + , Method LCMS02 [ka]

[0277] [ka] Enantiomer B was synthesized using a similar method to give: Enantiomer B of Example 21(b) as an off-white solid (35 mg, 21% yield) LCMS(ES, m / z): 310[M+H] + , Method LCMS02 [ka]

[0278] 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.

[0279] Example 22: (3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone [ka] To a solution of 8-phenyl-6-azaspiro[3.4]octane (0.2 g, 1.1 mmol) in MeOH (1 mL) were 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 hours and then concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 * Purification with 150 mm, 5 μm; mobile phase: 30–60% MeCN / 10 mmol / L aqueous NH4HCO3 (containing 0.1% NH3.H2O) over 7 min; flow rate: 30 mL / min) gave (3-hydroxyisoxazol-5-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone (180 mg, 54% yield) as a white solid. LCMS(ES, m / z): 299[M+H] + , Method LCMS11 [ka]

[0280] (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)) [ka] (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% aqueous HCl; Flow rate: 20 mL / min; Wavelength: 254 nm / 220 nm) to give the following: Enantiomer A (first eluting isomer) of Example 23(a) as a white solid (22 mg, 31% yield) LCMS(ES, m / z): 299[M+H] + , Method LCMS11 [ka] Enantiomer B (second eluting isomer) of Example 23(b) as a white solid (27 mg, 38% yield) LCMS(ES, m / z): 299[M+H] + , Method LCMS11 [ka]

[0281] 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.

[0282] Example 24: 3-[8-phenyl-6-azaspiro[3.4]octane-6-carbonyl]-4H-1,2,4-oxadiazol-5-one [ka] To a stirred solution of ethyl [(Z)-N'-hydroxycarbamimidoyl]formate (2.5 g, 19 mmol) in 1,4-dioxane (25 mL) at 80 °C, CDI (3.7 g, 23 mmol) and DBU (3.5 g, 23 mmol) were added 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 × 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 give ethyl 5-oxo-4H-1,2,4-oxadiazole-3-carboxylate (1.2 g, 40% yield) as a yellow solid. LCMS(ES, m / z): 157[MH] -

[0283] [ka] 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% aqueous FA; 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. LCMS(ES, m / z): 300[M+H] + , Method LCMS12 [ka]

[0284] (Example 25(a) to (d): Diastereomer A, Diastereomer B, Diastereomer C, and Diastereomer D of 2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one) [ka] To a solution of 3-(benzyloxy)cyclobutane-1-carboxylic acid (6.5 g, 32 mmol) in THF (65 mL) was added 2 M LAH in THF (26 mL, 52 mmol) at 0 °C, and the resulting mixture was stirred overnight. The reaction was quenched by the addition of 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 NaSO, 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. LCMS(ES, m / z): 193[M+H] +

[0285] [ka] To a solution of [3-(benzyloxy)cyclobutyl]methanol (4.5 g, 23 mmol) in DCM (10 mL) at 0 °C, Dess-Martin periodinane (12 g, 28 mmol) was added portionwise. The resulting mixture was stirred for 1 h. The mixture was filtered, washed with EtO (2 × 10 mL), and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (2 / 1) to give 3-(benzyloxy)cyclobutane-1-carbaldehyde (3.2 g, 71% yield) as a pale yellow oil. LCMS(ES, m / z): 191[M+H] +

[0286] [ka] 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 EtN (0.58 g, 5.7 mmol). The resulting mixture was stirred for 8 hours 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. LCMS(ES, m / z): 338[MH] -

[0287] [ka] 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 × 6.0 mL), and concentrated. The residue was dissolved in 4 M HCl in dioxane (10 mL) and stirred for 10 min. Then, it was concentrated. The residue was triturated with hexane (15 mL) to give 2-(benzyloxy)-8-phenyl-6-azaspiro[3.4]octane hydrochloride (1.2 g, 80% yield) as a white solid. LCMS(ES, m / z): 294[M+H] +

[0288] [ka] 2-(Benzyloxy)-8-phenyl-6-azaspiro[3.4]octane hydrochloride (1.2 g, 3.7 mmol), EtN (1.2 g, 11 mmol), and BocO (890 mg, 4.4 mmol) were dissolved in MeOH (12 mL), stirred for 3 h, and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (2 / 1) to give tert-butyl 2-(benzyloxy)-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (1.5 g, 93% yield) as a pale yellow oil. LCMS(ES, m / z): 394[M+H] +

[0289] [ka] 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 hours, 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. LCMS(ES, m / z): 304[M+H] +

[0290] [ka] 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 NaSO, and concentrated to give tert-butyl 2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carboxylate (340 mg, 48% yield) as a colorless oil. LCMS(ES, m / z): 306[M+H] +

[0291] [ka] 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 4 M HCl in 1,4-dioxane (1.5 mL). The resulting mixture was stirred for 30 minutes and then concentrated to give 2-fluoro-8-phenyl-6-azaspiro[3.4]octane hydrochloride (145 mg, 53% yield) as a white solid. LCMS(ES, m / z): 206[M+H] +

[0292] [ka] 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, and then 2-fluoro-8-phenyl-6-azaspiro[3.4]octane (150 mg, 0.7 mmol) was added. 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% aqueous NH3; flow rate: 90 mL / min; wavelength: 254 nm) to give 6-{2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-1H-pyrazin-2-one (95 mg, 41% yield) as a gray solid. LCMS(ES, m / z): 328[M+H] +

[0293] [ka] 6-{2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl}-1H-pyrazin-2-one (94 mg) was purified by preparative HPLC (column: CHIRALPAKIF-3, 50 * Separation on 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) gave the following:

[0294] Diastereomer A of Example 25(a) (first eluting diastereomer) was isolated as an off-white solid (21 mg, 38% yield). LCMS(ES, m / z): 328[M+H] + , Method LCMS14 [ka]

[0295] Diastereomer B of Example 25(b) (second eluting diastereomer) was isolated as an off-white solid (23 mg, 43% yield). LCMS(ES, m / z): 328[M+H] + , Method LCMS14 [ka]

[0296] Diastereomer C of Example 25(c) (third eluting diastereomer) was isolated as an off-white solid (10 mg, 11% yield). LCMS(ES, m / z): 328[M+H] + , Method LCMS14 [ka]

[0297] Diastereomer D of Example 25(d) (fourth eluting diastereomer) was isolated as an off-white solid (10 mg, 11%). LCMS(ES, m / z): 328[M+H] + , Method LCMS14 [ka]

[0298] Diastereomers A-D are as follows (stereochemistry not formally assigned): (R),(R)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one, (S),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one, (R),(S)-2-(2-fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one, and (S),(R)-2-(2-Fluoro-8-phenyl-6-azaspiro[3.4]octane-6-carbonyl)pyrimidin-4(3H)-one.

[0299] The following compounds were synthesized similarly using the appropriate acid, or equivalent, and amine. The amine was synthesized similarly to the previous example. Enantiomer A corresponds to the eutomer. Table 4: [Table 5] TIFF2026503519000174.tif221170TIFF2026503519000175.tif222170TIFF2026503519000176.tif223170TIFF20265035190 00177.tif223170TIFF2026503519000178.tif224170TIFF2026503519000179.tif224170TIFF2026503519000180.tif129170

[0300] (6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one (enantiomer A) of Example 35(a) and 6-(8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl)pyrazin-2(1H)-one (enantiomer B) of Example 35(b)) Step 1. Preparation of 1-[1-(4-fluorophenyl)-2-nitroethyl]cyclobutane-1-carbaldehyde [ka] To a stirred mixture of styrene, (£)-1-fluoro-4-(2-nitrovinyl)benzene (6.0 g, 36 mmol), and L-proline (4.1 g, 36 mmol, 1 equiv.) in THF (60 mL) was added cyclobutanecarbaldehyde (9.1 g, 110 mmol, 3 equiv.) and EtN (1.1 g, 11 mmol, 0.3 equiv.). 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 pale yellow oil. LCMS(ES, m / z): 250[MH] -

[0301] Step 2. Preparation of 6-oxo-1H-pyrazine-2-carboxylic acid [ka] 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 equiv.) and acetic acid (1.6 g, 27 mmol, 8 equiv.). The reaction mixture was stirred at 60° C. for 2 h, then cooled and filtered. The filtrate was concentrated, and the residue was dissolved in 4 M HCl in MeOH (20 mL). This 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. LCMS(ES, m / z): 206[M+H] +

[0302] Step 3. Preparation of 6-[8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one [ka] 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 equiv.) and NMI (0.29 g, 3.6 mmol, 2.5 equiv.). The reaction mixture was stirred for 15 minutes, after which 8-(4-fluorophenyl)-6-azaspiro[3.4]octane (0.35 g, 1.7 mmol, 1.2 equiv.) was added. The resulting mixture was stirred for 1 hour, 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% aqueous NH3·H2O 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. LCMS(ES, m / z): 328[M+H] +

[0303] 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) [ka] 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 the following: Example 35(a) 6-[-8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (Enantiomer A) as an off-white solid (27 mg, 22% yield) Rt=10.3 minutes. LCMS(ES, m / z): 328[M+H] + [ka] Example 35(b) 6-[8-(4-fluorophenyl)-6-azaspiro[3.4]octane-6-carbonyl]-1H-pyrazin-2-one (enantiomer B) as an off-white solid (24 mg, 20% yield) Rt=12.1 minutes LC-MS(ES, m / z): 328[M+H] + [ka]

[0304] 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.

[0305] The following compounds were synthesized similarly using the appropriate acid, or equivalent, and amine. The amine was synthesized similarly to the previous example. Enantiomer A corresponds to the eutomer. Table 5: [Table 6] TIFF2026503519000188.tif227170TIFF2026503519000189.tif222170TIFF20265035190 00190.tif225170TIFF2026503519000191.tif222170TIFF2026503519000192.tif226170 TIFF2026503519000193.tif224170TIFF2026503519000194.tif225170TIFF20265035190 00195.tif219170TIFF2026503519000196.tif227170TIFF2026503519000197.tif197170

[0306] Biological Examples Biological Example 1 - mPTP Activity Assay in Isolated Rat Liver Mitochondria and Isolated Rat Brain Mitochondria (Rat liver mitochondrial assay) Pharmacological inhibition or modulation of mPTP is performed using the well-characterized "Ca" pathway in isolated mitochondria. 2+ In vitro isolated mitochondria can measure intramitochondrial Ca retention in a mitochondrial Ca2+ / Ca ... 2+ Exogenous Ca concentration is increased until it reaches the threshold for mPTP activation. 2+ Once the pore is activated, mitochondrial integrity is compromised and stored Ca is released. 2+ Ca is released between the extra- and intra-mitochondrial compartments. 2+ The distribution of membrane-impermeable Ca 2+ Depending on the assay configuration, inhibition or modulation of mPTP can either delay pore opening or reduce the Ca required to induce mPTP opening. 2+ or increasing the concentration of

[0307] MPTP activity was measured in freshly isolated mitochondria from female Sprague Dawley (250-300 grams) rat livers using the following method: Cervical dislocation was performed on the rats. The livers were then perfused in situ with ~40 ml of cold Dulbecco's phosphate-buffered saline (DPBS), then dissected and transferred to 30 ml of isolation buffer (250 mM sucrose, 10 mM KCl, 1 mM EGTA, 1 mM EDTA, 25 mM HEPES, pH adjusted to 7.5 with 1 M NaOH). Each liver lobe was then removed from the buffer and minced into ~5 mm pieces using forceps and a scalpel. Then, the pieces were transferred to a 50 ml Potterton Dounce homogenization 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, supplemented with 0.1% bovine serum albumin (BSA) and complete protease inhibitor cocktail (1 tablet of inhibitor per 50 ml of buffer)). Homogenization was performed using a Teflon® pestle at 1800 rpm. The slurry was centrifuged at 800 g for 10 min at 4°C, and the supernatant was then centrifuged at 10,000 g for 10 min. The pellet was washed once with FLIPR assay buffer (75 mM mannitol, 25 mM sucrose, 5 mM monobasic potassium phosphate, 20 mM Tris base, 100 mM KCl, 0.1% BSA adjusted to pH 7.4 with 5 M HCl), centrifuged again, and resuspended in FLIPR assay buffer to a protein concentration of 8.8 mg / ml.

[0308] Test compounds (10 mM stock in DMSO) were serially diluted in half-log increments into DMSO to generate 10 test concentrations (final concentrations in the assay: 30 μM to 1 nM). Intermediate dilutions of 5 μl of DMSO sample were made into 247 μl of FLIPR assay buffer, after which 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 cyclosporine A.

[0309] A stock mitochondria / Fluo5N assay solution was prepared in 5.6 ml of FLIPR assay buffer (RT) supplemented with succinic acid disodium salt (10 mM), rotenone (1 μM), Fluo5N pentapotassium salt (2 μM), and 1 ml of mitochondrial suspension. It was then transferred (15 μl) to the assay plate containing the test compound and incubated at RT for 10 minutes. The assay plate was processed for fluorescence detection on either a FLIPR Tetra (Molecular Devices) or a CLARIOstar (BMG) plate reader. For dynamic fluorescence detection on the FLIPR, dye fluorescence was measured every 3 seconds for a total of 10 minutes. After 12 seconds, a 2.5 μl bolus of CaCl (75 μM) was added from the source plate containing 675 μM CaCl in FLIPR assay buffer. Alternatively, addition of 2.5 μl of CaCl was performed using a Viaflow 384, the plates were incubated at RT for 10 min, and dye fluorescence was measured after 10 min on a CLARIOstar plate reader. pIC values ​​for test compounds were calculated using the fluorescence values ​​collected at 10 min on either plate reader, and % inhibition was calculated using the DMSO control and cyclosporine A values ​​as 0% and 100%, respectively.

[0310] (Rat brain mitochondrial assay) MPTP activity was measured in freshly isolated brain mitochondria from female Sprague-Dawley rats (250-300 grams). Anesthetized rats were perfused in situ with ~40 ml of cold Dulbecco's phosphate-buffered saline (DPBS), after which 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). Brains were minced into ~5 mm pieces using forceps and a scalpel and then transferred to a 50 ml Potterton Dounce homogenization tube on ice containing 10 ml of ice-cold centrifugation buffer (same as above, with complete protease inhibitors added; 1 tablet per 50 ml of buffer). Homogenization was performed using a Teflon® pestle at 1800 rpm. The slurry was centrifuged at 2000 g for 10 min at 4°C, and the supernatant was then centrifuged at 12,000 g for 9 min. The pellet was resuspended in isolation buffer (as above, but with 0.02% digitonin added) using a Dounce homogenizer, centrifuged at 12,000 g for 11 min, and finally resuspended in 5 ml of modified isolation buffer (as above, but with EGTA reduced to 0.1 mM).

[0311] Test compounds were prepared in 384-well polypropylene assay plates as described above for the liver mitochondrial assay. A stock mitochondrial / Fluo5N assay solution was prepared in 5.6 ml of assay buffer (120 mM mannitol, 40 mM MOPS, 5 mM KH2PO4, 60 mM KCl, 10 mM pyruvate, 2 mM malate, 2 mM MgCl2, 20 μM ADP, 1.26 μM oligomycin A, adjusted to pH 7.4) supplemented with Fluo5N pentapotassium salt (2 μM) and 1 ml of mitochondrial suspension. 15 μl was then transferred to the assay plate containing the test compound and incubated at RT for 10 minutes. The assay plate was then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 seconds for a total of 10 minutes. After 12 seconds, a 2.5 μl bolus of Ca (75 μM) was added from a source plate containing 675 μM CaCl in FLIPR assay buffer. pIC values ​​for test compounds were calculated using fluorescence values ​​collected at 10 minutes, and % inhibition was calculated using the DMSO control and cyclosporine A values ​​as 0% and 100%, respectively.

[0312] Overall cytotoxicity was assessed in HEK293 and SHSY5Y cells using a standard cell viability assay (Cell Titre Glo; Promega) after 24–96 h of incubation with test compounds.

[0313] Results: mPTP pIC of certain example compounds of the present invention in the rat liver and / or brain mPTP assay 50 The values ​​are provided below in Table 6. These results demonstrate that the test compounds of the present invention exhibit inhibition of mPTP, with many example compounds exhibiting pIC values ​​of 6.0 or greater. 50 The values ​​shown are for the rat brain mitochondrial mPTP pIC of specific example compounds. Example 35a showed the highest activity in the rat liver mitochondrial assay. Example 36a showed the highest activity in the rat brain mitochondrial assay. Table 6 shows the rat brain mitochondrial mPTP pIC of specific example compounds. 50The values ​​are also shown. These results demonstrate that the tested example compounds are active on isolated rat liver mitochondria and isolated rat brain mitochondria. Table 6: Summary of results from Biological Example 1 [Table 7] TIFF2026503519000199.tif244170TIFF2026503519000200.tif40170NT=Untested

[0314] Conclusion: The results of Biological Example 1 demonstrate that a significant proportion of the test compounds of the present invention (or at least one stereoisomer thereof) are inhibitors of mPTP in the rat liver and / or brain mPTP assays. Many of the test compounds were highly potent, with pIC values ​​of 6.0 or greater in the rat liver assay. 50 value and / or pIC of 7.0 or greater in the rat brain assay 50 Therefore, the compounds of the present invention are believed to be useful agents, particularly for the treatment or prevention of diseases and disorders in which inhibition of mPTP provides a therapeutic or preventative effect.

[0315] Throughout this specification and the 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 specified integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of steps.

[0316] The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. These may take the form of product, composition, process, or use claims and may include, by way of example, and not limitation, the following claims:

[0317] 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 was specifically and individually indicated to be incorporated by reference in its entirety.

[0318] (References) [Table 8]

Claims

1. A compound according to formula (I): or a salt and / or solvate thereof 【Chemistry 1】 (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, C 0-6 Alkylene (C 3-6 cycloalkyl), C 0-6 alkylene (OH); or R 4a and R 5a together with the carbon atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or C 5-6 phenyl fused to a cycloalkyl, wherein the phenyl or C 5-6 The phenyl fused to the cycloalkyl may be one or more AA 1 may be optionally substituted by; AA 1 Ha, Halo, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r , or NHSO 2 R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo(=O), C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); However, the compound of formula (I) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: 【Chemistry 2】 isn't it).

2. A compound of formula (IB) according to claim 1: or a salt and / or solvate thereof 【Transformation 3】 (In the formula: R 1a is H or C 1-4 is alkyl; R 1b is H or C 1-4 is alkyl; R 2a H, halo, C 1-4 Alkyl or C 1-4 is haloalkyl; R 3a is H, halo, or C 1-4 is alkyl; R 4a is H or C 1-4 is alkyl; R 5a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Haloalkenyl, 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, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-4 Alkyl, C 1-4 optionally substituted with one or more groups selected from haloalkyl and halo; R 6a H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; x is 0, 1, or 2; AA is phenyl or one or more AA 1 C optionally substituted by 5-6 is a phenyl fused to a cycloalkyl; AA 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR q R r , or NHSO 2 R t and; R q is H or C 1-4 is alkyl; R r is H or C 1-4 is alkyl; R t is C 1-4 is alkyl; BA is a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl, which may be substituted with one or more B 1A and B 1A Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); provided that the compound of formula (IB) is 5-hydroxypyridin-3-yl)(8-phenyl-6-azaspiro[3.4]octan-6-yl)methanone: 【Chemistry 4】 isn't it).

3. Compounds according to formula (IB): 【Transformation 5】 3. The compound according to claim 1 or 2, or a salt and / or solvate thereof.

4. 2. The compound according to claim 1, or a salt and / or solvate thereof, wherein the compound is a pharmaceutically acceptable salt and / or solvate thereof.

5. R 1a and R 1b The compound according to any one of claims 1 to 4, or a salt and / or solvate thereof, wherein each is H.

6. R 2a and R 3a The compound according to any one of claims 1 to 5, or a salt and / or solvate thereof, wherein each is H.

7. R 4a and R 5a together with the atoms to which they are bonded, C 3-6 7. A compound according to any one of claims 1 to 6, or a salt and / or solvate thereof, which forms a cycloalkyl, for example cyclobutyl.

8. R 4a and R 5a The compound according to any one of claims 1 to 6, or a salt and / or solvate thereof, wherein each of

9. R 6a The compound according to any one of claims 1 to 8, or a salt and / or solvate thereof, wherein is H.

10. The compound according to any one of claims 1 to 9, or a salt and / or solvate thereof, wherein x is 1.

11. 11. The compound according to any one of claims 1 to 10, or a salt and / or solvate thereof, wherein AA is phenyl.

12. AA with 1 or more AA 1 and at least one AA 1 The compound according to any one of claims 1 to 11, or a salt and / or solvate thereof, wherein is halo.

13. BA, 【Transformation 6】 ;for example, 【Transformation 7】 13. The compound according to any one of claims 1 to 12, or a salt and / or solvate thereof, selected from the group consisting of: (In the formula: B 1B is H or C 1-6 alkyl, for example, methyl; B 2B is H or C 1-6 alkyl, for example, methyl; and B 2B is C 0-6 Alkylene (OH), for example, OH).

14. (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-phenylpiperidine-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 any one of salts and / or solvates thereof 2. The compound of claim 1, or a salt and / or solvate thereof, selected from the group consisting of:

15. 15. The compound according to any one of claims 1 to 14, which is a compound of formula (I), or a salt and / or solvate thereof.

16. 15. The compound according to any one of claims 1 to 14, which is a salt of a compound of formula (I), or a salt and / or solvate thereof.

17. 17. A compound according to any one of claims 1 to 16 for use as a medicament.

18. 17. 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. 17. The compound of 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 inhibition of mPTP provides a therapeutic or preventive effect, such as a disease or disorder selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease.

20. 19. A pharmaceutical composition according to claim 18 (wherein the proviso to formula (I) does not apply) for use in the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or preventive effect, such as a disease or disorder selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia and reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, age-related diseases, and renal diseases.

21. Use of a compound according to any one of claims 4 to 16 or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for treating or preventing a disease or disorder in which inhibition of mPTP provides a therapeutic or preventive effect, such as a disease or disorder selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease (wherein the proviso to formula (I) does not apply).

22. 19. A method for treating or preventing a disease or disorder in which inhibition of mPTP provides a therapeutic or preventive effect, such as a disease or disorder selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease, said method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 18 (wherein the proviso to formula (I) does not apply).

23. The disease or disorder is a degenerative or neurodegenerative disease (e.g., 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, and Friedreich's ataxia), particularly Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. ), disorders of the central nervous system (e.g., AIDS dementia complex, depressive disorders, schizophrenia, and epilepsy), ischemia and 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 decline, and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease), inflammatory or autoimmune diseases (e.g., acute pancreatitis, systemic lupus erythematosus, organ failure in sepsis, and liver inflammation), age-related diseases (e.g., bone repair, weakening of bones with aging in osteoporosis, and sarcopenia), kidney diseases (e.g., chronic kidney disease and chronic renal disease associated with APOL1 gene mutations), mitochondrial diseases (e.g., Reye's syndrome, Leber's hereditary optic neuropathy, and related disorders and disorders), and TDP-43 diseases or disorders, such as TDP-43-associated neurodegeneration (e.g., amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensorimotor neuropathy, primary lateral sclerosis, 23. The compound for use according to any one of claims 19 to 22, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method, selected from progressive muscular atrophy, inclusion body myopathy associated with early-onset Paget's disease of bone, and frontotemporal lobar degeneration dementia, Perry's disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and brain aging-related TDP-43 with sclerosis.

24. 24. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 18 to 23, wherein said compound is for administration to a human subject.

25. 25. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 18 to 24, for use in combination with a further therapeutic agent.

26. A compound of formula (IIB): or a salt thereof, for example a pharmaceutically acceptable salt 【Transformation 8】 (In the formula, R 1a , R 1b , R 2a , R 3a , R 4a , R 5a , R 6a , x and AA are as defined in any one of claims 1 to 25).

27. A compound of formula (IIIB): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 9】 wherein BA is as defined in any one of claims 1 to 26.

28. A compound of formula (IVB): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 10】 (In the formula, R 4a , R 5a , R 6a , and AA are as defined in any one of claims 1 to 27).

29. A compound of formula (VIIB): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 11】 (In the formula, R 4a , R 5a , R 6a and AA are as defined in any one of claims 1 to 28).

30. A compound of formula (VIIIB): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 12】 (In the formula, R 4a , R 5a , R 6a , and AA are as defined in any one of claims 1 to 29).

31. A compound of formula (XIB): or a salt thereof, for example a pharmaceutically acceptable salt. 【Chemistry 13】 (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a and AA are as defined in any one of claims 1 to 30).

32. A compound of formula (XIIB): or a salt thereof, for example a pharmaceutically acceptable salt. 【Chemistry 14】 (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a , and AA are as defined in any one of claims 1 to 31).

33. A compound of formula (XIIIB): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 15】 (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a , and AA are as defined in any one of claims 1 to 32).

34. A compound of formula (XIVB): or a salt thereof, for example a pharmaceutically acceptable salt. 【Chemistry 16】 (In the formula, R 1a , R 2a , R 1a / b , R 2a , R 3a , R 4a , R 5a and AA are as defined in any one of claims 1 to 33, and P is a nitrogen protecting group, such as BOC (tert-butyloxycarbonyl).

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