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 compounds. The compounds and compositions provided herein are useful as inhibitors of MAGL. In addition, the compounds and compositions as provided herein are useful for treating diseases and disorders that benefit from inhibition of MAGL.

Description

[0001] This application is a divisional application of the application filed on November 12, 2021, with application number 202180073621.0 and invention title "MAGL Inhibitor". Technical Field

[0002] This invention relates to compounds that are inhibitors of monoacylglycerol lipase (MAGL). Different aspects of the invention relate to pharmaceutical compositions comprising said compounds and the use of these compounds for treating diseases and disorders related to the regulation of signaling activity in the endocannabinoid system. Background Technology

[0003] 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-arachidonicylglycerol (2-AG) to arachidonic acid (AA) (Blankman et al. Chem Biol. 2007; Nomura et al. Science. 2011).

[0004] 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); modulates immune responses by activating CB2 receptors in microglia (Turcotte et al. Cell Mol Life Sci. 2016); and promotes neuroprotection, for example, through its effects on oligodendrocyte production and survival (Ilyasov et al. Front Neurosci. 2018).

[0005] AA is one of the most abundant fatty acids in the brain and a major precursor to eicosanoic acid-like substances such as prostaglandins and leukotrienes (which are known inflammatory mediators).

[0006] MAGL is located at the crossroads between endocannabinoids and eicosanoid signaling systems. Inhibition of MAGL or activation is a promising therapeutic approach for the prevention or treatment of brain disorders characterized by 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; Gil-Ordóñez et al. BiochemPharmacol. 2018).

[0007] WO 2019 / 046318 discloses a spirocyclic compound that is an inhibitor of MAGL.

[0008] WO 2019 / 046330 discloses a spirocyclic compound that is an inhibitor of MAGL.

[0009] Despite progress in MAGL research, compounds that are potent, effective, and selective MAGL inhibitors, and that are also effective in treating neurological and psychiatric disorders associated with diseases or disorders that would benefit from inhibiting MAGL activation, are still lacking. Summary of the Invention

[0010] The object of this invention is to provide a compound that inhibits MAGL. Therefore, this invention provides a compound having formula (I):

[0011] (I)

[0012] in

[0013] 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.

[0014] In another aspect of the invention, a pharmaceutical composition is provided comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

[0015] In another aspect of the invention, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided for the treatment of diseases or disorders selected from: 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.

[0016] In another aspect of the invention, a method is provided for treating neurological and / or mental disorders 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, the method comprising administering to a patient in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0017] In another aspect of the invention, the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder selected from: 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 is provided.

[0018] Other objects and advantages of the compounds described herein will become apparent from the following detailed description. However, it should be understood that detailed descriptions and specific examples are given only by way of illustration when specific embodiments are indicated, as various changes and variations within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description. Some headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents, or portions thereof (including, but not limited to, patents, patent applications, articles, books, manuals, and papers) referenced in this application are hereby expressly incorporated in their entirety by reference for any purpose.

[0019] By incorporating via reference

[0020] All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant. Attached Figure Description

[0021] Figure 1 Example 6: Analgesic effect in a rat formalin model; y-axis: count - hindlimb licking frequency; x-axis: time period (min). Indicates the significance level for post-hoc comparisons (relative to the mediator group): p < 0.05, p < 0.01, p < 0.001.

[0022] Figure 2 Example 8: Analgesic effect in a rat formalin model; y-axis: count - hindlimb licking frequency; x-axis: time period (min). Indicates the significance level for post-hoc comparisons (relative to the mediator group): p < 0.05, p < 0.01, p < 0.001.

[0023] Figure 3 Example 6's performance in the MEST model; y-axis: estimated seizure threshold (CC) 50 Current (mA); indicates the significance level for a post-hoc comparison (relative to the media group): p < 0.001.

[0024] Figure 4 Example 8 shows the effect in the MEST model; y-axis: estimated seizure threshold (CC) 50 Current (mA); indicates the significance level for a post-hoc comparison (relative to the media group): p < 0.001.

[0025] Figure 5Example 6: Effect in a karyolate-based seizure model; y-axis: count - number of animals from 12 groups showing forelimb clonus. Indicates significance level for post-hoc comparisons (relative to the mediator group): < 0.01, <0.001.

[0026] Figure 6 Example 8: Effect in a karyolate-based seizure model; y-axis: count - number of animals from 12 groups showing forelimb clonus. Indicates significance level for post-hoc comparisons (relative to the mediator group): < 0.001. Detailed Implementation

[0027] definition

[0028] 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 pertains. It should be understood that the general description above and the detailed description below are merely exemplary and illustrative and do not limit any of the claimed subject matter. In this application, the singular is used to include the plural unless otherwise specified. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used in the specification and appended claims include the plural referent. In this application, the use of “or” means “and / or” unless otherwise specified. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0029] The headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All documents, or portions thereof, cited in this application (including, but not limited to, patents, patent applications, articles, books, manuals, and papers) are hereby expressly incorporated in their entirety by reference for any purpose.

[0030] As used herein, the terms “acceptable” or “pharmaceutical acceptable” (in relation to formulations, compositions, or ingredients) mean that the compound does not have a lasting harmful effect on the overall health of the subject being treated or does not eliminate the biological activity or properties of the compound, and is relatively non-toxic.

[0031] As used herein, “improvement” in the symptoms of a particular disease, disorder, or condition by application of a particular compound or pharmaceutical composition means any reduction in severity, delay in onset, slowing of progression, or shortening in duration attributable to or related to the application of the compound or composition, whether permanent or temporary, persistent or transient.

[0032] As used herein, the term "anti-nociceptive effect" refers to the ability of a compound to increase a subject's tolerance to pain, treat pain, delay pain, and / or reduce pain.

[0033] As used herein, the terms “co-administration” and the like are intended to cover the administration of a chosen therapeutic agent to a single patient and to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0034] As used herein, the term "effective amount" or "therapeutic effective amount" refers to a sufficient amount of one or more administered agents or compounds that will, to a certain extent, reduce the symptoms of a disease or condition being treated. The result may be a reduction and / or alleviation of signs and symptoms, or induce any other desired change in the disease or biological system. For example, an "effective amount" for therapeutic use is an amount of a composition comprising compounds as disclosed herein that is necessary to provide a clinically significant reduction in the symptoms of a disease without undue adverse side effects. In any single case, the appropriate "effective amount" can be determined using techniques such as dose-escalation studies. The term "therapeutic effective amount" includes, for example, a preventative effective amount. The "effective amount" of the compounds disclosed herein is an effective amount to achieve the desired pharmacological effect or therapeutic improvement without undue adverse side effects. It should be understood that the "effective amount" or "therapeutic effective amount" can vary among subjects due to variations in the metabolism of compound (I), the subject's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the prescribing physician's judgment. By way of example only, a therapeutic effective amount can be determined through routine experiments, including but not limited to dose-escalation clinical trials.

[0035] As used in this article, the terms “inhibits,” “inhibiting,” or “inhibitor” for enzymes refer to the inhibition of enzyme activity.

[0036] As used herein, the term "separation" refers to the separation or removal of a component of interest from a non-component. The separated substance may be in a dry or semi-dry state, or in solution form, including but not limited to aqueous solutions. The separated component may be in a homogeneous state, or the separated component may be part of a pharmaceutical composition comprising additional pharmaceutically acceptable carriers and / or excipients.

[0037] As used herein, the term “modulation” means interacting 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.

[0038] As used herein, the term "modifier" refers to a compound that alters the activity of a molecule. For example, a modifier can cause an increase or decrease in the magnitude of a particular activity of a molecule compared to the magnitude of activity in the absence of the modifier. In some embodiments, a modifier is an inhibitor that reduces the magnitude of one or more activities of a molecule. In some embodiments, an inhibitor completely inhibits one or more activities of a molecule. In some embodiments, a modifier is an activator that increases the magnitude of at least one activity of a molecule. In some embodiments, the presence of a modifier produces an activity that is not present in the absence of the modifier.

[0039] As used herein, the term "preventative effective amount" refers to an amount of one or more compositions administered to a patient that will, to a certain extent, alleviate the symptoms of a disease, condition, or disorder being treated. In these preventative applications, these amounts may depend on the patient's health condition, weight, etc. Those skilled in the art will also consider determining these preventative effective amounts through routine experimental procedures, including, but not limited to, dose-escalation clinical trials.

[0040] As used herein, the term "subject" refers to an animal used for treatment, observation, or experimentation. By way of example only, a subject can be, but is not limited to, mammals, including but not limited to humans.

[0041] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Some exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or condition.

[0042] As used herein, the terms “treat,” “treating,” or “treatment” include alleviating, reducing, or improving symptoms of a disease or condition; preventing additional symptoms; improving or preventing the underlying metabolic cause of symptoms; inhibiting a disease or condition, such as inhibiting its development; relieving a disease or condition; causing a decline in a disease or condition; alleviating the condition caused by a disease or condition; or terminating the symptoms of a disease or condition. The terms “treat,” “treating,” or “treatment” include, but are not limited to, preventative and / or therapeutic treatments.

[0043] As used in this article, IC 50 This refers to achieving 50% inhibition of such a response in an experiment that measures the maximum response, such as the amount, concentration, or dose of a specific test compound used in MAGL inhibition.

[0044] As used in this article, EC 50This refers to the dose, concentration, or amount of a specific test compound that elicits a dose-dependent response when the maximum expression of a specific response is 50% induced, stimulated, or enhanced by the specific test compound.

[0045] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon having one to eight carbon atoms. The term "C1-C3 alkyl" means a straight-chain or branched hydrocarbon containing one to three 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.

[0046] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched hydrocarbon having 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-.

[0047] The term "alkoxy" refers to a part having the formula -OR', where R' indicates an alkyl group as defined above. Specifically, "C 1- "C3alkoxy" refers to a moiety in which the alkyl group has 1, 2, or 3 carbon atoms. 1- Examples of "C3 alkoxy" include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0048] As used herein, the term "cycloalkyl" refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. A cycloalkyl group can be a monocyclic cycloalkyl group (e.g., cyclopropyl) and preferably has between 3 and 7 carbon atoms in the ring.

[0049] The term "halogen" is intended to indicate a substituent selected from Group 7 of the periodic table, such as fluorine, chlorine, or bromine.

[0050] The terms “halogenated alkyl” or “halogenated alkoxy” are intended to refer to an alkyl or alkoxy group as defined above in which one, two, or three hydrogen atoms are replaced by halogens.

[0051] Similarly, the term "fluoroalkyl" is intended to refer to an alkyl group as defined above, in which one, two, or three hydrogen atoms are replaced by fluorine. An example of such a group is trifluoromethyl.

[0052] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0053] As used herein, the term "hydroxyalkyl" means at least one -OH group attached to the parent molecule via an alkylene group as defined herein.

[0054] As used herein, the term "hydroxy-haloalkyl" means at least one -OH group attached to a parent molecule portion via a haloalkyl group as defined herein.

[0055] As used herein, the term "hydroxyfluoroalkyl" means at least one -OH group attached to a parent molecule portion via a fluoroalkyl group as defined herein.

[0056] As used herein, the term "oxo" refers to an oxygen atom bonded to another atom via a double bond. When the oxygen atom is carbon, the resulting carbonyl group is indicated as -(CO)-.

[0057] The term "5-membered heteroaryl" refers to a 5-membered aromatic ring in which one, two, or three ring atoms are selected from O, N, or S. Examples of 5-membered heteroaryl groups of the present invention include thiophene, pyrrole, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, and thiadiazolyl.

[0058] The term "6-membered heteroaryl" refers to a 6-membered aromatic ring in which one, two or three ring atoms are independently selected from O, N or S. Examples of 6-membered heteroaryl in this invention include, but are not limited to, pyridinyl, pyridinyl, pyranyl, diazinyl and triazinyl.

[0059] As used herein, the terms "monocyclic heterocycle," "monocyclic ring," and "monocyclic" individually or in combination refer to a saturated or unsaturated non-aromatic ring comprising five to six ring atoms, wherein one or more of these ring atoms are heteroatoms. In some embodiments of the invention, a heterocyclic ring is intended to refer to a six-membered ring structure, wherein one or two heteroatoms are independently selected from N or O. Examples of six-membered heterocycles include, but are not limited to, tetrahydropyranyl, piperidinyl, and morpholinyl.

[0060] As used herein, the term "bicyclic heterocycle" refers to a monocyclic ring attached to a parent moiety and forming a fused ring, spirocyclic, or bridged ring system with a cycloalkyl, monocyclic heterocycle, benzene ring, or a 5- or 6-membered heteroaryl group of a monocyclic ring. The term "7-membered bicyclic heterocycle" means a bicyclic heterocycle as defined above having 7 ring atoms and containing at least one heteroatom selected from N, O, or S. Examples of 7-membered bicyclic heterocycles include, but are not limited to, 2-oxaspiro[3.3]heptane-6-yl. The term "9- or 10-membered bicyclic heterocycle" means a bicyclic heterocycle as defined above having 9 or 10 ring atoms and containing at least one heteroatom selected from N, O, or S. Examples of 9- or 10-membered bicyclic heterocycles include, but are not limited to, 5,6,7,8-tetrahydroimidazo[1,2-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-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, or 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl.

[0061] Embodiments of the present invention

[0062] In a first embodiment, the present invention relates to a compound having formula (I):

[0063] (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.

[0064] In another embodiment, the compound of the present invention is a compound having formula (Ia):

[0065] (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.

[0066] In another embodiment, the compound of the present invention is a compound having formula (Ib):

[0067] (Ib); 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.

[0068] In embodiments involving compounds having formula (I), (Ia) or (Ib) or pharmaceutically acceptable salts thereof, R1 represents -C(O)NHR2.

[0069] In embodiments relating to compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, R1 represents -C(O)NHR2; R2 represents 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 one of the following substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, cyano, -NHC(O)CH3, -C(O)NH2, -C(O)NHCH3, a 5-membered heteroaryl having one or two heteroatoms independently selected from N or O, -NHSO2CH3, -P(O)(CH3)2, and -OCH2COOH.

[0070] In embodiments relating to compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, 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 with 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.

[0071] In embodiments relating to compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, 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 substituent selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl, and cyano.

[0072] In embodiments relating to compounds having formula (I), (Ia) or (Ib) or pharmaceutically acceptable salts thereof, R2 represents a 6-membered heterocycle selected from the group consisting of tetrahydro-2H-pyran-4-yl, piperazine, and piperidinyl, wherein R2 is unsubstituted.

[0073] In embodiments involving compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, R2 is selected from the group consisting of:

[0074] In embodiments involving compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, R2 is selected from the group consisting of:

[0075] In embodiments relating to compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, R3 and R4 together with the N to which they are attached form a 9- or 10-membered bicyclic heterocycle selected from the group consisting of: 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydropyridino[3,4-d]pyrimidinyl, and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, wherein the 9- to 10-membered bicyclic heterocycle is unsubstituted or substituted with one substituent selected from C3-C6 cycloalkyl or C1-C3 haloalkyl.

[0076] In embodiments relating to compounds having formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts thereof, R3 and R4 together with the N to which they are attached form a 9- to 10-membered bicyclic heterocycle selected from the group consisting of:

[0077] In another embodiment, the compound of the present invention is a compound having formula (Ic) or a pharmaceutically acceptable salt thereof:

[0078] (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, 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.

[0079] In another embodiment, the compound of the present invention is a compound having formula (Id) or a pharmaceutically acceptable salt thereof:

[0080] (Id); 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, 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.

[0081] In embodiments involving compounds having formula (Ic) or (Id) or pharmaceutically acceptable salts thereof, where n is 0.

[0082] In embodiments relating to a compound having formula (Ic) or (Id) or a pharmaceutically acceptable salt thereof, wherein R5 represents a 5- or 6-membered heteroaryl group selected from the group consisting of: pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein R5 is unsubstituted or substituted with one substituent 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.

[0083] In embodiments relating to a compound having formula (Ic) or (Id) 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.

[0084] In embodiments relating to a compound having formula (Ic) or (Id) 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.

[0085] In embodiments involving compounds having formula (Ic) or (Id) or pharmaceutically acceptable salts thereof, R5 is unsubstituted.

[0086] In embodiments involving compounds having formula (Ic) or (Id) or pharmaceutically acceptable salts thereof, wherein R5 is selected from the group consisting of:

[0087] In embodiments involving compounds having formula (Ic) or (Id) or pharmaceutically acceptable salts thereof, wherein R5 is selected from the group consisting of:

[0088] In embodiments relating to compounds having formula (Ic) or (Id) or pharmaceutically acceptable salts thereof, R5 represents 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl2-oxaspiro[3.3]heptane-6-yl.

[0089] In embodiments involving compounds having formula (Ic) or (Id) or pharmaceutically acceptable salts thereof, where n is 0.

[0090] In another embodiment, the compound of the present invention is a compound having formula (Ie) or a pharmaceutically acceptable salt thereof:

[0091] (Ie); Wherein R7 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two N atoms, or a 5- or 6-membered heterocycle having one heteroatom selected from N or O; and Each phenyl group, 5- or 6-membered heteroaryl group, or 5- or 6-membered heterocycle is unsubstituted or substituted by one substituent selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, and cyano.

[0092] In another embodiment, the compound of the present invention is a compound having the formula (If) or a pharmaceutically acceptable salt thereof:

[0093] (If); Wherein R7 represents a phenyl group, a 5- or 6-membered heteroaryl group having one or two N atoms, or a 5- or 6-membered heterocycle having one heteroatom selected from N or O; and Each phenyl group, 5- or 6-membered heteroaryl group, or 5- or 6-membered heterocycle is unsubstituted or substituted by one substituent selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, and cyano.

[0094] In embodiments relating to compounds having the formulas (Ie) and (If) or pharmaceutically acceptable salts thereof, R7 represents pyridinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, and isoxazolyl, wherein R7 is unsubstituted or substituted with one substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, C1-C3 alkoxy, and cyano.

[0095] In embodiments relating to compounds having the formula (Ie) and (If) or pharmaceutically acceptable salts thereof, wherein R7 represents tetrahydro-2H-pyran-4-yl, piperazine, and piperidinyl, wherein R7 is unsubstituted or substituted with one substituent selected from the group consisting of: C1-C3 alkyl, C3-C6 cycloalkyl, and cyano.

[0096] In embodiments relating to compounds having the formula (Ie) or (If) or pharmaceutically acceptable salts thereof, wherein R7 represents tetrahydro-2H-pyran-4-yl, piperazine, or piperidinyl, wherein R7 is unsubstituted.

[0097] In another embodiment, the compounds of the present invention are selected from the group consisting of: (±)1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester; (±)1-(pyridazine-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.

[0098] In another embodiment, the compounds of the present invention are selected from the group consisting of: (±)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.

[0099] In another embodiment, the compounds of the present invention are selected from the group consisting of: (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.

[0100] In another embodiment, the compounds of the present invention are selected from the group consisting of: (S)-1-(pyridin-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; (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; (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; (S)-1-(isoxazo-4-ylcarbamoyl)-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; (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; (S)-1-(pyridin-4-ylcarbamoyl)-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; (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; (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; (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; (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; (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; (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; (S)-1-(pyridin-2-ylcarbamoyl)-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; (S)-1-(pyrazin-2-ylcarbamoyl)-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-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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (S)-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-((cyclohexanecarbonyl)carbamoyl)-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; (S)-1-(pyrimidin-5-ylcarbamoyl)-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; (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; (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; (S)-1-(pyridazin-4-ylcarbamoyl)-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; (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; (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; (S)-1-(morpholino-4-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; (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; (S)-1-(thiazolyl-5-ylcarbamoyl)-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; (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; (S)-1-(thiazolyl-2-ylcarbamoyl)-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; (S)-1-(p-Tolylcarbamoyl)-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; (S)-1-(benzylcarbamoyl)-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; (S)-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-((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-((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-isopropoxypyridin-3-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)methyl)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; (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; (S)-1-(isoxazo-3-ylcarbamoyl)-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; 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.

[0101] In another embodiment, the compounds of the present invention are selected from the group consisting of: (S)-1-(pyridazin-3-ylcarbamoyl)-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; (S)-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-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; (S)-1-(pyrimidin-5-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; (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; and (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; or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment, the compound of the present invention 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.

[0103] In one embodiment, the compound of the present invention is (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 or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment, the compound of the present invention is (S)-1-(pyridin-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.

[0105] In one embodiment, the compound of the present invention is (S)-1-(pyridin-2-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.

[0106] In one embodiment, the compound of the present invention is (S)-1-(pyrazin-2-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.

[0107] In one embodiment, the compound of the present invention is (S)-1-(pyrimidin-5-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.

[0108] In one embodiment, the compound of the present invention 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.

[0109] In one embodiment, the compound of the present invention is (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.

[0110] In one embodiment, the compound of the present invention is (S)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester.

[0111] In one embodiment, the compound of the present invention is (S)-1-(pyridin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester.

[0112] In one embodiment, the compound of the present invention is (S)-1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester.

[0113] In one embodiment, the compound of the present invention is (S)-1-(pyrimidin-5-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester.

[0114] In one embodiment, a pharmaceutical composition is provided comprising a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

[0115] In another embodiment, a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for use as a pharmaceutical agent.

[0116] In the implementation scheme, a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for the treatment of diseases or disorders selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, Huntington's disease, spasticity, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

[0117] In another embodiment, a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for treating pain. In another embodiment, the pain is neuropathic pain. In another embodiment, the pain is inflammatory pain. In another embodiment, 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, vascular 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, somatic symptom disorder, or functional dyspepsia.

[0118] In the implementation scheme, the use of compounds having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or pharmaceutically acceptable salts thereof in the manufacture of an agent for treating a disease or disorder selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, convulsions, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia is provided.

[0119] In the implementation plan, a method is provided for treating diseases or disorders selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, Huntington's disease, spasticity, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia, the method comprising administering to a patient in need a therapeutically effective amount of a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof.

[0120] The compounds of the present invention are generally used in free form or as pharmaceutically acceptable salts. When a compound having formula (I) contains a free base, such salts can be prepared in a conventional manner by treating a solution or suspension of the free base having formula (I) with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described below.

[0121] In the context of this invention, pharmaceutically acceptable salts are intended to indicate non-toxic, i.e., physiologically acceptable salts. The term pharmaceutically acceptable salts include salts formed with inorganic 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)).

[0122] The compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomer (i.e., enantiomer or diastereomer) as a separate, enantiomerically pure or partially purified optical isomer, and any mixture thereof (including racemic mixtures) (i.e., mixtures of stereoisomers) are included within the scope of the present invention.

[0123] In this context, it should be understood that when the enantiomeric form is specified, the compound is in an enantiomeric excess, for example, substantially in an enantiomeric pure form. Therefore, one embodiment of the invention relates to compounds of the invention 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%.

[0124] Racemic forms can be resolved into optical enantiomers by known methods, such as by separating their diastereomeric salts with an optically active acid and by treating with a base to isolate optically active amine compounds. Another method for resolving racemic forms into optically active enantiomers is based on chromatography on an optically active matrix. The compounds of the present invention can also be resolved by forming diastereomeric derivatives. Other methods for resolving optical isomers known to those skilled in the art can be used. 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. Absolute stereochemistry can be determined by methods known to those skilled in the art, such as vibrational circular dichroism (VCD) spectroscopy.

[0125] Furthermore, geometric isomers can be formed when double bonds or fully or partially saturated ring systems are present in the molecule. It is intended that any geometric isomer, or mixture thereof, as a separate, pure, or partially purified geometric isomer, be included within the scope of this invention. Similarly, molecules having rotationally restricted bonds can form geometric isomers. These are also intended to be included within the scope of this invention.

[0126] Furthermore, some of the compounds of the present invention may exist in different tautomer forms, and any tautomer forms that these compounds can form are intended to be included within the scope of the present invention.

[0127] The present invention also includes isotopically labeled compounds similar to the compounds claimed in formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or their pharmaceutically acceptable salts, wherein one or more atoms are represented by atoms of the same element, and whose atomic mass or mass number differs from that of atoms commonly found in nature (e.g., 2 H, 3 H, 11 C 13 C15 N、 18 F, etc.). Special mention. 2 H-substituted compounds, that is, compounds in which one or more H atoms are represented by deuterium.

[0128] In one embodiment of the invention, one or more of the hydrogen atoms in compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or their pharmaceutically acceptable salts are represented by deuterium. It should be recognized that in most synthetic compounds, elements are present in their native isotopic abundance, resulting in the inherent incorporation of deuterium. However, the native isotopic abundance of hydrogen isotopes such as deuterium is not significant relative to the degree of stable isotopic substitution of the compounds described herein (approximately 0.015%). Therefore, as used herein, designating an atom at a position as deuterium indicates that the abundance of deuterium is significantly greater than its native abundance. Any atom not designated as a specific isotope is intended to represent any stable isotope of that atom, as will be apparent to those skilled in the art.

[0129] Pharmaceutical Composition

[0130] The aforementioned compounds or pharmaceutically acceptable salts may be used as the sole active ingredient in the composition or in combination with other active ingredients. Additionally, one or more pharmaceutically acceptable carriers or diluents may be present in the composition.

[0131] The pharmaceutical composition may be specifically formulated for administration via any suitable route, such as oral, rectal, nasal, pulmonary, local (including buccal and sublingual), percutaneous, intracisional, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes, with oral administration being preferred. It will be understood that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, and the selected active ingredient.

[0132] Pharmaceutical compositions intended for oral administration include solid dosage forms such as capsules, tablets, sugar-coated pills, pellets, lozenges, powders, and granules. Where appropriate, they may be prepared by coating.

[0133] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.

[0134] Pharmaceutical compositions intended for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders intended to be reconstituted in a sterile injectable solution or dispersion prior to use.

[0135] Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalers, skin patches, and implants.

[0136] Conveniently, compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are administered in unit dosage forms containing the compound in amounts 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 the compounds of the present invention.

[0137] For parenteral administration, solutions of compounds having formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) in sterile aqueous solutions or aqueous propylene glycol can be used. If necessary, such aqueous solutions should be appropriately buffered and the liquid diluent should first be made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. The sterile aqueous media used can be readily obtained using standard techniques known to those skilled in the art. If necessary, aqueous solutions should be appropriately buffered and the liquid diluent should first be made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. The sterile aqueous media used can be readily obtained using standard techniques known to those skilled in the art.

[0138] Suitable drug carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers are lactose, kaolin, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Examples of liquid carriers are syrups, peanut oil, olive oil, phospholipids, polyethylene oxide, and water. Pharmaceutical compositions formed by combining compounds having formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or their pharmaceutically acceptable salts with pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.

[0139] The formulations of the present invention suitable for oral administration can be presented in discrete units such as capsules or tablets, each of which contains a predetermined amount of active ingredient and may include suitable excipients. Furthermore, the orally usable formulations can be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions.

[0140] If a solid carrier is used for oral administration, the formulation can be a tablet, such as a powder or pellet encapsulated in a hard gelatin capsule, or in the form of a sugar tablet or lozenge. The amount of solid carrier can vary, but is typically from about 25 mg to about 1 g.

[0141] 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).

[0142] 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.

[0143] Used to treat conditions

[0144] 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 with pathological features including 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.

[0145] Symptomatic treatment of multiple sclerosis

[0146] 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).

[0147] Exogenous cannabinoid preparations are approved treatments for spasms associated with MS. Sativex (a mixture of the CB1 agonist THC and another cannabis plant-derived alcohol (cannabidiol) in an oral mucosal spray) has been shown to reduce self-reported spasm-related symptoms. In a pivotal trial using a randomized discontinuation design, continued use of Sativex improved spasm frequency, spasm-induced sleep disruption, subject overall change impression, caregiver overall change impression, and physician overall change impression. Other clinical trials have demonstrated the activity of various exogenous cannabinoids in spasms 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 clinical trial designs and endpoints that can be used to demonstrate the benefits of MAGL inhibitors for spasms in MS.

[0148] 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 multiple sclerosis.

[0149] In the implementation scheme, a compound having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for treating one or more symptoms of multiple sclerosis selected from: fatigue, spasms, depression, behavioral disorders, stress-induced agitation, and pain.

[0150] It is believed that MAGL inhibitors will also be beneficial for the treatment of indications associated with autoimmune encephalomyelitis. Therefore, in an additional 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 Rasmussen encephalitis, systemic lupus erythematosus, Behcet's disease, Hashimoto's encephalopathy, and Sydenham's chorea.

[0151] Amyotrophic Lateral Sclerosis

[0152] Pryce et al., Handb Exp Pharmacol [Handbook of Experimental Pharmacology]. 2015; 231: 213-31, describe how patients with amyotrophic lateral sclerosis (ALS) typically experience muscle weakness and / or progressively worsening fasciculations, medullary symptoms, and eventually respiratory problems. In preclinical models of ALS, cannabinoids have been shown to potentially have significant neuroprotective effects.

[0153] Therefore, in the embodiments, a compound having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for the treatment of amyotrophic lateral sclerosis (ALS).

[0154] Central pain

[0155] Central pain is neuropathic pain caused by damage or dysfunction of the central nervous system, such as sequelae of stroke, multiple sclerosis, neuromyelitis optica, idiopathic inflammatory transverse myelitis, spinal cord injury, brachial-radial pain syndrome, and central craniofacial pain. The activity of exogenous cannabinoids in central pain associated with multiple sclerosis has been demonstrated. A 4-week randomized, double-blind, placebo-controlled parallel-group trial using an oral mucosal spray containing the CB1 agonist δ-9-tetrahydrocannabinol and cannabidiol (another alcohol derived from the Cannabis genus) THC / CBD in MS and central pain showed that the active agent was superior to placebo in reducing mean pain intensity (NRS-11) and sleep disturbances (Rog et al., Neurology. 2005). The same THC / CBD formulation was studied in a larger cohort of MS patients with central neuropathic pain using a two-stage design; in the second phase of this study, the time to treatment failure (the primary endpoint) was statistically favorable to THC / CBD, as were improvements in pain NRS-11 and sleep quality (Langford et al., J Neurol [Journal of Neurology]. 2013). Furthermore, cannabinol, a synthetic CB1 agonist associated with the structure of THC, has shown efficacy in MS-induced central neuropathic pain (Turcotte et al., Pain Med [Pain Medicine]. 2015). Studies of exogenous cannabinoids in central pain have shown activity, suggesting that MAGL inhibitors may also be effective in treating central pain. Therefore, in one embodiment, compounds having formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or pharmaceutically acceptable salts thereof are provided for the treatment of central pain.

[0156] Fibromyalgia

[0157] Fibromyalgia (FM) is a common, chronic, idiopathic condition characterized by diffuse body pain and the presence of pressure-touch evoked pain. Duloxetine and pregabalin are specifically labeled for treating pain in FM, and tricyclic antidepressants like amitriptyline, while not specifically labeled for FM treatment, are first-line agents. There is no clear pathological understanding of FM, nor are there validated preclinical models. However, studies of exogenous cannabinoids in FM have shown activity, suggesting that MAGL inhibitors may also be effective in treating FM. Pain (e.g., NRS-11, VAS pain) measurements and the fibromyalgia impact questionnaire (FIQ) (which measures the limitations of several daily living activities affected by FM) have demonstrated 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, January 2008, 35(1) 20-30). A survey of Spanish FM patients (cannabis users and non-users) was conducted to determine the effects of cannabis on a range of symptoms such as pain, stiffness, health, relaxation, and drowsiness; sensory relief of pain, sleep disturbances, stiffness, mood disorders, and anxiety was common (Fiz, PLoS One, 2011, 6(4), e18440). In an 8-week study of 40 patients, exogenous cannabinoid cannabinoid improved pain as measured on a 10 cm VAS and improved the FIQ domain and total FIQ score for anxiety compared to placebo (Skrabek et al., J pain [Journal of Pain Medicine]. 2008). In a study of 31 patients, cannabinoid improved the sleep index (insomnia severity index) compared to amitriptyline and was deemed non-inferior on pain measurements (McGill Pain Questionnaire) and FIQ (Ware, Anesth Analg [Regional Anesthesia and Pain Medicine], 2010, 110(2), 604-10). Therefore, in one embodiment, compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or pharmaceutically acceptable salts thereof are provided for the treatment of fibromyalgia.

[0158] migraine

[0159] Migraine is a common episodic disorder characterized by pain in the head and face. Migraine attacks can be acutely treated with NSAIDs, acetaminophen, various triptans (e.g., sumatriptan), and antiemetics, but some migraine sufferers are pain-unresponsive to existing treatments. Data suggest that the endocannabinoid pathway may be involved in migraines. CSF specimens in patients with chronic migraines and potentially analgesic-overloaded headaches showed higher levels of the endocannabinoid palmitole and lower levels of other cannabinoids compared to healthy controls (Sarchielli et al., Neuropsychopharmacology. 2007). Furthermore, a retrospective review of medical records from patients initially diagnosed with migraines participating in medical cannabis clinical trials revealed a decrease in migraine frequency after initiation of cannabis therapy (Rhyne et al., Pharmacotherapy. 2016), suggesting that MAGL inhibitors may also be effective in treating migraines. Therefore, in the embodiments, a compound having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for the treatment of migraine.

[0160] In another embodiment, this document discloses compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or pharmaceutically acceptable salts thereof for the treatment or prevention of chronic migraine, acute treatment of migraine, and hemiplegic migraine.

[0161] Mood and anxiety disorders

[0162] Mood and anxiety disorders are chronic, disabling conditions that cost both patients and society. In recent years, the endocannabinoid system has received increasing attention in relation to mood and anxiety disorders. A recent study by Bedse G et al., *Transl Psychiatry*, 2018, suggested that the use of MAGL inhibitors may have beneficial effects on stress-related psychopathology. Therefore, in one embodiment, this document discloses providing compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or pharmaceutically acceptable salts thereof for the treatment of mood and anxiety disorders.

[0163] In other embodiments disclosed herein, compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) or pharmaceutically acceptable salts thereof are provided for the treatment of mood and anxiety disorders selected from depression and GAD.

[0164] In other embodiments disclosed herein, compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or pharmaceutically acceptable salts thereof, are provided for the treatment of depression selected from: major depressive disorder; treatment-resistant depression; catatonic depression; melancholic depression; atypical depression; psychotic depression; perinatal depression; postpartum depression; bipolar disorder, including type I bipolar depression and type II bipolar depression; and mild, moderate, or severe depression. In other embodiments disclosed herein, compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or pharmaceutically acceptable salts thereof, are provided for the treatment of major depressive disorder.

[0165] In another embodiment disclosed herein, a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for the treatment of GAD.

[0166] Post-traumatic stress disorder

[0167] Post-traumatic stress disorder (PTSD) is a disorder associated with trauma or stress. Patients with PTSD will exhibit symptoms of trauma replay, avoidance, hyperexcitability, and negative cognition / emotion. A review in *Neuropsychopharmacology* by Hill et al., 2018, suggests that drugs affecting endocannabinoid signaling (such as MAGL inhibitors) may be beneficial for treating symptoms of PTSD. Therefore, in one embodiment disclosed herein, a compound having formula (I), (Ia), (Ib), (Id), (Ie), or (If) or a pharmaceutically acceptable salt thereof is provided for the treatment of PTSD.

[0168] Some embodiments disclosed herein are methods for modulating MAGL activity. Considered methods include, for example, exposing the enzyme to the compounds described herein. The ability of the compounds described herein to modulate or inhibit MAGL is evaluated using procedures known in the art and / or described herein. Another aspect of this disclosure provides methods for treating patients with diseases associated with MAGL expression or activity.

[0169] epilepsy

[0170] In a study by Sugaya et al., Cell Reports, 2016, it was shown that 2-AG is crucial for suppressing epileptic seizures. Therefore, in another embodiment, compounds having formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are used to treat epilepsy / seizure disorder.

[0171] In one embodiment, a compound having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is used to treat epilepsy / seizure disorder selected from the following: acute recurrent seizures, temporal lobe epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, or Angelman syndrome.

[0172] Combination therapy

[0173] This document also considers combination therapies, such as co-administering the compounds of the present invention with additional active agents as part of a specific treatment regimen designed to provide a beneficial effect through the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, the synergistic pharmacokinetic or pharmacodynamic effects produced by the combination of therapeutic agents. These therapeutic agents are typically administered in combination over a defined time period (usually weeks, months, or years, depending on the chosen combination). Combination therapies are intended to cover the sequential administration of multiple therapeutic agents, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner.

[0174] Substantial simultaneous administration is achieved, for example, by administering to a subject a single formulation or composition (e.g., tablets or capsules of each therapeutic agent in a fixed proportion), or multiple single formulations of each therapeutic agent (e.g., capsules). The sequential or substantially simultaneous administration of each therapeutic agent is achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents are administered via the same or different routes. For example, the first therapeutic agent in a selected combination is administered intravenously, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered intravenously.

[0175] Combination therapy also encompasses the further administration of the therapeutic agents described above in combination with other bioactive ingredients and non-pharmacological therapies. When combination therapy further includes non-pharmacological treatment, this non-pharmacological treatment is administered at any suitable time, provided that the beneficial effects from the combined action of the therapeutic agents and non-pharmacological treatments are achieved. For example, where appropriate, when non-pharmacological treatment is temporarily removed from the administration of the therapeutic agent, it may still provide beneficial effects for several days or even weeks.

[0176] The combined components are administered to the patient simultaneously or sequentially. It will be understood that these components are contained in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredient may be contained in a separate drug carrier, such as a conventional oral dosage form, which is administered simultaneously or sequentially.

[0177] For example, for the pain treatment under consideration, the disclosed compound is 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 nonsteroidal anti-inflammatory drug. Additional pain treatment agents co-administered, such as morphine, pregabalin, gabapentin, codeine, hydromorphone, hydrocodone, hydroxymorphone, fentanyl, tramadol, and levonorgestrel.

[0178] Other co-administered therapeutic agents considered include aspirin, naproxen, ibuprofen, disalicylate, diflunisal, dextro-ibuprofen, fenprofen, ketoprofen, oxapazine, loxoprofen, indomethacin, tometetin, sulingda, etodoxic acid, ketoroxyprofen, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonaban, and / or etoricoxib.

[0179] Experimental Section

[0180] Universal synthesis

[0181] Compounds having formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If) or their salts can be prepared by synthetic methods. The following schemes 1-3 and examples 1-34 are representative methods for synthesizing one or more of the compounds according to formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If). Schemes 1-3 provided are not intended to limit the scope of the invention in any way.

[0182] Option 1

[0183] 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 a heteroaryl or heterocyclic) 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 agent to form an acid halide. The amide formation 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 comprises a reaction with the intermediate of type IV and 1,1,1,3,3,3-hexafluoroprop-2-ol in a suitable solvent (e.g., MeCN) in the presence of a coupling agent such as CDI to provide the compound of the present invention.

[0184] Option 2

[0185] In alternative synthesis, the compound is provided as a tertiary amine in which the amide linker is a heteroaryl or heterocyclic group. As seen in Scheme 2, the type III intermediate undergoes alkylation in step ia) to form the type IIIa intermediate. The type IIIa intermediate can then undergo deprotection in step ii) and coupling in step iii) as described in Scheme 1 to provide the compound of the present invention.

[0186] Option 3

[0187] As shown in Scheme 3, some compounds of the present invention can be prepared from commercially available tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate, which undergoes aryl halogenation or heteroaryl halogenation (X is a halogen, R is a heteroaryl or phenyl), to form an intermediate of type VI. The remaining synthesis (steps ii) and iii) follows a procedure similar to that shown in Scheme 1.

[0188] List of abbreviations

[0189] As used above, and throughout the description of this invention, unless otherwise stated, the following abbreviations should be understood to have the following meanings: ACN or MeCN acetonitrile Bn benzyl BOC or Boc tert-butyl carbamate CDI 1,1'-carbonyldiimidazole Cyclohexyl DCE (dichloroethane) (ClCH2CH2Cl) DCM (dichloromethane (CH2Cl2)) DIPEA or DIEA (diisopropylethylamine) DMAP 4-( N,N -dimethylamino)pyridine DMF (dimethylformamide) DMA N,N -Dimethylacetamide DMSO (dimethyl sulfoxide) Equiv equivalent Et Ethyl EtOH (ethanol) EtOAc (ethyl acetate) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC (High Performance Liquid Chromatography) LAH Lithium Aluminum Hydrogen Me methyl MeOH (methanol) MS mass spectrometry NMM N -Methylmorpholine NMR (Nuclear Magnetic Resonance) PMB p-methoxybenzyl TEA Triethylamine TFA (trifluoroacetic acid) THF Tetrahydrofuran TLC (Thin Layer Chromatography) I. Chemical Synthesis Unless otherwise specified, reagents and solvents were used as received from the commercial supplier. Anhydrous solvents and dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and not optimized. Unless otherwise specified, column chromatography and thin-layer chromatography (TLC) were performed on silica gel. Spectra are given in ppm (δ) and coupling constants ( J Reported in Hertz. For proton spectra, the solvent peak is used as a reference peak.

[0190] Analytical methods

[0191] LC-MS method

[0192] The LC-MS system used for analysis 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: Method A The column is Kinetex EVO C18 50. 3.0 mm, 2.6 μm, which was achieved at 40°C with a binary gradient operation of water + 5 mM NH4HCO3 (A) and ACN (B) at a rate of 1.2 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0193] Gradient: 0.01 min 10% B

[0194] 2.00 min 95% B

[0195] 2.70 min 95% B

[0196] 2.75 min 10% B

[0197] Total running time: 3.00 min

[0198] Method B The column is Kinetex EVO C18 50. 3.0 mm, 2.6 μm, which was achieved at 40°C with a binary gradient operation of water + 5 mM NH4HCO3 (A) and ACN (B) at a rate of 1.2 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0199] Gradient: 0.01 min 10% B

[0200] 3.20 min 60% B

[0201] 4.00 min 95% B

[0202] 4.80 min 95% B

[0203] 4.90 min 10% B

[0204] Total running time: 5.00 min

[0205] Method C The column is Express C18 50. 3.0 mm, which was achieved at 40°C with a binary gradient operation of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at a rate of 1.5 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0206] Gradient: 0.01 min 20% B

[0207] 3.50 min 50% B

[0208] 4.30 min 95% B

[0209] 4.00 min 95% B

[0210] 5.10 min 5% B

[0211] Total running time: 5.30 min

[0212] Method D The column is HALO C18 30. 3.0 mm, 2 µm, was obtained by binary gradient operation at 40°C at 1.5 mL / min consisting of water + 0.05% TFA (A) and ACN + 0.05% TFA (B). Retention time (t) was expressed in minutes based on UV traces at 200 nm. R ).

[0213] Gradient: 0.01 min 5% B

[0214] 1.20 min 100% B

[0215] 1.80 min 100% B

[0216] 1.82 min 5% B

[0217] Total running time: 2.0 min

[0218] Method E The column is Poroshell HPH-C18 50. 3.0 mm, 2.7 μm, which was achieved at 40°C with a binary gradient operation of water + 6.5 mM NH4HCO3 + ammonia (pH = 10) (A) and ACN (B) at a rate of 1.2 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0219] Gradient: 0.01 min 10% B

[0220] 2.00 min 95% B

[0221] 2.70 min 95% B

[0222] 2.75 min 10% B

[0223] Total running time: 3.00 min

[0224] Method F The column is Express C18 50. 3.0 mm, which was achieved at 40°C with a binary gradient operation of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at a rate of 1.5 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0225] Gradient: 0.01 min 5% B

[0226] 2.00 min 95% B

[0227] 2.70 min 95% B

[0228] 2.80 min 5% B

[0229] Total running time: 3.0 min

[0230] Method G The column is Kinetex EVO C18 50. The wavelength range was 3.0 mm to 2.6 μm, achieved by a binary gradient operation at 40°C at a rate of 1.2 mL / min consisting of water + 5 mM NH4HCO3 (A) and ACN (B). Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0231] Gradient: 0.01 min 30% B

[0232] 3.20 min 70% B

[0233] 4.00 min 95% B

[0234] 4.80 min 95% B

[0235] 4.90 min 10% B

[0236] Total running time: 5.00 min

[0237] Method H The column is Poroshell HPH-C18 50. 3.0 mm, 2.7 μm, which was achieved at 40°C with a binary gradient operation of water + 5 mM NH4HCO3 (A) and acetonitrile (B) at a rate of 1.2 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0238] Gradient: 0.01 min 10% B

[0239] 3.20 min 60% B

[0240] 4.00 min 95% B

[0241] 4.80 min 95% B

[0242] 4.90 min 10% B

[0243] Total running time: 5.00 min

[0244] Method I The column is CORTECS C18 50. 2.1 mm, 2.7 µm, which was achieved at 40°C with a binary gradient operation of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 0.05% trifluoroacetic acid (B) at a flow rate of 1.5 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0245] Gradient: 0.01 min 5% B

[0246] 2.00 min 100% B

[0247] 2.80 min 100% B

[0248] 2.90 min 5% B

[0249] Total running time: 3.00 min

[0250] Method J The column is CORTECS C18 50. 2.1 mm, 2.7 µm, which was achieved at 40°C with a binary gradient operation of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 0.05% trifluoroacetic acid (B) at a rate of 1.0 mL / min. Retention time (t) is expressed in minutes based on UV traces at 254 nm. R ).

[0251] Gradient: 0.01 min 5% B

[0252] 3.20 min 60% B

[0253] 4.10 min 95% B

[0254] 5.00 min 95% B

[0255] 5.10 min 5% B

[0256] Total running time: 5.30 min

[0257] Method K The column is Express C18 50. 3.0 mm, which was achieved at 40°C with a binary gradient operation of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at a rate of 1.5 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0258] Gradient: 0.01 min 30% B

[0259] 3.50 min 60% B

[0260] 4.30 min 95% B

[0261] 4.00 min 95% B

[0262] 5.10 min 5% B

[0263] Total running time: 5.30 min

[0264] Method L The column is Kinetex EVO C18 50. 3.0 mm, 2.6 μm, which was achieved at 40°C with a binary gradient operation of water + 5 mM NH4HCO3 (A) and ACN (B) at a rate of 1.2 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0265] Gradient: 0.01 min 30% B

[0266] 3.20 min 50% B

[0267] 4.00 min 95% B

[0268] 4.80 min 95% B

[0269] 4.90 min 10% B

[0270] Total running time: 5.00 min

[0271] Method M The column is Poroshell HPH-C18 50. 3.0 mm, 2.7 μm, which was achieved at 40°C with a binary gradient operation of water + 6.5 mM NH4HCO3 + ammonia (pH = 10) (A) and ACN (B) at a rate of 1.2 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0272] Gradient: 0.01 min 10% B

[0273] 3.00 min 60% B

[0274] 4.00 min 95% B

[0275] 4.70 min 95% B

[0276] 4.90 min 10% B

[0277] Total running time: 5.00 min

[0278] Method N The column is Kinelex XB-C18 50. 3.0 mm, 2.6 μm, was obtained by binary gradient operation at 45°C at 1.5 mL / min consisting of water + 0.05% TFA (A) and CAN + 0.05% TFA (B). Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0279] Gradient: 0.01 min 5% B

[0280] 3.00 min 50% B

[0281] 4.00 min 100% B

[0282] 4.60 min 100% B

[0283] 4.70 min 5% B

[0284] Total running time: 5.20 min

[0285] Method O: The column is HALO C18 30 3.0 mm, 2 µm, was obtained by binary gradient operation at 40°C at 1.5 mL / min consisting of water + 0.05% TFA (A) and ACN + 0.05% TFA (B). Retention time (t) was expressed in minutes based on UV traces at 200 nm. R ).

[0286] Gradient: 2.20 min 100% B

[0287] 2.70 min 100% B

[0288] 2.72 min 5% B

[0289] Total running time: 3.0 min

[0290] Method P: The column was an Express C18 50 mm column, operated at 40°C with a binary gradient of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at a rate of 1.5 mL / min. Retention time (t) was expressed in minutes based on UV traces at 254 nm. R ).

[0291] Gradient: 0.01 min 2% B

[0292] 2.00 min 100% B

[0293] 2.70 min 100% B

[0294] 2.75 min 2% B

[0295] Total running time: 3.0 min

[0296] 1 H NMR method

[0297] Recorded at 300 or 400 MHz on Bruker Avance HD 1 1H NMR spectrum. Chemical shift values ​​relative to tetramethylsilane are expressed in ppm. The following abbreviations or combinations thereof are used for the multiplicity of NMR signals: br = broad, d = doublet, dd = double doublet, dt = double triplet, hept = septet, m = multiplet, q = quartet, quint = quintet, s = singlet, t = triplet, td = triple doublet.

[0298] Example 1: (±)1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0299] Step 1: Synthesis of tert-butyl 1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0300] In a vial, 255 mg of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (NantongMYBio-pharm. Co., Ltd.), 10 mg of DMF, and 10 mL of DCM were added. Oxygenate 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 provide tert-butyl 1-(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid. In another vial, 94.0 mg of pyridine-3-amine, 5 mL of THF, and 258 mg of DIPEA were added dropwise in THF (5 mL) at 0°C. The resulting solution was stirred overnight at room temperature and quenched by adding 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 subjected to chromatographic analysis on a silica gel column with EtOAc / petroleum ether (2 / 1) to provide tert-butyl 1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (160 mg). LCMS (ESI, m / z ): 332 [M+H + .

[0301] Step 2: Synthesis of N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0302] 160 mg of 1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester, DCM (5 mL), and TFA (5 mL) were placed in a vial. 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 of the solution was adjusted to 8 with a saturated sodium bicarbonate solution. The mixture was extracted with DCM (3 x 10 mL), and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide N-(pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide (112 mg). LCMS (ESI, m / z ): 232 [M+H + .

[0303] Step 3: Synthesis of (±)1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0304] 1,1,1,3,3,3-hexafluoroprop-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) were added to a vial. The resulting solution was stirred overnight at 80°C and quenched by adding water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL), 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, increased to 70% ACN over 7 min on a Waters 2767-5 chromatograph, then increased to 100% ACN over 0.1 min, held at 100% ACN for 1.9 min, then decreased to 40% ACN over 0.1 min, and held at 40% ACN for 1.9 min. Column: X-bridge preparative C18, 19. 150 mm 5 μm; Mobile phase: Phase A: NH4HCO3 aqueous solution (0.05%); Phase B: ACN; Detector, UV 220 & 254 nm. Purification yielded 32.7 mg of (±) 1,1,1,3,3,3-hexafluoroprop-2-yl 1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid. 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 + .

[0305] Example 2: (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, and

[0306] Example 3: (R)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester and

[0307] The racemic mixture (32.7 mg) prepared in Example 1 was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IG, 2). 25 cm, 5 μm; Mobile phase A: Hex (0.1% DEA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 17 min 5% B to 5% B; UV 220 / 254 nm), to provide: 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-hexafluoroprop-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 + .

[0308] and corresponding enantiomers

[0309] 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-hexafluoroprop-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 + .

[0310] Determination of the absolute configurations of Examples 2 and 3

[0311] The absolute configuration of Example 3 was determined using vibrational circular dichroism (VCD) (Appl. Spectrosc. 65 (7), 699 (2011)). The spectra were obtained using a dual-spectrum... PEM The values ​​were obtained using a Chirall R 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 Example 3 to be the (R)-enantiomer, and therefore Example 2 to be the (S)-enantiomer. These samples were analyzed by chiral HPLC under the following conditions: column: CHIRALPAK IC, 3.0. 100 mm, 3 μm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% over 2.0 min, then hold at 50% for 1.0 min; Detection: 220 nm.

[0312] Example 2: First eluted enantiomer (t) R = 0.944 min)

[0313] Example 3: Second eluted enantiomer (t) R = 1.154 min)

[0314] Preparation of intermediates with known absolute configurations: Synthesis

[0315] 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.

[0316] Step 1: Synthesis of 1-benzyl 6-(tert-butyl) ester of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid

[0317] 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.

[0318] Step 2: Synthesis of 6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester hydrochloride

[0319] A solution of crude 6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(tert-butyl) ester (297 g) in DCM (1.5 L) was added to a flask purged and maintained under an inert nitrogen atmosphere. HCl (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 under vacuum. The crude product was slurried with Et2O (10 V) to provide 198.3 g of 6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester.

[0320] Step 3: Synthesis of 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester of 6-azaspiro[2,5]octane-1,6-dicarboxylic acid

[0321] A solution of 1,1,1,3,3,3-hexafluoroprop-2-ol (393 g) in DCM (2 L) was added to a flask purged and maintained under an inert nitrogen atmosphere. The mixture was cooled to 0°C and triphosgene (106.9 g) was added in portions. Then, DIPEA (550 g) was added dropwise at 0°C–10°C. The mixture was stirred at this temperature for 1.5 h. Then, a solution of 6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester hydrochloride (198 g) in DCM (2 L) was 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 × 2 L). The combined organic layers were washed with brine (1 × 3 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was subjected to chromatographic analysis on a silica gel column with EtOAc / petroleum ether (1 / 30) to obtain 265 g of 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid.

[0322] Step 4: Separation of (S)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester (intermediate 2A) and (R)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester (intermediate 3A)

[0323] The racemic mixture (265 g) of 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester of 6-azaspiro[2,5]octane-1,6-dicarboxylic acid prepared in step 3 was separated by preparative SFC-HPLC (column: CHIRALPAK IG-3 3.0). 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 items, whose absolute configuration was determined after preparing the final products (Examples 2 and 3) and comparing the elution order on the chiral column: Intermediate 2A; 110 g of (S)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester. 1¹H 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] + as well as Intermediate 3A; 100 g of (R)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester. 1 ¹H 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] + .

[0324] Step 5-1: Synthesis of (S)-6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (intermediate 2B)

[0325] Will( SA solution of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropane-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 and displaced three times with H2, and then stirred at room temperature for 3 h under H2. The mixture was filtered and the filter cake was washed with THF (2 × 500 mL). The combined filtrates were concentrated under vacuum, and the crude product was co-evaporated with toluene (2 × 1 L) to give 90 g of crude (S)-6-(((1,1,1,3,3,3-hexafluoropropane-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid. 0.2 g of the crude product was purified by silica gel column chromatography to provide characterization data for purity. 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, 5.0Hz, 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] + .

[0326] Step 6-1: Synthesis of (S)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester (Example 2)

[0327] A solution of crude (S)-6-(((1,1,1,3,3,3-hexafluoroprop-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·HCl (30 mg) and HOBt (39 mg) were added, and the resulting mixture was stirred for 15 min. Pyridine-3-amine (18 mg) and DIEA (37 mg) were added. The final reaction mixture was stirred overnight at room temperature. The mixture was diluted with H2O (10 mL) and extracted with DCM (1 × 5 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative HPLC to provide (S)-1-(pyridine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-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] + .

[0328] CHIRALPAK IC, 3.0 100 mm, 3 µ m; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% over 2.0 min, held at 50% for 1.0 min; Detection: 220 nm: t R = 1.928min.

[0329] 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 (S)-enantiomer.

[0330] Step 5-2: Synthesis of (R)-6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (intermediate 3B)

[0331] A solution of (R)-6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropane-2-yl) ester (1.9 g, 4.3 mmol, 1.0 equivalent) 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 and displaced three times with H2 and stirred at room temperature for 2 h under H2. The mixture was filtered and the filter cake was washed with THF (2 × 50 mL). The combined filtrates were concentrated under vacuum to provide 1.5 g of crude (R)-6-(((1,1,1,3,3,3-hexafluoropropane-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid, which was used directly in the next step without further purification.

[0332] Step 6-2: Synthesis of (R)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester (Example 3)

[0333] A solution of crude (R)-6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (50 mg) in DCM (1 mL) was placed in a reaction flask. EDC·HCl (30 mg) and HOBt (39 mg) were added, and the resulting mixture was stirred for 15 min. Pyridine-3-amine (18 mg) and DIEA (37 mg) were added. The final reaction mixture was stirred overnight at room temperature. The mixture was diluted with H2O (10 mL) and extracted with DCM (1 × 5 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC to provide (R)-1-(pyridin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester (50 mg) as a white solid. 1H NMR (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). t R = 1.266 min. LCMS (ESI, m / z): 426 [M+H] + .

[0334] CHIRALPAK IC, 3.0 100 mm, 3 µm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% over 2.0 min, held at 50% for 1.0 min; Detection: 220 nm: t R = 2.030min.

[0335] After comparing 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 (R)-enantiomer.

[0336] As described below, intermediates 2B and 3B, which have known absolute configurations, were used in the synthesis of Examples 5, 6, 8 and 9.

[0337] Example 4: (±)1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0338] Step 1: Synthesis of tert-butyl 1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0339] As in step 1 of Example 1, 1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-1-carboxylic acid (600 mg), DMF (17.4 mg), oxaloyl chloride (386 mg), pyridazine-3-amine (245 mg), and 1-(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester was prepared to provide the title compound (360 mg). LCMS (ESI, m / z ): 333 [M+H + .

[0340] Step 2: Synthesis of N-(pyridazin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0341] As described in step 2 of Example 1, N-(pyridazin-3-yl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (180 mg) and TFA (5 mL) were used to prepare the title compound (125 mg). LCMS (ESI, m / z ): 233 [M+H + .

[0342] Step 3: Synthesis of 1,1,1,3,3,3-hexafluoroprop-2-yl ester of 1-[(pyridazin-3-yl)carbamoyl]-6-azaspiro[2,5]octane-6-carboxylic acid

[0343] As described in step 3 of Example 1, 1-[(pyridazin-3-yl)carbamoyl]-6-azaspiro[2.5]octane-1-carboxamide (125 mg), 1,1'-carbonyldiimidazole (105 mg), and 1,1,1,3,3,3-hexafluoroprop-2-ol (904 mg) were used to prepare 1,1,1,3,3,3-hexafluoroprop-2-yl ester of 1-[(pyridazin-3-yl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid (33.0 mg) to provide the title compound.

[0344] Example 5: (R)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester and

[0345] Example 6: (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester and

[0346] The racemic mixture (33.0 mg) prepared in Example 4 was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IC, 2). 25 cm, 5 μm; 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: 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-hexafluoroprop-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 µm; Mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% over 2.0 min, held at 50% for 1.0 min; Detection: 220 nm: t R = 0.814 min.

[0347] and corresponding enantiomers

[0348] 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-hexafluoroprop-2-yl ester. 1 H 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 µm; Mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% over 2.0 min, held at 50% for 1.0 min; Detection: 220 nm: t R = 1.080 min.

[0349] Synthesis of Example 5 using the known intermediate 3B:

[0350] (R)-6-(((1,1,1,3,3,3-hexafluoroprop-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 adding 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 under vacuum, and slurried with hexane / EA (10 / 1, 10 V) to provide 62 mg of (R)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-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] + CHIRALPAK AD, 3.0 100 mm, 3 μm; Mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% over 2.0 min, held at 50% for 1.0 min; Detection: 220 nm: t R = 0.805min.

[0351] Note that the retention time of the product prepared with intermediate 3B here matches that of the product prepared in Example 5 above. In this case, the racemic product was separated into its enantiomers by SFC, thus confirming the absolute configuration of the allocation assigned to Example 5 in the above preparation.

[0352] Synthesis of Example 6 using the known intermediate 2B:

[0353] (S)-6-(((1,1,1,3,3,3-hexafluoroprop-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 under a nitrogen inert atmosphere. 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 under vacuum to obtain crude acyl 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 under a nitrogen inert atmosphere. The previous solution of the acyl chloride in THF (500 mL) was added dropwise at room temperature. The resulting solution was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with 3 L of ice water and extracted with EtOAc (2 × 1 L). The combined organic phases were washed with H₂O (1 × 1 L) and brine (1 × 1 L), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 10) to provide 34.3 g of product. The product was slurried with n-hexane (20 V) and filtered to obtain 26.7 g of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester. The product was separated by slurrying with n-heptane (10 V) to provide 24.13 g of (S)-1-[(pyridazin-3-yl)carbamoyl]-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-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, 4.6Hz, 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% over 2.0 min, held at 50% for 1.0 min; Detection: 220 nm; R = 1.032 min.

[0354] Note that the retention time of the product prepared with intermediate 2B here matches that of the product prepared in Example 6 above. In this case, the racemic product was separated into its enantiomer by SFC, thus confirming the absolute configuration assigned to Example 6 in the above preparation.

[0355] Example 7: (±)-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

[0356] Step 1: Synthesis of tert-butyl 1-((tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0357] A flask was loaded 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) and DCM (2... Extracted and concentrated under reduced pressure (15 mL). The crude product was purified by silica gel chromatography (DCM: MeOH = 20:1) to provide 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 + .

[0358] Step 2: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0359] As described in step 2 of Example 1, N-(tetrahydro-2H-pyran-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (352 mg), TFA (1.5 mL), and DCM (3 mL) were used to prepare N-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octane-1-carboxamide to provide 500 mg of the (crude) title compound. LCMS (ESI, m / z ): 239[M+H] + .

[0360] 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-hexafluoroprop-2-yl ester

[0361] As described in step 3 of Example 1, 1-((tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octane-1-carboxamide (480 mg), CDI (392 mg), and 1,1,1,3,3,3-hexafluoroprop-2-ol (3389 mg) were used to prepare 1,1,1,3,3,3-hexafluoroprop-2-yl ester of 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 to provide a crude product (377 mg). The crude product was purified by reversed-phase column chromatography to provide the title compound (88 mg).

[0362] Example 8: (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, and

[0363] Example 9: (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 and

[0364] The racemic mixture (88 mg) prepared in Example 7 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% 2MNH3-MeOH) --HPLC; Flow rate: 50 mL / min; Gradient: 15% B; Column temperature: 35°C; Back pressure: 100 bar; UV 220 nm) to provide: 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-hexafluoroprop-2-yl ester 1 H NMR (400 MHz, chloroform-) d ) δ 5.78 (dq, J =12.0, 6.1 Hz, 1H), 5.52 (d, J = 7.9 Hz, 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, 5.4 Hz, 2H), 1.56 - 1.50(m, 2H), 1.50 - 1.40 (m, 2H), 1.34 (dd, J = 8.0, 5.3 Hz, 1H), 1.27 (d, J =4.6 Hz, 1H), 0.88 (dd, J = 8.0, 4.5 Hz, 1H). t R = 4.32 min. LCMS (Method D) (ESI, m / z ): 433 [M+H + (S,S) Whelk-01, 4.6 100 mm, 5 µm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 4 mL / min; Gradient: 5% to 20% over 2.0 min, held at 20% for 1.0 min; Detection: 220 nm: t R = 1.568 min.

[0365] and corresponding enantiomers

[0366] 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 1H NMR (400 MHz, chloroform-) d ) δ 5.78 (m, J =6.0 Hz, 1H), 5.51 (d, J = 8.0 Hz, 1H), 4.21 - 3.87 (m, 3H), 3.87 - 3.03 (m,6H), 1.93 (ddd, J = 12.9, 4.4, 2.2 Hz, 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, 5.3 Hz, 1H), 1.27 (d, J =4.6 Hz, 1H), 0.88 (dd, J = 8.0, 4.5 Hz, 1H). t R = 4.99 min. LCMS (Method A) (ESI, m / z ): 433 [M+H + (S,S) Whelk-01, 4.6 100 mm, 5 µm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 4 mL / min; Gradient: 5% to 20% over 2.0 min, held at 20% for 1.0 min; Detection: 220 nm: t R = 1.425 min

[0367] Synthesis of Example 8 using the known intermediate 2B:

[0368] (S)-6-[[(1,1,1,3,3,3-hexafluoroprop-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 under a nitrogen inert atmosphere. 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 under vacuum to obtain crude acyl chloride for later use. Oxane-4-amine (7.3 g), pyridine (9.5 g), and THF (400 mL) were added to another flask purged and maintained under a nitrogen inert atmosphere. A solution of acyl chloride in THF (200 mL) was added dropwise at room temperature. The resulting solution was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with ice water (1 × 3 L) and extracted with EtOAc (2 × 500 mL). The combined organic phases were washed with H2O (1 × 1 L) and brine (1 × 1 L), dried over anhydrous Na2SO4, and concentrated under vacuum. 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% NH4HCO3 in an H2O-MeCN system to provide 15.2 g of amorphous product. The product was finally recrystallized from MeCN / H2O = 1:1 (0.5V / 0.5V) 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-hexafluoroprop-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% over 2.0 min, held at 20% for 1.0 min; Detection: 220 nm: t R = 1.525 min.

[0369] Note that the retention time of the product prepared with intermediate 2B here matches that of Example 8 prepared above. In this case, the racemic product was separated into its enantiomers by SFC, thus confirming the absolute configuration assigned to Example 8 in the above preparation.

[0370] Synthesis of Example 9 using the known intermediate 3B:

[0371] A solution of crude (R)-6-(((1,1,1,3,3,3-hexafluoroprop-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 flask. EDC·HCl (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 overnight at room temperature. The mixture was diluted with H2O (10 mL) and extracted with DCM (1 × 5 mL). The combined organic phases were 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-hexafluoroprop-2-yl ester (37 mg). 1H NMR (300 MHz, chloroform-d) δ 5.76 (td, J = 6.1, 3.3Hz, 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, 4.6 100 mm, 5 mm; Mobile phase: Phase A: CO2, Phase B: IPA (0.1% DEA); Flow rate: 4 mL / min; Gradient: 5% to 20% over 2.0 min, held at 20% for 1.0 min; Detection: 220 nm: t R = 1.46 min.

[0372] Note that the retention time of the product prepared with intermediate 3B here matches that of Example 9 prepared above. In this case, the racemic product was separated into its enantiomer by SFC, thus confirming the absolute configuration assigned to Example 9 in the above preparation.

[0373] Example 10: (±)1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0374] Step 1: Synthesis of tert-butyl 1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0375] As described in step 1 of Example 1, 1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-1-carboxylic acid (500 mg), DCM (10 mL), DMF (14.0 mg), oxaloyl chloride (249 mg), pyrazine-2-amine (186 mg), pyridine (464 mg), and 1-(chloroformyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester was prepared to provide the title compound (190 mg). LCMS (ESI, m / z ): 333 [M+H + .

[0376] Step 2: Synthesis of tert-butyl 1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0377] 190 mg of 1-(pyrazin-2-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester and 5 mL of THF were placed in a vial. Sodium hydride (34.3 mg, 0.858 mmol, 1.50 equivalent, 60% in mineral oil) was added at 0°C. The resulting solution was stirred at 0°C for 0.5 h, and then methyl iodine (97.4 mg) was added. The resulting solution was stirred overnight at room temperature 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 analyzed by chromatography on a silica gel column to provide 140 mg of 1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester. LCMS (ESI, m / z ): 347 [M+H + .

[0378] Step 3: Synthesis of N-methyl-N-(pyrazin-2-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0379] As described in step 2 of Example 1, N-methyl-N-(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (140 mg), TFA (3 mL), and DCM (3 mL) were used to prepare N-methyl-N-(pyrazin-2-yl)-6-azaspiro[2.5]octane-1-carboxamide to provide the title compound (99.7 mg). LCMS (ESI, m / z ): 247 [M+H + .

[0380] Step 4: Synthesis of (±)1-(methyl(pyrazin-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0381] 1,1,1,3,3,3-hexafluoroprop-2-ol (102 mg, 0.606 mmol, 1.50 equivalent), DCM (10 mL), and triphosgene (67.8 mg) were placed in a vial. DIPEA (156 mg) was added at 0°C. The resulting solution was stirred at room temperature for 2 h, and 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.

[0382] Example 11: (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, peak 1, and

[0383] Example 12: (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, peak 2 and

[0384] The racemic mixture prepared in Example 10 was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IA column 2). 25 cm, 5 μm; Mobile phase A: Hex-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: Example 11: 12.5 mg of (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, 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 + .

[0385] and corresponding enantiomers

[0386] Example 12: 12.1 mg of (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, 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 + .

[0387] Determination of the absolute configurations of Examples 11 and 12

[0388] The absolute configurations of Examples 11 and 12 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 configurations of the final products (Examples 11 and 12). The first eluted enantiomer was ultimately determined to be the (R) enantiomer (Example 11), and therefore Example 12 is the (S) enantiomer.

[0389] Example 13: (±)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0390] Step 1: Synthesis of 1-benzyl 6-(tert-butyl) ester of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid

[0391] 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (300 mg), acetone (15 mL), K₂CO₃ (195 mg), and BnBr (220 mg) were packed into a vial. The resulting solution was stirred overnight at 60°C 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 analyzed by chromatography on a silica gel column with EtOAc to provide 1-benzyl 6-(tert-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(tert-butyl) ester (350 mg). LCMS (ESI, m / z ): 346 [M+H + .

[0392] Step 2: Synthesis of benzyl 6-azaspiro[2.5]octane-1-carboxylate

[0393] HCl (g) (3 mL) was added to 6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(tert-butyl) ester (350 mg) in DCM (6 mL). The resulting solution was stirred at room temperature for 2 h and concentrated under reduced pressure to provide 6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester (260 mg). LCMS (ESI, m / z ): 246 [M+H] + .

[0394] Step 3: Synthesis of 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester of 6-azaspiro[2,5]octane-1,6-dicarboxylic acid

[0395] As described in step 3 of Example 1, 6-azaspiro[2.5]octane-1-dicarboxylic acid benzyl ester (240 mg), ACN (4 mL), 1,1'-carbonyldiimidazole (205 mg), DIPEA (378 mg), and 1,1,1,3,3,3-hexafluoroprop-2-ol (820 mg) were used to prepare 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid to provide 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester of 6-azaspiro[2.5]octane-1,6-dicarboxylic acid (350 mg). LCMS (ESI, m / z ): 440 [M+H + .

[0396] Step 4: Synthesis of 6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid

[0397] A mixture of 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester (340 mg) and Pd / C (40 mg, 10% wt) in EtOAc (10 mL) was stirred overnight under H2. The reaction was cooled to room temperature and filtered. The mixture was concentrated under reduced pressure and filtered to provide 6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (240 mg). LCMS (ESI, m / z ): 350 [M+H] + .

[0398] Step 5: Synthesis of (±)1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0399] As described in step 1 of Example 5, 1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-6-azaspiro[2.5]octane-1-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) was prepared to provide the title compound (70 mg).

[0400] Example 14: (S)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, peak 1, and

[0401] Example 15: (R)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, peak 2 and

[0402] The racemic mixture (70 mg) prepared in Example 10 was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK IG, 2). 25 cm, 5 µm; 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 (UV220 & 254nm) to provide: Example 14: 15.0 mg of (S)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-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 + .

[0403] and corresponding enantiomers

[0404] Example 15: 9.7 mg of (R)-1-(isoxazo-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-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 + .

[0405] Determination of the absolute configurations of Examples 14 and 15

[0406] 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 products (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.

[0407] 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

[0408] Step 1: Synthesis of tert-butyl 1-(chlorocarbonyl)-6-azaspiro[2.5]octane-6-carboxylate

[0409] 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.

[0410] Step 2: Synthesis of tert-butyl 1-((2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0411] 2-(trifluoromethyl)pyrimidine-4-amine (200 mg) and THF (15 mL) were placed in a vial. Sodium hydride (49.0 mg, 1.23 mmol, 2.00 equivalent, 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 overnight at room temperature and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL), 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 analyzed by silica gel column chromatography with EtOAc / petroleum ether (1:3) to provide 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] + .

[0412] Step 3: Synthesis of N-(2-(trifluoromethyl)pyrimidin-4-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0413] As described in step 2 of Example 13, N-(2-(trifluoromethyl)pyrimidin-4-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (240 mg), 1,4-dioxane (4 mL), and concentrated hydrochloric acid (1 mL) were used to prepare the title compound (180 mg). LCMS (ESI, m / z): 301 [M+H] + .

[0414] 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-hexafluoroprop-2-yl ester

[0415] As described in step 3 of Example 1, (±)-1-((2-(trifluoromethyl)pyrimidin-4-yl)-6-azaspiro[2.5]octane-1-carboxamide (0.180 g), carbonyl diimidazole (0.146 g), ACN (15 mL), and 1,1,1,3,3,3-hexafluoroprop-2-ol (1.21 g) were used to prepare (±)-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 to provide the title compound.

[0416] Example 17: (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, peak 1, and

[0417] Example 18: (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, peak 2 and

[0418] The racemic mixture prepared in Example 16 was separated into two enantiomers by preparative chiral HPLC (column: CHIRALPAK AD-H, 2). 25 cm, 5 μm; Mobile phase A: Hex--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 5% B to 5% B over 11 min; UV 220 / 254 nm) to provide: 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-hexafluoroprop-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] + .

[0419] and corresponding enantiomers

[0420] 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-hexafluoroprop-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] + .

[0421] Determination of the absolute configurations of Examples 17 and 18

[0422] The absolute configurations of Examples 17 and 18 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 17 and 18). The second eluted enantiomer was ultimately determined to be the (R) enantiomer (Example 18), and therefore Example 17 is the (S) enantiomer.

[0423] Example 19: (±)-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

[0424] Step 1: Synthesis of tert-butyl 1-((6-iodopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0425] 6-Iodopyridine-3-amine (430.87 mg) was added to a stirred solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (500.00 mg), HATU (1116.95 mg), and DIEA (759.32 mg) in DMF (10.00 mL). 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient over 10 min; detector, UV 254 / 220 nm, to provide tert-butyl 1-((6-iodopyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (700 mg). LCMS (ESI, m / z): 458 [M+H] + .

[0426] Step 2: Synthesis of tert-butyl 1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0427] A mixture of tert-butyl 1-((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 overnight at 80°C under a nitrogen atmosphere. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient over 10 min; detector, UV 254 / 220 nm, to provide tert-butyl 1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (560 mg). LCMS (ESI, m / z): 408 [M+H]+.

[0428] Step 3: Synthesis of N-(6-(dimethylphosphoryl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide hydrochloride

[0429] As described in step 2 of Example 13, N-(6-(dimethylphosphoryl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide hydrochloride was prepared from 1-[[6-(dimethylphosphoryl)pyridin-3-yl]carbamoyl]-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (560.00 mg), DCM (5.00 mL), and HCl (g) (4 M in 1,4-dioxane, 5.00 mL, 20 mmol) 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-HCl+H + .

[0430] 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-hexafluoroprop-2-yl ester

[0431] As described in step 3 of Example 1, (±)-1-((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) were used to prepare 1,1,1,3,3,3-hexafluoroprop-2-yl ester of 1-(±)-1-((6-(dimethylphosphoryl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid to provide the title compound (400 mg) LCMS (ESI, m / z): 502 [M+H]. + .

[0432] 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-hexafluoroprop-2-yl ester, peak 1

[0433] 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-hexafluoroprop-2-yl ester, peak 2

[0434] The racemic mixture prepared in Example 19 was separated into two enantiomers (CHIRALART Cellulose-SB, 2) by chiral HPLC. 25 cm, 5 μm; 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 over 21 min; UV 220 / 254 nm) to provide: 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-hexafluoroprop-2-yl ester, peak 1. 1 H NMR (400 MHz, DMSO- d 6 ) δ10.67 (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] + .

[0435] and corresponding enantiomers

[0436] 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-hexafluoroprop-2-yl ester, peak 2. 1 H NMR (400 MHz, DMSO- d 6 ) 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] + .

[0437] Example 22: (±)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0438] Step 1: Synthesis of tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate

[0439] A mixture of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (600 mg, 2.34 mmol, 1.00 equivalent), HATU (1069 mg, 2.80 mmol, 1.20 equivalent), DIPEA (15.2 mg, 11.2 mmol, 5.00 equivalent), and NH4Cl (620 mg, 11.7 mmol, 5.00 equivalent) in DMF (10 mL) was stirred overnight at room temperature. The resulting mixture was quenched with 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 provide tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid (500 mg). LCMS (ESI, m / z): 255 [M+H] + .

[0440] Step 2: Synthesis of tert-butyl 1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0441] A mixture of 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (400 mg), 4-iodopyridine (386 mg), K₂CO₃ (433 mg), Ln (22 mg), and CuI (15 mg) 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 1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (360 mg). LCMS (ESI, m / z): 332 [M+H] + .

[0442] Step 3: Synthesis of N-(pyridin-4-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0443] 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 N-(pyridin-4-yl)-6-azaspiro[2.5]octane-1-carboxamide to provide the title compound (200 mg). LCMS (ESI, m / z ): 232[M+H + .

[0444] 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

[0445] 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).

[0446] Example 23: (R or S)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, peak 1, and

[0447] Example 24: (R or S)-1-(pyridin-4-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester, peak 2

[0448] The racemic mixture prepared in Example 22 was separated into two enantiomers (CHIRALPAK IF, 2) by chiral HPLC. 25 cm, 5 μm; Mobile phase A: Hex (10 mM NH3-MeOH), Mobile phase B: EtOH--HPLC; Flow rate: 15 mL / min; Gradient: 5% B to 5% B over 15 min; UV 220 / 254 nm) to provide: 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-hexafluoroprop-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 + .

[0449] and corresponding enantiomers

[0450] 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-hexafluoroprop-2-yl ester, peak 2. 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 = 11.917 min. LCMS (Method E) (ESI, m / z ): 426[M+H + .

[0451] Example 25: (±)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

[0452] Step 1: Synthesis of tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate

[0453] As described in step 1 of Example 19, 1-carbamoyl-6-azaspiro[2.5]octane-1-carboxylic acid (600 mg, 2.34 mmol, 1.00 equivalence), HATU (1069 mg, 2.80 mmol, 1.20 equivalence), DIPEA (15.2 mg, 11.2 mmol, 5.00 equivalence), and NH4Cl (620 mg, 11.7 mmol, 5.00 equivalence) in DMF (10 mL) was prepared to provide 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (500 mg). LCMS (ESI, m / z ): 255 [M+H + .

[0454] Step 2: Synthesis of tert-butyl 1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0455] To tetrahydro-2 at room temperature H DMF (30.0 mg) was added dropwise to a mixture of pyran-4-carboxylic acid (500.00 mg) and oxaloyl chloride (961 mg) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure before adding tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate (150 mg) and dimethylpyridine (127 mg) from DCM. The reaction mixture was stirred overnight at room temperature 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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography to provide tert-butyl 1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (230 mg). LCMS (ESI, m / z ): 367 [M+H] + .

[0456] Step 3. Synthesis of N-(tetrahydro-2H-pyran-4-carbonyl)-6-azaspiro[2.5]octane-1-carboxamide

[0457] As described in step 2 of Example 13, N-(tetrahydro-2H-pyran-4-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (230 mg), DCM (5 mL), and HCl (gas) / 1,4-dioxane (3 mL) were used to prepare N-(tetrahydro-2H-pyran-4-carbonyl)-6-azaspiro[2.5]octane-1-carboxamide to provide N -(tetrahydro-2) H 1-pyran-4-carbonyl)-6-azaspiro[2.5]octane-1-carboxamide (130 mg). LCMS (ESI, m / z ): 267[M+H] + .

[0458] 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-hexafluoroprop-2-yl ester

[0459] As described in step 3 of Example 1, by N -(tetrahydro-2) H (±)1-((tetrahydro-2H-pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-1-carboxamide (200 mg), CDI (146 mg), ACN (5 mL), DIPEA (489 mg, 3.79 mmol, 2.00 equivalent) and 1,1,1,3,3,3-hexafluoroprop-2-ol (634 mg) were used to prepare (±)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 to provide the title compound (100 mg).

[0460] 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-hexafluoroprop-2-yl ester, peak 1

[0461] 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-hexafluoroprop-2-yl ester, peak 2

[0462] The racemic mixture (100 mg) prepared in Example 25 was separated into two enantiomers (CHIRALPAK IF, 2) by chiral HPLC. 25 cm, 5 μm; Mobile phase A: Hex (10 mM NH3-MeOH), Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 10% B to 10% B over 25 min; UV 220 / 254 nm) to provide: Example 26: 41.5 mg of (R or S)-1-((tetrahydro-2-) H -pyran-4-carbonyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-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). t R = 8.356 min. LCMS (Method A) (ESI, m / z ): 461[M+H + .

[0463] and corresponding enantiomers

[0464] Example 27: 24.7 mg of (R or S)-1-((tetrahydro-2-) H -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 (400 MHz, 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 + .

[0465] 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

[0466] Step 1. Synthesis of 5-nitro-2-(1H-pyrazol-1-yl)pyridine

[0467] In a vial, 2-fluoro-5-nitropyridine (1.00 g, 7.04 mmol, 1.00 equivalent), 1H-pyrazole (575 mg), CsCO3 (5.10 mg), and DMF (10 mL) were placed. The resulting solution was stirred overnight at 100°C 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 rapid chromatography to provide 5-nitro-2-(1H-pyrazole-1-yl)pyridine (1.00 g). LCMS (ESI, m / z ): 191 [M+H] + .

[0468] Step 2: Synthesis of 6-(1H-pyrazol-1-yl)pyridin-3-amine

[0469] A mixture of 5-nitro-2-(1H-pyrazol-1-yl)pyridine (1.00 g) and Pd / C (20 mg, 10% wt) in MeOH (10 mL) was stirred overnight under H2. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to provide 6-(1H-pyrazol-1-yl)pyridine-3-amine (600 mg). LCMS (ESI, m / z ): 161 [M+H] + .

[0470] Step 3: Synthesis of tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0471] As described in step 1 of Example 7, tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid (300 mg), N-(5-aminopyridin-2-yl)acetamide (245 mg), EDCI (248 mg), HOBT (159 mg), and TEA (356 mg) were prepared in DCM (3 mL) to provide tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid (300 mg) LCMS (ESI, m / z ): 398 [M+H] + .

[0472] Step 4: Synthesis of N-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0473] As described in step 2 of Example 13, N-(6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-1-carboxamide was prepared from tert-butyl 1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-1-carboxamide (300 mg), DCM (6 mL), and HCl (g) (3 mL) to provide N-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide (200 mg). LCMS (ESI, m / z ): 298 [M+H] + .

[0474] Step 5: Synthesis of (±)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

[0475] As described in step 3 of Example 1, (±)1-((6-(1H-pyrazol-1-yl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide (200 mg), ACN (3 mL), 1,1'-carbonyldiimidazole (142 mg), DIPEA (261 mg), and 1,1,1,3,3,3-hexafluoroprop-2-ol (566 mg) were prepared to provide the title compound (240 mg).

[0476] Example 29: (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-hexafluoroprop-2-yl ester, peak 1

[0477] Example 30: (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-hexafluoroprop-2-yl ester, peak 2

[0478] The racemic mixture prepared in Example 28 was separated into two enantiomers (CHIRALPAK IF, 2) by chiral HPLC. 25 cm, 5 μm; 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 over 11 min; UV 220 / 254 nm) to provide: 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-hexafluoroprop-2-yl ester, peak 1. 1 H NMR (400 MHz, chloroform-) d ) δ8.55 - 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 + .

[0479] and corresponding enantiomers

[0480] 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-hexafluoroprop-2-yl ester, peak 2. 1 H NMR (400 MHz, chloroform-) d ) δ8.55 - 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 + .

[0481] 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

[0482] Step 1: Synthesis of 5-amino-N-methylpyridine amide

[0483] 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 + .

[0484] Step 2: Synthesis of tert-butyl 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate

[0485] 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). ） HATU (671 mg) and DIPEA (455 mg) were used to prepare tert-butyl 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate to provide tert-butyl 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (210 mg). LCMS (ESI, m / z ): 389 [M+H + .

[0486] Step 3: Synthesis of N-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide

[0487] As described in step 2 of Example 13, N-(6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate tert-butyl ester (210 mg) and HCl (g) (2 mL) in DCM (4 mL) was prepared to provide N-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide (140 mg). LCMS (ESI, m / z ): 289 [M+H] + .

[0488] Step 4: Synthesis of 1,1,1,3,3,3-hexafluoroprop-2-yl ester of 1-((6-(methylcarbamoyl)pyridin-3-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid

[0489] As described in step 3 of Example 1, 1-((6-(6-(methylcarbamoyl)pyridin-3-yl)-6-azaspiro[2.5]octane-1-carboxamide (140 mg), ACN (3 mL), 1,1'-carbonyldiimidazole (102 mg), DIPEA (188 mg), and 1,1,1,3,3,3-hexafluoroprop-2-ol (408 mg) were prepared to provide the title compound (160 mg).

[0490] 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-hexafluoroprop-2-yl ester, peak 1

[0491] 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-hexafluoroprop-2-yl ester, peak 2

[0492] The racemic mixture prepared in Example 31 was separated into two enantiomers (CHIRALPAK IF, 2) by chiral HPLC. 25 cm, 5 μm; 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 over 10.5 min; UV 220 / 254 nm) to provide: 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-hexafluoroprop-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] + .

[0493] 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-hexafluoroprop-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]+ .

[0494] Example 34: (±)1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0495] Step 1: Synthesis of tert-butyl 1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate

[0496] In a vial under nitrogen atmosphere, 150 mg of 6-((tert-butoxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid, 5 mL of THF, 74.0 mg of 1-cyclopropylpiperazine, 152 mg of DIPEA, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trione (50% EtOAc solution, 563 mg, 0.885 mmol, 1.50 equivalent) were added. The resulting solution was stirred at 60°C for 3 h and quenched with 10 mL of water. 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 subjected to chromatographic analysis on a silica gel column with EtOAc / petroleum ether (2 / 1) to provide tert-butyl 1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate (57.0 mg). LCMS (ESI, m / z ): 364 [M+H] + .

[0497] Step 2: Synthesis of (4-cyclopropylpiperazin-1-yl)(6-azaspiro[2.5]octane-1-yl) methyl ketone

[0498] As described in step 2 of Example 1, (4-cyclopropylpiperazin-1-yl)(6-azaspiro[2.5]octane-1-yl) methyl ketone was prepared from tert-butyl 1-(4-cyclopropylpiperazin-1-yl)carbonyl)-6-azaspiro[2.5]octane-6-carboxylate (207 mg), DCMe (5 mL), and TFA (5 mL) to provide the title compound (150 mg). LCMS (ESI, m / z ): 264 [M+H +.

[0499] Step 3: Synthesis of (±)1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester

[0500] As described in step 3 of Example 1, 1,1,3,3,3-hexafluoroprop-2-ol (287 mg), ACN (5 mL), 1,1'-carbonyldiimidazole (111 mg), and (4-cyclopropylpiperazin-1-yl)(6-azaspiro[2.5]octane-1-yl) methyl ketone (150 mg) were used to prepare (±)1-(4-cyclopropylpiperazin-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester. The crude product was purified by preparative HPLC using the following gradient conditions: On a Waters 2767-5 chromatograph, 20% CH3CN / 80% phase A was increased to 80% CH3CN over 10 min, 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 C10 ... 18 19 150 mm 5 μm; Mobile phase: Phase A: NH4HCO3 aqueous solution (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification yielded (±) 1-(4-cyclopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoroprop-2-yl ester (80.7 mg). 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 + .

[0501] Examples 35-189: Examples 35-189 were prepared by a procedure similar to that described in Examples 1-34. The absolute configurations of Examples 36, 105, 118, 142, 151, 162, and 174 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. The stereochemistry of the corresponding (S)-enantiomers (Examples 37, 106, 117, 141, 150, 163, and 175) was allocated as described above for Examples 12, 14, and 17.

[0502]

[0503] Example 190 - II. Biological Evaluation

[0504] The following in vitro and in vivo assays were used to test the compounds to evaluate their MAGL activity.

[0505] Protein proteometry based on in vitro competitive activity

[0506] PC3 human cell membrane proteome (50 μL, total protein concentration 2.0 mg / mL) was pre-incubated at 37°C with different concentrations of inhibitors. After 30 min, the ABPP probe JW912-Bodipy (1.0 μL, 50 μM DMSO solution) 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, serine hydrolase activity was determined by measuring the fluorescence intensity of the gel bands corresponding to MAGL using ImageJ 1.43u software. The intensity was converted to a percentage of enzyme activity by normalization relative to the DMSO control. The IC50 value was determined by fitting the percentage of enzyme activity to a 4-parameter sigmoid dose-response function of nonlinear regression in Prism GraphPad.

[0507] In vitro competitive substrate hydrolase activity assay

[0508] HEK293 cell lysates expressing recombinant human MAGL enzyme and 4-nitrophenylacetate (pNPA) substrate were diluted in 50 mM HEPES (pH 7.0) containing 200 mM KCl and 1 mM EDTA, respectively. The lysates (50 μL, approximately 1.2 μg total protein) were pre-incubated at 25°C with different concentrations of inhibitor. After 30 min, 2X pNPA substrate (50 μL, 2.5 mM) was added, and the rate of substrate conversion was monitored by measuring the increase in absorbance at 405 nm at 25°C for 20 minutes using a Biotek Neo2 microplate reader. After background subtraction and normalization relative to the DMSO control, the average rate was converted to a percentage of enzyme activity. The IC50 value was determined by fitting the percentage of enzyme activity to a 4-parameter sigmoid dose-response function using a nonlinear regression in Prism GraphPad.

[0509] in vivo

[0510] The inhibitor was administered to wild-type C57Bl / 6J via oral gavage in a polyethylene glycol medium. Each animal was sacrificed 4 hours after administration, and the brain proteome was prepared and analyzed according to previously established methods (see Niphakis, MJ et al. (2011) ACS Chem. Neurosci. [American Chemical Society, Chemical Neuroscience] and Long, JZ et al. Nat. Chem. Biol. [Nature Chemical Biology] 5: 37-44).

[0511] As shown in Table 1, the compounds exhibited activity in the experiments described herein.

[0512] Table 1

[0513] Example 191 - The role of acute treatment in a rat formalin paw model of inflammatory pain

[0514] In a rat formalin paw model, formalin was applied to the right paw of rats to induce pain (observed by the duration and frequency of hindlimb licking). Test compounds were administered to evaluate their efficacy in reducing the frequency of hindlimb licking, with the aim of translating into pain relief (e.g., acute and / or chronic pain in patients).

[0515] Experimental plan: Male Sprague Dawley rats were randomly assigned to three groups to allow for a balanced three-day test in the Laboras™ device to provide 10 treatment groups. On the day of the study, male Sprague Dawley rats were weighed, tail-tagged, and orally administered the medium, test compound (0.1, 0.3, 0.6, 1, 3, or 10 mg / kg), or pregabalin (30 mg / kg) at a dose volume of 5 mL / kg for a 4-hour pretest. For Example 6, the medium used was a 0.5% aqueous methylcellulose solution, and for Example 8, the medium used was 20% HP-b-CD. A maximum of six animals were administered at a time. Four hours later, the rats received a plantar injection of 50 μL of 2.5% v / v formalin solution in their right hind paw. The rats were immediately placed in Laboras™ cages, and data acquisition began. The primary measurements recorded using Laboras™ in the formalin paw model were the duration and frequency of hind limb licking. Movement was also reported as maximum speed, average speed during movement or over the whole-time bin, and distance traveled. The rats were removed from their cages 40 minutes after data collection was complete.

[0516] When removed from the test cage, rats were anesthetized with gaseous isoflurane (5% v / v isoflurane in oxygen) and blood samples were collected via cardiac puncture. The brains were then removed, rinsed in phosphate-buffered saline (PBS), hemi-sected in liquid nitrogen, and frozen.

[0517] Data Analysis / Statistics: Data were analyzed using Statistica software (TIBCO, US version 11.1). All data are expressed as mean ± standard error of mean (sem) to one decimal place. Data are presented as overall activity between 0 and 10 minutes (early stage) and between 10 and 30 minutes (delayed inflammatory stage), as well as time course data within 5-minute time blocks for the complete 40-minute data acquisition.

[0518] The time-series data were analyzed using repeated measures ANOVA, followed by one-way ANOVA at each time point and subsequent Dunnett's post-hoc test. One-way ANOVA and Dunnett's post-hoc test were used to analyze the early and late inflammatory phases of these data.

[0519] Outliers were defined as values ​​that deviated from the mean by more than two standard deviations and were excluded from the 0-10 min and 10-30 min data, as well as the time-series data. The significance level was set to p < 0.05.

[0520] like Figure 1As shown, administration of 0.6 mg / kg, 3 mg / kg, and 10 mg / kg in Example 6 demonstrated a statistically significant reduction in measurements of spontaneous pain (frequency of hindlimb licking) in the early and / or late stages of the test. Figure 2 As shown, administration of 1 mg / kg, 3 mg / kg and 10 mg / kg in Example 8 showed a statistically significant reduction in the measurement of spontaneous pain (frequency of hindlimb licking) in both the early and late stages of the test, and Example 8 additionally showed a statistically significant reduction in the measurement of spontaneous pain in the late stage at 0.3 mg / kg and 0.6 mg / kg.

[0521] Example 192 - Evaluation of the effect of the compounds of the present invention in a rat model of maximum electric shock seizure threshold (MEST).

[0522] Experimental plan: In the MEST model, a high-frequency, short-duration, low-intensity current is applied to induce tonic-clonic seizures. The MEST test allows for the identification of the anticonvulsant activity of compounds that may be used to treat generalized epileptic seizures.

[0523] Animals were randomly assigned to a mediator group, a compound treatment group, or a lamotrigine dose group. Animals were administered 5 mL / kg according to the treatment group (n = 12 or 16 / group), with the mediator (0.5% MC) of Example 6 administered orally, the mediator (10% HP-b-CD) of Example 8 administered orally for 240 min, and the test compound administered orally for 360 min for 360 min.

[0524] Using the shock titration “up-and-down method” (Kimball AW et al., 1957), the generation of tonic hindlimb extensor seizures in rats was individually assessed following a single corneal shock lasting 0.3 seconds. Therefore, the first rat in the treatment group was shocked with the expected or estimated CC50 current (the current that generates tonic hindlimb extensor seizures in 50% of animals). For subsequent animals, the stimulation intensity was adjusted logarithmically at 0.06:1, depending on whether the preceding rats showed or did not show tonic hindlimb extension. (1 + x 0.06) mA decrease or increase. This procedure was continued for all rats in the treatment group. The induced seizure was measured as all-or-nothing effect, with each animal scored as present (+) or absent (0).

[0525] Following the method of Kimball et al. (1957), data for each treatment group were recorded as the number of + and 0 values ​​at each current level used, and this information was then used to calculate the CC50 value (the current required for 50% of animals to show tonic hindlimb extension) ± standard error. Drug effect was calculated as the % change in CC50 compared to the mediator control group.

[0526] Statistical analysis: The significant differences between animals treated with drugs and controls were assessed using Litchfield and Wilcoxon (1949) or Dunnett's multiple comparison test following a one-way ANOVA.

[0527] result: The results showed that in rat MEST, Examples 6 and 8 exhibited anticonvulsant activity at 10 mg / kg (respectively...). Figure 3 and Figure 4 ).

[0528] Example 193 - Evaluation of the anticonvulsant activity of a compound in a rat model of erythrophylline-induced epileptic seizures.

[0529] Rhodophylline is an analogue of the excitatory neurotransmitter glutamate and acts as an agonist of rosine receptors. Following systemic injection, rosine induces a prolonged excitatory response, exhibiting many characteristics of temporal lobe epilepsy in humans.

[0530] Experimental plan: The method for detecting anticonvulsant activity related to glutamatergic mechanisms followed the method described by Ben-Ari et al. (Neuroscience, 6, 1361-1391, 1981).

[0531] Rats placed in individual Plexiglas cages (33 × 21 × 18 cm) were injected with erythrine (20 mg / kg intraperitoneally). Thirty minutes after injection, rats were observed for the following symptoms over a 120-minute period: forelimb clonus, rearing (standing on hind legs) and rearing with fall, clonic seizures, tonic seizures, and death. The presence of each symptom and the latency period of its first appearance were measured. The number of forelimb clonus episodes was counted.

[0532] Each group consisted of 12 rats. The test was conducted in a partially blinded manner.

[0533] The test substance will be evaluated at multiple doses (orally) 240 minutes before the test and compared with the corresponding mediator control group (Group 2, orally administered 10% HP-b-CD distilled aqueous solution 240 minutes before the test).

[0534] Four hours before the test, Example 6 was evaluated at 0.3, 1, 3, and 10 mg / kg (oral administration), and Example 8 was evaluated at 1, 3, and 10 mg / kg (oral administration), and compared with the mediator control group (oral administration of 10% HP-b-CD four hours before the test).

[0535] Sixty minutes before the test, diazepam (16 mg / kg) (0.5% HP-b-CD) was administered orally as a reference and compared with the median control.

[0536] Data Analysis / Statistics: Quantitative data (latency) of the test substance were analyzed by comparing the treatment group and the control group using the Kruskal-Wallis test followed by the Mann-Whitney U test. Quantitative data of the reference substance were analyzed using the Mann-Whitney U test.

[0537] Quantitative data (frequency) were analyzed by comparing the treatment group and the mediator control group using Fisher's Exact Probability test.

[0538] The results showed that Example 6 had a significant anticonvulsant effect in the erythrocyanine seizure test in rats at doses ranging from 0.3 to 10 mg / kg, and Example 8 at doses ranging from 1 to 10 mg / kg. At medium to high doses, the magnitudes of the effects of the compounds in Examples 6 and 8 were close to those observed with the reference substance (diazepam).

[0539] Example 194 - Rat Kp

[0540] Brain treatment was evaluated in male Sprague-Dawley rats (n = 3, standard body weight). Briefly, the test compound was formulated into a simple suspension in 0.5% HPMC aqueous solution and administered orally (5 mg / kg, 5 mL / kg). Four hours after administration, 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 rapidly washed with cold physiological 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. The concentrations of the test compound in blood and brain were quantified using matrix-matched calibration standards. Total blood, plasma, and brain concentration data were compared with calculated brain K. p (Total brain concentration: Total plasma concentration ratio), calculated brain potassium (k)p,uu The distribution curves of unbound brain concentration to unbound plasma concentration (ratio), free fractions in rat plasma and brain, and in vitro rat blood relative to plasma are presented together in Table 2. Total plasma concentration data (1 μM test compound) were calculated from total blood concentration data using the in vitro measured rat blood-to-plasma ratio. p,uu The free fractions in rat plasma and brain homogenate were determined in vitro by standard equilibration dialysis (1 µM test compound and 6 h equilibration (for buffer pH 7.4); for rat plasma analysis, 100 mM diisopropyl fluorophosphate stock solution was added to preheated rat plasma before adding the test item).

[0541] Table 2: Presentation of total concentration, brain potassium p and K p,uu (Mean, standard deviation, from n = 3 rats)

[0542] Example 195 - Solubility (Kinetic)

[0543] The kinetic solubility of the test items was determined in duplicate in PBS at pH 2.0 and pH 7.4. A stock solution (10 mM) of the test compound in DMSO was incubated at room temperature with shaking at 1,100 RPM for 2 hours. The sample was then filtered using a vacuum manifold, diluted, and analyzed by LC-MS / MS. Chromatographic conditions: Phenomenex Synergi 4μ Hydro-PR80A column (2.0 × 30 mm), coupled with a pre-protected column; mobile phase: 0.1% formic acid-acetonitrile solution and 0.1% formic acid-water solution; flow rate: 0.65 mL / min; column temperature: 40°C; injection volume: 3 μL.

[0544]

[0545] 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°C; ion spray voltage = +5500 V (positive MRM).

[0546] 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):

[0547] The kinetic solubility data are presented in Table 3.

[0548] Table 3: Kinetic solubility at pH 2 and pH 7.4

[0549] Example 196 - Solubility (Thermodynamics)

[0550] The thermodynamic solubility of the test sample was determined in duplicate in PBS at pH 7.4. The test sample (1.5 mg) in PBS was incubated at room temperature with shaking at 1100 rpm for 24 hours. The sample was then filtered using a vacuum manifold, diluted, and analyzed by LC-MS / MS. Chromatographic conditions: Phenomenex Synergi 4μ Hydro-PR 80A column (2.0 × 30 mm), coupled with a pre-protected column; mobile phase: 0.1% formic acid-acetonitrile solution and 0.1% formic acid aqueous solution; flow rate: 0.65 mL / min; column temperature: 40°C; injection volume: 10 μL.

[0551] Mobile phase: 0.1% formic acid acetonitrile solution (A) and 0.1% formic acid aqueous solution (B)

[0552] 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°C; ion spray voltage = +5500 V (positive MRM).

[0553] 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):

[0554] Thermodynamic solubility data are presented in Table 4.

[0555] Table 4: Thermodynamic solubility at pH 7.4

[0556] Example 197 - In vitro stability of human hepatocytes

[0557] Test item (1 μM) in commercially sourced, aggregated donor, cryopreserved human hepatocytes (0.5 × 10⁻⁶). 6Metabolic 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 rate (amplified unbound) CLint (in mL / min / kg), where the data are shown in Table 5: amplified unbound CLint = kV / N x proportionality factor. V = incubation volume (0.25 mL); N = number of hepatocytes / well (0.125 × 10⁻⁶). 5 (cells). The following lists the proportional factors for predicting in vivo intrinsic clearance:

[0558] Table 5: Magnified unbound CL int

Claims

1. A compound having formula (I): (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): (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 1-3, 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 1-3, 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 1-5, 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. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ic): (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, 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 or a pharmaceutically acceptable salt thereof according to any one of claims 7-9, 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 or a pharmaceutically acceptable salt thereof according to any one of claims 7-11, 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-(pyridazine-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. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, for use as a pharmaceutical agent.

17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or disorders selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, Huntington's disease, spasticity, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

18. Use of any compound of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating a disease or disorder selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, Huntington's disease, spasms, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia.

19. A method for treating a disease or disorder selected from the group consisting of: pain, epilepsy / seizure disorder, Alzheimer's disease, Huntington's disease, Huntington's disease, spasticity, multiple sclerosis, obsessive-compulsive disorder, Parkinson's disease, depression, post-traumatic stress disorder, generalized anxiety disorder, and dystonia, the method comprising administering to a patient in need a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14.

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