MPTP inhibitors

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to novel compounds as inhibitors of the mitochondrial permeability transition pore (mPTP). The invention also relates, inter alia, to such compounds for use as medicaments, in particular for the treatment or prevention of a degenerative, neurodegenerative or mitochondrial disease or other disease or condition in which inhibition of the mPTP provides a therapeutic or prophylactic effect. BACKGROUND

[0003] The mitochondrial permeability transition pore (mPTP) is a high conductance channel located on the inner mitochondrial membrane that is activated under certain cellular stress conditions, in particular under excess Ca 2+ and oxidative stress. It is permeable to solutes of molecular mass <1.5 kDa, voltage- and Ca 2+ dependent, and exhibits a characteristic large conductance. Once activated, oxidative phosphorylation is uncoupled, leading to loss of mitochondrial membrane potential and disruption of mitochondrial metabolism. In addition, solutes enter the mitochondrial matrix, leading to swelling and ultimately outer membrane rupture, followed by release of apoptogenic factors as well as chelated Ca 2+ , leading to eventual cell death via apoptosis or necrosis, depending on the cell type and physiology. It has thus been shown to be a key pathological event in a variety of degenerative and metabolic diseases.

[0004] Under normal physiological conditions, mitochondria play a key role in regulating cellular Ca 2+ homeostasis. Ca 2+ that enters the cell via cell surface channels (a common mechanism of cell signalling) is rapidly sequestered by mitochondria, preventing the accumulation of excess and toxic Ca 2+ in the cytoplasm. In cell types that experience high levels of Ca 2+ flux, such as neurons, skeletal muscle fibres and cardiomyocytes, this ‘buffering’ action of mitochondria is crucial to maintaining cellular health. However, there is a limit to the ability of mitochondria to sequester Ca 2+ and if the Ca 2+ levels within the mitochondria reach a certain threshold, a Ca 2+ sensitive mPTP is activated, leading to mitochondrial collapse and initiation of cell death. Activation of the mPTP in degenerative diseases can occur in a variety of ways depending on the disease, for example: 1) excess Ca 2+ entry into the cell and mitochondrial overload of Ca 2+ , 2) dysfunctional mitochondrial Ca 2+ efflux mechanisms, in particular reduced activity of the Ca 2+ efflux transporter NCLX, leading to Ca 2+ overload of the mitochondria.2+ overload, 3) excessive activity or upregulation of Ca 2+ uptake mechanisms, 4) oxidative stress, 5) sensitization of mPTP due to impaired mitochondrial function, i.e. mPTP activation at lower mitochondrial Ca 2+ concentrations, 6) Ca 2+ overload, 7) excessive activity or upregulation of Ca

[0005] While the properties and function of the mPTP can be studied in isolated mitochondria in simple in vitro assays, the molecular identity of the mPTP is not known. A number of proteins have been proposed to comprise the pore-forming complex, including ATP synthase and the adenine nucleotide translocator (ANT) protein family, but none of the proteins has been widely accepted as responsible for the formation of the pore. However, the peptidyl-prolyl cis-trans isomerase F (Ppif - Uniprot ID P30405, and also known as cyclophilin D) is recognized as a key regulator of the pore, although it does not form the transmembrane channel itself. Genetic or pharmacological inhibition of Ppif significantly reduces the sensitivity of the pore opening to Ca 2+ overload and other mPTP activators. Thus, genetic ablation or pharmacological inhibition of Ppif has been used to assess the involvement of the mPTP in pathological pathways in cellular and animal disease models. In this way, inhibition of the mPTP has been shown to be protective in a number of disease models, in particular those where Ca 2+ dysregulation and oxidative stress are known to cause cellular degeneration. Notably, 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), confirming the therapeutic potential of mPTP inhibition. In each of these diseases, genetic mutations in specific proteins that cause the genetic form of the disease and are expressed in mouse models (i.e. amyloid precursor protein, alpha-synuclein and superoxide dismutase 1, respectively) have been shown to cause Ca 2+ overload or sensitization of the mPTP. Recent evidence suggests that this can occur via a common mechanism in Alzheimer's disease, Parkinson's disease and Friedreich's ataxia. In each case, mitochondrial Ca 2+ overload has been reported in cells expressing the mutated disease-associated protein (amyloid precursor protein, PINK1 and ataxin, respectively). In each case, the disease-associated protein has been shown to interact with Ppif and to modulate its activity. Inhibition of Ppif has been shown to be protective in each of these models, confirming the therapeutic potential of mPTP inhibition. 2+Overload. In the case of Parkinson's disease, pathological aggregated forms of the protein alpha-synuclein, a misfolded protein commonly found in both sporadic and genetic cases of Parkinson's disease, have also been shown to sensitize and activate the mPTP.

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

[0007] In addition to demonstrating the benefits of Ppif inhibition in preclinical models, mPTP function has also been shown to be dysregulated in a variety of other disease indications. In particular, in many diseases, the threshold for mPTP activation in response to Ca 2+ The threshold for mPTP activation in response to Ca 2+ disorders.

[0008] mPTP inhibitors can also occur during disease pathogenesis, mitochondrial dysfunction, oxidative stress, inflammatory stress or Ca 2+ disorders.

[0009] The discovery and development of mPTP inhibitors has primarily focused on the identification of Ppif inhibitors. Cyclosporine A (CsA), originally identified as an immunosuppressant for its inhibitory activity on calcineurin, was also found to inhibit Ppif as well as other members of the peptidyl prolyl cis-trans isomerase (Ppi) enzyme family. Several cyclosporine A derivatives, such as Debio-25, NIM811, were subsequently developed that retained broad activity on the Ppi enzyme family without inhibiting calcineurin, however none of these derivatives have entered the market. To date, no potent, brain-penetrant, selective Ppif inhibitors have been reported. Other recent approaches to discover mPTP inhibitors utilize phenotypic screening in isolated mitochondria. These approaches have successfully identified potent small molecule mPTP inhibitors with Ppif-independent modes of action.

[0010] Yu et al. (2020, Cell, 183, 1-14) addresses the link between mPTP activation and mechanisms of TDP-43 proteinopathy (e.g. TARDNA binding protein 43 (TDP-43) associated neurodegeneration). Accumulation of the normal nuclear protein TDP-43 in the cytoplasm of neurons is a disease hallmark of almost all ALS cases and 40-50% of frontotemporal lobar degeneration (FTLD), some familial cases of which are caused by mutant forms of the protein. Both diseases are associated with a neuroinflammatory cytokine profile linked to upregulation of NF-kB and type I IFN pathways, directly implicating TDP-43 in neuroinflammation. Mutant or overexpressed WT TDP-43 in neurons mislocalizes to mitochondria and induces mitochondrial DNA (mtDNA) release into the cytoplasm. This mtDNA then activates the immune sensor cGAS-STING, triggering induction of innate immune genes (e.g. IL-6, TNFa and interferon beta). Inhibition of the mPTP with cyclosporine A or via Ppif knockout prevents TDP-43-induced mtDNA release and subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING extends survival of mutant mice expressing mutant TDP-43. The data suggest that mPTP activation mediates the toxic effects of TDP-43 in ALS and other diseases in which TDP-43 gene mutations cause disease or in which TDP-43 proteinopathy is observed.

[0011] Jang et al. (2021 American Journal of Physiology: Renal physiology, 2021321:4, F431-F442) highlights the potential therapeutic benefit of mPTP inhibition (via Ppif knockout) in a mouse model of kidney fibrosis. Unilateral ureteral obstruction was used to induce kidney fibrosis in WT and Ppif KO mice. Ppif KO mice had reduced inflammation, proximal tubule atrophy and fibrosis markers compared to WT. Measures of fibrosis included collagen deposition, a-SMA and TGFb expression and interstitial cell proliferation. This highlights the potential role of mPTP in cell damage / death-mediated tissue remodeling and fibrogenesis. Thus, mPTP inhibitors can be beneficial in diseases in which fibrosis is a key pathological mechanism, such as chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis.

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

[0013] There remains a need to discover additional compounds that act as mPTP inhibitors. Summary of the Invention

[0014] In a first aspect, the present invention provides a compound according to formula (I):

[0015]

[0016] in:

[0017] R 1 H or C 1-4 alkyl;

[0018] R 2 H, halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 0-4 Alkylene (OH);

[0019] R 3 is H, halogenated or C 1-4 alkyl;

[0020] R 4 is H, halogenated or C 1-4 alkyl;

[0021] R 5 For halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 0-6 Alkylene (C 3-6cycloalkyl), C 0-6 alkylene(OH); or R 4 and R 5 together with the carbon atom to which they are attached form a C 5-11 spiro carbocyclyl, 4- to 7-membered heterocyclyl, or C 3-6 cycloalkyl, wherein said spiro carbocyclyl, heterocyclyl, or cycloalkyl is optionally substituted with one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, and halo;

[0022] R 6 is H or C 1-4 alkyl;

[0023] R 7 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

[0024] A is monocyclic or bicyclic aryl, or monocyclic or bicyclic heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more A 1 ;

[0025] A 1 is independently selected from the group consisting of 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 ;

[0026] R g is H or C 1-4 alkyl;

[0027] R h is H or C 1-4 alkyl;

[0028] R j is C 1-4 alkyl;

[0029] or when A represents phenyl substituted with one or more A 1 , R 5 is joined and together represent (CH2) 1 v ​wherein v denotes 1, 2 or 3 and wherein one of said CH2groups can optionally be replaced by O;

[0030] B is a monocyclic or bicyclic heterocycle, or a monocyclic or bicyclic heteroaryl, wherein said heterocycle or heteroaryl can optionally be substituted by one or more B 1 substituents;

[0031] B 1 is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo (=0), thiooxo (=S) or C 0-6 alkylene(OH);

[0032] or a salt and / or solvate thereof,

[0033] and with the proviso that formula (I) is not N-((1 -benzylcyclobutyl)methyl)-6- hydroxypyrazine-2-carboxamide:

[0034]

[0035] 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 solvate (i.e. a pharmaceutically acceptable salt of a pharmaceutically acceptable solvate). In one embodiment, a compound of formula (I) is provided.

[0036] The present application 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 proviso of formula (I) does not apply.

[0037] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply.

[0038] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply.

[0039] The present application also provides a method of preventing or treating a disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, the method 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 proviso of Formula (I) does not apply.

[0040] Suitably, the disease or disorder is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, an ischemia-reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of aging, and a kidney disease.

[0041] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a mitochondrial disease, wherein the proviso of Formula (I) does not apply.

[0042] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a mitochondrial disease, wherein the proviso of Formula (I) does not apply.

[0043] The present application also provides a method of preventing or treating a mitochondrial disease in a subject, the method 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 proviso of Formula (I) does not apply.

[0044] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), wherein the proviso of Formula (I) does not apply.

[0045] The present application also provides the use of a compound of Formula (I), 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 TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), wherein the proviso of Formula (I) does not apply.

[0046] The present application also provides a method of treating or preventing a disease or disorder associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), the method 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 proviso of Formula (I) does not apply.

[0047] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0048] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0049] The present application also provides a method of treating or preventing a disease or condition associated with fibrosis, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply. DETAILED DESCRIPTION

[0050] The term "alkyl", as used herein, e.g. in C 1-4 In alkyl groups, whether alone or as part of a larger group, is a straight or branched chain fully saturated hydrocarbon chain containing the stated number of carbon atoms. C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and s-butyl. Reference to "propyl" includes n-propyl and i-propyl. Reference to "butyl" includes n-butyl, i-butyl, t-butyl and s-butyl.

[0051] The term "alkylthio", as used herein, e.g. "C 1-3 alkylthio", refers to an alkyl group as defined above (e.g. C 1-3 alkyl), singly bonded to a sulphur atom, e.g. -S-C 1-3 alkyl. C 1-3 Examples of alkylthio groups include methylthio, ethylthio and propylthio.

[0052] The term "alkylene", as used herein, e.g. C 1-4 alkylene or C 1-6 alkylene, whether alone or as part of a larger group (e.g. C 1-4 alkylene(OH), C 1-6 alkylene(OH) or C 1-6 alkylene(C 3-6 cycloalkyl)) is a difunctional straight or branched chain fully saturated hydrocarbon group containing the stated number of carbon atoms. C 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-). C 1-6 A branched example of an alkylene group is isopropylene (i.e. -CH(Me)CH2-). Reference to C0alkylene will be understood to mean that the alkylene chain is absent, e.g. C0alkylene(OH) represents OH.

[0053] The term "cycloalkyl", as used herein, e.g. in C1-4 alkylene(OH) (e.g. C 1-4 alkylene) means C 1-4 alkylene substituted with OH. Reference to C0 alkylene will be understood to mean that the alkylene chain is absent, e.g. C0 alkylene(OH) represents OH.

[0054] The term 'alkoxy', as used herein, e.g. in C 1-4 alkoxy or C 1-6 alkoxy means an alkyl group as defined hereinabove (e.g. C 1-4 alkyl) singly bonded to an oxygen atom. Examples of C 1-6 alkoxy include methoxy, ethoxy, 1 -propoxy, 2-propoxy, 1 -butoxy, 2-butoxy and 3-butoxy, especially methoxy.

[0055] The term 'halo' or 'halogen', as used herein, refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are bromo, fluoro and chloro, especially fluoro.

[0056] The term 'haloalkyl', as used herein, e.g. in C 1-4 haloalkyl or C 1-6 haloalkyl means a straight chain or branched alkyl group containing the stated number of carbon atoms which is substituted by one or more halo atoms, e.g. fluoromethyl (CH2F), difluoromethyl (CHF2), trifluoromethyl (CF3), 1 -fluoroethyl (CHFCH3) and 2-fluoroethyl (CH2CH2F).

[0057] The term 'haloalkoxy', as used herein, e.g. in C 1-4 haloalkoxy means a haloalkyl group as defined hereinabove (e.g. C 1-4 haloalkyl) singly bonded to an oxygen atom, e.g. trifluoromethoxy.

[0058] The term 'cycloalkyl', as used herein, e.g. in C 3-6 cycloalkyl, whether alone or as part of a larger group (e.g. C 0-6 alkylene(C 3-6 cycloalkyl)) is a fully saturated hydrocarbon ring containing the stated number of carbon atoms. Examples of C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclopropyl. Optionally, the cycloalkyl group can be substituted as defined herein.

[0059] The term 'alkenyl', as used herein, e.g. in C 2-6In alkynyl groups, reference is made to straight chain or branched hydrocarbon groups containing the specified number of carbon atoms and at least one carbon-carbon triple bond. The term encompasses CH≡CH2, CH2CH≡CH2, CH≡CHCH3, CH2CH2CH≡CH2, CH≡CHCH2CH3, CH2CH≡CHCH3, CH2CH2CH2CH≡CH2, CH≡CHCH2CH2CH3, CH2CH≡CHCH2CH3, CH2CH2CH≡CHCH3, CH≡CHCH≡CHCH3and CH2CH≡CHCH≡CH2. Branched variants are also included, for example CH(CH3)CH≡CH2and CH≡C(CH3)2.

[0060] The term 'haloalkenyl' as used herein, for example in C 2-6 In haloalkenyl groups, reference is made to straight chain or branched alkenyl chains containing the specified number of carbon atoms and at least one halogen atom (for example fluorine or chlorine, for example fluorine).

[0061] The term 'aryl' as used herein refers to a mono (i.e. phenyl) or polycyclic ring system containing at least one phenyl ring (for example comprising one or two, for example one additional ring), suitably the aryl group contains 6-10 ring members. The additional ring in the polycyclic ring system can be a saturated (for example forming an indane or tetrahydronaphthalene) or partially unsaturated (for example forming an indene) or fully unsaturated (for example forming a naphthalene) hydrocarbon ring, or the additional ring can be a saturated or partially unsaturated heterocyclic ring (for example forming a chromane). Suitably, aryl refers to a mono (i.e. phenyl) or bicyclic ring system containing at least one phenyl ring (and no heteroaryl rings).

[0062] The term 'heteroaryl' as used herein refers to a monocyclic or polycyclic (e.g. bicyclic) ring system having at least one ring with aromatic character and containing at least one heteroatom selected from N, O and S (e.g. N). Suitably, the heteroaryl group contains 5-10 ring members. In cases where the heteroaryl group contains more than one ring, not all rings must contain a heteroatom and not all rings must be aromatic in character. In some examples, the heteroaryl group 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, the heteroaryl group is bicyclic, e.g. a 5,5-, 5,6- or 6,6-bicyclic ring system (e.g. containing one, two or three heteroatoms selected from N, S and O). The heteroaryl group can contain one heteroatom selected from N, S and O (e.g. N and O, especially N). In other examples, the heteroaryl group can contain two heteroatoms selected from N, S and O. In other examples, the heteroaryl group can contain three heteroatoms selected from N, S and O (e.g. N and O). Examples of 6-membered heteroaryl groups include one nitrogen atom (pyridyl), two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl) and three nitrogen atoms (triazinyl). Other examples of heteroaryl groups include triazolyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzoxazolinyl, quinolinyl, isoquinolinyl and quinazolinyl.

[0063] As used herein, the term heterocycle means 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 sulphur (S). Suitably, the heterocyclic group contains 5-10 ring members. The heterocyclic group may, for example, be monocyclic or bicyclic. In bicyclic heterocyclic groups, there can be one or more heteroatoms in each ring or in only one ring. In cases where the heterocyclic group contains more than one ring, not all rings must contain a heteroatom. The heteroatoms can be S, O or N, and suitably O or N. The heterocycle can contain one heteroatom selected from N, S and O (e.g. N and O, especially N). In other examples, the heterocycle can contain two heteroatoms selected from N, S and O. In other examples, the heterocycle can 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 heterocycle. Examples of heterocycles include morpholinyl, tetrahydrofuran and tetrahydropyran.

[0064] As used herein, the term C 5-11 spiro carbocyclyl means a cyclic ring system containing 5 to 11 carbon atoms, wherein R 4 and R 5 are part of the spiro carbocyclyl group to which they are attached.

[0065] Examples include:

[0066]

[0067] C 5-11 Another example of a spirocarbocyclyl group is spiropentane.

[0068] When substituents are indicated in formula (I) in the embodiments and preferences described below as being optionally substituted, the optional substituents can be attached to an available carbon atom, which means to a carbon atom to which a hydrogen atom is attached, i.e. a C-H group, or the optional substituents can be attached to an available nitrogen atom, which means to a nitrogen atom to which a hydrogen atom is attached, i.e. an N-H group. The optional substituents replace a hydrogen atom attached to a carbon atom or a hydrogen atom attached to a nitrogen atom.

[0069] The present application provides a compound according to formula (I):

[0070]

[0071] wherein:

[0072] R 1 is H or C 1-4 alkyl;

[0073] R 2 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 0-4 alkylene(OH);

[0074] R 3 is H, halo, or C 1-4 alkyl;

[0075] R 4 is H, halo, or C 1-4 alkyl;

[0076] R 5 is 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 atom to which they are attached form a C 5-11 spirocarbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spirocarbocyclyl, heterocycle, or cycloalkyl group can be optionally substituted with one or more substituents selected from C 1-3 alkyl, C1-3 Haloalkyl and halogenated group substitution;

[0077] R 6 H or C 1-4 alkyl;

[0078] R 7 H, halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0079] A is a monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group, wherein the aryl or heteroaryl group may be optionally replaced by one or more A 1 replace;

[0080] A 1 Independently selected from the group consisting of: C 1-3 Alkylthio, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, CN, OH, NR g R h or NHSO2R j ;

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

[0082] R h H or C 1-4 alkyl;

[0083] R j C 1-4 alkyl;

[0084] Or when A represents one or more A 1 When phenyl is substituted, R 5 With the substituent A at the adjacent position 1 Join together and express together (CH2) v , wherein v represents 1, 2 or 3 and wherein one of the CH2 groups may optionally be replaced by O;

[0085] B is a monocyclic or bicyclic heterocycle, or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl may be optionally replaced by one or more B 1 replace;

[0086] B 1 For halogenated, C 1-6 Alkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo (=0), thioxo (=S) or C 0-6 alkylene(OH);

[0087] or salts and / or solvates thereof,

[0088] and with the proviso that formula (I) is not N-((1-benzylcyclobutyl)methyl)-6- hydroxypyrazine-2-carboxamide:

[0089]

[0090] In a second embodiment, the present application provides a compound according to formula (IA):

[0091]

[0092] wherein:

[0093] R 1 is H or C 1-4 alkyl;

[0094] R 2 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 0-4 alkylene(OH);

[0095] R 3 is H, halo or C 1-4 alkyl;

[0096] R 4 is H or C 1-4 alkyl;

[0097] R 5 is 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 atom to which they are attached form a C 3-6 cycloalkyl, wherein said cycloalkyl can optionally be substituted with one or more C 1-3 alkyl, C 1-3haloalkyl and halogen-substituted groups;

[0098] R 6 is H or C 1-4 alkyl;

[0099] R 7 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

[0100] A is a monocyclic or bicyclic aryl, or a monocyclic or bicyclic heteroaryl, which aryl or heteroaryl is optionally substituted by one or more A 1 substituents;

[0101] A 1 is 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 ;

[0102] R g is H or C 1-4 alkyl;

[0103] R h is H or C 1-4 alkyl;

[0104] R j is C 1-4 alkyl;

[0105] or when A represents phenyl which is substituted by one or more A 1 substituents, R 5 is joined to the adjacent substituent A 1 and together represent (CH2) v wherein v represents 1, 2 or 3 and wherein one of the CH2groups can optionally be replaced by O;

[0106] B is a monocyclic or bicyclic heterocycle, or a monocyclic or bicyclic heteroaryl, which heterocycle or heteroaryl can optionally be substituted by one or more B 1 substituents;

[0107] B 1 is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C0-6 Alkylene (OH);

[0108] or a salt and / or solvate thereof,

[0109] and with the proviso that formula (IA) is not N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide:

[0110]

[0111] The compounds according to formula (IA) or their salts and / or solvates are a subgenus of the compounds of formula (I) or their salts and / or solvates. The compounds according to formula (IA′) or their salts and / or solvates are a subgenus of the compounds of formula (IA) or their salts and / or solvates. The compounds according to formula (IA″) or their salts and / or solvates are a subgenus of the compounds of formula (IA) or their salts and / or solvates. The compounds according to formula (IA″′) or their salts and / or solvates are a subgenus of the compounds of formula (IA) or their salts and / or solvates. The following embodiments apply equally to the compounds of formula (I), (IA), (IA′), (IA″) and / or (IA″′) or their salts and / or solvates.

[0112] In one embodiment, R 1 is H. In a second embodiment, R 1 C 1-4 Alkyl groups, such as methyl.

[0113] In one embodiment, R 2 is H. In a second embodiment, R 2 In a third embodiment, R 2 In a fourth embodiment, R 2 C 1-4 In a fifth embodiment, R 2 C 1-4 In a sixth embodiment, R 2 C 1-4 In a seventh embodiment, R 2 C 1-4 In an eighth embodiment, R 2 C 0-4 Alkylene (OH), such as CH2CH2OH. In a ninth embodiment, R 2 C 1-4 Alkylene (OH), for example CH2CH2OH.

[0114] In one embodiment, R 3 is H. In a second embodiment, R 3halogenated. In a third embodiment, R 3 is fluorine. In a fourth embodiment, R 3 is C 1-4 alkyl. In a fifth embodiment, R 3 is methyl.

[0115] 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.

[0116] In one embodiment, R 4 is H. In a second embodiment, R 4 is C 1-4 alkyl, for example methyl. In a third embodiment, R 4 is halogenated, for example fluorine.

[0117] In one embodiment, R 5 is H. In a second embodiment, R 5 is halogenated. In a third embodiment, R 5 is C 1-6 alkyl, for example methyl, ethyl, n-propyl or i-propyl, especially ethyl. In a fourth embodiment, R 5 is C 1-6 halogenated alkyl. In a fifth embodiment, R 5 is C 1-6 alkoxy, for example OMe. In a sixth embodiment, R 5 is C 1-6 halogenated alkoxy. In a seventh embodiment, R 5 is C 2-6 alkenyl. In an eighth embodiment, R 5 is C 2-6 halogenated alkenyl. In a ninth embodiment, R 5 is C 0-6 alkylene(C 3-6 cycloalkyl), for example C 3-6 cycloalkyl, in particular cyclopropyl or cyclobutyl, especially cyclopropyl. In a tenth embodiment, R 5 is C 0-6 alkylene(OH), for example CH2OH or CH(Me)(OH). In an eleventh embodiment, R 5 is fluorine.

[0118] In a twelfth embodiment, R 5 is

[0119] 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 isopropyl. In one embodiment, R 4 is H and R 5 is cyclopropyl.

[0120] In one embodiment, R 4 is H and R 5 is C 0-6 alkylene(C 3-6 cycloalkyl), for example C 3-6 cycloalkyl.

[0121] In one embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl. Within such embodiments, the C 3-6 cycloalkyl can be substituted with one or more (for example one, two or three, for example one or two) groups selected from the group consisting of C 1-3 alkyl, C 1-3 haloalkyl and halo. Suitably, the C 3-6 cycloalkyl is unsubstituted. Suitably, R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring, for example a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, especially a cyclobutyl ring. In one embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl. Within such embodiments, the C 3-6 cycloalkyl can be substituted with one or more (for example one, two or three, for example one or two) groups selected from the group consisting of methyl, OCF3and fluoro.

[0122] In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a 4- to 7-membered heterocyclic ring. Within such embodiments, the 4- to 7-membered heterocyclic ring can be substituted with one or more (for example one, two or three, for example one or two, preferably one) groups selected from the group consisting of C 1-3 alkyl, for example methyl, C 1-3haloalkyl, such as OCF3, and halo, such as fluoro. In another embodiment, the 4- to 7- membered heterocycle is unsubstituted. In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a tetrahydrofuranyl or tetrahydropyranyl ring.

[0123] In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a C 5-11 spiro carbocyclyl. Within such embodiments, the C 5-11 spiro carbocyclyl can be substituted with one or more (such as one, two, or three, such as one or two, preferably one) groups selected from the group consisting of C 1-3 alkyl, such as methyl, C 1-3 haloalkyl, such as OCF3, and halo, such as fluoro. In another embodiment, the C 5-11 spiro carbocyclyl is unsubstituted. In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a spiro pentane ring.

[0124] In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a C 5-11 spiro carbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spiro carbocyclyl, heterocycle, or cycloalkyl.

[0125] In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form an unsubstituted C 5-11 spiro carbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl.

[0126] In another embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl, spiro pentane ring, or tetrahydrofuranyl or tetrahydropyranyl group.

[0127] In one embodiment, R 6 is H. In a second embodiment, R 6 is C 1-4 alkyl, such as methyl.

[0128] In one embodiment, R 7 is H. In a second embodiment, R 7 is halo. In a third embodiment, R 7halo, e.g. fluoro. In a fourth embodiment, R 7 is C 1-4 haloalkyl. In a fifth embodiment, R 7 is C 1-4 alkoxy, e.g. OMe. In a sixth embodiment, R 7 is C 1-4 haloalkoxy.

[0129] In one embodiment, R 6 is H and R 7 is H. In a second embodiment, R 6 is H and R 7 is methyl.

[0130] In one embodiment, at least one of R 2 , R 3 , R 4 , R 5 , R 6 or R 7 is not H. Suitably, one of R 4 and R 5 is not H.

[0131] In one embodiment, R 2 , R 3 , R 6 and R 7 are all H.

[0132] R 4 and R 5 may preferably have the stereochemical configuration:

[0133]

[0134] R 4 and R 5 may also have the stereochemical configuration:

[0135]

[0136] or, when R 4 is H, R 4 and R 5 may have the stereochemical configuration:

[0137]

[0138] In one embodiment, A is monocyclic aryl, e.g. 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.

[0139] In one embodiment, A is substituted with one or more (e.g. one, two or three, e.g. one or two, in particular one) A 1 substituents.

[0140] In one embodiment, A is substituted with two A 1 substituents.

[0141] In one embodiment, at least one A 1 is halo, e.g. F, Br or CI, in particular F. In a second embodiment, at least one A 1 is C 1-6 alkyl, e.g. methyl. In a third embodiment, at least one A 1 is C 1-6 haloalkyl. In a fourth embodiment, at least one A 1 is C 1-6 alkoxy, e.g. OMe. In a fifth embodiment, at least one A 1 is C 1-6 haloalkoxy. In a sixth embodiment, at least one A 1 is C 3-6 cycloalkyl. In a seventh embodiment, at least one A 1 is CN. In an eighth embodiment, at least one A 1 is OH. In a ninth embodiment, at least one A 1 is NR g R h . Suitably, R g is H. Suitably, R g is C 1-4 alkyl. Suitably, R h is H. Suitably, R h is C 1-4 alkyl. In a tenth embodiment, at least one A 1 is NHSO2R j . In an eleventh embodiment, at least one A 1 is C 1-3 alkylthio. In a twelfth embodiment, at least one A 1 is SMe.

[0142] In one embodiment, A is unsubstituted.

[0143] In one embodiment, A is phenyl substituted with one or two A 1-6 groups independently selected from halo or C 1 alkyl.

[0144] In one embodiment, A is phenyl substituted with one or two A 1-3Alkyl A 1 substituted phenyl groups.

[0145] In one embodiment, A is selected from the group consisting of:

[0146]

[0147] in:

[0148] A 1A is halogenated, such as F, Br or Cl; C 1-6 Alkyl, such as methyl; or C 1-6 an alkoxy group, such as OMe; and

[0149] A 1B is H or halo, such as F, Br or Cl, especially F.

[0150] In one embodiment, A is In a second embodiment, A is (A2). In a third embodiment, A is

[0151] In one embodiment, A is selected from the group consisting of:

[0152]

[0153] in:

[0154] A 1A is halogenated, such as F, Br or Cl; C 1-6 Alkyl, such as methyl; or C 1-6 an alkoxy group, such as OMe; and

[0155] A 1B is H or halo, such as F, Br or Cl, especially F.

[0156] In one embodiment, A is selected from the group consisting of:

[0157]

[0158] in:

[0159] A 1A is halogenated, such as F, Br or Cl; C 1-6 Alkyl, such as methyl; or C 1-6 Alkoxy, such as OMe.

[0160] In one embodiment, A is

[0161]

[0162] wherein A 1A is halo, for example F, and A 1B is halo, for example F.

[0163] In one embodiment, A 1A is halo, for example F, Br or CI. In a second embodiment, A 1A is C 1-6 alkyl, for example methyl. In a third embodiment, A 1A is C 1-6 alkoxy, for example OMe. In a fourth embodiment, A 1A is F.

[0164] In one embodiment, A 1B is H. In a second embodiment, A 1B is halo, for example F, Br or CI, especially F.

[0165] In one embodiment, when A represents phenyl substituted by one or more A 1 R 5 is joined to and together with the ortho substituent A 1 represents (CH2) v wherein v represents 1, 2 or 3 and wherein one of said CH2groups can optionally be replaced by O. Suitably, when A represents phenyl substituted by one or more A 1 R 5 is joined to and together with the ortho substituent A 1 represents (CH2) v wherein v represents 1, 2 or 3.

[0166] Suitably, when A represents phenyl substituted by one or more (for example one, two or three, for example one or two) A 1 R 5 is joined to and together with the ortho substituent A 1 represents (CH2) v wherein v represents 1, 2 or 3.

[0167] In one embodiment, v is 1. In one embodiment, v is 2. In one embodiment, v is 3.

[0168] In one embodiment, B is a monocyclic heterocycle. Suitably, B is a 5- or 6- membered monocyclic heterocycle. Suitably, B is a 6-membered monocyclic heterocycle. Suitably, 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. Suitably, B is a 5- or 6- membered monocyclic heteroaryl. In a fourth embodiment, B is a bicyclic heteroaryl. Suitably, B is a benzoxazolinone.

[0169] In one embodiment, B is substituted with one or more (e.g. one or two, in particular one) B 1 substituted. In one embodiment, B is substituted with one or more (e.g. one, two or three, e.g. one or two, in particular one) B 1 substituted.

[0170] In one embodiment, at least one B 1 is halo. In a second embodiment, at least one B 1 is halo, e.g. fluoro. In a third embodiment, at least one B 1 is C 1-6 alkyl, e.g. methyl. In a fourth embodiment, at least one B 1 is C 1-6 haloalkyl. In a fifth embodiment, at least one B 1 is C 1-6 alkoxy. In a sixth embodiment, at least one B 1 is C 1-6 haloalkoxy. In a seventh embodiment, at least one B 1 is C 0-6 alkylene(OH), e.g. OH. In an eighth embodiment, at least one B 1 is oxo (=0). In a ninth embodiment, at least one B 1 is thioxo (=S). In a tenth embodiment, at least one B 1 is C 1-3 alkyl, e.g. methyl.

[0171] In one embodiment, B is unsubstituted.

[0172] In one embodiment, B is selected from the group consisting of:

[0173]

[0174] e.g.

[0175] wherein:

[0176] B 1A is H or C 1-6 alkyl, e.g. methyl; and

[0177] B 2A is H or C 1-6 alkyl, e.g. methyl.

[0178] In another embodiment, B is selected from the group consisting of:

[0179]

[0180]

[0181] For example

[0182] wherein:

[0183] B 1A is H, halo, e.g. F, Br or CI, especially F, or C 1-6 alkyl, e.g. methyl; and

[0184] B 2A is H, halo, e.g. F, Br or CI, especially F, or C 1-6 alkyl, e.g. methyl.

[0185] In one embodiment, B is In a second embodiment, B is

[0186] In one embodiment, B 1A is H. In a second embodiment, B 1A is C 1-6 alkyl, e.g. methyl.

[0187] In one embodiment, B 2A is H. In a second embodiment, B 2A is C 1-6 alkyl, e.g. methyl.

[0188] In one embodiment, B is selected from the group consisting of:

[0189]

[0190] wherein

[0191] each B 3A is independently selected from C 1-6 alkyl, e.g. methyl; and C 0-6 alkylene(OH), e.g. OH; and

[0192] y is 1 or 2.

[0193] In one embodiment, B is selected from the group consisting of:

[0194]

[0195] wherein B 2A is C 1-3 alkyl, e.g. methyl.

[0196] In one embodiment, at least one B 3A is C 1-6alkyl, for example methyl. In a second embodiment, at least one B 3A is C 0-6 alkylene(OH), for example OH.

[0197] In one embodiment, y is 1. In a second embodiment, y is 2.

[0198] In one embodiment, the present application provides a compound of formula (IA'):

[0199]

[0200] wherein:

[0201] R 1′ is H;

[0202] R 2′ is H;

[0203] R 3′ is H or C 1-4 alkyl;

[0204] R 4 is H or C 1-4 alkyl;

[0205] R 5′ is H, C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5 together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0206] R 6′ is H;

[0207] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[0208] n' is 0, 1 or 2; and

[0209] A 1′ is halo or C 1-6 alkyl,

[0210] or salts and / or solvates thereof.

[0211] In another embodiment, the present application provides a compound of formula (IA'):

[0212]

[0213] wherein:

[0214] R 1′ is H;

[0215] R 2′ is H;

[0216] R 3′ is H or C 1-4 alkyl;

[0217] R 4 is H or C 1-4 alkyl;

[0218] R 5′ is C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5 together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0219] R 6′ is H;

[0220] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[0221] n' is 0, 1 or 2; and

[0222] A 1′ is halo or C 1-6 alkyl,

[0223] or salts and / or solvates thereof.

[0224] In one embodiment, the present application provides a compound of formula (IA"):

[0225]

[0226] wherein:

[0227] R 1′ is H;

[0228] R 2′ is H;

[0229] R 3′ is H or C 1-4 alkyl;

[0230] R 4 is H or C 1-4 alkyl;

[0231] R 5′ is H, C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5R' is H or C1-4alkyl; 3-6 cycloalkyl;

[0232] R 6′ is H;

[0233] R 7′ is H, C1-4alkyl or C3-6cycloalkyl; 1-6 alkyl or C3-6cycloalkyl; 1-6 alkoxy;

[0234] B 1A is H or C1-4alkyl; 1-6 alkyl, for example methyl;

[0235] n' is 0, 1 or 2; and

[0236] A 1′ is halo or C1-4alkyl; 1-6 alkyl,

[0237] or salts and / or solvates thereof.

[0238] In another embodiment, the present application provides a compound of formula (IA"):

[0239]

[0240] wherein:

[0241] R 1′ is H;

[0242] R 2′ is H;

[0243] R 3′ is H or C1-4alkyl; 1-4 alkyl;

[0244] R 4 ' is H or C1-4alkyl; 1-4 alkyl;

[0245] R 5′ is C1-4alkyl or C3-6cycloalkyl; 1-4 alkyl or C3-6cycloalkyl; 3-6 cycloalkyl; or R 4′ and R 5 ' together with the atom to which they are attached form a C3-6cycloalkyl; 3-6 cycloalkyl;

[0246] R 6′ is H;

[0247] R 7′ is H, C1-4alkyl or C3-6cycloalkyl; 1-6 alkyl or C3-6cycloalkyl; 1-6 alkoxy;

[0248] B 1A is H or C1-4alkyl; 1-6alkyl, for example methyl;

[0249] n' is 0, 1 or 2; and

[0250] A 1′ is halo or C 1-6 alkyl,

[0251] or salts and / or solvates thereof.

[0252] In one embodiment, the present application provides a compound of formula (IA'"):

[0253]

[0254] wherein:

[0255] R 1′ is H;

[0256] R 2′ is H;

[0257] R 3′ is H or C 1-4 alkyl;

[0258] R 4 ' is H or C 1-4 alkyl;

[0259] R 5′ is H, C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5 ' together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0260] R 6′ is H;

[0261] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[0262] B 1A is H or C 1-6 alkyl, for example methyl;

[0263] n' is 0, 1 or 2; and

[0264] A 1′ is halo or C 1-6 alkyl,

[0265] or salts and / or solvates thereof.

[0266] In one embodiment, the present application provides a compound of formula (IA'"):

[0267]

[0268] wherein:

[0269] R 1′ is H;

[0270] R 2′ is H;

[0271] R 3′ is H or C 1-4 alkyl;

[0272] R 4 is H or C 1-4 alkyl;

[0273] R 5′ is C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5 together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0274] R 6′ is H;

[0275] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[0276] B 1A is H or C 1-6 alkyl, for example methyl;

[0277] n' is 0, 1 or 2; and

[0278] A 1′ is halo or C 1-6 alkyl,

[0279] or salts and / or solvates thereof.

[0280] In one embodiment, R 3′ is H. In a second embodiment, R 3′ is C 1-4 alkyl, for example methyl or ethyl.

[0281] In one embodiment, R 4′ is H. In a second embodiment, R 4′ is C 1-4 alkyl, for example methyl.

[0282] In one embodiment, R 5′ is H. In a second embodiment, R 5′ is C1-4 In a third embodiment, R 5′ C 3-6 Cycloalkyl, for example cyclopropyl.

[0283] In one embodiment, R 4′ and R 5 ' together with the atoms to which it is connected form C 3-6 Cycloalkyl, for example cyclobutyl.

[0284] In one embodiment, R 7′ is H. In a second embodiment, R 7′ C 1-6 In a third embodiment, R 7′ C 1-6 Alkoxy, such as OMe.

[0285] In one embodiment, B 1A is H. In a second embodiment, B 1A C 1-6 Alkyl groups, such as methyl.

[0286] In one embodiment, n' is 0. In a second embodiment, n' is 1. In a third embodiment, n' is 2.

[0287] In one embodiment, A 1′ is halo, such as F, Br or Cl. In a second embodiment, A 1′ C 1-6 Alkyl groups, such as methyl.

[0288] In the following paragraphs, the references and preferences set out for the compounds of formula (I) or their salts and / or solvates and / or the compounds of formula (IA) or their salts and / or solvates with respect to salts, isomers, processes, pharmaceutical compositions, compounds, uses and methods for use also apply to the compounds of formula (IA′), (IA″) and (IA′″) or their salts and / or solvates.

[0289] In one embodiment, the compound of formula (I) is selected from the group consisting of:

[0290] N-((1-benzylcyclobutyl)methyl)-5-hydroxynicotinamide;

[0291] N-((1-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide;

[0292] N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide;

[0293] N-((l-benzylcyclobutyl)methyl)-lH-l,2,3-triazole-5-carboxamide;

[0294] N-((l-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide;

[0295] N-((l-benzylcyclobutyl)methyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[0296] N-((l-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0297] N-((l-benzylcyclobutyl)methyl)-5-methyl-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[0298] N-((l-benzylcyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0299] N-((l-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide;

[0300] N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide;

[0301] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide;

[0302] N-((l-benzylcyclobutyl)methyl)-l-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0303] N-((l-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0304] N-((l-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0305] N-((l-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0306] N-((l-benzylcyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0307] N-((l-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0308] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0309] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0310] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0311] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0312] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0313] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0314] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0315] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0316] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0317] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0318] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0319] N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0320] 1 -Methyl- N- (2-methyl-3-phenylpropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-3- carboxamide;

[0321] N-((1-Benzylcyclopropyl)methyl)-1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-3- carboxamide;

[0322] N- (2, 2-Dimethyl-1-phenylpentan-3-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole- 3-carboxamide;

[0323] 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;

[0324] N- (3- (2-Bromophenyl) -2, 2-dimethylpropyl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4- triazole-3-carboxamide;

[0325] N-((1-(2-Bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole- 3-carboxamide;

[0326] N- (3, 3-Dimethyl-4-phenylbutan-2-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole- 3-carboxamide;

[0327] (R) -N- (3, 3-Dimethyl-4-phenylbutan-2-yl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4- triazole-3-carboxamide;

[0328] N- (2-Benzylbutyl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-3-carboxamide;

[0329] N- (2-Benzyl-3-hydroxy-2-methylpropyl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole- 3-carboxamide;

[0330] N- (2-Benzyl-3-hydroxy-2-methylbutyl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole- 3-carboxamide;

[0331] N- (2-Methoxy-3-phenylpropyl) -1-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-3- carboxamide;

[0332] N-(2-Benzyl-2-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0333] N-(2-Benzyl-3-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0334] (S)-N-(2-Benzyl-3-methylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0335] N-((1-benzylcyclohexyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0336] N-((1-benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0337] N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide;

[0338] N-((1-(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide;

[0339] N-(2-cyclobutyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0340] N-((1-(1-(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0341] N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0342] (R)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0343] (S)-N-(2-Benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0344] N-(2-Benzylpentyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0345] N-(2,2-dimethyl-3-phenylpropyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[0346] N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;

[0347] 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;

[0348] 1-Methyl-N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0349] 1-Methyl-5-oxo-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0350] N-((1-(2-methoxybenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0351] 6-Oxo-N-((1-(pyridin-2-ylmethyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide;

[0352] N-((1-benzylcyclobutyl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide;

[0353] N-((1-benzylcyclobutyl)methyl)-3-methyl-1H-1,2,4-triazole-5-carboxamide;

[0354] N-(2-Benzyl-3-hydroxypropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0355] N-(2,2-dimethyl-3-phenylpropyl)-N,1-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0356] N-((1-(2,4-difluorobenzyl)cyclohexyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0357] N-((2S,3S)-3-Benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0358] N-(( 1 -(3 -methoxybenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0359] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0360] N-(( 1 -(3 -cyclopropylbenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0361] N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide;

[0362] N-(( 1 -(3 -chlorobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide;

[0363] 1 -methyl-5-oxo-N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[0364] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0365] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0366] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0367] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0368] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0369] N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[0370] N-((l-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5- dihydro-lH-l,2,4-triazole-3-carboxamide;

[0371] N-((l-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[0372] l-methyl-N-((l-(3-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0373] N-((l-(4-chloro-2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide;

[0374] N-((l-(4-chloro-2-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide;

[0375] N-((l-(2,4-difluorobenzyl)cyclopentyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0376] N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0377] N-((l-(2-fluoro-3-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide;

[0378] N-((l-(2,3-difluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0379] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide;

[0380] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide;

[0381] (S)-N-(2-(2,4-difluorobenzyl)butyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0382] N-((l-(3-bromobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0383] N-((l-(3-cyanobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; and

[0384] N-((l-(3,5-difluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0385] or a salt and / or solvate of any one of them.

[0386] In one embodiment, the compound of Formula (I) is selected from the group consisting of:

[0387] N-((l-benzylcyclobutyl)methyl)-5-hydroxynicotinamide;

[0388] N-((l-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide;

[0389] N-((l-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide;

[0390] N-((l-benzylcyclobutyl)methyl)-lH-l,2,3-triazole-5-carboxamide;

[0391] N-((l-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide;

[0392] N-((l-benzylcyclobutyl)methyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[0393] N-((l-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0394] N-((l-benzylcyclobutyl)methyl)-5-methyl-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[0395] N-((l-benzylcyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0396] N-((l-benzylcyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0397] N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide;

[0398] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0399] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0400] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0401] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0402] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0403] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0404] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0405] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0406] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0407] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0408] N-((l-(2,6-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide;

[0409] (R)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[0410] 1 -methyl-5-oxo- N-((1 -(1 -phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0411] 1 -methyl-5-oxo- N-((1 -(1 -phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0412] (S)-1 -methyl-5-oxo- N-((1 -(1 -phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0413] (R)-1 -methyl-5-oxo- N-((1 -(1 -phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0414] N-((1 -(methyloxy(phenyl)methyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[0415] 1 -methyl- N-((1 -(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0416] N-((1 -(2-chlorobenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0417] N-(2,2-dimethyl-3-phenylpropyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide;

[0418] 1 -methyl- N-(2-methyl-3-phenylpropyl)-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide;

[0419] N-((1 -benzylcyclopropyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide;

[0420] N-(2,2-dimethyl-1 -phenylpentan-3-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[0421] 1 -Methyl-5-oxo-N-( 1, 1, 1 -trifluoro-3, 3 -dimethyl-4-phenylbutan-2-yl)-4, 5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[0422] N-(3-(2-Bromophenyl)-2,2-dimethylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0423] N-((l-(2-Bromobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0424] N-(3,3-Dimethyl-4-phenylbutan-2-yl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0425] (S)-N-(3,3-Dimethyl-4-phenylbutan-2-yl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole- 3-carboxamide;

[0426] (R)-N-(3,3-Dimethyl-4-phenylbutan-2-yl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole- 3-carboxamide;

[0427] N-(2-Benzylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0428] N-(2-Benzyl-3-hydroxy-2-methylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0429] N-(2-Benzyl-3-hydroxy-2-methylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0430] N-(2-Methoxy-3-phenylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0431] N-(2-Benzyl-2-methylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0432] N-(2-Benzyl-3-methylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0433] N-[(2S)-2-Benzyl-3-methylbutyl]-1-methyl-5-oxo-4H-1,2,4-triazole-3-carboxamide;

[0434] 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;

[0435] N-((1-benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0436] N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide;

[0437] N-((1-(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide;

[0438] N-(2-cyclobutyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0439] N-((1-(1-(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0440] N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0441] (R)-N-(2-benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0442] (S)-N-(2-Benzylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0443] N-(2-Benzylpentyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0444] N-(2,2-dimethyl-3-phenylpropyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[0445] N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;

[0446] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0447] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0448] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0449] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0450] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0451] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0452] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0453] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0454] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0455] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0456] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0457] 1 -Methyl- N-((2-methyl-2,3-dihydro-1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0458] N-((l-(3-chlorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0459] N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0460] N-((l-(3-chlorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0461] 1 -methyl-5-oxo- N -(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide;

[0462] N-((l-(2,5-difluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0463] N-((l-(2-ethylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0464] N-((l-(2-fluoro-5-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0465] N-((l-(3-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[0466] N-((l-(3-chloro-2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0467] N-((l-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[0468] N-((l-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazole-3-carboxamide;

[0469] N-((l-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[0470] 1 -Methyl- N- (( 1 -(3 -methylbenzyl)cyclopentyl)methyl)-5-oxo-4, 5-dihydro- 1H- 1, 2, 4-triazole-3-carboxamide;

[0471] N-((1-(4-Chloro-2-fluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0472] N-((1-(4-Chloro-2-methylbenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0473] N-((1-(2,4-Difluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0474] N-(2-Cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0475] N-((1-(2-Fluoro-3-methylbenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0476] N-((1-(2,3-Difluorobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0477] (R)-N-(2-Cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0478] (S)-N-(2-Cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0479] (S)-N-(2-(2,4-Difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0480] N-((1-(3-Bromobenzyl)cyclopentyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0481] N-((1-(3-cyanobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0482] N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0483] (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0484] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0485] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0486] N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0487] 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;

[0488] N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0489] 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;

[0490] (R)-N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0491] (S)-1-methyl-5-oxo-N-(2-(2,4,6-trifluorobenzyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0492] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4-hydroxypicolinamide;

[0493] N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[0494] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-hydroxy-1-methyl-1H-pyrazole-3-carboxamide

[0495] (R)-N-(2-cyclopropyl-3-(4-fluoro-2-methylphenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazole-3-carboxamide;

[0496] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydropyrazine-2-carboxamide

[0497] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide

[0498] N-((2R,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0499] N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0500] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide;

[0501] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-2-oxo-2,3-dihydrooxazole-4-carboxamide;

[0502] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0503] N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[0504] N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[0505] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0506] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0507] N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0508] 6-Oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-1,6-dihydropyrazine-2-carboxamide;

[0509] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0510] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0511] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0512] N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0513] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0514] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0515] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[0516] 1-Methyl-5-oxo-N-((1-(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0517] 1-Methyl-5-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0518] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0519] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0520] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0521] N-((1-(3-ethylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0522] (S)-N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0523] N-(2-(3,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0524] N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0525] N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0526] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide;

[0527] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide;

[0528] N-(2-((2,3-dihydrobenzofuran-5-yl)methyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0529] N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[0530] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[0531] N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[0532] N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[0533] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide;

[0534] 1-Methyl-N-((1-(2-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0535] 1-Methyl-N-((1-(3-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0536] (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0537] N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-3-oxo-2,3-dihydroisoxazole-5-carboxamide;

[0538] N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0539] N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0540] N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0541] N-((2S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0542] (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0543] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0544] (S)-N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[0545] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-fluoro-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[0546] N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0547] N-((l-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[0548] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-l,2,4-triazine-3-carboxamide;

[0549] N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0550] N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0551] N-((l-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-l,2,4-triazine-3-carboxamide;

[0552] N-(2-(2,4-difluorobenzyl)-2-ethylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0553] N-((l-(3,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[0554] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[0555] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[0556] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[0557] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-(methoxymethyl)-4H-1,2,4-triazole-3-carboxamide;

[0558] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[0559] (S)-N-(2-(2,4-difluorobenzyl)butyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[0560] N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0561] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamide;

[0562] (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[0563] N-((1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0564] N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0565] N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0566] N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0567] (R)-5-Bromo-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0568] N-(3-(2-chloro-4,6-difluorophenyl)-2-cyclopropylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[0569] N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[0570] N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[0571] N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole- 3-carboxamide;

[0572] N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole- 3-carboxamide;

[0573] N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[0574] N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[0575] (S)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1 -methyl-5-oxo-4H-1,2,4- triazole-3-carboxamide;

[0576] (R)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1 -methyl-5-oxo-4H-1,2,4- triazole-3-carboxamide;

[0577] (S)-N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H- 1,2,4-triazole-3-carboxamide;

[0578] (R)-N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H- 1,2,4-triazole-3-carboxamide;

[0579] (R)-N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-l-methyl-5-oxo- 4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0580] (R)-N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-l-methyl-5-oxo- 4,5-dihydro-lH-l,2,4-triazole-3-carboxamide;

[0581] (S)-N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-5-oxo-4,5-dihydro- l,2,4-oxadiazole-3-carboxamide;

[0582] (R)-N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-5-oxo-4,5-dihydro- l,2,4-oxadiazole-3-carboxamide;

[0583] (S)-N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-6-oxo-l,6-dihydro- pyrimidine-2-carboxamide;

[0584] (R)-N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-6-oxo-l,6-dihydro- pyrimidine-2-carboxamide;

[0585] N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-l-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazole-3-carboxamide;

[0586] N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-l-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazole-3-carboxamide;

[0587] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-l-methyl-5-oxo-4,5- dihydro-lH-l,2,4-triazole-3-carboxamide;

[0588] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-l-methyl-5-oxo-4,5- dihydro-lH-l,2,4-triazole-3-carboxamide;

[0589] (R)-N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-l-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazole-3-carboxamide;

[0590] (S)-N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro- 1H-1,2,4-triazole-3-carboxamide;

[0591] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[0592] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[0593] (R)-N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazole-3-carboxamide;

[0594] (S)-N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazole-3-carboxamide;

[0595] N-(((1s,3r)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[0596] N-(((1r,3s)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[0597] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0598] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0599] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[0600] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[0601] (R)-N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazole-3-carboxamide;

[0602] (S)-N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[0603] (S)-N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0604] (R)-N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[0605] N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2- carboxamide;

[0606] N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2- carboxamide;

[0607] 5-chloro-N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2- carboxamide;

[0608] 5-chloro-N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2- carboxamide;

[0609] (S)-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2- carboxamide;

[0610] (R)-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H-pyrimidine-2- carboxamide;

[0611] (S)-5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2- carboxamide;

[0612] (R)-5-chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H-pyrimidine-2- carboxamide;

[0613] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[0614] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo- 1,6-dihydropyrimidine-2-carboxamide;

[0615] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo- 1,6-dihydropyrimidine-2-carboxamide;

[0616] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo- 1,6-dihydropyrimidine-2-carboxamide;

[0617] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole- 5-carboxamide;

[0618] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole- 5-carboxamide;

[0619] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole- 5-carboxamide;

[0620] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole- 5-carboxamide;

[0621] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro- 1,2,4-oxadiazole-3-carboxamide;

[0622] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro- 1,2,4-oxadiazole-3-carboxamide;

[0623] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro- 1,2,4-oxadiazole-3-carboxamide; and

[0624] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro- 1,2,4-oxadiazole-3-carboxamide;

[0625] or salts and / or solvates of any one thereof.

[0626] The definition of the compound of formula (I) is intended to include all tautomers of said compound.

[0627] The compounds of the application can be provided in the form of pharmaceutically acceptable salts and / or solvates thereof. In particular, the compounds of formula (I) can be provided in the form of pharmaceutically acceptable salts and / or solvates (e.g. pharmaceutically acceptable salts). In one embodiment, there is provided a compound of formula (I).

[0628] It will be appreciated that, for use in medicine, the salts of the compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compounds of formula (I) can be useful in the preparation of pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid addition salts 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 with 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 (for example oxalate or formate salts) can be used, for example, in the isolation of compounds of formula (I), and are included within the scope of the application.

[0629] Certain compounds of formula (I) can form acid or base salts by virtue of the presence of one or more basic or acidic groups. The present application includes within its scope any possible stoichiometric and non-stoichiometric form.

[0630] Compounds of formula (I) can be prepared in crystalline or non-crystalline form, and, if crystalline, can optionally be solvated, e.g. as hydrates. The present application includes within its scope any possible stoichiometric and non-stoichiometric solvates (e.g. hydrates) and compounds containing variable amounts of solvent (e.g. water).

[0631] It will be appreciated that the present application encompasses all stereoisomers of formula (I) and pharmaceutically acceptable derivatives thereof, including all geometric, tautomeric and optical forms, as well as mixtures (e.g. racemic mixtures) thereof. Where additional chiral centres are present in the compounds of formula (I), the present application includes within its scope all possible diastereomers, including mixtures thereof. The different isomeric forms can be separated or resolved one from the other by conventional methods, or any given isomer can be obtained by stereospecific synthesis or by stereospecific resolution.

[0632] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in Form (I) where all atoms of a given atomic number have the mass number (or mixture of mass numbers) that predominates in nature (herein referred to as the "natural isotopic form"), or (ii) where one or more atoms are replaced by an atom having the same atomic number but a mass number that is different from the mass number of the atom that predominates in nature (herein referred to as the "unnatural variant isotopic form"). It will be appreciated that atoms can occur naturally as mixtures of mass numbers. The term "unnatural variant isotopic form" also includes embodiments where the proportion of atoms of a given atomic number having a mass number that is less common in nature (herein referred to as "uncommon isotopes") has been increased relative to the proportion of naturally occurring atoms, for example to levels of >20%, >50%, >75%, >90%, >95% or >99% of the number of atoms of that atomic number (the latter embodiment being referred to as an "isotopically enriched variant form"). The term "unnatural variant isotopic form" also includes embodiments where the proportion of uncommon isotopes has been decreased relative to the proportion of naturally occurring isotopes. Isotopic forms can include radioactive forms (i.e. which incorporate a radioisotope) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0633] Thus, unnatural variant isotopic forms of the compounds can contain one or more artificial or uncommon isotopes, such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( i5 N), oxygen-15 ( i5 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), fluorine-18 ( 18 F), iodine-123 ( 123 I), iodine-125 ( 125 I), in one or more atoms, or can contain an increased proportion of said isotopes compared to the proportion that predominates in nature in one or more atoms.

[0634] For example, unnatural variant isotopic forms comprising a radioisotope can be used in drug and / or substrate tissue distribution studies. The radioisotopes tritium (i.e. H) and carbon-14 (i.e. C) are particularly useful in this regard. 3 For example, unnatural variant isotopic forms comprising a radioisotope can be used in drug and / or substrate tissue distribution studies. The radioisotopes tritium (i.e. H) and carbon-14 (i.e. C) are particularly useful in this regard. 14C) are particularly useful for this purpose due to their ease of incorporation and ready means of detection. Non-natural variant isotopic forms incorporating deuterium (i.e. 2 H or D) can offer certain therapeutic advantages due to greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements, and can therefore be preferred in some circumstances. In addition, non-natural variant isotopic forms incorporating positron emitting isotopes (e.g. 11 C, 18 F, 15 O and 13 N) can be made and can be used in Positron Emission Topography (PET) studies to examine substrate receptor occupancy.

[0635] In one embodiment, the compounds of the application are provided as natural isotopic forms.

[0636] In one embodiment, the compounds of the application are provided as non-natural variant isotopic forms. In a particular embodiment, the non-natural variant isotopic form is a form in which deuterium (i.e. 2 H or D) is incorporated in place of hydrogen as specified in the chemical structure at one or more atoms of the compounds of the application. In one embodiment, the atoms of the compounds of the application are in non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the application are in radioactive isotopic form. Suitably, the radioactive isotope is a stable isotope. Suitably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0637] In one embodiment, there is provided a compound of the application wherein a single atom of the compound is present in non-natural variant isotopic form. In another embodiment, there is provided a compound of the application wherein two or more atoms are present in non-natural variant isotopic form.

[0638] Non-natural isotopic variant forms can generally be prepared by routine techniques known to those skilled in the art or by the processes described herein (e.g. processes analogous to those described in the accompanying Examples for the preparation of natural isotopic forms). Thus, non-natural isotopic variant forms can be prepared by using appropriate isotopic variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of Formula (I) are intended for use in pharmaceutical compositions, it will be readily appreciated that each is preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% is on a weight for weight basis). Impure preparations of the compounds can be used to prepare more pure forms for use in pharmaceutical compositions.

[0639] In general, compounds of Formula (I) can be prepared according to techniques known to those of ordinary skill in the art of organic synthesis, and by the methods of the Representative Procedures, the procedures of the Examples below, and modifications thereof. In the schemes below, reactive groups can be protected and deprotected in accordance with techniques well known to those of ordinary skill in the art.

[0640] General Route

[0641] General routes that can be readily adapted to prepare examples of the compounds of the application are summarized below. In the description that follows, unless otherwise indicated, the groups 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).

[0642] Scheme 1

[0643]

[0644] Compounds of Formula (I) can be prepared by reacting a compound of Formula (II) with a compound of Formula (III) under amide coupling conditions using, for example, EDC.HCl (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride) as the agent in a solvent (e.g., dimethylformamide) at room temperature. Alternative conditions known to those of ordinary skill in the art can be used, for example, HATU (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) or PyBOP (Benzotriazol-1- yloxytris-pyrrolidino-phosphonium hexafluorophosphate) in the presence of a base (e.g., N,N'-diisopropylethylamine) and a solvent (e.g., dimethylformamide); or T3P (1- Propanephosphonic anhydride) in the presence of a base (e.g., triethylamine) and a solvent (e.g., dimethylformamide).

[0645] Compounds of Formula (II) and (III) are commercially available or can be prepared by methods known to those of ordinary skill in the art.

[0646] Scheme 2

[0647]

[0648] Compounds of formula (II) wherein B is (B5) can be prepared by reacting a compound of formula (IV) with a reagent such as CDI (1,1 '-carbonyldiimidazole) in a solvent such as dichloromethane followed by deprotection by ester hydrolysis with 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 a compound of formula (V) with a compound of formula (VI) in the presence of a base such as potassium carbonate and a solvent such as ethanol.

[0649] Compounds of formula (V) and (VI) are commercially available or can be prepared according to methods known to those skilled in the art.

[0650] Scheme 3

[0651]

[0652] Compounds of formula (III) wherein R 2 and R 3 are H can be prepared by reacting a compound of formula (VII) with a reducing agent such as lithium aluminium 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 such as lithium diisopropylamide in a solvent such as THF.

[0653] Compounds of formula (VIII) and (IX) are commercially available or can be prepared by methods known to those skilled in the art.

[0654] Scheme 4

[0655]

[0656] Compounds of formula (III) wherein R 4 and / or R 5 are not H can be prepared by reacting a compound of formula (X) under reducing conditions such as Rainey 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 such as an alkyl halide in the presence of a base such as LiHMDS (lithium bis(trimethylsilyl)amide) in a solvent such as tetrahydrofuran. The mono- or di-addition (i.e. addition of R 4 and / or R 5 ) can be controlled by adjusting the equivalents of the alkylating agent used.

[0657] Compounds of formula (XI) are commercially available or can be prepared by methods known to those skilled in the art.

[0658] Scheme 5

[0659]

[0660] Compounds of formula (III) wherein at least one of R 2 or R 3 is other than H can be prepared by reacting a compound of formula (VII) with a Grignard reagent (e.g. R 2 MgBr wherein R 2 is as defined elsewhere, e.g. C 1-4 alkyl)) followed by reduction, e.g. using sodium borohydride.

[0661] Scheme 6

[0662]

[0663] Alternatively, compounds of formula (III) wherein at least one of R 2 and R 3 is other than H can be prepared by reacting a compound of formula (XII) under reducing conditions (e.g. Pd on carbon) in the presence of H2in a solvent such as methanol. Compounds of formula (XII) can be prepared by reacting a compound of formula (XIII) with hydroxylamine (e.g. NH2OH HCI) in the presence of a base (e.g. triethylamine) in a solvent such as ethanol. Compounds of formula (XIII) can be prepared by reacting a compound of formula (VII) with an organolithium compound in a solvent such as tetrahydrofuran.

[0664] Compounds of formula (VII) are either commercially available or can be prepared by methods known to those skilled in the art.

[0665] Scheme 7

[0666]

[0667] Compounds of formula (III) wherein R 1 is other than H can be prepared by reacting a compound of formula (III) wherein R 1 is H under aminating conditions (e.g. formaldehyde) in the presence of formic acid.

[0668] Scheme 8

[0669]

[0670] Compounds of formula (VII) wherein R 7 is C 1-4The compound of formula (XIV) can be obtained by reacting a compound of formula (IX) with a commercially available aldehyde (e.g. benzaldehyde).

[0671] Scheme 9

[0672]

[0673] The compound of formula (III) (wherein R 2 is C 1-4 haloalkyl) can be prepared by reacting a compound of formula (XV) under deprotection conditions (e.g. 4N HC1 in methanol). The compound of formula (XV) can be obtained by reacting a compound of formula (XVI) with a nucleophile (e.g. Si(Me)3(CF3)) in the presence of a base (e.g. cesium fluoride) in a solvent such as tetrahydrofuran.

[0674] The compound of formula (XVI) is either commercially available or can be made by methods known to those skilled in the art.

[0675] Scheme 10

[0676]

[0677] The compound of formula (VII) (wherein R 4 and R 5 together with the atoms to which they are attached form a C 3-6 cycloalkyl, said cycloalkyl being substituted by one or more halo) can be prepared by reacting a compound of formula (XVII) with an appropriate reagent (e.g. diethylaminosulfur trifluoride) in a solvent such as dichloromethane. The compound of formula (XVII) can be obtained by reacting a compound of formula (XVIII) under oxidation conditions using an oxidizing agent (e.g. sodium periodate) in the presence of a catalyst (e.g. ruthenium trichloride) in a solvent (e.g. 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 diisopropylamide in a solvent such as THF.

[0678] The compound of formula (XIX) is either commercially available or can be made according to methods known to those skilled in the art.

[0679] Those skilled in the art will appreciate that protecting groups can be used throughout the synthetic schemes described herein to arrive at any of the above compounds or protected derivatives of the general formula. Protecting groups and means of their removal are described in "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. 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 p-methoxybenzyl (PMB). Examples of oxygen protecting groups include acetyl (Ac), methoxymethyl (MOM), p-methoxybenzyl (PMB), benzyl, tert-butyl, methyl, ethyl, tetrahydropyranyl (THP) and ethers and esters of silyl groups (e.g. ethers and esters of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM) and triisopropylsilyl (TIPS)). Particular examples of carboxylic acid protecting groups include alkyl esters (e.g. C 1-6 alkyl esters and C 1-6 haloalkyl esters, e.g. C 1-4 alkyl esters and C 1-4 haloalkyl esters), benzyl esters (including substituted benzyl esters, e.g. p-methoxybenzyl esters) and silyl esters.

[0680] Method

[0681] The present application also provides a process for preparing a compound of formula (I), or a salt and / or solvate thereof, which comprises reacting a compound of formula (II),

[0682]

[0683] wherein B is as defined for a compound of formula (I); or a salt thereof,

[0684] with a compound of formula (III),

[0685]

[0686] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6 and A are as defined for a compound of formula (I); or a salt thereof.

[0687] Intermediate

[0688] The present application also provides novel intermediates useful for the preparation of compounds of formula (I). Particular intermediates of interest are those of the general formula wherein the variable groups and the related preferences are as defined previously for compounds of formula (I). Thus, in one embodiment, the present application provides a compound selected from the group consisting of:

[0689] - a compound of formula (II):

[0690]

[0691] wherein B is as defined for compounds of formula (I);

[0692] - a compound of formula (III):

[0693]

[0694] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A are as defined for compounds of formula (I);

[0695] - a compound of formula (IV):

[0696]

[0697] wherein B 1 is as defined for compounds of formula (I);

[0698] - a compound of formula (VII):

[0699]

[0700] wherein R 4 , R 5 , R 6 , R 7 and A are as defined for compounds of formula (I);

[0701] - a compound of formula (XII):

[0702]

[0703] wherein R 2 , R 4 , R 5 , R 6 , R 7 and A are as defined for compounds of formula (I);

[0704] - a compound of formula (XIII):

[0705]

[0706] wherein R 2 , R 4 , R 5 , R 6 , R 7 and A are as defined for a compound of formula (I);

[0707] - a compound of formula (XIV):

[0708]

[0709] wherein R 4 , R 5 and A are as defined for a compound of formula (I);

[0710] - a compound of formula (XV):

[0711]

[0712] wherein R 1 , R 4 , R 5 , R 6 , R 7 and A are as defined for a compound of formula (I);

[0713] - a compound of formula (XVI):

[0714]

[0715] wherein R 4 , R 5 , R 6 , R 7 and A are as defined for a compound of formula (I);

[0716] - a compound of formula (XVII):

[0717]

[0718] wherein R 4 , R 5 , R 6 , R 7 and A are as defined for a compound of formula (I); and

[0719] - a compound of formula (XVIII):

[0720]

[0721] wherein R 4 , R 5 , R6 , R 7 and A are as defined for compounds of formula (I),

[0722] or a salt, e.g. a pharmaceutically acceptable salt, of either thereof.

[0723] Method of treatment

[0724] Compounds of formula (I) of the present application have utility as mPTP inhibitors.

[0725] Reference to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the context of the methods of treatment and prevention described below is understood to exclude the proviso of formula (I), i.e. N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide:

[0726]

[0727] These compounds are commercially available and the utility (e.g. therapeutic utility) of these compounds has not hitherto been described.

[0728] The present application therefore provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, in particular for use in the treatment or prevention of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect (e.g. those diseases and conditions referred to below), wherein the proviso of formula (I) does not apply.

[0729] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, in particular for use in the treatment of a disease or condition in which inhibition of mPTP provides a therapeutic effect (e.g. those diseases and conditions referred to below), wherein the proviso of formula (I) does not apply.

[0730] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament, in particular for use in the prevention of a disease or condition in which inhibition of mPTP provides a prophylactic effect (e.g. those diseases and conditions referred to below), wherein the proviso of formula (I) does not apply.

[0731] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament, in particular for use in the treatment or prevention of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect (e.g. those diseases and conditions referred to below), wherein the proviso of formula (I) does not apply.

[0732] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition in which inhibition of the mPTP provides a therapeutic effect, in particular for the treatment of a disease or condition mentioned below, wherein the proviso of Formula (I) does not apply.

[0733] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of a disease or condition in which inhibition of the mPTP provides a prophylactic effect, in particular for the prevention of a disease or condition mentioned below, wherein the proviso of Formula (I) does not apply.

[0734] The present application also provides a method of preventing or treating a disease or condition in which inhibition of the mPTP provides a therapeutic or prophylactic effect, in particular a disease or condition mentioned below, in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0735] The present application also provides a method of treating a disease or condition in which inhibition of the mPTP provides a therapeutic effect, in particular a disease or condition mentioned below, in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0736] The present application also provides a method of preventing a disease or condition in which inhibition of the mPTP provides a prophylactic effect, in particular a disease or condition mentioned below, in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0737] The term 'treatment' or 'treating' as used herein includes the control, reduction, diminishment, or regulation of a disease state or symptoms thereof.

[0738] The term 'prophylaxis' or 'preventing' is used herein to mean preventing a symptom of a disease or condition in a subject or preventing a recurrence of a symptom of a disease or condition in a subject afflicted with a disease or condition, and is not limited to the complete prevention of distress.

[0739] In one embodiment, the disease or condition is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, an ischemia or reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of aging, and a kidney disease.

[0740] In another embodiment, the disease or condition is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, an ischemic or reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of aging, a kidney disease, a hearing loss, an ocular disease or disorder, Charcot-Marie-Tooth disease (CMT la), and Leigh syndrome disease.

[0741] In a particular embodiment, the disease or condition 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. In a preferred embodiment, the disease or condition is Parkinson's disease. In a preferred embodiment, the disease or condition is Alzheimer's disease. In a preferred embodiment, the disease or condition is amyotrophic lateral sclerosis.

[0742] In another particular embodiment, the disease or condition is a central nervous system disease, such as AIDS dementia complex, depression, schizophrenia, and epilepsy.

[0743] In another embodiment, the disease or condition is an ischemic or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia reperfusion injury, and organ injury during transplantation.

[0744] In another embodiment, the disease or condition is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related disorders, obesity and feeding behavior, and nonalcoholic fatty liver disease.

[0745] In another embodiment, the disease or condition is a complication associated with a metabolic disease (e.g., diabetic neuropathy).

[0746] In another embodiment, the disease or condition is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis.

[0747] In another embodiment, the disease or condition is a disease of aging, such as bone repair, bone weakness in osteoporosis and sarcopenia.

[0748] In another embodiment, the disease or condition is a kidney disease, for example chronic kidney disease and chronic kidney disease associated with APOL1 genetic variants.

[0749] In another embodiment, the disease or condition is a hearing loss, for example hearing loss due to aging, noise, concussions, traumatic brain injury (TBI), drug-induced hearing loss, and / or genetic hearing loss, including spinal muscular atrophy (SMA) syndromes (SMA1, SMA2, SMA3, and SMA4, also known as type I, type II, type III, and type IV).

[0750] In another embodiment, the disease or condition is an ocular disease or condition, for example age-related macular degeneration.

[0751] In another embodiment, the disease or condition is Charcot-Marie-Tooth disease (CMT1a).

[0752] In another embodiment, the disease or condition is Leigh syndrome disease.

[0753] It is contemplated that the compounds of formula (I) are useful in the treatment or prevention of mitochondrial diseases.

[0754] Accordingly, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a mitochondrial disease, for example those diseases and conditions mentioned below, wherein the proviso of formula (I) does not apply.

[0755] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of a mitochondrial disease, for example those diseases and conditions mentioned below, wherein the proviso of formula (I) does not apply.

[0756] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention of a mitochondrial disease, for example those diseases and conditions mentioned below, wherein the proviso of formula (I) does not apply.

[0757] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a mitochondrial disease, for example those diseases and conditions mentioned below, wherein the proviso of formula (I) does not apply.

[0758] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment of a mitochondrial disease, for example those diseases and conditions mentioned below, wherein the proviso of formula (I) does not apply.

[0759] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for preventing a mitochondrial disease (such as those diseases and conditions mentioned below), wherein the proviso of Formula (I) does not apply.

[0760] The present application also provides a method of treating or preventing a mitochondrial disease (such as those diseases and conditions mentioned below) in an individual, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0761] The present application also provides a method of treating a mitochondrial disease (such as those diseases and conditions mentioned below) in an individual, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0762] The present application also provides a method of preventing a mitochondrial disease (such as those diseases and conditions mentioned below) in an individual, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0763] Suitably, the mitochondrial disease is selected from Reye syndrome, Leber’s hereditary optic neuropathy and related conditions and disorders, such as those disclosed in CA2884607A1 (Stealth Peptides International Inc.).

[0764] It is contemplated that the compounds of Formula (I) are useful in the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathy (such as TDP-43 associated neurodegeneration).

[0765] Accordingly, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathy (such as TDP-43 associated neurodegeneration), such as those diseases and conditions mentioned below, wherein the proviso of Formula (I) does not apply.

[0766] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a disease or disorder associated with TDP-43 proteinopathy (such as TDP-43 associated neurodegeneration), such as those diseases and conditions mentioned below, wherein the proviso of Formula (I) does not apply.

[0767] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, wherein the proviso of Formula (I) does not apply.

[0768] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, wherein the proviso of Formula (I) does not apply.

[0769] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, wherein the proviso of Formula (I) does not apply.

[0770] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, wherein the proviso of Formula (I) does not apply.

[0771] The present application also provides a method of treating or preventing a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, the method 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 proviso of Formula (I) does not apply.

[0772] The present application also provides a method of treating a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, the method 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 proviso of Formula (I) does not apply.

[0773] The present application also provides a method of preventing a disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration), such as those diseases and conditions referred to below, the method 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 proviso of Formula (I) does not apply.

[0774] Suitably, the disease or condition associated with TDP-43 proteinopathy (e.g. TDP-43 associated neurodegeneration) is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensory and motor neuronopathy, primary lateral sclerosis, progressive muscular atrophy, inclusion body myopathy associated with early onset Paget disease of the bone and frontotemporal dementia, Perry disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer’s disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and cerebral age-related TDP-43 with sclerosis.

[0775] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0776] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0777] The present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0778] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0779] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0780] The present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of a disease or condition associated with fibrosis, wherein the proviso of Formula (I) does not apply.

[0781] The present application also provides a method of treating or preventing a disease or condition associated with fibrosis, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0782] The present application also provides a method of treating a disease or condition associated with fibrosis, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0783] The present application also provides a method of preventing a disease or condition associated with fibrosis, the method comprising administering to an individual in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein the proviso of Formula (I) does not apply.

[0784] Suitably, the disease or condition associated with fibrosis is selected from chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[0785] Suitably, the individual is a mammal, in particular the individual is a human.

[0786] Pharmaceutical compositions

[0787] For use in therapy, the compounds of the present application are typically administered as pharmaceutical compositions. The present application also provides a pharmaceutical composition 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 proviso of Formula (I) does not apply.

[0788] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g. a salt) for use in the treatment or prevention of a disease or condition as described herein, wherein the proviso of Formula (I) does not apply. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g. a salt) for use in the treatment of a disease or condition as described herein, wherein the proviso of Formula (I) does not apply. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g. a salt) for use in the prevention of a disease or condition as described herein, wherein the proviso of Formula (I) does not apply.

[0789] In yet another embodiment, there is provided a method for treating or preventing a disease or disorder as described herein, comprising administering to an individual 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., salt) thereof, wherein the proviso of Formula (I) does not apply. In yet another embodiment, there is provided a method for treating a disease or disorder as described herein, comprising administering to an individual 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., salt) thereof, wherein the proviso of Formula (I) does not apply. In yet another embodiment, there is provided a method for preventing a disease or disorder as described herein, comprising administering to an individual 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., salt) thereof, wherein the proviso of Formula (I) does not apply. The pharmaceutical compositions of the present application can take the form of a pharmaceutical formulation as described hereinafter.

[0790] The present application 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 treating or preventing a disease or disorder as described herein, wherein the proviso of Formula (I) does not apply. The present application 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 treating a disease or disorder as described herein, wherein the proviso of Formula (I) does not apply. The present application 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 preventing a disease or disorder as described herein, wherein the proviso of Formula (I) does not apply.

[0791] The amount of active ingredient required to achieve a therapeutic effect will of course vary with the particular compound, the route of administration, the individual or individuals to be treated or prevented (including the type, species, age, body weight, sex and medical condition of the individual or individuals, and the renal and hepatic function of the individual or individuals), and the particular disease or disorder to be 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 disorder.

[0792] When used for the indicated effects, oral dosages of the compounds of the application for adult humans will be in the range of from about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day, suitably 0.01 mg / kg body weight / day (mg / kg / day) to 10 mg / kg / day, and most suitably 0.1 mg / kg / day to 5.0 mg / kg / day. For oral administration, the compositions are conveniently provided in tablet form or in other presentation forms 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 the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament usually contains from about 0.01 mg to about 500 mg and suitably from about 1 mg to about 100 mg of the active ingredient. Intravenous dosages during a constant rate infusion will most suitably be in the range of from about 0.1 to about 10 mg / kg / minute. Advantageously, the compounds of the application 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, suitably the compounds of the application can be administered in an intranasal form via topical use of suitable intranasal vehicles or via transdermal routes, using those transdermal skin patches well known to those of ordinary skill in that art. To be administered in a transdermal delivery system, it is understood that the dosages would be continuous rather than intermittent as with oral dosages.

[0793] Pharmaceutical formulations in accordance with this application include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), intranasal (also referred to as nasal administration), inhalation (including fine particle dusts or mists adapted for delivery via various types of metered dose pressurized aerosol devices, nebulizers, or atomizers), rectal, intraperitoneal, topical (including dermal, buccal, sublingual, and intraocular) and intrathecal administration, although the most suitable route can depend upon, for example, the condition and disorder of the recipient.

[0794] Suitable pharmaceutical formulations in accordance with this application are those suitable for oral, intrathecal, and parenteral administration; and more suitably those suitable for oral or intrathecal administration.

[0795] In one suitable embodiment, the compound according to Formula (I) is administered by intrathecal administration. Such a method of administration involves injection of the compound of the application into the spinal canal, or into the subarachnoid space, such that it reaches the cerebrospinal fluid. This is advantageous for administration of compounds that can not be able to cross the blood-brain barrier via other routes of administration, such as oral administration.

[0796] Suitable pharmaceutical formulations can be administered intrathecally by continuous infusion (e.g. with a catheter or pump), or by single bolus or by intermittent boluses. For intrathecal administration, the pharmaceutical composition can be administered continuously or intermittently. Intermittent administration can be, for example, every thirty minutes, every hour, every few hours, every 24 hours, every few days (e.g. every 48 or 72 hours) or any combination thereof.

[0797] When the pharmaceutical formulations of the application are to be administered continuously, an implantable delivery device, such as an implantable pump, can be employed. Examples of such delivery devices include devices that can be implanted subcutaneously in the body or in the skull and that provide an access port via which the pharmaceutical formulation can be delivered to the nerve or brain.

[0798] The intrathecal dose of the application will typically be less than 1 mg, for example less than 500 μg, for example less than 250 μg / kg body weight when administered as a single dose or intermittently when for an adult human, when used for the indicated effects. When administered continuously, the intrathecal dose of the application will typically be less than 250 μg / kg body weight / hour, for example less than 125 μg / kg body weight / hour for an adult human.

[0799] In another suitable embodiment, the compound according to Formula (I) is administered by intranasal, inhalation (including fine dusts or mists that can be generated by means of various types of metered-dose pressurized aerosol, spray, or insufflator) or insufflation. Such methods of administration allow for the administration of low doses of the compounds of the application, which can result in reduced side effects. For example, daily doses of the compounds of the application in the range of 10 to 0.01 μg, suitably 1 to 0.01 μg, and more suitably as low as 0.1 μg (100 ng) can be used.

[0800] The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0801] Formulations of the application suitable for oral administration can be presented as discrete units, such as capsules, cachets, pills or tablets; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste.

[0802] Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface-active, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or scored and can be formulated to provide a sustained or controlled release of the active ingredient therein. The compounds of Formula (I) can be administered, for example, in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the compounds of the present application, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The compounds of the present application can also be administered via liposomes.

[0803] Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose, and / or carboxymethylcellulose as viscosity enhancers, and sweeteners or flavorants such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitan, glucose, and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants, such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweetener, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of Formula (I) can also be delivered via the oral cavity via sublingual and / or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those formulating the compounds of the present application with fast dissolving diluents such as mannitol, lactose, sucrose and / or a cyclodextrin. High molecular weight excipients such as avicel or polyethylene glycols (PEG) can also be included in such formulations. Such formulations can also include excipients that aid in mucoadhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez) and release controlling agents such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavoring agents, coloring agents and stabilizers can also be added to facilitate manufacturing and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. 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 and the like.

[0804] 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 a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine (cephalin), or phosphatidyl choline (lecithin).

[0805] Formulations for parenteral administration include aqueous and nonaqueous sterile injection solutions which can contain anti-oxidants, buffers, bactericides, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. An exemplary composition for parenteral administration includes an injectable solution or suspension which can contain, for example, a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents, including synthetic glycerides, and fatty acids, including oleic acid or Cremaphor.

[0806] Exemplary compositions for intranasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0807] Formulations for rectal administration can be presented as a suppository, with a wax- coating, to give a depot effect for a longer period of time. Compositions formulated for rectal administration can be prepared in unit dosage forms for group or individual application.

[0808] Formulations for oral administration include tablets containing the active ingredient in a mixture with inert, non-toxic excipients or an appropriate carrier such as e.g. sweeteners, flavoring agents, coloring agents and / or binders, and tablets treated with suitable enteric coating.

[0809] Suitable unit dosage formulations are those containing a daily dose or a proper fraction thereof, as herein above described.

[0810] It will be appreciated that, in addition to the ingredients particularly mentioned above, the formulations according to the application can also include other agents conventional in the art, for example those suitable for oral administration which can include flavouring agents.

[0811] It is expected that the compounds of formula (I) exhibit the advantageous properties of mPTP inhibitory activity as demonstrated in the assays of Biological Examples 1 and 2 (preferably a pIC 50 values of 6.0 and above and / or a pIC 50 values of 7.0 and above in the rat brain assay).

[0812] Clause

[0813] The present application is further defined by the following clauses:

[0814] Clause 1. A compound according to formula (I):

[0815]

[0816] wherein:

[0817] R 1 is H or C 1-4 alkyl;

[0818] R 2 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 0-4 alkylene(OH);

[0819] R 3 is H, halo, or C 1-4 alkyl;

[0820] R 4 is H, halo, or C 1-4 alkyl;

[0821] R 5 is 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 form a C 5-11 spiro carbocyclyl, 4- to 7-membered heterocycle, or C3-6 cycloalkyl, wherein the spiro carbocyclyl, heterocyclyl or cycloalkyl group can optionally be substituted by one or more substituents selected from the group consisting of C 1-3 alkyl, C 1-3 haloalkyl and halogen;

[0822] R 6 is H or C 1-4 alkyl;

[0823] R 7 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0824] A is a monocyclic or bicyclic aryl, or a monocyclic or bicyclic heteroaryl, wherein the aryl or heteroaryl group can optionally be substituted by one or more A 1 substituents;

[0825] A 1 is independently selected from the group consisting of 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 ;

[0826] R g is H or C 1-4 alkyl;

[0827] R h is H or C 1-4 alkyl;

[0828] R j is C 1-4 alkyl;

[0829] or when A represents phenyl which is substituted by one or more A 1 substituents, R 5 is joined with the ortho substituent A 1 and together represent (CH2) v wherein v represents 1, 2 or 3 and wherein one of the CH2groups can optionally be replaced by O;

[0830] B is a monocyclic or bicyclic heterocyclyl, or a monocyclic or bicyclic heteroaryl, wherein the heterocyclyl or heteroaryl group can optionally be substituted by one or more B 1 substituents;

[0831] B 1 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo (=0), thioxo (=S) or C 0-6 alkylene(OH);

[0832] or salts and / or solvates thereof,

[0833] and with the proviso that formula (I) is not N-((1-benzylcyclobutyl)methyl)-6- hydroxypyrazine-2-carboxamide:

[0834]

[0835] Clause 2. The compound of formula (IA) according to clause 1 :

[0836]

[0837] wherein:

[0838] R 1 is H or C 1-4 alkyl;

[0839] R 2 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 0-4 alkylene(OH);

[0840] R 3 is H, halo or C 1-4 alkyl;

[0841] R 4 is H or C 1-4 alkyl;

[0842] R 5 is 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 form C 3-6Cycloalkyl, wherein the cycloalkyl may be optionally substituted by one or more selected from C 1-3 Alkyl, C 1-3 Haloalkyl and halogenated group substitution;

[0843] R 6 H or C 1-4 alkyl;

[0844] R 7 H, halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0845] A is a monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group, wherein the aryl group or heteroaryl group is optionally replaced by one or more A 1 replace;

[0846] A 1 For halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, CN, OH, NR g R h or NHSO2R j ;

[0847] R g H or C 1-4 alkyl;

[0848] R h H or C 1-4 alkyl;

[0849] R j C 1-4 alkyl;

[0850] Or when A represents one or more A 1 When the phenyl group is substituted, R 5 With the substituent A at the adjacent position 1 Join together and express together (CH2) v , wherein v represents 1, 2 or 3 and wherein one of the CH2 groups may optionally be replaced by O;

[0851] B is a monocyclic or bicyclic heterocyclic ring, or a monocyclic or bicyclic heteroaryl ring, which may be optionally replaced by one or more B 1 replace;

[0852] B 1 For halogenated, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 0-6 Alkylene (OH);

[0853] or a salt and / or solvate thereof,

[0854] and with the proviso that formula (IA) is not N-((1-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide:

[0855]

[0856] Item 3. The compound, salt and / or solvate according to Item 1 or Item 2, which is the compound, or a pharmaceutically acceptable salt and / or solvate thereof.

[0857] Clause 4. Pharmaceutically acceptable salts and solvates according to Clause 1 or Clause 2.

[0858] Clause 5. The pharmaceutically acceptable salt according to Clause 1 or Clause 2.

[0859] Clause 6. A pharmaceutically acceptable solvate according to Clause 1 or Clause 2.

[0860] Item 7. The compound according to Item 1 or Item 2.

[0861] 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):

[0862]

[0863] or a salt and / or solvate thereof.

[0864] Item 9. A compound according to any one of Items 1, 2 or 8, or a salt and / or solvate thereof, wherein R 1 For H.

[0865] Clause 10. A compound according to any one of clauses 1, 2 or 8, or a salt and / or solvate thereof, wherein R 1 C 1-4 Alkyl groups, such as methyl.

[0866] Clause 11. A compound according to any one of clauses 1, 2 or 8 to 10, or a salt and / or solvate thereof, wherein R 2 For H.

[0867] Clause 12. A compound according to any one of clauses 1, 2 or 8 to 10, or a salt and / or solvate thereof, wherein R 2 It is halogenated.

[0868] Clause 13. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 is C 1-4 alkyl, for example methyl or ethyl.

[0869] Clause 14. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 is C 1-4 haloalkyl, for example CF3.

[0870] Clause 15. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 is C 1-4 alkoxy.

[0871] Clause 16. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 is C 1-4 haloalkoxy.

[0872] Clause 17. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 is C 0-4 alkylene(OH), for example CH2CH2OH.

[0873] Clause 18. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-15, wherein R 3 is H.

[0874] Clause 19. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-17, wherein R 3 is halo.

[0875] Clause 20. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-17, wherein R 3 is C 1-4 alkyl.

[0876] Clause 21. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 and R 3 are each H.

[0877] Clause 22. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8-10, wherein R 2 is H and R 3 is methyl.

[0878] Clause 23. The compound of any one of clauses 1, 2, or 8 to 10, or a salt and / or solvate thereof, wherein R 2 is H and R 3 is ethyl.

[0879] Clause 24. The compound of any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, wherein R 4 is H.

[0880] Clause 25. The compound of any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, wherein R 4 is C 1-4 alkyl, for example methyl.

[0881] Clause 26. The compound of any one of clauses 1, 2, or 8 to 23, or a salt and / or solvate thereof, wherein R 4 is halo.

[0882] Clause 27. The compound of any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein R 5 is halo.

[0883] Clause 28. The compound of any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein R 5 is C 1-6 alkyl, for example methyl, ethyl, n-propyl, or i-propyl, especially ethyl.

[0884] Clause 29. The compound of any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein R 5 is C 1-6 haloalkyl.

[0885] Clause 30. The compound of any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein R 5 is C 1-6 alkoxy, for example OMe.

[0886] Clause 31. The compound of any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein R 5 is C 1-6 haloalkoxy.

[0887] Clause 32. The compound of any one of clauses 1, 2, or 8 to 26, or a salt and / or solvate thereof, wherein R 5 is C 2-6 alkenyl.

[0888] Clause 33. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 26, wherein R 5 is C 2-6 haloalkenyl.

[0889] Clause 34. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 26, wherein R 5 is C 0-6 alkylene(C 3-6 cycloalkyl), for example C 3-6 cycloalkyl, for example cyclopropyl or cyclobutyl, especially cyclopropyl.

[0890] Clause 35. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 26, wherein R 5 is C 3-6 cycloalkyl.

[0891] Clause 36. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 26, wherein R 5 is cyclobutyl.

[0892] Clause 37. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 26, wherein R 5 is cyclopropyl.

[0893] Clause 38. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 26, wherein R 5 is C 0-6 alkylene(OH).

[0894] Clause 39. The compound or salt and / or solvate thereof of clause 38, wherein R 5 is CH2OH or CH(Me)(OH).

[0895] Clause 40. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 are each methyl.

[0896] Clause 41. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 is H and R 5 is ethyl.

[0897] Clause 42. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 21, wherein R 4 is H and R 5isopropyl.

[0898] Clause 43. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 together with the carbon atom to which they are attached form a C 5-11 spiro carbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl, wherein the spiro carbocyclyl, heterocycle, or cycloalkyl is optionally substituted with one or more groups selected from C 1-3 alkyl, C 1-3 haloalkyl, and halo.

[0899] Clause 44. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 together with the carbon atom to which they are attached form an unsubstituted C 5-11 spiro carbocyclyl, 4- to 7-membered heterocycle, or C 3-6 cycloalkyl.

[0900] Clause 45. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 together with the atoms to which they are attached form a C 3-6 cycloalkyl.

[0901] Clause 46. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 together with the atoms to which they are attached form a 4-7 membered heterocycle.

[0902] Clause 47. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 together with the atoms to which they are attached form a C 5-11 spiro carbocyclyl.

[0903] Clause 48. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 23, wherein R 4 and R 5 together with the atoms to which they are attached form a spiro pentane.

[0904] Clause 49. The compound or salt and / or solvate thereof of clause 45, wherein R 4 and R 5 together with the atoms to which they are attached form a cyclopropyl ring, cyclobutyl ring, or cyclopentyl ring, in particular a cyclobutyl ring.

[0905] Clause 50. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 49, wherein R 6 is H.

[0906] Clause 51. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 49, wherein R 6 is C 1-4 alkyl, for example methyl.

[0907] Clause 52. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 51, wherein R 7 is H.

[0908] Clause 53. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 51, wherein R 7 is halo.

[0909] Clause 54. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 51, wherein R 7 is C 1-4 alkyl, for example methyl.

[0910] Clause 55. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 51, wherein R 7 is C 1-4 haloalkyl.

[0911] Clause 56. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 51, wherein R 7 is C 1-4 alkoxy, for example OMe.

[0912] Clause 57. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 51, wherein R 7 is C 1-4 haloalkoxy.

[0913] Clause 58. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 49, wherein R 6 is H and R 7 is H.

[0914] Clause 59. The compound or salt and / or solvate thereof of any one of clauses 1, 2, or 8 to 49, wherein R 6 is H and R 7 is methyl.

[0915] Clause 60. A compound according to any one of clauses 1, 2, or 8 to 59, or a salt and / or solvate thereof, wherein R 2 、R 3 、R 4 、R 6 or R 7 At least one of them is not H.

[0916] Clause 61. The compound according to any one of clauses 1, 2, or 8 to 60, or a salt and / or solvate thereof, wherein A is a monocyclic aryl group.

[0917] Clause 62. The compound according to clause 61, or a salt and / or solvate thereof, wherein A is phenyl.

[0918] Clause 63. The compound according to any one of clauses 1, 2, or 8 to 60, or a salt and / or solvate thereof, wherein A is a bicyclic aryl.

[0919] Clause 64. The compound according to any one of clauses 1, 2, or 8 to 60, or a salt and / or solvate thereof, wherein A is a monocyclic heteroaryl.

[0920] Clause 65. The compound according to any one of clauses 1, 2, or 8 to 60, or a salt and / or solvate thereof, wherein A is a bicyclic heteroaryl.

[0921] Item 66. A compound according to any one of items 61 to 65, or a salt and / or solvate thereof, wherein A is replaced by one or more (eg, one, two or three, such as one or two, especially one) A 1 replace.

[0922] Clause 67. A compound according to any one of clauses 61 to 65, or a salt and / or solvate thereof, wherein A is replaced by two A 1 replace.

[0923] Clause 68. A compound according to any one of clauses 61 to 65, or a salt and / or solvate thereof, wherein A is replaced by one A 1 replace.

[0924] Item 69. The compound according to Item 66, or a salt and / or solvate thereof, wherein at least one A 1 is halo, such as F, Br or Cl, especially F.

[0925] Item 70. The compound according to Item 66, or a salt and / or solvate thereof, wherein at least one A 1 is F, Br or Cl.

[0926] Item 71. The compound according to Item 66, or a salt and / or solvate thereof, wherein at least one A1 F.

[0927] Clause 72. The compound of any one of clauses 66-71, or salt and / or solvate thereof, wherein at least one A 1 F. 1-6 alkyl, for example methyl.

[0928] Clause 73. The compound of any one of clauses 66-72, or salt and / or solvate thereof, wherein at least one A 1 F. 1-6 haloalkyl.

[0929] Clause 74. The compound of any one of clauses 66-73, or salt and / or solvate thereof, wherein at least one A 1 F. 1-6 alkoxy, for example OMe.

[0930] Clause 75. The compound of any one of clauses 66-74, or salt and / or solvate thereof, wherein at least one A 1 F. 1-6 haloalkoxy.

[0931] Clause 76. The compound of any one of clauses 66-75, or salt and / or solvate thereof, wherein at least one A 1 F. 3-6 cycloalkyl.

[0932] Clause 77. The compound of any one of clauses 66-76, or salt and / or solvate thereof, wherein at least one A 1 F.

[0933] Clause 78. The compound of any one of clauses 66-77, or salt and / or solvate thereof, wherein at least one A 1 F.

[0934] Clause 79. The compound of any one of clauses 66-78, or salt and / or solvate thereof, wherein at least one A 1 F. g R h .

[0935] Clause 80. The compound of clause 79, or salt and / or solvate thereof, wherein R g F.

[0936] Clause 81. The compound of clause 79, or salt and / or solvate thereof, wherein R g F. 1-4 alkyl.

[0937] Clause 82. The compound or salt and / or solvate thereof of any one of clauses 79 to 81, wherein R h is H.

[0938] Clause 83. The compound or salt and / or solvate thereof of any one of clauses 79 to 81, wherein R h is C 1-4 alkyl.

[0939] Clause 84. The compound or salt and / or solvate thereof of any one of clauses 66 to 83, wherein at least one A 1 is NHSO2R j .

[0940] Clause 85. The compound or salt and / or solvate thereof of any one of clauses 66 to 84, wherein at least one A 1 is C 1-3 alkylthio.

[0941] Clause 86. The compound or salt and / or solvate thereof of any one of clauses 61 to 55, wherein A is unsubstituted.

[0942] Clause 87. The compound or salt and / or solvate thereof of clause 61 or 62, wherein A is selected from the group consisting of:

[0943]

[0944] wherein:

[0945] A 1A is halo, for example F, Br or CI; C 1-6 alkyl, for example methyl; or C 1-6 alkoxy, for example OMe; and

[0946] A 1B is H or halo, for example F, Br or CI, especially F.

[0947] Clause 88. The compound or salt and / or solvate thereof of clause 61 or 62, wherein A is phenyl substituted with one or more A 1 and wherein R 5 together with the ortho substituent A 1 together represent (CH2) v wherein v represents 1, 2 or 3 and wherein one of the CH2groups can optionally be replaced by O.

[0948] Clause 89. The compound or salt and / or solvate thereof of clause 61 or 62, wherein A is phenyl substituted with one or more A 1 and wherein R5 with the vicinal substituent A 1 together and together represent (CH2) v wherein v represents 1, 2 or 3.

[0949] Clause 90. The compound or salt and / or solvate thereof of clause 88 or 89, wherein v is 1.

[0950] Clause 91. The compound or salt and / or solvate thereof of clause 88 or 89, wherein v is 2.

[0951] Clause 92. The compound or salt and / or solvate thereof of clause 88 or 89, wherein v is 3.

[0952] Clause 93. The compound of any one of clauses 1, 2, or 8 to 92, or a salt and / or solvate thereof, wherein B is a monocyclic heterocycle.

[0953] Clause 94. The compound of clause 93, or a salt and / or solvate thereof, wherein B is a 5-membered monocyclic heterocycle.

[0954] Clause 95. The compound of clause 93, or a salt and / or solvate thereof, wherein B is a 6-membered monocyclic heterocycle.

[0955] Clause 96. The compound of any one of clauses 1, 2, or 8 to 92, or a salt and / or solvate thereof, wherein B is a monocyclic heteroaryl.

[0956] Clause 97. The compound of clause 96, or a salt and / or solvate thereof, wherein B is a 5-membered monocyclic heteroaryl.

[0957] Clause 98. The compound of clause 96, or a salt and / or solvate thereof, wherein B is a 6-membered monocyclic heteroaryl.

[0958] Clause 99. The compound of any one of clauses 1, 2, or 8 to 92, or a salt and / or solvate thereof, wherein B is a bicyclic heteroaryl.

[0959] Clause 100. The compound of clause 99, or a salt and / or solvate thereof, wherein B is a benzoxazolinone.

[0960] Clause 101. The compound of any one of clauses 93 to 100, or a salt and / or solvate thereof, wherein B is substituted with one or more (e.g. one or two, in particular one) B 1 substituents.

[0961] Clause 102. The compound of any one of clauses 93 to 100, or a salt and / or solvate thereof, wherein B is substituted with one or two B 1 substituents.

[0962] Clause 103. A compound according to any one of clauses 93 to 100, or a salt and / or solvate thereof, wherein B is replaced by one B 1 replace.

[0963] Item 104. A compound according to any one of Items 101 to 103, or a salt and / or solvate thereof, wherein at least one B 1 It is halogenated.

[0964] Clause 105. A compound according to any one of clauses 101 to 104, or a salt and / or solvate thereof, wherein at least one B 1 C 1-6 Alkyl groups, such as methyl.

[0965] Clause 106. A compound according to any one of clauses 101 to 105, or a salt and / or solvate thereof, wherein at least one B 1 C 1-6 Halogenated alkyl.

[0966] Clause 107. A compound according to any one of clauses 101 to 106, or a salt and / or solvate thereof, wherein at least one B 1 C 1-6 Alkoxy.

[0967] Clause 108. A compound according to any one of clauses 101 to 90, or a salt and / or solvate thereof, wherein at least one B 1 C 1-6 Halogenated alkoxy.

[0968] Item 109. A compound according to any one of Items 101 to 107, or a salt and / or solvate thereof, wherein at least one B 1 C 0-6 Alkylene (OH), such as OH.

[0969] Clause 110. A compound according to any one of clauses 101 to 108, or a salt and / or solvate thereof, wherein at least one B 1 It is an oxo group (=O).

[0970] Clause 111. A compound according to any one of clauses 101 to 109, or a salt and / or solvate thereof, wherein at least one B 1 It is a thio group (=S).

[0971] Clause 112. The compound or salt and / or solvate thereof according to any one of clauses 92 to 100, wherein B is unsubstituted.

[0972] Clause 113. The compound according to any one of clauses 93 to 111, or a salt and / or solvate thereof, wherein B is selected from the group consisting of:

[0973]

[0974]

[0975] For example

[0976] in:

[0977] B 1A H or C 1-6 an alkyl group, such as a methyl group; and

[0978] B 2A H or C 1-6 Alkyl groups, such as methyl.

[0979] Clause 114. The compound according to any one of clauses 93 to 111, or a salt and / or solvate thereof, wherein B is selected from the group consisting of:

[0980]

[0981] in:

[0982] Each B 3A Independently selected from C 1-6 Alkyl groups, such as methyl; and C 0-6 an alkylene group (OH), such as OH; and

[0983] y is 1 or 2.

[0984] Clause 115. A compound according to any one of clauses 93 to 111, or a salt and / or solvate thereof, wherein B is

[0985]

[0986] Clause 116. The compound according to Clause 1 or Clause 2, or a salt and / or solvate thereof, which is a compound of formula (IA′):

[0987]

[0988] in:

[0989] R 1′ is H;

[0990] R 2′ is H;

[0991] R 3′ H or C 1-4 alkyl;

[0992] R 4′ is H or C 1-4 alkyl;

[0993] R 5′ is H, C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5′ together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0994] R 6′ is H;

[0995] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[0996] n' is 0, 1 or 2; and

[0997] A 1′ is halo or C 1-6 alkyl,

[0998] or salts and / or solvates thereof.

[0999] Clause 117. The compound according to Clause 1 or Clause 2, or a salt and / or solvate thereof, which is a compound of Formula (IA’):

[1000]

[1001] wherein:

[1002] R 1′ is H;

[1003] R 2′ is H;

[1004] R 3′ is H or C 1-4 alkyl;

[1005] R 4′ is H or C 1-4 alkyl;

[1006] R 5′ is C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5′ together with the atom to which they are attached form a C 3-6 cycloalkyl;

[1007] R 6′ is H;

[1008] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[1009] n' is 0, 1 or 2; and

[1010] A 1′ is halo or C 1-6 alkyl,

[1011] or a salt and / or solvate thereof.

[1012] Clause 118. The compound according to Clause 1 or Clause 2, or a salt and / or solvate thereof, is a compound of Formula (IA"):

[1013]

[1014] wherein:

[1015] R 1′ is H;

[1016] R 2′ is H;

[1017] R 3′ is H or C 1-4 alkyl;

[1018] R 4′ is H or C 1-4 alkyl;

[1019] R 5′ is H, C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5′ together with the atom to which they are attached form C 3-6 cycloalkyl;

[1020] R 6′ is H;

[1021] R 7′ is H, C 1-6 alkyl or C 1-6 alkoxy;

[1022] B A1 is H or C 1-6 alkyl, for example methyl;

[1023] n' is 0, 1 or 2; and

[1024] A 1′ is halo or C 1-6 alkyl,

[1025] or a salt and / or solvate thereof.

[1026] Clause 119. The compound according to clause 1 or clause 2, or a salt and / or solvate thereof, which is a compound of formula (IA″):

[1027]

[1028] in:

[1029] R 1′ is H;

[1030] R 2′ is H;

[1031] R 3′ H or C 1-4 alkyl;

[1032] R 4′ H or C 1-4 alkyl;

[1033] R 5′ C 1-4 Alkyl or C 3-6 Cycloalkyl; or R 4′ and R 5′ Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl;

[1034] R 6′ is H;

[1035] R 7′ H, C 1-6 Alkyl or C 1-6 alkoxy;

[1036] B 1A H or C 1-6 Alkyl groups, such as methyl;

[1037] n′ is 0, 1 or 2; and

[1038] A 1′ is halogenated or C 1-6 alkyl,

[1039] or a salt and / or solvate thereof.

[1040] Clause 120. The compound according to Clause 1 or Clause 2, or a salt and / or solvate thereof, which is a compound of formula (IA'):

[1041]

[1042] in:

[1043] R 1′ is H;

[1044] R2′ H;

[1045] R 3′ H or C 1-4 alkyl;

[1046] R 4′ H or C 1-4 alkyl;

[1047] R 5′ H, C 1-4 alkyl or C 3-6 cycloalkyl; or R 4′ and R 5 ', together with the atom to which they are attached, form a C 3-6 cycloalkyl;

[1048] R 6′ H;

[1049] R 7′ H, C 1-6 alkyl or C 1-6 alkoxy;

[1050] B 1A H or C 1-6 alkyl, for example methyl;

[1051] n' is 0, 1 or 2; and

[1052] A 1′ halo or C 1-6 alkyl,

[1053] or salts and / or solvates thereof.

[1054] Clause 121. A compound according to Clause 1 or Clause 2, or a salt and / or solvate thereof, which is a compound of formula (IA'"):

[1055]

[1056] wherein:

[1057] R 1′ H;

[1058] R 2′ H;

[1059] R 3′ H or C 1-4 alkyl;

[1060] R 4′ H or C 1-4 alkyl;

[1061] R 5′ C 1-4 alkyl or C3-6 Cycloalkyl; or R 4′ and R 5′ Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl;

[1062] R 6′ is H;

[1063] R 7′ H, C 1-6 Alkyl or C 1-6 alkoxy;

[1064] B 1A H or C 1-6 Alkyl groups, such as methyl;

[1065] n′ is 0, 1 or 2; and

[1066] A 1′ is halogenated or C 1-6 alkyl,

[1067] or a salt and / or solvate thereof.

[1068] Clause 122. A compound according to any one of clauses 116 to 121, or a salt and / or solvate thereof, wherein R 3′ For H.

[1069] Clause 123. A compound according to any one of clauses 116 to 122, or a salt and / or solvate thereof, wherein R 4′ For H.

[1070] Clause 124. A compound according to any one of clauses 116 to 123, or a salt and / or solvate thereof, wherein R 5′ C 1-4 Alkyl groups such as methyl, ethyl or isopropyl.

[1071] Item 125 A compound according to any one of items 116 to 124, or a salt and / or solvate thereof, wherein R 5′ C 3-6 Cycloalkyl, for example cyclopropyl.

[1072] Clause 126. A compound according to any one of clauses 116 to 121, or a salt and / or solvate thereof, wherein R 4′ and R 5′ Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl, for example cyclobutyl.

[1073] Clause 127. A compound according to any one of clauses 116 to 126, or a salt and / or solvate thereof, wherein R 7′ For H.

[1074] Clause 128. The compound or salt and / or solvate thereof of any one of clauses 116-126, wherein R 7′ is C 1-6 alkyl, for example methyl.

[1075] Clause 129. The compound or salt and / or solvate thereof of any one of clauses 116-126, wherein R 7′ is C 1-6 alkoxy, for example OMe.

[1076] Clause 130. The compound or salt and / or solvate thereof of any one of clauses 116-129, wherein B 1A is H.

[1077] Clause 131. The compound or salt and / or solvate thereof of any one of clauses 116-129, wherein B 1A is C 1-6 alkyl, for example methyl.

[1078] Clause 132. The compound or salt and / or solvate thereof of any one of clauses 116-131, wherein n' is 2.

[1079] Clause 133. The compound or salt and / or solvate thereof of any one of clauses 116-132, wherein at least one A 1′ is halo, for example F, Br, or CI.

[1080] Clause 134. The compound or salt and / or solvate thereof of any one of clauses 116-133, wherein n' is 0.

[1081] Clause 135. The compound or salt and / or solvate thereof of clause 1, 2, or any one of clauses 8-134, wherein R 4 and R 5 have the following stereochemical configuration:

[1082]

[1083] Clause 136. The compound or salt and / or solvate thereof of clause 1 or clause 2, selected from the group consisting of:

[1084] N-((l-benzylcyclobutyl)methyl)-5-hydroxynicotinamide;

[1085] N-((l-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide;

[1086] N-((l-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide;

[1087] N-((1-benzylcyclobutyl)methyl)-1 H-1,2,3-triazole-5-carboxamide;

[1088] N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide;

[1089] N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1090] N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1091] N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1092] N-((1-benzylcyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole- 3-carboxamide;

[1093] N-((1-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide;

[1094] N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide;

[1095] N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide;

[1096] N-((1-benzylcyclobutyl)methyl)-1 -ethyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1097] N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2- carboxamide;

[1098] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2- carboxamide;

[1099] N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2- carboxamide;

[1100] N-((1-benzylcyclopentyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[1101] N-((1-(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2- carboxamide;

[1102] N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1103] N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1104] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1105] N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1106] (S)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1107] (R)-N-(1-(1-benzylcyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1108] 1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1109] 1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1110] (S)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1111] (R)-1-methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1112] N-((1-(methoxy(phenyl)methyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3- carboxamide;

[1113] 1 -Methyl- N- (( 1 -(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1114] N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1115] N-(2,2-dimethyl-3-phenylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide;

[1116] 1 -Methyl- N- (( 1 -(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1117] N-((1-(2-chlorobenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1118] N-(2,2-dimethyl-1 -phenylpentan-3-yl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole- 3-carboxamide;

[1119] 1 -Methyl-5-oxo- N- (( 1, 1, 1 -trifluoro-3, 3 -dimethyl-4-phenylbutan-2-yl)-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[1120] N-(3-(2-bromophenyl)-2,2-dimethylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1121] N-((1-(2-bromobenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1122] N-(3,3-dimethyl-4-phenylbutan-2-yl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole- 3-carboxamide;

[1123] (S)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1124] (R)-N-(3,3-dimethyl-4-phenylbutan-2-yl)-1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1125] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1126] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1127] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1128] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1129] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1130] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1131] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1132] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1133] N-((1 -benzylcyclohexyl)methyl)-6-oxo-1,6-dihydro-1,3-benzodiazepine-2- carboxamide;

[1134] N-((1 -benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-1,6-dihydro-1,3- benzodiazepine-2-carboxamide;

[1135] N-((1 -(3-fluorobenzyl)cyclobutyl)methyl)-6-hydroxy-1,3-benzodiazepine-2- carboxamide;

[1136] N-((1 -(4-fluorobenzyl)cyclobutyl)methyl)-6-hydroxy-1,3-benzodiazepine-2- carboxamide;

[1137] N-(2-benzyl-3-hydroxy-2-methylpropyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1138] N-(( 1 -( 1 -(2,4-difluorophenyl)ethyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[1139] N-(2-cyclopropyl-3-phenylpropyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide;

[1140] (R)-N-(2-benzylbutyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[1141] (S)-N-(2-benzylbutyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[1142] N-(2-benzylpentyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[1143] N-(2,2-dimethyl-3-phenylpropyl)-6-oxo- 1,6-dihydropyridazine-3-carboxamide;

[1144] N-(2,2-dimethyl-3-phenylpropyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide;

[1145] 1 -methyl-N-((2-methyl-2,3-dihydro- 1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1146] 1 -methyl-N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide;

[1147] 1 -methyl-5-oxo-N-(( 1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide;

[1148] N-(( 1 -(2-methoxybenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole- 3-carboxamide;

[1149] 6-oxo-N-(( 1 -(pyridin-2-ylmethyl)cyclobutyl)methyl)- 1,6-dihydropyridazine-2-carboxamide;

[1150] N-(( 1 -benzylcyclobutyl)methyl)- 1 -methyl-2-oxo-2,3-dihydro- 1 H-imidazole-4-carboxamide;

[1151] N-(2-benzyl-3-hydroxypropyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1152] N-(2,2-dimethyl-3-phenylpropyl)-N,1 -dimethyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1153] N-((1 -(2,4-difluorobenzyl)cyclohexyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1154] N-((2S,3S)-3-benzylpentan-2-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1155] N-((1 -(3-methoxybenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1156] N-((1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1157] N-((1 -(3-cyclopropylbenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1158] N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1159] N-((1 -(3-chlorobenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1160] 1 -methyl-5-oxo-N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1161] N-((1 -(2,5-difluorobenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1162] N-((1 -(2-ethylbenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1163] N-((l-(2-fluoro-5-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1164] N-((l-(3-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[1165] N-((l-(3-chloro-2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1166] N-((l-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1167] N-((l-(4-fluoro-2-(trifluoromethyl)benzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazole-3-carboxamide;

[1168] N-((l-benzylcyclobutyl)methyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide;

[1169] l-methyl-N-((l-(3-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide;

[1170] N-((l-(4-chloro-2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1171] N-((l-(4-chloro-2-methylbenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1172] N-((l-(2,4-difluorobenzyl)cyclopentyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole- 3-carboxamide;

[1173] N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole- 3-carboxamide;

[1174] N-((1-(2-fluoro-3-methylbenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1175] N-((1-(2,3-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1176] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1177] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1178] (S)-N-(2-(2,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1179] N-((1-(3-bromobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1180] N-((1-(3-cyanobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1181] N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1182] (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1183] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1184] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1185] N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1186] 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;

[1187] N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1188] 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;

[1189] (R)-N-(2-cyclopropyl-3-phenylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1190] (S)-1-methyl-5-oxo-N-(2-(2,4,6-trifluorobenzyl)butyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1191] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4-hydroxy-piperidinecarboxamide;

[1192] N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1193] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-hydroxy-1-methyl-1H-pyrazole-3-carboxamide

[1194] (R)-N-(2-cyclopropyl-3-(4-fluoro-2-methylphenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1195] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-pyrimidine-2-carboxamide

[1196] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydro-pyrimidine-2-carboxamide

[1197] N-((2R,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1198] N-((2S,3S)-3-benzylpentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide;

[1199] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-3-oxo-2,3-dihydroisoxazole-5- carboxamide;

[1200] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-2-oxo-2,3-dihydrooxazole-4- carboxamide;

[1201] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1202] N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1203] N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1204] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1205] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1206] N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1207] 6-oxo-N-((1-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-1,6-dihydropyrimidine-2- carboxamide;

[1208] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1209] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1210] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1211] N-((1 -(2,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1212] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1213] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1214] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydro- pyridazine-3-carboxamide;

[1215] 1 -methyl-5-oxo-N-((1 -(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1216] 1 -methyl-5-oxo-N-((1 -(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1217] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1218] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-1 -methyl-5-oxo-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide;

[1219] N-((1 -(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1220] N-((1 -(3-ethylbenzyl)cyclobutyl)methyl)-1 -methyl-5-oxo-4,5-dihydro-1 H-1,2,4- triazole-3-carboxamide;

[1221] (S)-N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-1,6-dihydro- pyrimidine-2-carboxamide;

[1222] N-(2-(3,4-difluorobenzyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1223] N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[1224] N-((1-(4-fluoro-2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1225] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1H-1,2,3-triazole-5-carboxamide;

[1226] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide;

[1227] N-(2-((2,3-dihydrobenzofuran-5-yl)methyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1228] N-((1-(2,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2-carboxamide;

[1229] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[1230] N-((1-(3,5-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[1231] N-((1-(3-fluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide;

[1232] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-4H-1,2,4-triazole-3-carboxamide;

[1233] 1-Methyl-N-((1-(2-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1234] 1-Methyl-N-((1-(3-(methylthio)benzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1235] (R)-N-(2-cyclopropyl-3-(2,4,6-trifluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine- 2-carboxamide;

[1236] N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-3-oxo-2,3-dihydroisoxazole- 5-carboxamide;

[1237] N-((4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-yl)methyl)-6-oxo-l,6-dihydropyrimidine- 2-carboxamide;

[1238] N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide;

[1239] N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide;

[1240] N-((2S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide;

[1241] (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide;

[1242] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1243] (S)-N-(2-(2,4-difluorobenzyl)butyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide;

[1244] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-fluoro-6-oxo-l,6-dihydropyrimidine- 2-carboxamide;

[1245] N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide;

[1246] N-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole- 3-carboxamide;

[1247] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide;

[1248] N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1249] N-((2S,3S)-2-Cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1250] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxamide;

[1251] N-(2-(2,4-difluorobenzyl)-2-ethylbutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1252] N-((1-(3,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[1253] (R)-N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[1254] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[1255] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[1256] N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-5-(methoxymethyl)-4H-1,2,4-triazole-3-carboxamide;

[1257] (R)-N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[1258] (S)-N-(2-(2,4-difluorobenzyl)butyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

[1259] N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1260] N-((1-(2,4-difluorobenzyl)cyclopentyl)methyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamide;

[1261] (R)-N-(2-cyclopropyl-3-(2,6-difluorophenyl)propyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1262] N-((1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1263] N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1264] N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1265] N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1266] (R)-5-bromo-N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1267] N-(3-(2-chloro-4,6-difluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1268] N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1269] N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1270] (N-((2S,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1271] N-((2R,3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazole-3-carboxamide;

[1272] N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1273] N-((2S,3S)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1274] (S)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4- triazole-3-carboxamide;

[1275] (R)-N-[2-cyclopropyl-2-methyl-3-(2,4,6-trifluorophenyl)propyl]-1-methyl-5-oxo-4H-1,2,4- triazole-3-carboxamide;

[1276] (S)-N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazole-3-carboxamide;

[1277] (R)-N-((2-(2,4-difluorobenzyl)tetrahydrofuran-2-yl)methyl)-1-methyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazole-3-carboxamide;

[1278] (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;

[1279] (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;

[1280] (S)-N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide;

[1281] (R)-N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide;

[1282] (S)-N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1283] (R)-N-((1-(2,4-difluorobenzyl)spiro[2.2]pentan-1-yl)methyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1284] N-((2S,3R)-2-cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1285] N-((2S,3S)-2-Cyclopropyl-3-(2,4-difluorophenyl)butyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1286] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1287] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1288] (R)-N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1289] (S)-N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1290] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1291] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1292] (R)-N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide;

[1293] (S)-N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-1-methyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazole-3-carboxamide;

[1294] N-(((1s,3r)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[1295] N-(((1r,3s)-1-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine- 2-carboxamide;

[1296] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1297] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1298] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1299] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide;

[1300] (R)-N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazole-3-carboxamide;

[1301] (S)-N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-1-methyl-5-oxo-4,5-dihydro-1H- 1,2,4-triazole-3-carboxamide;

[1302] (S)-N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1303] (R)-N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide;

[1304] N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H- pyrimidine-2-carboxamide;

[1305] N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo- 3H-pyrimidin-2-carboxamide;

[1306] 5-Chloro-N-[(2R)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo- 3H-pyrimidin-2-carboxamide;

[1307] 5-Chloro-N-[(2S)-2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl]-4-oxo- 3H-pyrimidin-2-carboxamide;

[1308] (S)-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H- pyrimidin-2-carboxamide;

[1309] (R)-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-5-fluoro-4-oxo-3H- pyrimidin-2-carboxamide;

[1310] (S)-5-Chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H- pyrimidin-2-carboxamide;

[1311] (R)-5-Chloro-N-[2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl]-4-oxo-3H- pyrimidin-2-carboxamide;

[1312] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo- 1,6-dihydropyrimidine-2-carboxamide;

[1313] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-methyl-6-oxo- 1,6-dihydropyrimidine-2-carboxamide;

[1314] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6- dihydropyrimidine-2-carboxamide;

[1315] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-1,6- dihydropyrimidine-2-carboxamide;

[1316] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole- 5-carboxamide;

[1317] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5- carboxamide;

[1318] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5- carboxamide;

[1319] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-3-hydroxyisoxazole-5- carboxamide;

[1320] (S)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide;

[1321] (R)-N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide;

[1322] (S)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide; and

[1323] (R)-N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide;

[1324] or a salt and / or solvate of any one of the foregoing.

[1325] 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 of formula (I) does not apply.

[1326] Clause 138. A compound according to any one of clauses 3 to 136, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament, wherein the proviso of formula (I) does not apply.

[1327] Clause 139. A compound according to any one of clauses 3 to 136, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prophylaxis of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply.

[1328] Clause 140. Use of a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 3 to 136 for the manufacture of a medicament for the treatment of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply.

[1329] Clause 141. A method of preventing or treating a condition in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 3 to 136, wherein the proviso of formula (I) does not apply.

[1330] Clause 142. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to any one of clauses 139 to 141, wherein the disease or condition is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, an ischemia reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of aging, and a kidney disease.

[1331] Clause 143. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to any one of clauses 139 to 141, wherein the disease or condition is selected from a degenerative or neurodegenerative disease, a central nervous system disorder, an ischemia reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of aging, a kidney disease, hearing loss, an ocular disease or disorder, Charcot-Marie-Tooth disease (CMT1a), and Leigh syndrome disease.

[1332] Clause 144. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to clause 143, wherein the disease or condition is a degenerative or neurodegenerative disease, such as Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington’s disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury (e.g., concussion), and Friedreich’s ataxia.

[1333] Clause 145. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to clause 143, wherein the disease or condition is a central nervous system disease, such as AIDS dementia complex, depression, schizophrenia, and epilepsy.

[1334] Clause 146. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is ischemia or reperfusion injury, for example acute myocardial infarction, stroke, renal ischemia reperfusion injury, and organ injury during transplantation.

[1335] Clause 147. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is a metabolic disease, for example liver steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related disorders, obesity and feeding behavior, and nonalcoholic fatty liver disease.

[1336] Clause 148. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is a metabolic disease, for example liver steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related disorders, obesity and feeding behavior, diabetic neuropathy, and nonalcoholic fatty liver disease.

[1337] Clause 149. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is an inflammatory or autoimmune disease, for example acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis.

[1338] Clause 150. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is a disease of aging, for example bone repair, bone frailty in aging in osteoporosis, and sarcopenia.

[1339] Clause 151. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is a kidney disease, for example chronic kidney disease associated with APOL1 genetic variants and chronic kidney disease.

[1340] Clause 152. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method of clause 143, wherein the disease or condition is a disease of aging, for example bone repair, bone frailty in aging in osteoporosis, and sarcopenia.

[1341] Clause 153. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to clause 143, wherein the disease or disorder is hearing loss, e.g., hearing loss due to aging, noise, concussion, traumatic brain injury (TBI), drug-induced hearing loss, and / or genetic hearing loss, including Spinal Muscular Atrophy (SMA) syndrome (SMA1, SMA2, SMA3, and SMA4, also known as type I, type II, type III, and type IV).

[1342] Clause 154. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to clause 143, wherein the disease or disorder is an ocular disease or disorder, e.g., age-related macular degeneration.

[1343] Clause 155. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to clause 143, wherein the disease or disorder is Charcot-Marie-Tooth disease (CMT1a).

[1344] Clause 156. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use or method according to clause 143, wherein the disease or disorder is Leigh syndrome disease.

[1345] Clause 157. A compound according to any one of clauses 3 to 136, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a mitochondrial disease, wherein the proviso of formula (I) does not apply.

[1346] Clause 158. A compound according to any one of clauses 3 to 136, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathies (e.g., TDP-43 associated neurodegeneration), wherein the proviso of formula (I) does not apply.

[1347] Clause 159. Use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of clauses 3 to 136, in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathies (e.g., TDP-43 associated neurodegeneration), wherein the proviso of formula (I) does not apply.

[1348] Clause 160. A method of treating or preventing a disease or disorder associated with TDP-43 proteinopathies (e.g., TDP-43 associated neurodegeneration), the method comprising administering to an individual 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 of formula (I) does not apply.

[1349] Clause 161. The compound or pharmaceutically acceptable salt and / or solvate for use, use, or method of any one of clauses 158-160, wherein the disease or disorder is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensory and motor neuronopathy, primary lateral sclerosis, progressive muscular atrophy, inclusion body myopathy associated with early onset Paget disease of the bone and frontotemporal dementia, Perry disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer’s disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and cerebral age-related TDP-43 with sclerosis.

[1350] Clause 162. The compound or pharmaceutically acceptable salt and / or solvate thereof of any one of clauses 3-136 for use in the treatment or prevention of a disease or disorder associated with fibrosis, wherein the proviso of formula (I) does not apply.

[1351] Clause 163. Use of a compound or pharmaceutically acceptable salt and / or solvate thereof of any one of clauses 3-136 for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis, wherein the proviso of formula (I) does not apply.

[1352] Clause 164. A method of treating or preventing a disease or disorder associated with fibrosis, the method comprising administering to an individual in need thereof an effective amount of a compound or pharmaceutically acceptable salt and / or solvate thereof of any one of clauses 3-136, wherein the proviso of formula (I) does not apply.

[1353] Clause 165. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, use, or method of any one of clauses 162-164, wherein the disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[1354] Clause 166. A method for preparing a compound of formula (I) or salt and / or solvate thereof of any one of clauses 1-136, the method comprising reacting a compound of formula (II),

[1355]

[1356] wherein B is as defined for a compound of formula (I); or a salt thereof,

[1357] with a compound of formula (III),

[1358]

[1359] wherein R 1 , R2 、R 3 、R 4 、R 5 、R 6 、R 6 and A are as defined for the compound of formula (I); or a salt thereof.

[1360] Clause 167. A compound selected from the group consisting of:

[1361] -Compound of formula (II):

[1362]

[1363] Wherein B is as defined in any of the preceding clauses;

[1364] -Compound of formula (III):

[1365]

[1366] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and A is as defined in any of the preceding clauses;

[1367] - Compounds of formula (IV):

[1368]

[1369] Among them B 1 As defined in any of the preceding clauses;

[1370] -Compound of formula (VII):

[1371]

[1372] where R 4 、R 5 、R 6 、R 7 and A is as defined in any of the preceding clauses;

[1373] -Compound of formula (XII):

[1374]

[1375] where R 2 、R 4 、R 5 、R 6 、R 7 and A is as defined in any of the preceding clauses;

[1376] - a compound of Formula (XIII):

[1377]

[1378] wherein R 2 , R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding clause;

[1379] - a compound of Formula (XIV):

[1380]

[1381] wherein R 4 , R 5 and A are as defined in any preceding clause;

[1382] - a compound of Formula (XV):

[1383]

[1384] wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding clause;

[1385] - a compound of Formula (XVI):

[1386]

[1387] wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding clause;

[1388] - a compound of Formula (XVII):

[1389]

[1390] wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding clause; and

[1391] - a compound of Formula (XVIII):

[1392]

[1393] wherein R 4 , R5 6 7 and A are as defined in any preceding clause,

[1394] or a salt, e.g., a pharmaceutically acceptable salt, of either thereof.

[1395] Clause 168. The compound, pharmaceutically acceptable salt and / or solvate thereof, use or method according to any one of clauses 1 to 95, wherein R 4 is H and R 5 is cyclopropyl.

[1396] The application is further illustrated by the following non-limiting examples.

[1397] Examples

[1398] The present application is illustrated by the following compounds. The following examples describe the laboratory synthesis of particular compounds of the present application and are not meant to limit the scope of the application in terms of compounds or processes in any way. It is understood that although specific reagents, solvents, temperatures, and time periods are used, there are many possible equivalent substitutes that can be used to produce similar results. The present application is intended to include such equivalents.

[1399] General Experimental Details

[1400] Unless otherwise indicated, the starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all compounds with chiral centers are racemic. When a reaction is described as being carried out in an analogous manner to a previously more fully described reaction, the general reaction conditions used are essentially the same. The work-up conditions used are of a standard type in the art, but can have been adjusted from one reaction to another. The starting materials can not necessarily have been prepared from the batch mentioned. The compounds synthesized can have various purities, ranging for example from 85% to 99%. The calculations of the number of moles and yields are in some cases adjusted for this.

[1401] The purity of the final compounds was confirmed by HPLC / MS analysis and was determined to be at least >90% and in the vast majority of cases >95%. Analytical LCMS was performed using the instruments shown in Table 1. The NMR spectra were recorded in Bruker 300 MHz instruments (ADVANCE III and ADVANCE III HD) at 300 K. 1 ​​H NMR. Rapid-Prep 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 x 100 mm, 3 um.

[1402] Table 1: Analytical LC-MS Conditions

[1403] Synthesis of example compounds

[1404] Abbreviations

[1405] CH3CN acetonitrile

[1406] Cs2CO3 cesium carbonate

[1407] DCM dichloromethane

[1408] DIPEA diisopropylethylamine

[1409] DMF dimethylformamide

[1410] Et3N triethylamine

[1411] EtOAc ethyl acetate

[1412] EtOH ethanol

[1413] FA formic acid

[1414] HATU 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[1415] HCl hydrochloric acid

[1416] K2CO3 potassium carbonate

[1417] K3PO4 potassium phosphate

[1418] LAH lithium aluminium hydride

[1419] LDA lithium diisopropylamide

[1420] LiHMDS lithium bis(trimethylsilyl)amide

[1421] MgSO4 magnesium sulfate

[1422] MeOH methanol

[1423] NaHC03 sodium bicarbonate

[1424] NaOAc sodium acetate

[1425] NaOH sodium hydroxide

[1426] Na2S04 sodium sulfate

[1427] NBS N-bromosuccinimide

[1428] NCS N-chlorosuccinimide

[1429] NH4CI ammonium chloride

[1430] PE petroleum ether

[1431] Pd(OAc)2 palladium(II) acetate

[1432] Pd(dppf)Cl2.CH2Cl2 [bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane

[1433] Pd(dppf)Cl2 [bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[1434] RT room temperature

[1435] o / n over night (16h)

[1436] TFA trifluoroacetic acid

[1437] THF tetrahydrofuran

[1438] THP tetrahydropyranyl

[1439] T3P propane phosphonic acid anhydride

[1440] Intermediate 1 : 1 -methyl-5-oxo-4H-1,2,4-triazole-3-carboxylic acid

[1441] Step 1 :

[1442]

[1443] To a 1 L round bottom flask was added methylhydrazine (35 g, 759.66 mmol, 1.00 equiv), K2CO3(209.98 g, 1519.33 mmol, 2.00 equiv), EtOH (350 mL), and ethyl 2-amino-2-sulfanylacetate (101.16 g, 759.66 mmol, 1.00 equiv) at room temperature. The mixture was stirred overnight, and the resulting mixture was filtered and the filter cake was washed with EtOH (3 x 20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 : 1) to give ethyl 2-imino-2-(2-methylhydrazino)acetate (7 g) as a yellow oil.

[1444] Step 2:

[1445]

[1446] To a 500 mL round bottom flask was added ethyl 2-imino-2-(2-methylhydrazino)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 phase flash chromatography. This resulted in ethyl 1-methyl-5-oxo-4H-l,2,4-triazole-3-carboxylate (4.5 g, 54% yield) as a light yellow solid.

[1447] Step 3:

[1448]

[1449] To a 250 mL round bottom flask was added ethyl 1-methyl-5-oxo-4H-l,2,4-triazole-3- carboxylate (2.5 g, 14.61 mmol, 1.00 equiv), EtOH (100 mL), and NaOH (1.75 g, 43.82 mmol, 3.00 equiv) at room temperature. The mixture was stirred at RT overnight. The mixture was acidified with concentrated HC1 to 5. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 1-methyl-5-oxo-4H-l,2,4-triazole-3-carboxylic acid (1.7 g, 81% yield) as a white solid.

[1450] LC-MS (ES, m / z): [M-H]"= 142

[1451] Method A: Chiral route

[1452] Intermediate 2: (R)-2-cyclopropyl-3-(2,4,6-trifluorophenyl)propan-l -amine

[1453]

[1454] Step 1 :

[1455] 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) portion-wise 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 removed in vacuo to give (R)-2-(benzylamino)-2-phenylethan-1-ol as a light yellow solid (16.2 g, 67.1 mmol, 92%).

[1456] Step 2:

[1457] 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 2 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 as a yellow oil (5040 mg, 42.5 mmol, 100%).

[1458] Step 3:

[1459] 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 before it was allowed to warm to room temperature and stirred for 15 minutes.

[1460] The reaction mixture was diluted with DCM (600 mL) and water (300 mL) and the layers separated. The aqueous fraction was extracted with DCM (300 mL). The organic layers were combined, passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a crude yellow oil. This was purified by flash column chromatography to give (R)-N-benzyl-2-cyclopropyl-N-(2-hydroxy-1-phenylethyl)acetamide as a light yellow gum (6535 mg, 19.4 mmol, 57%).

[1461] Step 4:

[1462] To (R)-N-benzyl-2-cyclopropyl-N-(2-hydroxy-l-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 1.4 M 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 before it was allowed to warm 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-l-phenylethyl)-3-(2,4,6-trifluorophenyl)propanamide as a pale yellow oil (1098 mg, 2.42 mmol, 59%).

[1463] Step 5:

[1464] To (R)-N-benzyl-2-cyclopropyl-N-((R)-2-hydroxy-l-phenylethyl)-3-(2,4,6- trifluorophenyl)propanamide (1098 mg, 2.42 mmol) in tetrahydrofuran (14 mL) at 0 °C under nitrogen was added 1.0 M lithium aluminium hydride in THF (4.2 mL, 4.24 mmol). The reaction was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction was cooled to below 10 °C, quenched with aqueous Rochelle's salt solution (30 mL) and extracted with EtOAc (100 mL). The organic layer was passed through a phase separator cartridge (Biotage) and the solvent was removed in vacuo to give a pale yellow oil. The crude material was dissolved in a minimum amount of MeOH and suctioned onto a 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-l-ol as a colourless oil (1027 mg, 2.34 mmol, 96%).

[1465] Step 6:

[1466] 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 carbon supported palladium (0.940 mmol). The reaction flask was evacuated then backfilled with nitrogen (x3) then hydrogen (x1 ). The reaction mixture was shaken at room temperature under a hydrogen atmosphere at 35 psi for 19 hours. UPLC showed no SM remaining, formation of desired product as well as some deprotection material (Bn group only removed). Additional Pd / C (excess) was added to the reaction mixture. The reaction flask was evacuated then backfilled with nitrogen (x3) then hydrogen (x1 ). The reaction mixture was shaken at room temperature under a hydrogen atmosphere at 35 psi for a further 5 hours. UPLC showed no SM remaining, formation of desired product and byproduct. The reaction was terminated to prevent loss of product and increase in impurities. The mixture was passed through a fritted filter, washed with MeOH (150 mL) and the solvent removed in vacuo. The gum was then dissolved in a minimum amount of MeOH and syringed onto an SCX-2 cartridge (Biotage). The cartridge was washed with MeOH (4 CV) and rinsed with 3.5 M NH3 / MeOH (6 CV) to give (R)-2-cyclopropyl-3-(2,4,6-trifluorophenyl)propan-1 -amine as a light yellow oil (128 mg, 0.336 mmol, 37%, 60% pure). This material was used as is for further use.

[1467] The following amine intermediates were synthesized using a similar method to that outlined above for Intermediate 2 (Method A) using commercially available starting materials or benzyl bromide intermediates:

[1468] Table 2:

[1469]

[1470]

[1471] Method B: KHMDS Route

[1472] Intermediate 13A: 1 -(3,4-difluorobenzyl)cyclobutan-1 -carbonitrile

[1473]

[1474] To a flask purged and maintained with nitrogen was added cyclobutanenitrile (0.25 mL, 2.66 mmol) and toluene (5.0 mL) and the solution cooled to 0 °C. To the reaction mixture was added dropwise potassium bis(trimethylsilyl)amide solution (1 M in THF) (4.5 mL, 4.47 mmol) and the reaction mixture stirred at 0 °C for 2 h. To this was then added 3,4-difluorobenzyl bromide (0.31 mL, 2.42 mmol) and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was quenched with aqueous NH4C1 solution (20 mL) and extracted with EtOAc (50 mL). The organic layer was passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a crude material.

[1475] This was purified by flash column chromatography to give 1-(3,4-difluorobenzyl)cyclobutane-1- carbonitrile as a yellow oil (366 mg, 1.77 mmol, 73%).

[1476] Using similar methods to that outlined above for Intermediate 13A (Method B), using commercially available starting materials or benzyl bromide intermediates, the following intermediates were synthesised:

[1477] Table 3:

[1478]

[1479]

[1480] Method C: LiTMP Route

[1481] Intermediate 29A: 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-carbonitrile

[1482]

[1483] A vacuum dried flask was evacuated and charged with N2, charged with tetrahydrofuran (10 mL) and 2,2,6,6-tetramethylpiperidine (1.1 mL, 6.18 mmol) and the solution cooled to -78 °C. N-Butyllithium (2.5 mL, 6.18 mmol) was added dropwise and the solution stirred for 15 min, warmed to -50 °C 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 stirred at -78 °C for 1 hr, 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 warmed to RT then heated to 60 °C for 1 hr. The temperature was reduced to 40 °C and the reaction stirred for over 2 days. The reaction was quenched with water and EtOAc (50 mL) and the organic layer separated. The solvent was removed in vacuo to give a crude material which was purified by flash column chromatography to give 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow oil (1.02 g, 3.62 mmol, 70%). cDilute, separate the layers, then extract the aqueous fraction with EtOAc (3x). Combine the organic fractions and wash with dilute citric acid, water and brine, then dry over MgS04and remove the solvent. Purify the crude material by flash column chromatography to give 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-carbonitrile as a pale yellow oil (998 mg, 4.21 mmol, 82%).

[1484] Method D: NaHMDS Route

[1485] Intermediate 30A: 2-(2,4-difluorobenzyl)tetrahydrofuran-2-carbonitrile

[1486]

[1487] To a flask purged and maintained with nitrogen, was added tetrahydrofuran-2- carbonitrile (225 mg, 2.32 mmol) in tetrahydrofuran (7.7 mL) and the solution was cooled to -78 °C. 1.0 M sodium bis(trimethylsilyl)amide solution in THF (2.3 mL, 2.32 mmol) was added dropwise and the mixture was stirred at -78 °C for 50 min. Then 2,4-difluorobenzyl bromide (99 uL, 0.773 mmol) in tetrahydrofuran (3.9 mL) was added and the mixture was stirred at -78 °C for 1.5 h. The reaction was quenched with NH4CI (6 mL) and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with H2O (30 mL), passed through a phase separator cartridge (Biotage), and concentrated in vacuo to give a crude oil. This was purified by flash column chromatography to give 2-(2,4-difluorobenzyl)tetrahydrofuran-2-carbonitrile as a colorless oil (92 mg, 0.412 mmol, 53%).

[1488] Intermediate 31A: 1-(2-(methylthio)benzyl)cyclobutane-1-carbonitrile

[1489]

[1490] Sodium bis(trimethylsilyl)amide (1.19 g, 6.48 mmol) was added to an ice-cold solution of cyclobutanenitrile (0.500 mL, 7.07 mmol) in toluene (10 mL) under N2. The reaction mixture was stirred at room temperature for 1 h, then 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 stirred at room temperature overnight, then heated to 40 °C for 30 min. Water was added and the solution was extracted with DCM (3x). The combined organic layers were washed successively with water and a saturated brine solution, dried (MgS04) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (Biotage Isolera Selekt, 25 g Sfar cartridge) eluting with isohexane-EtOAc (0-20%) to give 1-(2-(methylthio)benzyl)cyclobutane-1-carbonitrile (1.20 g, 94%) as a colourless oil.

[1491] Method E: LDA Route

[1492] Intermediate 32A: 3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropanenitrile

[1493]

[1494] To a 2-necked flask purged and maintained with an inert atmosphere of nitrogen, was added 2-cyclopropylacetonitrile (0.45 mL, 4.92 mmol) and tetrahydrofuran (12 mL) and the reaction mixture was cooled to -78 °C. To the reaction mixture was added dropwise lithium diisopropylamine (LDA 1 M in THF) (5.4 mL, 5.37 mmol) and the reaction mixture was stirred at -78 °C for 1 h. Then to this was added 2-chloro-4-fluorobenzylbromide (1000 mg, 4.47 mmol) and the reaction mixture was stirred further at -78 °C for 1 h. To the reaction mixture was added water and extracted with EtOAc (2x). 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 colourless oil.

[1495] Using a similar method to that outlined above for Intermediate 32A (Method E), the following intermediates were synthesised using commercially available starting materials or other amine intermediates:

[1496] Table 4:

[1497]

[1498] Method F: Horner-Wadsworth-Emmons Route

[1499] Intermediate 35A: 2-(Isoquinolin-6-ylmethyl)butyronitrile

[1500]

[1501] Step 1:

[1502] To sodium hydride (60% dispersion in oil) (27 mg, 0.668 mmol) in N,N- dimethylformamide (1.2 mL) at 0 °C was added diethyl cyanomethylphosphonate (103 uL, 0.636 mmol) and stirred at 0 °C for 10 min. 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 h. To the reaction mixture was added sodium hydride (60% dispersion in oil) (27 mg, 0.668 mmol) in N,N-dimethylformamide (1.2 mL) at 0 °C and stirred at 0 °C for 15 min. To this was then 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.

[1503] The reaction was concentrated, the residue was diluted with DCM (15 mL) and washed with brine (2 x 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-ylmethyl)butyronitrile as a yellow oil (90 mg, 0.432 mmol, 68%).

[1504] Step 2:

[1505] 2-(Isoquinolin-6-ylmethyl)butyronitrile (90 mg, 0.432 mmol) in methanol (10 mL) was evacuated and backfilled with nitrogen (x 3). Carbon supported palladium (10%) (50 mg, 0.470 mmol) was added and then the flask was backfilled with hydrogen at 1 atm. The reaction mixture was stirred at room temperature under a H2 balloon for 18 h. 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)butyronitrile as a light yellow oil (53 mg, 0.252 mmol, 58%).

[1506] The following intermediates were synthesised using a similar method to that outlined above for Intermediate 35A (Method F) using commercially available starting materials:

[1507] Table 5:

[1508] The following intermediates were synthesised using a similar method to that outlined above for Intermediate 35A (Method F) using commercially available starting materials:

[1509] Intermediate 38A: (E)-2-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methylene)butyronitrile

[1510]

[1511] To sodium hydride (60% dispersion in oil, 119 mg, 2.96 mmol) in N,N- dimethylformamide (5.0 mL) at 0 °C was added diethyl cyanomethylphosphonate (0.46 mL, 2.82 mmol) 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. To the reaction mixture was added N,N-dimethylformamide (5.0 mL) and sodium hydride (60% dispersion in oil, 119 mg, 2.96 mmol) at 0 °C and the reaction mixture was stirred for 15 minutes. To this was added 2,3-dihydrobenzo[b][l,4]dioxin-6-carboxaldehyde (463 mg, 2.82 mmol) in N,N-dimethylformamide (5.0 mL) 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 aqueous 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 cartridge) eluting with isohexane-EtOAc (0-30%) to give (2E)-2-(2,3-dihydro-l,4-benzodioxin-6-ylmethylidene)butyronitrile (380 mg, 1.77 mmol, 63%) as a yellow oil.

[1512] Intermediate 39A: 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropanenitrile

[1513]

[1514] To a 2-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)propionitrile (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, then iodomethane (0.728 mL, 11.6 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature while stirring was maintained for over 1 h. 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 and passed through a phase separator cartridge (Biotage) and concentrated in vacuo to give a crude oil. This was purified by flash column chromatography to give 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropionitrile (1.26 g, 5.69 mmol, 59%) as a yellow oil.

[1515] Method G: Nitrile Reduction

[1516] To convert the nitrile intermediates synthesized using Method B-F to the corresponding amines, reduction with LiAIH4was employed:

[1517] Preparation of Intermediate 13B: (1-(3,4-difluorobenzyl)cyclobutyl)methanamine

[1518]

[1519] To a 2-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 lithium aluminum hydride 1.0 M in THF (5.3 mL, 5.3 mmol) dropwise at 0-5°C. The resulting reaction mixture was stirred at room temperature for 1 hour.

[1520] The reaction was cooled to 0°C, quenched with an aqueous Rochelle 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 was removed in vacuo to give a crude oil. This was dissolved in a minimum amount of MeOH and suctioned onto a SCX-2 cartridge (Biotage). The cartridge was washed with MeOH (4 CV) and rinsed with NH3 / MeOH (6 CV) to give (1-(3,4-difluorobenzyl)cyclobutyl)methanamine (277 mg, 1.18 mmol, 67%) as a light yellow oil.

[1521] The following amine was synthesized using a similar procedure to Intermediate 13B above:

[1522] Table 6:

[1523]

[1524]

[1525]

[1526] Intermediate 38B: 2-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)butan-l- amine

[1527]

[1528] To (2E)-2-(2,3-dihydro-l,4-benzodioxin-6-ylmethylidenecyanacetate (380 mg, 1.77 mmol) in THF (8.0 mL) was added dropwise lithium aluminium hydride solution (1.0 M in THF, 5.30 mL, 5.30 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours, cooled to 0 °C, quenched with aqueous Rochelle salt solution and extracted with EtOAc. The organic phase was washed with saturated aqueous salt solution, passed through a phase separator cartridge (Biotage) and the solvent 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-l,4-benzodioxin-6-ylmethyl)butan-l-amine as a yellow oil (350 mg, 90%).

[1529] Method H: Head Group Synthesis

[1530] Intermediate 40: 5-fluoro-6-methoxy-l,6-dihydropyrimidine-2-carboxylic acid

[1531]

[1532] Step 1:

[1533] To 2-chloro-5-fluoro-6-methoxy-l,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. Tetra(triphenylphosphine)palladium(0) (355 mg, 0.308 mmol) was then added thereto and nitrogen was bubbled through the reaction mixture for a further 10 minutes. The reaction mixture was heated at 90 °C for 3 days.

[1534] 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 removed in vacuo to give a crude oil.

[1535] This was purified by flash column chromatography to give 5-fluoro-4-methoxy- pyrimidine-2-carbonitrile as a yellow oil (45 mg, 0.293 mmol, 10%).

[1536] Step 2:

[1537] To 5-fluoro-4-methoxy-pyrimidine-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 1 M aqueous HC1. The aqueous fraction was washed with DCM (4 x 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 as a white solid (200 mg). The solid was presumed to be mainly NaCl salt. The final compound was used as is in the next coupling step.

[1538] Intermediate 41 : 1 -Methyl-5-thioxo-4,5-dihydro-1 H-1,2,4-triazole-3-carboxylic acid

[1539]

[1540] Step 1 :

[1541] l-methylhydrazine-1 -thiocarboxamide (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 2-chloro-2-oxoethyl acetate (1.2 mL, 10.5 mmol) was added dropwise. The reaction mixture changed from colourless to deep orange. It was allowed to warm to room temperature and stirred overnight. The reaction mixture was acidified to pH 5 using aqueous HC1 and then extracted with DCM (3 x 20 mL). The combined organic fractions were concentrated under vacuum to give 2-(2- aminomethylthioyl-2-methylhydrazino)-2-oxoethyl acetate as an orange gum (1686 mg, 8.2152 mmol, 86%).

[1542] Step 2:

[1543] Ethyl 2-(2-aminomethylsulfinyl-2-methylhydrazino)-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. H20 (10 mL) was added and the reaction was further heated to 90 C for 1 h. The reaction mixture was concentrated and the residue was re-dissolved in a minimum amount of water / EtOH (4 mL) and extracted with DCM (5 x 30 mL). The organic phases were combined and passed through a phase separator cartridge (Biotage) 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%).

[1544] Intermediate 42: Ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxylate

[1545]

[1546] To ethyl 2-amino-2-sulfanylacetate (500 mg, 3.75 mmol) in ethanol (15 mL) was added hydrazine hydrate (184 uL, 3.75 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. Ethyl glyoxylate (50% in toluene) (0.76 mL, 7.51 mmol) was then added and the reaction mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added and washed with DCM (20 mL). UPLC showed that there was an impurity in the organic layer and product in the aqueous solution. The aqueous layer was concentrated in vacuo to give ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-3-carboxylate as a crude brown oil (473 mg, 2.29 mmol, 61%).

[1547] Intermediate 43: Ethyl 5-ethoxy-1,3,4-oxadiazole-2-carboxylate

[1548]

[1549] Ethyl carbazate (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 as a yellow oil (140 mg, 0.75 mmol, 16%). The crude product was used without purification in further steps.

[1550] Intermediate 44: 4-Methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxylic acid

[1551]

[1552] Dissolve 5-(hydroxymethyl)-4-methyl-2,4-dihydro-3H-l,2,4-triazol-3-one (400 mg, 3.10 mmol) in water (10 mL). Add potassium permanganate (1469 mg, 9.29 mmol), followed by 1 M NaOH solution in water (4.65 mL, 4.65 mmol). Heat the reaction mixture to 80 C overnight. Filter the reaction mixture over celite to remove insoluble inorganics and evaporate the filtrate to dryness to give crude 4-methyl-5-oxo-lH-l,2,4-triazole-3-carboxylic acid (1160 mg, 8.1062 mmol, 262%). Use the crude product without purification in the further step.

[1553] Intermediate 45: 2-(2,4-Difluorobenzyl)-2-fluorobutan-l -amine

[1554]

[1555] Step 1:

[1556] To sodium hydride (60% dispersion in oil) (638 mg, 15.9 mmol) in tetrahydrofuran (8.0 mL) under nitrogen was added diethyl ethylmalonate (2.0 mL, 10.6 mmol) in tetrahydrofuran (4.0 mL). The reaction mixture was stirred at room temperature for 15 minutes. To this was then added dropwise 2,4-difluorobenzyl bromide (1.5 mL, 11.7 mmol) in tetrahydrofuran (4.0 mL). The resulting mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to 0 °C and acidified with 1 M aqueous HC1 (10 mL) and extracted with Et20 (3 x 60 mL). The organic layers were combined and washed with saturated aqueous NaHC03(15 mL), brine (15 mL), then passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a crude colourless oil. This was purified by flash column chromatography to give diethyl 2-(2,4-difluorobenzyl)-2-ethylmalonate as a colourless oil (2575 mg, 7.54 mmol, 71%).

[1557] Step 2:

[1558] To a flask was added Selectfluor (4974 mg, 14.0 mmol), potassium phosphate dibasic (4891 mg, 28.1 mmol) and silver nitrate (328 mg, 1.40 mmol) 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. The reaction was quenched with 3M aqueous HC1 (10 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were combined, passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give 2-(2,4-difluorobenzyl)-2-fluorobutanoic acid as a crude orange oil (1880 mg, 5.66 mmol, 81%).

[1559] Step 3:

[1560] To a flask was added Selectfluor (4974 mg, 14.0 mmol), potassium phosphate dibasic (4891 mg, 28.1 mmol) and silver nitrate (328 mg, 1.40 mmol) 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. The reaction was quenched with 3M aqueous HC1 (10 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were combined, passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give 2-(2,4-difluorobenzyl)-2-fluorobutanoic acid as a crude orange oil (1880 mg, 5.66 mmol, 81%).

[1561] Step 4:

[1562] To 2-(2,4-difluorobenzyl)-2-fluorobutyric acid (746 mg, 2.25 mmol) in tetrahydrofuran (75 mL) at 0 °C was added ethyl chloroformate (301 uL, 3.15 mmol) and triethylamine (0.94 mL, 6.75 mmol) and the reaction mixture was stirred at 0 °C for 30 min. To this was then added 1 M aqueous ammonium chloride solution (10 mL, 10.0 mmol) and the resulting reaction mixture was further stirred at 0 °C for 30 min. To the reaction mixture was added water (60 mL) and extracted with EtOAc (3 x 80 mL). The organic layers were combined, washed with brine (80 mL), passed through a phase separator cartridge (Biotage) and the solvent removed in vacuo to give a crude solid. This was purified by flash column chromatography to give 2-(2,4-difluorobenzyl)-2-fluorobutyramide (450 mg, 1.94 mmol, 86%) as a white solid.

[1563] Step 5:

[1564] To a stirred solution of 2-(2,4-difluorobenzyl)-2-fluorobutyramide (400 mg, 1.56 mmol) in acetonitrile (8.0 mL) at room temperature was added phosphorus pentoxide (884 mg, 3.11 mmol) and the reaction mixture was stirred at reflux for 4 h. To the reaction mixture was added DCM (40 mL) and washed with dilute aqueous NaHC03solution (15 mL) and water (15 mL). The organic layer was passed through a phase separator cartridge (Biotage) and the solvent 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 colourless oil.

[1565] Step 6:

[1566] To 2-(2,4-difluorobenzyl)-2-fluorobutyronitrile (273 mg, 1.28 mmol) in methanol (12 mL) at 0 °C was added nickel (II) chloride hexahydrate (31 mg, 0.131 mmol) and di-tert-butyl dicarbonate (315 mg, 1.44 mmol). The reaction was cooled to -5 °C and sodium borohydride (99 mg, 2.63 mmol) was added very slowly over a 2 minute time course. The reaction was then warmed to room temperature and stirred overnight. To this was then added diethylenetriamine (142 uL, 1.31 mmol) and the reaction mixture was further stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous NaHC03(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).

[1567] Step 7:

[1568] 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 hour. The solvent was removed in vacuo and the oil was dissolved in a minimum amount of MeOH and suctioned onto a SCX-2 cartridge (Biotage). The column was rinsed with MeOH (4 CV) followed by 3.5 M NH3 / MeOH (6 CV). Fractions containing the product were combined and the solvent removed in vacuo to give 2-(2,4-difluorobenzyl)-2-fluorobutan-1-amine as a SCX-2 post- crude and as a light yellow oil (254 mg, 35% pure by UPLC). This was used in the subsequent step.

[1569] Intermediate 46: C1 methylated amine

[1570]

[1571] Step 1:

[1572] Combine 2,4-difluorobenzaldehyde (8.03 g, 56.5 mmol) and triethyl phosphonoacetate (13 mL, 56.5 mmol) in THF (150 ml). Add sodium hydride (60% dispersion in oil) (2.37 g, 98.9 mmol) portionwise over 5 min at room temperature, heat to reflux for 3.5 hr, then stir at room temperature for 16 hr. Add water (50 mL) and stir the reaction at room temperature for 30 min. Extract the product from the aqueous fraction into EtOAc and dry the organic layer over MgSO4, decant and evaporate to a yellow oil. Purify by flash column chromatography to give ethyl 2-(2,4-difluorobenzylidene)butanoate (8.06 g, 35 mnol, 63%).

[1573] Step 2:

[1574] Dissolve ethyl 2-(2,4-difluorobenzylidene)butanoate (9.92 g, 41.3 mmol) in ethanol (5 mL) and add water (35 mL) and sodium hydroxide (2.81 g, 70.1 mmol). Heat the reaction to 80 °C overnight. Cool the reaction to room temperature and further dilute with water (25 mL). Adjust the pH to pH 2 with aqueous HCl to give a white precipitate. Extract the product into EtOAc and dry the organic fraction over MgSO4, filter and evaporate the solvent to give 2-(2,4-difluorobenzylidene)butanoic acid as a light pink solid (8.3 g, 39.1 mmol, 95%).

[1575] Step 3:

[1576] Combine freshly made (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) and place under vacuum then purge with Ar. Add anhydrous methanol and degas the material and place under an Ar atmosphere. Add triethylamine (0.56 mL, 3.97 mmol) and degas the reaction and purge with hydrogen (3x) and stir the reaction under a hydrogen balloon at room temperature for 16 hr. Evaporate the reaction then add water and acidify with aqueous HCl to pH=l then extract the product into EtOAc. Wash the organic layer with water and brine and dry over MgSO4, filter then remove the solvent in vacuo to give the product (S)-2-(2,4-difluorobenzyl)butanoic acid as a white solid (3.3 g, 14 mmol, 100%).

[1577] Step 4:

[1578] (S)-2-(2,4-difluorobenzyl)butyric acid (3.3 g, 14 mmol), N,O-dimethylhydroxylamine hydrochloride (1.6 g, 16 mmol), HATU (6 g, 16 mmol), N,N-diisopropylethylamine (7.4 g, 58 mmol, 10 mL) were combined in DMF (100 mL) and stirred at RT for 16 hr. 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 washed with water, then brine and dried over MgSO4, filtered and the solvent evaporated. Purification by column chromatography gave (S)-2-(2,4-difluorobenzyl)-N-methoxy-N-methylbutanamide as a clear yellow oil (3.3 g, 13 mmol, 79%).

[1579] Step 5:

[1580] (S)-2-(2,4-difluorobenzyl)-N-methoxy-N-methylbutanamide (3.0 g, 12 mmol) was dissolved in dry 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 stirred at -78°C for 30 min, then allowed to warm to room temperature with stirring for a further 2 hr. The reaction was concentrated in vacuo to a thick slurry and worked up by addition of 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 as a yellow oil (2.45 g, 11.5 mmol, 99%).

[1581] Step 6:

[1582] (S)-3-(2,4-difluorobenzyl)pentan-2-one (150 mg, 0.707 mmol) and titanium (IV) isopropoxide (402 mg, 430 uL, 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 then methanol (5 ml) was added. The solution was stirred at 0 °C for 10 min to equilibrate then sodium borohydride (53 mg, 2.42 mmol) was added. The reaction was then warmed to RT and stirred for 16 hr. Water was added, forming a white precipitate 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 and dried over MgS04, 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 as a yellow oil (204 mg, 0.64 mmol, 91%).

[1583] Step 7:

[1584] (R)-N-((3S)-3-(2,4-difluorobenzyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (204 mg, 0.643 mmol) was dissolved in methanol (10 mL) and 4M HC1 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 a SCX-2 column (Biotage). The column was washed with MeOH then rinsed with 2M NH3 / methanol and the solvent removed to give the crude product (3S)-3-(2,4-difluorobenzyl)pentan-2-amine as a light yellow oil (70 mg, 0.328 mmol, 51.07%). This was used as is further.

[1585] The following chiral amines were synthesised using a similar method:

[1586] Table 7:

[1587]

[1588] The following intermediates were synthesised using a similar method to that outlined above for Intermediate 13A (Method B) using commercially available starting materials:

[1589] Table 8:

[1590]

[1591] Intermediate 48B: l-(2,4-difluorobenzyl)-3-fluorocyclobutan-l-carbonitrile

[1592]

[1593] Step 1:

[1594] 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-etherate (366 μL, 2.97 mmol) was added and the mixture was stirred at 65° C. for 4 hours. The mixture was washed with saturated NaHhCO 3(水溶液) (30 mL) and extracted with DCM (30 mL). The organic phase was washed successively with saturated Na2SO 3(水溶液) In 40mL 4- (2- (2,4- difluorobenzyl) -3- hydroxycyclobutane -1- carbonitrile (300mg, 48%) is added into the 4- (2,4- difluorobenzyl) -3- hydroxycyclobutane -1- carbonitrile (300mg, 48%) of 4- (2,4- difluorobenzyl) -3- hydroxycyclobutane -1- carbonitrile.Washed, then washed with water (30mL).The organic phase is passed through a phase separator and the eluent is evaporated in a vacuum.The crude product is purified by flash chromatography (Biotage, 25g Sfar columns) eluted with isohexane-EtOAc (0-60%) to give 1- (2,4- difluorobenzyl) -3- hydroxycyclobutane -1- carbonitrile (300mg, 48%) as a colorless oil.

[1595] Step 2:

[1596] To 1-(2,4-difluorobenzyl)-3-hydroxycyclobutane-1-carbonitrile (200 mg, 0.896 mmol) in dichloromethane (3.6 mL) was added (diethylamino)sulfur trifluoride (237 μL, 1.79 mmol) dropwise at -78°C and the mixture was stirred at room temperature for 4 days. The reaction mixture was cooled to 0°C and eluted with cold saturated NaHhCO 3(水溶液) Quenched. The aqueous phase was extracted with DCM (3x). The combined organics were passed through a phase separator and the eluent was evaporated in vacuo.

[1597] A separate reaction was also carried out at -78°C using 1-(2,4-difluorobenzyl)-3-hydroxycyclobutane-1-carbonitrile (50 mg, 0.224 mmol) in DCM (0.9 mL). (Diethylamino)sulfur trifluoride (59 μL, 0.448 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 7 days. The reaction mixture was cooled to 0°C and washed with cold saturated NaHhCO 3(水溶液) The mixture was quenched with 4% paraformaldehyde (1.5 mL). The aqueous phase was extracted with DCM (5 mL). The combined organics were passed through a phase separator and the eluent was evaporated in vacuo.

[1598] The two crude mixtures were combined and the desired product was purified by eluting with isohexane-EtOAc. cPurification by flash chromatography (Biotage, 25 g Sfar cartridge) eluting with 0-40% EtOAc in hexanes afforded 1 -(2,4-difluorobenzyl)-3-fluorocyclobutane-1 - carbonitrile (122 mg, 48% combined yield) as a colorless oil.

[1599] The following intermediates were synthesized using similar methods to those outlined above for Intermediate 32A (Method E) using commercially available starting materials or benzyl bromide intermediates 68:

[1600] Table 9:

[1601]

[1602] Intermediate 54A: 2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropanenitrile

[1603]

[1604] 2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropanenitrile was synthesized using a similar method to Intermediate 39A (2-cyclopropyl-3-(2,4-difluorophenyl)-2- methylpropanenitrile).

[1605] The following amines were synthesized using similar methods to those outlined above for Intermediate 13A (Method G, cyanide reduction). Sometimes, additional heating was applied to the reaction for several hours to complete the conversion:

[1606] Table 10:

[1607]

[1608] Intermediate 55: 5-bromo-6-oxo-1,6 dihydropyrimidine-2-carboxylic acid

[1609]

[1610] 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 and then at rt for 16 h. The solution was adjusted to pH 3 with 1 M HCI and the mixture was concentrated in vacuo to give the crude product as a white solid. The crude product was used in the next step without further purification.

[1611] Intermediates 56 and 57: 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropan-1 - amine enantiomers A and B

[1612]

[1613] Isolate 2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropan-1 -amine (Intermediate 39B) (18 g, 80 mmol) by SFC using the following conditions: Column: CHIRALPAK AD-H, 3*25 cm, 10 pm; Mobile phase: 45% EtOH (containing 0.1% 2M NH3 in MeOH) / C02; Flow rate: 100 mL / min; Sample solvent: MeOH; Injection volume: 1.5 mL. Concentration of the appropriate fractions gave:

[1614] Enantiomer A. Rt 3.9 min

[1615] LCMS (ES, m / z): 226.2 [M+H] +

[1616] 1 H-NMR: (300 MHz, DMSO-d6, ppm): δ 7.33 (td, J = 8.7, 6.9 Hz, 1 H), 7.11 (ddd, J = 10.4, 9.4, 2.6 Hz, 1 H), 6.98 (tdd, J = 8.5, 2.7, 1.0 Hz, 1 H), 2.59 (d, J = 1.9 Hz, 2H), 2.36 (d, J = 1.8 Hz, 2H), 1.39 (s, 2H), 0.67 (tt, J = 8.6, 5.7 Hz, 1 H), 0.41 (d, J = 1.3 Hz, 3H), 0.26 - 0.07 (m, 3H), 0.04 - 0.09 (m, 1 H);

[1617] 19 F-NMR: (282 MHz, DMSO-d6, ppm): δ -111.2, -113.7.

[1618] Enantiomer B. Rt 1.98 min

[1619] LCMS (ES, m / z): 226.2 [M+H] +

[1620] 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 7.33 (td, J = 8.7, 6.9 Hz, 1 H), 7.11 (ddd, J = 10.4, 9.4, 2.6 Hz, 1 H), 6.98 (tdd, J = 8.5, 2.7, 1.0 Hz, 1 H), 2.59 (d, J = 1.9 Hz, 2 H), 2.36 (d, J = 1.8 Hz, 2 H), 1.39 (s, 2 H), 0.67 (tt, J = 8.6, 5.7 Hz, 1 H), 0.41 (d, J = 1.3 Hz, 3 H), 0.26 - 0.07 (m, 3 H), 0.04 - 0.09 (m, 1 H);

[1621] 19 F-NMR: (282 MHz, DMSO-d6, ppm): δ -111.2, -113.7.

[1622] Intermediate 58 and 59: (2S)-2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropan-1 - amine enantiomer A and enantiomer B

[1623]

[1624] (2S)-2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropan-1 -amine (5.7 g, 36% yield) as a light yellow oil.

[1625] Enantiomer A. Rt 2.5 min

[1626] (2S)-2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropan-1 -amine (5.7 g, 36% yield) as a light yellow oil.

[1627] LCMS: (ES, m / z): 208.1 [M+H] +

[1628] 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 7.28 - 7.17 (m, 2 H), 7.12 - 7.01 (m, 2 H), 2.55 (s, 2 H), 2.32 (s, 2 H), 1.50 (s, 2 H), 0.65 - 0.57 (m, 1 H), 0.41 (s, 3 H), 0.27 - 0.11 (m, 3 H), 0.10 - 0.01 (m, 1 H).

[1629] 19 F NMR: (282 MHz, DMSO-d6, ppm): δ -117.9.

[1630] Enantiomer B. Rt 1.95 min

[1631] LCMS: (ES, m / z): 208.2 [M+H] +

[1632] 1 HNMR: (300 MHz, DMSO-d6, ppm): δ 7.29-7.15 (m, 2H), 7.11-7.04 (m, 2H), 2.56 (s, 2H), 2.33 (s, 2H), 1.76 (s, 2H), 0.67-0.57 (m, 1H), 0.41 (s, 3H), 0.26-0.10 (m, 3H), 0.09-0.02 (m, 1H).

[1633] 19 F NMR: (282 MHz, DMSO-d6, ppm): δ -117.7.

[1634] Benzyl alcohol intermediates:

[1635] Intermediate 60: (2-(Methoxymethyl)phenyl)methanol

[1636]

[1637] To a 3-necked flask purged and maintained with an atmosphere of 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. The reaction was cooled to 0 °C, quenched with aqueous Rochelle 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 was removed in vacuo to give a crude oil. The crude was purified by flash column to give (2-(methoxymethyl)phenyl)methanol (774 mg, 5.08 mmol, 94%) as a colorless oil.

[1638] The following compounds were synthesized using a similar method to that outlined above for Intermediate 60:

[1639] Table 11:

[1640]

[1641] Intermediate 62: (3-ethylphenyl)methanol

[1642]

[1643] Step 1:

[1644] To a microwave vial was added (3-iodophenyl)methanol (814 uL, 6.41 mmol), bis(triphenylphosphine)palladium(II) chloride (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 sonicating. To the reaction mixture was added (trimethylsilyl)ethyne (1367 uL, 9.60 mmol) and it was stirred in a microwave reactor at 100 °C for 2 hours. The reaction mixture was diluted with EtOAc (150 mL) and washed with 1 M HC1 (80 mL x 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.

[1645] Step 2:

[1646] 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.

[1647] The solvent was removed in vacuo, 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.

[1648] Step 3:

[1649] To (3-ethynylphenyl)methanol (758 mg, 5.74 mmol) in ethanol (80 mL) was added platinum (IV) Adam's catalyst (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 atm. The reaction mixture was stirred at room temperature under a H2atmosphere for 1 hour. The mixture was filtered through a silica 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.

[1650] Benzyl bromide intermediates

[1651] Intermediate 63: l-(l-bromoethyl)-2,4-difluorobenzene

[1652]

[1653] To l-(2,4-difluorophenyl)ethan-l-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.

[1654] 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.

[1655] This was purified by flash column chromatography to give l-(l-bromoethyl)-2,4- difluorobenzene (2.96 g, 13.4 mmol, 85%) as a colourless oil.

[1656] The following compounds were synthesised using a similar method 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 varying lengths of time:

[1657] Table 12:

[1658]

[1659] Intermediate 69: 2-(2,4-difluorobenzyl)-N-methylbutan-l-amine

[1660]

[1661] Step 1:

[1662] 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) and extracted with DCM (3 x 10 mL), the combined organic fractions were washed with brine (10 mL) and passed through a phase separator cartridge (Biotage) and evaporated to dryness. The material was purified by flash column chromatography to give tert-butyl (2-(2,4-difluorobenzyl)butyl)carbamate (330 mg, 1.10 mmol, 100%) as a colourless oil.

[1663] Step 2:

[1664] Tert-butyl (2-(2,4-difluorobenzyl)butyl)carbamate (330 mg, 1.10 mmol) was dissolved in tetrahydrofuran (10 mL) under N2and cooled to 0 °C. Sodium hydride (60% dispersion in oil) (53 mg, 1.32 mmol) was added portionwise over 5 min and the solution stirred for ~10 min. Methyl iodide (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 x 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 give tert-butyl (2-(2,4-difluorobenzyl)butyl)(methyl)carbamate (200 mg, 0.638 mmol, 58%) as a colourless oil.

[1665] Step 3:

[1666] 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 at room temperature overnight, then diluted with water (15 mL) and extracted with DCM (3 x 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 colourless oil.

[1667] Example 1 : N-((1 -benzylcyclobutyl)methyl)-5-hydroxynicotinamide

[1668]

[1669] A 500-mL 3 -necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with cyclobutanenitrile (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 at -78 °C under stirring and further stirred at -78 °C for 1 hr. Benzyl bromide (15.18 g, 88.76 mmol, 1.20 equiv) was added dropwise under stirring and the resulting solution was stirred at -78 °C for 1 hr. The reaction was quenched by the addition of 100 mL of water and extracted with 3 x 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 onto a silica gel column eluted with THF: petroleum ether (0: 100-1 : 50). This resulted in 7 g (55% yield) of 1-benzylcyclobutan-1-carbonitrile as a light yellow oil.

[1670]

[1671] A 500-mL 3 -necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 1-benzylcyclobutan-1-carbonitrile (5.10 g, 29.78 mmol, 1.00 equiv) and THF (150.00 mL). LiAIH4(2.26 g, 59.56 mmol, 2.00 equiv) was added portionwise at 0-5 °C. The resulting solution was stirred at room temperature for 2 hours 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 and again 2.5 mL of water. The solids were filtered off and the filtrate was concentrated. This resulted in 3 g (57% yield) of 1-(1-benzylcyclobutyl)methanamine as a colorless liquid.

[1672]

[1673] A 8-mL sealed tube was charged with 1-(1-benzylcyclobutyl)methanamine (110.00 mg, 0.63 mmol, 1.00 equiv), 5-hydroxypicolinic acid (104.76 mg, 0.75 mmol, 1.2 equiv), EDCI.HC1 (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 resulted in 24.3 mg of N-[(1-benzylcyclobutyl)methyl]-5-hydroxypicolinamide hydrochloride as an off-white solid.

[1674] LC-MS (ES, m / z): [M+H] +＝ 297

[1675] H-NMR (300 MHz, DMSO-d6, ppm): δ 10.87 (br s, 1H), 8.63-8.60 (m, 2H), 8.36 (s, 1H), 7.81 (s, 1H), 7.33-7.19 (m, 5H), 3.30 (d, J = 6.0 Hz, 2H), 2.76 (s, 2H), 1.86-1.64 (m, 6H).

[1676] Example 2: N-((l-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide

[1677]

[1678] Prepared as for Example 1 using l-(l-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).

[1679] LC-MS (ES, m / z): [M+H] + =298

[1680] H-NMR (300 MHz, DMSO-d6, ppm): δ 8.25-8.20 (m, 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.31-7.17 (m, 5H), 3.23 (d, J = 6.3 Hz, 2H), 2.64 (s, 2H), 1.82-1.63 (m, 6H).

[1681] Example 3: N-((l-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide

[1682]

[1683] A 40-mL vial purged and maintained with 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 (2 M aqueous solution) (12.00 mL), Pd2(dba)3 (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 HC1 (3 mol / L) and the resulting solution was extracted with 2 x 15 mL of ethyl acetate. The organic layer was concentrated and the residue was purified by flash preparative HPLC. This resulted in 130 mg (61% yield) of 5-hydroxy-6-methylpyridine-3-carboxylic acid.

[1684]

[1685] A 40-mL vial purged and maintained with 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 (2 M aqueous solution) (12.00 mL), Pd2(dba)3 (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 HC1 (3 mol / L) and the resulting solution was extracted with 2 x 15 mL of ethyl acetate. The organic layer was concentrated and the residue was purified by flash preparative HPLC. This resulted in 130 mg (61% yield) of 5-hydroxy-6-methylpyridine-3-carboxylic acid.

[1686] LC-MS (ES, m / z): [M+H] + = 311

[1687] H-NMR (300 MHz, DMSO-d6, ppm): 10.02 (s, 1H), 8.44-8.38 (m, 2H), 7.49 (s, 1H), 7.32-7.19 (m, 5H), 3.32-3.27 (m, 2H), 2.75 (s, 2H), 2.37 (s, 3H), 1.85-1.63 (m, 6H).

[1688] Example 4: N-((1-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide

[1689]

[1690] A vial purged and maintained with 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 (2 M in water) (12.00 mL), Pd2(dba)3 (63.58 mg, 0.069 mmol, 0.05 equiv), t-BuXphos (58.97 mg, 0.139 mmol, 0.10 equiv). The resulting solution was stirred at 90 °C for 12 hr. The reaction mixture was cooled to room temperature and the pH of the solution was adjusted to 5 with HC1 (3 mol / L). The resulting solution was extracted with 2 x 15 mL ethyl acetate and the organic layer was concentrated and the residue was purified by flash preparative HPLC. This resulted in 130 mg (61% yield) of 5-hydroxy-4-methylpyridine-3-carboxylic acid as a white solid.

[1691]

[1692] A vial purged and maintained with 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 (2 M in water) (12.00 mL), Pd2(dba)3 (63.58 mg, 0.069 mmol, 0.05 equiv), t-BuXphos (58.97 mg, 0.139 mmol, 0.10 equiv). The resulting solution was stirred at 90 °C for 12 hr. The reaction mixture was cooled to room temperature and the pH of the solution was adjusted to 5 with HC1 (3 mol / L). The resulting solution was extracted with 2 x 15 mL ethyl acetate and the organic layer was concentrated and the residue was purified by flash preparative HPLC. This resulted in 130 mg (61% yield) of 5-hydroxy-4-methylpyridine-3-carboxylic acid as a white solid.

[1693] LC-MS (ES, m / z): [M+H] + = 311

[1694] H-NMR (300 MHz, DMSO-d6, ppm): 9.87 (s, 1H), 8.43-8.41 (m, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.33-7.20 (m, 5H), 7.09 (d, J = 2.7 Hz, 1H), 3.32-3.14 (m, 2H), 2.80 (s, 2H), 2.41 (s, 3H), 1.97-1.70 (m, 6H).

[1695] Example 5: N-((l-benzylcyclobutyl)methyl)-lH-l,2,3-triazole-5-carboxamide

[1696]

[1697] Prepared according to Example 1 using 3H-l,2,3-triazine-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). This resulted in 18 mg of N-[(1-benzylcyclobutyl)methyl]-3H-1,2,3-triazine-4-carboxamide as an off-white solid.

[1698] LC-MS (ES, m / z): [M+H] + = 271

[1699] H-NMR (300 MHz, DMSO-d6, ppm): 8.32-8.30 (m, 2H), 7.32-7.21 (m, 5H), 3.31-3.29 (m, 2H), 2.73 (s, 2H), 1.91-1.62 (m, 6H).

[1700] Example 6: N-((1-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4- carboxamide

[1701]

[1702] 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 resulted in 15 mg of N-[(1-benzylcyclobutyl)methyl]-2-oxo-3H-pyrimidine-4-carboxamide as an off-white solid.

[1703] LC-MS (ES, m / z): [M+H] + = 298

[1704] H-NMR (400 MHz, DMSO-d6, ppm) δ, 8.66-8.57 (m, 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.31-7.20 (m, 5H), 6.87 (d, J = 6.0 Hz, 1H), 3.29 (d, J = 6.4 Hz, 2H), 2.71 (s, 2H), 1.84-1.81 (m, 4H), 1.75-1.71 (m, 1H), 1.69-1.59 (m, 1H).

[1705] Example 7: N-((1-benzylcyclobutyl)methyl)-6-oxo-1,6-dihydropyrimidine-2- carboxamide

[1706]

[1707] 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 resulted in 10 mg of N-[(1-benzylcyclobutyl)methyl]-4-oxo-3H-pyrimidine-2-carboxamide as an off-white solid.

[1708] LC-MS (ES, m / z): [M+H] + = 298

[1709] H-NMR (300 MHz, DMSO-d6, PPm) δ 8.783 (m, 1H), 7.95-7.92 (m, 1H), 7.30-7.21 (m, 5H), 6.38-6.36 (m, 1H), 3.35-3.30 (m, 2H), 2.71 (s, 2H), 1.86-1.61 (m, 6H),

[1710] Example 8: N-((1-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-1H-1,2,4-triazole-3- carboxamide

[1711]

[1712] 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 was added T3P (187.78 mg, 0.590 mmol, 1.50 equiv) and TEA (119.44 mg, 1.179 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. 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

[1713] Example 9: N-((1-benzylcyclobutyl)methyl)-5-methyl-6-oxo-1,6-dihydro-pyrimidine-2- carboxamide

[1714]

[1715] To a stirred mixture of 2,4-dichloro-5-methylpyrimidine (5 g, 30.67 mmol, 1.00 equiv) in THF and water was added NaOH (9.82 g, 245.40 mmol, 8.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 10 h. The mixture was acidified with concentrated HC1 to pH 5 and the aqueous layer was extracted with EtOAc (3 x 40 mL), dried over sodium sulfate and concentrated. The crude product was used directly for the next step.

[1716]

[1717] 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)Cl2(10%), 50 mg) in a pressure vessel. The mixture was purged with nitrogen for 5 min and then pressurized with carbon monoxide to 20 atm at 120 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The mixture was concentrated and this resulted in methyl 5-methyl-4-oxo-3H-pyrimidine-2-carboxylate (250 mg, 43% yield) as a yellow solid.

[1718]

[1719] To a stirred mixture of methyl 5-methyl-4-oxo-3H-pyrimidine-2-carboxylate (190 mg, 1.13 mmol, 1.00 equiv) and MeOH (5 mL) in water was added NaOH (90.39 mg, 2.26 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified with 1 M aqueous HC1 to pH-6. The precipitated solid was collected to yield 5-methyl-4-oxo-3H-pyrimidine-2-carboxylic acid (60 mg, 34% yield) as an off-white solid.

[1720]

[1721] Prepared as for 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).

[1722] LC-MS (ES, m / z): [M+H] + = 312

[1723] H-NMR (400 MHz, DMSO-d6, ppm) δ 8.79-8.76 (m, 1H), 7.89 (s, 1H), 7.31-7.19 (m, 5H), 3.30-3.28 (d, J = 6.4 Hz, 2H), 2.71 (s, 2H), 1.97 (s, 3H), 1.85-1.81 (m, 4H), 1.77-1.70 (m, 1H), 1.68-1.59 (m, 1H)

[1724] Example 10: N-((l-benzylcyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide

[1725]

[1726] Prepared as for Example 8 using l-(l-benzylcyclobutyl)methanamine (Example 1, 310 mg, 1.77 mmol, 1.00 equiv) and l-methyl-5-oxo-4H-l,2,4-triazole-3- carboxylic acid (Intermediate 1, 278.41 mg, 1.95 mmol, 1.10 equiv).

[1727] LC-MS (ES, m / z): [M+H] + = 301

[1728] H-NMR (300 MHz, DMSO-d6, ppm): 11.67 (br s, 1H), 8.51-8.48 (m, 1H), 7.31-7.19 (m, 5H), 3.56 (s, 3H), 3.25-3.23 (m, 2H), 2.70 (s, 2H), 1.86-1.59 (m, 6H).

[1729] Example 11: N-((l-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2- carboxamide

[1730]

[1731] 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% in water) (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 EtOAc and washed with 2 x 80 mL 10% NaHCO3and 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 :5-1 :3). This resulted in 130 mg (40% yield) of [(1-benzylcyclobutyl)methyl](methyl)amine as a colorless oil.

[1732]

[1733] A 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.HC1 (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 resulted in 12.2 mg of N-[(1-benzylcyclobutyl)methyl]-6-hydroxy-N-methylpyrazine-2-carboxamide as a light yellow solid.

[1734] LC-MS (ES, m / z): [M+H] + = 312

[1735] H-NMR (300 MHz, DMSO-d6, ppm): δ 8.08 (s, 1H), 7.92 (s, 1H), 7.27-7.21 (m, 5H), 3.68 (s, 2H), 3.01 (s, 3H), 2.74-2.72 (m, 2H), 2.05-1.85 (m, 4H), 1.74-1.55 (m, 2H).

[1736] Example 12: N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide

[1737]

[1738] A 100-mL 3-necked 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 CH3I (2164.07 mg, 15.246 mmol, 4.00 equiv). The resulting solution was stirred at -70 °C for 2 hr. The reaction was then quenched by the addition of 20 mL of water and extracted with 2 x 20 mL of ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated. This resulted in 500 mg of 2,2-dimethyl-3-phenylpropanenitrile as a light yellow oil which was used in further reactions without further purification.

[1739]

[1740] A 100-mL sealed tube was charged with 2,2-dimethyl-3-phenylpropanenitrile (500.00 mg, crude), Raney Ni (269.03 mg), and NH3.H2O (11.00 mg) in MeOH (20.00 mL). H2(g) (20 ATM) was introduced into the above sealed tube at 20 °C. The resulting solution was stirred at 20 °C for 10 hr. The solids were filtered off and the filtrate was concentrated. This resulted in 450 mg of 2,2-dimethyl-3-phenylpropan-1-amine as a light yellow oil.

[1741]

[1742] Prepared as for 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).

[1743] LC-MS (ES, m / z): [M+H] + = 286

[1744] H-NMR (300 MHz, DMSO-d6, ppm) δ 8.50 (s, 1H), 8.30 (s, 2H), 7.32-7.30 (m, 2H), 7.24-7.17 (m, 3H), 3.21 (d, J = 6.6 Hz, 2H), 2.55 (s, 2H), 0.84 (s, 6H).

[1745] Example 13: N-((1-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2- carboxamide

[1746]

[1747] A 250-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with cyclobutanenitrile (2.00 g, 24.65 mmol, 1.00 equiv) and THF (100.00 mL). This was followed by the dropwise addition of LDA (2.0 M in THF) (14.2 mL, 28.35 mmol, 1.15 equiv) at -78 °C under stirring. The resulting solution was stirred at this temperature for 30 min 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 1 h. The reaction was then quenched by the addition of 50 mL of water and extracted with 2 x 50 mL of ethyl acetate, the organic layer was dried and concentrated. The residue was applied onto a silica gel column eluted with ethyl acetate / petroleum ether (1 / 20). This resulted in 2.5 g (53% yield) of 1-[(2-fluorophenyl)methyl]cyclobutane-1-carbonitrile as a light yellow oil.

[1748]

[1749] A 250-mL 3 -necked 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 portionwise addition of LiAlH4(0.93 g, 22.18 mmol, 2.00 equiv) at 0-5 °C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and quenched by the addition of 2.5 mL of water, followed by the addition of 7.5 mL of 15% NaOH and again 2.5 mL of water. The solids were filtered off and the filtrate was concentrated. This resulted in 2.1 g (97% yield) of 1-[1-[(2-fluorophenyl)methyl]cyclobutyl]methanamine as a light yellow oil.

[1750]

[1751] Prepared as for Example 1 using 1-[1-[(2-fluorophenyl)methyl]cyclobutyl]methanamine (100.00 mg, 0.517 mmol, 1.00 equiv) and 6-hydroxy-1,3-benzothiazine-2-carboxylic acid (72.49 mg, 0.517 mmol, 1.00 equiv).

[1752] LC-MS (ES, m / z): [M+H] + = 316

[1753] H-NMR (300 MHz, DMSO-d6, ppm) δ 8.53-8.41 (m, 2H), 8.31 (s, 1H), 7.40-7.33 (m, 1H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 2H), 3.50 (s, 2H), 2.77 (s, 2H), 1.91-1.78 (m, 5H), 1.68-1.58 (m, 1H).

[1754] Example 14: N-((l-benzylcyclobutyl)methyl)-l-ethyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide

[1755]

[1756] To a stirred mixture of ethyl carbamothioate (1 g, 7.51 mmol, 1.00 equiv) and ethylhydrazine (451.30 mg, 7.51 mmol, 1.00 equiv) in acetonitrile was added K2CO3(2075.63 mg, 15.02 mmol, 2.00 equiv) portion-wise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight and filtered. The filter cake was washed with DCM (2 x 250 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with DCM / MeOH (10:1) to afford [(Z)-N'-(ethylamino)carbamimidoyl] ethyl carbonate as a light yellow oil (1.1 g, 92% yield).

[1757]

[1758] To a stirred mixture of [(Z)-N'-(ethylamino)carbamimidoyl] ethyl carbonate (1 g, 6.28 mmol, 1.00 equiv) in THF was added CDI (1.02 g, 6.28 mmol, 1.00 equiv) portion-wise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight and concentrated. The residue was purified by preparative HPLC to afford ethyl 1-ethyl-5-oxo-4H-l,2,4-triazole-3-carboxylate as a light yellow solid (300 mg, 26% yield).

[1759]

[1760] 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 H2O 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 as a light yellow solid (100 mg, 43% yield).

[1761]

[1762] As prepared for 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).

[1763] LC-MS (ES, m / z): [M+H] +＝ 315

[1764] H-NMR (400 MHz, DMSO-d6, ppm) 612.24 (br s, 1 H), 8.45-8.42 (m, 1 H), 7.31 -7.25 (m, 4H), 7.24-7.19 (m, 1 H), 3.77-3.72 (m, 2H), 3.30-3.25 (m, 2H), 2.70 (s, 2H), 1.81 -1.69 (m, 5H), 1.65-1.59 (m, 1 H), 1.26-1.24 (m, 3H),

[1765] Example 15: N-((1 -(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine- 2-carboxamide

[1766]

[1767] Cyclobutanenitrile (1.00 g, 12.33 mmol, 1.00 equivalent) and THF (50.00 mL) are placed in a 250-mL 3-neck round-bottom flask purged and maintained with an inert nitrogen atmosphere. Thereafter, LDA (2.0 M in THF) (6.78 mL, 13.56 mmol, 1.10 equivalent) is added dropwise at -78 ° C. The resulting solution is stirred at this temperature for 30 min and a solution of 2- (bromomethyl) -1,3-difluorobenzene (3.06 g, 14.79 mmol, 1.20 equivalent) in THF (10 mL) is added dropwise at -78 ° C. The reaction mixture is warmed to room temperature and stirred for another 1 h. The reactant is then quenched with 50 mL of water and extracted with 2 × 50 mL of ethyl acetate, and the organic layer is dried and concentrated. The residue was applied onto 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 light yellow oil.

[1768]

[1769] 1-[(2,6-difluorophenyl)methyl]cyclobutane-1-carbonitrile (450.00mg, 2.17mmol, 1.00 equivalent) and THF (15.00mL) are placed in a 50-mL 3-neck round-bottom flask purged and maintained under an inert nitrogen atmosphere. Thereafter, LiAlH (164.84g, 4.34mmol, 2.00 equivalent) is added portionwise at 0-5°C. The resulting solution is warmed to room temperature and stirred for 2hr. The reaction mixture is cooled to 0°C and quenched by adding 2.5mL water, 7.5mL 15% NaOH and another 2.5mL water. The solid is filtered off and the filtrate is concentrated. This produces 390mg (85% yield) of 1-[1-[(2,6-difluorophenyl)methyl]cyclobutyl]methylamine as a light yellow oil.

[1770]

[1771] Prepared as for 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).

[1772] LC-MS (ES, m / z): [M+H] + =334

[1773] H-NMR (300 MHz, DMSO-d6, ppm): 8.53-8.46 (m, 2H), 8.31 (m, 1H), 7.39-7.32 (m, 1H), 7.15-7.10 (m, 2H), 3.44-3.42 (m, 2H), 2.73 (s, 2H), 1.98-1.64 (m, 6H).

[1774] Example 16: N-((l-(2,4-difluorobenzyl)cyclobutyl)methyl)-6-oxo-l,6-dihydropyrazine-2- carboxamide

[1775]

[1776] Prepared as for l-[(2,6-difluorophenyl)methyl]cyclobutan-l-carbonitrile (Example 16) using cyclobutanenitrile (1.00 g, 12.33 mmol, 1.00 equiv) and THF (50.00 mL) and l-(bromomethyl)-2,4-difluorobenzene (3.06 g, 14.79 mmol, 1.20 equiv).

[1777]

[1778] Prepared as for l-[l-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using l-[(2,6-difluorophenyl)methyl]cyclobutan-l-carbonitrile (450.00 mg, 2.17 mmol, 1.00 equiv) and LiAlH4(164.84 mg, 4.34 mmol, 2.00 equiv).

[1779]

[1780] Prepared as for Example 1 using l-[l-[(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).

[1781] LC-MS (ES, m / z): [M+H]+ + = 334

[1782] H-NMR (300 MHz, DMSO-d6, ppm): 8.51-8.39 (m, 2H), 8.30 (s, 1H), 7.48-7.40 (m, 1H), 7.24-7.17 (m, 1H), 7.08-7.03 (m, 1H), 3.68-3.36 (m, 2H), 2.73 (s, 2H), 1.91-1.62 (m, 6H).

[1783] Example 17: N-((l-(2,3-difluorobenzyl)cyclobutyl)methyl)-6-oxo-l,6- dihydropyrazine-2-carboxamide

[1784]

[1785] As for 14 (2,6-difluorophenyl)methyl]cyclobutane-l-carbonitrile (Example 16), using cyclobutane carbonitrile (0.50 g, 6.16 mmol, 1.00 equiv) and THF (10 mL) and l-(bromomethyl)-2,3-difluorobenzene (1.53 g, 7.40 mmol, 1.20 equiv).

[1786]

[1787] As for l-[l-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16), using 14 (2,6-difluorophenyl)methyl]cyclobutane-l-carbonitrile (450.00 mg, 2.17 mmol, 1.00 equiv) and LiAlH4(164.84 mg, 4.34 mmol, 2.00 equiv).

[1788]

[1789] As for Example 1, using l-[l-[(2,3-difluorophenyl)methyl]cyclobutyl]methanamine (50.00 mg, 0.24 mmol, 1.00 equiv) and 6-hydroxy-3,4-dihydro-2H-pyran-2-carboxylic acid (33.16 mg, 0.24 mmol, 1.00 equiv).

[1790] LC-MS (ES, m / z): [M+H] + = 334

[1791] H-NMR (300 MHz, DMSO-d6, ppm): 8.51-8.41 (m, 2H), 8.31 (m, IH), 7.31-7.16 (m, 3H), 3.40-3.34 (m, 2H), 3.10 (s, 2H), 2.07-1.24 (m, 6H).

[1792] Example 18: N-((l-benzylcyclopentyl)methyl)-6-oxo-l,6-dihydropyrazine-2- carboxamide

[1793]

[1794] Prepared as for 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 procedure for 1 -(1 -benzylcyclobutyl)methanamine using cyclopentanecarbonitrile (Example 1 ), 50.00 mg, 0.26 mmol, 1.00 equiv).

[1795] LC-MS (ES, m / z): [M+H] + = 312

[1796] H-NMR (300 MHz, DMSO-d6, ppm): 11.98 (br s, 1 H), 8.55-8.22 (m, 3H), 7.32-7.21 (m, 5H), 3.22-3.20 (m, 2H), 2.51 (s, 2H), 1.58-1.44 (m, 8H).

[1797] Example 19: N-((1 -(2-methylbenzyl)cyclobutyl)methyl)-6-oxo-1,6-dihydropyrazine-2- carboxamide

[1798]

[1799] 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).

[1800]

[1801] 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 LiAIH4(215.10 mg, 5.67 mmol, 3.00 equiv).

[1802]

[1803] Prepared as for 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).

[1804] LC-MS (ES, m / z): [M+H] + = 312

[1805] H-NMR (300 MHz, DMSO-d6, ppm): 8.49-8.41 (m, 2H), 8.21 (s, 1H), 7.19-7.11 (m, 5H), 3.52-3.48 (m, 2H), 2.79 (s, 2H), 2.20 (s, 3H), 1.99-1.56 (m, 6H)

[1806] Example 20: N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide

[1807]

[1808] Prepared as for l-[l-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using cyclobutanenitrile (1.2 g, 14.79 mmol, 1.00 equiv) and l-(bromomethyl)-2- fluorobenzene (3.08 g, 16.27 mmol, 1.10 equiv).

[1809]

[1810] Prepared as for l-[l-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using l-[(2-fluorophenyl)methyl]cyclobutane-l-carbonitrile (500.00 mg, 2.642 mmol, 1.00 equiv) and LiAlH4(200.57 mg, 5.284 mmol, 2.00 equiv).

[1811]

[1812] Prepared as for Example 3 using l-[l-[(2-fluorophenyl)methyl]cyclobutyl]methanamine (30.00 mg, 0.155 mmol, 1.00 equiv) and l-methyl-5-oxo-4H-l,2,4-triazole-3-carboxylic acid (Intermediate 1, 22.21 mg, 0.155 mmol, 1.00 equiv).

[1813] LC-MS (ES, m / z): [M+H]+=319

[1814] H-NMR (300 MHz, DMSO-d6, ppm) δ 12.28 (s, 1H), 8.57-8.54 (m, 1H), 7.41-7.36 (m, 1H), 7.33-7.24 (m, 1H), 7.20-7.12 (m, 2H), 3.30-3.28 (m, 2H), 2.73 (s, 2H), 1.89-1.64 (m, 5H), 1.61-1.52 (m, 1H)

[1815] Example 21 : N-((1-(2,6-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5- dihydro-1H-1,2,4-triazole-3-carboxamide

[1816]

[1817] Prepared as for 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).

[1818] LC-MS (ES, m / z): [M+H] + = 337

[1819] H-NMR (300 MHz, DMSO-d6, ppm): 12.28 (s, 1H), 8.64-8.60 (m, 1H), 7.40-7.34 (m, 1H), 7.15-7.09 (m, 2H), 3.37-3.32 (m, 5H), 2.72 (s, 2H), 1.86-1.51 (m, 6H).

[1820] Example 22: N-((1-(2,4-difluorobenzyl)cyclobutyl)methyl)-1-methyl-5-oxo-4,5- dihydro-1H-1,2,4-triazole-3-carboxamide

[1821]

[1822] Prepared as for 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).

[1823] LC-MS (ES, m / z): [M+H] + = 337

[1824] H-NMR (300 MHz, DMSO-d6, ppm): 12.29 (s, 1H), 8.61-8.57 (m, 1H), 7.50-7.42 (m, 1H), 7.24-7.18 (m, 1H), 7.17-7.02 (m, 1H), 3.37 (s, 3H), 3.32-3.27 (m, 2H), 2.71 (s, 2H), 1.86-1.59 (m, 6H).

[1825] Example 23: N-(l-(l-benzylcyclobutyl)ethyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide

[1826]

[1827] To a stirred mixture of l-benzylcyclobutane-l-carbonitrile (2.9 g, 16.935 mmol, 1.00 equiv) in THF was added 1M CH3Li (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 adding saturated NH4Cl (aq) (20 mL) at -78 °C. The aqueous layer was extracted with EtOAc (2 x 40 mL). The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EA (7: 1) to give l-(l-benzylcyclobutyl)ethanone (1.5 g, 47% yield) as a light yellow oil.

[1828]

[1829] To a stirred mixture of l-(l-benzylcyclobutyl)ethanone (1.4 g, 7.436 mmol, 1.00 equiv) and NH2OH.HCl (0.52 g, 7.436 mmol, 1.00 equiv) in EtOH was added TEA (2.26 g, 22.308 mmol, 3.00 equiv) portion-wise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 10 h and quenched with water at room temperature. The aqueous layer was extracted with EtOAc (2 x 20 mL) and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 : 1) to give (Z)-N-[l-(l-benzylcyclobutyl)ethylidene]hydroxylamine (350 mg, 23% yield) as a light yellow oil.

[1830]

[1831] 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 nitrogen atmosphere. The mixture was hydrogenated at room temperature under hydrogen atmosphere using a hydrogen balloon for 5 h. The resulting mixture was filtered and the catalyst was washed with MeOH (2 x 20 mL). The filtrate was concentrated under reduced pressure. This resulted in 1-(1-benzylcyclobutyl)ethanamine (180 mg) as a light yellow solid.

[1832]

[1833] As for 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).

[1834] LC-MS (ES, m / z): [M+H] + = 315

[1835] H-NMR (400 MHz, DMSO-d6, ppm) δ 12.21 (br s, 1H), 8.15-8.13 (m, 1H), 7.32-7.21 (m, 5H), 4.16-4.12 (m, 1H), 3.30 (s, 3H), 2.82-2.62 (m, 2H), 2.10-1.30 (m, 6H), 1.12-1.10 (m, 3H).

[1836] 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)

[1837]

[1838] N-[1-(1-benzyloxycyclobutyl)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 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH - preparative; Flow: 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: 1.82 min) to give N-(1-(1-benzyloxycyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide as an off-white solid (13 mg) and N-(1-(1-benzyloxycyclobutyl)ethyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide as an off-white solid (9.1 mg).

[1839] LC-MS Enantiomer A (ES, m / z): [M+H] + = 315

[1840] LC-MS Enantiomer B (ES, m / z):

[1841] [M+H] + = 315

[1842] H-NMR Enantiomer A (400 MHz, DMSO-d6, ppm) δ 12.20 (br s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.33-7.23 (m, 5H), 4.17-4.13 (m, 1H), 3.36 (s, 3H), 2.82-2.63 (m, 2H), 2.08-1.98 (m, 1H), 1.87-1.81 (m, 2H), 1.77-1.67 (m, 1H), 1.66-1.53 (m, 1H), 1.44-1.33 (m, 1H) 1.13 (d, J = 8.0 pHz, 3H)

[1843] H-NMR Enantiomer B (400 MHz, DMSO-d6, ppm) δ 12.20 (br s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.33-7.23 (m, 5H), 4.17-4.13 (m, 1H), 3.36 (s, 3H), 2.82-2.63 (m, 2H), 2.08-1.98 (m, 1H), 1.87-1.81 (m, 2H), 1.77-1.67 (m, 1H), 1.66-1.53 (m, 1H), 1.44-1.33 (m, 1H) 1.13 (d, J = 8.0 Hz, 3H)

[1844] 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.

[1845] Example 25: 1-Methyl-5-oxo-N-((1-(1-phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

[1846]

[1847] In a 100-mL round-bottom flask, to a solution of cyclobutanenitrile (1.31 g, 16.15 mmol, 1.00 equiv) in THF (10 mL) was added dropwise LDA (1M in THF, 19.5 mL, 19.50 mmol) at -78°C under N2atmosphere. 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 THF was added dropwise and the mixture was stirred for another 60 min. The reaction was quenched with water / saturated NH4Cl (30 mL), then the mixture was extracted with ether / EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to give the crude product which was directly purified by flash chromatography (EtOAc / PE = 1 / 3) to give a mixture. This resulted in 1-(1-phenylethyl)cyclobutane-1-carbonitrile (1.25 g, 42% yield) as a light yellow oil.

[1848]

[1849] To a stirred solution of 1-(1-phenylethyl)cyclobutan-1 -amine (500 mg, 2.70 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0 °C under nitrogen atmosphere was added LAH (204.86 mg, 5.40 mmol, 2.00 equiv) portion wise. The reaction was quenched by the addition of 15% NaOH (aq.) (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 yielded 1-[1-(1- phenylethyl)cyclobutyl]methanamine (350 mg, 69% yield) as a light yellow oil.

[1850]

[1851] As prepared for 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).

[1852] LC-MS (ES, m / z): [M+H] + = 315

[1853] H-NMR (400 MHz, DMSO-d6, ppm): 11.50 (br s, 1 H), 8.38 (s, 1 H), 7.30-7.17 (m, 5H), 3.52-3.31 (m, 4H), 3.31-3.16 (m, 1 H), 2.89-2.84 (m, 1 H), 2.01-1.94 (m, 1 H), 1.83-1.77 (m, 2H), 1.69-1.68 (m, 2H), 1.52-1.49 (m, 1 H), 1.18-1.25 (m, 3H).

[1854] Example 26 and 27: 1 -methyl-5-oxo-N-((1 -(1 -phenylethyl)cyclobutyl)methyl)- 4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide (enantiomer A) and 1 -methyl-5- oxo-N-((1 -(1 -phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4-triazole-3- carboxamide (enantiomer B)

[1855]

[1856] 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-1 H-1,2,4-triazole-3-carboxamide enantiomer A (20 mg) as a white solid and 1 -methyl-5-oxo-N-({1 -[(1 R)-1 - phenylethyl]cyclobutyl}methyl)-4H-1,2,4-triazole-3-carboxamide enantiomer B (30 mg) as a white solid.

[1857] LC-MS (enantiomer A) (ES, m / z): [M+H] + = 315

[1858] LC-MS (enantiomer B) (ES, m / z): [M+H] + = 315

[1859] H-NMR (enantiomer A) (300 MHz, DMSO-d6, ppm): 12.00 (br s, 1 H), 8.41-8.37 (m, 1 H), 7.28-7.19 (m, 5H), 3.37-3.35 (m, 1 H), 3.19 (s, 3H), 3.17-3.15 (m, 1 H), 2.90-2.83 (m, 1 H), 2.01-1.53 (m, 6H), 1.28-1.23 (m, 3H).

[1860] H-NMR (enantiomer B) (300 MHz, DMSO-d6, ppm): 12.00 (br s, 1 H), 8.41-8.37 (m, 1 H), 7.28-7.19 (m, 5H), 3.37-3.35 (m, 1 H), 3.19 (s, 3H), 3.17-3.15 (m, 1 H), 2.90-2.83 (m, 1 H), 2.01-1.53 (m, 6H), 1.28-1.23 (m, 3H).

[1861] One of the enantiomers A and B is (S)-1 -methyl-5-oxo-N-(’(1 -(1 - phenylethyl)cyclobutyl)methyl)-4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide and the other is (R)-1 -methyl-5-oxo-N-(’(1 -(1 -phenylethyl)cyclobutyl)methyl)-4,5-dihydro- 1 H-1,2,4-triazole-3-carboxamide.

[1862] Example 28: N-((1 -(methoxy(phenyl)methyl)cyclobutyl)methyl)-1 -methyl-5-oxo- 4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide

[1863] Example 28: N-((1 -(methoxy(phenyl)methyl)cyclobutyl)methyl)-1 -methyl-5-oxo- 4,5-dihydro-1 H-1,2,4-triazole-3-carboxamide

[1864] To a solution of cyclobutanenitrile (2.29 g, 28.27 mmol, 1.00 equiv) in THF (20 mL) at -78 °C under N2atmosphere was added LDA (1 M in THF, 36.75 mL, 36.75 mmol, 1.30 equiv) dropwise. The reaction mixture was stirred at -78 °C for 30 min, then a solution of benzaldehyde (3 g, 28.27 mmol, 1.00 equiv) in 5 mL THF was added dropwise and the mixture was stirred for another 60 min. The reaction was quenched with water / saturated NH4Cl 30 mL) and the mixture was extracted with ether / EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2S04and concentrated under vacuum to give the crude product which was directly purified by flash chromatography (EtOAc / PE = 1 / 3) to give a mixture. This resulted in 1-[hydroxy(phenyl)methyl]cyclobutane-1-carbonitrile (1.8 g, 34% yield) as a light yellow oil.

[1865]

[1866] To a solution of 1-[hydroxy(phenyl)methyl]cyclobutane-1-carbonitrile (400 mg, 2.14 mmol, 1.00 equiv) in DMF was added NaHH (111 mg, 2.78 mmol, 1.30 equiv) at 0 °C. The mixture was stirred for 15 min. CH3I (333.54 mg, 2.350 mmol, 1.10 equiv) was added and the mixture was warmed to RT and stirred for 5 h. The reaction mixture was quenched by water and extracted with DCM (3 x 25 mL). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE / EtOAc (5:1) to give 1-[methoxy(phenyl)methyl]cyclobutane-1-carbonitrile (300 mg, 70% yield) as a light yellow oil.

[1867]

[1868] To a stirred solution / mixture of 1-[methoxy(phenyl)methyl]cyclobutan-1- carbonitrile (260 mg, 1.29 mmol, 1.00 equiv) in diethyl ether (10 mL) was added LAH (98.06 mg, 2.58 mmol, 2.00 equiv) portion-wise 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 (15% aqueous solution) (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 yielded 1-{1-[methoxy(phenyl)methyl]cyclobutyl}methanamine (220 mg, 83% yield) as a light yellow oil.

[1869]

[1870] Prepared as for 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).

[1871] LC-MS (ES, m / z): [M+H] + = 331

[1872] H-NMR (400 MHz, DMSO-d6, ppm): 12.28 (s, 1H), 8.29 (s, 1H), 7.39-7.30 (m, 5H), 4.27 (s, 1H), 3.35-3.20 (m, 5H), 3.16 (s, 3H), 2.10-1.93 (m, 2H), 1.80-1.71 (m, 2H), 1.65-1.55 (m, 2H).

[1873] Example 29: 1-methyl-N-((1-(2-methylbenzyl)cyclobutyl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide

[1874]

[1875] Prepared as for 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).

[1876] LC-MS (ES, m / z): [M+H] + = 315

[1877] H-NMR (400 MHz, DMSO-d6, ppm): 12.27 (s, 1H), 8.66 (s, 1H), 7.15-7.11 (m, 4H), 3.42 (s, 2H), 3.36 (s, 3H), 2.67 (s, 2H), 2.19 (s, 3H), 1.82-1.69 (m, 5H), 1.50-1.46 (m, 1H).

[1878] Example 30: N-((l-(2-chlorobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide

[1879]

[1880] Prepared as for l-[l-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using l-(bromomethyl)-2-chlorobenzene (1 g, 4.867 mmol, 1.00 equiv) and cyclobutanenitrile (0.39 g, 4.867 mmol, 1.00 equiv).

[1881]

[1882] Prepared as for l-[l-[(2,6-difluorophenyl)methyl]cyclobutyl]methanamine (Example 16) using l-[(2-chlorophenyl)methyl]cyclobutane-l-carbonitrile (500 mg, 2.431 mmol, 1.00 equiv) and LiAlH4(184.52 mg, 4.862 mmol, 2.00 equiv).

[1883]

[1884] Prepared as for Example 8 using l-{l-[(2-chlorophenyl)methyl]cyclobutyl}methanamine (50 mg, 0.238 mmol, 1.00 equiv) and l-methyl-5-oxo-2H-l,2,4-triazole-3-carboxylic acid (34.12 mg, 0.238 mmol, 1.00 equiv).

[1885] LC-MS (ES, m / z): [M+H] + = 335

[1886] H-NMR (400 MHz, DMSO-d6, ppm) δ 12.28 (br s, 1H), 8.65-8.62 (m, 1H), 7.45-7.41 (m, 2H), 7.32-7.24 (m, 2H),...

Claims

1. A compound of Formula (I): wherein: W is 0, 1, or 2 or salts and / or solvates thereof, R 1 R is H or C 1-4 alkyl; R 2 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 R is H, halo or C 1-4 alkyl; R 4 R is H, halo or C 1-4 alkyl; R 5 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 atom to which they are attached form a C 5-11 spiro carbocyclic, 4- to 7-membered heterocyclic ring, or C 3-6 cycloalkyl, wherein said spiro carbocyclic, heterocycloalkyl, or cycloalkyl can be optionally substituted with one or more groups selected from C 1-3 alkyl, C 1-3 haloalkyl, and halo; R 6 is H or C 1-4 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, said aryl or heteroaryl being optionally substituted with one or more A 1 substituents; A 1 independently selected from the group consisting of 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 ; R g is H or C 1-4 alkyl; R h is H or C 1-4 alkyl; R j is C 1-4 alkyl; and provided that Formula (I) is not N-((l-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2- carboxamide: or when A represents a substituted phenyl group which is substituted by one or more A 1 R 5 together with the ortho-positioned substituent A 1 (CH2) v wherein v represents 1, 2 or 3 and wherein one of the CH2groups can optionally be replaced by O; B is a monocyclic or bicyclic heterocycle, or a monocyclic or bicyclic heteroaryl, wherein the heterocycle or heteroaryl can be optionally substituted with one or more B 1 substituents; B 1 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo (=0) or thioxo (=S), C 0-6 alkylene(OH); or salts and / or solvates thereof.

2. A compound of Formula (IA) according to claim 1: wherein: or salts and / or solvates thereof, and provided that Formula (IA) is not N-((l-benzylcyclobutyl)methyl)-6-hydroxypyrazine-2- carboxamide: R 1 is H or C 1-4 alkyl; R 2 is 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 alkyl; R 4 is H or C 1-4 alkyl; R 5 is 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 atom to which they are attached form a C 3-6 cycloalkyl, wherein said cycloalkyl can optionally be substituted with one or more groups selected from C 1-3 alkyl, C 1-3 haloalkyl and halo; R 6 is H or C 1-4 alkyl; R 7 H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; A is monocyclic or bicyclic aryl, or monocyclic or bicyclic heteroaryl, said aryl or heteroaryl being optionally substituted with one or more A 1 substituted: A 1 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 ; R g is H or C 1-4 alkyl; R h is H or C 1-4 alkyl; R j is C 1-4 alkyl; or when A represents a substituted phenyl group which is substituted by one or more A 1 R1represents H or A 5 together with the ortho-positioned substituent A 1 and together represent (CH2) v wherein v represents 1, 2 or 3 and wherein one of said CH2groups can optionally be replaced by O; B is a monocyclic or bicyclic heterocycle, or a monocyclic or bicyclic heteroaryl, which heterocycle or heteroaryl can be optionally substituted with one or more B 1 substituents; B 1 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 0-6 alkylene(OH); 3. A compound according to claim 1 or claim 2, or a salt and / or solvate thereof, which is the compound or a pharmaceutically acceptable salt and / or solvate thereof.

4. A compound according to any one of claims 1 to 3, or a salt and / or solvate thereof, which is a compound of Formula (IA): or salts and / or solvates thereof.

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

12. A compound according to any one of claims 4 to 11, or a salt and / or solvate thereof, wherein A is selected from the group consisting of:

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

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

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

8. A compound or salt and / or solvate thereof according to any one of claims 4 to 6, wherein R 5 is C0-6alkylene(C 3-6 cycloalkyl), for example C 3-6 cycloalkyl, for example cyclopropyl or cyclobutyl, especially cyclopropyl.

9. A compound according to any one of claims 4 to 6, or a salt and / or solvate thereof, wherein R 4 and R 5 together with the atoms to which they are attached form a C 3-6 cycloalkyl, for example a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring, especially a cyclobutyl ring.

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

13. A compound according to any one of claims 4 to 12, or a salt and / or solvate thereof, wherein B is selected from the group consisting of: wherein: A 1A halo, for example F, Br or CI; C 1-6 alkyl, for example methyl; or C 1-6 alkoxy, for example OMe; and A 1B is H or halo, e.g. F, Br or CI, especially F.

14. A compound according to claim 1, or a salt and / or solvate thereof, which is selected from the group consisting of: For example N-((l-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide; B 1A H or C 1-6 alkyl, for example methyl; and B 2A H or C 1-6 alkyl, for example methyl. N-((l-benzylcyclobutyl)methyl)-5-hydroxy-6-methylnicotinamide; N-((l-benzylcyclobutyl)methyl)-5-hydroxy-4-methylnicotinamide; N-((l-benzylcyclobutyl)methyl)-lH-l,2,3-triazole-5-carboxamide; N-((l-benzylcyclobutyl)methyl)-2-oxo-2,3-dihydropyrimidine-4-carboxamide; N-((l-benzylcyclobutyl)methyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide; N-((l-benzylcyclobutyl)methyl)-5-oxo-2,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-((l-benzylcyclobutyl)methyl)-5-methyl-6-oxo-l,6-dihydropyrimidine-2-carboxamide; N-((l-benzylcyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-((l-benzylcyclobutyl)methyl)-6-hydroxy-N-methylpyrazine-2-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-6-hydroxypyrazine-2-carboxamide; N-((l-(2-fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((l-benzylcyclobutyl)methyl)-l-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-((l-(2,6-difluorobenzyl)cyclobutyl)methyl)-6-oxo-l,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- 1 H- 1,2,4-triazole-3-carboxamide; N-(3-(2-Bromophenyl)-2,2-dimethylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide; N-((l-(2-Bromobenzyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4- triazole-3-carboxamide; N-(3,3-Dimethyl-4-phenylbutan-2-yl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-(3,3-Dimethyl-4-phenylbutan-2-yl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-(2-Benzylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(2-Benzyl-3-hydroxy-2-methylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-(2-Benzyl-3-hydroxy-2-methylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-(2-Methoxy-3-phenylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-(2-Benzyl-2-methylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-((l-Benzylcyclohexyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide; N-((l-Benzyl-3,3-difluorocyclobutyl)methyl)-6-oxo-l,6-dihydropyrazine-2-carboxamide; N-((l-(3-Fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-((l-(4-Fluorobenzyl)cyclobutyl)methyl)-6-hydroxypyrazine-2-carboxamide; N-(2-Cyclobutyl-3-phenylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-((l-(l-(2,4-Difluorophenyl)ethyl)cyclobutyl)methyl)-l-methyl-5-oxo-4,5-dihydro-lH- 1,2,4-triazole-3-carboxamide; N-(2-Cyclopropyl-3-phenylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3- carboxamide; N-(2-Benzylbutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(2-Benzylpentyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,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- 1 H-inden-2-yl)methyl)-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; 1 -methyl- N-(3-methyl-3-phenylbutyl)-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide; 1 -methyl-5-oxo- N-(( 1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; N-(( 1 -(2-methoxybenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 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- 1 H-imidazole-4-carboxamide; N-(2-benzyl-3-hydroxypropyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide; N-(2,2-dimethyl-3-phenylpropyl)-N, 1 -dimethyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide; N-(( 1 -(2,4-difluorobenzyl)cyclohexyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; N-((2S,3S)-3-benzylpentan-2-yl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3-carboxamide; N-(( 1 -(3-methoxybenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; N-(( 1 -(2-(difluoromethyl)benzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole- 3-carboxamide; N-(( 1 -(3-cyclopropylbenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; N-(2-cyclopropyl-3-(3-fluorophenyl)propyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; N-(( 1 -(3-chlorobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; 1 -methyl-5-oxo- N-(2-(thiophen-2-ylmethyl)butyl)-4,5-dihydro- 1 H- 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 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)- 1 -methyl-5-thioxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)- 1 -methyl-5-thioxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)- 1 -methyl-5-thioxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; 1 -methyl-5-oxo-N-(2-(2,4,6-trifluorobenzyl)butyl)-4,5-dihydro- 1 H- 1,2,4-triazole-3- carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(2-cyclopropyl-3-(3,4-difluorophenyl)propyl)- 1 -methyl-5-thioxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(( 1 -(3 -cyanobenzyl)cyclobutyl)methyl)- 1 -methyl-5-oxo-4,5-dihydro- 1 H- 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)-3-oxo-2,3-dihydroisoxazole-5- carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-3-oxo-2,3-dihydroisoxazole-5- carboxamide; N-((l-(3,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(-3-(2,4-difluorobenzyl)pentan-2-yl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole- 3-carboxamide; N-((l-(3,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; 6-oxo-N-((l-(2,4,5-trifluorobenzyl)cyclobutyl)methyl)-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-((l-(2,4-difluorobenzyl)cyclopentyl)methyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-l,6-dihydropyridazine-3- carboxamide; 1 -methyl-5-oxo-N-(( 1 -(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; 1 -methyl-5-oxo-N-(( 1 -(2,3,4-trifluorobenzyl)cyclobutyl)methyl)-4,5-dihydro- 1 H- 1,2,4- triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- carboxamide; N-(2-cyclopropyl-3-(2,5-difluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2- 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)cyclopentyl)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-((l-(2,4-difluorobenzyl)spiro[2.2]pentan-l-yl)methyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(3-(2-chloro-4-fluorophenyl)-2-cyclopropylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(2-cyclopropyl-3-(2,4-difluorophenyl)-2-methylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)-4,4,4-trifluorobutyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-((l-(2,4-difluorobenzyl)-3-fluorocyclobutyl)methyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)propyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-6-oxo-l,6-dihydropyrimidine-2-carboxamide; N-(3-(4-chloro-2-fluorophenyl)-2-cyclopropylpropyl)-l-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazole-3-carboxamide; N-(2-(2,4-difluorobenzyl)-2-fluorobutyl)-6-oxo-l,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-l,6-dihydropyrimidine-2-carboxamide; N-(2-cyclopropyl-3-(4-fluorophenyl)-2-methylpropyl)-5-methyl-6-oxo-l,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 a salt and / or solvate of any of the foregoing.

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

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

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), or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 3 to 14, and a pharmaceutically acceptable carrier or excipient.

19. 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 condition in which inhibition of mPTP provides a therapeutic or prophylactic effect.

20. 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 condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply, for example a disease or condition selected from the group consisting of a degenerative or neurodegenerative disease, a central nervous system disorder, an ischaemia reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of ageing and a renal disease.

21. A compound according to any one of claims 3 to 14, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition according to claim 18, for use in the treatment or prevention of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply, for example a disease or condition selected from the group consisting of a degenerative or neurodegenerative disease, a central nervous system disorder, an ischaemia reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of ageing and a renal disease.

22. The 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 the treatment or prevention of a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply, for example a disease or condition selected from the group consisting of a degenerative or neurodegenerative disease, a central nervous system disorder, an ischaemia reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of ageing and a renal disease.

23. A method of treating or preventing a disease or condition in which inhibition of mPTP provides a therapeutic or prophylactic effect, wherein the proviso of formula (I) does not apply, for example a disease or condition selected from the group consisting of a degenerative or neurodegenerative disease, a central nervous system disorder, an ischemia reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, a disease of aging, and a kidney disease, the method comprising administering to an individual in need thereof an effective amount of a compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 14 or a pharmaceutical composition according to claim 18.

24. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use, the pharmaceutical composition for use, the use, or the method according to any one of claims 18 to 23, wherein the disease or condition is selected from the group consisting of a degenerative or neurodegenerative disease (e.g. Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington’s disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich’s ataxia, in particular Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis), a central nervous system disorder (e.g. AIDS dementia complex, depression, schizophrenia, and epilepsy), an ischemia reperfusion injury (e.g. acute myocardial infarction, stroke, renal ischemia reperfusion injury, and organ injury during transplantation), a metabolic disease (e.g. liver steatosis, diabetes, diabetic neuropathy, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and feeding behavior, and non-alcoholic fatty liver disease), an inflammatory or autoimmune disease (e.g. acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis), a disease of aging (e.g. bone repair, bone frailty in osteoporosis and sarcopenia in aging, and kidney disease), a kidney disease (e.g. chronic kidney disease associated with APOL1 genetic variants and chronic kidney disease), a mitochondrial disease (e.g. Leigh syndrome, Leber’s hereditary optic neuropathy, and related disorders and conditions), and a TDP-43 disease or condition, e.g. TDP-43 associated neurodegeneration (e.g. amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensory and motor neuropathy, primary lateral sclerosis, progressive muscular atrophy, inclusion body myopathy associated with early-onset Paget disease of bone and frontotemporal dementia, Perry disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer’s disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and TDP-43 encephalopathy with sclerosis of the brain associated with age).

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

26. The compound, 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 another therapeutic agent.

27. A compound of formula (II): wherein B is as defined in any preceding claim; or a salt, e.g. a pharmaceutically acceptable salt thereof.

28. A compound of formula (III):

29. A compound of formula (IV): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; or a salt, e.g., a pharmaceutically acceptable salt thereof. or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein B 1 as defined in any preceding claim; 30. A compound of formula (VII): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; 31. A compound of formula (XII): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 2 , R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; 32. A compound of formula (XIII): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 2 , R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; 33. A compound of formula (XIV): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 4 , R 5 and A are as defined in any preceding claim; 34. A compound of formula (XV): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; 35. A compound of formula (XVI): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; 36. A compound of formula (XVII): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim; 37. A compound of formula (XVIII): or a salt, e.g. a pharmaceutically acceptable salt thereof. wherein R 4 , R 5 , R 6 , R 7 and A are as defined in any preceding claim, ​

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