mPTP inhibitors

Abstract

The present invention relates to compounds of formula (I) and related embodiments. [Formula 1] TIFF2026503521000592.tif18170

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 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H, halo, or C 1-4 is alkyl; R 5 Ha, Halo, 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 4 and R 5 together with the carbon atoms to which they are attached, C 5-11 Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spirocarbocyclyl, heterocycle, or cycloalkyl is C 1-3 Alkyl, C 1-3 optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more A 1 may be optionally substituted by; A 1 is C 1-3 Alkylthio, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR g R h , or NHSO2R j are independently selected from the group consisting of: R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 Is it alkyl? Or A is 1 or more 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) v wherein v represents 1, 2, or 3, and one of the CH groups may optionally be replaced by O; B 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 1 may be optionally substituted by; B 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, oxo (=O), thiooxo (=S), or C 0-6 alkylene (OH); provided that formula (I) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: [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] As used herein, "alkylthio" refers to any group, e.g., "C 1-3 The term "alkylthio" refers to an alkyl group, as defined above, singly bonded to a sulfur atom (e.g., C 1-3 alkyl group), e.g., -SC 1-3 Refers to alkyl. C 1-3 Examples of alkylthio include methylthio, ethylthio, and propylthio.

[0031] 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.

[0032] 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.

[0033] 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. 1-6 Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, and 3-butoxy, especially methoxy.

[0034] 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.

[0035] 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).

[0036] In the present specification, for example, C 1-4 The term "haloalkoxy" as used in haloalkoxy refers to a haloalkyl group, as defined above, singly bonded to an oxygen atom (e.g., C 1-4 haloalkyl groups), such as trifluoromethoxy.

[0037] 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.

[0038] In the present specification, for example, C 2-6 The 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.

[0039] 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.

[0040] 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).

[0041] 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.

[0042] 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). Preferably, the heterocyclic group contains 5 to 10 ring members. The heterocyclic group may be, for example, monocyclic or bicyclic. In a bicyclic heterocyclic group, one or more heteroatoms may be present in each ring or in only one of the rings. When a heterocyclic group contains multiple rings, not all rings must contain heteroatoms. The heteroatom may be S, O, or N, preferably O or N. The heterocycle may contain one heteroatom selected from N, S, and O, for example, N and O, especially N. In another example, 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, e.g., N and O. In some examples, the heterocycle is monocyclic, e.g., a 5- or 6-membered heterocyclic ring. Examples of heterocycles include morpholinyl, tetrahydrofuran, and tetrahydropyran.

[0043] As used herein, C 5-11 The term spirocarbocyclyl refers to the R 4 and R 5 together with the carbon to which they are attached form part of a spirocarbocyclyl group, meaning a cyclic ring system containing 5 to 11 carbon atoms.

[0044] For example, [ka] :C 5-11 Another example of a spirocarbocyclyl is spiropentane.

[0045] When a substituent is indicated as being optionally substituted in formula (I), in the embodiments and preferences presented below, the optional substituent may be attached to an available carbon atom (which means a carbon atom that is 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 that is 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.

[0046] The present invention provides a compound according to formula (I): or a salt and / or solvate thereof [ka] (In the formula: R 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl; C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H, halo, or C 1-4 is alkyl; R 5 Ha, Halo, 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 4 and R 5 together with the carbon atoms to which they are attached, C 5-11Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spirocarbocyclyl, heterocycle, or cycloalkyl is C 1-3 Alkyl, C 1-3 optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more A 1 may be optionally substituted by; A 1 is C 1-3 Alkylthio, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR g R h , or NHSO2R j are independently selected from the group consisting of: R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 Is it alkyl? Or A is 1 or more 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) vwherein v represents 1, 2, or 3, and one of the CH groups may optionally be replaced by O; B 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 1 may be optionally substituted by; B 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo (=O), thiooxo (=S), or C 0-6 alkylene (OH); provided that formula (I) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: [ka] isn't it).

[0047] In a second embodiment, the present invention provides a compound according to formula (IA): or a salt and / or solvate thereof [ka] (In the formula: R 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl; C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H or C 1-4 is alkyl; R 5 H, halo, C 1-6 Alkyl, C1-6 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 4 and R 5 together with the atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-3 Alkyl, C 1-3 optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is 1 or more A 1 is a monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl optionally substituted by A 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 g R h , or NHSO2R j and; R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 Is it alkyl? Or A is 1 or more 1When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) v wherein v represents 1, 2, or 3, and one of the CH groups may optionally be replaced by O; B is 1 or more B 1 a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl optionally substituted by B 1 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 (IA) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: [ka] isn't it).

[0048] Compounds according to formula (IA) or salts and / or solvates thereof are a sub-genus of compounds of formula (I) or salts and / or solvates thereof. Compounds according to formula (IA') or salts and / or solvates thereof are a sub-genus of compounds of formula (IA) or salts and / or solvates thereof. Compounds according to formula (IA'') or salts and / or solvates thereof are a sub-genus of compounds of formula (IA) or salts and / or solvates thereof. Compounds according to formula (IA''') or salts and / or solvates thereof are a sub-genus of compounds of formula (IA) or salts and / or solvates thereof. The following embodiments apply equally to compounds of formula (I), (IA), (IA'), (IA''), and / or (IA''') or salts and / or solvates thereof.

[0049] In one embodiment, R 1 is H. In a second embodiment, R 1 is C 1-4Alkyl, for example, methyl.

[0050] In one embodiment, R 2 is H. In a second embodiment, R 2 is halo. In a third embodiment, R 2 is fluoro. In a fourth embodiment, R 2 is C 1-4 alkyl, for example, methyl or ethyl. In a fifth embodiment, R 2 is C 1-4 In a sixth embodiment, R 2 is C 1-4 In a seventh embodiment, R 2 is C 1-4 In an eighth embodiment, R 2 is C 0-4 alkylene (OH), for example, CH2CH2OH. In a ninth embodiment, R 2 is C 1-4 Alkylene (OH), for example, CH2CH2OH.

[0051] In one embodiment, R 3 is H. In a second embodiment, R 3 is halo. In a third embodiment, R 3 is fluoro. In a fourth embodiment, R 3 is C 1-4 In a fifth embodiment, R 3 is methyl.

[0052] In one embodiment, R 2 and R 3 are each H. In a second embodiment, R 2 is H and R 3 is methyl. In a third embodiment, R 2 is H and R 3 is ethyl.

[0053] In one embodiment, R 4is H. In a second embodiment, R 4 is C 1-4 alkyl, for example, methyl. In a third embodiment, R 4 is halo, for example fluoro.

[0054] In one embodiment, R 5 is H. In a second embodiment, R 5 is halo. In a third embodiment, R 5 is C 1-6 Alkyl, for example methyl, ethyl, n-propyl, or iso-propyl, especially ethyl. In a fourth embodiment, R 5 is C 1-6 In a fifth embodiment, R 5 is C 1-6 In a sixth embodiment, R 5 is C 1-6 In a seventh embodiment, R 5 is C 2-6 In an eighth embodiment, R 5 is C 2-6 In a ninth embodiment, R 5 is C 0-6 Alkylene (C 3-6 cycloalkyl), e.g., C 3-6 In a tenth embodiment, R is cycloalkyl, in particular cyclopropyl or cyclobutyl, especially cyclopropyl. 5 is C 0-6 alkylene(OH), for example, CHOH or CH(Me)(OH). In an eleventh embodiment, R 5 is fluoro.

[0055] In a twelfth embodiment, R 5 teeth, [ka] is.

[0056] In one embodiment, R 4 and R 5 are each methyl. In a second embodiment, R 4 is H and R 5 is ethyl. In a third embodiment, R 4 is H and R 5 is iso-propyl. In one embodiment, R 4 is H and R 5 is cyclopropyl.

[0057] In one embodiment, R 4 is H and R 5 is C 0-6 Alkylene (C 3-6 cycloalkyl), e.g., C 3-6 It is cycloalkyl.

[0058] In one embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, C 3-6 In such an embodiment, C 3-6 Cycloalkyl is C 1-3 Alkyl, C 1-3 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 unsubstituted. Preferably, R 4 and R 5 together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring, e.g., a cyclopropyl, cyclobutyl, cyclopentyl ring, especially a cyclobutyl ring. 4 and R 5 together with the carbon atoms to which they are attached, C 3-6 In such an embodiment, C 3-6The cycloalkyl may be optionally substituted with one or more (eg, one, two, or three, eg, one or two) groups selected from the group consisting of methyl, OCF3, and fluoro.

[0059] In another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached form a 4- to 7-membered heterocycle. In such embodiments, the 4- to 7-membered heterocycle is 1-3 Alkyl, e.g., methyl, C 1-3 It may be substituted with one or more (e.g., one, two, or three, e.g., one or two, preferably one) groups selected from the group consisting of haloalkyl, e.g., OCF3, and halo, e.g., fluoro. In another embodiment, the 4- to 7-membered heterocycle is unsubstituted. In another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached form a tetrahydrofuran or tetrahydropyran ring.

[0060] In another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, C 5-11 In such an embodiment, C forms a spirocarbocyclyl. 5-11 Spirocarbocyclyl is C 1-3 Alkyl, e.g., methyl, C 1-3 In another embodiment, C may be substituted with one or more (e.g., one, two, or three, e.g., one or two, preferably one) groups selected from the group consisting of haloalkyl, e.g., OCF3, and halo, e.g., fluoro. 5-11 The spirocarbocyclyl is unsubstituted. In another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached form a spiropentane ring.

[0061] In another embodiment, R 4 and R 5together with the carbon atoms to which they are attached, C 5-11 Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 Forms a cycloalkyl, wherein said spirocarbocyclyl, heterocycle, or cycloalkyl.

[0062] In another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, are unsubstituted C 5-11 Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 Forms a cycloalkyl.

[0063] In another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached form a cyclobutyl, cyclopentyl, spiropentane ring, or a tetrahydrofuran or tetrahydropyran group.

[0064] In one embodiment, R 6 is H. In a second embodiment, R 6 is C 1-4 Alkyl, for example, methyl.

[0065] In one embodiment, R 7 is H. In a second embodiment, R 7 is halo. In a third embodiment, R 7 is halo, for example fluoro. In a fourth embodiment, R 7 is C 1-4 In a fifth embodiment, R 7 is C 1-4 In a sixth embodiment, R 7 is C 1-4 It is haloalkoxy.

[0066] In one embodiment, R 6 is H and R 7 is H. In a second embodiment, R 6 is H and R7 is methyl.

[0067] In one embodiment, R 2 , R 3 , R 4 , R 5 , R 6 , or R 7 At least one of R is not H. 4 and R 5 One of them is not H.

[0068] In one embodiment, R 2 , R 3 , R 6 , and R 7 are all H.

[0069] R 4 and R 5 is preferably of the following stereochemistry: [ka] may have:

[0070] R 4 and R 5 has the following stereochemistry: [ka] It may also have

[0071] Or, R 4 When is H, R 4 and R 5 has the following stereochemistry: [ka] may have:

[0072] In one embodiment, A is monocyclic aryl, for example, phenyl. In a second embodiment, A is bicyclic aryl. In a third embodiment, A is monocyclic heteroaryl. In a fourth embodiment, A is bicyclic heteroaryl. A is optionally substituted, i.e., substituted or unsubstituted.

[0073] In one embodiment, A is one or more (e.g., one, two, or three, e.g., one or two, in particular one) A 1 has been replaced by

[0074] In one embodiment, A is two A 1 has been replaced by

[0075] In one embodiment, at least one A 1 is halo, for example F, Br, or Cl, especially F. In a second embodiment, at least one A 1 is C 1-6 In a third embodiment, at least one A is an alkyl, for example, methyl. 1 is C 1-6 In a fourth embodiment, at least one A is haloalkyl. 1 is C 1-6 In a fifth embodiment, at least one A is alkoxy, for example, OMe. 1 is C 1-6 In a sixth embodiment, at least one A is haloalkoxy. 1 is C 3-6 In a seventh embodiment, at least one A is cycloalkyl. 1 is CN. In an eighth embodiment, at least one A 1 In a ninth embodiment, at least one A is OH. 1 is NR g R h Preferably, R g is H. Preferably, R g is C 1-4 Preferably, R his H. Preferably, R h is C 1-4 In a tenth embodiment, at least one A is alkyl. 1 is NHSO2R j In an eleventh embodiment, at least one A 1 is C 1-3 In a twelfth embodiment, at least one A is alkylthio. 1 is SMe.

[0076] In one embodiment, A is unsubstituted.

[0077] In one embodiment, A is halo or C 1-6 one or two A independently selected from alkyl 1 It is a phenyl substituted by a group.

[0078] In one embodiment, A is F or C 1-3 one or two A independently selected from alkyl 1 It is a phenyl substituted by a group.

[0079] In one embodiment, A is [ka] (where: A 1A is halo, e.g., F, Br, or Cl; C 1-6 alkyl, for example, methyl; or C 1-6 alkoxy, for example, OMe; and A 1B is H or halo, for example F, Br, or Cl, especially F). In one embodiment, A is selected from the group consisting of: [ka] In a second embodiment, A is [ka] In a third embodiment, A is [ka] is.

[0080] In one embodiment, A is [ka] (where: A 1A is halo, e.g., F, Br, or Cl; C 1-6 alkyl, for example, methyl; or C 1-6 alkoxy, for example, OMe; and A 1B is H or halo, for example F, Br, or Cl, especially F). : selected from the group consisting of:

[0081] In one embodiment, A is [ka] (where: A 1A is halo, e.g., F, Br, or Cl; C 1-6 alkyl, for example, methyl; or C 1-6 alkoxy, for example, OMe) : selected from the group consisting of:

[0082] In one embodiment, A is [ka] where A 1A is a halo, e.g., F, and A 1B is a halo, e.g., F.

[0083] In one embodiment, A 1A is halo, for example, F, Br, or Cl. 1A is C 1-6In a third embodiment, A is an alkyl group, for example, methyl. 1A is C 1-6 In a fourth embodiment, A is alkoxy, for example OMe. 1A is F.

[0084] In one embodiment, A 1B is H. In a second embodiment, A 1B is halo, for example F, Br, or Cl, especially F.

[0085] In one embodiment, A is one or more A 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) v (wherein v represents 1, 2, or 3, and one of the CH groups may optionally be replaced by O). Suitably, A is 1 or more A 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) v (wherein v represents 1, 2, or 3).

[0086] Preferably, A is 1 or more. 1 (e.g., when representing phenyl substituted with one, two, or three, e.g., one or two, R 5 is the ortho-position substituent A 1 Combined together, (CH2) v (wherein v represents 1, 2, or 3).

[0087] In one embodiment, v is 1. In one embodiment, v is 2. In one embodiment, v is 3.

[0088] In one embodiment, B is a monocyclic heterocycle. Preferably, B is a 5- or 6-membered monocyclic heterocycle. Preferably, B is a 6-membered monocyclic heterocycle. Preferably, B is a 5-membered monocyclic heterocycle. In a second embodiment, B is a bicyclic heterocycle. In a third embodiment, B is a monocyclic heteroaryl. Preferably, B is a 5- or 6-membered monocyclic heteroaryl. In a fourth embodiment, B is a bicyclic heteroaryl. Preferably, B is a benzoxazolinone.

[0089] In one embodiment, B is one or more (e.g., one or two, especially one) B 1 In one embodiment, B is substituted with one or more (e.g., one, two, or three, e.g., one or two, especially one) B 1 has been replaced by

[0090] In one embodiment, at least one B 1 is halo. In a second embodiment, at least one B 1 is halo, for example fluoro. In a third embodiment, at least one B 1 is C 1-6 In a fourth embodiment, at least one B 1 is C 1-6 In a fifth embodiment, at least one B is haloalkyl. 1 is C 1-6 In a sixth embodiment, at least one B 1 is C 1-6 In a seventh embodiment, at least one B is haloalkoxy. 1 is C 0-6 alkylene (OH), for example, OH. In an eighth embodiment, at least one B 1 is oxo (=O). In a ninth embodiment, at least one B 1 is thioxo (=S). In a tenth embodiment, at least one B 1 is C 1-3Alkyl, for example, methyl.

[0091] In one embodiment, B is unsubstituted.

[0092] In one embodiment, B is [ka] ,for example, [ka] (where: B 1A is H or C 1-6 alkyl, for example, methyl; and B 2A is H or C 1-6 alkyl, e.g., methyl) is selected from the group consisting of:

[0093] In another embodiment, B is [ka] ;for example, [ka] (where: B 1A is H, halo, e.g., F, Br, or Cl, especially F or C 1-6 alkyl, for example, methyl; and B 2A is H, halo, e.g., F, Br, or Cl, especially F or C 1-6 alkyl, e.g., methyl) In one embodiment, B is selected from the group consisting of: [ka] In a second embodiment, B is [ka] is.

[0094] In one embodiment, B 1A is H. In a second embodiment, B 1A is C 1-6 Alkyl, for example, methyl.

[0095] In one embodiment, B 2A is H. In a second embodiment, B 2A is C 1-6 Alkyl, for example, methyl.

[0096] In one embodiment, B is [ka] (where, Each B 3A is C 1-6 alkyl, for example, methyl; and C 0-6 independently selected from alkylene (OH), e.g., OH; and y is 1 or 2) : selected from the group consisting of:

[0097] In one embodiment, B is [ka] (where B 2A is C 1-3 alkyl, e.g., methyl) : selected from the group consisting of:

[0098] In one embodiment, at least one B 3A is C 1-6 In a second embodiment, at least one B 3A is C 0-6 Alkylene (OH), for example, OH.

[0099] In one embodiment, y is 1. In a second embodiment, y is 2.

[0100] In one embodiment, the present invention provides a compound of formula (IA'): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is H, C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl).

[0101] In another embodiment, the present invention provides a compound of formula (IA'): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4is alkyl; R 5' is C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl).

[0102] In one embodiment, the present invention provides a compound of formula (IA″): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is H, C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl).

[0103] In another embodiment, the present invention provides a compound of formula (IA″): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl).

[0104] In one embodiment, the present invention provides a compound of formula (IA'''): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is H, C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl).

[0105] In one embodiment, the present invention provides a compound of formula (IA'''): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is C 1-4 Alkyl or C3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl).

[0106] In one embodiment, R 3' is H. In a second embodiment, R 3' is C 1-4 Alkyl, for example, methyl or ethyl.

[0107] In one embodiment, R 4' is H. In a second embodiment, R 4' is C 1-4 Alkyl, for example, methyl.

[0108] In one embodiment, R 5' is H. In a second embodiment, R 5' is C 1-4 alkyl, for example, methyl, ethyl, or iso-propyl. In a third embodiment, R 5' is C 3-6 Cycloalkyl, for example, cyclopropyl.

[0109] In one embodiment, R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forms a cycloalkyl, for example, cyclobutyl.

[0110] In one embodiment, R 7' is H. In a second embodiment, R 7' is C 1-6 alkyl, for example, methyl. In a third embodiment, R 7' is C 1-6 Alkoxy, for example, OMe.

[0111] In one embodiment, B 1A is H. In a second embodiment, B 1A is C 1-6 Alkyl, for example, methyl.

[0112] In one embodiment, n' is 0. In a second embodiment, n' is 1. In a third embodiment, n' is 2.

[0113] In one embodiment, A 1' is halo, for example, F, Br, or Cl. 1' is C 1-6 Alkyl, for example, methyl.

[0114] 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 and / or compounds of formula (IA) or salts and / or solvates thereof apply equally to compounds of formula (IA'), (IA"), and (IA'"), or salts and / or solvates thereof.

[0115] In one embodiment, the compound of formula (I) is N-((1-benzylcyclobutyl)methyl)-5-hydroxynicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3 carboxamide; (S)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(methoxy(phenyl)methyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(2-methyl-3-phenylpropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclopropyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-1-phenylpentan-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-(1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(2-bromophenyl)-2,2-dimethylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-methoxy-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-N-(2-benzyl-3-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclohexyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-(2-cyclobutyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(1-(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylpentyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; 1-methyl-N-((2-methyl-2,3-dihydro-1H-inden-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 6-oxo-N-((1-(pyridin-2-ylmethyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide; N-((1-benzylcyclobutyl)methyl)-3-methyl-1H-1,2,4-triazole-5-carboxamide; N-(2-benzyl-3-hydroxypropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-N,1-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclohexyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-(difluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyclopropylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-5-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; 1-Methyl-N-((1-(3-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-3-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyanobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; and N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; or any one of salts and / or solvates thereof : selected from the group consisting of:

[0116] In one embodiment, the compound of formula (I) is N-((1-benzylcyclobutyl)methyl)-5-hydroxynicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3 carboxamide; (S)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(methoxy(phenyl)methyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(2-methyl-3-phenylpropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclopropyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-1-phenylpentan-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-(1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(2-bromophenyl)-2,2-dimethylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-methoxy-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-[(2S)-2-benzyl-3-methylbutyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; N-[(2R)-2-benzyl-3-methylbutyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide N-((1-benzylcyclohexyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-(2-cyclobutyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(1-(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylpentyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; 1-methyl-N-((2-methyl-2,3-dihydro-1H-inden-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 6-oxo-N-((1-(pyridin-2-ylmethyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide; N-(2-benzyl-3-hydroxypropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-N,1-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclohexyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-(difluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyclopropylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-5-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; 1-Methyl-N-((1-(3-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-3-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyanobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-1-Methyl-5-oxo-N-(2-(2,4,6-trifluorobenzyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4-hydroxypicolinamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-hydroxy-1-methyl-1H-pyrazole-3-carboxamide (R)-N-(2-cyclopropyl-3-(4-fluoro-2-methylphenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide N-((2R,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-2-oxo-2,3-dihydrooxazole-4-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; 6-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; 1-Methyl-5-oxo-N-((1-(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(3-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(2-(3,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide; N-(2-((2,3-dihydrobenzofuran-5-yl)methyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(3-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((2S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-fluoro-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide; N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide; N-(2-(2,4-difluorobenzyl)-2-ethylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-(methoxymethyl)-4H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-5-Bromo-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(2-chloro-4,6-difluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; (R)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; (S)—N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)—N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (S)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)—N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(((1s,3r)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(((1r,3s)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; 5-chloro-N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; 5-chloro-N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; (S)—N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; (R)-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide (S)-5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; (R)-5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; and (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; or any one of salts and / or solvates thereof : selected from the group consisting of:

[0117] The definition of a compound of formula (I) is intended to include all tautomers of the compound.

[0118] 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:

[0119] 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.

[0120] 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.

[0121] 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).

[0122] 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.

[0123] 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.

[0124] 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( 14C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F), iodine-123( 123 I), iodine-125( 125 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.

[0125] 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.

[0126] In one embodiment, the compounds of the invention are provided in natural isotopic form.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] (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 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, and B are as defined above for compounds of formula (I).

[0132] (Scheme 1) [ka] Compounds of formula (I) can be prepared by reacting compounds of formula (II) with compounds of formula (III) 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.

[0133] Compounds of formula (II) and (III) are commercially available or can be prepared by methods known to those skilled in the art.

[0134] (Scheme 2) [ka] Compounds of formula (II) (wherein B is (B5)) can be prepared by reacting compounds of formula (IV) with a reagent such as CDI (1,1'-carbonyldiimidazole) in a solvent such as dichloromethane, followed by deprotection by ester hydrolysis using a base such as sodium hydroxide in a solvent such as a mixture of ethanol and water. Compounds of formula (IV) can be prepared by reacting compounds of formula (V) with compounds of formula (VI) in the presence of a base such as potassium carbonate and a solvent such as ethanol.

[0135] Compounds of formula (V) and (VI) are commercially available or can be made according to methods known to those skilled in the art.

[0136] (Scheme 3) [ka] A compound of formula (III) 2 and R 3 is H) can be prepared by reacting a compound of formula (VII) with a reducing agent, for example, lithium aluminum hydride, in a solvent such as THF. Compounds of formula (VII) can be prepared by reacting a compound of formula (VIII) with a compound of formula (IX) in the presence of a base, for example, lithium di-isopropylamide, in a solvent such as THF.

[0137] Compounds of formula (VIII) and (IX) are commercially available or can be made by methods known to those skilled in the art.

[0138] (Scheme 4) [ka] A compound of formula (III) 4 and / or R 5 is not H) can be prepared by reacting a compound of formula (X) under reducing conditions, for example, Raney nickel and H2, in a solvent such as methanol. Compounds of formula (X) can be prepared by reacting a compound of formula (XI) with an alkylating agent, for example, an alkyl halide, in the presence of a base such as LiHMDS (lithium bis(trimethylsilyl)amide), in a solvent such as tetrahydrofuran. Mono- or di-addition (i.e., R 4 and / or R 5 The addition of the alkylating agent can be controlled by adjusting the equivalent amount of the alkylating agent used.

[0139] Compounds of formula (XI) are commercially available or can be made by methods known to those skilled in the art.

[0140] (Scheme 5) [ka] A compound of formula (III) 2 or R 3 wherein at least one of is not H, can be reacted with a compound of formula (VII) using a Grignard reagent, e.g., R 2 MgBr (where R 2 is defined elsewhere, e.g., C 1-4 The compound can be prepared by reacting the compound with a substituted aryl group (which is an alkyl group) followed by reduction, for example with sodium borohydride.

[0141] (Scheme 6) [ka] Alternatively, a compound of formula (III) 2 or R 3wherein at least one of is not H) can be prepared by reacting a compound of formula (XII) under reducing conditions, for example, on Pd on carbon in the presence of H, in a solvent such as methanol. Compounds of formula (XII) can be prepared by reacting a compound of formula (XIII) with a hydroxylamine, for example, NHOH, in the presence of a base, for example, triethylamine, in a solvent such as ethanol. . Compounds of formula (XIII) can be prepared by reacting compounds of formula (VII) with an organolithium compound in a solvent such as tetrahydrofuran.

[0142] Compounds of formula (VII) are commercially available or can be made by methods known to those skilled in the art.

[0143] (Scheme 7) [ka] A compound of formula (III) 1 is not H) can be prepared by the process of preparing a compound of formula (III) 1 is H) can be prepared by reaction under amination conditions, for example, formamide in the presence of formic acid.

[0144] (Scheme 8) [ka] A compound of formula (VII) 7 is C 1-4 The compound of formula (XIV) can be obtained by reacting the compound of formula (IX) with an alkylating agent such as methyl iodide in the presence of a base such as sodium hydride in a solvent such as dimethylformamide. The compound of formula (XIV) can be obtained by reacting the compound of formula (IX) with a commercially available aldehyde such as benzaldehyde.

[0145] (Scheme 9) [ka] A compound of formula (III) 2 is C 1-4 The compound of formula (XVI) can be prepared by reacting a compound of formula (XVI) with a nucleophile such as Si(Me)3(CF3) in the presence of a base such as cesium fluoride in a solvent such as tetrahydrofuran.

[0146] Compounds of formula (XVI) are commercially available or can be made by methods known to those skilled in the art.

[0147] (Scheme 10) [ka] A compound of formula (VII) 4 and R 5 C is substituted by one or more halo atoms together with the atoms to which they are attached 3-6 The compound of formula (XVII) can be prepared by reacting a compound of formula (XVII) with a suitable reagent, such as diethylaminosulfur trifluoride, in a solvent such as dichloromethane. The compound of formula (XVII) can be obtained by reacting a compound of formula (XVIII) under oxidative conditions using an oxidizing agent, such as sodium periodate, in the presence of a catalyst, such as ruthenium trichloride, in a solvent such as a mixture of dichloromethane, acetonitrile, and water. The compound of formula (XVIII) can be obtained by reacting a compound of formula (XIX) with a compound of formula (VIII) in the presence of a base, such as lithium di-isopropylamide, in a solvent such as THF.

[0148] Compounds of formula (XIX) are commercially available or can be made according to methods known to those skilled in the art.

[0149] 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.

[0150] (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] wherein B is as defined for compounds of formula (I). or a salt thereof, a compound of formula (III) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6 and A is as defined for compounds of formula (I). or a salt thereof.

[0151] (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 (II): [ka] wherein B is as defined for compounds of formula (I). a compound of formula (III): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). a compound of formula (IV): [ka] (In the formula, B 1 are as defined for compounds of formula (I) a compound of formula (VII): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). a compound of formula (XII): [ka] (In the formula, R 2 , R 4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). a compound of formula (XIII): [ka] (In the formula, R 2 , R 4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). a compound of formula (XIV): [ka] (In the formula, R 4 , R 5 and A is as defined for compounds of formula (I). a compound of formula (XV): [ka] (In the formula, R 1 , R 4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). a compound of formula (XVI): [ka] (In the formula, R4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). a compound of formula (XVII): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 and A are as defined for compounds of formula (I); and a compound of formula (XVIII): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 and A is as defined for compounds of formula (I). or a salt, for example a pharmaceutically acceptable salt, of any one thereof, selected from the group consisting of:

[0152] (Treatment method) The compounds of formula (I) of the present invention have utility as inhibitors of mPTP.

[0153] References to compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof in the context of the methods of treatment and prophylaxis below include the proviso to formula (I), i.e., N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: [ka] It is understood that this does not include

[0154] These compounds are commercially available and to date, no utility (eg, therapeutic utility) has been described for these compounds.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[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 diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned hereinafter.

[0161] 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).

[0162] 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).

[0163] 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).

[0164] As used herein, the term "treatment" or "treating" includes controlling, alleviating, reducing, or modulating a disease state or its symptoms.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] In another embodiment, the disease or disorder is a complication associated with a metabolic disease, eg, diabetic neuropathy.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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).

[0177] In another embodiment, the disease or disorder is an ocular disease or disorder, such as age-related macular degeneration.

[0178] In another embodiment, the disease or disorder is Charcot-Marie-Tooth disease (CMT1a).

[0179] In another embodiment, the disease or disorder is Leigh's syndrome disease.

[0180] The compounds of formula (I) are believed to be useful in the treatment or prevention of mitochondrial diseases.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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).

[0188] 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).

[0189] 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).

[0190] 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).

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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).

[0199] 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).

[0200] 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).

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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).

[0209] 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).

[0210] 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).

[0211] 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.

[0212] Preferably, the subject is a mammal, and in particular, the subject is a human.

[0213] (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).

[0214] 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.

[0215] 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.

[0216] 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).

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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).

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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).

[0235] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0236] 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.

[0237] Compounds of formula (I) have a pIC of 6.0 or greater in the rat liver assay, as shown in the assays of Biological Examples 1 and 2. 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.

[0238] (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 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl; C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H, halo, or C 1-4 is alkyl; R 5 Ha, Halo, 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 4 and R 5 together with the atoms to which they are attached, C 5-11 Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spirocarbocyclyl, heterocycle, or cycloalkyl is C 1-3 Alkyl, C 1-3 optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more A 1 may be optionally substituted by; A 1 is C 1-3 Alkylthio, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR g R h , or NHSO2R j are independently selected from the group consisting of: R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 Is it alkyl? Or A is 1 or more 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) v wherein v represents 1, 2, or 3, and one of the CH groups may optionally be replaced by O; B 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 1 may be optionally substituted by; B 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, oxo (=O), thiooxo (=S), or C 0-6 alkylene (OH); provided that formula (I) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: [ka] isn't it). Clause 2. A compound of formula (IA) according to claim 1: or a salt and / or solvate thereof [ka] (In the formula: R 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl; C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H or C 1-4 is alkyl; R 5 H, halo, 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 4 and R 5 together with the atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-3 Alkyl, C 1-3optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is 1 or more A 1 is a monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl optionally substituted by A 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 g R h , or NHSO2R j and; R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 Is it alkyl? Or A is 1 or more 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH2) v wherein v represents 1, 2, or 3, and one of the CH groups may optionally be replaced by O; B is 1 or more B 1 a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl optionally substituted by B 1 Ha, Halo, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 0-6 alkylene (OH); wherein formula (IA) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: [ka] isn't it). Clause 3. A compound, salt and / or solvate according to Clause 1 or Clause 2, which is said compound, a pharmaceutically acceptable salt and / or solvate thereof. Clause 4. Pharmaceutically acceptable salts and solvates according to Clause 1 or Clause 2. Clause 5. A pharmaceutically acceptable salt according to Clause 1 or Clause 2. Clause 6. A pharmaceutically acceptable solvate according to Clause 1 or Clause 2. Clause 7. A compound according to clause 1 or clause 2. 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 (IA): or a salt and / or solvate thereof [ka] . Article 9.R 1 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 1 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 2 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 2 11. The compound according to any one of clauses 1, 2 or 8-10, or a salt and / or solvate thereof, wherein is halo. Article 13.R 2 C 1-411. 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 or ethyl. Article 14.R 2 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 haloalkyl, for example CF3. Article 15.R 2 C 1-4 11. The compound according to any one of clauses 1, 2, or 8 to 10, or a salt and / or solvate thereof, which is alkoxy. Article 16.R 2 C 1-4 11. The compound according to any one of clauses 1, 2, or 8 to 10, or a salt and / or solvate thereof, which is haloalkoxy. Article 17.R 2 C 0-4 11. The compound according to any one of clauses 1, 2, or 8-10, or a salt and / or solvate thereof, wherein alkylene (OH), for example CH2CH2OH. Article 18.R 3 16. The compound according to any one of clauses 1, 2 or 8 to 15, or a salt and / or solvate thereof, wherein Article 19.R 3 18. The compound according to any one of clauses 1, 2 or 8-17, or a salt and / or solvate thereof, wherein is halo. Article 20.R 3 C 1-4 18. The compound according to any one of clauses 1, 2, or 8 to 17, or a salt and / or solvate thereof, wherein R is alkyl. Article 21.R 2 and R 3 11. The compound according to any one of clauses 1, 2, or 8-10, or a salt and / or solvate thereof, wherein each is H. Article 22.R 2 is H and R 3 11. The compound according to any one of clauses 1, 2, or 8 to 10, or a salt and / or solvate thereof, wherein is methyl. Article 23.R 2 is H and R3 11. The compound according to any one of clauses 1, 2, or 8 to 10, or a salt and / or solvate thereof, wherein is ethyl. Article 24.R 4 24. The compound according to any one of clauses 1, 2 or 8 to 23, or a salt and / or solvate thereof, wherein Article 25.R 4 C 1-4 24. The compound according to any one of clauses 1, 2 or 8-23, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl. Article 26.R 4 24. The compound according to any one of clauses 1, 2 or 8 to 23, or a salt and / or solvate thereof, wherein is halo. Article 27.R 5 27. The compound according to any one of clauses 1, 2 or 8 to 26, or a salt and / or solvate thereof, wherein is halo. Article 28.R 5 But C 1-6 27. A compound according to any one of clauses 1, 2 or 8 to 26, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl, ethyl, n-propyl or iso-propyl, especially ethyl. Article 29.R 5 C 1-6 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, which is haloalkyl. Article 30.R 5 C 1-6 27. The compound according to any one of clauses 1, 2 or 8-26, or a salt and / or solvate thereof, which is alkoxy, for example OMe. Article 31.R 5 C 1-6 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, which is haloalkoxy. Article 32.R 5 C 2-6 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, which is alkenyl. Article 33.R 5 C2-6 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, which is haloalkenyl. Article 34.R 5 But C 0-6 Alkylene (C 3-6 cycloalkyl), e.g., C 3-6 27. A compound according to any one of clauses 1, 2 or 8 to 26, or a salt and / or solvate thereof, which is cycloalkyl, for example cyclopropyl or cyclobutyl, especially cyclopropyl. Article 35.R 5 C 3-6 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, which is cycloalkyl. Article 36.R 5 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein is cyclobutyl. Article 37.R 5 27. The compound according to any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein is cyclopropyl. Article 38.R 5 C 0-6 27. The compound according to any one of clauses 1, 2, or 8-26, or a salt and / or solvate thereof, wherein alkylene(OH). Article 39.R 5 39. The compound according to clause 38, or a salt and / or solvate thereof, wherein is CH2OH or CH(Me)(OH). Article 40.R 4 and R 5 24. The compound according to any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, wherein each is methyl. Article 41.R 4 is H and R 5 24. The compound according to any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, wherein is ethyl. Article 42.R 4 is H and R 522. The compound according to any one of clauses 1, 2, or 8-21, or a salt and / or solvate thereof, wherein is iso-propyl. Article 43.R 4 and R 5 together with the carbon atoms to which they are attached, C 5-11 Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spirocarbocyclyl, heterocycle, or cycloalkyl is C 1-3 Alkyl, C 1-3 24. The compound according to any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, optionally substituted with one or more groups selected from haloalkyl and halo. Article 44.R 4 and R 5 together with the carbon atoms to which they are attached, unsubstituted C 5-11 Spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 A compound according to any one of clauses 1, 2 or 8 to 23, or a salt and / or solvate thereof, which forms a cycloalkyl. Article 45.R 4 and R 5 together with the atoms to which they are bonded, C 3-6 A compound according to any one of clauses 1, 2 or 8 to 23, or a salt and / or solvate thereof, which forms a cycloalkyl. Article 46.R 4 and R 5 together with the atom to which they are attached form a 4- to 7-membered heterocycle, or a salt and / or solvate thereof. Article 47.R 4 and R 5 together with the atoms to which they are bonded, C 5-11 24. The compound according to any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, which forms a spirocarbocyclyl. Article 48.R 4 and R 5together with the atom to which they are attached form a spiropentane, or a salt and / or solvate thereof. Article 49.R 4 and R 5 together with the atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl ring, especially a cyclobutyl ring, or a salt and / or solvate thereof. Article 50.R 6 50. The compound according to any one of clauses 1, 2 or 8-49, or a salt and / or solvate thereof, wherein Article 51.R 6 C 1-4 49. The compound or salt and / or solvate thereof according to any one of clauses 1, 2 or 8-49, wherein alkyl is, for example, methyl. Article 52.R 7 52. The compound according to any one of clauses 1, 2 or 8 to 51, or a salt and / or solvate thereof, wherein Article 53.R 7 52. The compound according to any one of clauses 1, 2 or 8 to 51, or a salt and / or solvate thereof, wherein is halo. Article 54.R 7 C 1-4 52. The compound according to any one of clauses 1, 2 or 8 to 51, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl. Article 55.R 7 C 1-4 52. The compound according to any one of clauses 1, 2, or 8 to 51, or a salt and / or solvate thereof, which is haloalkyl. Article 56.R 7 C 1-4 52. The compound according to any one of clauses 1, 2 or 8-51, or a salt and / or solvate thereof, which is alkoxy, for example OMe. Article 57.R 7 C 1-4 52. The compound according to any one of clauses 1, 2, or 8 to 51, or a salt and / or solvate thereof, which is haloalkoxy. Article 58.R6 is H and R 7 50. The compound according to any one of clauses 1, 2 or 8-49, or a salt and / or solvate thereof, wherein Article 59.R 6 is H and R 7 49. The compound according to any one of clauses 1, 2, or 8 to 49, or a salt and / or solvate thereof, wherein is methyl. Article 60.R 2 , R 3 , R 4 , R 6 , or R 7 60. The compound according to any one of clauses 1, 2 or 8-59, or a salt and / or solvate thereof, wherein at least one of: Clause 61. The compound according to any one of clauses 1, 2, or 8-60, or a salt and / or solvate thereof, wherein A is monocyclic aryl. Clause 62. A compound according to Clause 61, or a salt and / or solvate thereof, wherein A is phenyl. Clause 63. The compound according to any one of clauses 1, 2, or 8-60, or a salt and / or solvate thereof, wherein A is bicyclic aryl. Clause 64. The compound according to any one of clauses 1, 2, or 8-60, or a salt and / or solvate thereof, wherein A is monocyclic heteroaryl. Clause 65. The compound according to any one of clauses 1, 2, or 8-60, or a salt and / or solvate thereof, wherein A is bicyclic heteroaryl. Article 66. A is one or more (e.g., one, two, or three, e.g., one or two, in particular, one) A 1 66. The compound according to any one of clauses 61 to 65, or a salt and / or solvate thereof, substituted by: Article 67. Two A's 1 66. The compound according to any one of clauses 61 to 65, or a salt and / or solvate thereof, substituted by: Article 68. A is one A 1 66. The compound according to any one of clauses 61 to 65, or a salt and / or solvate thereof, substituted by: Article 69. At least one A 1 67. The compound according to clause 66, wherein is halo, for example F, Br or Cl, especially F, or a salt and / or solvate thereof. Article 70. At least one A 1 67. The compound according to clause 66, or a salt and / or solvate thereof, wherein is F, Br, or Cl. Article 71. At least one A 1 67. The compound according to clause 66, or a salt and / or solvate thereof, wherein is F. Article 72. At least one A 1 C 1-6 72. The compound according to any one of clauses 66 to 71, or a salt and / or solvate thereof, which is alkyl, for example methyl. Article 73. At least one A 1 C 1-6 73. The compound according to any one of clauses 66 to 72, or a salt and / or solvate thereof, which is haloalkyl. Article 74. At least one A 1 C 1-6 74. The compound according to any one of clauses 66 to 73, or a salt and / or solvate thereof, which is alkoxy, for example OMe. Article 75. At least one A 1 C 1-6 75. The compound according to any one of clauses 66 to 74, or a salt and / or solvate thereof, which is haloalkoxy. Article 76. At least one A 1 C 3-6 76. The compound according to any one of clauses 66 to 75, or a salt and / or solvate thereof, which is cycloalkyl. Article 77. At least one A 1 77. The compound according to any one of clauses 66 to 76, or a salt and / or solvate thereof, wherein is CN. Article 78. At least one A 1 78. The compound according to any one of clauses 66 to 77, or a salt and / or solvate thereof, wherein is OH. Article 79. At least one A 1 NR g R h79. The compound according to any one of clauses 66 to 78, or a salt and / or solvate thereof, wherein Article 80. R g 79. The compound according to clause 79, or a salt and / or solvate thereof, wherein is H. Article 81.R g C 1-4 79. The compound according to clause 79, or a salt and / or solvate thereof, wherein R is alkyl. Article 82.R h 82. The compound according to any one of clauses 79 to 81, or a salt and / or solvate thereof, wherein is H. Article 83.R h C 1-4 82. The compound according to any one of clauses 79 to 81, or a salt and / or solvate thereof, wherein: Article 84. At least one A 1 NHSO2R j 84. The compound according to any one of clauses 66 to 83, or a salt and / or solvate thereof, wherein Article 85. At least one A 1 C 1-3 85. The compound according to any one of clauses 66 to 84, or a salt and / or solvate thereof, which is alkylthio. Clause 86. A compound according to any one of clauses 61 to 55, or a salt and / or solvate thereof, wherein A is unsubstituted. Article 87. If A: [ka] (In the formula: A 1A is halo, e.g., F, Br, or Cl; C 1-6 alkyl, for example, methyl; or C 1-6 alkoxy, for example, OMe; and A 1B is H or halo, for example F, Br, or Cl, especially F 63. A compound according to clause 61 or 62, or a salt and / or solvate thereof, selected from the group consisting of: Article 88. A is 1 or more A 1and R 5 is the ortho-position substituent A 1 Combined together, (CH2) v 63. A compound according to clause 61 or 62, or a salt and / or solvate thereof, wherein v represents 1, 2 or 3, and one of the CH2 groups may optionally be replaced by O. Article 89. A is 1 or more A 1 and R 5 is the ortho-position substituent A 1 Combined together, (CH2) v 63. The compound according to clause 61 or 62, or a salt and / or solvate thereof, wherein v represents 1, 2 or 3. Clause 90. A compound according to clause 88 or 89, or a salt and / or solvate thereof, wherein v is 1. Clause 91. A compound or salt and / or solvate according to clause 88 or 89, wherein v is 2. Clause 92. A compound or salt and / or solvate according to clause 88 or 89, wherein v is 3. Clause 93. The compound according to any one of clauses 1, 2, or 8 to 92, or a salt and / or solvate thereof, wherein B is a monocyclic heterocycle. Clause 94. The compound according to Clause 93, or a salt and / or solvate thereof, wherein B is a 5-membered monocyclic heterocycle. Clause 95. A compound according to Clause 93 or a salt and / or solvate thereof, wherein B is a 6-membered monocyclic heterocycle. Clause 96. The compound according to any one of clauses 1, 2, or 8-92, or a salt and / or solvate thereof, wherein B is monocyclic heteroaryl. Clause 97. The compound according to Clause 96, or a salt and / or solvate thereof, wherein B is a 5-membered monocyclic heteroaryl. Clause 98. The compound according to Clause 96, or a salt and / or solvate thereof, wherein B is a 6-membered monocyclic heteroaryl. Clause 99. The compound according to any one of clauses 1, 2, or 8-92, or a salt and / or solvate thereof, wherein B is bicyclic heteroaryl. Clause 100. A compound according to Clause 99 or a salt and / or solvate thereof, wherein B is a benzoxazolinone. Article 101. B is one or more (e.g., one or two, in particular, one) B 1 101. The compound according to any one of clauses 93 to 100, or a salt and / or solvate thereof, substituted by: Article 102. One or two B 1 101. The compound according to any one of clauses 93 to 100, or a salt and / or solvate thereof, substituted by: Article 103. B is one B 1 101. The compound according to any one of clauses 93 to 100, or a salt and / or solvate thereof, substituted by: Article 104. At least one B 1 104. The compound according to any one of clauses 101 to 103, or a salt and / or solvate thereof, wherein is halo. Article 105. At least one B 1 C 1-6 105. The compound according to any one of clauses 101 to 104, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl. Article 106. At least one B 1 C 1-6 106. The compound according to any one of clauses 101 to 105, or a salt and / or solvate thereof, which is haloalkyl. Article 107. At least one B 1 C 1-6 107. The compound according to any one of clauses 101 to 106, or a salt and / or solvate thereof, which is alkoxy. Article 108. At least one B 1 C 1-6 101. The compound according to any one of clauses 101 to 90, or a salt and / or solvate thereof, which is haloalkoxy. Article 109. At least one B 1 C 0-6 108. The compound according to any one of clauses 101 to 107, or a salt and / or solvate thereof, which is alkylene (OH), such as OH. Article 110. At least one B 1 109. The compound according to any one of clauses 101 to 108, or a salt and / or solvate thereof, wherein is oxo (=O). Article 111. At least one B 1 109. The compound according to any one of clauses 101 to 109, or a salt and / or solvate thereof, wherein is thioxo (=S). Clause 112. A compound according to any one of clauses 92 to 100, or a salt and / or solvate thereof, wherein B is unsubstituted. Article 113. If B: [ka] for example, [ka] (In the formula: B 1A is H or C 1-6 alkyl, for example, methyl; and B 2A is H or C 1-6 alkyl, e.g., methyl) 112. The compound according to any one of clauses 93 to 111, or a salt and / or solvate thereof, selected from the group consisting of: Article 114. If B: [ka] (In the formula: Each B 3A is C 1-6 alkyl, for example, methyl; and C 0-6 independently selected from alkylene (OH), e.g., OH; and y is 1 or 2) 112. The compound according to any one of clauses 93 to 111, or a salt and / or solvate thereof, selected from the group consisting of: Article 115. If B: [ka] 112. The compound according to any one of clauses 93 to 111, or a salt and / or solvate thereof, wherein Article 116. A compound according to Article 1 or Article 2, which is a compound of formula (IA'): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is H, C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl). Article 117. A compound according to Article 1 or Article 2, which is a compound of formula (IA'): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl). Article 118. A compound according to Article 1 or Article 2, which is a compound of formula (IA″): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is H, C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B A1 is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl). Article 119. A compound according to Article 1 or Article 2, which is a compound of formula (IA″): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl). Clause 120. A compound according to clause 1 or clause 2, which is a compound of formula (IA'''): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is H, C 1-4 Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl). Article 121. A compound according to Article 1 or Article 2, which is a compound of formula (IA'''): or a salt and / or solvate thereof [ka] (In the formula: R 1' is H; R 2' is H; R 3' is H or C 1-4 is alkyl; R 4' is H or C 1-4 is alkyl; R 5' is C 1-4Alkyl or C 3-6 cycloalkyl; or R 4' and R 5' together with the atoms to which they are attached, C 3-6 Forming a cycloalkyl; R 6' is H; R 7' is H, C 1-6 Alkyl or C 1-6 is alkoxy; B 1A is H or C 1-6 alkyl, for example, methyl; n' is 0, 1, or 2; and A 1' is halo or C 1-6 (It is alkyl). Article 122.R 3' 122. The compound according to any one of clauses 116 to 121, or a salt and / or solvate thereof, wherein is H. Article 123.R 4' 123. The compound according to any one of clauses 116 to 122, or a salt and / or solvate thereof, wherein is H. Article 124.R 5' But C 1-4 124. The compound according to any one of clauses 116 to 123, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl, ethyl, or iso-propyl. Article 125 R 5' C 3-6 125. The compound according to any one of clauses 116 to 124, or a salt and / or solvate thereof, which is cycloalkyl, for example cyclopropyl. Article 126.R 4' and R 5' together with the atoms to which they are bonded, C 3-6 122. A compound according to any one of clauses 116 to 121, or a salt and / or solvate thereof, which forms a cycloalkyl, for example cyclobutyl. Article 127.R 7' 127. The compound according to any one of clauses 116 to 126, or a salt and / or solvate thereof, wherein is H. Article 128.R7' C 1-6 127. The compound according to any one of clauses 116 to 126, or a salt and / or solvate thereof, which is alkyl, for example methyl. Article 129.R 7' C 1-6 127. The compound according to any one of clauses 116 to 126, or a salt and / or solvate thereof, which is alkoxy, for example OMe. Article 130.B 1A 129. The compound according to any one of clauses 116 to 129, or a salt and / or solvate thereof, wherein is H. Article 131.B 1A C 1-6 129. The compound according to any one of clauses 116 to 129, or a salt and / or solvate thereof, which is alkyl, for example methyl. Clause 132. The compound according to any one of Clauses 116 to 131, or a salt and / or solvate thereof, wherein n' is 2. Article 133. At least one A 1' 133. The compound according to any one of clauses 116 to 132, or a salt and / or solvate thereof, wherein is halo, for example F, Br, or Cl. Clause 134. The compound according to any one of Clauses 116 to 133, or a salt and / or solvate thereof, wherein n' is 0. Article 135.R 4 and R 5 but with the following stereochemistry: [ka] 135. The compound according to any one of clauses 1, 2 or 8 to 134, or a salt and / or solvate thereof, having the formula: Article 136. N-((1-benzylcyclobutyl)methyl)-5-hydroxynicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3 carboxamide; (S)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(methoxy(phenyl)methyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(2-methyl-3-phenylpropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclopropyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-1-phenylpentan-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-(1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(2-bromophenyl)-2,2-dimethylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-methoxy-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-[(2S)-2-benzyl-3-methylbutyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; N-[(2R)-2-benzyl-3-methylbutyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclohexyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-(2-cyclobutyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(1-(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylpentyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; 1-methyl-N-((2-methyl-2,3-dihydro-1H-inden-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 6-oxo-N-((1-(pyridin-2-ylmethyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide; N-(2-benzyl-3-hydroxypropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-N,1-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclohexyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-(difluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyclopropylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-5-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; 1-Methyl-N-((1-(3-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-3-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyanobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)-1-Methyl-5-oxo-N-(2-(2,4,6-trifluorobenzyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4-hydroxypicolinamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-hydroxy-1-methyl-1H-pyrazole-3-carboxamide (R)-N-(2-cyclopropyl-3-(4-fluoro-2-methylphenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide N-((2R,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-2-oxo-2,3-dihydrooxazole-4-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; 6-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; 1-Methyl-5-oxo-N-((1-(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(3-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(2-(3,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide; N-(2-((2,3-dihydrobenzofuran-5-yl)methyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(3-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((2S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-fluoro-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide; N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide; N-(2-(2,4-difluorobenzyl)-2-ethylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-(methoxymethyl)-4H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)butyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-5-Bromo-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(2-chloro-4,6-difluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; (R)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; (S)—N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)—N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (S)—N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (R)-N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)—N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(((1s,3r)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(((1r,3s)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (S)—N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; 5-chloro-N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; 5-chloro-N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; (S)—N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; (R)-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide (S)-5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; (R)-5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; (S)—N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; (S)—N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; and (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; or any one of salts and / or solvates thereof 10. A compound according to clause 1 or clause 2, or a salt and / or solvate thereof, selected from the group consisting of: Clause 137. A pharmaceutical composition comprising a compound according to any one of clauses 3 to 136 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 138. A compound according to any one of clauses 3 to 136 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply) for use as a pharmaceutical. Clause 139. A compound according to any one of clauses 3 to 136 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 140. Use of a compound according to any one of clauses 3 to 136 or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment 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 141. 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 according to any one of clauses 3 to 136 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 142. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to any one of clauses 139 to 141, 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 143. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to any one of clauses 139 to 141, 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 144. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 143, 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 145. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, wherein said disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorders, schizophrenia, and epilepsy. Clause 146. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 143, 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 147. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, 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 148. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, 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 149. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, 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 150. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, wherein said disease or disorder is an age-related disease, such as bone repair, weakening of bone with age in osteoporosis, and sarcopenia. Clause 151. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 143, wherein said disease or disorder is a renal disease, such as chronic renal disease and chronic renal disease associated with APOL1 gene mutations. Article 152. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, wherein said disease or disorder is an age-related disease, such as bone repair, weakening of bone with age in osteoporosis, and sarcopenia. Article 153. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to Article 143, 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 154. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 143, wherein said disease or disorder is an ocular disease or disorder, for example age-related macular degeneration. Clause 155. A compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 143, wherein said disease or disorder is Charcot-Marie-Tooth disease (CMT1a). Clause 156. A compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to clause 143, wherein said disease or disorder is Leigh's syndrome disease. Article 157. A compound according to any one of Articles 3 to 136 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 mitochondrial disease. Clause 158. A compound according to any one of clauses 3 to 136 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 159. Use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to any one of Articles 3 to 136 in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, wherein the proviso to formula (I) does not apply. Clause 160. 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 136 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 161. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use or method according to any one of clauses 158 to 160, 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 162. A compound according to any one of Articles 3 to 136 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 163. Use of a compound according to any one of Articles 3 to 136 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 164. 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 136 or a pharmaceutically acceptable salt and / or solvate thereof (wherein the proviso to formula (I) does not apply). Clause 165. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, use, or method according to any one of clauses 162 to 164, wherein said disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis. Clause 166. A process for the preparation of a compound of formula (I) according to any one of clauses 1 to 136, comprising the step of: [ka] wherein B is as defined for compounds of formula (I). a compound of formula (III) or a salt thereof [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6 and A is as defined for compounds of formula (I). The process comprising reacting Article 167.- Compounds of formula (II): [ka] wherein B is as described in any one of clauses 1 to 166; a compound of formula (III): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of clauses 1 to 166); a compound of formula (IV): [ka] (In the formula, B 1 is as set out in any one of clauses 1 to 166); a compound of formula (VII): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of clauses 1 to 166); a compound of formula (XII): [ka] (In the formula, R 2 , R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of clauses 1 to 166); a compound of formula (XIII): [ka] (In the formula, R 2 , R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of clauses 1 to 166); a compound of formula (XIV): [ka] (In the formula, R 4 , R 5 , and A is as defined in any one of clauses 1 to 166); a compound of formula (XV): [ka] (In the formula, R 4 , R 5 , R 6 , R 7, and A is as defined in any one of clauses 1 to 166); a compound of formula (XVI): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of clauses 1 to 166); a compound of formula (XVII): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 and A is as defined in any one of clauses 1 to 166); and a compound of formula (XVIII): [ka] (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of clauses 1 to 166). or a salt, such as a pharmaceutically acceptable salt, of any one of these. Article 168.R 4 is H and R 5 96. The compound for use, its pharmaceutically acceptable salt and / or solvate, use or method according to any one of clauses 1 to 95, wherein is cyclopropyl.

[0239] The present invention is further illustrated by the following non-limiting examples. [Example]

[0240] (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.

[0241] (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.

[0242] 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. 1 H NMR was recorded at 300 K on a Bruker 300 MHz instrument (ADVANCE III and ADVANCE III HD). Flash preparative HPLC was performed using the following columns: XBridge Prep C18 OBD column, 5 um, 19 x 150 mm; Welch Xtimate C18, 21.2 x 250 mm, 5 um; SunFire Prep C18 OBD 19 x 150 mm x 5 um. SFC purification was performed using the following columns: (a) CHIRALPAK AS-H, 3 *25 cm, 5 um, (b) SFC-YMC cellulose-SB, 4.6 × 100 mm, 3 um. Table 1: Analytical LC-MS conditions [Table 1]

[0243] (Synthesis of Example Compounds) (abbreviation) [Table 2]

[0244] (Intermediate 1: 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid) Step 1: [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.

[0245] Step 2: [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.

[0246] Step 3: [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

[0247] (Method A: Chiral Route) (Intermediate 2: (R)-2-cyclopropyl-3-(2,4,6-trifluorophenyl)propan-1-amine) [ka] Step 1: To (R)-2-amino-2-phenylethan-1-ol (10 g, 72.9 mmol) in methanol (250 mL) was added benzaldehyde (7.4 mL, 72.9 mmol), and the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added sodium borohydride (3420 mg, 90.4 mmol) in portions, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (600 mL) and extracted with DCM (3 x 600 mL). The organic layers were combined, washed with brine (800 mL), passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give (R)-2-(benzylamino)-2-phenylethan-1-ol (16.2 g, 67.1 mmol, 92%) as a pale yellow solid.

[0248] Step 2: To a solution of 2-cyclopropylacetic acid (4.1 mL, 42.5 mmol) in DCM (90 mL) was added a solution of oxalyl chloride (7.3 mL, 85.1 mmol) in DCM (10 mL). To this was added two drops of DMF, and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo to give 2-cyclopropylacetyl chloride (5040 mg, 42.5 mmol, 100%) as a yellow oil.

[0249] Step 3: To (R)-2-(benzylamino)-2-phenylethan-1-ol (7710 mg, 33.9 mmol) in DCM (210 mL) was added sodium hydroxide (2849 mg, 71.2 mmol) in water (115 mL) and the reaction mixture was cooled to −10° C. To this was added 2-cyclopropylacetyl chloride (5027 mg, 42.4 mmol) in DCM (20 mL) and the reaction mixture was stirred at −10° C. for 15 minutes, then allowed to warm to room temperature and stirred for 15 minutes.

[0250] The reaction mixture was diluted with DCM (600 mL) and water (300 mL), and the layers were separated. The aqueous fraction was extracted with DCM (300 mL). The organic layers were combined and passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give a crude yellow oil, which was purified by flash column chromatography to give (R)-N-benzyl-2-cyclopropyl-N-(2-hydroxy-1-phenylethyl)acetamide (6535 mg, 19.4 mmol, 57%) as a pale yellow gum.

[0251] Step 4: To (R)-N-benzyl-2-cyclopropyl-N-(2-hydroxy-1-phenylethyl)acetamide (1250 mg, 4.04 mmol) in tetrahydrofuran (18 mL) was added lithium chloride (685 mg, 16.2 mmol), and the reaction mixture was cooled to −78° C. To this was added dropwise a 1.4 M solution of sec-butyllithium in cyclohexane (14 mL, 20.2 mmol), and the reaction mixture was stirred at −78° C. for 30 minutes. To this was then added dropwise 2,4,6-trifluorobenzyl bromide (1.0 mL, 7.60 mmol), and the reaction mixture was stirred at −78° C. for 1 hour, then warmed to room temperature over 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl solution (80 mL) and extracted with EtOAc (150 mL). The organic layer was passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give a crude oil. This was purified by flash column chromatography to give (R)-N-benzyl-2-cyclopropyl-N-((R)-2-hydroxy-1-phenylethyl)-3-(2,4,6-trifluorophenyl)propanamide (1098 mg, 2.42 mmol, 59%) as a pale yellow oil.

[0252] Step 5: To (R)-N-benzyl-2-cyclopropyl-N-((R)-2-hydroxy-1-phenylethyl)-3-(2,4,6-trifluorophenyl)propanamide (1098 mg, 2.42 mmol) in tetrahydrofuran (14 mL) under nitrogen was added 1.0 M lithium aluminum hydride in THF (4.2 mL, 4.24 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred at room temperature for 2 hours.

[0253] The reaction was cooled to below 10°C, quenched with aqueous Rochelle's salt (30 mL), and extracted with EtOAc (100 mL). The organic layer was passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a pale yellow oil. The crude material was dissolved in a minimal amount of MeOH and pipetted onto an SCX-2 cartridge (Biotage). The cartridge was washed with MeOH (4 CV) and flushed with 3.5 M NH3 / MeOH (6 CV) to give (R)-2-(benzyl((R)-2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)amino)-2-phenylethan-1-ol (1027 mg, 2.34 mmol, 96%) as a colorless oil.

[0254] Step 6: To (R)-2-(benzyl((R)-2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)amino)-2-phenylethan-1-ol (550 mg, 0.9 mmol) in ethanol (40 mL) in a 500 mL Parr flask was added 10% wt palladium on carbon (0.940 mmol). The reaction flask was evacuated and then backfilled with nitrogen (×3), then hydrogen (×1). The reaction mixture was shaken under a hydrogen atmosphere at 35 psi at room temperature for 19 hours. UPLC showed that no SM remained and the desired product and partially deprotected material (only the Bn group was removed) had formed. Additional Pd / C (excess) was added to the reaction mixture. The reaction flask was evacuated and then backfilled with nitrogen (×3), then hydrogen (×1). The reaction mixture was shaken under a hydrogen atmosphere at 35 psi at room temperature for an additional 5 hours. UPLC showed that no SM remained and the desired product and by-products were formed. The reaction was stopped to prevent loss of product and the buildup of impurities. The mixture was passed through a sintered filter, washed with MeOH (150 mL), and the solvent was removed in vacuo. The gum was then dissolved in a minimal amount of MeOH and pipetted onto an SCX-2 cartridge (Biotage). The cartridge was washed with MeOH (4 CV) and flushed with 3.5 M NH3 / MeOH (6 CV) to afford (R)-2-cyclopropyl-3-(2,4,6-trifluorophenyl)propan-1-amine (128 mg, 0.336 mmol, 37%, 60% pure) as a pale yellow oil. This material was used further as is.

[0255] The following amine intermediates were synthesized using methods similar to those outlined above for Intermediate 2 (Method A) using commercially available starting materials or benzyl bromide intermediates: Table 2: [Table 3]

[0256] (Method B: KHMDS route) (Intermediate 13A: 1-(3,4-difluorobenzyl)cyclobutane-1-carbonitrile) [ka] To a flask purged and maintained with nitrogen, cyclobutanecarbonitrile (0.25 mL, 2.66 mmol) and toluene (5.0 mL) were added, and the solution was cooled to 0° C. To the reaction mixture, potassium bis(trimethylsilyl)amide solution (1 M in THF) (4.5 mL, 4.47 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 hours. To this was then added 3,4-difluorobenzyl bromide (0.31 mL, 2.42 mmol), and the reaction mixture was stirred at room temperature for 18 hours.

[0257] The reaction mixture was quenched with aqueous NH4Cl solution (20 mL) and extracted with EtOAc (50 mL). The organic layer was passed through a phase separator cartridge (Biotage) and the solvent was removed in vacuo to give the crude product.

[0258] This was purified by flash column chromatography to 1-(3,4-difluorobenzyl)cyclobutane-1-carbonitrile (366 mg, 1.77 mmol, 73%) as a yellow oil.

[0259] The following intermediates were synthesized using methods similar to those outlined above for Intermediate 13A (Method B) using commercially available starting materials or benzyl bromide intermediates: Table 3: [Table 4]

[0260] (Method C: LiTMP route) (Intermediate 29A: 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-carbonitrile) [ka] A vacuum-dried flask evacuated and filled with N2 was charged with tetrahydrofuran (10 mL) and 2,2,6,6-tetramethylpiperidine (1.1 mL, 6.18 mmol), and the solution was cooled to -78°C. n-Butyllithium (2.5 mL, 6.18 mmol) was added dropwise, and the solution was stirred for 15 minutes, allowed to warm to -50°C, and then cooled back to -78°C. Tetrahydro-2H-pyran-4-carbonitrile (572 mg, 5.15 mmol) was added as a solution in THF (2 mL), and the mixture was stirred at -78°C for 1 hour, then warmed to -50°C, then cooled to -78°C, and 2,4-difluorobenzyl bromide (0.66 mL, 5.15 mmol) was added. The solution was allowed to warm to RT and then heated to 60°C for 1 hour. The temperature was reduced to 40°C and the reaction was stirred for 2 days.

[0261] The reaction was diluted with water and EtOAc, the layers were separated, and the aqueous fraction was extracted with EtOAc (3x). The organic fractions were combined and washed with dilute citric acid, water, and brine, then dried over MgSO4 and the solvent was removed. The crude material was purified by flash column chromatography to give 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-carbonitrile (998 mg, 4.21 mmol, 82%) as a pale yellow oil.

[0262] (Method D: NaHMDS route) (Intermediate 30A: 2-(2,4-difluorobenzyl)tetrahydrofuran-2-carbonitrile) [ka] To a flask purged and maintained with nitrogen, tetrahydrofuran-2-carbonitrile (225 mg, 2.32 mmol) in tetrahydrofuran (7.7 mL) was added and the solution was cooled to −78° C. A 1.0 M solution of sodium bis(trimethylsilyl)amide in THF (2.3 mL, 2.32 mmol) was added dropwise, and the mixture was stirred at −78° C. for 50 minutes. 2,4-Difluorobenzyl bromide (99 μL, 0.773 mmol) in tetrahydrofuran (3.9 mL) was then added, and the mixture was stirred at −78° C. for 1.5 hours. The reaction was quenched with NH4Cl (6 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with HO (30 mL), passed through a phase separator cartridge (Biotage), and concentrated in vacuo to give a crude oil.

[0263] This was purified by flash column chromatography to give 2-(2,4-difluorobenzyl)tetrahydrofuran-2-carbonitrile (92 mg, 0.412 mmol, 53%) as a colorless oil.

[0264] (Intermediate 31A: 1-(2-(methylthio)benzyl)cyclobutane-1-carbonitrile) [ka] Sodium bis(trimethylsilyl)amide (1.19 g, 6.48 mmol) was added to an ice-cold solution of cyclobutanecarbonitrile (0.500 mL, 7.07 mmol) in toluene (10 mL) under N2. The reaction mixture was stirred at room temperature for 1 h, after which a solution of 1-(bromomethyl)-2-methylsulfanyl-benzene (Intermediate 66) (1.28 g, 5.90 mmol) in toluene (5 mL) was added. The reaction was allowed to stir at room temperature overnight and then heated to 40 °C for 30 min. Water was added and the solution was extracted with DCM (3x). The combined organics were washed successively with water and saturated brine solution, dried (MgSO4), and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (Biotage Isolera Selekt, 25 g Sfar column) eluting with isohexane-EtOAc (0–20%) to afford 1-(2-(methylthio)benzyl)cyclobutane-1-carbonitrile (1.20 g, 94%) as a colorless oil.

[0265] (Method E: LDA pathway) (Intermediate 32A: 3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropanenitrile) [ka] To a two-neck flask purged and maintained with nitrogen, 2-cyclopropylacetonitrile (0.45 mL, 4.92 mmol) and tetrahydrofuran (12 mL) were added, and the reaction mixture was cooled to −78° C. To the reaction mixture, lithium diisopropylamide (LDA, 1 M in THF) (5.4 mL, 5.37 mmol) was added dropwise, and the reaction mixture was stirred at −78° C. for 1 hour. To this was then added 2-chloro-4-fluorobenzyl bromide (1000 mg, 4.47 mmol), and the reaction mixture was stirred at −78° C. for an additional 1 hour. Water was added to the reaction mixture, and it was extracted with EtOAc (2×). The combined organic layers were passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give a crude oil. This was purified by flash column chromatography to give 3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropanenitrile (414 mg, 1.85 mmol, 41%) as a colorless oil.

[0266] The following intermediates were synthesized using methods similar to those outlined above for Intermediate 32A (Method E) using commercially available starting materials or other amine intermediates: Table 4: [Table 5]

[0267] (Method F: Horner-Wandsworth-Emmons pathway) (Intermediate 35A: 2-(isoquinolin-6-ylmethyl)butanenitrile) [ka] Step 1: To sodium hydride (60% dispersion in oil) (27 mg, 0.668 mmol) in N,N-dimethylformamide (1.2 mL) was added diethyl cyanomethylphosphonate (103 uL, 0.636 mmol) at 0° C. and stirred for 10 minutes at 0° C. To this was added bromoethane (52 uL, 0.700 mmol) and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour.

[0268] To the reaction mixture, N,N-dimethylformamide (1.2 mL) and sodium hydride (60% dispersion in oil) (27 mg, 0.668 mmol) were added at 0° C. and stirred for 15 minutes at 0° C. Then, to this was added isoquinoline-6-carboxaldehyde (100 mg, 0.636 mmol) in N,N-dimethylformamide (1.2 mL), and the reaction mixture was stirred at room temperature overnight.

[0269] The reaction was concentrated, and the residue was diluted with DCM (15 mL) and washed with brine (2 × 15 mL). The organic layer was passed through a phase separator cartridge (Biotage) and concentrated in vacuo to give a dark purple oil. The crude material was purified by flash column chromatography to give 2-(isoquinolin-6-ylmethylene)butanenitrile (90 mg, 0.432 mmol, 68%) as a yellow oil.

[0270] Step 2: 2-(Isoquinolin-6-ylmethylene)butanenitrile (90 mg, 0.432 mmol) in methanol (10 mL) was evacuated and backfilled with nitrogen (×3). Palladium on carbon (10%) (50 mg, 0.470 mmol) was added, and then the flask was backfilled with hydrogen at 1 atmosphere. The reaction mixture was stirred under a H balloon at room temperature for 18 hours.

[0271] The reaction was filtered through a Celite cartridge (Biotage) and washed with MeOH. The solvent was removed in vacuo to give 2-(isoquinolin-6-ylmethyl)butanenitrile (53 mg, 0.252 mmol, 58%) as a pale yellow oil.

[0272] The following intermediates were synthesized using commercially available starting materials using methods similar to those outlined above for Intermediate 35A (Method F): Table 5: [Table 6]

[0273] (Intermediate 38A: (E)-2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methylene)butanenitrile) [ka] Diethyl cyanomethylphosphonate (0.46 mL, 2.82 mmol) was added to sodium hydride (60% dispersion in oil, 119 mg, 2.96 mmol) in N,N-dimethylformamide (5.0 mL) at 0°C, and the reaction mixture was stirred for 10 minutes. Bromoethane (0.23 mL, 3.10 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. N,N-dimethylformamide (5.0 mL) and sodium hydride (60% dispersion in mineral oil, 119 mg, 2.96 mmol) were added to the reaction mixture at 0°C, and the reaction mixture was stirred for 15 minutes. 2,3-Dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (463 mg, 2.82 mmol) in N,N-dimethylformamide (5.0 mL) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was dissolved in chloroform. The solution was washed with saturated brine solution, and the organic phase was passed through a phase separator cartridge (Biotage). The solvent was evaporated in vacuo, and the crude product was purified by flash column chromatography (Biotage Isolera Four, 25 g Sfar column) eluting with isohexane-EtOAc (0-30%) to give (2E)-2-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)butanenitrile (380 mg, 1.77 mmol, 63%) as a yellow oil.

[0274] (Intermediate 39A: 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropanenitrile) [ka] To a two-necked flask purged and maintained with nitrogen was added diisopropylamine (1.58 mL, 11.6 mmol) in tetrahydrofuran (22 mL). The mixture was cooled to -78°C, and n-butyllithium (4.63 mL, 11.6 mmol) was added dropwise. After 5 minutes at -78°C, 2-cyclopropyl-3-(2,4-difluorophenyl)propanenitrile (2.00 g, 9.65 mmol) in tetrahydrofuran (22 mL) was added dropwise over 10 minutes. The mixture was stirred at -78°C for 20 minutes, after which iodomethane (0.728 mL, 11.6 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature with continued stirring for 1 hour. Water (40 mL) and EtOAc (60 mL) were added, and the layers were separated. The aqueous layer was further extracted with EtOAc (2 x 40 mL). The organic layers were combined, passed through a phase separator cartridge (Biotage), and concentrated in vacuo to give a crude oil, which was purified by flash column chromatography to give 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropanenitrile (1.26 g, 5.69 mmol, 59%) as a yellow oil.

[0275] (Method G: Nitrile Reduction) LiAlH4 reduction was utilized to convert the nitrile intermediates synthesized using Methods B-F to the corresponding amines:

[0276] Preparation of Intermediate 13B: (1-(3,4-difluorobenzyl)cyclobutyl)methanamine [ka] To a two-necked flask purged and maintained with nitrogen was added 1-(3,4-difluorobenzyl)cyclobutane-1-carbonitrile (366 mg, 1.77 mmol) in tetrahydrofuran (8.0 mL). The reaction mixture was cooled to 0°C, and to this was added dropwise 1.0 M lithium aluminum hydride in THF (5.3 mL, 5.3 mmol) at 0-5°C. The resulting reaction mixture was stirred at room temperature for 1 hour.

[0277] The reaction was cooled to 0° C., quenched with aqueous Rochelle's salt solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a crude oil.

[0278] This was dissolved in a minimal amount of MeOH and pipetted onto an SCX-2 cartridge (Biotage). The cartridge was washed with MeOH (4 CV) and flushed with NH / MeOH (6 CV) to give (1-(3,4-difluorobenzyl)cyclobutyl)methanamine (277 mg, 1.18 mmol, 67%) as a pale yellow oil.

[0279] The below amine was synthesized using a similar method to intermediate 13B above: Table 6: [Table 7] TIFF2026503521000108.tif238170TIFF2026503521000109.tif202170

[0280] Intermediate 38B: 2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)butan-1-amine [ka] To (2E)-2-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)butanenitrile (380 mg, 1.77 mmol) in THF (8.0 mL) at 0° C. was added lithium aluminum hydride solution (1.0 M in THF, 5.30 mL, 5.30 mmol) dropwise. The mixture was stirred at room temperature for 2 hours, cooled to 0° C., quenched with aqueous Rochelle's salt solution, and extracted with EtOAc. The organic phase was washed with saturated brine solution, passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo. The crude material was dissolved in a minimum amount of MeOH and loaded onto an SCX-2 cartridge (Biotage). The cartridge was washed with MeOH and eluted with NH3-MeOH. The solvent was evaporated in vacuo to give 2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)butan-1-amine (350 mg, 90%) as a yellow oil.

[0281] (Method H: Head group synthesis) (Intermediate 40: 5-fluoro-6-methoxy-1,6-dihydropyrimidine-2-carboxylic acid) [ka] Step 1: To 2-chloro-5-fluoro-6-methoxy-1,6-dihydropyrimidine (500 mg, 3.08 mmol) in N,N-dimethylformamide (7.0 mL) was added zinc cyanide (361 mg, 3.08 mmol), and nitrogen was bubbled through the reaction mixture for 10 minutes. To this was then added tetrakis(triphenylphosphine)palladium(0) (355 mg, 0.308 mmol), and nitrogen was bubbled through the reaction mixture for an additional 10 minutes. The reaction mixture was heated at 90° C. for 3 days.

[0282] The reaction mixture was quenched with concentrated aqueous ammonium hydroxide (1 mL) and brine (5 mL) and extracted with EtOAc (2 x 10 mL). The organic layers were combined, washed with brine (5 mL), passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give a crude oil.

[0283] This was purified by flash column chromatography to give 5-fluoro-4-methoxypyrimidine-2-carbonitrile (45 mg, 0.293 mmol, 10%) as a yellow oil.

[0284] Step 2: To 5-fluoro-4-methoxypyrimidine-2-carbonitrile (45 mg, 0.293 mmol) was added 1 M sodium hydroxide solution (3.0 mL, 78.0 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 3 with aqueous 1 M HCl. The aqueous fraction was washed with DCM (4 × 10 mL). Attempts to extract the desired product were unsuccessful. The solvent was removed in vacuo to give crude 5-fluoro-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid (200 mg) as a white solid. The solid appeared to be primarily the NaCl salt. The final compound was carried forward as is to the next coupling step.

[0285] (Intermediate 41: 1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid) [ka] Step 1: 1-Methylhydrazine-1-carbothioamide (1000 mg, 9.51 mmol), triethylamine (13 mL, 95.1 mmol), and 4-(dimethylamino)pyridine (46 mg, 0.380 mmol) were dissolved in DCM (20 mL). The reaction was cooled to 0°C, and ethyl 2-chloro-2-oxoacetate (1.2 mL, 10.5 mmol) was added dropwise. The reaction mixture turned from colorless to deep orange. It was allowed to warm to room temperature and stirred overnight. The reaction mixture was acidified to pH 5 with aqueous HCl, after which it was extracted with DCM (3 × 20 mL). The combined organic fractions were concentrated in vacuo to afford an orange gum of ethyl 2-(2-carbamothioyl-2-methylhydrazineyl)-2-oxoacetate (1686 mg, 8.2152 mmol, 86%).

[0286] Step 2: Ethyl 2-(2-carbamothioyl-2-methylhydrazineyl)-2-oxoacetate (1600 mg, 7.8 mmol) was dissolved in MeOH (10 mL). NaOH (936 mg, 23.4 mmol) was added and the reaction was heated to 60°C for 1 h. HO (10 mL) was added and the reaction was heated to 90°C for an additional 1 h. The reaction mixture was concentrated, and the residue was redissolved in minimal water / EtOH (4 mL) and extracted with DCM (5 x 30 mL). The organic phases were combined, passed through a phase separator cartridge (Biotage), and then concentrated to give 1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid as a yellow gum (300 mg, 1.88 mmol, 24%).

[0287] (Intermediate 42: Ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxylate) [ka] To ethyl 2-amino-2-thioxoacetate (500 mg, 3.75 mmol) in ethanol (15 mL) was added hydrazine hydrate (184 μL, 3.75 mmol), and the reaction mixture was stirred at room temperature for 1.5 hours. To this was then added ethyl glyoxalate (50% in toluene) (0.76 mL, 7.51 mmol), and the reaction mixture was stirred at reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added and washed with DCM (20 mL). UPLC showed impurities in the organic layer and product in the aqueous phase. The aqueous layer was concentrated in vacuo to give ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxylate (473 mg, 2.29 mmol, 61%) as a crude brown oil.

[0288] (Intermediate 43: Ethyl 5-ethoxy-1,3,4-oxadiazole-2-carboxylate) [ka] Ethyl hydrazine carboxylate (500 mg, 4.80 mmol), ethyl chlorooxoacetate (0.54 mL, 4.80 mmol), triethylamine (2.0 mL, 14.4 mmol), and p-toluenesulfonyl chloride (916 mg, 4.80 mmol) were combined and stirred in DCM at room temperature for 3 h. The reaction mixture was evaporated and purified by flash column chromatography to give crude ethyl 5-ethoxy-1,3,4-oxadiazole-2-carboxylate (140 mg, 0.75 mmol, 16%) as a yellow oil. The crude material was used in further steps without purification.

[0289] (Intermediate 44: 4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid) [ka] 5-(Hydroxymethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (400 mg, 3.10 mmol) was dissolved in water (10 mL). Potassium permanganate (1469 mg, 9.29 mmol) was added, followed by a solution of 1 M NaOH in water (4.65 mL, 4.65 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was filtered through Celite to remove insoluble inorganics, and the filtrate was evaporated to dryness to give crude 4-methyl-5-oxo-1H-1,2,4-triazole-3-carboxylic acid (1160 mg, 8.1062 mmol, 262%). The crude material was used in further steps without purification.

[0290] (Intermediate 45: 2-(2,4-difluorobenzyl)-2-fluorobutan-1-amine) [ka] Step 1: To sodium hydride (60% dispersion in oil) (638 mg, 15.9 mmol) in tetrahydrofuran (8.0 mL) was added diethyl ethyl malonate (2.0 mL, 10.6 mmol) in tetrahydrofuran (4.0 mL) under nitrogen. The reaction mixture was stirred at room temperature for 15 minutes. To this was then added 2,4-difluorobenzyl bromide (1.5 mL, 11.7 mmol) in tetrahydrofuran (4.0 mL), dropwise. The resulting mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to 0 °C, acidified with aqueous 1 M HCl (10 mL), and extracted with EtO (3 × 60 mL). The organic layers were combined, washed with saturated aqueous NaHCO solution (15 mL), brine (15 mL), and then passed through a phase separator cartridge (Biotage). The solvent was removed in vacuo to give a crude colorless oil. This was purified by flash column chromatography to give diethyl 2-(2,4-difluorobenzyl)-2-ethylmalonate (2575 mg, 7.54 mmol, 71%) as a colorless oil.

[0291] Step 2: To diethyl 2-(2,4-difluorobenzyl)-2-ethylmalonate (2575 mg, 7.54 mmol) in ethanol (14 mL) was added aqueous 5 M NaOH solution (5.9 mL, 35.3 mmol), and the reaction mixture was refluxed for 18 hours. The solvent was removed in vacuo, and then water (10 mL) was added to the residue and washed with isohexane (15 mL). The aqueous fraction was cooled to 0 °C, acidified with aqueous 5 M HCl, and extracted with EtO (3 × 15 mL). The organic layers were combined, washed with brine, passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give 2-(2,4-difluorobenzyl)-2-ethylmalonic acid (1910 mg, 7.03 mmol, 93%) as an orange oil.

[0292] Step 3: Selectfluor (4974 mg, 14.0 mmol), dipotassium hydrogen phosphate (4891 mg, 28.1 mmol), and silver nitrate (328 mg, 1.40 mmol) were added to a flask and purged with nitrogen for 10 minutes. To this was then added 2-(2,4-difluorobenzyl)-2-ethylmalonic acid (1908 mg, 7.02 mmol) in cyclopentyl methyl ether (CPME) (35 mL) and water (35 mL), and the reaction mixture was purged with nitrogen for 10 minutes. The mixture was stirred at room temperature for 16 hours.

[0293] The reaction was quenched with aqueous 3 M HCl (10 mL) and extracted with EtOAc (2 × 30 mL). The organic layers were combined, passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give 2-(2,4-difluorobenzyl)-2-fluorobutanoic acid (1880 mg, 5.66 mmol, 81%) as a crude orange oil.

[0294] Step 4: To 2-(2,4-difluorobenzyl)-2-fluorobutanoic acid (746 mg, 2.25 mmol) in tetrahydrofuran (75 mL) at 0 °C was added ethyl chloroformate (301 μL, 3.15 mmol) and triethylamine (0.94 mL, 6.75 mmol), and the reaction mixture was stirred at 0 °C for 30 minutes. To this was then added aqueous 1 M ammonium chloride (10 mL, 10.0 mmol), and the resulting reaction mixture was stirred at 0 °C for an additional 30 minutes. Water (60 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 80 mL). The organic layers were combined, washed with brine (80 mL), passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give a crude solid. This was purified by flash column chromatography to give 2-(2,4-difluorobenzyl)-2-fluorobutanamide (450 mg, 1.94 mmol, 86%) as a white solid.

[0295] Step 5: To a stirred solution of 2-(2,4-difluorobenzyl)-2-fluorobutanamide (400 mg, 1.56 mmol) in acetonitrile (8.0 mL) at room temperature, phosphorus pentoxide (884 mg, 3.11 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. DCM (40 mL) was added to the reaction mixture and washed with dilute aqueous NaHCO solution (15 mL) and water (15 mL). The organic layer was passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo to give the product as a crude yellow oil. The oil was purified by flash column chromatography to give 2-(2,4-difluorobenzyl)-2-fluorobutanenitrile (273 mg, 1.28 mmol, 82%) as a colorless oil.

[0296] Step 6: To 2-(2,4-difluorobenzyl)-2-fluorobutanenitrile (273 mg, 1.28 mmol) in methanol (12 mL) was added nickel(II) chloride hexahydrate (31 mg, 0.131 mmol) and di-tert-butyl dicarbonate (315 mg, 1.44 mmol) at 0 °C. The reaction was cooled to -5 °C, and sodium borohydride (99 mg, 2.63 mmol) was added very slowly over 2 minutes. The reaction was then allowed to warm to room temperature and stirred overnight. To this was then added diethylenetriamine (142 uL, 1.31 mmol), and the reaction mixture was stirred for an additional 30 minutes. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (40 mL) and extracted with EtOAc (3 x 80 mL). The organic layers were combined, washed with brine (100 mL), passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give tert-butyl (2-(2,4-difluorobenzyl)-2-fluorobutyl)carbamate as a crude oil (227 mg).

[0297] Step 7: To crude tert-butyl (2-(2,4-difluorobenzyl)-2-fluorobutyl)carbamate (508 mg, 1.60 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the oil was dissolved in a minimum amount of MeOH and pipetted onto an SCX-2 cartridge (Biotage). The column was flushed with MeOH (4 CV) followed by 3.5 M NH3 / MeOH (6 CV). The product-containing fractions were combined, and the solvent was removed in vacuo to give the crude product after SCX-2, 2-(2,4-difluorobenzyl)-2-fluorobutan-1-amine (254 mg, 35% pure by UPLC), as a pale yellow oil, which was used in the subsequent step.

[0298] (Intermediate 46: C1 methylated amine) [ka] Step 1: 2,4-Difluorobenzaldehyde (8.03 g, 56.5 mmol) and triethyl 2-phosphonobutyrate (13 mL, 56.5 mmol) were combined in THF (150 mL). Sodium hydride (60% dispersion in oil) (2.37 g, 98.9 mmol) was added portionwise over 5 minutes at room temperature, heated to reflux for 3.5 hours, and then stirred at room temperature for 16 hours. Water was added (50 mL), and the reaction was stirred at room temperature for 30 minutes. The product was extracted from the aqueous fraction into EtOAc, and the organic layer was dried over MgSO, decanted, and evaporated to a yellow oil. Flash column chromatography afforded ethyl 2-(2,4-difluorobenzylidene)butanoate (8.06 g, 35 mmol, 63%).

[0299] Step 2: Ethyl 2-(2,4-difluorobenzylidene)butanoate (9.92 g, 41.3 mmol) was suspended in ethanol (5 mL) and water (35 mL), and sodium hydroxide (2.81 g, 70.1 mmol) was added. The reaction was heated to 80 °C overnight. The reaction was cooled to room temperature and further diluted with water (25 mL). The pH was adjusted to pH 2 with aqueous HCl, resulting in a white precipitate. The product was extracted into EtOAc, and the organic fraction was dried over MgSO, filtered, and the solvent was evaporated to give 2-(2,4-difluorobenzylidene)butanoic acid (8.3 g, 39.1 mmol, 95%) as a pale pink solid.

[0300] Step 3: Freshly prepared (Sa,S)-DTB-Bn-SIPHOX-Ir-(COD)-BARF catalyst (100 mg, 0.052 mmol) and 2-(2,4-difluorobenzylidene)butanoic acid (3.0 g, 14.1 mmol) were combined and placed under vacuum, then purged with Ar. Anhydrous methanol was added, and the material was again degassed and placed under an Ar atmosphere. Triethylamine (0.56 mL, 3.97 mmol) was added, and the reaction was degassed and purged with hydrogen gas (3×), and the reaction was stirred at room temperature under a hydrogen balloon for 16 hours. The reaction was evaporated, then water was added and acidified to pH = 1 with aqueous HCl, and the product was then extracted into EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and then the solvent was removed in vacuo to give the product (S)-2-(2,4-difluorobenzyl)butanoic acid (3.3 g, 14 mmol, 100%) as a white solid.

[0301] Step 4: (S)-2-(2,4-Difluorobenzyl)butanoic acid (3.3 g, 14 mmol), N,O-dimethylhydroxylamine hydrochloride (1.6 g, 16 mmol), HATU (6 g, 16 mmol), and N,N-diisopropylethylamine (7.4 g, 58 mmol, 10 mL) were combined in DMF (100 mL) and stirred at RT for 16 h. The reaction was poured onto water-ice and stirred, then partitioned with EtOAc and the layers separated. The aqueous fraction was extracted with EtOAc, and the combined organics were washed with water, then brine, dried over MgSO4, filtered, and the solvent evaporated. Purification by column chromatography afforded (S)-2-(2,4-difluorobenzyl)-N-methoxy-N-methylbutanamide (3.3 g, 13 mmol, 79%) as a clear yellow oil.

[0302] Step 5: (S)-2-(2,4-Difluorobenzyl)-N-methoxy-N-methylbutanamide (3.0 g, 12 mmol) was taken up in anhydrous THF (30 ml) and cooled to −78° C. under nitrogen. Methylmagnesium bromide solution (3.0 M, 15.8 ml, 47.7 mmol) was added dropwise via syringe, and the reaction was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature with stirring for an additional 2 hours. The reaction was concentrated in vacuo to a thick slurry, worked up by adding dilute citric acid and water, stirred, and the product extracted into EtOAc. The organic fraction was washed with water, then brine, and dried over MgSO4. The suspension was filtered and evaporated to give (S)-3-(2,4-difluorobenzyl)pentan-2-one (2.45 g, 11.5 mmol, 99%) as a yellow oil.

[0303] Step 6: (S)-3-(2,4-Difluorobenzyl)pentan-2-one (150 mg, 0.707 mmol) and titanium(IV) isopropoxide (402 mg, 430 μL, 1.41 mmol) were combined, and (R)-2-methylpropane-2-sulfinamide (146 mg, 1.20 mmol) was added. The reaction mixture was heated to 50°C for 2 days. The cloudy suspension was cooled to 0°C, after which methanol (5 mL) was added. The solution was stirred at 0°C for 10 minutes to equilibrate, after which sodium borohydride (53 mg, 2.42 mmol) was added. The reaction was then warmed to RT and stirred for 16 hours. Upon addition of water, a white precipitate formed, which was removed by filtration through Celite, and the resulting aqueous layer was extracted with EtOAc. The organic layer was washed with water, then brine, dried over MgSO, then the solvent was removed and dried under vacuum overnight to give (R)-N-((3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (204 mg, 0.64 mmol, 91%) as a yellow oil.

[0304] Step 7: (R)—N-((3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (204 mg, 0.643 mmol) was taken up in methanol (10 mL) and 4 M HCl in dioxane (806 ul, 3.2 mmol) was added. The reaction was stirred at room temperature overnight. The material was concentrated in vacuo, redissolved in methanol, and loaded onto an SCX-2 column (Biotage). The column was washed with MeOH and then flushed with 2 M NH3 / methanol and the solvent removed to give the crude product (3S)-3-(2,4-difluorobenzyl)pentan-2-amine (70 mg, 0.328 mmol, 51.07%) as a pale yellow oil, which was used further as is.

[0305] Using a similar method, the following chiral amines were synthesized: Table 7: [Table 8]

[0306] The following intermediates were synthesized using commercially available starting materials using methods similar to those outlined above for Intermediate 13A (Method B): Table 8: [Table 9]

[0307] (Intermediate 48B: 1-(2,4-difluorobenzyl)-3-fluorocyclobutane-1-carbonitrile) [ka] Step 1: 1-(2,4-Difluorobenzyl)-3-methoxycyclobutane-1-carbonitrile (670 mg, 2.82 mmol) and tetrabutylammonium iodide (1.10 g, 2.97 mmol) were dissolved in chloroform (4.5 mL). Boron trifluoride diethyl etherate (366 μL, 2.97 mmol) was added, and the mixture was stirred at 65° C. for 4 hours. The mixture was diluted with saturated NaHCO 3 3(aq) (30 mL) and extracted with DCM (30 mL). The organic phase was diluted with saturated NaSO 3(aq) The resulting mixture was washed successively with water (30 mL). The organic phase was passed through a phase separator and the eluent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage, 25 g Sfar column) eluting with isohexane-EtOAc (0-60%) to give 1-(2,4-difluorobenzyl)-3-hydroxycyclobutane-1-carbonitrile (300 mg, 48%) as a colorless oil.

[0308] Step 2: To 1-(2,4-difluorobenzyl)-3-hydroxycyclobutane-1-carbonitrile (200 mg, 0.896 mmol) in dichloromethane (3.6 mL) at -78 °C, (diethylamino)sulfur trifluoride (237 μL, 1.79 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 days. The reaction mixture was cooled to 0 °C and cooled with cold saturated NaHCO 3(aq) The mixture was quenched with HCl. The aqueous phase was extracted with DCM (3x). The combined organics were passed through a phase separator and the eluent was evaporated in vacuo.

[0309] A separate reaction was also carried out using 1-(2,4-difluorobenzyl)-3-hydroxycyclobutane-1-carbonitrile (50 mg, 0.224 mmol) in DCM (0.9 mL) at -78 °C. To this solution, (diethylamino)sulfur trifluoride (59 μL, 0.448 mmol) was added dropwise. The mixture was stirred at room temperature for 7 days. The reaction mixture was cooled to 0 °C and cooled with cold saturated NaHCO 3 3(aq) (1.5 mL). The aqueous phase was extracted with DCM (5 mL). The combined organics were passed through a phase separator and the eluent evaporated in vacuo.

[0310] The two crude mixtures were combined and the desired product was purified by flash chromatography (Biotage, 25 g Sfar column) eluting with isohexane-EtOAc (0–40%) to afford 1-(2,4-difluorobenzyl)-3-fluorocyclobutane-1-carbonitrile (122 mg, 48% combined yield) as a colorless oil.

[0311] The following intermediates were synthesized using methods similar to those outlined above for intermediate 32A (Method E) using commercially available starting materials or benzyl bromide intermediate 68: Table 9: [Table 10]

[0312] (Intermediate 54A: 2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropanenitrile) [ka] 2-Cyclopropyl-3-(4-fluorophenyl)-2-methylpropanenitrile was synthesized using a similar method to intermediate 39A (2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropanenitrile).

[0313] The following amines were synthesized using a method similar to that outlined above for the nitrile reduction of intermediate 13A (Method G). Occasionally, additional heat was applied to the reaction for several hours to drive the conversion to completion: Table 10: [Table 11]

[0314] (Intermediate 55: 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid) [ka] 5-Bromo-4-methoxy-pyrimidine-2-carbonitrile (250 mg, 1.17 mmol) in 1 M sodium hydroxide solution (4.0 mL, 4.00 mmol) was stirred at 35° C. for 6 h, then at rt for 16 h. The solution was adjusted to pH 3 with 1 M HCl, and the mixture was concentrated in vacuo to give the crude product as a white solid. The crude product was carried on to the next step without further purification.

[0315] Intermediates 56 and 57: 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropan-1-amine (Enantiomers A and B) [ka] 2-Cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropan-1-amine (Intermediate 39B) (18 g, 80 mmol) was purified using a CHIRALPAK AY-H column under the following conditions: *Separation was performed by SFC using a 25 cm, 10 μm column; mobile phase: 45% EtOH (containing 0.1% 2M NH in MeOH) / CO; flow rate: 100 mL / min, sample solvent: MeOH; injection volume: 1.5 mL. Concentration of the appropriate fractions gave the following: Enantiomer A. Rt 3.9 min LCMS(ES, m / z): 226.2[M+H] + [ka] Enantiomer B. Rt 1.98 min LCMS(ES, m / z): 226.2[M+H] + [ka]

[0316] Intermediates 58 and 59: 2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropan-1-amine (Enantiomer A and Enantiomer B) [ka] 2-Cyclopropyl-3-(4-fluorophenyl)-2-methylpropan-1-amine (Intermediate 54B) (15 g, 72 mmol) was purified using a CHIRALPAK AY-H column under the following conditions: * Purification by SFC using 25 cm, 10 μm; mobile phase: 50% EtOH (containing 0.1% 2M NH in MeOH) / CO; flow rate: 100 mL / min; sample solvent: MeOH; injection volume: 1 mL. Concentration of appropriate fractions gave the following: Enantiomer A. Rt 2.5 min (2S)-2-Cyclopropyl-3-(4-fluorophenyl)-2-methylpropan-1-amine (5.7 g, 36% yield) as a pale yellow oil LCMS: (ES, m / z): 208.1 [M+H] + [ka] Enantiomer B. Rt 1.95 min LCMS: (ES, m / z): 208.2 [M+H] + [ka]

[0317] (Benzyl alcohol intermediate:) (Intermediate 60: (2-(methoxymethyl)phenyl)methanol) [ka] To a three-necked flask purged and maintained with nitrogen was added 2-(methoxymethyl)benzoic acid (900 mg, 5.42 mmol) in tetrahydrofuran (18 mL). The reaction mixture was cooled to 0°C, and to this was added dropwise 1.0 M lithium aluminum hydride in THF (16.2 mL, 16.2 mmol) at 0-5°C. The resulting reaction mixture was stirred at room temperature for 2 hours.

[0318] The reaction was cooled to 0° C., quenched with aqueous Rochelle's salt solution (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a crude oil.

[0319] The crude material was purified by flash column to give (2-(methoxymethyl)phenyl)methanol (774 mg, 5.08 mmol, 94%) as a colorless oil.

[0320] The following compounds were synthesized using methods similar to those outlined above for intermediate 60: Table 11: [Table 12]

[0321] (Intermediate 62: (3-ethylphenyl)methanol) [ka] Step 1: To a microwave vial was added (3-iodophenyl)methanol (814 μL, 6.41 mmol), bis(triphenylphosphine)palladium(II) dichloride (84 mg, 0.120 mmol), copper(I) iodide (49 mg, 0.255 mmol), and triethylamine (7.5 mL, 54.0 mmol), and the reaction mixture was purged with nitrogen for 10 minutes while being sonicated. (Trimethylsilyl)acetylene (1367 μL, 9.60 mmol) was added to the reaction mixture, which was stirred at 100° C. in a microwave reactor for 2 hours.

[0322] The reaction mixture was diluted with EtOAc (150 mL) and washed with 1 M HCl (80 mL × 2), water (80 mL), and brine (80 mL). The organic layer was passed through a phase separator cartridge (Biotage) and the solvent was removed in vacuo. The crude material was purified by flash column chromatography to give (3-((trimethylsilyl)ethynyl)phenyl)methanol (1.05 g, 4.89 mmol, 76%) as an orange oil.

[0323] Step 2: To (3-((trimethylsilyl)ethynyl)phenyl)methanol (1290 mg, 6.31 mmol) in methanol (18 mL) was added potassium carbonate (4363 mg, 31.6 mmol) and the reaction mixture was stirred at room temperature for 1 hour.

[0324] The solvent was removed in vacuo, and the residue was diluted with water (100 mL) and washed with diethyl ether (3 x 100 mL). The organic layers were combined, passed through a phase separator cartridge (Biotage), and the solvent was removed in vacuo. The oil was purified by flash column chromatography to give (3-ethynylphenyl)methanol (759 mg, 5.74 mmol, 91%) as a yellow oil.

[0325] Step 3: To (3-ethynylphenyl)methanol (758 mg, 5.74 mmol) in ethanol (80 mL) was added Adams' catalyst of platinum(IV) oxide (391 mg, 1.72 mmol). The reaction mixture was evacuated and backfilled with nitrogen (x3), and then the flask was backfilled with hydrogen at 1 atmosphere. The reaction mixture was stirred under an atmosphere of H at room temperature for 1 hour.

[0326] The mixture was filtered through a Celite cartridge (Biotage) and washed with MeOH (3 CV). The solvent was removed in vacuo to give (3-ethylphenyl)methanol (575 mg, 4.22 mmol, 74%) as a yellow oil.

[0327] (Benzyl bromide intermediate) (Intermediate 63: 1-(1-bromoethyl)-2,4-difluorobenzene) [ka] To 1-(2,4-difluorophenyl)ethan-1-ol (2500 mg, 15.8 mmol) in diethyl ether (80 mL) was added phosphorus tribromide (1.7 mL, 17.4 mmol) and the mixture was stirred at room temperature overnight.

[0328] The reaction was diluted with Et2O (20 mL) and H2O (50 mL) was added. The organic layer was passed through a phase separator cartridge (Biotage) and concentrated under reduced pressure to give a crude oil.

[0329] This was purified by flash column chromatography to give 1-(1-bromoethyl)-2,4-difluorobenzene (2.96 g, 13.4 mmol, 85%) as a colorless oil.

[0330] The following compounds were synthesized using methods similar to that outlined above for intermediate 63, using commercially available starting materials or benzyl alcohol intermediates. In some cases, the reaction mixture was stirred at room temperature for different lengths of time: Table 12: [Table 13]

[0331] (Intermediate 69: 2-(2,4-difluorobenzyl)-N-methylbutan-1-amine) [ka] Step 1: Di-tert-butyl dicarbonate (361 mg, 1.66 mmol) was dissolved in tetrahydrofuran (3.0 mL) under nitrogen, and 2-(2,4-difluorobenzyl)butan-1-amine (220 mg, 1.10 mmol) was added as a solution in tetrahydrofuran (3.0 mL), followed by triethylamine (0.18 mL, 1.33 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water (5 mL), extracted with DCM (3 × 10 mL), and the combined organic fractions were washed with brine (10 mL), passed through a phase separator cartridge (Biotage), and evaporated to dryness. The material was purified by flash column chromatography to afford tert-butyl (2-(2,4-difluorobenzyl)butyl)carbamate (330 mg, 1.10 mmol, 100%) as a colorless oil.

[0332] Step 2: tert-Butyl (2-(2,4-difluorobenzyl)butyl)carbamate (330 mg, 1.10 mmol) was dissolved in tetrahydrofuran (10 mL) under N2 and cooled to 0 °C. Sodium hydride (60% dispersion in oil) (53 mg, 1.32 mmol) was added portionwise over 5 min, and the solution was stirred for approximately 10 min. Iodomethane (83 uL, 1.32 mmol) was added, and the solution was allowed to warm to room temperature over 3 h. The reaction was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and passed through a phase separator cartridge (Biotage). The solution was evaporated to dryness, and the residue was purified by flash column chromatography to afford tert-butyl (2-(2,4-difluorobenzyl)butyl)(methyl)carbamate (200 mg, 0.638 mmol, 58%) as a colorless oil.

[0333] Step 3: tert-Butyl (2-(2,4-difluorobenzyl)butyl)(methyl)carbamate (200 mg, 0.638 mmol) was dissolved in 1,4-dioxane (10 mL) and 1 M hydrochloric acid in dioxane (319 uL, 1.28 mmol) was added. The solution was stirred overnight at room temperature, diluted with water (15 mL), and then extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (15 mL) and passed through a phase separator cartridge (Biotage). The solution was evaporated and the residue was purified by flash column chromatography to give 2-(2,4-difluorobenzyl)-N-methylbutan-1-amine (120 mg, 0.563 mmol, 88%) as a colorless oil.

[0334] Example 1: N-((1-benzylcyclobutyl)methyl)-5-hydroxynicotinamide [ka] A 500-mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with cyclobutanecarbonitrile (6.00 g, 73.97 mmol, 1.00 equiv.) and THF (200 mL). LDA (43.00 mL, 317.11 mmol, 1.20 equiv.) was added dropwise with stirring at -78 °C and stirred for an additional 1 h at -78 °C. Benzyl bromide (15.18 g, 88.76 mmol, 1.20 equiv.) was added dropwise with stirring, and the resulting solution was stirred at -78 °C for 1 h. The reaction was quenched by the addition of 100 mL of water, extracted with 3 × 200 mL of ethyl acetate, and the combined fractions were washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column eluted with THF:petroleum ether (0:100 to 1:50). This gave 7 g (55% yield) of 1-benzylcyclobutane-1-carbonitrile as a pale yellow oil.

[0335] [ka] A 500-mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 1-benzylcyclobutane-1-carbonitrile (5.10 g, 29.78 mmol, 1.00 equiv.) and THF (150.00 mL). LiAlH4 (2.26 g, 59.56 mmol, 2.00 equiv.) was added in small portions at 0–5 °C. The resulting solution was stirred at room temperature for 2 h and cooled to 0 °C. The reaction was quenched by the addition of 2.5 mL of water, followed by the addition of 7.5 mL of 15% NaOH, followed by another 2.5 mL of water. The solids were filtered off, and the filtrate was concentrated. This afforded 3 g (57% yield) of 1-(1-benzylcyclobutyl)methanamine as a colorless liquid.

[0336] [ka] An 8-mL sealed tube was charged with 1-(1-benzylcyclobutyl)methanamine (110.00 mg, 0.63 mmol, 1.00 equiv.), 5-hydroxypyridine-3-carboxylic acid (104.76 mg, 0.75 mmol, 1.2 equiv.), EDCI.HCl (180.46 mg, 0.94 mmol, 1.50 equiv.), DIPEA (203.175 mg, 1.575 mmol, 2.5 equiv.), and DMF (3.00 mL). The resulting solution was stirred at room temperature overnight. The mixture was purified by preparative HPLC. This afforded 24.3 mg of N-[(1-benzylcyclobutyl)methyl]-5-hydroxypyridine-3-carboxamide hydrochloride as an off-white solid. LC-MS (ES, m / z): [M+H] + =297 [ka]

[0337] Example 2: N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide [ka] Prepared as in Example 1 using 1-(1-benzylcyclobutyl)methanamine (300.00 mg, 1.71 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (287.75 mg, 2.05 mmol, 1.20 equiv) to give the product as a white solid (23.3 mg). LC-MS (ES, m / z): [M+H] + =298 [ka]

[0338] Example 3: N-((1-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide [ka] A 40-mL vial purged and maintained under an inert atmosphere of nitrogen was charged with 5-bromo-6-methylpyridine-3-carboxylic acid (300.00 mg, 1.39 mmol, 1.00 equiv.), dioxane / KOH (aqueous 2 M) (12.00 mL), Pd(dba) (63.58 mg, 0.069 mmol, 0.05 equiv.), and t-BuXphos (58.97 mg, 0.139 mmol, 0.10 equiv.). The resulting solution was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with 10 mL of water. The pH of the solution was adjusted to 5 with HCl (3 mol / L), and the resulting solution was extracted with 2 × 15 mL of ethyl acetate. The organic layer was concentrated, and the residue was purified by flash preparative HPLC. This afforded 130 mg (61% yield) of 5-hydroxy-6-methylpyridine-3-carboxylic acid.

[0339] [ka] A vial was charged with 5-hydroxy-6-methylpyridine-3-carboxylic acid (100.00 mg, 0.653 mmol, 1.00 equiv), DMF (3.00 mL), HATU (322.78 mg, 0.85 mmol, 1.30 equiv), DIPEA (168.79 mg, 1.31 mmol, 2.00 equiv), and 1-(1-benzylcyclobutyl)methanamine (125.90 mg, 0.72 mmol, 1.10 equiv). The resulting solution was stirred at room temperature for 5 hours. The mixture was concentrated and purified by preparative HPLC. This afforded 20 mg of N-[(1-benzylcyclobutyl)methyl]-5-hydroxy-6-methylpyridine-3-carboxamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =311 [ka]

[0340] Example 4: N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide [ka] A vial purged and maintained under an inert atmosphere of nitrogen was charged with 5-bromo-4-methylpyridine-3-carboxylic acid (300.00 mg, 1.389 mmol, 1.00 equiv), dioxane / KOH (aqueous 2 M) (12.00 mL), Pd(dba) (63.58 mg, 0.069 mmol, 0.05 equiv), and t-BuXphos (58.97 mg, 0.139 mmol, 0.10 equiv). The resulting solution was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature, and the pH of the solution was adjusted to 5 with HCl (3 mol / L). The resulting solution was washed with 2 × 15 mL of ethyl acetate, the organic layer was concentrated, and the residue was purified by flash preparative HPLC. This afforded 130 mg (61% yield) of 5-hydroxy-4-methylpyridine-3-carboxylic acid as a white solid.

[0341] [ka] To a solution of 5-hydroxy-4-methylpyridine-3-carboxylic acid (80.00 mg, 0.522 mmol, 1.00 equiv.), DMF (3.00 mL), 1-(1-benzylcyclobutyl)methanamine (100.72 mg, 0.574 mmol, 1.10 equiv.), DIPEA (135.04 mg, 1.044 mmol, 2.00 equiv.), and PyBop (353.41 mg, 0.679 mmol, 1.30 equiv.) was added. The resulting solution was stirred at room temperature for 5 hours, concentrated, and purified by preparative HPLC. This afforded 15 mg of N-[(1-benzylcyclobutyl)methyl]-5-hydroxy-4-methylpyridine-3-carboxamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =311 [ka]

[0342] Example 5: N-((1-benzylcyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide [ka] Prepared as in Example 3 using 3H-1,2,3-triazole-4-carboxylic acid (40.00 mg, 0.35 mmol, 1.00 equiv) and 1-(1-benzylcyclobutyl)methanamine (65.10 mg, 0.37 mmol, 1.05 equiv), to yield 18 mg of N-[(1-benzylcyclobutyl)methyl]-3H-1,2,3-triazole-4-carboxamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =271 [ka]

[0343] Example 6: N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide [ka] Prepared according to Example 1 using 1-(1-benzylcyclobutyl)methanamine (100.00 mg, 0.571 mmol, 1.00 equiv) and 2-oxo-3H-pyrimidine-4-carboxylic acid (79.93 mg, 0.571 mmol, 1.00 equiv). This gave 15 mg of N-[(1-benzylcyclobutyl)methyl]-2-oxo-3H-pyrimidine-4-carboxamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =298 [ka]

[0344] Example 7: N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide [ka] Prepared according to Example 3 using 1-(1-benzylcyclobutyl)methanamine (60.00 mg, 0.342 mmol, 1.00 equiv) and 4-oxo-3H-pyrimidine-2-carboxylic acid (47.96 mg, 0.342 mmol, 1.00 equiv). This afforded 10 mg of N-[(1-benzylcyclobutyl)methyl]-4-oxo-3H-pyrimidine-2-carboxamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =298 [ka]

[0345] Example 8: N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a stirred mixture of (1-benzylcyclobutyl)methanamine (68.7 mg, 0.393 mmol, 1.00 equiv.) and 5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid (50.70 mg, 0.393 mmol, 1.00 equiv.) in DMF, T3P (187.78 mg, 0.590 mmol, 1.50 equiv.) and TEA (119.44 mg, 1.179 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was purified by preparative HPLC to give N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3-carboxamide (9 mg) as an off-white solid. LC-MS (ES, m / z): [M+H] + =287

[0346] Example 9: N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide [ka] To a stirred mixture of 2,4-dichloro-5-methylpyrimidine (5 g, 30.67 mmol, 1.00 equiv.) in THF and water, NaOH (9.82 g, 245.40 mmol, 8.00 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 10 h under a nitrogen atmosphere. The mixture was acidified to pH 5 with concentrated HCl, and the aqueous layer was extracted with EtOAc (3×40 mL), dried over sodium sulfate, and concentrated. The crude product was used directly in the next step.

[0347] [ka] To a solution of 2-chloro-5-methyl-3H-pyrimidin-4-one (500 mg, 3.46 mmol, 1.00 equiv.) in 10 mL of MeOH was added TEA (1049.98 mg, 10.38 mmol, 3.00 equiv.) and Pd(dppf)Cl (10%, 50 mg) in a pressure vessel. The mixture was purged with nitrogen for 5 minutes and then pressurized to 20 atmospheres with carbon monoxide at 120 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The mixture was concentrated to give methyl 5-methyl-4-oxo-3H-pyrimidine-2-carboxylate (250 mg, 43% yield) as a yellow solid.

[0348] [ka] To a stirred mixture of methyl 5-methyl-4-oxo-3H-pyrimidine-2-carboxylate (190 mg, 1.13 mmol, 1.00 equiv.) in water and MeOH (5 mL) was added NaOH (90.39 mg, 2.26 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified to pH-6 with 1 M aqueous HCl. The precipitated solid was collected to give 5-methyl-4-oxo-3H-pyrimidine-2-carboxylic acid (60 mg, 34% yield) as an off-white solid.

[0349] [ka] Prepared as in Example 8 using 5-methyl-4-oxo-3H-pyrimidine-2-carboxylic acid (50 mg, 0.324 mmol, 1.00 equiv) and 1-(1-benzylcyclobutyl)methanamine (56.86 mg, 0.324 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =312 [ka]

[0350] Example 10: N-((1-benzylcyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as in Example 8 using 1-(1-benzylcyclobutyl)methanamine (Example 1, 310 mg, 1.77 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 278.41 mg, 1.95 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =301 [ka]

[0351] Example 11: N-((1-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide [ka] A 40-mL sealed tube was charged with 1-(1-benzylcyclobutyl)methanamine (Example 1, 300.00 mg, 1.71 mmol, 1.00 equiv), HCOOH (5.00 mL), and HCHO (37% aqueous) (5.00 mL). The resulting solution was stirred at 55 °C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated, and the resulting solution was diluted with 150 mL of EtOAc and washed with 2 × 80 mL of 10% NaHCO3 and saturated NaCl. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column eluted with THF:PE (1:5 to 1:3). This afforded 130 mg (40% yield) of [(1-benzylcyclobutyl)methyl](methyl)amine as a colorless oil.

[0352] [ka] An 8-mL sealed tube was charged with [(1-benzylcyclobutyl)methyl](methyl)amine (130.00 mg, 0.69 mmol, 1.00 equiv.), 6-hydroxypyrazine-2-carboxylic acid (115.45 mg, 0.82 mmol, 1.20 equiv.), EDCI.HCl (197.47 mg, 1.03 mmol, 1.50 equiv.), and DMF (4.00 mL). The resulting solution was stirred at room temperature overnight and purified by flash preparative HPLC. This afforded 12.2 mg of N-[(1-benzylcyclobutyl)methyl]-6-hydroxy-N-methylpyrazine-2-carboxamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =312 [ka]

[0353] Example 12: N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide [ka] A 100-mL three-neck round-bottom flask was charged with benzylacetonitrile (500.00 mg, 3.81 mmol, 1.00 equiv) and THF (20.00 mL) and cooled to -70 °C. LiHMDS (3188.91 mg, 19.06 mmol, 5.00 equiv) was added dropwise, followed by CHI (2164.07 mg, 15.246 mmol, 4.00 equiv). The resulting solution was stirred at -70 °C for 2 h. The reaction was then quenched by the addition of 20 mL of water and extracted with 2 × 20 mL of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. This afforded 500 mg of 2,2-dimethyl-3-phenylpropanenitrile as a pale yellow oil, which was used in the next step without further purification.

[0354] [ka] A 100-mL sealed tube was charged with 2,2-dimethyl-3-phenylpropanenitrile (500.00 mg, crude), Raney Ni (269.03 mg), and NH3.HO (11.00 mg) in MeOH (20.00 mL). To the above was introduced H2 (g) (20 atm) at 20 °C. The resulting solution was stirred at 20 °C for 10 h. The solid was filtered off, and the filtrate was concentrated. This afforded 450 mg of 2,2-dimethyl-3-phenylpropan-1-amine as a pale yellow oil.

[0355] [ka] Prepared as in Example 1 using 2,2-dimethyl-3-phenylpropan-1-amine (100.00 mg, 0.613 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (85.81 mg, 0.613 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =286 [ka]

[0356] Example 13: N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide [ka] A 250-mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with cyclobutanecarbonitrile (2.00 g, 24.65 mmol, 1.00 equiv.) and THF (100.00 mL). Following this, LDA (2.0 M in THF) (14.2 mL, 28.35 mmol, 1.15 equiv.) was added dropwise with stirring at −78°C. The resulting solution was stirred at this temperature for 30 minutes, and a solution of 1-(bromomethyl)-2-fluorobenzene (5.13 g, 27.14 mmol, 1.10 equiv.) in THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. The reaction was then quenched by the addition of 50 mL of water, extracted with 2 × 50 mL of ethyl acetate, and the organic layer was dried and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 20). This gave 2.5 g (53% yield) of 1-[(2-fluorophenyl)methyl]cyclobutane-1-carbonitrile as a pale yellow oil.

[0357] [ka] A 250-mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 1-[(2-fluorophenyl)methyl]cyclobutane-1-carbonitrile (2.10 g, 11.09 mmol, 1.00 equiv.) and THF (100.00 mL). This was followed by the addition of LiAlH (0.93 g, 22.18 mmol, 2.00 equiv.) in small portions at 0–5°C. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was cooled to 0°C and quenched by the addition of 2.5 mL of water, followed by 7.5 mL of 15% NaOH, and again by the addition of 2.5 mL of water. The solids were filtered off, and the filtrate was concentrated. This afforded 2.1 g (97% yield) of 1-[1-[(2-fluorophenyl)methyl]cyclobutyl]methanamine as a pale yellow oil.

[0358] [ka] Prepared as in Example 1 using 1-[1-[(2-fluorophenyl)methyl]cyclobutyl]methanamine (100.00 mg, 0.517 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (72.49 mg, 0.517 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =316 [ka]

[0359] Example 14: N-((1-benzylcyclobutyl)methyl)-1-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a stirred mixture of ethyl carbamothioylformate (1 g, 7.51 mmol, 1.00 equiv.) and ethylhydrazine (451.30 mg, 7.51 mmol, 1.00 equiv.) in acetonitrile, K2CO3 (2075.63 mg, 15.02 mmol, 2.00 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and filtered. The filter cake was washed with DCM (2 × 250 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give ethyl [(Z)-N'-(ethylamino)carbamimidoyl]formate (1.1 g, 92% yield) as a pale yellow oil.

[0360] [ka] To a stirred mixture of ethyl [(Z)-N'-(ethylamino)carbamimidoyl]formate (1 g, 6.28 mmol, 1.00 equiv.) in THF, CDI (1.02 g, 6.28 mmol, 1.00 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and concentrated. The residue was purified by preparative HPLC to give ethyl 1-ethyl-5-oxo-4H-1,2,4-triazole-3-carboxylate (300 mg, 26% yield) as a pale yellow solid.

[0361] [ka] To a stirred mixture of ethyl 1-ethyl-5-oxo-4H-1,2,4-triazole-3-carboxylate (270 mg, 1.458 mmol, 1.00 equiv) in EtOH and HO was added NaOH (116.63 mg, 2.916 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred overnight, and the mixture was concentrated. The crude product was purified by preparative HPLC to give 1-ethyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (100 mg, 43% yield) as a pale yellow solid.

[0362] [ka] Prepared as in Example 1 using 1-ethyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (50 mg, 0.318 mmol, 1.00 equiv) and 1-(1-benzylcyclobutyl)methanamine (55.77 mg, 0.318 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =315 [ka]

[0363] Example 15: N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide [ka] A 250-mL, three-necked, round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with cyclobutanecarbonitrile (1.00 g, 12.33 mmol, 1.00 equiv) and THF (50.00 mL). Following this, LDA (2.0 M in THF) (6.78 mL, 13.56 mmol, 1.10 equiv) was added dropwise with stirring at −78°C. The resulting solution was stirred at this temperature for 30 minutes, and a solution of 2-(bromomethyl)-1,3-difluorobenzene (3.06 g, 14.79 mmol, 1.20 equiv) in THF (10 mL) was added dropwise at −78°C. The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. The reaction was then quenched by the addition of 50 mL of water, extracted with 2×50 mL of ethyl acetate, and the organic layer was dried and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 20) to give 1.24 g (48% yield) of 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile as a pale yellow oil.

[0364] [ka] A 50-mL three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (450.00 mg, 2.17 mmol, 1.00 equiv) and THF (15.00 mL). This was followed by the addition of LiAlH (164.84 mg, 4.34 mmol, 2.00 equiv) in small portions at 0–5°C. The resulting solution was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0°C and quenched by the addition of 2.5 mL of water, 7.5 mL of 15% NaOH, and an additional 2.5 mL of water. The solids were filtered off, and the filtrate was concentrated. This afforded 390 mg (85% yield) of 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine as a pale yellow oil.

[0365] [ka] Prepared as in Example 1 using 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (50.00 mg, 0.24 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (33.16 mg, 0.24 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =334 [ka]

[0366] Example 16: N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide [ka] Prepared as for 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (Example 16) using cyclobutanecarbonitrile (1.00 g, 12.33 mmol, 1.00 equiv) and THF (50.00 mL) and 1-(bromomethyl)-2,4-difluorobenzene (3.06 g, 14.79 mmol, 1.20 equiv).

[0367] [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (450.00 mg, 2.17 mmol, 1.00 equiv) and LiAlH (164.84 mg, 4.34 mmol, 2.00 equiv).

[0368] [ka] Prepared as in Example 1 using 1-[1-[(2,4-difluorophenyl)methyl]cyclobutyl]methanamine (45.00 mg, 0.21 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (29.84 mg, 0.21 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =334 [ka]

[0369] Example 17: N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide [ka] Prepared as for 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (Example 16) using cyclobutanecarbonitrile (0.50 g, 6.16 mmol, 1.00 equiv) and THF (10 mL) and 1-(bromomethyl)-2,3-difluorobenzene (1.53 g, 7.40 mmol, 1.20 equiv).

[0370] [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (450.00 mg, 2.17 mmol, 1.00 equiv) and LiAlH (164.84 mg, 4.34 mmol, 2.00 equiv).

[0371] [ka] Prepared as in Example 1 using 1-[1-[(2,3-difluorophenyl)methyl]cyclobutyl]methanamine (50.00 mg, 0.24 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (33.16 mg, 0.24 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =334 [ka]

[0372] Example 18: N-((1-benzylcyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide [ka] Prepared as in Example 3 using 6-hydroxypyrazine-2-carboxylic acid (37.00 mg, 0.26 mmol, 1.00 equiv.) and 1-(1-benzylcyclopentyl)methanamine (prepared according to the method for 1-(1-benzylcyclobutyl)methanamine using cyclopentanecarbonitrile (Example 1), 50.00 mg, 0.26 mmol, 1.00 equiv.). LC-MS (ES, m / z): [M+H] + =312 [ka]

[0373] Example 19: N-((1-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using cyclobutanecarbonitrile (1.2 g, 14.79 mmol, 1.00 equiv) and 1-(bromomethyl)-2-methylbenzene (3.01 g, 16.27 mmol, 1.10 equiv).

[0374] [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-[(2-methylphenyl)methyl]cyclobutane-1-carbonitrile (350 mg, 1.89 mmol, 1.00 equiv) and LiAlH (215.10 mg, 5.67 mmol, 3.00 equiv).

[0375] [ka] Prepared as in Example 8 using 1-{1-[(2-methylphenyl)methyl]cyclobutyl}methanamine (100 mg, 0.53 mmol, 1.00 equiv) and 6-hydroxypyrazine-2-carboxylic acid (81.41 mg, 0.58 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =312 [ka]

[0376] Example 20: N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using cyclobutanecarbonitrile (1.2 g, 14.79 mmol, 1.00 equiv) and 1-(bromomethyl)-2-fluorobenzene (3.08 g, 16.27 mmol, 1.10 equiv).

[0377] [ka] Prepared similarly as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-[(2-fluorophenyl)methyl]cyclobutane-1-carbonitrile (500.00 mg, 2.642 mmol, 1.00 equiv) and LiAlH (200.57 mg, 5.284 mmol, 2.00 equiv).

[0378] [ka] Prepared as in Example 3 using 1-[1-[(2-fluorophenyl)methyl]cyclobutyl]methanamine (30.00 mg, 0.155 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 22.21 mg, 0.155 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H]+ = 319 [ka]

[0379] Example 21: N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as in Example 8 using 1-{1-[(2,6-difluorophenyl)methyl]cyclobutyl}methanamine (Example 16, 40 mg, 0.19 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 29.81 mg, 0.21 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =337 [ka]

[0380] Example 22: N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as in Example 8 using 1-{1-[(2,4-difluorophenyl)methyl]cyclobutyl}methanamine (Example 17, 40 mg, 0.19 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 29.81 mg, 0.21 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =337 [ka]

[0381] Example 23: N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3 carboxamide [ka] To a stirred mixture of 1-benzylcyclobutane-1-carbonitrile (2.9 g, 16.935 mmol, 1.00 equiv) in THF was added 1 M CHLi (16.9 mL, 1.00 equiv) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred for 3 h and quenched by the addition of saturated NHCl (aqueous) (20 mL) at −78° C. The aqueous layer was extracted with EtOAc (2×40 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EA (7:1) to afford 1-(1-benzylcyclobutyl)ethanone (1.5 g, 47% yield) as a pale yellow oil.

[0382] [ka] To a stirred mixture of 1-(1-benzylcyclobutyl)ethanone (1.4 g, 7.436 mmol, 1.00 equiv.) and NHOH.HCl (0.52 g, 7.436 mmol, 1.00 equiv.) in EtOH, TEA (2.26 g, 22.308 mmol, 3.00 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 h under a nitrogen atmosphere and quenched with water at room temperature. The aqueous layer was extracted with EtOAc (2 × 20 mL) and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford (Z)-N-[1-(1-benzylcyclobutyl)ethylidene]hydroxylamine (350 mg, 23% yield) as a pale yellow oil.

[0383] [ka] To a solution of (Z)-N-[1-(1-benzylcyclobutyl)ethylidene]hydroxylamine (250 mg, 1.230 mmol, 1.00 equiv) in 50 mL of MeOH was added Pd / C (0.1 g) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature for 5 hours under a hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered, and the catalyst was washed with MeOH (2 × 20 mL). The filtrate was concentrated under reduced pressure. This afforded 1-(1-benzylcyclobutyl)ethanamine (180 mg) as a pale yellow solid.

[0384] [ka] Prepared as in Example 8 using 1-(1-benzylcyclobutyl)ethanamine (100 mg, 0.528 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 75.59 mg, 0.528 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =315 [ka]

[0385] (Example 24A and B: N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Enantiomer B) and N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Enantiomer A)) [ka] N-[1-(1-benzylcyclobutyl)ethyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide (Example 23) was purified by preparative SFC (column: CHIRAL ART cellulose-SB, 3 * 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH-----Preparative; Flow rate: 80 mL / min; Gradient: Isocratic 35% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.6; RT2 (min): 5.5; Sample solvent: MeOH--HPLC; Injection volume: 3 mL; Number of runs: 4, Retention time of Enantiomer A: 1.47 min; Retention time of Enantiomer B: Purification by chromatography (HPLC: 1.82 min) gave N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (13 mg) as an off-white solid and N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (9.1 mg) as an off-white solid. LC-MS (enantiomer A) (ES, m / z): [M+H] + =315 LC-MS (enantiomer B) (ES, m / z): [M+H] + =315 [ka]

[0386] One of the enantiomers A and B is (S)—N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide, and the other is (R)—N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide.

[0387] Example 25: 1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] In a 100-mL round-bottom flask, LDA (1 M in THF, 19.5 mL, 19.50 mmol) was added dropwise to a solution of cyclobutanecarbonitrile (1.31 g, 16.15 mmol, 1.00 equiv.) in THF (10 mL) under a N2 atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. Then, a solution of (1-bromoethyl)benzene (3 g, 16.21 mmol, 1.00 equiv.) in 5 mL of THF was added dropwise, and the mixture was stirred for an additional 60 min. The reaction was quenched with water / saturated NH4Cl (30 mL), and then the mixture was extracted with ether / EtOAc (2 × 40 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (EtOAc / PE = 1 / 3 mixture). This gave 1-(1-phenylethyl)cyclobutane-1-carbonitrile (1.25 g, 42% yield) as a pale yellow oil.

[0388] [ka] To a stirred solution of 1-(1-phenylethyl)cyclobutane-1-carbonitrile (500 mg, 2.70 mmol, 1.00 equiv) in diethyl ether was added LAH (204.86 mg, 5.40 mmol, 2.00 equiv) in small portions at 0°C under a nitrogen atmosphere. The reaction was quenched by the addition of 15% NaOH (aqueous) (0.2 mL) at 0°C. The resulting mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. This afforded 1-[1-(1-phenylethyl)cyclobutyl]methanamine (350 mg, 69% yield) as a pale yellow oil.

[0389] [ka] Prepared as in Example 8 using 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 30.24 mg, 0.211 mmol, 1.00 equiv) and 1-[1-(1-phenylethyl)cyclobutyl]methanamine (40 mg, 0.211 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =315 [ka]

[0390] Examples 26 and 27: 1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Enantiomer A) and 1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Enantiomer B) [ka] The racemic product Example 25 (50 mg) was purified by chiral SFC to give 1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (enantiomer A) (20 mg) as a white solid and 1-methyl-5-oxo-N-({1-[(1R)-1-phenylethyl]cyclobutyl}methyl)-4H-1,2,4-triazole-3-carboxamide (enantiomer B) (30 mg) as a white solid. LC-MS (enantiomer A) (ES, m / z): [M+H] + =315 LC-MS (enantiomer B) (ES, m / z): [M+H] + =315 [ka]

[0391] One of the enantiomers A and B is (S)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide, and the other is (R)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide.

[0392] Example 28: N-((1-(methoxy(phenyl)methyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a solution of cyclobutanecarbonitrile (2.29 g, 28.27 mmol, 1.00 equiv.) in THF (20 mL) was added LDA (1 M in THF, 36.75 mL, 36.75 mmol, 1.30 equiv.) dropwise under a N atmosphere at −78 °C. The reaction mixture was stirred at −78 °C for 30 min, after which a solution of benzaldehyde (3 g, 28.27 mmol, 1.00 equiv.) in 5 mL of THF was added dropwise, and the mixture was stirred for an additional 60 min. The reaction was quenched with water / saturated NH4Cl (30 mL), and the mixture was extracted with ether / EtOAc (2 × 40 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (EtOAc / PE = 1 / 3 mixture). This gave 1-[hydroxy(phenyl)methyl]cyclobutane-1-carbonitrile (1.8 g, 34% yield) as a pale yellow oil.

[0393] [ka] To a solution of 1-[hydroxy(phenyl)methyl]cyclobutane-1-carbonitrile (400 mg, 2.14 mmol, 1.00 equiv) in DMF was added NaH (111 mg, 2.78 mmol, 1.30 equiv) at 0 °C. The mixture was stirred for 15 min. CHI (333.54 mg, 2.350 mmol, 1.10 equiv) was added, and the mixture was allowed to warm to RT and stirred for 5 h. The reaction mixture was quenched with water and extracted with DCM (3 × 25 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to afford 1-[methoxy(phenyl)methyl]cyclobutane-1-carbonitrile (300 mg, 70% yield) as a pale yellow oil.

[0394] [ka] To a stirred solution / mixture of 1-[methoxy(phenyl)methyl]cyclobutane-1-carbonitrile (260 mg, 1.29 mmol, 1.00 equiv) in ethyl ether (10 mL) was added LAH (98.06 mg, 2.58 mmol, 2.00 equiv) in small portions at 0° C. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched by the addition of NaOH (aqueous 15%) (0.02 mL) at 0° C. The resulting mixture was filtered; the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This afforded 1-{1-[methoxy(phenyl)methyl]cyclobutyl}methanamine (220 mg, 83% yield) as a pale yellow oil.

[0395] [ka] Prepared as in Example 8 using 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 9.76 mg, 0.068 mmol, 1.00 equiv) and 1-{1-[methoxy(phenyl)methyl]cyclobutyl}methanamine (14 mg, 0.068 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =331 [ka]

[0396] Example 29: 1-methyl-N-((1-(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as in Example 3 using 1-{1-[(2-methylphenyl)methyl]cyclobutyl}methanamine (Example 21, 45 mg, 0.24 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 37.42 mg, 0.26 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =315 [ka]

[0397] Example 30: N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-(bromomethyl)-2-chlorobenzene (1 g, 4.867 mmol, 1.00 equiv) and cyclobutanecarbonitrile (0.39 g, 4.867 mmol, 1.00 equiv).

[0398] [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-[(2-chlorophenyl)methyl]cyclobutane-1-carbonitrile (500 mg, 2.431 mmol, 1.00 equiv) and LiAlH (184.52 mg, 4.862 mmol, 2.00 equiv).

[0399] [ka] Prepared as in Example 8 using 1-{1-[(2-chlorophenyl)methyl]cyclobutyl}methanamine (50 mg, 0.238 mmol, 1.00 equiv) and 1-methyl-5-oxo-2H-1,2,4-triazole-3-carboxylic acid (34.12 mg, 0.238 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =335 [ka]

[0400] Example 31: N-(2,2-dimethyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a stirred solution of benzylacetonitrile (1 g, 7.623 mmol, 1.00 equiv) and CHI (5.41 g, 38.115 mmol, 5.00 equiv) in THF under a nitrogen atmosphere was added dropwise a 2.0 M THF solution of LDA (19.06 mL, 38.12 mmol, 5.00 equiv) at −78 °C. The resulting mixture was stirred at −78 °C for 2 h and quenched by the addition of saturated NH4Cl (aqueous) (20 mL) at −78 °C. The aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 2,2-dimethyl-3-phenylpropanenitrile (0.9 g, 74% yield) as a pale yellow oil.

[0401] [ka] To a stirred solution / mixture of 2,2-dimethyl-3-phenylpropanenitrile (500 mg, 3.140 mmol, 1.00 equiv.) in THF, LiAlH (119.18 mg, 3.140 mmol, 1.00 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere and quenched with water at room temperature. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated to afford 2,2-dimethyl-3-phenylpropan-1-amine (300 mg, 58% yield) as a pale yellow oil.

[0402] [ka] Prepared according to Example 8 using 1-[1-(cyclohexylmethyl)cyclobutyl]methanamine (100 mg, 0.552 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 78.92 mg, 0.552 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =289 [ka]

[0403] Example 32: 1-methyl-N-(2-methyl-3-phenylpropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a stirred solution of benzylacetonitrile (1 g, 7.623 mmol, 1.00 equiv) in THF was added dropwise a 2.0 M THF solution of LDA (4.193 mL, 8.385 mmol, 1.10 equiv) at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 30 minutes under a nitrogen atmosphere, and CHI (1.19 g, 8.385 mmol, 1.10 equiv) was added dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 hour under a nitrogen atmosphere. The reaction was quenched by the addition of saturated NH4Cl (aq) at −30° C. The aqueous layer was extracted with EtOAc (2 × 30 mL). The organic layer was concentrated, and the crude product was used directly in the next step without further purification.

[0404] [ka] To a stirred solution of 2-methyl-3-phenylpropanenitrile (900 mg, 6.198 mmol, 1.00 equiv) in THF was added LiAlH (470.49 mg, 12.396 mmol, 2.00 equiv) in small portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere and quenched by the addition of water (0.5 mL) at 0° C. The resulting mixture was filtered, and the filter cake was washed with THF (2×20 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0405] [ka] Prepared as in Example 8 using 2-methyl-3-phenylpropan-1-amine (50 mg, 0.335 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 47.94 mg, 0.335 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =275 [ka]

[0406] Example 33: N-((1-benzylcyclopropyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared similarly as for 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (Example 16) using cyclopropylnitrile (1 g, 14.905 mmol, 1.00 equiv) and benzyl bromide (3.06 g, 17.886 mmol, 1.20 equiv).

[0407] [ka] Prepared as for 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using 1-benzylcyclopropane-1-carbonitrile (500 mg, 3.180 mmol, 1.00 equiv) and LiAlH (241.41 mg, 6.360 mmol, 2.00 equiv).

[0408] [ka] Prepared as in Example 8 using 1-(1-benzylcyclopropyl)methanamine (100 mg, 0.620 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 88.75 mg, 0.620 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =287 [ka]

[0409] Example 34: N-(2,2-dimethyl-1-phenylpentan-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as for 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (Example 16) using isobutyronitrile (0.40 g, 5.85 mmol, 1.00 equiv) and benzyl bromide (1 g, 5.847 mmol, 1.00 equiv).

[0410] [ka] To a stirred solution of 2,2-dimethyl-3-phenylpropanenitrile (500 mg, 3.14 mmol, 1.00 equiv) in PhMe (10 mL) was added ethylmagnesium bromide (627.72 mg, 4.71 mmol, 1.50 equiv) dropwise at 0 °C and stirred at 85 °C under a nitrogen atmosphere for 60 min. The reaction was monitored by LCMS. The reaction was cooled and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and NaBH (178.20 mg, 4.71 mmol, 1.50 equiv) was added portionwise at 0 °C and stirred at room temperature for 1 h. The reaction was diluted with EtOAc (50 mL) and quenched by the addition of saturated sodium hyposulfite (aqueous) (10 mL) at room temperature. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give 2,2-dimethyl-1-phenylpentan-3-amine (300 mg, 50% yield) as a pale yellow oil.

[0411] [ka] Prepared according to example 3 using 2,2-dimethyl-1-phenylpentan-3-amine (50 mg, 0.26 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 41.14 mg, 0.29 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =317 [ka]

[0412] Example 35: 1-methyl-5-oxo-N-(1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a 100 mL three-necked round-bottom flask containing 2,2-dimethyl-3-phenylpropanal (2 g, 12.33 mmol, 1.00 equiv.), DCE (40 mL), and tert-butanesulfinamide (2.24 g, 18.492 mmol, 1.50 equiv.) under a nitrogen atmosphere at room temperature, MgSO (0.90 g, 36.984 mmol, 3.00 equiv.) and PPTS (0.62 g, 2.466 mmol, 0.20 equiv.) were added. The resulting mixture was stirred at 85 °C for 12 h. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give N-[(1Z)-2,2-dimethyl-3-phenylpropylidene]-2-methylpropane-2-sulfinamide (1.6 g, 49% yield).

[0413] [ka] To a stirred solution / mixture of N-[(1Z)-2,2-dimethyl-3-phenylpropylidene]-2-methylpropane-2-sulfinamide (1.5 g, 5.651 mmol, 1.00 equiv.) in THF (30 mL) at room temperature under a nitrogen atmosphere, CsF (0.43 g, 2.825 mmol, 0.5 equiv.) was added dropwise, followed by trifluoromethyltrimethylsilane (2.81 g, 19.779 mmol, 3.50 equiv.). The resulting mixture was stirred at room temperature for 10 hours, and the resulting mixture was diluted with EtOAc (100 mL). The reaction was quenched by the addition of water / ice (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined fractions were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give N-(3-benzyl-1,1,1-trifluoro-3-methylbutan-2-yl)-2-methylpropane-2-sulfinamide (0.42 g, 22% yield) as a yellow oil.

[0414] [ka] To a 100 mL three-necked round-bottom flask containing N-(3-benzyl-1,1,1-trifluoro-3-methylbutan-2-yl)-2-methylpropane-2-sulfinamide (0.42 g, 1.252 mmol, 1.00 equiv.) and methanol (10 mL) was added 4 N HCl in MeOH (1.57 mL, 6.260 mmol, 5.00 equiv.) at room temperature. The resulting mixture was stirred for 3 hours and concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO3 (aqueous), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined fractions were concentrated in vacuo. This afforded 1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-amine (130 mg, 45% yield) as a yellow oil.

[0415] [ka] Prepared as in Example 8 using 1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-amine (90 mg, 0.393 mmol, 1.00 equiv) and 1-methyl-5-oxo-2H-1,2,4-triazole-3-carboxylic acid (56.30 mg, 0.393 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =357 [ka]

[0416] Example 36: N-(3-(2-bromophenyl)-2,2-dimethylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as for 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (Example 16) using 1-bromo-2-(bromomethyl)benzene (2 g, 8.00 mmol, 1.00 equiv) and isobutyronitrile (0.55 g, 8.00 mmol, 1.00 equiv).

[0417] [ka] To a stirred solution of 3-(2-bromophenyl)-2,2-dimethylpropanenitrile (1 g, 4.20 mmol, 1.00 equiv) in THF under a nitrogen atmosphere at 0 °C was added 1 M BH-THF (21 mL g, 21.00 mmol, 5.00 equiv) dropwise. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 5 h. The reaction was quenched by the addition of MeOH (10 mL) at 0 °C. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give 3-(2-bromophenyl)-2,2-dimethylpropan-1-amine (0.5 g, 49% yield) as a pale yellow oil.

[0418] [ka] Prepared as in Example 8 using 3-(2-bromophenyl)-2,2-dimethylpropan-1-amine (50 mg, 0.206 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 29.55 mg, 0.206 mmol, 1.00 equiv). LC-MS (ES, m / z): [M+H] + =367 [ka]

[0419] Example 37: N-((1-(2-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] Prepared as in Example 8 using 1-{1-[(2-bromophenyl)methyl]cyclobutyl}methanamine (prepared from cyclobutanecarbonitrile and 1-bromo-2-(bromomethyl)benzene according to Steps 1-2 of Example 37, 100 mg, 0.393 mmol, 1.00 equiv.) and 1-methyl-5-oxo-2H-1,2,4-triazole-3-carboxylic acid (56.30 mg, 0.393 mmol, 1.00 equiv.). LC-MS (ES, m / z): [M+H] + =379 [ka]

[0420] Example 38: N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] To a stirred solution of 2,2-dimethyl-3-phenylpropanenitrile (500 mg, 3.14 mmol, 1.00 equiv) in PhMe (10 mL) was added 1 M bromo(methyl)magnesium (4.7 mL, 4.71 mmol, 1.50 equiv) dropwise over 30 min at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 60 min under a nitrogen atmosphere and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and NaBH (178.20 mg, 4.71 mmol, 1.50 equiv) was added in small portions at 0 °C. The reaction mixture was allowed to warm to room temperature and concentrated. The residue was dissolved in EtOAc (50 mL) and quenched by the addition of saturated sodium hyposulfite (aqueous) (10 mL). The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give 3,3-dimethyl-4-phenylbutan-2-amine (300 mg, 54% yield) as a pale yellow oil.

[0421] [ka] Prepared as in Example 3 using 3,3-dimethyl-4-phenylbutan-2-amine (50 mg, 0.28 mmol, 1.00 equiv) and 1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid (Intermediate 1, 44.39 mg, 0.31 mmol, 1.10 equiv). LC-MS (ES, m / z): [M+H] + =303 [ka]

[0422] (Examples 39A and 39B: N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Enantiomer B) and N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Enantiomer A)) [ka] N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Example 38, 45 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 (enantiomer A) (16 mg, 35%) as an off-white solid and (enantiomer B) (16 mg, 35%) as an off-white solid. Retention time for isomer A: 1.68 min; retention time for isomer B: 2.10 min. LCMS (enantiomer A) (ES, m / z): [M+H] = 303 LCMS (enantiomer B) (ES, m / z): [M+H] = 303 [ka]

[0423] One of the enantiomers A and B is (S)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide, and the other is (R)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide.

[0424] Example 40: N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide [ka] In a 50-mL round-bottom flask, LDA (0.5 mL, 9.87 mmol, 1.5 equiv.) was added dropwise to a solution of butyronitrile (500 mg, 7.24 mmol, 1.1 equiv.) in THF (30 mL) at −78 °C under a N atmosphere. The reaction mixture was stirred at −78 °C for 30 min. A solution of BnBr (1124.96 mg, 6.58 mmol, 1 equiv.) in 10 mL of THF was added dropwise, and the mixture was stirred for an additional 60 min. The reaction was quenched with water / saturated NH Cl (5 mL), and then the mixture was extra...

Claims

1. A compound according to formula (I): or a salt and / or solvate thereof 【Chemistry 1】 (In the formula: R 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl; C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H, halo, or C 1-4 is alkyl; R 5 Ha, Halo, 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 4 and R 5 together with the carbon atoms to which they are attached, C 5-11 spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spirocarbocyclyl, heterocycloalkyl, or cycloalkyl is C 1-3 Alkyl, C 1-3 optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is 1 or more A 1 is a monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl optionally substituted by A 1 is C 1-3 Alkylthio, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, CN, OH, NR g R h , or NHSO 2 R j are independently selected from the group consisting of: R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 is alkyl; W is 0, 1, or 2, Or A is 1 or more 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH 2 ) v (wherein v represents 1, 2, or 3, and the CH 2 one of the groups is optionally substituted by O; B 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 1 may be optionally substituted by; B 1 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo (=O), or thiooxo (=S), C 0-6 alkylene (OH); provided that formula (I) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: 【Chemistry 2】 or its salts and / or solvates).

2. A compound of formula (IA) according to claim 1: or a salt and / or solvate thereof 【Transformation 3】 (In the formula: R 1 is H or C 1-4 is alkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl; C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 0-4 alkylene (OH); R 3 is H, halo, or C 1-4 is alkyl; R 4 is H or C 1-4 is alkyl; R 5 H, halo, 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 4 and R 5 together with the atoms to which they are attached, C 3-6 Forms a cycloalkyl, wherein the cycloalkyl is C 1-3 Alkyl, C 1-3 optionally substituted with one or more groups selected from haloalkyl and halo; R 6 is H or C 1-4 is alkyl; R 7 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; A is 1 or more A 1 is a monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl optionally substituted by A 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 g R h , or NHSO 2 R j and; R g is H or C 1-4 is alkyl; R h is H or C 1-4 is alkyl; R j is C 1-4 Is it alkyl; Or A is 1 or more 1 When R represents a phenyl substituted by 5 is the ortho-position substituent A 1 Combined together, (CH 2 ) v (wherein v represents 1, 2, or 3, and the CH 2 one of the groups is optionally substituted by O; B is 1 or more B 1 a monocyclic or bicyclic heterocycle or a monocyclic or bicyclic heteroaryl optionally substituted by B 1 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 (IA) is N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide: 【Chemistry 4】 isn't it).

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

4. Compounds according to formula (IA): 【Transformation 5】 4. The compound according to any one of claims 1 to 3, or a salt and / or solvate thereof.

5. R 1 , R 2 , and R 3 and each are H, or a salt and / or solvate thereof according to claim 4.

6. R 4 The compound according to claim 4 or 5, or a salt and / or solvate thereof, wherein is H.

7. R 5 But C 1-6 7. The compound according to any one of claims 4 to 6, or a salt and / or solvate thereof, wherein alkyl is, for example, methyl, ethyl, n-propyl, or iso-propyl, especially ethyl.

8. R 5 But C 0-6 Alkylene (C 3-6 cycloalkyl), e.g., C 3-6 A compound according to any one of claims 4 to 6, or a salt and / or solvate thereof, which is cycloalkyl, such as cyclopropyl or cyclobutyl, especially cyclopropyl.

9. R 4 and R 5 together with the atoms to which they are bonded, C 3-6 7. A compound according to any one of claims 4 to 6, or a salt and / or solvate thereof, which forms a cycloalkyl, such as a cyclopropyl, cyclobutyl or cyclopentyl ring, especially a cyclobutyl ring.

10. R 6 is H and R 7 The compound according to any one of claims 4 to 9, or a salt and / or solvate thereof, wherein is H.

11. The compound according to any one of claims 4 to 10, or a salt and / or solvate thereof, wherein A is phenyl.

12. A, 【Transformation 6】 (In the formula: A 1A is halo, e.g., F, Br, or Cl; C 1-6 alkyl, for example, methyl; or C 1-6 alkoxy, for example, OMe; and A 1B is H or halo, for example F, Br, or Cl, especially F 12. The compound according to any one of claims 4 to 11, or a salt and / or solvate thereof, selected from the group consisting of:

13. B, 【Transformation 7】 for example, 【Transformation 8】 (In the formula: B 1A is H or C 1-6 alkyl, for example, methyl; and B 2A is H or C 1-6 alkyl, e.g., methyl) 13. The compound according to any one of claims 4 to 12, or a salt and / or solvate thereof, selected from the group consisting of:

14. N-((1-benzylcyclobutyl)methyl)-5-hydroxynicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide; N-((1-benzylcyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3 carboxamide; N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(methoxy(phenyl)methyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(2-methyl-3-phenylpropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclopropyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-1-phenylpentan-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-(1,1,1-trifluoro-3,3-dimethyl-4-phenylbutan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(2-bromophenyl)-2,2-dimethylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3,3-dimethyl-4-phenylbutan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-3-hydroxy-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-methoxy-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzyl-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclohexyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((1-(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-(2-cyclobutyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(1-(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-benzylpentyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; 1-methyl-N-((2-methyl-2,3-dihydro-1H-inden-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 6-oxo-N-((1-(pyridin-2-ylmethyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; N-((1-benzylcyclobutyl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide; N-(2-benzyl-3-hydroxypropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-N,1-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclohexyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-(difluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyclopropylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chlorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-5-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; 1-Methyl-N-((1-(3-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-chloro-2-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2-fluoro-3-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3-cyanobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-methyl-5-oxo-N-(2-(2,4,6-trifluorobenzyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4-hydroxypicolinamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-hydroxy-1-methyl-1H-pyrazole-3-carboxamide; N-(2-cyclopropyl-3-(4-fluoro-2-methylphenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-2-oxo-2,3-dihydrooxazole-4-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; 6-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; 1-Methyl-5-oxo-N-((1-(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-5-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(3-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-(2-(3,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide; N-(2-((2,3-dihydrobenzofuran-5-yl)methyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(2-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; 1-Methyl-N-((1-(3-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide; N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-((2S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-fluoro-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide; N-(2-(2,4-difluorobenzyl)-2-ethylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-(methoxymethyl)-4H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)butyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamide; N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; 5-Bromo-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(2-chloro-4,6-difluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (N-(-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; (N-(-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide; N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-((1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-[2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; 5-chloro-N-[2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide; 5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; and N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; 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. A compound according to any one of claims 3 to 14 for use as a medicament.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 3 to 14 or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier or excipient.

19. 15. A compound according to any one of claims 3 to 14, 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 prophylactic effect.

20. 15. A compound according to any one of claims 3 to 14 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 (wherein the proviso to formula (I) does not apply).

21. A compound according to any one of claims 3 to 14 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), 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.

22. Use of a compound according to any one of claims 3 to 14 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).

23. 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 3 to 14 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).

24. 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 neuropathy, 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 damage in sepsis, and hepatitis), age-related diseases (e.g., bone repair, weakening of bones with age in osteoporosis, and sarcopenia), kidney diseases (e.g., chronic kidney disease and chronic renal failure 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, etc.).

24. The compound for use according to any one of claims 18 to 23, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method, wherein the compound is selected from the group consisting of: myopathy associated with skeletal degeneration, 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.

25. 25. 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 24, wherein said compound is for administration to a human subject.

26. 26. 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 25, for use in combination with a further therapeutic agent.

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

28. A compound of formula (III): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 10】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 27).

29. A compound of formula (IV): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 11】 (In the formula, B 1 is as defined in any one of claims 1 to 28).

30. A compound of formula (VII): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 12】 (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 29).

31. A compound of formula (XII): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 13】 (In the formula, R 2 , R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 30).

32. A compound of formula (XIII): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 14】 (In the formula, R 2 , R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 31).

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

34. A compound of formula (XV): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 16】 (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 33).

35. A compound of formula (XVI): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 17】 (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 34).

36. A compound of formula (XVII): or a salt thereof, for example a pharmaceutically acceptable salt [Chemistry 18] (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 35).

37. A compound of formula (XVIII): or a salt thereof, for example a pharmaceutically acceptable salt 【Chemistry 19】 (In the formula, R 4 , R 5 , R 6 , R 7 , and A is as defined in any one of claims 1 to 36).

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