MAGL inhibitors

Abstract

Provided herein are substituted 6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester compounds and pharmaceutical compositions comprising the same. The compounds and compositions provided herein are useful as inhibitors of MAGL. Further, the compounds and compositions as provided herein are useful in the treatment of diseases and disorders that benefit from the inhibition of MAGL.

Description

TECHNICAL FIELD

[0001] The present invention relates to compounds that are monoacylglycerol lipase (MAGL) inhibitors. Different aspects of the invention relate to pharmaceutical compositions comprising said compounds and the use of these compounds for the treatment of diseases and disorders related to the modulation of endocannabinoid system signaling activities. BACKGROUND

[0002] MAGL is a member of the serine hydrolase superfamily. MAGL is expressed throughout the brain in neurons, microglia, astrocytes and oligodendrocytes. MAGL is the major enzyme controlling the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) (Blankman et al. Chem Biol. 2007; Nomura et al. Science. 2011).

[0003] 2-AG is the most abundant endocannabinoid ligand in the brain, where it acts as a retrograde messenger to reduce excessive neurotransmission by activating presynaptic CB1 receptors (Kano et al. Physiol Rev. 2009; Katona and Freund. Physiol Rev. 2009); to modulate immune responses by activating CB2 receptors of microglia (Turcotte et al. Cell Mol Life Sci. 2016); and to promote neuroprotection by, for example, its effects on oligodendrocyte production and survival (Ilyasov et al. Front Neurosci. 2018).

[0004] AA is one of the most abundant fatty acids in the brain and is the main precursor of eicosanoids such as prostaglandins and leukotrienes, which are known inflammatory mediators.

[0005] MAGL sits at the crossroads between the endocannabinoid and eicosanoid signaling systems. Inhibition or activation of MAGL is a promising therapeutic approach for the prevention or treatment of brain disorders whose pathological features include excessive neurotransmission, neuroinflammation or neurodegeneration, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, epilepsy, pain, migraine, addiction, anxiety, depression and other stress-related disorders (Grabner et al. Pharmacol Ther. 2017; Mulvihill et al. Life Sci. 2013; et al. Biochem Pharmacol. 2018).

[0006] WO 2019 / 046318 discloses spiro compounds that are MAGL inhibitors.

[0007] WO 2019 / 046330 discloses spiro compounds that are MAGL inhibitors.

[0008] Despite the progress in MAGL research, there remains a need for compounds that are potent, efficacious and selective MAGL inhibitors and are also effective in treating neurological and psychiatric disorders related to diseases or disorders that would benefit from inhibition of MAGL activation. SUMMARY

[0009] It is an object of the present invention to provide compounds that inhibit MAGL. Accordingly, the present invention provides a compound of Formula (I):

[0010]

[0011] wherein

[0012] R1represents -C(O)NHR2, -C(O)N(CH3)R2, -C(O)NR3R4, -C(O)NHCH2R2, or -C(O)NHC(O)R2;

[0013] R2represents phenyl, 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S, 6-membered heterocycle having one or two heteroatoms independently selected from N or O, C3-C7cycloalkyl, or 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O;

[0014] R3and R4together with the N to which they are attached form a 9- or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms independently selected from N or O, or a 6-membered heterocycle having one or two heteroatoms independently selected from N or O; and

[0015] wherein each phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7cycloalkyl, 7-membered bicyclic heterocycle, or 9- or 10-membered bicyclic heterocycle is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH;

[0016] or a pharmaceutically acceptable salt thereof.

[0017] In a further aspect of the application, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

[0018] In a further aspect of the application, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from pain, epilepsy / seizure disorders, Alzheimer’s disease, Huntington’s Chorea, Huntington’s disease, multiple sclerosis, obsessive compulsive disorder, Parkinson’s disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

[0019] In a further aspect of the application, there is provided a method for the treatment of a neurological and / or psychiatric disorder selected from pain, epilepsy / seizure disorders, Alzheimer’s disease, Huntington’s Chorea, Huntington’s disease, multiple sclerosis, obsessive compulsive disorder, Parkinson’s disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0020] In a further aspect of the application, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from pain, epilepsy / seizure disorders, Alzheimer’s disease, Huntington’s Chorea, Huntington’s disease, multiple sclerosis, obsessive compulsive disorder, Parkinson’s disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

[0021] Other objects and advantages of the compounds described herein will become apparent from the following detailed description. It is to be understood, however, that the detailed description and specific examples, while indicating the preferred embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[0022] Incorporated by Reference

[0023] All publications and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant to the disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1Example 6 anti-pain effect in the rat formalin model; y-axis: counts - hind paw licking frequency; x-axis: time period (min). Indicated is the level of significance of post-hoc comparisons (vs vehicle group): * p<0.05, ** p<0.01, *** p<0.001.

[0025] Figure 2 Example 8 anti-pain effect in the rat formalin model; y-axis: counts - hind paw licking frequency; x-axis: time period (min). Indicated is the level of significance of post-hoc comparisons (vs vehicle group): * p<0.05, ** p<0.01, *** p<0.001.

[0026] Figure 3 Example 6 effect in the MEST model; y-axis: estimated seizure threshold (CC 50 current (mA); indicated is the level of significance of post-hoc comparisons (vs vehicle group): *** p<0.001.

[0027] Figure 4 Example 8 effect in the MEST model; y-axis: estimated seizure threshold (CC 50 current (mA); indicated is the level of significance of post-hoc comparisons (vs vehicle group): *** p<0.001.

[0028] Figure 5 Example 6 effect in the kainic acid seizure model; y-axis: counts - number of animals from 12 groups showing forelimb clonus. Indicated is the level of significance of post-hoc comparisons (vs vehicle group): ** <0.01, *** <0.001.

[0029] Figure 6 Example 8 effect in the kainic acid seizure model; y-axis: counts - number of animals from 12 groups showing forelimb clonus. Indicated is the level of significance of post-hoc comparisons (vs vehicle group): *** <0.001. DETAILED DESCRIPTION

[0030] DEFINITIONS

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural, unless specifically stated otherwise. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0032] The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[0033] As used herein, the term "acceptable" or "pharmaceutically acceptable" (in reference to a formulation, composition or ingredient) means having no persistent detrimental effects on the general health of the subject being treated or no detrimental effects on the biological activity or properties of the compound, and is relatively nontoxic.

[0034] As used herein, "improvement" in the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any reduction, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient, that is attributable to or associated with administration of the compound or composition, regardless of the severity.

[0035] As used herein, the term "anti-nociceptive effect" relates to the ability of a compound to increase a subject's tolerance to pain, treat pain, delay pain, and / or reduce pain.

[0036] As used herein, the term "co-administration" and the like, contemplate administration of selected therapeutic agents to a single patient and are intended to embrace the administration of two or more agents as part of a multipledose regimen. As used herein, the term "co-administration" and the like, contemplate administration of selected therapeutic agents to a single patient and are intended to embrace the administration of two or more agents as part of a multiple dose regimen.

[0037] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound being administered to reduce to some extent the symptoms of the disease or disorder being treated. The result can be a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein that is needed to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate "effective amount" in any individual case can be determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective, at dosages and to some extent, to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that "an effective amount" or "a therapeutically effective amount" can vary from subject to subject, due to variation in metabolism of the compound (I), age, body weight, general condition of the subject, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example, only, dosages can be determined by a routine experiment including, but not limited to, a dose escalation clinical trial.

[0038] As used herein, the term "inhibits," "inhibiting," or "inhibitor" of an enzyme refers to the inhibition of the activity of the enzyme.

[0039] As used herein, the term "isolated" means that the component of interest is separated or removed from components not of interest. The isolated substance can be in a dry or semi-dry state, or in solution, including but not limited to an aqueous solution. The isolated component can be in a homogeneous state or the isolated component can be part of a pharmaceutical composition comprising additional pharmaceutically acceptable carriers and / or excipients.

[0040] As used herein, the term "modulate" means to interact, directly or indirectly, with a target to alter the activity of the target, including, by way of example only, increasing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.

[0041] As used herein, the term "modulator" refers to a compound that changes the activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a particular activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator that increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator results in an activity that does not exist in the absence of the modulator.

[0042] As used herein, the term "prophylactically effective amount" refers to the amount of a composition to be administered to a patient that will lessen, to some extent, one or more of the symptoms of the disease, condition, or disorder being treated. In these prophylactic applications, the amounts can depend on the health of the patient, weight of the patient, and the like. It will also be considered within the skill of the art, by routine experimentation, to determine these prophylactically effective amounts, including but not limited to, dose escalation clinical trials.

[0043] As used herein, the term "subject" refers to an animal that is the object of treatment, observation or experiment. By way of example only, a subject can be, but is not limited to, a mammal, including but not limited to, a human.

[0044] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[0045] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing or ameliorating a disease or condition symptom, preventing additional symptoms, ameliorating or preventing the underlying metabolic cause of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms "treat," "treating," or "treatment" include, without limitation, prophylactic and / or therapeutic treatment.

[0046] As used herein, IC 50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of such response, e.g., inhibition of MAGL, in an assay measuring maximal response.

[0047] As used herein, EC 50 refers to the dose, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of a particular response induced, elicited or enhanced by the particular test compound.

[0048] As used herein, the term "alkyl" refers to a straight chain (i.e., unbranched) or branched saturated hydrocarbon having from one to eight carbon atoms. The term "C1-C3 alkyl" means a straight chain or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, n-hexyl, n-heptyl, and n-octyl.

[0049] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched hydrocarbon having from 1 to 10 carbon atoms. Representative examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH(CH3)-, and -CH2CH2CH2CH2CH2-.

[0050] The term "alkoxy" refers to a moiety of the formula -OR', wherein R' denotes an alkyl group as defined above. In particular, "C 1- "C3alkoxy" refers to a moiety wherein the alkyl moiety has 1, 2, or 3 carbon atoms. Examples of "C 1- "C3alkoxy" refers to a moiety wherein the alkyl moiety has 1, 2, or 3 carbon atoms. Examples of "C

[0051] As used herein, the term "cycloalkyl" refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. Cycloalkyl groups can be monocyclic cycloalkyl groups (e.g. cyclopropyl) and preferably have between 3 and 7 carbon atoms in the ring.

[0052] The term "halogen" is intended to designate a substituent selected from the 7thmain group of the periodic table, such as fluorine, chlorine or bromine.

[0053] The term "haloalkyl" or "haloalkoxy" is intended to mean an alkyl or alkoxy group as defined above wherein 1, 2, or 3 hydrogens are replaced by halogen.

[0054] Similarly, the term "fluoroalkyl" is intended to mean an alkyl group as defined above wherein 1, 2, or 3 hydrogens are replaced by fluorine. An example of such a group is trifluoromethyl.

[0055] As used herein, the term "hydroxyl" or "hydroxy" means an -OH group.

[0056] As used herein, the term "hydroxyalkyl" means at least one -OH group attached to the parent molecular moiety through an alkylene group as defined herein.

[0057] As used herein, the term "hydroxyhaloalkyl" means at least one -OH group attached to the parent molecular moiety through a haloalkyl group as defined herein.

[0058] As used herein, the term "hydroxyfluoroalkyl" means at least one -OH group attached to the parent molecular moiety through a fluoroalkyl group as defined herein.

[0059] As used herein, the term "oxo" refers to an oxygen atom attached to another atom through a double bond. When the atom to which the oxygen is attached is carbon, the carbonyl formed is indicated as -(CO)-.

[0060] The term "5-membered heteroaryl" refers to a 5-membered aromatic ring in which 1, 2, or 3 ring atoms are selected from O, N, or S. Examples of 5-membered heteroaryl groups of the present application include thienyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, and thiadiazolyl.

[0061] The term "6-membered heteroaryl" refers to a 6-membered aromatic ring in which 1, 2, or 3 ring atoms are independently selected from O, N, or S. Examples of 6-membered heteroaryl groups of the present application include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyranyl, diazinyl, and triazinyl.

[0062] As used herein, the terms "monocyclic heterocyclic ring," "monoheterocyclic ring," and "monoheterocycle" alone or in combination, refer to a saturated or unsaturated non-aromatic ring comprising from 5 to 6 ring atoms, wherein one or more of the ring atoms are heteroatoms. In some embodiments of the present application, the heterocyclic ring is intended to mean a 6-membered ring structure in which 1 or 2 heteroatoms are independently selected from N or O. Examples of 6-membered heterocyclic rings include, but are not limited to, tetrahydropyranyl, piperidinyl, and morpholinyl.

[0063] As used herein, the term "bicyclic heterocyclic ring" refers to a monoheterocyclic ring that is attached to a parent moiety and forms a fused, spiro, or bridged ring system with a cycloalkyl, monocyclic heterocyclic ring, benzene ring, or monocyclic 5- or 6-membered heteroaryl. The term "7-membered bicyclic heterocyclic ring" means a bicyclic heterocyclic ring as defined above having 7 ring atoms and containing at least 1 heteroatom selected from N, O, or S. Examples of 7-membered bicyclic heterocyclic rings include, but are not limited to, 2-oxaspiro[3.3]heptan-6-yl. The term "9- or 10-membered bicyclic heterocyclic ring" means a bicyclic heterocyclic ring as defined above having 9 or 10 ring atoms and containing at least 1 heteroatom selected from N, O, or S. Examples of 9- or 10-membered bicyclic heterocyclic rings include, but are not limited to, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 3-cyclopropyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, or 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl.

[0064] Embodiments of the present application

[0065] In a first embodiment, the present application relates to a compound of Formula (I):

[0066]

[0067] wherein:

[0068] R1represents -C(O)NHR2, -C(O)N(CH3)R2, -C(O)NR3R4, -C(O)NHCH2R2, or -C(O)NHC(O)R2;

[0069] R2represents phenyl, 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S, 6-membered heterocycle having one or two heteroatoms independently selected from N or O, C3-C7cycloalkyl, or 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O;

[0070] R3and R4together with the N to which they are attached form a 9- or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms independently selected from N or O, or a 6-membered heterocycle having one or two heteroatoms independently selected from N or O; and

[0071] wherein each phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7cycloalkyl, 7-membered bicyclic heterocycle, or 9- or 10-membered bicyclic heterocycle is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH;

[0072] or a pharmaceutically acceptable salt thereof.

[0073] In a further embodiment, the compound of the present application is a compound of Formula (Ia):

[0074]

[0075] wherein:

[0076] R1represents -C(O)NHR2, -C(O)N(CH3)R2, -C(O)NR3R4, -C(O)NHCH2R2, or -C(O)NHC(O)R2;

[0077] R2represents phenyl, 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S, 6-membered heterocycle having one or two heteroatoms independently selected from N or O, C3-C7cycloalkyl, or 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O;

[0078] R3and R4together with the N to which they are attached form a 9- or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms independently selected from N or O, or a 6-membered heterocycle having one or two heteroatoms independently selected from N or O; and

[0079] wherein each phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7cycloalkyl, 7-membered bicyclic heterocycle, or 9- or 10-membered bicyclic heterocycle is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH;

[0080] or a pharmaceutically acceptable salt thereof.

[0081] In further embodiments, the compounds of the present application are compounds of Formula (Ib):

[0082]

[0083] wherein:

[0084] R1represents -C(O)NHR2, -C(O)N(CH3)R2, -C(O)NR3R4, -C(O)NHCH2R2, or -C(O)NHC(O)R2;

[0085] R2represents phenyl, 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O and S, 6-membered heterocycle having one or two heteroatoms independently selected from N or O, C3-C7cycloalkyl, or 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O;

[0086] R3and R4together with the N to which they are attached form a 9- or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms independently selected from N or O, or a 6-membered heterocycle having one or two heteroatoms independently selected from N or O; and

[0087] wherein each phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7cycloalkyl, 7-membered bicyclic heterocycle, or 9- or 10-membered bicyclic heterocycle is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH;

[0088] or a pharmaceutically acceptable salt thereof.

[0089] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R1represents -C(O)NHR2.

[0090] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R1represents -C(O)NHR2; R2represents a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S, or a 6-membered heterocycle having one or two heteroatoms independently selected from N or O; wherein each 5- or 6-membered heteroaryl or 6-membered heterocycle is independently unsubstituted or substituted with 1 substituent selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH.

[0091] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R2represents a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1 substituent selected from the group consisting of halogen, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having 1 or 2 heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH.

[0092] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R2represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, wherein said R2is unsubstituted or substituted with 1 substituent selected from the group consisting of C1-C3alkyl, C3-C6cycloalkyl, and cyano.

[0093] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R2represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, wherein said R2is unsubstituted.

[0094] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R2is selected from the group consisting of:

[0095]

[0096] wherein * indicates the point of attachment.

[0097] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R2is selected from the group consisting of:

[0098]

[0099] wherein * indicates the point of attachment.

[0100] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R3and R4together with the N to which they are attached form a 9- to 10-membered bicyclic heterocycle selected from the group consisting of 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, and 6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazinyl, wherein said 9- to 10-membered bicyclic heterocycle is unsubstituted or substituted with 1 substituent selected from C3-C6cycloalkyl or C1-C3haloalkyl.

[0101] In embodiments relating to compounds of Formula (I), (la), or (lb), or pharmaceutically acceptable salts thereof, wherein R3and R4together with the N to which they are attached form a 9- to 10-membered bicyclic heterocycle selected from the group consisting of:

[0102]

[0103] The asterisk (*) indicates the attachment point.

[0104] In another embodiment, the compound of the present invention is a compound having formula (Ic) or a pharmaceutically acceptable salt thereof:

[0105]

[0106] in:

[0107] R5 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two heteroatoms independently selected from N, O and S, a 6-membered heterocycle, a C3-C7 cycloalkyl group, or a 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O.

[0108] R6 represents hydrogen or methyl;

[0109] W is either -CH2- or -C(O)-;

[0110] n is 0 or 1; and

[0111] Each of the phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7 cycloalkyl, and 7-membered bicyclic heterocycle is unsubstituted or substituted by one or two substituents independently selected from the following: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH;

[0112] Or its pharmaceutically acceptable salt.

[0113] In another embodiment, the compound of the present invention is a compound having formula (Id) or a pharmaceutically acceptable salt thereof:

[0114]

[0115] in:

[0116] R5 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two heteroatoms independently selected from N, O and S, a 6-membered heterocycle, a C3-C7 cycloalkyl group, or a 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O.

[0117] R6 represents hydrogen or methyl;

[0118] W is either -CH2- or -C(O)-;

[0119] n is 0 or 1; and

[0120] wherein each phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7cycloalkyl, 7-membered bicyclic heterocycle is unsubstituted or substituted with one or two substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH;

[0121] or a pharmaceutically acceptable salt thereof.

[0122] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein n is 0.

[0123] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5represents a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein said R5is unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl, C1-C3alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH.

[0124] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5represents a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl, wherein said 6-membered heteroaryl is unsubstituted.

[0125] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, wherein said R5is unsubstituted or substituted with one substituent selected from the group consisting of C1-C3alkyl, C3-C6cycloalkyl, and cyano.

[0126] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5is unsubstituted.

[0127] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5is selected from the group consisting of:

[0128]

[0129] wherein * indicates the point of attachment.

[0130] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5is selected from the group consisting of:

[0131]

[0132] wherein * indicates the point of attachment.

[0133] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein R5represents 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl 2- oxaspiro[3.3]heptan-6-yl.

[0134] In embodiments involving compounds of Formula (Ic) or (Id), or pharmaceutically acceptable salts thereof, wherein n is 0.

[0135] In further embodiments, the compounds of the present application are compounds of Formula (Ie), or pharmaceutically acceptable salts thereof:

[0136]

[0137] wherein R7represents phenyl, 5- or 6-membered heteroaryl having one or two N atoms, or 5- or 6-membered heterocyclo having one heteroatom atom selected from N or O; and

[0138] wherein each phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclo is unsubstituted or substituted with 1 substituent selected from the group consisting of halogen, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl, C1-C3alkoxy, and cyano.

[0139] In further embodiments, the compounds of the present application are compounds of Formula (If), or pharmaceutically acceptable salts thereof:

[0140]

[0141] wherein R7represents phenyl, 5- or 6-membered heteroaryl having one or two N atoms, or 5- or 6-membered heterocyclo having one heteroatom atom selected from N or O; and

[0142] wherein each phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocycle is unsubstituted or substituted with 1 substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, and cyano.

[0143] In embodiments relating to compounds of Formula (Ie) and (If), or pharmaceutically acceptable salts thereof, wherein R7represents pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein said R7is unsubstituted or substituted with 1 substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, and cyano.

[0144] In embodiments relating to compounds of Formula (Ie) and (If), or pharmaceutically acceptable salts thereof, wherein R7represents tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, wherein said R7is unsubstituted or substituted with 1 substituent selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl, and cyano.

[0145] In embodiments relating to compounds of Formula (Ie) or (If), or pharmaceutically acceptable salts thereof, wherein R7represents tetrahydro-2H-pyran-4-yl, piperazinyl, or piperidinyl, wherein said R7is unsubstituted.

[0146] In further embodiments, the compounds of the present application are selected from the group consisting of:

[0147] (±) 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0148] (±) 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0149] (±) 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0150] (±) 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0151] (±) 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0152] (±) 1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0153] (±) 1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0154] (±) 1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0155] (±) 1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0156] (±) 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0157] (±) 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0158] (±) 1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0159] (±) 1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0160] (±) 1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0161] (±) 1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0162] (±) 1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0163] (±) 1 -(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0164] (±) 1 -(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0165] (±) 1 -(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0166] (±) 1 -(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0167] (±) 1 -(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0168] (±) 1 -(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5] octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0169] (±) 1 -((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0170] (±) 1 -((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0171] (±) 1 -((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0172] (±) 1 -(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0173] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0174] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0175] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0176] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0177] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0178] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0179] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0180] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0181] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0182] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0183] (±) 1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0184] (±) 1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0185] (±) 1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0186] (±) 1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0187] (±) 1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0188] (±) 1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0189] (±) 1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0190] (±) 1-(thiazol-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0191] (±) 1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0192] (±) 1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0193] (±) 1-(thiazol-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0194] (±) 1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0195] (±) 1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0196] (±)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0197] (±) 1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0198] (±) 1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0199] (±) 1-((pyridazin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0200] (±) 1-((2-oxaspiro[3.3]heptan-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0201] (±) 1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0202] (±) 1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0203] (±) 1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0204] (±) 1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0205] (±) 1-((6-carbamoylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0206] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0207] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0208] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0209] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0210] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0211] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0212] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester; and

[0213] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester; or a pharmaceutically acceptable salt thereof.

[0214] In further embodiments, the compounds of the present application are selected from the group consisting of:

[0215] (±) 1 -(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0216] (±) 1 -(5, 6, 7, 8-Tetrahydroimidazo[ 1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester;

[0217] (±) 1 -(5, 6, 7, 8-Tetrahydroimidazo[ 1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester;

[0218] (±) 1 -(5, 6, 7, 8-Tetrahydroimidazo[ 1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester; and

[0219] (±) 1 -(5, 6, 7, 8-Tetrahydroimidazo[ 1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester; or a pharmaceutically acceptable salt thereof.

[0220] In further embodiments, the compounds of the application are selected from the group consisting of:

[0221] (R)- 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester;

[0222] (S)- 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester;

[0223] (R)- 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester;

[0224] (S)- 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester;

[0225] (R)- 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester;

[0226] (S)- 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester;

[0227] (R)-1-(methyl(piperidin-4-ylcarbamoyl))-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0228] (S)-1-(methyl(piperidin-4-ylcarbamoyl))-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0229] (R)-1-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0230] (S)-1-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0231] (R)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0232] (S)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0233] (R)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0234] (S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0235] (R)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0236] (S)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0237] (R)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0238] (S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0239] (R)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0240] (S)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0241] (R)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0242] (S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0243] (R)-1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0244] (S)-1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0245] (R)-1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0246] (S)-1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0247] (R)-1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0248] (S)-1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0249] (R)-1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0250] (S)-1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0251] (R)-1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0252] (S)-1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0253] (R)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0254] (S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0255] (R)-1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0256] (S)-1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0257] (R)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0258] (S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0259] (R)-1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0260] (S)-1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0261] (R)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0262] (S)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0263] (R)-1-((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0264] (S)-1-((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0265] (R)-1-((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0266] (S)-1-((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0267] (R)-1-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0268] (S)-1-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0269] (R)-1-(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0270] (S)-1-(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0271] (R)-1-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0272] (S)-1-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0273] (R)-1-(((6-methylpyridin-3-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0274] (S)-1-(((6-methylpyridin-3-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0275] (R)-1-(((2-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0276] (S)-1-(((2-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0277] (R)-1-(((pyridin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0278] (S)-1-(((pyridin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0279] (R)-1-(((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0280] (S)-1-((cyclohexanecarbonyl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0281] (R)-1-(benzoylaminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0282] (S)-1-(benzoylaminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0283] (R)-1-(pyrimidin-5-ylaminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0284] (S)-1-(pyrimidin-5-ylaminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0285] (R)-1-((2-(trifluoromethyl)pyrimidin-5-yl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0286] (S)-1-((2-(trifluoromethyl)pyrimidin-5-yl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0287] (R)-1-((2-methylpyrimidin-5-yl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0288] (S)-1-((2-methylpyrimidin-5-yl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0289] (R)-1-((6-methylpyridazin-3-yl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0290] (S)-1-((6-methylpyridazin-3-yl)aminocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0291] (R)-1-(pyridazin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0292] (S)-1-(pyridazin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0293] (R)-1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0294] (S)-1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0295] (R)-1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0296] (S)-1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0297] (R)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0298] (S)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0299] (R)-1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0300] (S)-1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0301] (R)-1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0302] (S)-1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0303] (R)-1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0304] (S)-1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0305] (R)-1-(thiazol-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0306] (S)-1-(thiazol-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0307] (R)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0308] (S)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0309] (R)-1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0310] (S)-1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0311] (R)-1-(thiazol-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0312] (S)-1-(thiazol-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0313] (R)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0314] (S)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0315] (R)-1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0316] (S)-1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0317] (R)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0318] (S)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0319] (R)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0320] (S)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0321] (R)-1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0322] (S)-1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0323] (R)-1-((pyridazin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0324] (S)-1-((pyridazin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0325] (R)-1-((2-oxaspiro[3.3]heptan-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0326] (S)-1-((2-oxaspiro[3.3]heptan-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0327] (R)-1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0328] (S)-1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0329] (R)-1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0330] (S)-1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0331] (R)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0332] (S)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0333] (R)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0334] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0335] (R)-1-((6-carbamoylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0336] (S)-1-((6-carbamoylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0337] (R)-1-(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0338] (S)-1-(isoxazol-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0339] (R)-1-((6-(methylsulfonamido)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0340] (S)-1-((6-(methylsulfonamido)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0341] (R)-2-((5-(6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octan-1- ylamido)pyridin-2-yl)oxy)acetic acid; and

[0342] (S)-2-((5-(6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octan-1- ylamido)pyridin-2-yl)oxy)acetic acid; or a pharmaceutically acceptable salt thereof.

[0343] In further embodiments, the compounds of the present application are selected from the group consisting of:

[0344] (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0345] (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0346] (S)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0347] (S)-1-(methyl(piperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0348] (S)-1-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0349] (S)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0350] (S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0351] (S)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0352] (S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0353] (S)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0354] (S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0355] (S)-1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0356] (S)-1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0357] (S)-1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0358] (S)-1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0359] (S)-1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0360] (S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0361] (S)-1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0362] (S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0363] (S)-1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0364] (S)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0365] (S)-1-((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0366] (S)-1-((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0367] (S)-1-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0368] (S)-1-(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0369] (S)-1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0370] (S)-1-((6-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0371] (S)-1-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0372] (S)-1-((pyridin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0373] (S)-1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0374] (S)-1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0375] (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0376] (S)-1-((2-(trifluoromethyl)pyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0377] (S)-1-((2-methylpyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0378] (S)-1-((6-methylpyridazin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0379] (S)-1-(pyridazin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0380] (S)-1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0381] (S)-1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0382] (S)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0383] (S)-1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0384] (S)-1-(4-cyanopiperidine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0385] (S)-1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0386] (S)-1-(thiazol-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0387] (S)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0388] (S)-1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0389] (S)-1-(thiazol-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0390] (S)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0391] (S)-1-(p-tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0392] (S)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0393] (S)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0394] (S)-1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0395] (S)-1-((pyridazin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0396] (S)-1-((2-oxaspiro[3.3]heptan-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0397] (S)-1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0398] (S)-1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0399] (S)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0400] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0401] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0402] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0403] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester; and

[0404] (S)-2-((5-(6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octan-1- ylcarbamoyl)pyridin-2-yl)oxy)acetic acid; or a pharmaceutically acceptable salt thereof.

[0405] In further embodiments, the compound of the application is selected from the group consisting of:

[0406] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0407] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0408] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0409] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0410] (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester;

[0411] (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0412] (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0413] (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0414] (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester;

[0415] In one embodiment, the compound of the application is (S)-1-(pyrimidin-5-ylcarbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0416] In one embodiment, the compound of the application is (S)-1-(pyrimidin-5-ylcarbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0417] In one embodiment, the compound of the application is (S)-1-(pyrimidin-5-ylcarbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0418] In one embodiment, the compound of the application is (S)-1-(pyrimidin-5-ylcarbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0419] In one embodiment, the compound of the application is (S)-1-(pyrimidin-5-ylcarbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0420] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0421] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0422] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0423] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0424] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0425] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0426] In one embodiment, the compound of the application is (S)-1-(pyridin-4- ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, or a pharmaceutically acceptable salt thereof.

[0427] In embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

[0428] In further embodiments, there is provided a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0429] In embodiments, there is provided a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the group consisting of pain, epilepsy / seizure disorders, Alzheimer’s disease, Huntington’s Chorea, Huntington’s disease, spasticity, multiple sclerosis, obsessive compulsive disorder, Parkinson’s disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

[0430] In further embodiments, there is provided a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of pain. In further embodiments, the pain is neuropathic pain. In embodiments, the pain is inflammatory pain. In further embodiments, the pain is selected from the group consisting of acute pain, cancer pain, chronic pain, pain caused by peripheral neuropathy, central pain, pain caused by spinal cord injury, pain caused by stroke, complex regional pain syndrome, fibromyalgia, migraine, vaso-occlusive painful crisis in sickle cell disease, pain associated with multiple sclerosis, lower back pain, abdominal pain associated with irritable bowel syndrome, functional chest pain, rheumatoid arthritis, osteoarthritis, somatoform disorders, or functional dyspepsia.

[0431] In embodiments, there is provided use of a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of pain, epilepsy / seizure disorders, Alzheimer’s disease, Huntington’s Chorea, Huntington’s disease, spasticity, multiple sclerosis, obsessive compulsive disorder, Parkinson’s disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

[0432] In embodiments, there is provided a method for the treatment of a disease or disorder selected from the group consisting of pain, epilepsy / seizure disorders, Alzheimer’s disease, Huntington’s Chorea, Huntington’s disease, spasticity, multiple sclerosis, obsessive compulsive disorder, Parkinson’s disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof.

[0433] The compounds of the present application are generally used in the form of free substances or in the form of their pharmaceutically acceptable salts. When the compounds of formula (I) contain a free base, such salts can be prepared in the customary manner by treating a solution or suspension of the free base of formula (I) with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described below.

[0434] In the context of the present application, pharmaceutically acceptable salts are intended to indicate salts that are not toxic, i.e. physiologically acceptable salts. The term pharmaceutically acceptable salts includes salts with inorganic acids and / or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid.

[0435] The compounds of the present application can have one or more asymmetric centers and it is intended that any optical isomer (i.e. enantiomeric or diastereomeric) of the compounds of the present application either isolated, in pure form or in admixture, including racemic mixtures (i.e. mixtures of stereoisomers) are included within the scope of the present application.

[0436] In this context, it is to be understood that when an enantiomeric form is indicated, the compound is in enantiomeric excess, for example substantially in enantiomeric pure form. Accordingly, one embodiment of the present application relates to a compound of the present application having an enantiomeric excess (ee) of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

[0437] The racemic forms can be resolved into the optical antipodes by known methods, for example by separation of diastereomeric salts thereof with an optically active acid and liberation of the optically active amine compound by treatment with alkali. Another method for resolving the racemates into the optical antipodes is based on chromatography on an optically active matrix. The compounds of the present application can also be resolved into their diastereomeric forms by formation of diastereomeric derivatives. Additional methods for resolving optical isomers are known to those of ordinary skill in the art. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons (New York, 1981). Optically active compounds can also be prepared from optically active starting materials or by using chiral catalysis. The absolute stereochemistry is assigned based on the known stereochemistry of the starting materials or the stereochemistry of the compounds as determined by techniques known to those of ordinary skill in the art, such as vibrational circular dichroism (VCD) spectroscopy analysis.

[0438] In addition, when there are double bonds or fully or partially saturated ring systems in the molecule, geometric isomers can be formed. It is intended that any geometric isomer or mixture thereof as separated, pure or partially purified, is included within the scope of the present application. Likewise, molecules with restricted rotation bonds can form geometric isomers. These are also intended to be included within the scope of the present application.

[0439] In addition, some of the compounds of the present application can exist in different tautomeric forms and any tautomeric form that the compounds are capable of existing in is intended to be included within the scope of the present application.

[0440] The present application also includes isotopically-labeled compounds, which are identical to those recited in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or pharmaceutically acceptable salts thereof, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the atomic mass or mass number usually found in nature (e.g. 2 H, 3 H, 11 C, 13 C, 15 N, 18 F, etc.). Specifically mentioned are 2 H substituted compounds, i.e. compounds in which one or more H atoms are replaced by deuterium.

[0441] In one embodiment of the application, one or more of the hydrogen atoms of the compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, are represented by deuterium. It is recognized that in most synthetic compounds, the elements are present in the natural isotopic abundance and result in the inherent incorporation of deuterium. However, the natural isotopic abundance of the hydrogen isotope, such as deuterium, is not significant (about 0.015%) relative to the degree of stable isotope substitution of the compounds described herein. Thus, as used herein, the designation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium. Any atom not designated as a particular isotope is intended to denote any stable isotope of that atom, as will be apparent to one of ordinary skill in the art.

[0442] Pharmaceutical compositions

[0443] The above-mentioned compounds or pharmaceutically acceptable salts can be present in the composition as the sole active ingredient or in combination with other active ingredients. Additionally, one or more pharmaceutically acceptable carriers or diluents can be present in the composition.

[0444] The pharmaceutical compositions can be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition of the subject to be treated and on the nature of the condition to be treated and on the active ingredients selected.

[0445] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, sugar-coated tablets, pills, troches, powders and granules. Where appropriate, they can be prepared with coatings.

[0446] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

[0447] Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.

[0448] Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.

[0449] Conveniently, the compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), or (If) are administered in unit dosage form comprising said compounds in an amount of from about 0.1 to 500 mg, such as 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of a compound of the application.

[0450] For parenteral administration, solutions of the compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), or (If) can be used in sterile aqueous solution, solutions in aqueous propylene glycol. Such aqueous solutions should be properly buffered and, if necessary, rendered isotonic with sufficient saline or glucose. Aqueous solutions, particularly sterile aqueous solutions, are especially useful for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed will be apparent to those of ordinary skill in the art. Aqueous solutions should be properly buffered and, if necessary, rendered isotonic with sufficient saline or glucose. Aqueous solutions are especially useful for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed will be apparent to those of ordinary skill in the art.

[0451] Suitable pharmaceutical carriers include inert solid diluents or filler, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.

[0452] Formulations of the application suitable for oral administration can be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and can include suitable excipients. Additionally, oral formulations can be presented as powders or granules, as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.

[0453] If a solid carrier is used for oral administration, the formulation can be a tablet, e.g., in a powder or granular form, in a hard gelatin capsule, or in a sugar-coated or film-coated tablet. The amount of solid carrier can vary but will usually be from about 25 mg to about 1 g.

[0454] If a liquid carrier is used, the formulation may be in the form of syrup, emulsion, soft gelatin capsule, or sterile injectable liquid (e.g., aqueous or non-aqueous liquid suspension or solution).

[0455] Tablets can be prepared by mixing the active ingredient with common adjuvants and / or diluents, followed by compression of the mixture in a conventional tableting machine. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, etc. Any other adjuvants or additives commonly used for this purpose, such as colorants, flavorings, preservatives, etc., may be used, provided they are compatible with the active ingredient.

[0456] Used to treat conditions

[0457] The compounds of the present invention are intended for the treatment of diseases and disorders related to the regulation of signaling activity in the endocannabinoid system, wherein MAGL inhibitors may be therapeutically beneficial. As described above, the compounds of the present invention may be beneficial in indications where pathological features include excessive neurotransmission, neuroinflammation, or neurodegeneration. Accordingly, in one embodiment, a compound having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for the treatment of disorders or diseases selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

[0458] Symptomatic treatment of multiple sclerosis

[0459] Almost all MS patients across all subtypes experience one or more symptoms, including spasms, pain, sleep disturbances, bladder dysfunction, and fatigue. Disease-modifying treatments do not improve symptoms. Spasms affect more than 80% of MS patients; 34% have moderate, severe, or complete spasms. Severe spasms are associated with the cost and level of care and are independently associated with quality of life in MS. Two recent reviews support the use of exocannabinoids for the treatment of MS spasms and pain (Whiting et al., JAMA. 2015; Hill et al., JAMA. 2015).

[0460] Exogenous cannabinoid preparations are approved treatments for spasticity associated with MS. Sativex, an oromucosal spray mixture of the CB1 agonist THC and another cannabinoid plant-derived alcohol (cannabidiol), has been shown to reduce self-reported spasticity-related symptoms. In a pivotal trial of Sativex using a randomized discontinuation design, continued Sativex improved spasticity frequency, sleep disruption due to spasticity, subject global impression of change, caregiver global impression of change, and physician global impression of change. Other clinical trials have shown activity of various exogenous cannabinoids in spasticity due to MS (Zajicek et al., Lancet. 2003; Collin et al., Eur J Neurol. 2007; Collin et al., Neurol Res. 2010). These parallel-group studies exemplify the clinical trial design and endpoints that can be used to show that MAGL inhibitors are beneficial in spasticity in MS.

[0461] In embodiments, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.

[0462] In embodiments, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of one or more symptoms of multiple sclerosis selected from the group consisting of fatigue, spasticity, depression, behavioral disorder, stress-induced agitation, and pain.

[0463] It is believed that MAGL inhibitors will also be beneficial in treating indications associated with autoimmune encephalomyelitis. Accordingly, in further embodiments, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of Rasmussen encephalitis, systemic lupus erythematosus, Behcet's disease, Hashimoto's encephalopathy, and Sydenham's chorea.

[0464] Amyotrophic lateral sclerosis

[0465] How patients with amyotrophic lateral sclerosis (ALS) typically experience muscle weakness and / or progressive worsening of fasciculations, bulbar symptoms, and ultimately respiratory problems is described in Pryce et al. Handb Exp Pharmacol. 2015; 231 :213-31. In preclinical models of ALS, cannabinoids have been shown to have significant neuroprotective effects.

[0466] Thus, in embodiments, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of amyotrophic lateral sclerosis.

[0467] Central pain

[0468] Central pain is neuropathic pain caused by damage or dysfunction in the central nervous system, such as post-stroke sequelae, multiple sclerosis, neuromyelitis optica, idiopathic inflammatory transverse myelitis, spinal cord injury, brachial-radial pain syndrome, and central craniofacial pain. Exogenous cannabinoids have been demonstrated to be active in central pain associated with multiple sclerosis. A 4-week randomized, double-blind, placebo-controlled parallel-group trial of oral mucosal spray THC / CBD containing the CB1 agonists delta-9-tetrahydrocannabinol and cannabidiol (another alcohol derived from Cannabis) in MS and central pain showed that the active agent was superior to placebo in reducing average pain intensity (NRS-11) and sleep disturbances (Rog et al. Neurology. 2005). The same THC / CBD formulation was studied in a larger group of MS patients with central neuropathic pain using a two-stage design; in the second stage of this study, time to treatment failure (primary endpoint) was statistically in favor of THC / CBD, as was improvement in pain NRS-11 and sleep quality (Langford et al. J Neurol. 2013). In addition, nabilone, a synthetic CB1 agonist related in structure to THC, showed efficacy in MS-induced central neuropathic pain (Turcotte et al. Pain Med. 2015). Studies of exogenous cannabinoids in central pain have shown activity, suggesting that MAGL inhibitors can also have efficacy in the treatment of central pain. Thus, in one embodiment, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of central pain.

[0469] Fibromyalgia

[0470] Fibromyalgia (FM) is a common, chronic, idiopathic disorder characterized by diffuse body pain and the presence of pressure allodynia. Duloxetine and pregabalin are specifically labeled for the treatment of pain in FM, and tricyclic antidepressants like amitriptyline, while not specifically labeled for FM treatment, are first-line agents. There is no clear understanding of the pathology of FM, nor is there a validated preclinical model. However, studies of exogenous cannabinoids in FM have shown activity, suggesting that MAGL inhibitors can also have efficacy in treating FM. Pain (e.g., NRS-11, Pain VAS) measures and the Fibromyalgia Impact Questionnaire (FIQ) (measures limitations in several activities of daily living affected by FM) have proven drug activity in FM clinical trials (Burckhardt et al., The fibromyalgia impact questionnaire: development and validation, J Rheumatol. 1991, 728-33); (Mease et al., The Journal of Rheumatology, 2008 Jan, 35(1) 20-30). A survey of Spanish FM patients (cannabis users and non-users) was conducted to determine the impact of cannabis on a range of disease symptoms such as pain, stiffness, health, relaxation, and tiredness; relief of feelings of pain, sleep disturbance, stiffness, mood disturbance, and anxiety were common (Fiz, PLoS One, 2011, 6(4), e18440). In an 8-week, 40-patient study, the exogenous cannabinoid nabilone improved pain measured on a 10 cm VAS, and improved the FIQ domain of anxiety and the total FIQ score compared to placebo (Skrabek et al., J Pain. 2008). In a 31-patient study, nabilone improved the sleep index (index of severity of insomnia) compared to amitriptyline, and was judged to be non-inferior in pain measures (McGill Pain Questionnaire) and FIQ (Ware, Anesth Analg, 2010, 110(2), 604-10). Thus, in one embodiment, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of fibromyalgia.

[0471] Migraine

[0472] Migraine is a common episodic disorder of headache and facial pain. Migraine attacks can be acutely treated with NSAIDs, acetaminophen, various triptans (e.g., sumatriptan), and antiemetics, but some migraine patients are refractory to existing treatment regimens. Data suggest that the endocannabinoid pathway can be involved in migraine. In patients with chronic migraine and possibly overuse headache, CSF specimens showed higher levels of the endocannabinoid palmitoylethanolamide and lower levels of cannabinoid compared to healthy controls (Sarchielli et al., Neuropsychopharmacology. 2007). In addition, a retrospective chart review of patients enrolled in a clinical with medical cannabis found a reduction in the frequency of migraine after starting cannabis treatment (Rhyne et al., Pharmacotherapy. 2016), suggesting that MAGL inhibitors can also be effective in treating migraine. Accordingly, in embodiments, there is provided a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of migraine.

[0473] In further embodiments, disclosed herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of chronic migraine, acute treatment of migraine, and migraine with hemiplegia.

[0474] Mood and anxiety disorders

[0475] Mood and anxiety disorders are chronic disabling conditions that carry a cost to both patients and society. In recent years, the endocannabinoid system has received increasing attention with respect to mood and anxiety disorders. In a recent study by Bedse G et al., Transl Psychiatry. 2018, it was shown that use of MAGL inhibitors can have beneficial effects on stress-related psychopathology. Accordingly, in one embodiment, disclosed herein is the provision of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of mood and anxiety disorders.

[0476] In further embodiments disclosed herein, there is provided a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of mood and anxiety disorders selected from depression and GAD.

[0477] In additional embodiments disclosed herein, there is provided a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of a depressive disorder selected from the group consisting of major depressive disorder; treatment-resistant depression; catatonic depression; melancholic depression; atypical depression; psychotic depression; peripartum depression; postpartum depression; bipolar depression, including bipolar I and bipolar II depression; and mild, moderate, or severe depression. In additional embodiments disclosed herein, a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, is for use in the treatment of major depressive disorder.

[0478] In additional embodiments disclosed herein, there is provided a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of GAD.

[0479] Post-traumatic stress disorder

[0480] Post-traumatic stress disorder (PTSD) is a disorder associated with trauma or stress. Patients with PTSD will have symptoms of re-experiencing the trauma, avoidance, hyperarousal, and negative cognitions / emotions. In a review by Hill et al., Neuropsychopharmacology 2018, it was suggested that drugs that affect endocannabinoid signaling, such as MAGL inhibitors, can be beneficial for treating symptoms of PTSD. Thus, in one embodiment disclosed herein, there is provided a compound of Formula (I), (la), (lb), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment of PTSD.

[0481] In some embodiments disclosed herein are methods of modulating MAGL activity. Contemplated methods, for example, include exposing the enzyme to a compound described herein. The ability of a compound described herein to modulate or inhibit MAGL is evaluated by procedures known in the art and / or described herein. Another aspect of the disclosure provides methods of treating a patient for a disease associated with MAGL expression or activity.

[0482] Epilepsy

[0483] In a study by Sugaya et al., Cell Rep. 2016, it was suggested that 2-AG is critical for the suppression of seizures. Thus, in another embodiment, a compound of Formula (I), (la), (lb), (lc), (Id), (le), or (If) is used to treat epilepsy / seizure disorders.

[0484] In one embodiment, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is used to treat an epilepsy / seizure disorder selected from acute repetitive seizures, temporal lobe epilepsy, Dravet syndrome, Lennox Gastaut syndrome, or Angelman syndrome.

[0485] Combination therapy

[0486] Also contemplated herein is combination therapy, e.g., co-administration of a compound of the application and an additional active agent, as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of the therapeutic agents. The beneficial effect of the combination includes, but is not limited to, a pharmacokinetic or pharmacodynamic interaction of the therapeutic agents resulting from their combination. Co-administration of the therapeutic agents in a combination is typically carried out within the same patient, and generally within a defined period of time (usually weeks, months, or years, depending on the combination chosen). Combination therapy is intended to embrace administration of the therapeutic agents in sequential regimen, i.e., wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of these therapeutic agents, in a substantially simultaneous manner.

[0487] Substantially simultaneous administration is achieved, e.g., by administration of a single formulation or composition to the subject (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent), or multiple single formulations of each therapeutic agent (e.g., capsules). Sequential or substantially simultaneous administration of each therapeutic agent is achieved by any appropriate route, including but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination chosen is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0488] Combination therapy also embraces administration of the therapeutic agents as described above, in further combination with other biologically active ingredients and non-pharmaceutical therapies. When the combination therapy further includes a non-pharmaceutical treatment, the non-pharmaceutical treatment is performed at any suitable time, so long as a beneficial effect from the combined action of the therapeutic agents and the non-pharmaceutical treatment is obtained. For example, where appropriate, a beneficial effect is still obtained when the non-pharmaceutical treatment is removed from the administration of the therapeutic agents for a temporary period of time, which can be days or even weeks.

[0489] The components of the combination are administered to a patient simultaneously or sequentially. It will be understood that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered at the same time or sequentially.

[0490] For example, for the pain treatment contemplated, the disclosed compounds are co-administered with another pain treatment agent such as an opioid, a cannabinoid receptor (CB1 or CB2) modulator, a COX-2 inhibitor, acetaminophen, and / or a non-steroidal anti-inflammatory drug. Additional therapeutic agents co-administered, for example, for the treatment of pain, include morphine, pregabalin, gabapentin, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.

[0491] Other contemplated therapeutic agents for co-administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, celecoxib, parecoxib, lumiracoxib, and / or etoricoxib.

[0492] Experimental Section

[0493] General Synthesis

[0494] Compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), and (If), or salts thereof, can be prepared by synthetic methods. The following Schemes 1-3 and Examples 1-34 are representative methods that can be used to synthesize one or more of the compounds according to Formula (I), (la), (lb), (Ic), (Id), (Ie), and (If). The provided Schemes 1-3 are not intended to limit the scope of the application in any way.

[0495] Scheme 1

[0496]

[0497] As shown in Scheme 1, 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (II) can be reacted with a primary amine (R can be heteroaryl or heterocycle) in the presence of a suitable base and solvent (e.g., DIPEA and THF) to form an intermediate of Type III. Alternatively, prior to step i), the intermediate of Type II can be subjected to an acid halogenating reagent to form an acid halide. The amide forming step i) is followed by deprotection in step ii) in a suitable acid and solvent (e.g., TFA and DCM) to provide an intermediate of Type IV. The deprotection step is followed by a coupling reaction in step iii) which includes a reaction with an intermediate of Type IV and 1,1,1,3,3,3-hexafluoropropan-2-ol in the presence of a coupling agent such as CDI in an appropriate solvent (e.g., MeCN) to provide a compound of the application.

[0498] Scheme 2

[0499]

[0500] In an alternative synthesis, compounds are provided in which the amide linker is a tertiary amine (R can be heteroaryl or heterocycle). As seen in Scheme 2, an intermediate of type III is subjected to alkylation in step ia) to form an intermediate of type Ilia. The intermediate of type Ilia can then be subjected to deprotection in step ii) and coupling in step iii) as described in Scheme 1 to provide a compound of the invention.

[0501] Scheme 3

[0502]

[0503] As shown in Scheme 3, some compounds of the invention can be made starting from commercially available tert-butyl l-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate which is subjected to an aryl or heteroaryl halide (X is halogen, R is heteroaryl or phenyl) to form an intermediate of type VI. The remaining synthesis (steps ii) and iii)) follows a similar procedure as shown in Scheme 1.

[0504] List of Abbreviations

[0505] As used above and throughout the description of the application, unless otherwise stated, the following abbreviations shall be understood to have the following meanings:

[0506] ACN or MeCN acetonitrile

[0507] Bn benzyl

[0508] BOC or Boc tert-butyi carbamate

[0509] CDI 1,1'-carbonyldiimidazole

[0510] Cy cyclohexyl

[0511] DCE dichloroethane (CI CH2CH2CI)

[0512] DCM dichloromethane (CH2CI2)

[0513] DIPEA or DIEA diisopropylethylamine

[0514] DMAP 4-(N,N-dimethylamino)pyridine

[0515] DMF dimethylformamide

[0516] DMA N,N-dimethylacetamide

[0517] DMSO dimethyl sulfoxide

[0518] equiv equivalent

[0519] Et ethyl

[0520] EtOH ethanol

[0521] EtOAc ethyl acetate

[0522] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0523] HPLC high performance liquid chromatography

[0524] LAH lithium aluminum hydride

[0525] Me methyl

[0526] MeOH methanol

[0527] MS mass spectrometry

[0528] NMM N-methylmorpholine

[0529] NMR nuclear magnetic resonance

[0530] PMB p-methoxybenzyl

[0531] TEA triethylamine

[0532] TFA trifluoroacetic acid

[0533] THF tetrahydrofuran

[0534] TLC thin layer chromatography

[0535] I. Chemical Synthesis

[0536] Reagents and solvents were used as received from commercial suppliers unless otherwise noted. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. For proton spectra, the solvent peak was used as the reference peak.

[0537] Analytical Methods

[0538] LC-MS Method

[0539] The analytical LC-MS system was equipped with a Shimadzu LCMS-2020, a PDA detector (operating at 254 nm), an ELSD detector, and an ESI source operating in positive ion mode. LC-conditions:

[0540] Method A Column is Kinetex EVO C18 50*3.0mm, 2.6pm operated at 40°C with a binary gradient of water + 5mM NH4HC03(A) and ACN (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0541] Gradient: 0.01 min 10% B

[0542] 2.00 min 95% B

[0543] 2.70 min 95% B

[0544] 2.75 min 10% B

[0545] Total run time: 3.00 min

[0546] Method B Column is Kinetex EVO C18 50*3.0mm, 2.6pm operated at 40°C with a binary gradient of water + 5mM NH4HC03(A) and ACN (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0547] Gradient: 0.01 min 10% B

[0548] 3.20 min 60% B

[0549] 4.00 min 95% B

[0550] 4.80 min 95% B

[0551] 4.90 min 10% B

[0552] Total run time: 5.00 min

[0553] Method C Column is Express C18 50*3.0mm operated at 40°C with a binary gradient of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at 1.5 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0554] Gradient: 0.01 min 20% B

[0555] 3.50 min 50% B ​​​

[0556] 4.30 min 95% B

[0557] 4.00 min 95% B

[0558] 5.10 min 5% B

[0559] Total run time: 5.30 min

[0560] Method D Column is HALO C18 30*3.0 mm, 2 pm operated at 40 °C with a binary gradient of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at 1.5 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 200 nm. R

[0561] Gradient: 0.01 min 5% B

[0562] 1.20 min 100% B

[0563] 1.80 min 100% B

[0564] 1.82 min 5% B

[0565] Total run time: 2.0 min

[0566] Method E Column is Poroshell HPH-C18 50*3.0 mm, 2.7 pm operated at 40 °C with a binary gradient of water + 6.5 mM NH4HC03+ ammonia (pH = 10) (A) and ACN (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0567] Gradient: 0.01 min 10% B

[0568] 2.00 min 95% B

[0569] 2.70 min 95% B

[0570] 2.75 min 10% B

[0571] Total run time: 3.00 min

[0572] Method F ​​Column is Poroshell HPH-C18 50*3.0mm, 2.7pm, operated at 40°C with a binary gradient of water + 5mM NH4HCO3(A) and acetonitrile (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0573] Gradient: 0.01 min 5% B

[0574] 2.00 min 95% B

[0575] 2.70 min 95% B

[0576] 2.80 min 5% B

[0577] Total run time: 3.0 min

[0578] Method G Column is Poroshell HPH-C18 50*3.0mm, 2.7pm, operated at 40°C with a binary gradient of water + 5mM NH4HCO3(A) and acetonitrile (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0579] Gradient: 0.01 min 30% B

[0580] 3.20 min 70% B

[0581] 4.00 min 95% B

[0582] 4.80 min 95% B

[0583] 4.90 min 10% B

[0584] Total run time: 5.00 min

[0585] Method H Column is Poroshell HPH-C18 50*3.0mm, 2.7pm, operated at 40°C with a binary gradient of water + 5mM NH4HCO3(A) and acetonitrile (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0586] Gradient: 0.01 min 10% B

[0587] 3.20 min 60% B

[0588] 4.00 min 95% B​​​

[0589] 4.80 min 95% B

[0590] 4.90 min 10% B

[0591] Total run time: 5.00 min

[0592] Method I Column: CORTECS C18 50*2.1 mm, 2.7 pm operated at 40 °C with a binary gradient of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 0.05% trifluoroacetic acid (B) at 1.5 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0593] Gradient: 0.01 min 5% B

[0594] 2.00 min 100% B

[0595] 2.80 min 100% B

[0596] 2.90 min 5% B

[0597] Total run time: 3.00 min

[0598] Method J Column: CORTECS C18 50*2.1 mm, 2.7 pm operated at 40 °C with a binary gradient of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 0.05% trifluoroacetic acid (B) at 1.0 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0599] Gradient: 0.01 min 5% B

[0600] 3.20 min 60% B

[0601] 4.10 min 95% B

[0602] 5.00 min 95% B

[0603] 5.10 min 5% B

[0604] Total run time: 5.30 min

[0605] Method K ​​Column is Kinetex EVO C18 50*3.0mm, 2.6pm, operated at 40°C with a binary gradient of water + 5mM NH4HCO3(A) and ACN (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0606] Gradient: 0.01 min 30% B

[0607] 3.50 min 60% B

[0608] 4.30 min 95% B

[0609] 4.00 min 95% B

[0610] 5.10 min 5% B

[0611] Total run time: 5.30 min

[0612] Method L Column is Kinetex EVO C18 50*3.0mm, 2.6pm, operated at 40°C with a binary gradient of water + 5mM NH4HCO3(A) and ACN (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0613] Gradient: 0.01 min 30% B

[0614] 3.20 min 50% B

[0615] 4.00 min 95% B

[0616] 4.80 min 95% B

[0617] 4.90 min 10% B

[0618] Total run time: 5.00 min

[0619] Method M: Column is Poroshell HPH-C18 50*3.0mm, 2.7pm, operated at 40°C with a binary gradient of water + 6.5mM NH4HCO3 + ammonia (pH=10) (A) and ACN (B) at 1.2 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0620] Gradient: 0.01 min 10% B

[0621] 3.00 min 60% B​​​

[0622] 4.00 min 95% B

[0623] 4.70 min 95% B

[0624] 4.90 min 10% B

[0625] Total run time: 5.00 min

[0626] Method N Column is Kinelex XB-C18 50*3.0 mm, 2.6 pm operated at 45 °C with a binary gradient of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at 1.5 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0627] Gradient: 0.01 min 5% B

[0628] 3.00 min 50% B

[0629] 4.00 min 100% B

[0630] 4.60 min 100% B

[0631] 4.70 min 5% B

[0632] Total run time: 5.20 min

[0633] Method O: Column is HALO C18 30*3.0 mm, 2 pm operated at 40 °C with a binary gradient of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at 1.5 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 200 nm. R

[0634] Gradient: 2.20 min 100% B

[0635] 2.70 min 100% B

[0636] 2.72 min 5% B

[0637] Total run time: 3.0 min

[0638] Method P: ​​Column was an Express C18 50 mm, which was operated at 40 °C with a binary gradient consisting of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at 1.5 mL / min. Retention times (tR) are expressed in minutes based on UV-trace at 254 nm. R

[0639] Gradient: 0.01 min 2% B

[0640] 2.00 min 100% B

[0641] 2.70 min 100% B

[0642] 2.75 min 2% B

[0643] Total run time: 3.0 min

[0644] 1 H NMR method

[0645] H NMR spectra were recorded on a Bruker Avance HD at 300 or 400 MHz 1 Chemical shift values are reported in ppm relative to tetramethylsilane. The following abbreviations or combinations thereof are used for multiplicity in NMR signals: br = broad, d = doublet, dd = doublet of doublets, dt = doublet of triplets, hept = heptet, m = multiplet, q = quartet, quint = quintet, s = singlet, t = triplet, td = triplet of doublets.

[0646] Example 1: (±) 1 -(Pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0647]

[0648] racemic

[0649] Step 1 : Synthesis of tert-butyl 1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate

[0650]

[0651] ​A vial was charged with 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1 -carboxylic acid (255 mg) (Nantong MYBio-pharm. Co., Ltd.), DMF (10 mg) and DCM (10 mL). Glyoxyl chloride (189 mg) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 2 h and concentrated under reduced pressure to give tert-butyl 1 -(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylate. Another vial was charged with pyridin-3-amine (94.0 mg), THF (5 mL) and DIPEA (258 mg). Tert-butyl 1 -(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylate in THF (5 mL) was added dropwise at 0 °C. The resulting solution was stirred at room temperature overnight and quenched by the addition of water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the organic layers combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc / petroleum ether (2 / 1) to give tert-butyl 1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (160 mg). LCMS (ESI, m / z): 332 [M+H] + .

[0652] Step 2: Synthesis of N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1 -carboxamide

[0653]

[0654] A vial was charged with tert-butyl 1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (160 mg), DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was dissolved in water (10 mL). The pH value of the solution was adjusted to 8 with a saturated solution of sodium bicarbonate. The mixture was extracted with DCM (3 x 10 mL) and the organic layers combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1 -carboxamide (112 mg). LCMS (ESI, m / z): 232 [M+H] m . x 10 m L) washed with brine (2 + .

[0655] Step 3: Synthesis of (±) tert-butyl 1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate

[0656]

[0657] A vial was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (489 mg), ACN (5 mL), 1,1'- carbonyldiimidazole (94.0 mg), and N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide (112 mg). The resulting solution was stirred at 80 °C overnight and quenched by the addition of water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: 40% ACN / 60% Phase A increasing to 70% ACN over 7 min, then increasing to 100% ACN over 0.1 min, holding at 100% ACN for 1.9 min, then decreasing to 40% ACN over 0.1 min, and holding at 40% for 1.9 min. Column: X-bridge preparative C18, 19*150mm 5um; Mobile Phase: Phase A: NH4HC03in water (0.05%); Phase B: ACN; Detector, UV 220 & 254 nm. Purification provided 32.7 mg of (±) 1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. 1 H NMR (300 MHz, Chloroform-d) δ 8.57 (br, 1H), 8.40-8.32 (m, 2H), 8.17 (d, J = 7.8 Hz, 1H), 7.30-7.29 (m, 1H), 5.86-5.69 (m, 1H), 3.72-3.49 (m, 4H), 1.97-1.84 (m, 2H), 1.62-1.54 (m, 2H), 1.46-1.39 (m, 2H), 1.03-0.95 (m, 1H). LCMS (ESI, m / z): 426 [M+H] + .

[0658] Example 2: (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, and

[0659] Example 3: (R)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0660]

[0661] The racemic mixture prepared in Example 1 (32.7 mg) was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IG, 2*25 cm, 5 pm; mobile phase A: Hex (0.1% DEA) - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 5% B to 5% B over 17 min; UV 220 / 254 nm) to provide:

[0662] Example 2 9.0 mg of (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (br, 1H), 8.49 (br, 1H), 8.24 (br, 1H), 8.01 (s, 1H), 7.33 (br, 1H), 5.77 (br, 1H), 3.73-3.63 (m, 1H), 3.59-3.39 (m, 3H), 1.96 (br, 2H), 1.87-1.59 (m, 2H), 1.48 (br, 1H), 1.40 (s, 1H), 1.04 (s, 1H).t R = 11.695 min. LCMS (Method A) (ESI, m / z): 426 [M+H] + .

[0663] and the corresponding enantiomer

[0664] Example 3 9.8 mg of (R)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (br, 1H), 8.35 (br, 1H), 8.22 (br, 1H), 8.04 (s, 1H), 7.32 (br, 1H), 5.87 (br, 1H), 3.80-3.70 (m, 1H), 3.73-3.41 (m, 3H), 1.87 (br, 2H), 1.63-1.59 (m, 2H), 1.48 (br, 1H), 1.40 (s, 1H), 1.04 (s, 1H).t R = 14.452 min. LCMS (Method B) (ESI, m / z): 426 [M+H] + .

[0665] Determination of the absolute configuration of Example 2 and Example 3

[0666] The absolute configuration of Example 3 was determined using vibrational circular dichroism (VCD) (Appl. Spectrosc. 65(7), 699(2011)). Spectra were obtained using a Chirall R with a DualPEM VCD spectrometer and compared with calculated values ​​(using the DFT calculation method and basis set of CPCM (chloroform) = B3LYP / 6311Gdp). VCD spectroscopic analysis of Example 3 relative to the calculated VCD spectra of the (R)-enantiomer determined that Example 3 was the (R)-enantiomer and therefore Example 2 was the (S)-enantiomer. These samples were analyzed by chiral HPLC under the following conditions: column: CHIRALPAK IC, 3.0*100mm, 3μm; mobile phase: phase A: CO2, phase B: IPA (0.1% DEA); flow rate: 2mL / min; gradient: 10% to 50% over 2.0 min, held at 50% for 1.0 min; detection: 220nm.

[0667] Example 2: First eluted enantiomer (t) R =0.944min)

[0668] Example 3: Second eluted enantiomer (t) R =1.154min)

[0669] Preparation of intermediates with known absolute configurations: Synthesis

[0670] With this information, structural unit intermediates 2A and 3A are transformed into Examples 2 and 3, as described below. The absolute configurations of the enantiomers are then determined by comparing the elution order with that of Examples 2 and 3, which are known above. The synthesis details of Examples 2 and 3 with known absolute configurations are summarized below.

[0671] Step 1: Synthesis of 1-benzyl 6-(tert-butyl) ester of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid

[0672]

[0673] A solution of 240 g of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid in acetone (5 L) was added to a flask purged and maintained under an inert nitrogen atmosphere. Benzyl bromide (170.6 g) and K₂CO₃ (259.8 g) were added. The resulting solution was refluxed for 2–3 h. The reaction was then cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The combined filtrates were concentrated under vacuum to give 297 g of crude 1-benzyl 6-(tert-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylic acid.

[0674] Step 2: Synthesis of benzyl 6-azaspiro[2.5]octane-l-carboxylate hydrochloride

[0675]

[0676] A solution of crude 1 -benzyl 6-(tert-butyl) 6-azaspiro[2.5]octane- 1,6-dicarboxylate (297 g) in DCM (1.5 L) was added to a flask purged and maintained with an inert atmosphere of nitrogen. HC1 (g) in 1,4-dioxane (4 M, 1.5 L) was added dropwise. The resulting solution was stirred at room temperature for 1 h and concentrated in vacuo. The crude product was slurry with Et20 (10 V) to afford 198.3 g of benzyl 6-azaspiro[2.5]octane-l -carboxylate.

[0677] Step 3: Synthesis of 1 -benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane- 1,6-dicarboxylate

[0678]

[0679] A solution of 1,1,1,3,3,3-hexafluoropropan-2-ol (393 g) in DCM (2 L) was added to a flask purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to 0 °C and added triphosgene (106.9 g) portionwise. DIPEA (550 g) was then added dropwise at 0 °C to 10 °C. The mixture was stirred at this temperature for 1.5 h. A solution of benzyl 6-azaspiro[2.5]octane-l -carboxylate hydrochloride (198 g) in DCM (2 L) was then added dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched by pouring into water (6 L) and then extracted with DCM (2 x 2 L). The combined organic layers were washed with brine (1 x 3 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 30) to afford 265 g of 1 -benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane- 1,6-dicarboxylate.

[0680] Step 4: Separation of (S)-1 -benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane- 1,6-dicarboxylate (Intermediate 2A) and (R)-1 -benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane- 1,6-dicarboxylate (Intermediate 3A)

[0681]

[0682] The racemic mixture of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) ester prepared in Step 3 (265 g) was separated by preparative SFC-HPLC (column: CHIRALPAK IG-33.0*50 mm, 3 µm; mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 2% B; 220 nm) to provide the following, whose absolute configuration was determined after preparing the final products (Example 2 and Example 3) and comparing the elution order on chiral columns:

[0683] Intermediate 2A; (S)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) ester. 110 g. 1 H NMR (300 MHz, Chloroform-d) δ 7.46-7.28 (m, 5H), 5.75 (p, J = 6.3 Hz, 1H), 5.13 (s, 2H), 3.57 (m, 3H), 3.28 (m, 1H), 1.86-1.61 (m, 3H), 1.56-1.36 (m, 2H), 1.27-1.19 (m, 1H), 0.99 (dd, J = 8.2, 4.7 Hz, 1H).t R = 1.572 min. LCMS (Method O) (ESI, m / z): 440 [M+H] + and

[0684] Intermediate 3A; (R)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) ester. 100 g. 1 H NMR (300 MHz, Chloroform-d) δ 7.36 (d, J = 2.6 Hz, 5H), 5.75 (p, J = 6.3 Hz, 1H), 5.13 (d, J = 1.4 Hz, 2H), 3.71–3.40 (m, 3H), 3.39-3.13 (m, 1H), 1.71 (ddd, J = 29.4, 9.4, 5.2 Hz, 3H), 1.57-1.36 (m, 2H), 1.23 (d, J = 5.2 Hz, 1H), 0.99 (dd, J = 8.1, 4.7 Hz, 1H).t R = 1.572 min. LCMS (Method O) (ESI, m / z): 440 [M+H] + .

[0685] Step 5-1: Synthesis of (S)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 2B)

[0686]

[0687] A solution of (S)-6-azaspiro[2.5]octane-l,6-dicarboxylic acid 1-benzyl 6-(l,l,l,3,3,3- hexafluoropropan-2-yl) ester (110 g) in THF (2 L) was added to a flask. Wet Pd / C (22 g, 10% wt, 50% H2O) was added to the mixture. The resulting mixture was purged with H2and replaced three times, and then stirred under H2at room temperature for 3 h. The mixture was filtered and the filter cake was washed with THF (2 x 500 mL). The combined filtrates were concentrated in vacuo and the crude product was co-evaporated with toluene (2 x 1 L) to give 90 g of crude (S)-6-(((l,l,l,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-l- carboxylic acid. 0.2 g of the crude product was purified by silica gel column chromatography to provide pure characterization data. 1 H NMR (300 MHz, Chloroform-d) δ 5.78 (h, J = 6.3 Hz, 1H), 3.79 - 3.40 (m, 4H), 1.85 (q, J = 6.1 Hz, 2H), 1.65 (dd, J = 8.0, 5.4 Hz, 1H), 1.54 (dq, J = 10.9, 5.8, 5.0 Hz, 2H), 1.28 (t, J = 5.1 Hz, 1H), 1.09 (dd, J = 8.1, 4.8 Hz, 1H). t R = 1.441 min. LCMS (Method O) (ESI, m / z): 350 [M+H] + .

[0688] Step 6-1: Synthesis of (S)-l-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester (Example 2)

[0689]

[0690] A solution of crude (S)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6- azaspiro[2.5]octane-1 -carboxylic acid (50 mg) in DCM (1 mL) was placed in a reaction vial. EDC HCI (30 mg) and HOBt (39 mg) were added and the resulting mixture was stirred for 15 min. Pyridin-3-amine (18 mg) and DIEA (37 mg) were added. The final reaction mixture was stirred at room temperature overnight. The mixture was diluted with H2O (10 mL) and extracted with DCM (1 x 5 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative HPLC to give (S)-1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester (35 mg). 1 H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.27 (dd, J = 41.0, 6.5 Hz, 2H), 7.96 (s, 1H), 7.30 (dd, J = 8.4, 4.7 Hz, 1H), 5.76 (dd, J = 11.6, 6.0 Hz, 1H), 3.79 - 3.35 (m, 4H), 1.85 (d, J = 6.0 Hz, 2H), 1.58 (dd, J = 8.0, 5.3 Hz, 2H), 1.51 - 1.35 (m, 2H), 1.02 (dd, J = 8.1, 4.7 Hz, 1H). t R = 1.255 min. LCMS (Method O) (ESI, m / z): 426 [M+H] + .

[0691] CHIRALPAK IC, 3.0*100 mm, 3 pm; mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); flow rate: 2 mL / min; gradient: 10% to 50% in 2.0 min, hold at 50% for 1.0 min; detection: 220 nm: t R = 1.928 min.

[0692] After converting intermediate 2B to Example 2 and comparing the elution order of Example 2 (prepared in step 6-1) with Example 3 (prepared in step 6-2) by chiral chromatography, the absolute configuration of intermediate 2B was determined to be the (S)-enantiomer.

[0693] Step 5-2: Synthesis of (R)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6- azaspiro[2.5]octane-1 -carboxylic acid (intermediate 3B)

[0694]

[0695] A solution of (R)-6-azaspiro[2.5]octane-l,6-dicarboxylic acid 1-benzyl 6-(l,l,l,3,3,3- hexafluoropropan-2-yl) ester (1.9 g, 4.3 mmol, 1.0 equiv) in THF (40 mL) was placed in a flask. Wet Pd / C (0.38 g, 10% wt, 50% H2O) was added to the mixture. The resulting mixture was purged with H2and replaced three times and stirred under H2at room temperature for 2 h. The mixture was filtered and the filter cake was washed with THF (2 x 50 mL). The combined filtrate was concentrated in vacuo to provide 1.5 g of crude (R)-6-(((l,l,l,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-l- carboxylic acid which was used directly in the next step without further purification.

[0696] Step 6-2: Synthesis of (R)-l-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester (Example 3)

[0697]

[0698] A solution of crude (R)-6-(((l,l,l,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6- azaspiro[2.5]octane-l -carboxylic acid (50 mg) in DCM (1 mL) was placed in a reaction vial. EDC HCI (30 mg) and HOBt (39 mg) were added and the resulting mixture was stirred for 15 min. Pyridin-3-amine (18 mg) and DIEA (37 mg) were added. The final reaction mixture was stirred at room temperature overnight. The mixture was diluted with H2O (10 mL) and extracted with DCM (1 x 5 mL). The combined organic phase was dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by preparative HPLC to provide (R)-l-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester (50 mg) as a white solid. 1HNMR (300 MHz, chloroform-d) δ 8.59 (t, J = 3.2 Hz, 1H), 8.33 (dd, J = 4.8, 1.4 Hz, 1H), 8.17 (d, J = 8.6 Hz, 2H), 7.32 - 7.26 (m, 1H), 5.76 (h, J = 6.1 Hz, 1H), 3.74 - 3.35 (m, 4H), 1.86 (t, J = 6.0 Hz, 2H), 1.59 (dd, J = 8.0, 5.2 Hz, 2H), 1.37 (t, J = 5.0 Hz, 2H), 1.00 (dd, J = 8.0, 4.6 Hz, 1H). tR= 1.266 min. LCMS (ESI, m / z): 426 [M+H] + .

[0699] CHIRALPAK IC, 3.0*100 mm, 3 pm; mobile phase: phase A: C02, phase B: IPA (0.1% DEA); flow rate: 2 mL / min; gradient: 10% to 50% in 2.0 min, 1.0 min hold at 50%; detection: 220 nm : t R = 2.030 m i n .

[0700] Upon comparison of the elution order of Example 2 (prepared in Step 6-1) and Example 3 (prepared in Step 6-2) by chiral chromatography, the absolute configuration of intermediate 3B was determined to be the (R)-enantiomer.

[0701] Intermediate 2B and 3B with known absolute configuration were used in the synthesis of Examples 5, 6, 8 and 9 as described below.

[0702] Example 4: (±) 1 -(Pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0703]

[0704] racemic

[0705] Step 1: Synthesis of tert-butyl 1 -(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate

[0706]

[0707] 1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester was prepared as described in Example 1, Step 1, using 6-[(tert-butoxy)carbonyl]-6-azaspiro[2.5]octane-1 - carboxylic acid (600 mg), DMF (17.4 mg), oxalyl chloride (386 mg), pyridin-3-amine (245 mg), and 1 -(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester to provide the title compound (360 mg). LCMS (ESI, m / z): 333 [M+H] + .

[0708] Step 2: Synthesis of N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1 -carboxamide

[0709]

[0710] N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1 -carboxamide was prepared as described in Example 1, Step 2, using 1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (180 mg) and TFA (5 mL) to provide the title compound (125 mg). LCMS (ESI, m / z): 233 [M+H] + .

[0711] Step 3: Synthesis of 1 -[(pyridin-3-yl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0712]

[0713] 1 -[(pyridin-3-yl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester was prepared as described in Example 1, Step 3, using N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1 -carboxamide (125 mg), 1,1 '- carbonyldiimidazole (105 mg), and 1,1,1,3,3,3-hexafluoropropan-2-ol (904 mg) to provide the title compound (33.0 mg).

[0714] Example 5: (R)-1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester and

[0715] Example 6: (S)-1 -(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0716]

[0717] The racemic mixture prepared in Example 4 (33.0 mg) was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IC, 2*25 cm, 5 pm; mobile phase A: Hex - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B over 7 min; UV 220 / 254 nm) to provide:

[0718] Example 5: 15.3 mg of (R)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. 1 H NMR (400 MHz, Chloroform-d) δ 12.2 - 12.0 (m, 1H), 8.87 (s, 1H), 8.75 (br, 1H), 7.66 (br, 1H), 5.80 - 5.74 (m, 1H), 3.72 - 3.64 (m, 3H), 3.43 - 3.37 (m, 1H), 2.49 (t, J = 6.4 Hz, 1H), 1.94 - 1.86 (m, 2H), 1.70 - 1.58 (m, 2H), 1.44 (s, 1H), 1.17 - 1.14 (m, 1H). t R = 5.118 min. LCMS (Method C) (ESI, m / z): 427 [M+H] + . CHIRALPAK AD, 3.0*100 mm, 3 pm; mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 10% to 50% in 2.0 min, hold at 50% for 1.0 min; detection: 220 nm: t R = 0.814 min.

[0719] and the corresponding enantiomer

[0720] Example 6: 10.1 mg of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. 1H NMR (400 MHz, Chloroform-d) δ 11.2 (s, 1H), 8.87 (s, 1H), 8.75 (br, 1H), 7.66 (br, 1H), 5.80-5.74 (m, 1H), 3.72-3.64 (m, 3H), 3.43-3.37 (m, 1H), 2.49 (t, J = 6.4 Hz, 1H), 1.94-1.86 (m, 2H), 1.70-1.58 (m, 2H), 1.44 (s, 1H), 1.17-1.14 (m, 1H).t R = 6.025 min. LCMS (Method C) (ESI, m / z): 427 [M+H] + . CHIRALPAK AD, 3.0*100 mm, 3 pm; mobile phase: Phase A: C02, Phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 10% to 50% in 2.0 min, 50% for 1.0 min; detection: 220 nm: t R = 1.080 min.

[0721] Example 5 was synthesized using known intermediate 3B:

[0722]

[0723] (R)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1 - carboxylic acid (Intermediate 3B) (200 mg), DMF (5 mg) and THF (10 mL) were added to a flask. (COCl)2(100 mg) was added dropwise over 60 min at 0 °C with stirring. The solvent was then removed and THF (2 mL) was added. The resulting solution was added dropwise to a solution of pyridine (90 mg) in THF (2 mL) and pyridazine-3-amine (66 mg). The solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of water. The resulting solution was extracted with EtOAc (3 x 20 mL) and the organic layers were combined and dried over anhydrous sodium sulfate, concentrated in vacuo and slurry with hexane / EA (10 / 1, 10V) to afford 62 mg of (R)-1 -(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. LCMS (ESI, m / z): 427 [M+H]+.1H NMR (300 MHz, chloroform-d) δ 10.81 (s, 1H), 8.86 (d, J = 4.7 Hz, 1H), 8.61 (d, J = 9.1 Hz, 1H), 7.55 (s, 1H), 5.86 - 5.61 (m, 1H), 3.76 - 3.27 (m, 4H), 2.28 (dd, J = 7.9, 5.4 Hz, 1H), 1.86 (q, J = 6.4 Hz, 4H), 1.41 (t, J = 4.9 Hz, 1H), 1.10 (dd, J = 7.9, 4.6 Hz, 1H).t R = 1.439 min. LCMS (Method O) (ESI, m / z): 427 [M+H]+. + = 1.439 min. LCMS (Method O) (ESI, m / z): 427 [M+H]+. R = 0.805 min.

[0724] Note that the retention time of the product prepared here with Intermediate 3B matches the retention time of Example 5 prepared above, in this case the racemic product was separated into its enantiomers by SFC, confirming the absolute configuration of the assignment made to Example 5 in the preparation above.

[0725] Example 6 was synthesized with known intermediate 2B:

[0726]

[0727] (S)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1 - carboxylic acid (Intermediate 2B) (38.5 g), DCM (800 mL) and DMF (0.40 g) were added to a flask purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to 0 °C and (COCl)2(11.5 g) was added dropwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was then concentrated in vacuo to obtain crude acid chloride for later use. Pyridazine-3-amine (12.6 g), pyridine (17.4 g) and THF (800 mL) were added to another flask purged and maintained with an inert atmosphere of nitrogen. The previous acid chloride in THF (500 mL) was added dropwise at room temperature. The resulting solution was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with 3 L of ice water and extracted with EtOAc (2 x 1 L). The combined organic phase was washed with H2O (1 x 1 L) and brine (1 x 1 L), dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 10) to give 34.3 g of the product. The product was slurry with n-hexane (20 V) and filtered to give 26.7 g of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. The product was isolated by slurry with n-heptane (10 V) to give 24.13 g of (S)-1-[(pyridazin-3-yl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester (Example 6). 1 H NMR (300 MHz, Chloroform-d) δ 10.82 (s, 1H), 8.87 (d, J = 4.7 Hz, 1H), 8.61 (d, J = 9.1 Hz, 1H), 7.55 (s, 1H), 5.90-5.62 (m, 1H), 3.73-3.27 (m, 4H), 2.26 (dd, J = 8.0, 5.4 Hz, 1H), 1.95-1.72 (m, 4H), 1.41 (t, J = 5.0 Hz, 1H), 1.11 (dd, J = 7.9, 4.6 Hz, 1H). t R = 1.443 min. LCMS (Method O) (ESI, m / z): 427 [M+H] + . CHIRALPAK AD, 3.0*100 mm, 3 mm; mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 10% to 50% in 2.0 min, hold at 50% for 1.0 min; detection: 220 nm: t R = 1.032 min.

[0728] Note that the retention time of the product prepared here with intermediate 2B matches the retention time of Example 6 prepared above, in this case the racemic product was separated into its enantiomers by SFC to confirm the absolute configuration of the assignment made to Example 6 in the preparation above.

[0729] Example 7: (±)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0730]

[0731] racemic

[0732] Step 1: Synthesis of tert-butyl 1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0733]

[0734] A flask was charged with 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (300 mg), EDCI (294 mg), HOBT (238 mg), TEA (356 mg), tetrahydro-2H-pyran-4-amine (154 mg) and DCM (5 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction was then quenched with water (10 mL), extracted with DCM (2*15 mL) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM:MeOH = 20:1) to afford tert-butyl 1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (352 mg). LCMS (ESI, m / z): 339 [M+H] + .

[0735] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0736]

[0737] N-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octane-1-carboxamide was prepared as described in Example 1 Step 2 with tert-butyl 1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (352 mg), TFA (1.5 mL) and DCM (3 mL) to afford 500 mg of the (crude) title compound. LCMS (ESI, m / z): 239 [M+H] + .

[0738] Step 3: Synthesis of (±) 1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0739]

[0740] 1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester was prepared from N-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octane-1-carboxamide (480 mg), CDI (392 mg), and 1,1,1,3,3,3-hexafluoropropan-2-ol (3389 mg) as described in Example 1, Step 3 to provide crude product (377 mg). The crude product was purified by reverse phase column chromatography to provide the title compound (88 mg).

[0741] Example 8: (S)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, and

[0742] Example 9: (R)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0743]

[0744] The racemic mixture prepared in Example 7 (88 mg) was separated into two enantiomers by preparative SFC-HPLC (column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH (0.5% 2M NH3-MeOH) - HPLC; flow rate: 50 mL / min; gradient: 15% B; column temperature: 35 °C; back pressure: 100 bar; UV 220 nm) to provide:

[0745] Example 8: 13 mg of (S)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane- 6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester 1H NMR (400MHz, chloroform-d) δ5.78(dq,J=12.0,6.1Hz,1H),5.52(d,J=7.9Hz,1H),4.09-3.93(m,3H),3.72-3.40(m,6H),1.97-1.87(m,2H),1.81(dd ,J=10.9,5.4Hz,2H),1.56-1.50(m,2H),1.50-1.40(m,2H),1.34(dd,J=8.0,5.3Hz,1H),1.27(d,J=4.6Hz,1H),0.88(dd,J=8.0,4.5Hz,1H). t R = 4.32 min. LCMS (Method D) (ESI, m / z): 433 [M+H] + (S,S)Whelk-01, 4.6*100mm, 5μm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 4mL / min; Gradient: 5% to 20% over 2.0min, held at 20% for 1.0min; Detection: 220nm:t R =1.568min.

[0746] and corresponding enantiomers

[0747] Example 9: 15.4 mg of (R)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester 1 H NMR (400MHz, chloroform-d) δ5.78(m,J=6.0Hz,1H),5.51(d,J=8.0Hz,1H),4.21-3.87(m,3H),3.87-3.03(m,6H),1.93(ddd,J=12.9,4.4,2.2Hz,2H) ,1.87-1.70(m,2H),1.55-1.48(m,2H),1.48-1.38(m,2H),1.34(dd,J=8.0,5.3Hz,1H),1.27(d,J=4.6Hz,1H),0.88(dd,J=8.0,4.5Hz,1H). t R = 4.99 min. LCMS (Method A) (ESI, m / z): 433 [M+H] + (S,S)Whelk-01, 4.6*100mm, 5μm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 4mL / min; Gradient: 5% to 20% over 2.0min, held at 20% for 1.0min; Detection: 220nm:t R= 1.425 min

[0748] Example 8 was synthesized using known intermediate 2B:

[0749]

[0750] (S)-6-[[(1,1,1,3,3,3-hexafluoropropan-2-yl)oxy]carbonyl]-6-azaspiro[2.5]octane-1- carboxylic acid (intermediate 2B) (21.0 g), DCM (400 mL) and DMF (0.22 g) were added to a flask purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to 0 °C and (COCl)2(11.5 g) was added dropwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was then concentrated in vacuo to obtain crude acid chloride for later use. Oxan-4-amine (7.3 g), pyridine (9.5 g) and THF (400 mL) were added to another flask purged and maintained with an inert atmosphere of nitrogen. A solution of the acid chloride in THF (200 mL) was added dropwise at room temperature. The resulting solution was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with ice water (1 x 3 L) and extracted with EtOAc (2 x 500 mL). The combined organic phase was washed with H2O (1 x 1 L) and brine (1 x 1 L), dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 10) to provide 20.7 g of product. The product was further purified by silica gel column chromatography with 0.1% NH4HCO3in H2O-MeCN system to provide 15.2 g of amorphous product. The product was finally recrystallized from MeCN / H2O = 1:1 (0.5 V / 0.5 V) to provide 11.97 g of (S)-1-[(oxan-4-yl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester. 1 H NMR (300 MHz, Chloroform-d) δ 5.76 (s, 1H), 5.49 (d, J = 8.0 Hz, 1H), 3.96 (d, J = 12.1 Hz, 3H), 3.72 - 3.34 (m, 6H), 2.00 - 1.72 (m, 4H), 1.54 - 1.37 (m, 4H), 1.35 - 1.20 (m, 2H), 0.86 (dd, J = 7.9, 4.4 Hz, 1H). t R = 1.442 min. LCMS (Method O) (ESI, m / z): 433 [M+H] +(S,S) Whelk-01, 4.6*100 mm, 5 mm; mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); flow rate: 4 mL / min; gradient: 5% to 20% in 2.0 min, hold at 20% for 1.0 min; detection: 220 nm: t R = 1.525 min.

[0751] Note that the retention time of the product prepared here with intermediate 2B matches the retention time of Example 8 prepared above, in this case the racemic product was separated into its enantiomers by SFC, confirming the absolute configuration of the assignment made to Example 8 in the preparation above.

[0752] Example 9 was synthesized using known intermediate 3B:

[0753]

[0754] A solution of crude (R)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6- azaspiro[2.5]octane-1-carboxylic acid (intermediate 3B) (50 mg) and DCM (1 mL) was placed in a reaction vial. EDC HCI (30.3 mg) and HOBt (38.7 mg) were added and the resulting mixture was stirred for 15 min. Tetrahydro-2H-pyran-4-amine (18.8 mg) and DIEA (37.0 mg) were added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with H2O (10 mL) and extracted with DCM (1 x 5 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to provide (R)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester (37 mg).1H NMR (300 MHz, Chloroform-d) δ 5.76 (td, J = 6.1, 3.3 Hz, 1H), 5.50 (d, J = 8.0 Hz, 1H), 3.96 (d, J = 12.5 Hz, 3H), 3.70 - 3.36 (m, 6H), 1.98 - 1.72 (m, 4H), 1.55 - 1.39 (m, 4H), 1.37 - 1.19 (m, 2H), 0.86 (dd, J = 7.9, 4.4 Hz, 1H). t R = 1.442 min. LCMS (Method P) (ESI, m / z): 433 [M+H] +(S,S) Whelk-01, 4.6*100mm, 5mm; mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); flow rate: 4 mL / min; gradient: 5% to 20% in 2.0 min, hold at 20% for 1.0 min; detection: 220 nm: t R = 1.46 min.

[0755] Note that the retention time of the product prepared here with intermediate 3B matches the retention time of Example 9 prepared above, in this case the racemic product was separated into its enantiomers by SFC, confirming the absolute configuration of the assignment made to Example 9 in the preparation above.

[0756] Example 10: (±) 1-(methyl(piperidin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0757]

[0758] racemic

[0759] Step 1: Synthesis of tert-butyl 1-(piperidin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate

[0760]

[0761] Tert-butyl 1-(piperidin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate was prepared from 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (500 mg), DCM (10 mL), DMF (14.0 mg), oxalyl chloride (249 mg), piperidin-4-amine (186 mg), pyridine (464 mg), and tert-butyl 1-(chloroformyl)-6-azaspiro[2.5]octane-6-carboxylate as described in Step 1 of Example 1 to provide the title compound (190 mg). LCMS (ESI, m / z): 333 [M+H] + .

[0762] Step 2: Synthesis of tert-butyl 1-(methyl(piperidin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate

[0763]

[0764] A vial was charged with 1 -(piperidin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid tert-butyl ester (100 mg) and THF (5 mL). Sodium hydride (30.2 mg, 0.758 mmol, 1.50 equiv, 60% in mineral oil) was added at 0 °C. The resulting solution was stirred at 0 °C for 0.5 h, then methyl iodide (97.4 mg) was added. The resulting solution was stirred at room temperature overnight and quenched with water (10 ml). The mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1 -(methyl(piperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (100 mg). LCMS (ESI, m / z): 347 [M+H] + .

[0765] Step 3: Synthesis of N-methyl-N-(pyrazin-2-yl)-6-azaspiro[2.5]octane-1 -carboxamide

[0766]

[0767] N-methyl-N-(pyrazin-2-yl)-6-azaspiro[2.5]octane-1 -carboxamide was prepared from 1 -(methyl(piperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (100 mg), TFA (3 mL) and DCM (3 mL) as described in Example 1 Step 2 to provide the title compound (99.7 mg). LCMS (ESI, m / z): 247 [M+H] + .

[0768] Step 4: Synthesis of (±) 1 -(methyl(piperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0769]

[0770] A small vial was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (102 mg, 0.606 mmol, 1.50 equiv), DCM (10 mL) and triphosgene (67.8 mg). DIPEA (156 mg) was added at 0 °C. The resulting solution was stirred at room temperature for 2 h, then N-methyl-N-(pyrazin-2-yl)-6-azaspiro[2.5]octane-1 -carboxamide (99.7 mg) was added. The resulting solution was stirred at room temperature overnight and then quenched with water (10 mL). The solution was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.

[0771] Example 11: (R)-1-(methyl(p yrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1, and

[0772] Example 12: (S)-1-(methyl(p yrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0773]

[0774] The racemic mixture prepared in Example 10 was separated into two enantiomers by preparative chiral-HPLC (column: CHIRALPAK IA column 2*25 cm, 5 pm; mobile phase A: Hexane - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B over 11 min; detector, UV 220 & 254 nm) to provide:

[0775] Example 11: 12.5 mg of (R)-1-(methyl(p yrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.45 (d, J = 7.31 Hz, 2H), 5.83 - 5.76 (m, 1H), 3.82 - 3.75 (m, 2H), 3.52 (s, 3H), 3.46 - 3.37 (m, 2H), 1.88 - 1.79 (m, 1H), 1.73 - 1.62 (m, 3H), 1.48 - 1.45 (m, 1H), 1.33 - 1.26 (m, 1H), 0.91 - 0.88 (m, 1H). t R= 7.897 min. LCMS (Method E) (ESI, m / z): 441 [M+H] + .

[0776] and the corresponding enantiomers

[0777] Example 12: 12.1 mg of (S)-1-(methyl(piperazin-1-ylcarbonyl)-6-azaspiro[2.5]octane-6- carboxylate, peak 2. 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.46 (d, J = 7.50 Hz, 2H), 5.83 - 5.75 (m, 1H), 3.81 - 3.76 (m, 2H), 3.52 (s, 3H), 3.45 - 3.37 (m, 2H), 1.88 - 1.79 (m, 1H), 1.72 - 1.59 (m, 3H), 1.47 - 1.45 (m, 1H), 1.33 - 1.26 (m, 1H), 0.92 - 0.88 (m, 1H). t R = 9.487 min. LCMS (Method E) (ESI, m / z): 441 [M+H] + .

[0778] Determination of the absolute configuration of Example 11 and Example 12

[0779] The absolute configuration of Examples 11 and 12 was determined in a similar manner to Example 3, where the resynthesis of the final compound using an intermediate of known absolute configuration allowed the assignment of the absolute configuration of the final product (Example 11 and Example 12). It was finally determined that the first eluting enantiomer was the (R) enantiomer (Example 11), and therefore Example 12 was the (S)-enantiomer.

[0780] Example 13: (±)-1-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3- hexafluoropropan-2-yl ester

[0781]

[0782] racemic

[0783] Step 1: Synthesis of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(tert-butyl) ester

[0784]

[0785] A vial was charged with 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1- carboxylic acid (300 mg), acetone (15 mL), K2CO3(195 mg), and BnBr (220 mg). The resulting solution was stirred at 60 °C overnight and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc to provide 1-benzyl 6-(tert-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (350 mg). LCMS (ESI, m / z): 346 [M+H] + .

[0786] Step 2: Synthesis of benzyl 6-azaspiro[2.5]octane-1-carboxylate

[0787]

[0788] To 1-benzyl 6-(tert-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (350 mg) in DCM (6 mL) was added HCl (g) (3 mL). The resulting solution was stirred at room temperature for 2 h and concentrated under reduced pressure to provide benzyl 6-azaspiro[2.5]octane-1-carboxylate (260 mg). LCMS (ESI, m / z): 246 [M+H] + .

[0789] Step 3: Synthesis of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate

[0790]

[0791] Benzyl 6-azaspiro[2.5]octane-1-carboxylate (240 mg), ACN (4 mL), 1,1'- carbonyldiimidazole (205 mg), DIPEA (378 mg), and 1,1,1,3,3,3-hexafluoropropan-2-ol (820 mg) were used as described in Example 1, Step 3 to provide 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (350 mg). LCMS (ESI, m / z): 440 [M+H] + .

[0792] Step 4: Synthesis of 6-(((l,l,l,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6- azaspiro[2.5]octane-l-carboxylic acid

[0793]

[0794] A mixture of 6-azaspiro[2.5]octane-l,6-dicarboxylic acid 1-benzyl 6-(l,l,l,3,3,3- hexafluoropropan-2-yl) ester (340 mg) and Pd / C (40 mg, 10% wt) in EtOAc (10 mL) was stirred under H2overnight. The reaction was cooled to room temperature and filtered. Concentration under reduced pressure to filter to provide 6-(((l,l,l,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-l- carboxylic acid (240 mg). LCMS (ESI, m / z): 350 [M+H] + .

[0795] Step 5: Synthesis of (±)l-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester

[0796]

[0797] (±)l-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3- hexafluoropropan-2-yl ester was prepared from 6-(((l,l,l,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-l-carboxylic acid (100 mg), isoxazol-4-amine (44.7 mg), EDCI (60.5 mg), HOBT (38.7 mg), and TEA (86.8 mg) in DCM (2 mL) as described in Example 5, Step 1 to provide the title compound (70 mg).

[0798] Example 14: (S)-l-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester, Peak 1, and

[0799] Example 15: (R)-l-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-yl ester, Peak 2

[0800] The racemic mixture prepared in Example 10 (70 mg) was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IG, 2*25 cm, 5 pm; mobile phase A: Hex (0.5% 2M NH3-MeOH) - HPLC, mobile phase B: IPA - HPLC; flow rate: 20 mL / min; gradient: 20% B to 30% B over 7.5 min; detector, UV 220 & 254 nm) to provide:

[0801] Example 14: 15.0 mg of (S)-1-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.37 (s, 1H), 7.48 (s, 1H), 5.86-5.70 (m, 1H), 3.79-3.66 (m, 1H), 3.65-3.43 (m, 3H), 1.93-1.75 (m, 2H), 1.69-1.42 (m, 3H), 1.41-1.34 (m, 1H), 1.11-0.99 (m, 1H).t R = 5.612 min. LCMS (Method E) (ESI, m / z): 416 [M+H] + .

[0802] and the corresponding enantiomer

[0803] Example 15: 9.7 mg of (R)-1-(isoxazol-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2. 1 H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.37 (s, 1H), 7.48 (s, 1H), 5.84-5.70 (m, 1H), 3.79-3.65 (m, 1H), 3.64-3.42 (m, 3H), 1.93-1.76 (m, 2H), 1.70-1.42 (m, 3H), 1.41-1.35 (m, 1H), 1.10-0.99 (m, 1H).t R = 6.706 min. LCMS (Method E) (ESI, m / z): 416 [M+H] + .

[0804] Determination of the absolute configuration of Example 14 and Example 15

[0805] The absolute configurations of Examples 14 and 15 were determined in a manner similar to that of Example 3, wherein the resynthesis of the final compound using an intermediate having a known absolute configuration allowed for the allocation of the absolute configuration of the final product (Examples 14 and 15). The second eluted enantiomer was ultimately determined to be the (R) enantiomer (Example 15), and therefore Example 14 is the (S) enantiomer.

[0806] Example 16: (±)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0807]

[0808] racemic

[0809] Step 1: Synthesis of tert-butyl 1-(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylate

[0810]

[0811] 255 mg of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid and 10 mL of DCM were placed in a vial. 201 mg of 1-chloro-N,N,2-trimethylprop-1-en-1-amine was added dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h and concentrated under reduced pressure to provide 274 mg of tert-butyl 1-(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid.

[0812] Step 2: Synthesis of tert-butyl 1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0813]

[0814] A vial was charged with 2-(trifluoromethyl)pyrimidin-4-amine (200 mg) and THF (15 mL). Sodium hydride (49.0 mg, 1.23 mmol, 2.00 equiv, 60% in mineral oil) was added at 0 °C. The resulting suspension was stirred at room temperature for 0.5 h and tert-butyl 1-(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylate (252 mg) was added. The resulting solution was stirred at room temperature overnight and quenched by water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc / petroleum ether (1:3) to afford tert-butyl 1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (240 mg). LCMS (ESI, m / z): 401 [M+H] + .

[0815] Step 3: Synthesis of N-(2-(trifluoromethyl)pyrimidin-4-yl)-6-azaspiro[2.5]octane-1- carboxamide

[0816]

[0817] N-(2-(trifluoromethyl)pyrimidin-4-yl)-6-azaspiro[2.5]octane-1-carboxamide was prepared from tert-butyl 1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (240 mg), 1,4-dioxane (4 mL) and concentrated hydrochloric acid (1 mL) as described in Example 13, Step 2 to afford the title compound (180 mg). LCMS (ESI, m / z): 301 [M+H] + .

[0818] Step 4: Synthesis of (±)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane- 6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0819]

[0820] (R)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2 was prepared from N-(2-(trifluoromethyl)pyrimidin-4-yl)-6-azaspiro[2.5]octane-1 -carboxamide (0.180 g), carbonyldiimidazole (0.146 g), ACN (15 mL), and 1,1,1,3,3,3-hexafluoropropan-2-ol (1.21 g) as described in Example 1 Step 3 to provide the title compound.

[0821] Example 17: (S)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1, and

[0822] Example 18: (R)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0823]

[0824] The racemic mixture prepared in Example 16 was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK AD-H, 2*25 cm, 5 pm; mobile phase A: Hexane - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 5% B to 5% B in 11 min; UV 220 / 254 nm) to provide:

[0825] Example 17: 15.8 mg of (S)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J = 5.6 Hz, 1H), 8.50-8.20 (m, 2H), 5.77 (br, 1H), 3.84-3.68 (m, 1H), 3.68-3.38 (m, 3H), 1.85 (br, 2H), 1.68-1.58 (m, 2H), 1.58-1.40 (m, 2H), 1.22-1.02 (m, 1H). t R = 7.674 min. LCMS (Method F) (ESI, m / z): 495 [M+H] + .

[0826] and the corresponding enantiomer (R)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2 was prepared from N-(2-(trifluoromethyl)pyrimidin-4-yl)-6-azaspiro[2.5]octane-1 -carboxamide (0.180 g), carbonyldiimidazole (0.146 g), ACN (15 mL), and 1,1,1,3,3,3-hexafluoropropan-2-ol (1.21 g) as described in Example 1 Step 3 to provide the title compound.

[0827] Example 18: 17.2 mg of (R)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2. 1 H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J = 5.6 Hz, 1H), 8.50-8.20 (m, 2H), 5.77 (br, 1H), 3.84-3.68 (m, 1H), 3.68-3.38 (m, 3H), 1.85 (br, 2H), 1.68-1.58 (m, 2H), 1.58-1.40 (m, 2H), 1.22-1.02 (m, 1H). t R = 9.747 min. LCMS (Method F) (ESI, m / z): 495 [M+H] + .

[0828] Determination of the absolute configuration of Example 17 and Example 18

[0829] The absolute configuration of Examples 17 and 18 was determined in a similar manner to Example 3, where the resynthesis of the final compound using an intermediate with a known absolute configuration allowed the assignment of the absolute configuration of the final product (Example 17 and Example 18). It was finally determined that the second eluting enantiomer was the (R) enantiomer (Example 18), and thus Example 17 was the (S)-enantiomer.

[0830] Example 19: (±)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0831]

[0832] racemic

[0833] Step 1: Synthesis of tert-butyl 1-((6-iodopyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylate

[0834]

[0835] To a stirred solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-l- carboxylic acid (500.00 mg), HATU (1116.95 mg) and DIEA (759.32 mg) in DMF (10.00 mL) was added 6-iodopyridin-3-amine (430.87 mg) at room temperature. The resulting mixture was stirred overnight and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 / 220 nm to afford tert-butyl l-((6-iodopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (700 mg). LCMS (ESI, m / z): 458 [M+H] + .

[0836] Step 2: Synthesis of tert-butyl l-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylate

[0837]

[0838] A mixture of tert-butyl l-((6-iodopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (700.00 mg), Pd2(dba)3 (140.17 mg), XantPhos (88.57 mg), Et3N (464.67 mg) and (methylphosphino)methane (238.94 mg) in 1,4-dioxane (10.00 mL) was stirred at 80 °C under nitrogen atmosphere overnight. The resulting mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 / 220 nm to afford tert-butyl l-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (560 mg). LCMS (ESI, m / z): 408 [M+H]+.

[0839] Step 3: Synthesis of N-(6-(dimethylphosphoryl)pyridin-3-yl)-6-azaspiro[2.5]octane-1- carboxamide hydrochloride

[0840]

[0841] N-(6-(dimethylphosphoryl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide hydrochloride was prepared from tert-butyl 1-[[6-(dimethylphosphoryl)pyridin-3-yl]carbamoyl]-6- azaspiro[2.5]octane-6-carboxylate (560.00 mg), DCM (5.00 mL) and HC1 (g) (4 M in 1,4- dioxane, 5.00 mL, 20 mmol) as described in Example 13, Step 2 to provide the title compound (400 mg). The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 308 [M-HC1+H] + .

[0842] Step 4: Synthesis of (±)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0843]

[0844] (±)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester was prepared from N-(6-(dimethylphosphoryl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide hydrochloride (350.00 mg), DIPEA (525.00 mg), hexafluoroisopropanol (341.86 mg) and CDI (214.33 mg) in MeCN (10.00 mL) as described in Example 1, Step 3 to provide the title compound (400 mg) LCMS (ESI, m / z): 502 [M+H] + .

[0845] Example 20: (R or S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1

[0846] Example 21: (R or S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0847]

[0848] The racemic mixture prepared in Example 19 was separated by chiral HPLC (CHIRALART Cellulose-SB, 2*25 cm, 5 pm; mobile phase A: Hex (0.2% DEA) - HPLC, mobile phase B: EtOH:DCM = 1 : 1 - HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 21 min; UV 220 / 254 nm) to provide:

[0849] Example 20: 135.2 mg of (R or S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.89-8.87 (m, 1H), 8.22-8.18 (m, 1H), 7.90-7.86 (m, 1H), 6.59-6.54 (m, 1H), 3.62-3.56 (m, 2H), 3.54-3.49 (m, 1H), 3.33 (s, 1H), 1.87-1.83 (m, 1H), 1.69 (s, 2H), 1.65-1.59 (m, 6H), 1.51 (s, 2H), 1.20-1.11 (m, 1H), 1.06-0.99 (m, 1H). t R = 8.88 min. LCMS (Method D) (ESI, m / z): 502 [M+H] + .

[0850] and the corresponding enantiomer

[0851] Example 21: 122.5 mg of (R or S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2. 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.89-8.87 (m, 1H), 8.22-8.18 (m, 1H), 7.90-7.86 (m, 1H), 6.59-6.54 (m, 1H), 3.62-3.56 (m, 2H), 3.55 - 3.47 (m, 1H), 3.33 (s, 1H), 1.89-1.81 (m, 1H), 1.70 (s, 1H), 1.66-1.59 (m, 7H), 1.51 (s, 2H), 1.21-1.11 (m, 1H), 1.06-0.98 (m, 1H). t R = 11.641 min. LCMS (Method D) (ESI, m / z): 502 [M+H] + .

[0852] Example 22: (±)-1-(Pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0853]

[0854] Step 1: Synthesis of tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate

[0855]

[0856] A mixture of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (600 mg, 2.34 mmol, 1.00 equiv), HATU (1069 mg, 2.80 mmol, 1.20 equiv), DIPEA (15.2 mg, 11.2 mmol, 5.00 equiv) and NH4Cl (620 mg, 11.7 mmol, 5.00 equiv) in DMF (10 mL) was stirred at room temperature overnight. The resulting mixture was quenched by water (50 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (8:1) to afford tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate (500 mg). LCMS (ESI, m / z): 255 [M+H] + .

[0857] Step 2: Synthesis of tert-butyl 1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylate

[0858]

[0859] A mixture of 400 mg 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester, 386 mg 4-iodopyridine, 433 mg K₂CO₃, 22 mg Ln, and 15 mg CuI in toluene (30 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL) and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (8:1) to provide 360 ​​mg 1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester. LCMS (ESI, m / z): 332 [M+H] + .

[0860] Step 3: Synthesis of N-(pyridin-4-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0861]

[0862] As described in step 2 of Example 13, N-(pyridin-4-yl)-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (360 mg), DCM (5 mL), and HCl (gas) / 1,4-dioxane (3 mL) were used to prepare the title compound (200 mg). LCMS (ESI, m / z): 232 [M+H] + .

[0863] Step 4: Synthesis of (±)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0864]

[0865] As described in step 3 of Example 1, (±)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-1-carboxamide (440 mg), CDI (369 mg), ACN (5 mL), DIPEA (489 mg), and 1,1,1,3,3,3-hexafluoroprop-2-ol (1603 mg) were used to prepare (±)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester to provide the title compound (100 mg).

[0866] Example 23: (R or S)-1-(Pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1, and

[0867] Example 24: (R or S)-1-(Pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0868]

[0869] The racemic mixture prepared in Example 22 was separated into two enantiomers by chiral HPLC (CHIRALPAK IF, 2*25 cm, 5 pm; mobile phase A: Hex (10 mM NH3-MeOH), mobile phase B: EtOH - HPLC; flow rate: 15 mL / min; gradient: 5% B to 5% B in 15 min; UV 220 / 254 nm) to provide:

[0870] Example 23: 32.9 mg of (R or S)-1-(Pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 9.11-8.88 (m, 1H), 8.59-8.30 (m, 2H), 7.68-7.44 (m, 2H), 5.79-5.60 (m, 1H), 3.80-3.36 (m, 4H), 1.96-1.77 (m, 2H), 1.73-1.51 (m, 2H), 1.50-1.34 (m, 2H), 1.08-0.99 (m, 1H). t R = 9.807 min. LCMS (Method E) (ESI, m / z): 426 [M+H] + .

[0871] and the corresponding enantiomer

[0872] Example 24: 32.2 mg of (R or S)-1-(Pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2. 1H NMR (400 MHz, Chloroform-d) δ 9.11-8.88 (m, 1H), 8.59-8.30 (m, 2H), 7.68-7.44 (m, 2H), 5.79-5.60 (m, 1H), 3.80-3.36 (m, 4H), 1.96-1.77 (m, 2H), 1.73-1.51 (m, 2H), 1.50-1.34 (m, 2H), 1.08-0.99 (m, 1H).t R = 11.917 min. LCMS (Method E) (ESI, m / z): 426 [M+H] + .

[0873] Example 25: (±) 1-((tetrahydro-2H-pyran-4-carbonyl)aminocarbonyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0874]

[0875] Step 1: Synthesis of tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate

[0876]

[0877] Tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate was prepared as described in Example 19, Step 1, from 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1- carboxylic acid (600 mg, 2.34 mmol, 1.00 equiv), HATU (1069 mg, 2.80 mmol, 1.20 equiv), DIPEA (15.2 mg, 11.2 mmol, 5.00 equiv), NH4Cl (620 mg, 11.7 mmol, 5.00 equiv) in DMF (10 mL) to afford tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate (500 mg). LCMS (ESI, m / z): 255 [M+H] + .

[0878] Step 2: Synthesis of tert-butyl 1-((tetrahydro-2H-pyran-4-carbonyl)aminocarbonyl)-6- azaspiro[2.5]octane-6-carboxylate

[0879]

[0880] To a mixture of tetrahydro-2H-pyran-4-carboxylic acid (500.00 mg) and oxalyl chloride (961 mg) in DCM (10 mL) was added DMF (30.0 mg) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure before adding 1- carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (150 mg) and dimethylpyridine (127 mg) in DCM. The reaction mixture was stirred at room temperature overnight and quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 30 mL) and the combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to provide 1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (230 mg). LCMS (ESI, m / z): 367 [M+H] + .

[0881] Step 3. Synthesis of N-(tetrahydro-2H-pyran-4-carbonyl)-6-azaspiro[2.5]octane-1- carboxamide

[0882]

[0883] N-(tetrahydro-2H-pyran-4-carbonyl)-6-azaspiro[2.5]octane-1-carboxamide was prepared from 1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid tert-butyl ester (230 mg), DCM (5 mL) and a solution of HC1 (gas) / 1,4- dioxane (3 mL) as described in Example 13, Step 2 to provide N-(tetrahydro-2H-pyran-4- carbonyl)-6-azaspiro[2.5]octane-1-carboxamide (130 mg). LCMS (ESI, m / z): 267 [M+H] + .

[0884] Step 4: Synthesis of (±) 1-(((tetrahydro-2H-pyran-4-carbonyl))carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0885]

[0886] (R or S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester was prepared from N- (tetrahydro-2H-pyran-4-carbonyl)-6-azaspiro[2.5]octane-1 -carboxamide (200 mg), CDI (146 mg), ACN (5 mL), DIPEA (489 mg, 3.79 mmol, 2.00 equiv), and 1,1,1,3,3,3-hexafluoropropan-2-ol (634 mg) as described in Example 1 Step 3 to provide the title compound (100 mg).

[0887] Example 26: Synthesis of (R or S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1

[0888] Example 27: Synthesis of (R or S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0889]

[0890] The racemic mixture prepared in Example 25 (100 mg) was separated into two enantiomers by chiral HPLC (CHIRALPAK IF, 2*25 cm, 5 pm; mobile phase A: Hex (10 mM NH3-MeOH), mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 25 min; UV 220 / 254 nm) to provide:

[0891] Example 26: 41.5 mg of (R or S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 - 8.31 (m, 1H), 5.91 - 5.69 (m, 1H), 4.15 - 3.96 (m, 2H), 3.78 - 3.59 (m, 3H), 3.56 - 3.39 (m, 2H), 3.34 - 3.20 (m, 1H), 2.90 - 2.74 (m, 1H), 2.50 - 2.40 (m, 1H), 1.90 - 1.77 (m, 4H), 1.73 - 1.62 (m, 3H), 1.60 - 1.51 (m, 1H), 1.48 - 1.39 (m, 1H), 1.11 - 1.01 (m, 1H). tR = 8.356 min. LCMS (Method A) (ESI, m / z): 461 [M+H] + .

[0892] and corresponding enantiomers

[0893] Example 27: 24.7 mg of (R or S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, peak 2. 1 H NMR (400MHz, chloroform-d) δ8.43-8.31(m,1H),5.91-5.69(m,1H),4.15-3.96(m,2H),3.78-3.59(m,3H),3.56-3.39(m,2H),3.34-3.20(m,1H) ,2.90-2.74(m,1H),2.50-2.40(m,1H),1.90-1.77(m,4H),1.73-1.62(m,3H),1.60-1.51(m,1H),1.48-1.39(m,1H),1.11-1.01(m,1H). t R = 16.403 min. LCMS (Method A) (ESI, m / z): 461 [M+H] + .

[0894] Example 28: (±)1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0895]

[0896] Step 1. Synthesis of 5-nitro-2-(1H-pyrazol-1-yl)pyridine

[0897]

[0898] A vial was charged with 2-fluoro-5-nitropyridine (1.00 g, 7.04 mmol, 1.00 equiv), 1H- pyrazole (575 mg), Cs2C03(5.10 mg), and DMF (10 mL). The resulting solution was stirred at 100 °C overnight and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to provide 5-nitro-2-(1H-pyrazol-1-yl)pyridine (1.00 g). LCMS (ESI, m / z): 191 [M+H] + .

[0899] Step 2: Synthesis of 6-(1H-pyrazol-1-yl)pyridin-3-amine

[0900]

[0901] A mixture of 5-nitro-2-(1H-pyrazol-1-yl)pyridine (1.00 g) and Pd / C (20 mg, 10% w.t) in MeOH (10 mL) was stirred under H2overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to provide 6-(1H-pyrazol-1-yl)pyridin-3-amine (600 mg). LCMS (ESI, m / z): 161 [M+H] + .

[0902] Step 3: Synthesis of tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylate

[0903]

[0904] Tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (300 mg) was prepared from 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1- carboxylic acid (300 mg), N-(5-aminopyridin-2-yl)acetamide (245 mg), EDCI (248 mg), HOBT (159 mg), and TEA (356 mg) in DCM (3 mL) as described in Example 7, Step 1 to provide tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (300 mg). LCMS (ESI, m / z): 398 [M+H] + .

[0905] Step 4: Synthesis of N-(6-(lH-pyrazol-l-yl)pyridin-3-yl)-6-azaspiro[2.5]octane-l- carboxamide

[0906]

[0907] N-(6-(lH-pyrazol-l-yl)pyridin-3-yl)-6-azaspiro[2.5]octane-l-carboxamide was prepared from tert-butyl l-((6-(lH-pyrazol-l-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylate (300 mg), DCM (6 mL) and HC1 (g) (3 mL) as described in Example 13, Step 2 to provide N-(6-(lH-pyrazol-l-yl)pyridin-3-yl)-6-azaspiro[2.5]octane-l- carboxamide (200 mg). LCMS (ESI, m / z): 298 [M+H] + .

[0908] Step 5: Synthesis of (±)l-((6-(lH-pyrazol-l-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0909]

[0910] (±)l-((6-(lH-pyrazol-l-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester was prepared from N-(6-(lH-pyrazol-l- yl)pyridin-3-yl)-6-azaspiro[2.5]octane-l-carboxamide (200 mg), ACN (3 mL), 1,1'- carbonyldiimidazole (142 mg), DIPEA (261 mg) and 1,1,1,3,3,3-hexafluoropropan-2-ol (566 mg) as described in Example 1, Step 3 to provide the title compound (240 mg).

[0911] Example 29: (R or S)-l-((6-(lH-pyrazol-l-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1

[0912] Example 30: (R or S)-l-((6-(lH-pyrazol-l-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0913]

[0914] The racemic mixture prepared in Example 28 was separated by chiral HPLC (CHIRALPAK IF, 2*25 cm, 5 pm; mobile phase A: Hex (0.5% 2M NH3-MeOH) - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 11 min; UV 220 / 254 nm) to provide:

[0915] Example 29: 84.2 mg of (R or S)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.55-8.45 (m, 2H), 8.22 (d, J = 8.5 Hz, 2H), 8.00-7.93 (m, 1H), 7.78-7.65 (m, 2H), 6.51-6.46 (m, 1H), 5.84-5.72 (m, 1H), 3.81-3.43 (m, 4H), 1.95-1.81 (m, 2H), 1.72-1.53 (m, 2H), 1.53-1.37 (m, 2H), 1.10-1.00 (m, 1H).t R = 5.29 min. LCMS (Method G) (ESI, m / z): 492 [M+H] + .

[0916] and the corresponding enantiomer

[0917] Example 30: 86.1 mg of (R or S)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2. 1 H NMR (400 MHz, Chloroform-d) δ 8.55-8.43 (m, 2H), 8.27 (d, J = 8.5 Hz, 2H), 8.01-7.93 (m, 1H), 7.79-7.64 (m, 2H), 6.50-6.45 (m, 1H), 5.86-5.70 (m, 1H), 3.80-3.42 (m, 4H), 1.94-1.81 (m, 2H), 1.74-1.53 (m, 2H), 1.55-1.39 (m, 2H), 1.11-0.99 (m, 1H).t R = 7.84 min. LCMS (Method E) (ESI, m / z): 492 [M+H] + .

[0918] Example 31: (±)1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0919]

[0920] Step 1: Synthesis of 5-amino-N-methylpyridine amide

[0921]

[0922] Methyl 5-aminopyridinecarboxylate (500 mg) was added to a solution of MeNH2 (204 mg, 6.58 mmol, 2.00 equivalence) in EtOH (5 mL). The resulting solution was stirred overnight at 80 °C at room temperature and then quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 20 mL), and the organic layers were combined, washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide 5-amino-N-methylpyridine amide (400 mg). LCMS (ESI, m / z): 152 [M+H] + .

[0923] Step 2: Synthesis of tert-butyl 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0924]

[0925] As described in step 1 of Example 19, 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (300 mg) and 5-amino-N-methylpyridine amide (231 mg) were prepared in DMF (5 mL). ) 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester was prepared from HATU (671 mg) and DIPEA (455 mg) to provide 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (210 mg). LCMS (ESI, m / z): 389 [M+H] + .

[0926] Step 3: Synthesis of N-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0927]

[0928] N-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-l-carboxamide was prepared from tert-butyl 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (210 mg) and HC1 (g) (2 mL) in DCM (4 mL) as described in Example 13, Step 2 to provide N-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-l-carboxamide (140 mg). LCMS (ESI, m / z): 289 [M+H] + .

[0929] Step 4: Synthesis of 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0930]

[0931] 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester was prepared from N-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-l-carboxamide (140 mg), ACN (3 mL), 1,1'- carbonyldiimidazole (102 mg), DIPEA (188 mg), and 1,1,1,3,3,3-hexafluoropropan-2-ol (408 mg) as described in Example 1, Step 3 to provide the title compound (160 mg).

[0932] Example 32: (R or S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1

[0933] Example 33: (R or S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2

[0934]

[0935] The racemic mixture prepared in Example 31 was separated by chiral HPLC (CHIRALPAK IF, 2*25 cm, 5 pm; mobile phase A: Hex (0.5% 2M NH3-MeOH) - HPLC, mobile phase B: EtOH - HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 10.5 min; UV 220 / 254 nm) to provide:

[0936] Example 32: 33.1 mg of (R or S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.70-8.46 (m, 1H), 8.39-8.16 (m, 2H), 8.22 (s, 1H), 8.10 (s, 1H), 5.88-5.67 (m, 1H), 3.74 (s, 1H), 3.56 (s, 3H), 3.16-2.97 (m, 3H), 1.87 (s, 2H), 1.79-1.36 (s, 4H), 1.07 (s, 1H).t R = 6.605 min. LCMS (Method A) (ESI, m / z): 483 [M+H] + .

[0937] Example 33: 31.8 mg of (R or S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester, Peak 2. 1 H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.47 (s, 1H), 8.15 (s, 2H), 8.00 (d, J=5.5 Hz, 1H), 5.86-5.68 (m, 1H), 3.78-3.67 (m, 1H), 3.65-3.47 (m, 3H), 3.04 (d, J=4.8 Hz, 3H), 1.95-1.79 (m, 2H), 1.78-1.38 (m, 4H), 1.09-1.01 (s, 1H).t R = 8.899 min. LCMS (Method E) (ESI, m / z): 483 [M+H] + .

[0938] Example 34: (±) 1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6- carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0939]

[0940] Step 1: Synthesis of tert-butyl 1-(4-cyclopropylpiperazine-l-carbonyl)-6- azaspiro[2.5]octane-6-carboxylate

[0941]

[0942] A small vial was charged with 6-((tert-butoxy)carbonyl)-6-azaspiro[2.5]octane-l- carboxylic acid (150 mg), THF (5 mL), 1-cyclopropylpiperazine (74.0 mg), DIPEA (152 mg), and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane-2,4,6-trione (50% in EtOAc, 563 mg, 0.885 mmol, 1.50 equiv) under nitrogen. The resulting solution was stirred at 60 °C for 3 h and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc / petroleum ether (2 / 1) to provide tert-butyl 1-(4-cyclopropylpiperazine-l-carbonyl)-6-azaspiro[2.5]octane-6- carboxylate (57.0 mg). LCMS (ESI, m / z): 364 [M+H] + .

[0943] Step 2: Synthesis of (4-cyclopropylpiperazin-l-yl)(6-azaspiro[2.5]octan-l- yl)methanone

[0944]

[0945] (4-cyclopropylpiperazin-l-yl)(6-azaspiro[2.5]octan-l-yl)methanone was prepared from tert-butyl 1-(4-cyclopropylpiperazine-l-carbonyl)-6-azaspiro[2.5]octane-6- carboxylate (207 mg), DCMe (5 mL), and TFA (5 mL) as described in Example 1, Step 2 to provide the title compound (150 mg). LCMS (ESI, m / z): 264 [M+H] + .

[0946] Step 3: Synthesis of (±) 1-(4-cyclopropylpiperazine-l-carbonyl)-6-azaspiro[2.5]octane- 6-carboxylic acid 1,1,1,3,3,3-hexafluoropropan-2-yl ester

[0947]

[0948] (±) 1 -(4-cyclopropylpiperazine- 1 -carbonyl)-6-azaspiro[2.5]octan-6- methyl 1,1,1,3,3,3-hexafluoropropan-2-yl ester was prepared from 1,1,1,3,3,3- hexafluoropropan-2-ol (287 mg), ACN (5 mL), 1,1'-carbonyldiimidazole (111 mg), and (4-cyclopropylpiperazin-1-yl)(6-azaspiro[2.5]octan-1-yl)methanone (150 mg) as described in Example 1, Step 3. The crude product was purified by preparative HPLC using the following gradient conditions: 20% CH3CN / 80% Phase A increased to 80% CH3CN over 10 min on a Waters 2767-5 chromatograph, then increased to 100% CH3CN over 0.1 min, held at 100% CH3CN for 1.9 min, then decreased to 20% CH3CN over 0.1 min, and held at 20% for 1.9 min. Column: X-bridge preparative C18, 19*150mm 5μm; mobile phase: Phase A: NH4HCO3 in water (0.05%); Phase B: CH3CN; Detector, UV 220 & 254 nm. Purification gave (±) 1 -(4-cyclopropylpiperazine- 1 -carbonyl)-6-azaspiro[2.5]octan-6- methyl 1,1,1,3,3,3-hexafluoropropan-2-yl ester (80.7 mg). 18 1 H NMR (300 MHz, chloroform-d) δ 5.79-5.74 (m, 1H), 3.38-3.81 (m, 8H), 2.71-2.01 (m, 4H), 1.72-1.58 (m, 5H), 1.26-1.53 (m, 2H), 0.85-0.71 (m, 1H), 0.40 (br, 4H). LCMS (Method E) (ESI, m / z): 458 [M+H] + .

[0949] Examples 35-189: Example 35-189 was prepared by an analogous procedure to that described in Examples 1-34. The absolute configuration of Examples 36, 105, 118, 142, 151, 162, and 174 was determined in an analogous manner to Example 3, wherein resynthesis of the final compound using an intermediate of known absolute configuration allowed assignment of the absolute configuration of the final product. The stereochemistry of the corresponding (S)-enantiomer (Examples 37, 106, 117, 141, 150, 163, and 175) was assigned as described above for Examples 12, 14, and 17.

[0950]

[0951] ​

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986] Example 190-II. Biological Evaluation

[0987] Compounds were tested using the following in vitro and in vivo assays to assess their MAGL activity.

[0988] Proteomic profiling based on in vitro competition activity

[0989] PC3 human cell membrane proteome (50 μL, total protein concentration 2.0 mg / mL) was pre-incubated with different concentrations of inhibitors at 37 °C. After 30 min, ABPP probe JW912-Bodipy (1.0 μL, 50 μM in DMSO) was added and the mixture was incubated at room temperature for 30 min. The reaction was quenched with SDS-loaded buffer (15 μL - 4X) and run on SDS-PAGE. After gel imaging, the fluorescence intensity of the gel band corresponding to MAGL was measured by using ImageJ 1.43u software to determine the serine hydrolase activity. The intensity was converted to percentage of enzyme activity by normalizing to DMSO control. IC50 values were determined by fitting the percentage of enzyme activity to a 4-parameter sigmoidal dose response function in Prism GraphPad by non-linear regression.

[0990] In vitro competition substrate hydrolase activity assay

[0991] HEK293 cell lysate expressing recombinant human MAGL enzyme and 4-nitrophenyl acetate (pNPA) substrate were diluted in 50 mM HEPES (pH 7.0) containing 200 mM KCl and 1 mM EDTA, respectively. Lysate (50 μL, ~1.2 μg total protein) was pre-incubated with different concentrations of inhibitors at 25 °C. After 30 min, 2X pNPA substrate (50 μL, 2.5 mM) was added, and the rate of substrate turnover was monitored by measuring absorbance increase at wavelength 405 nm for 20 min at 25 °C using a Biotek Neo2 plate reader. After background subtraction and normalization to DMSO control, the average velocity was converted to percentage of enzyme activity. IC50 values were determined by fitting the percentage of enzyme activity to a 4-parameter sigmoidal dose response function in Prism GraphPad by non-linear regression.

[0992] In vivo

[0993] Wild-type C57B1 / 6J were administered inhibitors in polyethylene glycol vehicle via oral gavage. Four hours after administration, each animal was sacrificed, and brain proteomes were prepared and analyzed according to previously established methods (see Niphakis, M. J. et al. (2011) ACS Chem. Neurosci. and Long, J. Z. et al. Nat. Chem. Biol. 5:37-44).

[0994] As shown in Table 1, compounds demonstrated activity in the assays described herein.

[0995] Table 1

[0996]

[0997]

[0998]

[0999]

[1000]

[1001] Example 191 - Acute treatment effects in the rat formalin paw model of inflammatory pain

[1002] In the rat formalin paw model, formalin was administered to the right hind paw of a rat to induce pain (observed by duration and frequency of hind paw licking). Test compounds were administered to evaluate their efficacy in reducing the frequency of hind paw licking, which is suggestive of translation to pain (such as acute and / or chronic pain in patients) relief.

[1003] Experimental protocol:

[1004] Male Sprague Dawley rats were divided into three groups to enable a balanced design for three days of testing in Laboras TM A total of 10 treatment groups were tested in a three-day study in the Laboras TM Cage. Data collection started immediately. Licking duration and frequency were recorded for the hind paw. Movement was also reported as maximum speed, average speed while moving or whole-time bin and distance travelled. At the end of the 40 min, when data collection was complete, the rats were removed from the cage. TM The primary measures recorded for the formalin paw model were hind paw licking duration and frequency. Movement was also reported as maximum speed, average speed while moving or whole-time bin and distance travelled. At the end of the 40 min, when data collection was complete, the rats were removed from the cage.

[1005] When removed from the test cage, rats were anaesthetised with gaseous isoflurane (5% v / v isoflurane in oxygen) and blood samples were collected by cardiac puncture. The brains were then removed, rinsed in phosphate buffered saline (PBS), hemi-sected in liquid nitrogen and frozen separately.

[1006] Data analysis / statistics:

[1007] Data were analysed using Statistica software (TIBCO, version 11.1 for the USA). All data are presented as mean ± standard error of the mean (sem) to one decimal place. Data are presented as overall activity between 0 and 10 minutes (early phase) and 10 and 30 minutes (delayed inflammatory phase) as well as time course data in 5 min time bins for the full 40 min data collection.

[1008] Time course data were analysed by repeated measures analysis of variance (ANOVA) followed by one-way ANOVA and subsequent Dunnett’s post-hoc test at each time point. Early phase and delayed inflammatory phase data were analysed with one-way ANOVA and Dunnett’s post-hoc test.

[1009] Outliers were defined as values falling more than two standard deviations from the mean, and were excluded from the 0-10 min and 10-30 min data as well as the time course data. The level of significance was set at p < 0.05.

[1010] As shown in Figure 1 Example 6 administered at 0.6 mg / kg, 3 mg / kg and 10 mg / kg showed statistically significant reductions in the measure of spontaneous pain (hind paw licking frequency) at both the early and late stages of the test. As shown in Figure 2 Example 8 administered at 1 mg / kg, 3 mg / kg and 10 mg / kg showed statistically significant reductions in the measure of spontaneous pain (hind paw licking frequency) at both the early and late stages of the test, and Example 8 additionally showed statistically significant reductions in the measure of spontaneous pain at 0.3 mg / kg and 0.6 mg / kg at the late stage.

[1011] Example 192 - Assessment of the effect of compounds of the invention in the maximal electroshock seizure threshold (MEST) model in rats

[1012] Experimental protocol:

[1013] In the MEST model, a low intensity current of high frequency and short duration is applied to induce tonic convulsions. The MEST test allows the identification of anticonvulsant activity of compounds that can be useful in the treatment of generalized seizures.

[1014] Animals were randomly assigned to vehicle, compound treatment or Lamotrigine dose groups. Animals were dosed according to treatment group (n = 12 or 16 / group) at 5 mL / kg, with vehicle (0.5% MC) for Example 6, vehicle (10% HP-b-CD) for Example 8, test compound at 10 mg / kg orally for a 240 min pre-treatment period, or Lamotrigine orally for a 360 min pre-treatment period.

[1015] Using the shock titration "up and down" method (Kimball AW et al., 1957), rats were individually assessed for the production of tonic hind limb extension seizures following a single corneal delivery of an electric shock of 0.3 second duration. Thus, the first rat in a treatment group was shocked at the expected or estimated CC50 current (the current that produces tonic hind limb extension seizures in 50% of the animals). For subsequent animals, the intensity of stimulation was decreased or increased by a logarithmic 0.06:10 Λ mA for rats that did or did not show tonic hind extension, respectively, from the previous rat. This procedure was continued for all rats in a treatment group. The seizure-inducing measure was taken as an all-or-none effect, with each animal scored as present (+) or absent (0).

[1016] Data from each treatment group were recorded as the number of + and 0 at each current level used according to the method of Kimball et al. (1957) and this information was then used to calculate the CC50 value (current required to show tonic hind limb extension in 50% of the animals) ± standard error. Drug effect was calculated as % change in CC50 compared to vehicle control group.

[1017] Statistical analysis:

[1018] Significant differences between drug treated animals and controls were assessed according to Litchfield and Wilcoxon (1949) or one-way ANOVA followed by Dunnett’s multiple comparison test.

[1019] Results:

[1020] The results show that there is anticonvulsant activity of Example 6 and Example 8 at 10 mg / kg in the MEST in rats Figure 3 and Figure 4 ).

[1021] Example 193 - Evaluation of the anticonvulsant activity of test compounds in the kainic acid seizure model in rats

[1022] Kainic acid is an analogue of the excitatory neurotransmitter glutamate and acts as an agonist at kainic acid receptors. After systemic injection, kainic acid induces prolonged excitatory responses with many features of human temporal lobe epilepsy.

[1023] Experimental protocol:

[1024] The method to detect anticonvulsant activity related to glutamatergic mechanisms follows the method described by Ben-Ari et al. (Neuroscience, 6, 1361-1391, 1981).

[1025] Rats placed in individual Plexiglas cages (33 x 21 x 18 cm) were injected with kainic acid (20 mg / kg i.p.). The appearance of the following symptoms was noted over a 120 min period, 30 min after kainic acid injection: forelimb clonus, rearing on the hind legs, rearing on the hind legs with concomitant falling, clonic convulsions, tonic convulsions and death. The presence of each symptom and the latency to the first appearance of the symptoms were measured. The number of forelimb clonus was counted.

[1026] Twelve rats were studied per group. The test was performed in part blind.

[1027] The test substance will be evaluated at multiple doses (p.o.) 240 minutes prior to testing and compared to the corresponding vehicle control group (Group 2, p.o. 240 minutes prior to testing with a 10% HP-b-CD solution in distilled water).

[1028] Example 6 will be evaluated at 0.3, 1, 3 and 10 mg / kg (p.o.) and Example 8 at 1, 3 and 10 mg / kg (p.o.) 4 hours prior to testing and compared to the vehicle control group (p.o. 4 hours prior to testing with 10% HP-b-CD).

[1029] Diazepam (16 mg / kg) (0.5% HP-b-CD) will be administered p.o. 60 minutes prior to testing as a reference and compared to the vehicle control.

[1030] Data analysis / statistics:

[1031] Quantitative data (latency) for the test substance will be analyzed by using the Kruskal-Wallis test followed by the Mann-Whitney U test to compare treatment groups to the vehicle control. Quantitative data for the reference will be analyzed using the Mann-Whitney U test.

[1032] Quantitative data (frequency) will be analyzed by using the Fisher's Exact Probability test to compare treatment groups to the vehicle control.

[1033] The results indicate a clear anticonvulsant effect of Example 6 in the range of 0.3-10 mg / kg and Example 8 in the range of 1-10 mg / kg in the rat tunicamycin seizure test. At the mid-high doses, the magnitude of the effect of the Example 6 and Example 8 compounds is close to that observed with the reference (diazepam).

[1034] Example 194 - Rat Kp

[1035] Brain disposition was evaluated in male Sprague-Dawley rats (n=3, standard weight). Briefly, test compounds were formulated as simple suspensions in 0.5% HPMC in water and then administered via oral gavage (5 mg / kg, 5 mL / kg). Four hours post-dose, rats were sacrificed and peripheral blood and brain samples were collected. Blood (0.1 mL) was obtained by cardiac puncture and immediately added to 0.4 mL CH3CN for precipitation. Samples were stored at -75 + / - 15 °C prior to analysis. Brain tissue samples were collected after complete exsanguination of the animals and the tissue was immediately washed with cold saline. After sectioning, brain sections were immediately frozen in liquid nitrogen and stored at -75 + / - 15 °C prior to analysis. Blood and brain samples were analyzed by LC / MS / MS using optimized analytical methods. Control matrix-matched calibration standards were used to quantify the concentration of test compounds in blood and brain. Total blood, plasma, and brain concentration data were used to calculate brain K p (overall brain concentration: overall plasma concentration ratio), calculated brain k p,uu (uncoupled brain concentration: uncoupled plasma concentration ratio), free fraction in rat plasma and brain, and in vitro rat blood versus plasma distribution curves are presented in Table 2. Total plasma concentration data were calculated from total blood concentration data using the in vitro measured rat blood to plasma ratio (1 μΜ test compound). For k p,uu Determination, free fraction in rat plasma and brain homogenate was measured in vitro by standard equilibrium dialysis (1 μΜ test compound and 6 h equilibration (pH 7.4 against buffer); for rat plasma analysis, 100 mM diisopropyl fluorophosphate stock solution was added to pre-warmed rat plasma prior to addition of test article).

[1036] Table 2: Presentation of total concentration, brain K p and K p,uu (mean, standard deviation, from n=3 rats)

[1037]

[1038] Example 195 - Solubility (kinetics)

[1039] The kinetic solubility of the test articles was determined in pH 2.0 and pH 7.4 PBS in duplicate. Stock solutions of the test compounds in DMSO (10 mM) were incubated at room temperature for 2 hours at 1,100 RPM shaking. The samples were then filtered using a vacuum manifold, diluted, and analyzed by LC-MS / MS. Chromatographic conditions: Phenomenex Synergi 4μ Hydro-PR 80A column (2.0 x 30 mm) coupled with a guard column; mobile phase = 0.1% formic acid in acetonitrile and 0.1% formic acid in water; flow rate = 0.65 mL / min; column temperature = 40 °C; injection volume: 3 μL.

[1040] Time (min) 0 0.8 1.1 1.2 1.4 ％A 5 100 100 5 5

[1041] Mass spectrometry conditions: Ion spray source; ESI ionization model; MRM scan type; collision gas = 6 L / min; gas curtain gas = 30 L / min; nebulizer gas = 50 L / min; auxiliary gas = 50 L / min; temperature = 500 °C; ion spray voltage = +5500 v (positive MRM).

[1042] The filtered solutions were analyzed and quantified against standards of known concentration in DMSO using UPLC coupled with mass spectrometry peak identification and quantification. The solubility values for the test articles were calculated using Microsoft Excel as follows (DF is the dilution factor):

[1043]

[1044] The kinetic solubility data are presented in Table 3.

[1045] Table 3: Kinetic solubility at pH 2 and pH 7.4

[1046] Example pH 2 solubility (μΜ) pH 7.4 solubility (μΜ) 2 30.34 188.64 6 240.44 106.34 8 308.09 256.47 17 0.07 20 309.76 24 197.25 29 8.63 40 163.13 100.48 43 233.41 60 258.78 66 8.74 76 1.33 78 16.97 12.57 81 130.5 90 32.98 96 236.99 99 28.53 112 185.13 108.74 117 250.82 127 275.38 291.87 181 295.59

[1047] Example 196 - Solubility (thermodynamic)

[1048] The kinetic solubility of the test articles was determined in pH 2.0 and pH 7.4 PBS in duplicate. Stock solutions of the test compounds in DMSO (10 mM) were incubated at room temperature for 2 hours at 1,100 RPM shaking. The samples were then filtered using a vacuum manifold, diluted, and analyzed by LC-MS / MS. Chromatographic conditions: Phenomenex Synergi 4μ Hydro-PR 80A column (2.0 x 30 mm) coupled with a guard column; mobile phase = 0.1% formic acid in acetonitrile and 0.1% formic acid in water; flow rate = 0.65 mL / min; column temperature = 40 °C; injection volume: 3 μL.

[1049] Mobile phase: 0.1% formic acid acetonitrile solution (A) and 0.1% formic acid aqueous solution (B)

[1050] Time (min) 0 0.3 0.8 1.1 1.2 1.4 ％A 5 5 100 100 5 5

[1051] Mass spectrometry conditions: spray gun ion source; ESI ionization model; MRM scan type; collision gas = 6 L / min; curtain gas = 30 L / min; nebulizing gas = 50 L / min; auxiliary gas = 50 L / min; temperature = 500℃; ion spray voltage = +5500 V (positive MRM).

[1052] UPLC combined with mass spectrometry peak identification and quantification was used to analyze and quantify the filtered solution of DMSO with standards of known concentrations. The solubility values ​​of the test items were calculated using Microsoft Excel as follows (DF is the dilution factor):

[1053]

[1054] Thermodynamic solubility data are presented in Table 4.

[1055] Table 4: Thermodynamic solubility at pH 7.4

[1056] Example pH 7.4 solubility (mg / mL) 2 0.0918 6 0.0715 8 0.6064

[1057] Example 197 - In vitro stability of human hepatocytes

[1058] Test item (1 μM) in commercially sourced, aggregated donor, cryopreserved human hepatocytes (0.5 × 10⁻⁶). 6 Metabolic stability in cells per mL was determined in duplicate. int The reaction (250 μL) was initiated by adding the test compound. Aliquots (25 μL) were taken at 0, 15, 30, 45, 60, 90, 120, and 240 minutes, and the protein was then lysed with ice-cold acetonitrile containing an internal standard, followed by centrifugation (3220 g, 25 min). The supernatant was used for LC-MS / MS analysis. The in vitro half-life (in vitro t1 / 2) was determined by the slope value: in vitro t 1 / 2 = -0.693 / k. In vitro t-tests were performed using the following equation (the average of two determined values). 1 / 2 (In minutes) converted to amplified unbound intrinsic clearance (amplified unbound CLIt, in mL / min / kg), where the data are shown in Table 5: Amplified unbound CLIt = kV / N x scaling factor. V = incubation volume (0.25 mL); N = number of hepatocytes / well (0.125 × 10⁻⁶). 5 (per cell). The following lists the proportional factors for predicting in vivo intrinsic clearance:

[1059]

[1060] Table 5: Amplified Unbound CL int

[1061]

Claims

1. A compound having formula (I): in: R1 represents -C(O)NHR2, -C(O)N(CH3)R2, -C(O)NR3R4, -C(O)NHCH2R2 or -C(O)NHC(O)R2; R2 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two heteroatoms independently selected from N, O and S, a 6-membered heterocycle having one or two heteroatoms independently selected from N or O, a C3-C7 cycloalkyl group, or a 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O. R3 and R4, together with the N atoms to which they are attached, form 9- or 10-membered bicyclic heterocycles having 1 to 4 independent heteroatoms selected from N or O, or 6-membered heterocycles having one or two independent heteroatoms selected from N or O; and Each of the phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7 cycloalkyl, 7-membered bicyclic heterocycle, or 9- or 10-membered bicyclic heterocycle is unsubstituted or substituted by one or two substituents independently selected from the following: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, having the structure of formula (Ia): in: R1 represents -C(O)NHR2, -C(O)N(CH3)R2, -C(O)NR3R4, -C(O)NHCH2R2 or -C(O)NHC(O)R2; R2 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two heteroatoms independently selected from N, O and S, a 6-membered heterocycle having one or two heteroatoms independently selected from N or O, a C3-C7 cycloalkyl group, or a 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O. R3 and R4, together with the N atoms to which they are attached, form 9- or 10-membered bicyclic heterocycles having 1 to 4 independent heteroatoms selected from N or O, or 6-membered heterocycles having one or two independent heteroatoms selected from N or O; and Each of the phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7 cycloalkyl, 7-membered bicyclic heterocycle, or 9- or 10-membered bicyclic heterocycle is unsubstituted or substituted by one or two substituents independently selected from the following: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH; Or its pharmaceutically acceptable salt.

3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein, R1 represents -C(O)NHR2.

4. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein, R2 represents a 5- or 6-membered heteroaryl group selected from the group consisting of: pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one of the following substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, a 5-membered heteroaryl group having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH.

5. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein, R2 represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazine, and piperidinyl, wherein R2 is unsubstituted or substituted by one of the substituents selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl, and cyano.

6. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein, R2 represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazinyl, and piperidinyl, wherein R2 is unsubstituted.

7. A compound having the structure of formula (Ic): in: R5 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two heteroatoms independently selected from N, O and S, a 6-membered heterocycle having one or two heteroatoms independently selected from N or O, a C3-C7 cycloalkyl group, or a 7-membered bicyclic heterocycle having one or two heteroatoms independently selected from N or O. R6 represents hydrogen or methyl; W is either -CH2- or -C(O)-; n is 0 or 1; and Each of the phenyl, 5- or 6-membered heteroaryl, 6-membered heterocycle, C3-C7 cycloalkyl, and 7-membered bicyclic heterocycle is unsubstituted or substituted by one or two substituents independently selected from the following: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH; Or its pharmaceutically acceptable salt.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein, n is 0.

9. The compound according to any one of claims 7-8, or a pharmaceutically acceptable salt thereof, wherein, R5 represents a 5- or 6-membered heteroaryl group selected from the group consisting of: pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by one of the following substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, a 5-membered heteroaryl group having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH.

10. The compound according to any one of claims 7-8, or a pharmaceutically acceptable salt thereof, wherein, R5 represents a 6-membered heteroaryl group selected from the group consisting of pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl, wherein the 6-membered heteroaryl group is unsubstituted.

11. The compound according to any one of claims 7-8, or a pharmaceutically acceptable salt thereof, wherein, R5 represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazine, and piperidinyl, wherein R5 is unsubstituted or substituted by one substituent selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl, and cyano.

12. The compound according to any one of claims 7-8, or a pharmaceutically acceptable salt thereof, wherein, R5 is not replaced.

13. The compound according to claim 1, wherein, The compound was selected from the group consisting of the following: (±)1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (±)1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (±)1-(5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (±)1-((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((pyridin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((2-(trifluoromethyl)pyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((2-methylpyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-methylpyridazin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyridazin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(morpholine-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(4-cyanopiperidin-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(thiazol-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(thiazol-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(p-Tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((pyridazine-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((2-oxaspiro[3.3]heptane-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (±)1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-carbamoylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(isoxazo-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-((6-(methylsulfonamido)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)2-((5-(6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carbamate)pyridin-2-yl)oxy)acetic acid; (±)1-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (±)1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(methyl(pyridazin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; and (±)1-((6-cyanopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein, The compound was selected from the group consisting of the following: (R)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-methoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((5-fluoropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(methyl(pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(methyl(pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (S)-1-(2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (S)-1-(2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (R)-1-((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((5-chloropyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((2-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(((6-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-methylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((pyridin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((pyridin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((cyclohexanecarbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(benzoylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((2-(trifluoromethyl)pyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((2-(trifluoromethyl)pyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((2-methylpyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((2-methylpyrimidin-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-methylpyridazin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-methylpyridazin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(pyridazin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(pyridazin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((5-methylpyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((1-methylpiperidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(morpholino-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(morpholino-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(4-cyanopiperidin-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(4-cyanopiperidin-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((1-methyl-1H-pyrazol-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(thiazolyl-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(thiazolyl-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((1-methyl-1H-pyrazol-5-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(thiazolyl-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(thiazolyl-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(phenylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(p-Tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(p-Tolylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((3-fluorophenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(benzylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((pyrimidin-5-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((pyridazin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((pyridazin-3-ylmethyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((2-oxaspiro[3.3]heptane-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((2-oxaspiro[3.3]heptane-6-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (S)-1-((6-cyclopropylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropyl-2-yl ester; (R)-1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-isopropoxypyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-acetamidopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-carbamoylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-carbamoylpyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-(isoxazo-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-(isoxazo-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-1-((6-(methylsulfonamido)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (S)-1-((6-(methylsulfonamido)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (R)-2-((5-(6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carbamate)pyridin-2-yl)oxy)acetic acid; and (S)-2-((5-(6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carbamate)pyridin-2-yl)oxy)acetic acid; or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein it is (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein it is (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, wherein it is (S)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

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