Piperidinyl-3-(aryloxy)propanamides and propanoates

Abstract

To provide novel modulators of somatostatin receptor 4 (SSTR4) for treating diseases, disorders, and conditions associated with SSTR4, including Alzheimer's disease.SOLUTION: For example, a compound of the following formula is illustrated.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to piperidinyl-3-(aryloxy)propanamide and propanoate derivatives which are regulators of somatostatin receptor 4 (SSTR4), pharmaceutical compositions containing them, and their use for treating SSTR4-related diseases, disorders, and conditions including Alzheimer's disease.

Background Art

[0002] Somatostatin receptor 4 (SSTR4) is a G protein-coupled receptor for the peptide somatostatin. SSTR4 couples with Gi (inhibitory G protein) which inhibits the production of cyclic AMP. SSTR4 is expressed abundantly in the central nervous system (CNS), and to a lesser extent in dorsal root ganglia and the intestine. See M.A. Meyer, “Highly Expressed Genes within Hippocampal Sector CA1: Implications for the Physiology of Memory,” Neurology International 6(2):5388 (2014). SSTR4 is highly conserved among different species. For example, the SSTR4 protein sequences of human, mouse, and rat share more than 87% identity at the amino acid level. These factors (predominant expression in the brain and a high degree of sequence homology across different species) suggest that SSTR4 has an important role in physiology.

[0003] Experiments using the bacTRAP technique have indicated that SSTR4 has the strongest expression in pyramidal neurons in the cortex and in the CA1 region of the hippocampus. This CNS expression is conserved in humans, non-human primates, and mice. The hippocampus is important for learning and memory. L.R. Squire and A.J. Dede, “Conscious See “Sleep and Unconscious Memory Systems,” Cold Spring Harbor Perspectives in Biology 7:a021667 (2015). In fact, the CA1 region of the hippocampus is the last station in the trisynaptic circuit that governs learning. This circuit begins in the entorhinal cortex (which also contains SSTR4), extends into the dentate gyrus, then CA3, and finally reaches the CA1 region of the hippocampus. CA1 projects out of the hippocampus via the subiculum. This circuit encodes all types of information from the external world in order to generate memories and learn new knowledge.

[0004] Alzheimer's disease is characterized by the degeneration of neurons within this circuit (primarily in the entorhinal cortex and the CA1 region of the hippocampus). See A. Serrano-Pozo et al., “Neuropathological Alterations in Alzheimer Disease,” Cold Spring Harbor Perspectives in Medicine 1:a006189 (2011). Additionally, hippocampal sst4 appears to selectively control the use of cognitive strategies by switching from multiple hippocampus-based associations to simple striatum-based behavioral responses. See F. Gastambide et al., “Hippocampal SSTR4 Somatostatin Receptors Control the Selection of Memory Strategies,” Psychopharmacology (Berl) 202(1-3):153-63 (2009). This finding provides strong rationale for using SSTR4 agonists as a pharmacological approach to improving striatum-based learning (ibid).

[0005] Furthermore, recent research has pointed out that in Alzheimer's disease patients, in addition to cognitive impairment, hyperactivity of the hippocampus is also a major factor in disease progression. See M.A. Busche et al., “Decreased Amyloid-β and Increased Neuronal Hyperactivity by Immunotherapy in Alzheimer’s Models,” Nature Neuroscience 18(12):1725-27 (2015). K. Yamamoto et al., “Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease,” Cell Reports 11(6):859-65 (2015) should also be referred to. Activation of the SSTR4 receptor has been shown to play a role in the control of neuronal activity. See C. Qiu et al., “Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures,” Journal of Neuroscience 28(14):3567-76 (2008). Therefore, agonists for the receptor would likely be good pharmacological tools for inhibiting and controlling neuronal activity in the cortex and hippocampus.

[0006] SSTR4 agonists are expected to be useful for the treatment of Alzheimer's disease and other CNS disorders (such as epilepsy and depression).

Summary of the Invention

[0007] The present invention provides piperidinyl-3-(aryloxy)propanamide and propanoate derivatives and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing piperidinyl-3-(aryloxy)propanamide and propanoate derivatives, and their use for treating SSTR4-related diseases, disorders and conditions, including Alzheimer's disease and other CNS disorders.

[0008] One aspect of the present invention is a compound of formula 1:

[0009] [Chemical formula]

[0010] or a pharmaceutically acceptable salt thereof (wherein, X 1 is selected from N and CR 1 ; X 2 is selected from N and CR 2 ; X 3 is selected from N and CR 3 ; X 4 is selected from N and CR 4 ; provided that no more than two of X 1 , X 2 , X 3 and X 4 are N; X 13 is NR 13 , X 14 is CR 15 R 16 or X 13 is CH 2 , X 14 is NR 14 ; L is selected from NR 8 and O; r is selected from 0 and 1; s is selected from 0 and 1; R 1 , R 2 and R 3 are each independently selected from (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted with 0 to 3 optional substituents independently selected from halo) ; R 4 is selected from (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted with from 0 to 3 optional substituents independently selected from halo) ; R 5 is selected from (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted with from 0 to 3 optional substituents independently selected from halo, oxo, and phenyl (which is optionally substituted with from 0 to 3 optional substituents independently selected from halo)) ; or R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl; R 6 and R 7 are each independently selected from halo and C 1-3 alkyl, or R 6 and R 7 together with the carbon atom to which they are attached form C 3-4 cycloalkane-1,1-diyl; R 8 is selected from H and C 1-4 alkyl; R 9 and R 10 are each (a) hydrogen, halo, hydroxy, and cyano; (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted with from 0 to 3 optional substituents independently selected from halo); and (c) phenyl and C1-5 heteroaryl (each is optionally substituted with 0 to 3 optional substituents independently selected from halo, C 1-4 alkyl, and C 1-4 alkoxy), and the C 1-5 heteroaryl substituent is a monocyclic ring having 5 to 6 ring members (where 1 to 4 of the ring members are heteroatoms), each of the heteroatoms being independently selected from N, O, and S, provided that no more than one of the ring members is O or S, phenyl, and C 1-5 the C on the heteroaryl 1-4 alkyl and C 1-4 the optional substituents of the alkoxy are each independently substituted with 0 to 3 optional substituents independently selected from halo) is independently selected from; or R 9 and R 10 together with the carbon atom to which they are attached form a C 3-4 cycloalkane-1,1-diyl; R 11 and R 12 are each (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is optionally substituted with 0 to 3 optional substituents independently selected from halo) is independently selected from; or R 11 and R 12 together with the carbon atom to which they are attached form a C 3-4 cycloalkane-1,1-diyl; R 13 and R 14 are each (a) hydrogen; and (b) C 1-4 alkyl (which is optionally substituted with 0 to 3 optional substituents independently selected from cyano, oxo, and phenyl (which is optionally substituted with 0 to 3 optional substituents independently selected from halo)) is independently selected from; R 15 and R 16 each is, (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted with 0 to 3 optional substituents independently selected from halo), independently selected from; or R 15 and R 16 together with the carbon atom to which they are attached form C 3-4 cycloalkane-1,1-diyl); is provided.

[0011] Another aspect of the invention provides a compound selected from the group of compounds described in the examples and pharmaceutically acceptable salts thereof.

[0012] A further aspect of the invention provides a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph; and a pharmaceutically acceptable excipient.

[0013] An additional aspect of the invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds and pharmaceutically acceptable salts defined in the preceding paragraph for use as a medicament.

[0014] Another aspect of the invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds and pharmaceutically acceptable salts defined in the preceding paragraph for the treatment of a disease, disorder or condition associated with SSTR4.

[0015] A further aspect of the invention provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with SSTR4.

[0016] An additional aspect of the invention provides a method of treating a disease, disorder or condition associated with SSTR4, the method comprising administering to a subject an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0017] Another aspect of the invention provides a method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, disorder or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and attention deficit hyperactivity disorder.

[0018] A further aspect of the invention provides an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph; and at least one additional pharmacologically active agent.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Unless otherwise indicated, the present disclosure uses the definitions provided below.

[0020] "Substituted", when used in connection with a chemical substituent or moiety (e.g., a C 1-6 alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced by one or more non-hydrogen atoms or groups, provided that the valence requirements are met and a chemically stable compound results from the substitution.

[0021] "About" or "approximately", when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to the values of all variables within the experimental error of the indicated value or within ± 10 percent of the indicated value, whichever is greater.

[0022] "Alkyl" generally refers to straight-chain and branched saturated hydrocarbon groups having a specified number of carbon atoms (e.g., C 1-4 alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, etc.). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, penta-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

[0023] "Alkandiyl" is as defined above for alkyl and generally refers to a divalent alkyl group having a specified number of carbon atoms (e.g., C 1-4 alkandiyl refers to an alkandiyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 alkandiyl refers to an alkandiyl group having 1 to 6 carbon atoms, etc.). Examples of alkandiyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0024] "Alkenyl" refers to a group of linear and branched hydrocarbons having one or more carbon-carbon double bonds and generally having a defined number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0025] "Alkynyl" refers to a group of linear or branched hydrocarbons having one or more triple carbon-carbon bonds and generally having a defined number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0026] "Halo", "halogen", and "halogeno" are used interchangeably and can refer to fluoro, chloro, bromo, and iodo.

[0027] "Haloalkyl", "haloalkenyl", and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups, respectively, as defined above, and substituted by one or more halogen atoms, generally having a defined number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0028] "Cycloalkyl" refers to saturated monocyclic hydrocarbon groups and saturated bicyclic hydrocarbon groups generally having a defined number of carbon atoms that form a ring (s). (e.g., C 3-8Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members). As the bicyclic hydrocarbon group, separated rings (two rings not sharing carbon atoms), spiro rings (two rings sharing one carbon atom), fused rings (two rings sharing two carbon atoms and the bond between the two common carbon atoms), and bridged rings (two rings sharing two carbon atoms but not a common bond) can be mentioned. The cycloalkyl group can be bonded through any ring atom as long as such bonding does not violate the valence requirements, and at the indicated positions, it can optionally contain one or more non-hydrogen substituents as long as such substitution does not violate the valence requirements.

[0029] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, etc. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, etc. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, etc. Examples of separated bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutane cyclopentane, bi(cyclopentane), cyclobutane cyclohexane, cyclopentane cyclohexane, bi(cyclohexane), etc.

[0030] "Cycloalkanediyl" is as defined above for cycloalkyl and generally refers to a divalent cycloalkyl group having a defined number of carbon atoms (e.g., C 3-4 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 4 (i.e., 3 or 4) carbon atoms, C 3-6The cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms (etc.). Examples of the cycloalkanediyl group include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0031] "Cycloalkylidene" means that the cycloalkyl is as defined above, and refers to a divalent monocyclic cycloalkyl group that is bonded through a single carbon atom of the group and generally has a specified number of carbon atoms constituting the ring (for example, C 3-6 Cycloalkylidene refers to a cycloalkylidene group having 3 to 6 carbon atoms as ring members). Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0032] "Cycloalkenyl" generally refers to a partially unsaturated monocyclic hydrocarbon group and a bicyclic hydrocarbon group having a specified number of carbon atoms constituting the ring(s). Similar to the cycloalkyl group, the bicyclic cycloalkenyl group can include separated rings, spiro rings, fused rings, or bridged rings. Similarly, the cycloalkenyl group can be bonded through any ring atom and, at the indicated positions, can optionally contain one or more non-hydrogen substituents provided that such bonding or substitution does not violate the valence requirements. Examples of the cycloalkenyl group include partially unsaturated analogs of the cycloalkyl groups described above (for example, cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, etc.).

[0033] "Aryl" refers to a fully unsaturated monocyclic aromatic hydrocarbon and a polycyclic hydrocarbon having at least one aromatic ring, and both the monocyclic aryl group and the polycyclic aryl group generally have a specified number of carbon atoms constituting their ring members (for example, C 6-14"Aryl" refers to an aryl group having 6 to 14 carbon atoms as ring members). This group can be bonded through any ring atom and, at the indicated positions, can optionally contain one or more non-hydrogen substituents provided that such bonding or substitution does not violate the valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from cycloheptatriene cation, and the like.

[0034] "Arylene" refers to a divalent aryl group where aryl is as defined above. An example of an arylene group is phenylene (i.e., benzene-1,2-diyl).

[0035] "Heterocycle" and "heterocyclyl" are used interchangeably and can refer to a saturated or partially unsaturated monocyclic or bicyclic group having ring atoms consisting of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups generally have a defined number of carbon atoms in their ring(s) (e.g., C 2-6Heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members). Similar to the bicyclic cycloalkyl group, examples of the bicyclic heterocyclyl include separated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl group can be attached via any ring atom and, at the indicated positions, can optionally contain one or more non-hydrogen substituents provided that such attachment or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of the heterocyclyl group include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, and 1,2-dihydropyrazolo[1,5-d][1,2,4]triazinyl.

[0036] "Heterocycl-diyl" refers to a heterocyclyl group attached through two ring atoms of the group, where the heterocyclyl is as defined above. They generally have a defined number of carbon atoms in their ring(s) (e.g., C 2-6"Heterocyclic-diyl" refers to a heterocyclic-diyl group having, as ring members, 2 to 6 carbon atoms and 1 to 4 heteroatoms. Examples of the heterocyclic-diyl group include polyvalent analogs of the heterocyclic groups described above (for example, morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, etc.).

[0037] "Heteroaromatic" and "heteroaryl" are used interchangeably and each of the groups can refer to an unsaturated monocyclic aromatic group having ring atoms consisting of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a polycyclic group having at least one aromatic ring. Both the monocyclic group and the polycyclic group generally have a defined number of carbon atoms as ring members (for example C 1-9Heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members), and any bicyclic group (in which any of the monocyclic heterocycles listed above is fused to a benzene ring) can be mentioned. The heteroaryl group can be bonded through any ring atom (or ring atom for a fused ring), and at the indicated positions, if such bonding or substitution does not violate the valence requirements or result in a chemically unstable compound, it can optionally contain one or more non-hydrogen substituents. Examples of heteroaryl groups include monocyclic groups (e.g., pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, etc.).

[0038] Examples of the heteroaryl group include bicyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benz[d]imidazolyl, benz[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a] pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, etc.) may also be mentioned.,

[0039] "Heteroarylene" refers to a heteroaryl group bonded through two ring atoms of a group, where the heteroaryl is as defined above. They generally have a defined number of carbon atoms in their ring(s) (e.g., C 3-5 Heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members). Examples of heteroarylene groups include polyvalent analogs of the heteroaryl groups described above (e.g., pyr idine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, etc.).

[0040] "Oxo" refers to a double-bonded oxygen (=O).

[0041] A "leaving group" refers to any group that detaches from a molecule during a fragmentation process (including substitution reactions, elimination reactions, and addition - elimination reactions). A leaving group can be nucleofugic (where the group detaches along with the pair of electrons that was originally provided as the bond between the leaving group and the molecule) or electrofugic (where the group detaches without a pair of electrons). The ability of a nucleofugic leaving group to leave depends on its base strength, and the strongest bases are the worst leaving groups. Common nucleofugic leaving groups include nitrogen (e.g., from diazonium salts); sulfonates such as alkyl sulfonates (e.g., mesylate), fluoroalkyl sulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and aryl sulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases (NH 2 - and OH - etc.) can be made into better leaving groups by treatment with an acid. Common electrofugic leaving groups include protons, CO 2 , and metals.

[0042] "Opposite enantiomer" refers to a molecule that is the non - superimposable mirror image of a reference molecule and can be obtained by inversion of all the stereocenters of the reference molecule. For example, if the reference molecule has an S absolute stereochemical configuration, the opposite enantiomer has an R absolute stereochemical configuration. Similarly, if the reference molecule has an S,S absolute stereochemical configuration, the opposite enantiomer has an R,R stereochemical configuration, etc.

[0043] "Stereoisomer(s)" of a compound with a given stereochemical configuration refers to the opposite enantiomers and any diastereomers of the compound, including the geometric isomers (Z / E) of the compound. For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers would include the opposite enantiomer with an R,S,Z configuration, as well as its diastereomers with S,S,Z, R,R,Z, S,R,E, R,S,E, S,S,E, and R,R,E configurations. If the stereochemical configuration of the compound is not specified, "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0044] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound with a specific stereochemical configuration, which constitutes at least about 95% of the sample.

[0045] "Pure stereoisomer" and variations thereof refer to a sample containing a compound with a specific stereochemical configuration, which constitutes at least about 99.5% of the sample.

[0046] "Subject" refers to mammals, including humans.

[0047] "Pharmaceutically acceptable" substances refer to substances suitable for administration to a subject.

[0048] "Treat" refers to restoring, alleviating, inhibiting the progression of, or preventing a disease, disorder, or condition to which such term applies, or restoring, alleviating, inhibiting the progression of, or preventing one or more symptoms of such disease, disorder, or condition.

[0049] "Treat" refers to the act of "treating" as defined immediately above.

[0050] "Drug", "drug substance", "active pharmaceutical ingredient", etc. refer to compounds that can be used for the treatment of a subject in need of treatment (e.g., a compound of Formula 1, including sub-concept compounds and compounds specifically named in the specification).

[0051] "Effective amount" of a drug, "therapeutically effective amount" of a drug, etc. refer to the amount of a drug that is used for the treatment of a subject and can, inter alia, depend on the weight and age of the subject, as well as the route of administration.

[0052] "Excipient" refers to any diluent or vehicle for a drug.

[0053] "Pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0054] "Drug product", "pharmaceutical dosage form", "dosage form", "final dosage form", etc. refer to a pharmaceutical composition suitable for the treatment of a subject in need of treatment and can generally be in the form of a subpackage containing tablets, capsules, powders or granules, a solution or suspension, a patch, a film, etc.

[0055] "Conditions associated with SSTR4" and similar phrases relate to diseases, disorders or conditions in a subject in which activation of SSTR4 may provide a therapeutic or prophylactic benefit.

[0056] The following abbreviations may be used in the specification. Ac (acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous); BINAP (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl); Boc (tert-butoxycarbonyl); Cbz (carbobenzyloxy); dba (dibenzylideneacetone); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloroethane); DCM (dichloromethane); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine, Hunig's base); DMA (N,N-dimethylacetamide); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); dppf (1,1’-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC 50 (effective concentration at half the maximum response); EDA (ethoxylated dodecyl alcohol, Brj® 35); EDC (N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq (equivalent); Et (ethyl); Et 3 N (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V)); HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); AcOH (acetic acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC 50(Concentration at 50% inhibition); IPA (isopropanol); IPAc (isopropyl acetate); IPE (isopropyl ether); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperoxybenzoic acid); Me (methyl); MeOH (methanol); MTBE (methyl tert-butyl ether); mp (melting point); NaOt-Bu (sodium tert-butoxide); NMM (N-methylmorpholine); NMP (N-methyl-pyrrolidone); OTf (triflate); PE (petroleum ether); Ph (phenyl); pEC 50 (-log 10 (EC 50 ), wherein EC 50 is given in molar (M) units); pIC 50 (-log 10 (IC 50 ), wherein IC 50 is given in molar (M) units); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); RT (room temperature, approximately 20 °C to 25 °C); T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide); TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMS (trimethylsilyl); and tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer).

[0057] As described below, the present disclosure relates to compounds of Formula 1 and their pharmaceutically acceptable salts. The present disclosure also relates to materials and methods for preparing the compounds of Formula 1, pharmaceutical compositions containing them, and the use of the compounds of Formula 1 and their pharmaceutically acceptable salts (optionally in combination with other pharmacologically active agents) for treating CNS diseases, disorders or conditions including Alzheimer's disease and other diseases, disorders or conditions associated with SSTR4.

[0058] The compound of formula 1 includes those as follows, where (1) X 1 is selected from N and CR 1 ; X 2 is selected from N and CR 2 ; X 3 is selected from N and CR 3 ; provided that no more than two of X 4 is selected from N and CR 4 X 1 X 2 X 3 and X 4 are N; X 13 is NR 13 and X 14 is CR 15 R 16 or X 13 is CH 2 and X 14 is NR 14 ; L is selected from NR 8 and O; r is selected from 0 and 1; s is selected from 0 and 1; R 1 R 2 and R 3 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted by 0 - 3 optional substituents independently selected from halo) independently selected from; R 4 is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4alkoxy (each substituted by 0 to 3 optional substituents independently selected from halo) selected from; R 5 is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each substituted by 0 to 3 optional substituents independently selected from halo, oxo, and phenyl (which is substituted by 0 to 3 optional substituents independently selected from halo)) selected from; or R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl; R 6 and R 7 are each independently selected from halo and C 1-3 alkyl, or R 6 and R 7 together with the carbon atom to which they are attached form C 3-4 cycloalkane-1,1-diyl; R 8 is selected from H and C 1-4 alkyl; R 9 and R 10 are each (a) hydrogen, halo, hydroxy, and cyano; (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each substituted by 0 to 3 optional substituents independently selected from halo); and (c) phenyl and C 1-5 heteroaryl (each substituted by 0 to 3 optional substituents independently selected from halo, C 1-4 alkyl, and C 1-4 alkoxy, and C 1-5The heteroaryl substituent is a monocyclic ring having 5 to 6 ring members, where 1 to 4 of the ring members are heteroatoms, each of the heteroatoms being independently selected from N, O, and S, provided that no more than one of the ring members is O or S, phenyl, and C 1-5 C on the heteroaryl 1-4 Alkyl and C 1-4 Any substituent of the alkoxy is independently substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or R 9 and R 10 together with the carbon atom to which they are attached form a C 3-4 cycloalkane-1,1-diyl; R 11 and R 12 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each being substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or R 11 and R 12 together with the carbon atom to which they are attached form a C 3-4 cycloalkane-1,1-diyl; R 13 and R 14 each is (a) hydrogen; and (b) C 1-4 alkyl (which is substituted by 0 to 3 optional substituents independently selected from cyano, oxo, and phenyl (which is substituted by 0 to 3 optional substituents independently selected from halo)) independently selected from; R 15 and R 16 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4Alkyl, C 3-6 Cycloalkyl, and C 1-4 Alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; or R 15 and R 16 together with the carbon atom to which they are attached, form C 3-4 Cycloalkan-1,1-diyl.

[0059] In addition to the embodiment (1) in the preceding paragraph, the compound of formula 1 includes those in which (2) X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 and so on.

[0060] In addition to the embodiment (2) in the preceding paragraph, the compound of formula 1 includes those as follows, where (3) R 1 , R 2 , R 3 and R 4 are each (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; (4) R 1 , R 2 , R 3 and R 4 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) selected independently from; (5)R 1 、R 2 、R 3 and R 4 are each, (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each optionally substituted with 0 - 3 substituents independently selected from halo) ), or are selected independently from; (6)R (6)R 1 、R 2 、R 3 and R 4 are each, (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each optionally substituted with 0 - 3 substituents independently selected from halo) ), or are selected independently from; (7)R 1 、R 2 、R 3 and R 4 are each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl? (8)R 1 、R 2 、R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl? (9)R 1 and R 2 are each independently selected from hydrogen and methyl; R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl? (10)R 1 、R 2 、R 3 and R 4 is each hydrogen; or (11)R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl.

[0061] In addition to embodiment (1), the compound of formula 1, wherein (12) X 1 is N, X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 is also included.

[0062] In addition to embodiment (12) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (13) R 2 , R 3 and R 4 are each independently selected from (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted with 0 - 3 substituents independently selected from halo) or are each independently selected from (14) R 2 , R 3 and R 4 are each independently selected from (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted with 0 - 3 substituents independently selected from halo) or are each independently selected from (15) R 2 , R 3 and R 4 are each independently selected from (a) hydrogen, halo, and cyano; and (b) C 1-4Alkyl and C 3-6 cycloalkyl (each optionally substituted with 0 - 3 optional substituents independently selected from halo) is independently selected from; (16) R 2 , R 3 and R 4 are each, (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each optionally substituted with 0 - 3 optional substituents independently selected from halo) is independently selected from; (17) R 2 , R 3 and R 4 are each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; (18) R 2 , R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (19) R 2 is selected from hydrogen and methyl; R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (20) R 2 , R 3 and R 4 each is hydrogen; or (21) R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta - 1 - ene - 1,2 - diyl or furan - 2,3 - diyl.

[0063] In addition to embodiment (1), the compound of formula 1 is one in which (22) X 1 is CR 1 , X 2 is N, X 3 is CR 3and X 4 is CR 4 including those which are such.

[0064] In addition to the embodiment (22) in the preceding paragraph, the compound of formula 1 includes those as follows, where in the formula, (23)R 1 , R 3 and R 4 are each (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) selected independently from (24)R 1 , R 3 and R 4 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) selected independently from (25)R 1 , R 3 and R 4 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each of which is substituted by 0 to 3 optional substituents independently selected from halo) selected independently from (26)R 1 , R 3 and R 4 are each (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each of which is substituted by 0 to 3 optional substituents independently selected from halo) selected independently from; (27)R 1 、R 3 and R 4 are each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl? (28)R 1 、R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl? (29)R 1 is selected from hydrogen and methyl; R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl? (30)R 1 、R 3 and R 4 each is hydrogen; or (31)R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl.

[0065] In addition to embodiment (1), the compound of formula 1 includes those in which, in the formula, (32)X 1 is CR 1 and X 2 is CR 2 and X 3 is N and X 4 is CR 4 and is CR

[0066] In addition to embodiment (32) in the preceding paragraph, the compound of formula 1 includes those as follows, in the formula, (33)R 1 、R 2 and R 4 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or (34)R 1 , R 2 and R 4 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or (35)R 1 , R 2 and R 4 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each optionally substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or (36)R 1 , R 2 and R 4 are each (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each optionally substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or (37)R 1 , R 2 and R 4 each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (38)R 1 , R 2 and R 4are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (39)R 1 and R 2 are each independently selected from hydrogen and methyl; R 4 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (40)R 1 , R 2 and R 4 each is hydrogen; or (41)R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl.

[0067] In addition to embodiment (1), the compound of formula 1 includes those in which, (42) X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , X 4 is N.

[0068] In addition to embodiment (42) in the preceding paragraph, the compound of formula 1 includes those as follows, in which (43)R 1 , R 2 and R 3 each is (a) hydrogen, halo, hydroxy, and cyano; and (b)C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each substituted by 0 to 3 optional substituents independently selected from halo) and are independently selected from; (44)R 1 , R 2 and R 3 each is (a) Hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each optionally substituted by 0 - 3 optional substituents independently selected from halo) selected independently from; (45) R 1 , R 2 and R 3 are each, (a) Hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each optionally substituted by 0 - 3 optional substituents independently selected from halo) selected independently from; (46) R 1 , R 2 and R 3 are each, (a) Hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each optionally substituted by 0 - 3 optional substituents independently selected from halo) selected independently from; (47) R 1 , R 2 and R 3 are each selected independently from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; (48) R 1 , R 2 and R 3 are each selected independently from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (49) R 1 and R 2 are each selected independently from hydrogen and methyl; R 3 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (50) R 1 , R 2and R 3 each is hydrogen.

[0069] In addition to embodiment (1), the compound of formula 1, wherein (51) X 1 is N, X 2 is N, X 3 is CR 3 and X 4 is CR 4 are included.

[0070] In addition to embodiment (51) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (52) R 3 and R 4 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each is substituted with 0 to 3 optional substituents independently selected from halo) are independently selected from; (53) R 3 and R 4 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each is substituted with 0 to 3 optional substituents independently selected from halo) are independently selected from; (54) R 3 and R 4 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each is substituted with 0 to 3 optional substituents independently selected from halo) are independently selected from; (55) R 3 and R 4 each is (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each substituted by 0 to 3 optional substituents independently selected from halo) are independently selected from; (56) R 3 and R 4 are each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; (57) R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (58) R 3 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (59) R 3 and R 4 are hydrogen; or (60) R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl.

[0071] In addition to embodiment (1), the compound of formula 1 includes those in which, (61) X 1 is N, X 2 is CR 2 is N, X 3 is N, X 4 is CR 4 is.

[0072] In addition to embodiment (61) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (62) R 2 and R 4 are each (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted by 0 to 3 optional substituents selected from halo) are each independently selected from; (63)R 2 and R 4 are each, (a) hydrogen, halo, and cyano; and (b)C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each independently substituted by 0 to 3 optional substituents selected from halo) are each independently selected from; (64)R 2 and R 4 are each, (a) hydrogen, halo, and cyano; and (b)C 1-4 alkyl and C 3-6 cycloalkyl (each independently substituted by 0 to 3 optional substituents selected from halo) are each independently selected from; (65)R 2 and R 4 are each, (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each independently substituted by 0 to 3 optional substituents selected from halo) are each independently selected from; (66)R 2 and R 4 are each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; (67)R 2 and R 4 are each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (68)R 2 is selected from hydrogen and methyl; R 4is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (69)R 2 and R 4 each is hydrogen; or (70)R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl.

[0073] In addition to embodiment (1), the compound of formula 1 includes those in which, in formula, (71)X 1 is N, X 2 is CR 2 and X 3 is CR 3 and X 4 is N.

[0074] In addition to embodiment (71) in the preceding paragraph, the compound of formula 1 includes those as follows, in formula (72)R 2 and R 3 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; (73)R 2 and R 3 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; (74)R 2 and R 3 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each optionally substituted with 0 - 3 optional substituents independently selected from halo) are independently selected from; or (75) R 2 and R 3 each is, (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each optionally substituted with 0 - 3 optional substituents independently selected from halo) are independently selected from; or (76) R 2 and R 3 each is independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (77) R 2 and R 3 each is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (78) R 2 is selected from hydrogen and methyl; R 3 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (79) R 2 and R 3 each is hydrogen.

[0075] In addition to embodiment (1), the compound of formula 1, wherein, (80) X 1 is CR 1 and X 2 is N, X 3 is N, X 4 is CR 4 is included.

[0076] In addition to embodiment (80) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (81) R1 and R 4 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each is substituted with 0 to 3 optional substituents independently selected from halo) independently selected from; or (82) R 1 and R 4 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each is substituted with 0 to 3 optional substituents independently selected from halo) independently selected from; or (83) R 1 and R 4 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each is substituted with 0 to 3 optional substituents independently selected from halo) independently selected from; or (84) R 1 and R 4 each is (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each is substituted with 0 to 3 optional substituents independently selected from halo) independently selected from; or (85) R 1 and R 4 each is independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (86) R 1 and R 4is each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (87)R 1 is selected from hydrogen and methyl; R 4 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl? (88)R 1 and R 4 each is hydrogen; or (89)R 4 and R 5 together with the carbon atom to which they are attached form cyclopenta-1-ene-1,2-diyl or furan-2,3-diyl.

[0077] In addition to embodiment (1), the compound of formula 1 includes those in which, (90)X 1 is CR 1 and X 2 is N, and X 3 is CR 3 and X 4 is N.

[0078] In addition to embodiment (90) in the preceding paragraph, the compound of formula 1 includes those as follows, in which (91)R 1 and R 3 each is (a) hydrogen, halo, hydroxy, and cyano; and (b)C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; (92)R 1 and R 3 each is (a) hydrogen, halo, and cyano; and (b)C 1-4 alkyl, C 3-6 cycloalkyl, and C1-4 Alkoxy (each substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; (93)R 1 and R 3 each is (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; (94)R 1 and R 3 each is (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; (95)R 1 and R 3 each is independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; (96)R 1 and R 3 each is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (97)R 1 is selected from hydrogen and methyl; R 3 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; or (98)R 1 and R 3 each is hydrogen.

[0079] In addition to embodiment (1), the compound of formula 1 is, in which, (99)X 1 is CR 1 and X 2 is CR 2 and X 3is N, and X 4 includes those in which it is N.

[0080] In addition to the embodiment (99) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (100)R 1 and R 2 are each (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) are independently selected from; (101)R 1 and R 2 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) are independently selected from; (102)R 1 and R 2 are each (a) hydrogen, halo, and cyano; and (b) C 1-4 alkyl and C 3-6 cycloalkyl (each of which is substituted by 0 to 3 optional substituents independently selected from halo) are independently selected from; (103)R 1 and R 2 are each (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl (each of which is substituted by 0 to 3 optional substituents independently selected from halo) are independently selected from; (104)R 1 and R 2is each independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl; (105)R 1 and R 2 is each independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and cyclopropyl; (106)R 1 and R 2 is each independently selected from hydrogen and methyl; or (107)R 1 and R 2 each is hydrogen.

[0081] In addition to, or as an alternative to, one of embodiments (1) to (107) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (108)R 5 is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each is substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl (which is substituted with 0 to 3 optional substituents independently selected from halo)) selected from; (109)R 5 is (a) halo and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each is substituted with 0 to 3 optional substituents independently selected from halo) selected from; (110)R 5 is (a) fluoro, chloro, bromo, and cyano; and (b) methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and isopropoxy (each substituted with 0 to 3 optional substituents independently selected from halo) is selected from; (111)R 5 is (a) fluoro, chloro, bromo, and cyano; and (b) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each substituted with 0 to 3 optional substituents independently selected from fluoro) is selected from; (112)R 5 is selected from fluoro, chloro, bromo, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy; (113)R 5 is selected from chloro, methyl, ethyl, cyclopropyl, trifluoromethyl, and trifluoromethoxy; or (114)R 5 is selected from methyl, cyclopropyl, trifluoromethyl, and trifluoromethoxy.

[0082] In addition to, or as an alternative to, one of embodiments (1) to (114) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (115)R and R 6 and R 7 are each independently selected from fluoro and methyl, or together with the carbon atom to which they are attached, form cyclopropane-1,1-diyl or cyclobutane-1,1-diyl; (116)R 6 and R 7 are both fluoro or both methyl, or together with the carbon atom to which they are attached, form cyclopropane-1,1-diyl or cyclobutane-1,1-diyl; (117) R 6 and R 7 are both methyl; or (118) R 6 and R 7 are both fluoro.

[0083] In addition to, or in place of, one of embodiments (1) to (118) in the preceding paragraph, the compound of formula 1 includes those in which, (119) L is NR 8 as defined herein.

[0084] In addition to embodiment (119) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (120) R 8 is selected from hydrogen and methyl; or (121) R 8 is hydrogen.

[0085] In addition to, or in place of, one of embodiments (1) to (118) in the preceding paragraph, the compound of formula 1 includes those in which, (122) L is O.

[0086] In addition to, or in place of, one of embodiments (1) to (122) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (123) R 9 and R 10 each is (a) hydrogen, halo, hydroxy, and cyano; (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted with 0 to 3 optional substituents independently selected from halo); and (c) phenyl and C 1-5 heteroaryl (each of which is substituted with 0 to 3 optional substituents independently selected from halo, C 1-4 alkyl, and C 1-4 alkoxy, and C 1-5The heteroaryl substituent is a monocyclic ring having 5 to 6 ring members (where 1 to 4 of the ring members are heteroatoms), each of the heteroatoms being independently selected from N, O, and S, provided that no more than one of the ring members is O or S, phenyl, and C 1-5 C on the heteroaryl 1-4 alkyl and C 1-4 Any substituent of the alkoxy is independently substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; (124)R 9 and R 10 are each (a) hydrogen and halo; (b) C 1-4 alkyl and C 1-4 alkoxy (each being substituted by 0 to 3 optional substituents independently selected from halo); and (c) phenyl and C 1-5 heteroaryl (each being substituted by 0 to 3 optional substituents independently selected from halo and C 1-4 alkyl, and the C 1-5 The heteroaryl substituent is a monocyclic ring having 5 to 6 ring members (where 1 or 2 of the ring members are heteroatoms), each of the heteroatoms being N, phenyl, and C 1-5 C on the heteroaryl 1-4 Any substituent of the alkyl is independently substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from; (125)R 9 and R 10 are each (a) hydrogen and halo; (b) C 1-4 alkyl and C 1-4 alkoxy (each being substituted by 0 to 3 optional substituents independently selected from halo); and (c) phenyl, pyridinyl, and pyrazolyl (each being substituted by halo and C 1-40 to 3 optional substituents independently selected from alkyl (which is substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; or (126)R 9 and R 10 each is (a) hydrogen and halo; (b) methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo); and (c) phenyl, pyridinyl, and pyrazolyl (each of which is substituted by 0 to 3 optional substituents independently selected from halo and methyl (which is substituted by 0 to 3 optional substituents independently selected from halo)) independently selected from; or (127)R 9 and R 10 each is (a) hydrogen, fluoro, and chloro; (b) methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy; and (c) phenyl, pyridinyl, and pyrazolyl (each of which is substituted by 0 to 3 optional substituents independently selected from fluoro, chloro, and methyl (which is substituted by 0 to 3 optional substituents independently selected from fluoro)) independently selected from; or (128)R 9 and R 10 are selected from hydrogen, halo, and C 1-4 alkyl; or (129)R 9 and R 10 are the same and are selected from hydrogen, fluoro, and methyl; or (130)R 9 and R 10 are hydrogen; or (131)R 9 and R 10 together with the carbon atom to which they are attached, C 3-4form a cycloalkane-1,1-diyl; or (132)R 9 and R 10 together with the carbon atom to which they are attached form a cyclopropane-1,1-diyl.

[0087] In addition to, or alternatively to, one of embodiments (1) to (132) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (133)R 11 and R 12 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) independently selected from; (134)R 11 and R 12 each is independently selected from hydrogen and C 1-4 alkyl (which is substituted by 0 to 3 optional substituents independently selected from halo); (135)R 11 and R 12 each is independently selected from hydrogen and C 1-4 alkyl; (136)R 11 and R 12 each is independently selected from hydrogen, methyl, and ethyl; (137)R 11 and R 12 are the same and are selected from hydrogen, halo, and C 1-4 alkyl; (138)R 11 and R 12 are the same and are selected from hydrogen and methyl; (139)R 11 and R 12 is hydrogen; (140)R 11 and R12 together with the carbon atom to which they are attached, form a C 3-4 cycloalkane-1,1-diyl; or (141)R 11 and R 12 together with the carbon atom to which they are attached, form a cyclopropane-1,1-diyl.

[0088] In addition to, or alternatively to, one of embodiments (1) to (141) in the preceding paragraph, the compound of formula 1 is such that, in formula, (142)X 13 is NR 13 and X 14 is CR 15 R 16 is included.

[0089] In addition to embodiment (142) in the preceding paragraph, the compound of formula 1 includes those as follows, in formula (143)R 13 is (a) hydrogen; and (b) C 1-4 alkyl (which is substituted with 0 to 3 optional substituents independently selected from cyano, oxo, and phenyl (which is substituted with 0 to 3 optional substituents independently selected from halo)) selected from; (144)R 13 is hydrogen and C 1-4 alkyl (which is substituted with 0 to 3 optional substituents independently selected from cyano, oxo, and phenyl (which is substituted with 0 to 1 optional substituents independently selected from halo)) selected from; (145)R 13 is selected from hydrogen, methyl, cyanomethyl, and benzoylmethyl (which is substituted with 0 to 1 optional substituents independently selected from halo); (146)R 13 is selected from hydrogen, methyl, cyanomethyl, and chlorobenzoylmethyl; (147)R 13is selected from hydrogen and methyl; or (148)R 13 is methyl.

[0090] In addition to, or as an alternative to, one of embodiments (142) to (148) in the preceding paragraph, the compound of formula 1 includes those as follows, wherein (149)R 15 and R 16 each is (a) hydrogen, halo, hydroxy, and cyano; and (b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy (each of which is substituted by 0 to 3 optional substituents independently selected from halo) is independently selected from (150)R 15 and R 16 each is independently selected from hydrogen and C 1-4 alkyl (which is substituted by 0 to 3 optional substituents independently selected from halo); or (151)R 15 and R 16 each is independently selected from hydrogen, methyl, and ethyl; or (152)R 15 and R 16 is hydrogen; or (153)R 15 and R 16 together with the carbon atom to which they are attached, form C 3-4 cycloalkane-1,1-diyl; or (154)R 15 and R 16 together with the carbon atom to which they are attached, form cyclobutane-1,1-diyl.

[0091] In addition to, or as an alternative to, one of embodiments (1) to (141) in the preceding paragraph, the compound of formula 1 is such that, (155) X 13 is CH 2 and X14 is NR 14 including those that are

[0092] In addition to the embodiments (155) in the preceding paragraph, the compound of formula 1 includes those as follows, where (156)R 14 is (a) hydrogen; and (b) C 1-4 alkyl (which is substituted by 0 to 3 optional substituents independently selected from cyano, oxo, and phenyl (which is substituted by 0 to 3 optional substituents independently selected from halo)) selected from; or (157)R 14 is selected from hydrogen and C 1-4 alkyl; or (158)R 14 is C 1-4 alkyl.

[0093] In addition to, or in place of, one of the embodiments (1) to (158) in the preceding paragraph, the compound of formula 1 includes those as follows, where (159)r is 0; or (160)r is 1.

[0094] In addition to, or in place of, one of the embodiments (1) to (160) in the preceding paragraph, the compound of formula 1 includes those as follows, where (161)s is 0; or (162)s is 1.

[0095] The compound of formula 1 includes all the compounds specifically named in the embodiments (1) to (162) and examples described in the preceding paragraph, and may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, the compound of formula 1 that is a salt may exist as a complex, solvate, hydrate, and liquid crystal.

[0096] The compound of formula 1 can form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including divalent acids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, etc.), and non-toxic salts derived from organic acids (such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.). Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0097] Pharmaceutically acceptable base salts include salts derived from bases that include amines in addition to metal cations such as alkali metal cations or alkaline earth metal cations. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see S.M. Berge et al., J. Pharm. Sci. (1977) 66:1-19. See also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0098] Pharmaceutically acceptable salts can be prepared using various methods. For example, the compound of formula 1 can be reacted with a suitable acid or base to obtain the desired salt. Alternatively, a precursor of the compound of formula 1 is reacted with an acid or base to remove a protecting group labile to the acid or base, or to open a lactone group or lactam group of the precursor. In addition, the salt of the compound of formula 1 can be converted to another salt (or the free form) via treatment with a suitable acid or base, or via contact with an ion exchange resin. Following the reaction, if the salt precipitates from the solution, it can be isolated by filtration or by evaporation to recover the salt. The degree of ionization of the salt can vary from complete ionization to almost no ionization.

[0099] The compounds of formula 1 can exist in the continuum of solid phases ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and exhibits physical properties of a solid or liquid depending on temperature. Typically, such materials do not give a characteristic X-ray diffraction pattern and, although presenting solid properties, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, characterized by a state change (typically a second-order ("glass transition")). The term "crystalline" refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a characteristic X-ray diffraction pattern with defined peaks. Such materials will also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is characterized by a (typically first-order) phase change ("melting point").

[0100] The compounds of formula 1 can also exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex containing the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent can be isotopically substituted (e.g., D 2 O, acetone-d 6 , DMSO-d 6 ).

[0101] The currently accepted classification system for solvates and hydrates of organic compounds differentiates solvates and hydrates of the separation site, channel, and metal ion coordination. See, for example, K.R. Morris (H.G. Brittain ed.) Polymorphism in Pharmaceutical Solids (1995). Solvates and hydrates of the separation site are those in which solvent (e.g., water) molecules are separated from each other by intervening molecules of the organic compound without direct contact. In channel solvates, the solvent molecules are located in lattice channels where they are adjacent to other solvent molecules. In metal ion coordination solvates, the solvent molecules bind to metal ions.

[0102] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, as in the case of channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, typically non-stoichiometry will be observed.

[0103] The compound of formula 1 may also exist as a multi-component complex (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. Examples of this type of complex include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents that are bound together via non-covalent interactions, but can also be complexes of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, recrystallization from a solvent, or physically grinding the components together. See, for example, O. Almarsson and M. J. Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0104] When subjected to suitable conditions, the compound of formula 1 can exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state lies between the true crystalline state and the true liquid state (either molten or dissolved). Mesomorphism resulting from a change in temperature is described as "thermotropic", and mesomorphism resulting from the addition of a second component (e.g., water or another solvent) is described as "lyotropic". Compounds having the ability to form lyotropic mesophases are described as "amphiphilic", and these include polar ionic moieties (e.g., -COO - Na + 、-COO - K + 、-SO 3- Na + ) or a polar nonionic moiety (-N - N + (CH 3 ) 3 etc.). For example, see N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

[0105] Each compound of Formula 1 can exist as a polymorph, stereoisomer, tautomer, or some combination thereof, can be isotopically labeled, can result from the administration of a prodrug, or can form metabolites following administration.

[0106] A “prodrug” refers to a compound that has little or no pharmacological activity but is converted to a compound having the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared, for example, as described in H. Bundgaard, Design of Prodrugs (1985), by replacing appropriate functional groups present in a pharmacologically active compound with a “pro moiety”. Examples of prodrugs include ester derivatives, ether derivatives, or amide derivatives of compounds of Formula 1 having a carboxylic acid functional group, a hydroxy functional group, or an amino functional group, respectively. For further consideration of prodrugs, see, for example, T. Higuchi and V. Stella “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series 14 (1975) and E.B. Roche ed., Bioreversible Carriers in Drug Design (1987).

[0107] "Metabolite" refers to a compound formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl derivatives, hydroxy derivatives, secondary amino derivatives, primary amino derivatives, phenol derivatives, and carboxylic acid derivatives of the compound of formula 1 having a methyl group, an alkoxy group, a tertiary amino group, a secondary amino group, a phenyl group, and an amide group, respectively.

[0108] The compound of formula 1 may exist as stereoisomers resulting from the presence of one or more stereocenters, one or more double bonds, or both. The stereoisomers can be pure, substantially pure, or a mixture. Such stereoisomers can also result from optically active acid addition salts or base salts, for example, when the counterion is D-lactate or L-lysine.

[0109] The compound of formula 1 may exist as tautomers, which are isomers resulting from tautomerization. Examples of tautomerism include imine-enamine, keto-enol, oxime-nitroso, and amide-imido acid tautomerism.

[0110] The compound of formula 1 may exhibit two or more types of isomerism.

[0111] Geometric (cis / trans) isomers can be separated by conventional techniques (e.g., chromatography and fractional crystallization).

[0112] Conventional techniques for the preparation or isolation of compounds having a specific stereochemical configuration include chiral synthesis from a suitable optically pure precursor, or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, a racemate (or racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol, or an acid or base such as tartaric acid or 1-phenylethylamine if the compound of formula 1 contains an acidic or basic moiety). The resulting mixture of diastereomers is separated by chromatography, fractional crystallization, etc., and the appropriate diastereomer can be converted to the compound having the required stereochemical configuration. For further consideration of techniques for the separation of stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0113] The compounds of formula 1 may retain isotopic variations in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than is usually found in nature. Suitable isotopes for incorporation in the compounds of formula 1 include, for example, isotopes of hydrogen ( 2 H and 3 H, etc.); isotopes of carbon ( 11 C, 13 C and 14 C, etc.); isotopes of nitrogen ( 13 N and 15 N, etc.); isotopes of oxygen ( 15 O, 17 O and 18 O, etc.); isotopes of sulfur ( 35 S, etc.); isotopes of fluorine ( 18 F, etc.); isotopes of chlorine ( 36 Cl, etc.), and isotopes of iodine ( 123 I and 125 I, etc.). Isotopic variations (e.g., deuterium, 2The use of (H) may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements). In addition, certain isotope variations of the disclosed compounds can incorporate radioactive isotopes (e.g., tritium, 3 H or 14 C), which can be useful in tissue distribution studies of drugs and / or substrates. Substitution with positron-emitting isotopes ( 11 C, 18 F, 15 O and 13 N, etc.) can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotope-labeled compounds can be prepared by processes similar to those described elsewhere in this disclosure using appropriate isotope-labeled reagents in place of the unlabeled reagents.

[0114] The compounds of formula 1 can be prepared using the techniques described below. Some of the schemes and examples can omit details of common reactions (such as oxidation, reduction, etc.), separation techniques (such as extraction, evaporation, precipitation, chromatography, filtration, milling, crystallization, etc.), and analytical procedures, which are known to those skilled in the art of organic chemistry. Details of such reactions and techniques can be found in numerous treatises (e.g., Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith et al., Compendium of Organic Synthetic Methods (since 1974)). Starting materials and reagents can be obtained from commercial sources or prepared using literature methods. Some of the reaction schemes can omit minor products resulting from chemical conversions (such as alcohols from hydrolysis of esters, CO 2 etc. from decarboxylation of dicarboxylic acids). In addition, in some cases, reaction intermediates can be used in subsequent steps without isolation or purification (i.e., in situ).

[0115] In some of the following reaction schemes and examples, certain compounds can be prepared using protecting groups, which prevent unwanted chemical reactions at reaction sites that would otherwise occur. Protecting groups can also be used to facilitate solubility or otherwise modify the physical properties of the compound. For a discussion of protecting group strategies, a description of materials and methods for the installation and removal of protecting groups, and a compilation of useful protecting groups for common functional groups (including amines, carboxylic acids, alcohols, ketones, aldehydes, etc.), see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0116] Generally, the chemical transformations described throughout the specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions can benefit from the use of an excess of one or more reactants. In addition, many of the reactions disclosed throughout the specification can be carried out at approximately room temperature (RT) and ambient pressure, although depending on reaction kinetics, yield, etc., some reactions can be carried out at high pressure or using higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78 °C to 0 °C). Any reference in this disclosure and the claims to stoichiometric ranges, temperature ranges, pH ranges, etc. includes the indicated endpoints whether or not the word "range" is explicitly used.

[0117] Many of the chemical transformations can also use one or more suitable solvents, which can affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents can be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or some combinations. Representative solvents include saturated aliphatic hydrocarbons (such as n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (such as methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (such as diethyl ether, di-isopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (such as acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (such as formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (such as carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1,-dioxide); and phosphorus-containing solvents (such as hexamethylphosphoric triamide).

[0118] In the following scheme, substituent identifiers (L, r, s, R 5 、R 6 、R 7 、R 9 、R 10 、R11 , R 12 , X 1 , X 2 , X 3 , X 4 , X 13 and X 14 ) are as defined above for Formula 1. However, as previously described, some of the starting materials and intermediates can contain protecting groups, which are removed prior to the final product. In such cases, the substituent identifier refers to the moieties defined in Formula 1 and those moieties with appropriate protecting groups. For example, a starting material or intermediate in a scheme can contain an X 13 substituent having a reactive amine. In such a case, X 13 will include a moiety with or without, for example, a Boc group or a Cbz group attached to the amine.

[0119] Scheme A shows a general method for preparing a compound of Formula 1 (Formula 1A) where L is NR 8 . According to the method, a propanoic acid derivative (A1) is reacted with a piperidinylamine (A2, r = 0) or piperidinylmethanamine (A2, r = 1) (wherein X 13 = NR 13 and X 14 = CR 15 R 16 , or X 13 = CH 2 and X 14 = NR 14 , and both R 13 and R 14 are other than H). The reaction is carried out using a non-nucleophilic base (e.g., Et 3 N, DIPEA) and one or more compatible polar solvents (e.g., DCM, DMA , DMF, THF) in the presence of a standard amide coupling agent (HATU, DCC, EDC hydrochloride, T3P, or 2-chloro-1-methylpyridin-1-ium iodide, etc.). The amide coupling can be carried out at a temperature in the range of room temperature to about 80 °C. The reaction can be facilitated using HOBt. Although not shown in Scheme A, the propanamide (Formula 1A, R8 =H) is reacted with an alkyl halide (e.g., R 8 I, R 8 =C 1-4 alkyl) in the presence of a strong non-nucleophilic base (e.g., NaH) and a suitable polar aprotic solvent (e.g., DMF) to obtain an N-alkylpropanamide (Formula 1A, R 8 =C 1-4 alkyl).

[0120]

Chemical Formula

[0121] Scheme A

[0122] Scheme B also shows a general method for preparing the compound of Formula 1 (Formula 1A) when L is NR 8 . According to the method, a propanoic acid derivative (A1) is reacted with a piperidinylamine (B1 or B2, r = 0) or a piperidinylmethanamine (B1 or B2, r = 1) (wherein PG is an amine protecting group such as Boc or Cbz). Amide coupling is carried out using the reagents and conditions described in Scheme A to obtain a protected piperidinylpropanamide or piperidinylmethylpropanamide (B3 or B4). Following the removal of PG, the deprotected piperidine derivative (B5 or B6) is reacted with an alkyl aldehyde (B 7 or B 8 ) in the presence of a mild reducing agent (such as sodium cyanoborohydride or sodium triacetoxyborohydride) and a suitable solvent (e.g., DCM, MeOH) to obtain the compound of Formula 1A. Propanoamide (Formula 1A, R 8 =H) is reacted with an alkyl halide (e.g., R 8 I, R 8 =C 1-4 alkyl) in the presence of a strong non-nucleophilic base (e.g., NaH) and a suitable polar aprotic solvent (e.g., DMF) to obtain an N-alkylpropanamide (Formula 1A, R 8 =C1-4 (alkyl) can be obtained.

[0123]

Chemical formula

[0124] Scheme B

[0125] Scheme C shows a general method for preparing the compound of formula 1 (formula 1B) when L is O. According to the method, a propanoic acid derivative (A1) is reacted with hydroxypiperidine (C1, r = 0) or hydroxymethylpiperidine (C1, r = 1) (wherein X 13 =NR 13 and X 14 =CR 15 R 16 or X 13 =CH 2 and X 14 =NR 14 and both R 13 and R 14 are other than H). The reaction is carried out at approximately room temperature in the presence of DCC, a catalytic amount of DMAP, and one or more compatible polar solvents (e.g., DCM, DMA, DMF) to obtain piperidinyl propanoate or piperidinyl methyl propanoate (formula 1B).

[0126]

Chemical formula

[0127] Scheme D shows a method for preparing the compound of formula 1 when L is O. According to the method, a propanoic acid derivative (A1) is reacted with hydroxypiperidine (D1 or D2, r = 0) or hydroxymethylpiperidine (D1 or D2, r = 1) (wherein PG is an amine protecting group (such as Boc or Cbz, etc.)). The reaction is carried out in the presence of DCC, a catalytic amount of DMAP, and one or more compatible polar solvents (such as DCM, DMA, DMF). The esterification is typically carried out at room temperature to obtain the protected piperidinyl propanoate or piperidinylmethyl propanoate (D3 or D4). Following the removal of PG, the deprotected piperidine derivative (D5 or D6) is reacted with an alkyl aldehyde (B 7 or B 8 ) in the presence of a mild reducing agent (such as sodium cyanoborohydride or sodium triacetoxyborohydride, etc.) and a compatible solvent (such as DCM, MeOH) to obtain the compound of formula 1B.

[0128]

Chemical formula

[0129] Scheme E shows a general method for preparing the compound of formula 1. According to the method, an alcohol (E1) is first treated with a strong base (such as NaH) in the presence of a compatible solvent (such as DMF, THF), and then reacted with an aryl or heteroaryl halide (E2, R 17 = halo) (which contains a nitrogen ring atom or an electron-withdrawing group ortho or para to R 17 ). The first step is typically carried out at a temperature of 0 °C to room temperature, and the second step is typically carried out at room temperature to about 80 °C. The alcohol (E1) contains a piperidinyl moiety (wherein X 13 = NR 13 and X 14 = CR 15 R 16 , or X 13 = CH 2 and X 14 = NR14 wherein R 13 and R 14 are both other than H). Alternatively, the piperidinyl moiety contains an amine protecting group (e.g., Boc or Cbz), which is subsequently removed to give a compound of formula 1 where R 13 or R 14 is H. In addition, the product (formula 1, R 8 =H) is reacted with an alkyl halide (e.g., R 8 I, R 8 =C 1-4 alkyl) in the presence of a strong non-nucleophilic base (e.g., NaH) and a suitable polar aprotic solvent (e.g., DMF) to obtain an N-alkylpropanamide (formula 1, R 8 =C 1-4 alkyl).

[0130]

Chemical formula

[0131] The methods shown in the scheme can be varied as desired. For example, protecting groups can be added or removed and the product can be further elaborated, e.g., by alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynylation, etc., to obtain the desired final product. Further, any intermediate or final product containing a mixture of stereoisomers can be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or derivatization with optically pure reagents as described above to obtain the desired stereoisomer.

[0132] Compounds of formula 1, including the compounds named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, should be evaluated for their biomedical properties (solubility and solution stability over pH, permeability, etc.) to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use can be administered as crystalline or amorphous products and can be obtained, for example, as solid plugs, powders, or films, by methods such as precipitation, crystallization, lyophilization, spray drying, evaporation drying, microwave drying, or high frequency drying.

[0133] Compounds of formula 1 can be administered alone or in combination with each other or with one or more pharmacologically active compounds different from the compounds of formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends, inter alia, on the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0134] Compounds of formula 1 can be administered orally. Oral administration includes swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or additionally, oral administration can include mucosal administration (e.g., buccal administration, sublingual administration, sublingual administration) such that the compound enters the bloodstream through the oral mucosa.

[0135] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, such as tablets; soft capsules or hard capsules containing multiple microparticles or nanoparticles, liquids, or powders; lozenges that can be filled with liquid; chewing gums; gels; fast-dispersing dosage forms; films; obules; sprays; and buccal patches or mucoadhesive patches, etc. Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as filling substances in soft capsules or hard capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), typically with a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and include one or more emulsifiers, suspending agents, or both. Liquid formulations can also be prepared by reconstitution of solids (e.g., from sachets).

[0136] The compound of formula 1 can also be used in fast-soluble and rapidly disintegrating dosage forms (such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986, etc.).

[0137] For tablet dosage forms, depending on the dose, the pharmaceutical active ingredient (API) can constitute from about 1 wt% to about 80 wt% of the dosage form, more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets can contain one or more disintegrants, binders, diluents, surfactants, fluidizing agents, lubricants, antioxidants, colorants, flavoring agents, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium cellulose glycolate, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 alkyl-substituted hydroxypropylcellulose, starch, α-starch, and sodium alginate. Generally, the disintegrant will constitute from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.

[0138] Binders are generally used to impart adhesion quality to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, α-starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents (such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate, etc.).

[0139] Tablets may also contain surfactants (such as sodium lauryl sulfate and polysorbate 80, etc.) and fluidizing agents (such as silicon dioxide and talc, etc.). When present, the surfactant may constitute about 0.2 wt% to about 5 wt% of the tablet, and the fluidizing agent may constitute about 0.2 wt% to about 1 wt% of the tablet.

[0140] Tablets may contain lubricants (such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate, etc.). The lubricant may constitute about 0.25 wt% to about 10 wt% or about 0.5 wt% to about 3 wt% of the tablet.

[0141] The tablet blend can be compressed directly or by roller compression to form tablets. The tablet blend or aliquots of the blend can alternatively be wet granulated, dry granulated or melt granulated, melt congealed, or extruded prior to tableting. If desired, one or more of the components can be sized by sieving or milling or both prior to blending. The final dosage form can include one or more layers and can be coated or uncoated or encapsulated. Exemplary tablets can contain up to about 80 wt% API, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant. In addition to considerations of blending, granulation, milling, sieving, tableting, coating, for a description of alternative techniques for the preparation of pharmaceutical products, see A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H.A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2d ed. , 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0142] Consumable oral films for human or animal use are flexible water-soluble or water-swellable thin film dosage forms that can be rapidly soluble or mucoadhesive. In addition to the API, typical films include one or more film-forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film components can include antioxidants, colorants, flavorants and flavor enhancers, preservatives, salivary stimulants, cooling agents, co-solvents (such as oils), emollients, bulking agents, defoamers, surfactants, and taste modifiers. Some components of the formulation can perform more than one function.

[0143] The amount of API in the film can depend on its solubility in addition to the required dosage. If water-soluble, the API will typically constitute from about 1 wt% to about 80 wt% of the non-solvent components (solute) in the film, or from about 20 wt% to about 50 wt% of the solute in the film. APIs with lower solubility can constitute a higher proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.

[0144] The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and will typically constitute from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film.

[0145] The film dosage form is typically prepared by evaporation drying of a thin aqueous film coated onto a peelable backing support or paper, which can be carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in a freeze dryer, or in a vacuum oven.

[0146] Solid formulations useful for oral administration can include immediate release formulations and modified release formulations. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. For a general description of suitable modified release formulations, see U.S. Patent No. 6,106,864. For details of other useful release technologies (such as high energy dispersion and osmotic and coated particles), see Verma et al, Pharmaceutical Technology On-line (2001) 25(2):1-14.

[0147] The compound of Formula 1 can also be administered directly into the bloodstream, muscle, or viscera of a subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, intra-articular, and subcutaneous administration. Suitable devices for parenteral administration include needle syringes (including microneedle syringes), needleless syringes, and infusion devices.

[0148] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (e.g., a pH of about 3 to about 9). However, for some applications, the compound of Formula 1 may be more preferably formulated as a sterilized non-aqueous solution or in a dry form combined with a suitable vehicle (such as sterilized pyrogen-free water). Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily achieved using standard pharmaceutical techniques.

[0149] The solubility of the compounds used in the preparation of parenteral solutions can be increased through appropriate formulation techniques (such as incorporation of solubility-enhancing agents). Formulations for parenteral administration can be formulated to provide immediate release or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compound of Formula 1 can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents, as well as semi-solids and suspensions containing drug-loaded DL-lactic acid-glycolic acid copolymer (PGLA) microspheres.

[0150] The compound of formula 1 can also be administered topically, intradermally or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers can include alcohols, water, mineral oil, petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations can also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0151] Other means of topical administration include electroporation, iontophoresis, sonophoresis, sonophoresis, and delivery by micro-needle or needle-free (e.g., Powderject™ and Bioject™) injection. Formulations for topical administration can be formulated to be immediate release or modified release as described above.

[0152] The compound of formula 1 can be administered nasally or by inhalation, typically in the form of a dry powder, an aerosol spray or a nasal drop. A dry powder can be administered using an inhaler, which can contain the API alone, a powder blend of the API and a diluent (such as lactose), or mixed component particles containing the API and a phospholipid (such as phosphatidylcholine). For nasal use, the powder can contain a bioadhesive (such as chitosan, cyclodextrin). An aerosol spray can be generated from a solution or suspension containing the API, one or more agents (such as EtOH with or without water) for dispersing, solubilizing or extending the release of the API, one or more solvents (such as 1,1,1,2 - tetrafluoroethane or 1,1,1,2,3,3,3 - heptafluoropropane) served as propellants, and optional surfactants (such as sorbitan trioleate, oleic acid or oligolactic acid, etc.) using a pressurized container, a pump, a nebulizer, an atomizer or a sprayer. An atomizer using electrohydrodynamics can be used to produce a fine mist.

[0153] Before use in the formulation of a dry powder or suspension, the pharmaceutical product is usually micronized to a particle size suitable for delivery by inhalation (typically, 90% of the particles have a maximum dimension of less than 5 microns based on volume). This can be achieved by any suitable size - reduction method (such as a spiral jet mill, a fluidized bed jet mill, supercritical fluid processing, high - pressure homogenization, or spray drying, etc.).

[0154] Capsules, blisters and cartridges (such as those made from gelatin or hydroxypropylmethylcellulose) used in inhalers or ventilators can be formulated to contain a powder mixture of the active compound, a suitable powder base (such as lactose or starch), and performance modifiers (such as L - leucine, mannitol or magnesium stearate, etc.). Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0155] A solution suitable for use in an atomizer that uses electrohydrodynamics to generate fine mist The agent contains about 1 μg to about 20 mg of API per actuation, and the actuation volume can vary from about 1 μL to about 100 μL. A typical formulation may include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0156] Formulations for inhalation, intranasal administration, or both can be formulated to provide immediate release or modified release, for example, using PGLA. Suitable flavoring agents (such as menthol and levomenthol) or sweetening agents (such as saccharin or sodium saccharin) can be added to formulations intended for inhalation / intranasal administration.

[0157] In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a measured amount. The unit is typically arranged to administer a measured dose or "single dose" containing about 10 μg to about 1000 μg of API. The total daily dose typically ranges from about 100 μg to about 10 mg, which can be administered as a single dose or more commonly as divided doses throughout the day.

[0158] The active compound can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a conventional suppository base, but various alternatives can be used if appropriate. Formulations for rectal or vaginal administration can be formulated to provide immediate release or modified release as described above.

[0159] The compound of formula 1 can also be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for administration to the eye and ear include ointments, gels, biodegradable implants (such as absorbable gel sponges, collagen), non-biodegradable implants (such as silicone), wafers, lenses, and particulate or vesicular systems (such as niosomes or liposomes). The formulations can contain one or more polymers and preservatives (such as benzalkonium chloride). Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers (such as hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (such as gelan gum). Such formulations can also be delivered by iontophoresis. Formulations for eye or ear administration can be formulated to provide immediate release or modified release as described above.

[0160] To improve solubility, dissolution rate, taste, bioavailability, or stability, the compound of formula 1 can be combined with soluble macromolecular entities (including cyclodextrins and their derivatives and polyethylene glycol-containing polymers). For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the API, cyclodextrins can be used as adjuvant additives (i.e., as carriers, diluents, or solubilizers). α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0161] As pointed out above, one or more compounds of Formula 1 (including specifically the compounds named above, as well as their pharmaceutically active complexes, salts, solvates and hydrates) can be combined with each other or with one or more other pharmaceutically active compounds to treat various diseases, conditions, and disorders. In such cases, the active compounds can be combined as described above in a single dosage form or provided in the form of a kit suitable for co-administration of the compositions. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device (such as a divided bottle or a divided foil packet) for separately holding the two pharmaceutical compositions. An example of such a kit is the well-known blister pack used for packaging tablets or capsules. The kit is suitable for administration of different dosage forms (e.g., oral and parenteral), or for administration of different pharmaceutical compositions at separate dosing intervals, or for titration of different pharmaceutical compositions with respect to each other. To assist patient compliance, the kit typically includes instructions for administration and can be provided with memory aids.

[0162] For administration to human patients, the total daily dose of the claimed and disclosed compounds typically ranges from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require only a total daily dose of about 0.1 mg to about 300 mg. The total daily dose is administered as a single dose or divided doses and may, at the discretion of the physician, deviate from the typical ranges given above. These dosages are based on an average human subject having a body weight of about 60 kg to about 70 kg, but the physician will be able to determine the appropriate dosage for patients whose body weight deviates from this weight range (e.g., infants).

[0163] As pointed out above, the compounds of Formula 1 can be used to treat diseases, disorders, and conditions for which activation of SSTR4 is indicated. Such diseases, disorders, and conditions generally relate to any unhealthy or abnormal condition in a subject for which activation of SSTR4 provides a therapeutic benefit. More particularly, the compounds of Formula 1 can be used to treat diseases, disorders or conditions of the CNS, including Alzheimer's disease, and other forms of dementia associated with one or more medical conditions (i.e., major or mild neurocognitive disorder), frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or pharmaceutical use, HIV infection, prion disease, Parkinson's disease, and Huntington's disease. The compounds of Formula 1 can also be used to treat major or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism. In addition, the compounds of Formula 1 can be used to treat anxiety and to treat epilepsy.

[0164] The claimed and disclosed compounds can be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases or conditions in which SSTR4 is implicated. Such combinations can provide significant therapeutic advantages (including fewer side effects, improved ability to treat patient populations not receiving adequate medical services, or synergistic activity). For example, the compounds of formula 1 (which include the specifically named compounds above, as well as their pharmaceutically acceptable complexes, salts, solvates and hydrates) can be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for the treatment of Alzheimer's disease (β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate, and NSAIDs such as sulindac), vitamin E, and anti-amyloid antibodies, etc.). Specific examples of compounds used in the treatment of Alzheimer's disease include donepezil, rivastigmine, memantine and galantamine.

[0165] In addition to drugs used for improving cognitive ability, the compounds of formula 1 can be combined with sedatives, hypnotics, anxiolytics, antipsychotics, psychotropics, and other pharmaceuticals used in the treatment of Alzheimer's disease. For example, the compounds of formula 1 can be used in combination with antidepressants and / or schizophrenia One or more agents (amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and dipracidone, etc.) for the treatment of a disorder (atypical antipsychotic or typical antipsychotic) can be combined.

[0166] Similarly, the compound of formula 1 can be combined with one or more agents (antianxiety agents) for the treatment of anxiety (benzodiazepines (alprazolam, chlordiazepoxide, clobazam, clonazepam, chlorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazeepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone, etc.).

[0167] The compound of formula 1 can also be combined with one or more agents (antiepileptic drugs or anticonvulsants) for the treatment of epilepsy (acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide, etc.).

[0168] Biological activity

[0169] The biological activity of the compound of Formula 1 with respect to SSTR4 can be determined using the following in vitro and in vivo methods.

[0170] Inhibition of Forskolin-stimulated cAMP in cells overexpressing SSTR4

[0171] This cell-based assay measures the ability of a compound to inhibit Forskolin-stimulated cAMP in CHO-K1 cells overexpressing SSTR4. CHO-K1 cells overexpressing SSTR4 (CHO-SSTR4) are purchased from DiscoveRx (product code 95-0059C2). CHO-SSTR4 cells are maintained in F12K medium containing 10% fetal bovine serum (Hyclone), 1% penicillin / streptomycin (Life technologies), and 800 μg / mL G418 (Life technologies). To perform the assay, 3000 cells per well are plated in 50 μL of complete medium in a white 384-well plate (Corning 3570) and the cells are allowed to adhere in a 37 °C, 5% CO 2 incubator for 16 hours. The next day, the culture medium is removed from the cells and the cells are washed (added then removed) with Krebs Ringer buffer (ZenBio, KRB-1000mL). The test compound is suspended in DMSO and diluted in stimulation buffer (Krebs Ringer buffer + 0.5% BSA (Roche), 300 μM IBMX (Sigma) and 350 nM forskolin (Sigma)). The cells are incubated for 30 minutes at room temperature in 10 μL of compound / stimulation buffer. Cellular cAMP levels are detected using the HTRF LANCE Ultra cAMP kit (Perkin Elmer, catalog number TRF0264).

[0172] Perform the assay according to the manufacturer's instructions. Add 5 μL of diluted Eu-W8044-labeled streptavidin (dilution: 1:50, in cAMP detection buffer) to each well. Then add 5 μL of diluted biotin cAMP (dilution: 1:150, in cAMP detection buffer) to each well. Cover the plate and incubate for 60 minutes at room temperature on a shaker. Read HTRF (665 nm / 615 nm) on a Perkin Elmer ENVISION plate reader. Activity Use Base for Screening Data Management to generate pEC 50 values.

[0173] SSTR4 I-125 Somatostatin Competitive Binding Assay

[0174] This membrane-based assay measures the ability of a compound to competitively inhibit the binding of I-125-labeled somatostatin to SSTR4 in membranes from CHO-K1 cells overexpressing SSTR4. Membranes from CHO-K1 cells overexpressing SSTR4 are purchased from Perkin Elmer (catalog number ES-524-M400UA). Test compounds are suspended in DMSO and then in assay buffer (25 mM HEPES (pH 7.4), 10 mM MgCl 2 , 1 mM CaCl 2, diluted in 0.5% BSA + 0.2 nM I-125-labeled somatostatin (Perkin Elmer catalog number NEX389). Add 50 μL of compound / I-125 somatostatin in assay buffer per well to a 96-well polypropylene plate. Then add 1 μg of SSTR4 membrane in 50 μL of assay buffer per well. Incubate the plate at room temperature for 60 minutes. Pre-soak a FilterMat A filter (Perkin Elmer catalog number 1450-421) in 0.5% PEI (Sigma catalog number P3143). Transfer the contents of the assay plate to the filter using a TomTech harvester and wash 5 times with 20 mM HEPES, 100 mM NaCl. Dry the filter in a microwave oven and then transfer it to a sample bag containing a scintillator sheet (Perkin Elmer catalog number 1450-441). Use a heat block to melt the scintillator sheet onto the filter. Then read the filter in a MicroBeta scintillation counter. Use Activity Base for Screening Data Management to generate a binding Ki curve and report the results as pIC 50 and report the results as pIC

[0175] SSTR1 I-125 Somatostatin Competition Binding Assay for Selectivity against SSTR4

[0176] This membrane-based assay measures the ability of a compound to competitively inhibit the binding of I-125-labeled somatostatin to SSTR1 in membranes from CHO-K1 cells overexpressing SSTR1. Membranes from CHO-K1 cells overexpressing SSTR1 are purchased from Perkin Elmer (catalog number ES-520-M400UA). Test compounds are suspended in DMSO and then in assay buffer (25 mM HEPES (pH 7.4), 10 mM MgCl 2 , 1 mM CaCl 2, dilute in 0.5% BSA + 0.4 nM I-125-labeled somatostatin (Perkin Elmer catalog number NEX389). Add 50 μL of compound / I-125 somatostatin in assay buffer per well to a 96-well polypropylene plate. Then add 10 μg of SSTR1 membrane in 50 μL of assay buffer per well. Incubate the plate at room temperature for 60 minutes. Pre-soak FilterMat A filters (Perkin Elmer catalog number 1450-421) in 0.5% PEI (Sigma catalog number P3143). Transfer the contents of the assay plate to the filters by a TomTech harvester and wash 5 times with 20 mM HEPES, 100 mM NaCl Do this. Dry the filters in a microwave oven and then transfer them to a sample bag containing a scintillator sheet (Perkin Elmer catalog number 1450-441). Use a heat block to melt the scintillator sheet onto the filters. Then read the filters in a MicroBeta scintillation counter. Use Activity Base for Screening Data Management to generate a binding Ki curve and report the results as pIC 50 Report as.

[0177] In vivo screening using subcutaneous pentylenetetrazole (PTZ)

[0178] 6 - 8 week - old Swiss - Webster mice are used in a subcutaneous PTZ seizure model. PTZ is a GABAergic agent that blocks GABA receptors, thereby disinhibiting all CNS systems and inducing seizures in animals. Seizures can be assayed and quantified by observing the animals in the study. Thus, this model provides a screening model for testing compounds with antiseizure activity (which is derived from the activity of the compound against the inhibitory receptor SSTR4) in mice. According to the method, before the start of the experiment, 6 - 8 week - old Swiss - Webster mice are acclimated to the laboratory (1 hour). Then the animals (n = 6 / group) are randomly dosed with vehicle or test compound, and 15 minutes later, PTZ is administered subcutaneously. The animals are scored based on the time it takes for seizures that impair the ability to stand to occur. The time is scored as the latency to seizures. The number and severity of seizures are also scored but not used in the final data.

Example

[0179] The following examples are illustrative and are intended to be non - limiting and represent specific embodiments of the present invention.

[0180] 1 1H nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (δ) are given as parts per million from the low - field side of tetramethylsilane using the conventional abbreviations for the names of the major peaks (s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad line)). The following abbreviations are used for common solvents. CDCl 3 (deuterochloroform), DMSO - d 6 (deuterated dimethyl sulfoxide), CD 3 OD (deuterated methanol), CD 3 CN (deuterated acetonitrile), and THF - d 8 (deuterated tetrahydrofuran). Mass spectra ([M + H] +The m / z values were recorded using either electrospray ionization (ESI-MS) mass spectrometry or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0181] When indicated, intermediate preparations and example compounds are purified by HPLC. Tables 1-3 list the equipment, materials, and conditions for some of the HPLC separations.

[0182] [Table 1]

[0183] [Table 2]

[0184] [Table 3]

[0185] In the preparations and examples, enantiomers can be separated using supercritical fluid chromatography (SFC). Table 4 lists the equipment, materials, and conditions for some of the SFC separations.

[0186] [Table 4]

[0187] In addition to HPLC, some of the preparations and examples can use flash chromatography or preparative thin layer chromatography (TLC). Preparative TLC is typically run on silica gel 60 F 254 plates.

[0188] After isolation by chromatography, the solvent can be removed and the product dried in a centrifugal evaporator (e.g., GeneVac™), rotary evaporator, evacuated flask, etc. Reactions in an inert atmosphere (e.g., nitrogen) or reactive atmosphere (e.g., H 2 ) are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0189] Preparation 1: Methyl 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoate

[0190] [Chemical formula]

[0191] Diisopropyl azodicarboxylate (1.02 g, 5.04 mmol) was slowly added to a solution of 3-methylpyridin-2-ol (0.500 g, 4.58 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (0.606 g, 4.58 mmol), and triphenylphosphine (1.32 g, 5.04 mmol) in THF (6 mL) at 0 °C. The solution was warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 solution (2×) and brine. The organic layer was dried over Na 2 SO 4 and filtered, then concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography eluting with a gradient of 0–100% EtOAc in heptane. The fractions containing the desired product were evaporated to give the title compound (0.324 g, 33%). ESI-MS [M+H] + C 12 H 17 NO 3 calculated for, 224.12; found, 224.1.

[0192] Preparation 2: 2,2-Dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid

[0193] [Chemical formula]

[0194] A solution of methyl 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoate (0.324 g, 1.52 mmol) in THF (8.13 mL) and water (2.71 mL) was treated with lithium hydroxide hydrate (0.183 g, 7.66 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (0.321 g, quantitative), which was used without further purification. ESI-MS [M+H] + C 11 H 15 NO 3 Calculated for, 210.1 1; Found, 210.1.

[0195] Preparation 3: 3-(2-Ethylphenoxy)-2,2-dimethylpropanoic acid

[0196] [Chemical formula]

[0197] To methyl 2,2-dimethyl-3-(tosyloxy)propanoate (0.800 g, 2.79 mmol) in DMF (5 mL) were added 2-ethylphenol (0.683 g, 5.59 mmol) and Cs 2 CO 3 (1.82 g, 5.59 mmol). The solution was heated at 80 °C overnight, then quenched with water, acidified to pH 2 with concentrated HCl, extracted with EtOAc, and washed with brine. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound as a semi-solid (0.200 g, 32%). This was used without further purification. ESI-MS [M+H] + C 13 H 18 O 3 Calculated for, 223.13; found, 223.1.

[0198] Preparation 4: 2-(4-Aminopiperidin-1-yl)-1-(4-chlorophenyl)ethan-1-one

[0199]

Chemical Structure

[0200] Step A: tert-Butyl (1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)carbamate

[0201]

Chemical Structure

[0202] To a solution of tert-butyl piperidin-4-ylcarbamate (2.00 g, 9.99 mmol) and DIPEA (1.78 mL, 10.3 mmol) in THF (10 mL) was added 2-bromo-1-(4-chlorophenyl)ethanone (2.20 g, 9.42 mmol). The reaction mixture was heated in a sealed tube at 90 °C overnight, then cooled and extracted into EtOAc and washed sequentially with 1 N NaOH and brine. The combined organic layers were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure to afford the title compound as an off-white semi-solid (3.32 g, presumed quantitative). ESI-MS [M+H] + C 18 H 25 ClN 2 O 3 Calculated for 353.16; found, 354.3.

[0203] Step B: 2-(4-Aminopiperidin-1-yl)-1-(4-chlorophenyl)ethan-1-one To a solution of tert-butyl (1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)carbamate (3.32 g, 9.41 mmol) in methanol (20 mL) was added 6N HCl in methanol (7.84 mL, 47.0 mmol). The reaction mixture was stirred until the reaction was complete and then concentrated to remove the excess methanol. The white precipitate formed was collected by filtration and dried to give the title compound (1.5 g, 63%).

[0204] Preparation 5: 1-(Hydroxymethyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0205]

Chem.

[0206] Step A: (1-((Benzyloxy)methyl)cyclopropyl)methanol

[0207]

Chem.

[0208] Sodium hydride (60 wt%, 1.261 g, 31.5 mmol) was added in one portion to a solution of cyclopropane-1,1-diyl dimethanol (2.30 g, 28.7 mmol) in DMF (71.7 mL) at 0 °C. The solution was stirred for 15 minutes and then (bromoethyl)benzene (3.38 mL, 28.3 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was quenched with saturated aqueous NH 4 Cl and extracted with Et 2 O, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude material was purified by automated flash silica column chromatography eluting with 40% EtOAc in heptane to give the title compound (3.115 g, 57%).

[0209] Step B: 1-((Benzyloxy)methyl)cyclopropane-1-carboxylic acid

[0210]

Chem.

[0211] H 2 SO 4 A solution of 2 M CrO in aqueous solution 3 (15.23 mL, 30.5 mmol, 2.1 equiv) was slowly added dropwise at room temperature to a stirred solution of (1-((benzyloxy)methyl)cyclopropyl)methanol (2.788 g, 14.50 mmol) in acetone (48.3 mL). The reaction mixture was stirred for 30 minutes and then quenched with isopropanol (1 mL). The mixture was stirred for 10 minutes and then concentrated under reduced pressure. The crude material was taken up in water and extracted with Et 2 O, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound (2.688 g, 90%) as a white crystalline solid.

[0212] Step C: 1-((Benzyloxy)methyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0213]

Chem.

[0214] To a solution of 1-methylpiperidin-4-amine (2.232 g, 19.6 mmol) and 1-((benzyloxy)methyl)cyclopropane-1-carboxylic acid (2.688 g, 13.03 mmol) in DMF (65.2 mL) were added HATU (7.43 g, 19.6 mmol) and DIPEA (6.83 mL, 39.1 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with water, extracted with EtOAc, washed with brine, and dried over Na 2 SO 4It was dried over, filtered, and concentrated under reduced pressure. The crude material was purified by automated flash silica column chromatography eluting with 80% EtOAc in heptane to afford the title compound as a pale yellow solid (2.805 g, 71%).

[0215] Step D: 1-(Hydroxymethyl)-N-(1-methylpiperidin-4-yl)cycl opropane-1-carboxamide

[0216] A solution of 1-((benzyloxy)methyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide (2.805 g, 9.28 mmol) and Pd-C (10 wt%, 0.987 g, 0.928 mmol) in methanol (105 mL) and EtOAc (10.54 mL) was stirred under a hydrogen atmosphere for 3 h. The solution was filtered through Celite® and concentrated in vacuo to afford the title compound, which was used without further purification (1.97 g, presumed quantitative). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.11 (br s, 1 H), 5.06 (br s , 1 H), 3.86 - 3.77 (m, 1 H), 3.58 - 3.49 (m, 2 H), 3.47 - 3.38 (m, 2 H), 3.10 - 2.98 (m, 2 H), 3.11 (s, 3 H), 1.98 - 1.86 (m, 2 H), 1.68 - 1.56 (m, 2H); ESI-MS [M+H] + C 11 H 20 N 2 O 2 For calculated, 213.16; found, 213.20.

[0217] Preparation 6: Methyl 2,2-dimethyl-3-(tosyloxy)propanoate

[0218] [Chemical formula]

[0219] To a mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (0.962 mL, 7.57 mmol) and DMAP (0.092 g, 0.76 mmol) in pyridine (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (1.44 g, 7.57 mmol). The reaction mixture was stirred overnight at room temperature. Hexane (100 mL) was added. The white precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude residue was taken up in hexane (50 mL), and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.9 g, 88%) as a clear oil. 1 H N MR (400 MHz, CDCl 3 ) δ ppm 1.20 (s, 6 H), 1.21 (s, 1 H), 2.47 (s, 3 H), 3.63 (s, 3 H), 4.02 (s, 2 H), 7.37 (d, J = 7.8 Hz, 2 H), 7.77 - 7. 81 (m, 2 H); ESI-MS [M+H] + C 13 H 18 O 5 Calculation for value, 287.1; found, 287.1.

[0220] Preparation 7: Methyl 3-(2-chlorophenoxy)-2,2-dimethylpropanoate

[0221] [Chemical formula]

[0222] A 500 mL three-necked round-bottom flask was charged with 2-chlorophenol (5.00 g, 38.9 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (5.14 g, 38.9 mmol), and toluene (100 mL). The resulting solution was cooled to 2 °C under nitrogen. Triphenylphosphine (10.20 g, 38.9 mmol) was added. Next, DIAD (7.56 mL, 38.9 mmol) was added over 20 minutes. The reaction mixture was heated to 80 °C for 15 hours and then cooled to room temperature. The mixture was washed with 1 M aqueous NaOH solution (20 mL) and rinsed with MTBE. The organic phase was washed with 1 M aqueous HCl solution (20 mL) and water (20 mL). The solid was removed by filtration. The filtrate was concentrated to dryness, diluted with heptane (20 mL), filtered to remove the solid, and rinsed with heptane (40 mL). The combined filtrates were concentrated and dried under reduced pressure to give a pale yellow oil (9.44 g, presumed to be quantitative) and used without further purification. ESI-MS [M+H] aOH aqueous solution (20 mL), rinsed with MTBE. The organic phase was washed with 1 M aqueous HCl solution (20 mL) and water (20 mL). The solid was removed by filtration. The filtrate was concentrated to dryness, diluted with heptane (20 mL), filtered to remove the solid, and rinsed with heptane (40 mL). The combined filtrates were concentrated and dried under reduced pressure to give a pale yellow oil (9.44 g, presumed to be quantitative) and used without further purification. ESI-MS [M+H] + C 12 H 15 ClO 3 Calculated for, 243.079; Found, 243.10.

[0223] Preparation 8: Methyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenoxy)propanoate

[0224]

Chemical formula

[0225] The title compound was prepared in a manner similar to Preparation 7 using 2-(trifluoromethyl)phenol (0.500 g, 3.08 mmol) instead of 2-chlorophenol. The product was isolated as a peach-colored liquid (642.9 mg, 75%). ESI-MS [M+H] + C 13 H 15 F 3 O 3Calculated value for, 277.10; Measured value, 277.1.

[0226] Preparation 9: Methyl 3-(4-cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethylpropanoate

[0227]

Chem.

[0228] Preparation 10: Methyl 2,2-dimethyl-3-phenoxypropanoate

[0229]

Chem.

[0230] The title compound (184 mg, 17%) was prepared in a manner similar to Preparation 7 using phenol (0.500 g, 5.31 mmol) instead of 2-chlorophenol. ESI-MS [M+H] + C 12 H 16 O 3 Calculated value for, 209.12; Measured value, 209.2.

[0231] Preparation 11: 3-(2-Chlorophenoxy)-2,2-dimethylpropanoic acid

[0232]

Chem.

[0233] To a solution of methyl 3-(2-chlorophenoxy)-2,2-dimethylpropanoate (9.44 g, 38.9 mmol) in MeOH (50 mL) was added water (15 mL) and lithium hydroxide (1.863 g, 78.0 mmol). The reaction mixture was stirred at room temperature for 2 h. THF (10 mL) was added to improve mixing and the reaction mixture was stirred at room temperature for an additional 2.5 h and at 40 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated to about 45 g under reduced pressure. The concentrate was partitioned between water and toluene and extracted with toluene. The aqueous phase was acidified to pH 1 with HCl and then extracted with EtOAc. The combined organic layers were washed with water, concentrated and dried under reduced pressure to afford the title compound (7.30 g, 82%) as a pale yellow crystalline solid. ESI-MS [M+H] + C 11 H 13 ClO 3 Calculated for, 229.06; found, 229.0.

[0234] Preparation 12: 2,2-Dimethyl-3-(2-(trifluoromethyl)phenoxy)propanoic acid

[0235]

Chem.

[0236] A solution of methyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenoxy)propanoate (642.9 mg, 2.327 mmol) in a mixture of methanol (8.73 mL) and water (2.91 mL) was treated with lithium hydroxide hydrate (391 mg, 9.31 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then acidified with 1 M aqueous HCl and extracted with DCM. The organic phase was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to afford the title compound (391.4 mg, 64%) as a colorless oil. ESI-MS [M+H] + C 12 H 13 F 3 O3 Calculated value for it: 263.10; Measured value, 263.1.

[0237] Preparation 13: 3-(4-Cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethylpropanoic acid

[0238]

Chem.

[0239] To a solution of methyl 3-(4-cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethylpropanoate (412 mg, 1.37 mmol) in THF (7 mL) and water (2.33 mL) was added lithium hydroxide (164 mg, 6.84 mmol). The reaction mixture was stirred at room temperature overnight and then acidified with 1 M aqueous HCl and extracted with DCM. The organic phase was washed with brine and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound (200 mg, 51%).

[0240] Preparation 14: 2,2-Dimethyl-3-phenoxypropanoic acid

[0241]

Chem.

[0242] The title compound (114 mg, 66%) was prepared in a manner similar to Preparation 13 using methyl 2,2-dimethyl-3-phenoxypropanoate (184 mg, 0.888 mmol) instead of methyl 3-(4-cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethylpropanoate.

[0243] Preparation 15: 3-Hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0244]

Chem.

[0245] Methyl 3-hydroxy-2,2-dimethylpropanoate (1.736 g, 13.14 mmol) and 1-methylpiperidin-4-amine (1.00 g, 8.76 mmol) were combined in a 30 mL microwave vial to give a brown solution. The reaction mixture was heated at 190 °C for 3 days and then purified by automated flash silica column chromatography (60 g NH column) eluting with a gradient of 0 - 10% MeOH in DCM. The fractions containing the desired product were evaporated to give the title compound (1.0 g, 53%) as a yellowish brown solid. ESI-MS [M+H] + C 11 H 22 N 2 O 2 Calculated for, 215.17; found 215.2.

[0246] Preparation 16: Methyl 3-((3-cyanopyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0247]

Chemical Structure

[0248] To a 125 mL round bottom flask was added 2-hydroxynicotinonitrile (0.300 g, 2.50 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (0.660 g, 5.00 mmol) and THF (20 mL) to give a brown solution. The reaction mixture was cooled to 0 °C. Triphenylphosphine (1.31 g, 5.00 mmol) and DIAD (0.984 mL, 5.00 mmol) were added and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was treated with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO 4 and filtered, and concentrated under reduced pressure. The residue was purified by automated flash silica column Purified by mu chromatography (40 g column). The fraction was evaporated to give the title compound (0.585 g, presumed to be quantitative) as a colorless syrup.

[0249] Preparation 17: 3 - ((3 - cyanopyridin - 2 - yl)oxy)-2,2 - dimethylpropanoic acid

[0250]

Chem.

[0251] Methyl 3 - ((3 - cyanopyridin - 2 - yl)oxy)-2,2 - dimethylpropanoate (0.583 g, 2.49 mmol) and dioxane (12 mL) were combined in a 250 mL round - bottom flask to give a colorless solution. To this solution, 2 M aqueous LiOH (4.98 mL, 9.96 mmol) was added. The reaction mixture was stirred at room temperature overnight, then acidified to pH 5 with 1 N aqueous HCl and concentrated to dryness to give the title compound (0.548 g, presumed to be quantitative) as a pink film. ESI - MS [M + H] + C 11 H 12 N 2 O 3 Calculated for, 221.09; found, 221.1.

[0252] Preparation 18: (R)-3 - hydroxy - 2,2 - dimethyl - N-(1 - methylpyrrolidin - 3 - yl)propanamide

[0253]

Chem.

[0254] A solution of 3-hydroxy-2,2-dimethylpropanoic acid (0.517 g, 4.37 mmol), (R)-1-methylpyrrolidin-3-amine (0.438 g, 4.37 mmol), HATU (1.829 g, 4.81 mmol) and DIPEA (1.52 mL, 8.75 mmol) in DMF (5 mL) was stirred overnight at room temperature in a 100 mL round-bottom flask. The reaction mixture was concentrated under reduced pressure and the residue was purified by automated flash silica column chromatography (30 g NH column) eluting with a gradient of 0 - 5% MeOH in DCM. The fractions containing the desired product were evaporated to give the title compound (0.819 g, 94%) as a yellowish-brown syrup. ESI-MS [M+H] + C 10 H 20 N 2 O 2 Calculated for, 201.16; Found, 201.1.

[0255] Preparation 19: Methyl 3-((5-bromopyrimidin-4-yl)oxy)-2,2-dimethylpropanoate

[0256]

Chem.

[0257] DMF (8 mL) was added to a 100 mL round-bottom flask containing sodium hydride (60 wt%, 0.155 g, 3.88 mmol) to give a white suspension. Methyl 3-hydroxy-2,2-dimethylpropanoate (0.342 g, 2.58 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. Then a solution of 5-bromo-4-chloropyrimidine (0.500 g, 2.58 mmol) in DMF (2 mL) was added. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic phase was washed with brine and dried over MgSO 4It was dried, filtered, and concentrated over. The residue was purified via automated flash silica column chromatography (40 g column) eluting with a gradient of 20 - 50% EtOAc in heptane. The fractions containing the desired product were evaporated to give the title compound (0.362 g, 48%) as a brown syrup. ESI-MS [M+H] + C 10 H 13 BrN 2 O 3 Calculated for, 289.0 2, 291.02; Found 291.0.

[0258] Preparation 20: Methyl 3 - ((5 - cyclopropylpyrimidin - 4 - yl)oxy)-2,2 - dimethylpropanoate

[0259]

Chemical Structure

[0260] Methyl 3 - ((5 - bromopyrimidin - 4 - yl)oxy)-2,2 - dimethylpropanoate (0.362 g, 1.25 mmol), cyclopropylboronic acid (0.129 g, 1.50 mmol), 2 M Na 2 CO 3 aqueous solution (2.50 mL, 5.01 mmol), Pd(dppf)Cl 2 (0.102 g, 0.125 mmol), 1,2 - dimethoxyethane (6 mL) and water (2.5 mL) were combined in a 20 mL microwave vial to give a yellow - brown suspension. The reaction mixture was irradiated in a Biotage® microwave reactor at 130 °C for 90 minutes. The mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO 4 and filtered and concentrated to give the crude title compound (0.313 g, presumed quantitative) as a yellow - brown film and used without purification. ESI-MS [M+H] + C 13 H 18 N 2 O 3Calculated value for, 251.13; Measured value, 251.4.

[0261] Preparation 21: 3 - ((5 - Cyclopropylpyrimidin - 4 - yl)oxy)-2,2 - dimethylpropanoic acid

[0262]

Chem.

[0263] To a 250 mL round - bottom flask charged with methyl 3 - ((5 - cyclopropylpyrimidin - 4 - yl)oxy)-2,2 - dimethylpropanoate (0.313 g, 1.25 mmol), 2 M aqueous LiOH solution (2.50 mL, 5.01 mmol) and dioxane (8 mL) were added to obtain a yellow - brown solution. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to obtain the title compound (0.296 g, presumed to be quantitative) and this was used without further purification. ESI - MS [M + H] + C 12 H 16 N 2 O 3 Calculated value for, 237.12; Measured value, 237.4.

[0264] Preparation 22: 1 - (Hydroxymethyl)-N-(1 - methylpiperidin - 4 - yl)cyclobutane - 1 - carboxamide

[0265]

Chem.

[0266] In a 100 mL round-bottom flask, 1-(hydroxymethyl)cyclobutanecarboxylic acid (0.500 g, 3.84 mmol), 1-methylpiperidin-4-amine (0.439 g, 3.84 mmol), HATU (1.607 g, 4.23 mmol), DIPEA (2.008 mL, 11.53 mmol) and DMF (6 mL) were combined to give a yellow solution. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified by automated silica column chromatography (60 g NH column) eluting with a gradient of 0 - 5% MeOH in DCM. The fractions containing the desired product were evaporated to give the title compound as a white film. ESI-MS [M+H] + C 12 H 22 N 2 O 2 Calculated for, 227.18; Found, 227.2.

[0267] Preparation 23: Methyl 3-((3-bromo-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0268]

Chem.

[0269] The title compound was prepared in a manner similar to Preparation 19 using 3-bromo-2-fluoro-5-methylpyridine (0.500 g, 2.63 mmol) instead of 5-bromo-4-chloropyrimidine. The product was isolated as a colorless syrup (0.452 g, 57%). ESI-MS [M+H] + C 12 H 16 BrNO 3 Calculated for, 302 .04; Found, 302.1.

[0270] Preparation 24: Methyl 3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0271] [Chemical formula]

[0272] The title compound was prepared in a manner similar to Preparation 20 using methyl 3-((3-bromo-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate (0.452 g, 1.50 mmol) instead of methyl 3-((5-bromopyrimidin-4-yl)oxy)-2,2-dimethylpropanoate. The product was purified by automated flash silica column chromatography (40 g column) eluting with a gradient of 20 - 50% EtOAc in heptane to afford the title compound (0.277 g, 70%) as a colorless syrup. ESI-MS [M+H] + C 15 H 21 NO 3 Calculated for, 2 64.16; Found, 264.5.

[0273] Preparation 25: 3-((3-Cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid

[0274] [Chemical formula]

[0275] The title compound was prepared in a manner similar to Preparation 21 using methyl 3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate (0.277 g, 1.05 mmol) instead of methyl 3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethylpropanoate. The product (0.263 g, presumed to be quantitative) was used without further purification. ESI-MS [M +H] + C 14 H 19 NO 3 Calculated for, 250.14; Found, 250.4 .

[0276] Preparation 26: Methyl 3-((5-bromo-3-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0277] [Chemical formula]

[0278] The title compound was prepared in a manner similar to Preparation 19, using 5-bromo-2-fluoro-3-methylpyridine (0.500 g, 2.63 mmol) instead of 5-bromo-4-chloropyrimidine. The product was isolated as a colorless syrup (0.795 g, presumed to be quantitative) and used without purification. ESI-MS [M+H] + C 12 H 16 BrNO 3 Calculated for, 302.04; Found, 302.0.

[0279] Preparation 27: Methyl 3-((5-cyclopropyl-3-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0280] [Chemical formula]

[0281] The title compound was prepared in a manner similar to Preparation 20, using methyl 3-((5-bromo-3-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate (0.795 g, 2.63 mmol) instead of methyl 3-((5-bromopyrimidin-4-yl)oxy)-2,2-dimethylpropanoate. The product was purified by automated flash silica column chromatography (40 g column) eluting with 20% EtOAc in heptane to give a colorless film (0.114 g, 16%). ESI-MS [M+H] + C 15 H 21 NO 3Calculated value for, 264.16; Measured value, 264 .4.

[0282] Preparation 28: 3-((5-Cyclopropyl-3-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid

[0283]

Chem.

[0284] The title compound was prepared in a manner similar to Preparation 21 using methyl 3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate (0.114 g, 0.433 mmol) instead of methyl 3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethylpropanoate. The product (0.108 g, presumed to be quantitative) was used without further purification. ESI-MS M+H] + C 14 H 19 NO 3 Calculated value for, 250.14; Measured value, 250. 4.

[0285] Preparation 29: Methyl 3-((3-bromo-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0286]

Chem.

[0287] The title compound was prepared in a manner similar to Preparation 19 using 3-bromo-2-fluoro-6-methylpyridine (0.500 g, 2.63 mmol) instead of 5-bromo-4-chloropyrimidine. The product was isolated as a colorless syrup (0.795 g, presumed to be quantitative) and used without purification. ESI-MS [M+H] + C 12 H 16 BrNO3 Calculated value for, 302.04; Measured value, 302.0.

[0288] Preparation 30: Methyl 3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0289]

Chem.

[0290] The title compound was prepared in a manner similar to Preparation 20, using methyl 3-((3-bromo-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate (0.795 g, 2.63 mmol) instead of methyl 3-((5-bromopyrimidin-4-yl)oxy)-2,2-dimethylpropanoate. The product (0.693 g, presumed to be quantitative) was used without further purification. ESI-MS [M+H] + C 15 H 21 NO 3 Calculated value for, 264.16; Measured value, 264.5.

[0291] Preparation 31: 3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid

[0292]

Chem.

[0293] The title compound was prepared in a manner similar to Preparation 21, using methyl 3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoate (0.693 g, 2.63 mmol) instead of methyl 3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethylpropanoate. The product (0.656 g, presumed to be quantitative) was used without further purification. ESI-MS [M +H] + C14 H 19 NO 3 Calculated value for, 250.14; Measured value, 250.4 .

[0294] Preparation 32: Methyl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate

[0295]

Chemical formula

[0296] To a mixture of methyl 3-hydroxy-2,2-dimethyl-propanoate (3.60 g, 27.2 mmol) in DMF (30 mL) was added NaH (60 wt%, 1.45 g, 36.3 mmol). The mixture was stirred at room temperature for 30 minutes. Next, 2-fluoro-3-(trifluoromethyl)pyridine (3.00 g, 18.2 mmol) was added and the reaction mixture was stirred at room temperature overnight and then poured into water and acidified to pH 6 with 1 M aqueous HCl (10 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure to obtain a crude product, which was purified by flash silica column chromatography eluting with petroleum ether and EtOAc to give the title compound (2.2 g, 43%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.33 (s, 6 H), 3.69 (s, 3 H), 4.41 (s, 2 H), 6.90 - 7.03 (m, 1 H), 7. 85 (br d, J = 6.8 Hz, 1 H), 8.30 (br d, J = 4.4 Hz, 1 H); ESI-MS [M+H] + C 12 H 14 F 3 NO 3 Calculation for Value, 278.10; Measured value, 277.9.

[0297] Preparation 33: 2,2-Dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid

[0298]

Chem.

[0299] To a solution of methyl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate (2.2 g, 7.94 mmol) in dioxane (22 mL) was added 2 M aqueous lithium hydroxide solution (11.90 mL, 23.8 mmol). The reaction mixture was stirred at room temperature overnight and then acidified to pH 5 with 1 M aqueous HCl and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na 2SO 2 SO 4 4, filtered, and concentrated under reduced pressure to give the title compound (1.7 g, 80%) as a yellow solid. 1 1H NMR (400 MHz, CDCl 3 3) δ ppm 1.37 (s, 6 H), 4.43 (s, 2 H), 6.93 - 7.02 (m, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 8.30 (d, J = 4.5 Hz, 1 H); ESI-MS [M+H] + 12C 11 11H 12 3F 3 1N1O 3 Calculated for C12H11F3NO2: 264.08; Measured value, 263.9.

[0300] Preparation 34: trans-3-(4-Chlorophenyl)-1-methyl-4-nitropyrrolidine

[0301]

Chem.

[0302] In a 250 mL round-bottom flask, (E)-1-chloro-4-(2-nitrovinyl)benzene (2.00 g, 10.9 mmol), 2-(methylamino)acetic acid (2.426 g, 27.2 mmol), and paraformaldehyde (1.963 g, 65.4 mmol) were combined in toluene (120 mL) to obtain a green solution. The mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 20 - 50% EtOAc in heptane. The fractions were evaporated to give the title compound (2.01 g, 77%) as a pale brown syrup. ESI-MS [M+H] + C 11 H 13 ClN 2 O 2 Calculated for, 241.07; found, 241.1.

[0303] Preparation 35: trans-4-(4-chlorophenyl)-1-methylpyrrolidin-3-amine

[0304] [Chemical Structure]

[0305] In a 250 mL round-bottom flask, trans-3-(4-chlorophenyl)-1-methyl-4-nitropyrrolidine (2.01 g, 8.35 mmol) and zinc (4.37 g, 66.8 mmol) were combined in ethanol (23 mL) and acetic acid (23 mL) to obtain a gray suspension. The mixture was stirred at 60 °C overnight and then filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in DCM and treated with saturated aqueous NaHCO 3 . The organic phase was concentrated, and the residue was purified by automated flash silica column chromatography (80 g NH column) eluting with a gradient of 0 - 10% MeOH in DCM. The fractions were evaporated to give the title compound (1.13 g, 64%) as a brown syrup. ESI-M S [M+H] + C 11 H15 ClN 2 Calculated value for, 211.09; Measured value, 211.1.

[0306] Preparation 36: trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-hydroxy-2,2-dimethylpropanamide

[0307]

Chemical formula

[0308] In a 250 mL round-bottom flask, 3-hydroxy-2,2-dimethylpropanoic acid (0.634 g, 5.36 mmol), trans-4-(4-chlorophenyl)-1-methylpyrrolidin-3-amine (1.13 g, 5.36 mmol), HATU (2.447 g, 6.44 mmol) and DIPEA (2.80 mL, 16.1 mmol) were combined in DMF (12 mL) to obtain a yellow solution. The reaction mixture was stirred overnight at room temperature. The mixture was treated with water and extracted with EtOAc. The organic phase was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 0-10% MeOH in DCM. The fractions were evaporated to give the title compound as a syrup (1.36 g, 82%). ESI-MS [M+H] + C 16 H 23 ClN 2 O 2 Calculated value for, 311.14; Measured value, 311.4.

[0309] Preparation 37: 2-nitro-1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-ol

[0310]

Chemical formula

[0311] In a 250 mL round-bottom flask, 6-(trifluoromethyl)nicotinaldehyde (5.05 g, 28.8 mmol) and triethylamine (4.02 mL, 28.8 mmol) were dissolved in nitromethane (37.1 mL, 681 mmol) to obtain a yellow solution. The mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure and purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 0 - 5% MeOH in DCM. The fractions were evaporated to give the title compound as an off-white solid (6.47 g, 95%). ESI-MS [M+H] + C 8 H 7 F 3 N 2 O 3 Calculated for, 237.05; found, 237.1.

[0312] Preparation 38: (E)-5-(2-Nitrovinyl)-2-(trifluoromethyl)pyridine

[0313]

Chem.

[0314] In a 250 mL round-bottom flask, 2-nitro-1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (6.47 g, 27.4 mmol) was dissolved in DCM (100 mL) to obtain a yellow solution. Acetic anhydride (2.59 mL, 27.4 mmol) and N,N-dimethylpyridin-4-amine (0.167 g, 1.37 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h and then treated with saturated aqueous NaHCO 3 The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic phases were concentrated under reduced pressure and purified by automated flash chromatography (80 g column) eluting with a gradient of 10 - 20% EtOAc in heptane. The fractions were evaporated to give the title compound as a yellow solid (5.74 g, 96%). ESI-MS [M+H] + C 8 H 5 F3 N 2 O 2 Calculated value for, 219.03; measured value, 219.04.

[0315] Preparation 39: trans-5-(1-Methyl-4-nitropyrrolidin-3-yl)-2-(trifluoromethyl)pyridine

[0316]

Chem.

[0317] The title compound was prepared in a manner similar to Preparation 34 using (E)-5-(2-nitrovinyl)-2-(trifluoromethyl)pyridine (5.74 g, 23.6 mmol) instead of (E)-1-chloro-4-(2-nitrovinyl)benzene. The product was isolated as a yellowish-brown syrup (5.88 g, 81%). ESI-MS [M+H] + C 11 H 12 F 3 N 3 O 2 Calculated value for, 276.09; measured value, 276.2.

[0318] Preparation 40: trans-1-Methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine

[0319]

Chem.

[0320] The title compound (3.94 g, 75%) was prepared in a manner similar to Preparation 35 using trans-5-(1-methyl-4-nitropyrrolidin-3-yl)-2-(trifluoromethyl)pyridine (5.88 g, 21.4 mmol) instead of trans-3-(4-chlorophenyl)-1-methyl-4-nitropyrrolidine. ESI-MS [M+H] + C 11 H14F 3N 3 Calculated value for, 246.11; Measured value, 246.1.

[0321] Preparation 41: trans-3-Hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide amide

[0322]

Chem.

[0323] The title compound was prepared in a manner similar to Preparation 36 using trans-1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (2.0 g, 5.3 mmol) instead of trans-4-(4-chlorophenyl)-1-methylpyrrolidin-3-amine. The product was isolated as a brown syrup (1.5 g, 82%). ESI-MS [M+H] + C 16 H 22 F 3 N 3 O 2 Calculated value for, 3 46.17; Measured value, 346.5.

[0324] Preparation 42: 1-(6-Methylpyridin-3-yl)-2-nitroethan-1-ol

[0325]

Chem.

[0326] The title compound was prepared in a manner similar to Preparation 37 using 6-methylnicotinaldehyde (4.90 g, 40.5 mmol) and triethylamine (5.64 mL, 40.5 mmol) in nitromethane (52.1 mL, 955 mmol). The product was isolated as an off-white solid (6.1 g, 83%). ESI-MS [M+H] + C 8 H10 N 2 O 3 Calculated value for, 183.07; measured value, 183.01.

[0327] Preparation 43: (E)-2-Methyl-5-(2-nitrovinyl)pyridine

[0328]

Chemical formula

[0329] The title compound was prepared in a manner similar to Preparation 38, using 1-(6-methylpyridin-3-yl)-2-nitroethan-1-ol (6.10 g, 33.5 mmol) instead of 2-nitro-1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-ol. The product was isolated as a yellow solid (4.35 g, 79%). ESI-MS [M+H] + C 8 H 8 N 2 O 2 Calculated value for, 165.06; measured value, 165.1.

[0330] Preparation 44: trans-2-Methyl-5-(1-methyl-4-nitropyrrolidin-3-yl)pyridine

[0331]

Chemical formula

[0332] The title compound was prepared in a manner similar to Preparation 34, using (E)-2-methyl-5-(2-nitrovinyl)pyridine (4.35 g, 26.5 mmol) instead of (E)-1-chloro-4-(2-nitrovinyl)benzene. The product was isolated as a yellowish-brown syrup (4.23 g, 72%). ESI-MS [M+H] + C 11 H 15 N 3 O 2Calculated value for, 222.12; Measured value, 222.1.

[0333] Preparation 45: trans-1-Methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-amine

[0334]

Chem.

[0335] The title compound was prepared in a manner similar to Preparation 35, using trans-2-Methyl-5-(1-methyl-4-nitropyrrolidin-3-yl)pyridine (4.23 g, 19.1 mmol) instead of trans-3-(4-chlorophenyl)-1-methyl-4-nitropyrrolidine. The product was isolated as a yellowish-brown syrup (2.15 g, 59%). ESI-MS [M+H] + C 11 H 17 N 3 Calculated value for, 192.14; Measured value, 192.1.

[0336] Preparation 46: trans-3-Hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide

[0337]

Chem.

[0338] The title compound was prepared in a manner similar to Preparation 36, using trans-1-Methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-amine (1.02 g, 5.33 mmol) instead of trans-4-(4-chlorophenyl)-1-methylpyrrolidin-3-amine. The product was isolated as a yellowish-brown syrup (1.14 g, 73%). ESI-MS [M+H] + C 16 H 25 N 3 O 2Calculated value for, 292.19; Measured value, 292.2.

[0339] Preparation 47: trans-1-Methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine

[0340]

Chemical formula

[0341] Step A: 1-(1-Methyl-1H-pyrazol-4-yl)-2-nitroethan-1-ol

[0342]

Chemical formula

[0343] In a 250 mL round-bottom flask, 1-methyl-1H-pyrazole-4-carbaldehyde (5.00 g, 45.4 mmol) was dissolved in nitromethane (55 mL) to obtain a pale yellow solution. Triethylamine (6.33 mL, 45.4 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Excess nitromethane was removed to obtain the title compound (7.77 g, presumed to be quantitative) as a crude residue, which was used without further purification. ESI-MS [M+H] + C 6 H 9 N 3 O 3 Calculated value for, 172. 07; Measured value, 172.2.

[0344] Step B: (E)-1-Methyl-4-(2-nitrovinyl)-1H-pyrazole

[0345]

Chemical formula

[0346] In a 250 mL round-bottom flask, 1-(1-methyl-1H-pyrazol-4-yl)-2-nitroethan-1-ol (7.77 g, 45.4 mmol) was dissolved in DCM (100 mL) to obtain a brown solution. Acetic anhydride (4.29 mL, 45.4 mmol) and DMAP (0.277 g, 2.27 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then quenched with water. The organic layer was separated, and the aqueous phase was extracted with DCM (40 mL). The combined organic layers were washed with saturated aqueous NH 4 Cl, dried over MgSO 4 , filtered, and concentrated under reduced pressure to obtain the title compound (6.66 g, 96%) as a brown solid, which was used without further purification. ESI-MS [M+H] + C 6 H 7 N 3 O 2 calculated for, 154.05; found, 154.2.

[0347] Step C: 4-(trans-1-benzyl-4-nitropyrrolidin-3-yl)-1-methyl-1H-pyrazole

[0348]

Chemical Structure

[0349] In a 250 mL round-bottom flask, (E)-1-methyl-4-(2-nitrovinyl)-1H-pyrazole (3.00 g, 19.6 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (7.07 g, 29.8 mmol) were combined in DCM (35 mL) to obtain a yellowish-brown solution. The reaction mixture was cooled to 0 °C, and TFA (0.150 mL, 1.96 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC method A to obtain the title compound (0.862 g, 15%) as a colorless syrup. ESI-MS [M+H] + C 15 H 18 N 4O 2 Calculated value for it is 287.15; measured value, 287.4.

[0350] Step D: trans-1-benzyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine

[0351]

Chemical formula

[0352] In a 125 mL round-bottom flask, a gray suspension of 4-(trans-1-benzyl-4-nitropyrrolidin-3-yl)-1-methyl-1H-pyrazole (0.862 g, 3.01 mmol) and zinc powder (1.575 g, 24.08 mmol) in methanol (8 mL) and acetic acid (8 mL) was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in DCM, neutralized with aqueous ammonium hydroxide, and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (30 g NH column) eluting with a gradient of 0 - 10% methanol in DCM to give the title compound (0.772 g, presumed to be quantitative). ESI-MS [M+H] + C 15 H 20 N 4 Calculated value for 257.18; measured value, 257.3.

[0353] Step E: tert-butyl (trans-1-benzyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate

[0354]

Chemical formula

[0355] In a 250 mL round-bottom flask, trans-1-benzyl-4-(1-methyl-1H (-Pyrazol-4-yl)pyrrolidin-3-amine (0.772 g, 3.01 mmol) and di-tert-butyl dicarbonate (0.657 g, 3.01 mmol) were dissolved in THF (10 mL) to obtain a yellowish-brown solution. Triethylamine (0.629 mL, 4.52 mmol) was added and the mixture was stirred at room temperature for 6 h. The reaction mixture was treated with water and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered, concentrated to give the title compound as a brown syrup (1.073 g, presumed quantitative) and used this without further purification. ESI-MS [M+H] + C 20 H 28 N 4 O 2 calculated for, 357.23; found, 357.4.

[0356] Step F: tert-Butyl (trans-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate

[0357]

Chemical formula

[0358] In a 250 mL round-bottom flask, tert-butyl (trans-1-benzyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate (1.073 g, 3.01 mmol) was dissolved in methanol (50 mL) to obtain a brown solution. The reaction mixture was treated with ammonium formate (0.949 g, 15.0 mmol) and palladium on carbon (10%, 0.128 g, 0.120 mmol). The reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Additional ammonium formate (0.949 g, 15.0 mmol) was added and the reaction mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound as a purple solid (0.802 g, presumed quantitative). ESI-MS [M+H] + C 13 H 22N 4 O 2 Calculated value for N, 267.18; measured value, 267.3.

[0359] Step G: tert-Butyl (trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate

[0360]

Chemical formula

[0361] In a 250 mL round-bottom flask, tert-butyl (trans-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate (0.802 g, 3.01 mmol) and formaldehyde (37% aqueous solution, 0.658 mL, 8.43 mmol) were dissolved in methanol (30 mL) to obtain a brown solution. The reaction mixture was treated with NaBH 4 (0.342 g, 9.03 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO 4 , filtered, and concentrated. The residue was purified by automated flash silica column chromatography (30 g NH column) eluting with a gradient of 0 - 5% methanol in DCM. The fractions were evaporated to give the title compound (0.544 g, 64%) as a yellow-brown film. ESI-MS [M+H] + C 14 H 24 N 4 O 2 Calculated value for C, H, N, O, 281.20; measured value [M - 55], 225.2.

[0362] Step H: trans-1-Methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine

[0363] In a 250 mL round-bottom flask, a solution of tert-butyl (trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate (0.544 g, 1.94 mmol) in dioxane (2 mL) was treated with HCl (4 M in dioxane, 1.94 mL, 7.76 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated to dryness to afford the HCl salt of the title compound (0.433 g, quantitative), which was used without further purification. ESI-MS [M+H] + C 9 H 16 N 4 Calculated for, 181.14; found, 181.2.

[0364] Preparation 48: trans-5-(1-Benzyl-4-nitropyrrolidin-3-yl)-2-methylpyridine

[0365]

Chem.

[0366] In a 250 mL round-bottom flask, (E)-2-methyl-5-(2-nitrovinyl)pyridine (2.50 g, 15.2 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (5.50 g, 23.1 mmol) were combined in DCM (30 mL) to afford a yellowish-brown solution. The reaction mixture was cooled to 0 °C and TFA (0.117 mL, 1.52 mmol) was added. After stirring at 0 °C for 30 minutes, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 0–100% EtOAc in heptane. The fractions were evaporated to afford the title compound (4.47 g, 99%) as a pale brown syrup. ESI-MS [M+H] + C 17 H 19 N 3 O 2 Calculated for, 298.15; found, 298.3.

[0367] Preparation 49: trans-1-Benzyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-amine

[0368]

Chemical formula

[0369] The title compound was prepared in a manner similar to Preparation 35 using trans-5-(1-benzyl-4-nitropyrrolidin-3-yl)-2-methylpyridine (4.47 g, 15.03 mmol) instead of trans-3-(4-chlorophenyl)-1-methyl-4-nitropyrrolidine. )-2-methylpyridine (4.47 g, 15.03 mmol). The product was isolated as a pale yellow syrup (1.47 g, 37%). ESI-MS [M+H] + C 17 H 21 N 3 Calculated for, 268.17; Found, 268.3.

[0370] Preparation 50: trans-N-(1-Benzyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0371]

Chemical formula

[0372] In a 250 mL round-bottom flask, 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.150 g, 0.422 mmol), trans-1-benzyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-amine (0.113 g, 0.422 mmol), HATU (0.192 g, 0.506 mmol) and DIPEA (0.220 mL, 1.265 mmol) were combined in DMF (6 mL) to give a yellow solution. The reaction mixture was stirred overnight at room temperature, then treated with water and extracted with EtOAc. The organic phase was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (40 g column) eluting with a gradient of 30 - 90% hexane in EtOAc. The fractions were evaporated to give the title compound (0.15 g, 69%). ESI-MS [M+H] + C 28 H 31 F 3 N 4 O 2 calculated for, 513.24; found, 513.6.

[0373] Preparation 51: trans-2,2-Dimethyl-N-(4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0374]

Chemical formula

[0375] In a 250 mL round-bottom flask, trans-N-(1-benzyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide (0.15 g, 0.29 mmol) was dissolved in methanol (8 mL) to give a colorless solution. Ammonium formate (0.092 g, 1.5 mmol) and palladium on activated carbon (10 wt%, 0.012 g, 0.012 mmol) were added. The reaction mixture was stirred at 90 °C for 1 h under nitrogen and then filtered. The filtrate was concentrated to give the title compound (0.108 g, 87%) as a colorless film, which was used without further purification. ESI-MS [M+H] + C 21 H 25 F 3 N 4 O 2 Calculated for, 423.19; found, 423.5.

[0376] Preparation 52: Methyl 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoate (Alternative Procedure)

[0377]

Chemical Structure

[0378] Methyl 3-hydroxy-2,2-dimethylpropanoate (2.97 g, 22.5 mmol) was dissolved in DMF (20 mL) to give a colorless solution. Sodium hydride (60 wt%, 1.12 g, 28.1 mmol) was added. After stirring at room temperature for 30 min, 2-fluoro-3-methylpyridine (2.08 g, 18.7 mmol) was added. After completion of the reaction, the mixture was treated with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic phase was dried over MgSO 4 filtered, and concentrated. The residue was purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 0 - 20% EtOAc in heptane. The fractions containing the product were evaporated to give the title compound (0.77 g, 18%) as a colorless oil. ESI-MS [M+H] + C 12 H 17 NO 3 Calculated for, 224.13; found, 224.2.

[0379] Preparation 53: 2,2-Dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid

[0380] [Chemical formula]

[0381] Methyl 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoate (0.77 g, 3.45 mmol) was dissolved in dioxane (14 mL) to obtain a colorless solution. Lithium hydroxide (2 M, 6.90 mL, 13.8 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to obtain the lithium salt of the title compound (1.04 g, presumed to be quantitative) as a white solid, which was used without further purification. ESI-MS [M+H] + C 11 H 15 NO 3 Calculated for, 2 10.11; Found, 210.2.

[0382] Preparation 54: (E)-1,3-Dimethyl-4-(2-nitrovinyl)-1H-pyrazole

[0383] [Chemical formula]

[0384] To a solution of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (1.00 g, 8.06 mmol) in nitromethane (35 mL) was added ammonium acetate (0.155 g, 2.01 mmol). The reaction mixture was heated to reflux overnight. Excess nitromethane was removed under reduced pressure. The residue was purified by automated flash silica column chromatography (40 g column) eluting with a gradient of 20 - 50% EtOAc in heptane. The fractions were evaporated to give the title compound (1.31 g, 97%) as a yellow solid. ESI-MS [M+H] + C 7 H 9 N3 O 2 Calculated value for, 168.08; Measured value, 168.2.

[0385] Preparation 55: trans-4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine

[0386]

Chemical formula

[0387] The HCl salt (0.274 g) of the title compound was prepared in a manner similar to Steps C - H of Preparation 47, using (E)-1,3-dimethyl-4-(2-nitrovinyl)-1H-pyrazole (1.31 g, 7.84 mmol) instead of (E)-1-methyl-4-(2-nitrovinyl)-1H-pyrazole. ESI-MS [M+H] + C 10 H 18 N 4 Calculated value for, 195.16; Measured value, 195.2.

[0388] Preparation 56: Methyl 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanoate

[0389]

Chemical formula

[0390] The title compound was prepared in a manner similar to Preparation 52, using 3-cyclopropyl-3-fluoropyridine (2.00 g, 14.6 mmol) instead of 2-fluoro-3-methylpyridine. The product was isolated as a brown oil (3.63 g, presumed to be quantitative) and used without further purification.

[0391] Preparation 57: 3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid

[0392] [ka]

[0393] In a 250 mL round bottom flask, methyl 3-((3-cyclopropylpyridine-2-yl) (3.63 g, 14.6 mmol) and 2 M aqueous lithium hydroxide (29.2 mL, 58.3 mmol) were combined in dioxane (50 mL) to give a brown solution. The reaction mixture was stirred at room temperature overnight, then acidified to pH 5 with 1N HCl and extracted with EtOAc. The organic phase was washed with MgSO 4 The mixture was dried over hexanes, filtered and concentrated to give the title compound (3.43 g, presumed quantitative) as a light brown syrup which was used without further purification. ESI-MS [M +H] + C 13 H 17 NO 3 Calculated value for, 236.13; measured value, 236.2 .

[0394] Preparation 58: (E)-1,5-Dimethyl-4-(2-nitrovinyl)-1H-pyrazole

[0395] [ka]

[0396] The title compound was prepared in a manner similar to preparation 54, using 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (0.83 g, 6.7 mmol) instead of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde. The product was isolated as a colorless oil (1.118 g, assumed quantitative). ESI-MS [M+H] + C 7 H 9 N 3 O 2 Calculated value for 168.08; measured value, 168.2.

[0397] Preparation 59: trans-4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine

[0398]

Chemical formula

[0399] The HCl salt (0.629 g) of the title compound was prepared in a manner similar to Steps C - H of Preparation 47, using (E)-1,5-dimethyl-4-(2-nitrovinyl)-1H-pyrazole (1.118 g, 6.69 mmol) instead of (E)-1-methyl-4-(2-nitrovinyl)-1H-pyrazole. ESI-MS [M+H] + C 10 H 18 N 4 Calculated value for, 195.16; Measured value, 195.2.

[0400] Preparation 60: tert-Butyl 4-amino-3-ethylpiperidine-1-carboxylate

[0401]

Chemical formula

[0402] A solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (1.00 g, 4.40 mmol) and ammonium formate (1.11 g, 17.6 mmol) in methanol (30 mL) was stirred at room temperature for 10 minutes. Palladium on carbon (10 wt%, 0.140 g, 0.132 mmol) was added and the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.962 g, 96%) as a pale brown syrup, which was used without further purification.

[0403] Preparation 61: tert-Butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate

[0404] [Chemistry]

[0405] The title compound was prepared in a manner similar to Preparation 60 using tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (1.00 g, 4.40 mmol) instead of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate. The product was used without further purification (0.998 g, 99%).

[0406] Preparation 62: tert-Butyl 4-amino-3-fluoropiperidine-1-carboxylate

[0407] [Chemistry]

[0408] Step A: tert-Butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate

[0409] [Chemistry]

[0410] A colorless solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (1.05 g, 4.83 mmol) and phenylmethanamine (0.581 mL, 5.32 mmol) in DCM (20 mL) was treated with sodium triacetoxyborohydride (1.537 g, 7.25 mmol). The reaction mixture was stirred at room temperature for 2 h, then treated with a saturated aqueous solution of NaHCO 3 and neutralized with NaCO 3 and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO 4 filtered, concentrated to give the title compound as a colorless syrup (1.49 g, quantitative), which was used without further purification. ESI-MS [M+H] +C 17 H 25 FN 2 O 2 Calculated value for, 309.20; Measured value [M - 55], 253.2.

[0411] Step B: tert-Butyl 4-amino-3-fluoropiperidine-1-carboxylate

[0412] The title compound was prepared in a manner similar to Preparation 60 using tert-butyl 4-(benzylamino)-3-fluoropiperidine- 1-carboxylate (1.49 g, 4.83 mmol) instead of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate. The product was isolated as a white solid (1.05 g, quantitative) and used without further purification. ESI-MS [M+H] + C 10 H 19 FN 2 O 2 Calculated value for, 219.15; Measured value [M - tert-butoxy], 145.1.

[0413] Preparation 63: tert-Butyl 8-amino-5-azaspiro[2.5]octane-5-carboxylate

[0414]

Chemical Structure

[0415] The title compound was prepared in a manner similar to Preparation 60 using tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.00 g, 4.44 mmol) instead of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate. The product was isolated as a white solid (0.226 g, 22%) and used without further purification. ESI-MS [M+H] + C 12 H 22 N 2 O 2Calculated value for, 227.32; Measured value [M-55], 171.2.

[0416] Preparation 64: tert-Butyl 4-amino-3-chloropiperidine-1-carboxylate

[0417]

Chem.

[0418] The title compound was prepared in a manner similar to Preparation 62 using tert-butyl 3-chloro-4-oxopiperidine-1-carboxylate (1.00 g, 4.28 mmol) instead of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate. The product was isolated as a white solid (1.005 g, presumed to be quantitative) and used without further purification. ESI-MS [M+H] + C 10 H 19 ClN 2 O 2 Calculated value for, 235.12; Measured value [M-55], 179.1.

[0419] Preparation 65: Methyl 2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoate

[0420]

Chem.

[0421] Sodium hydride (60 wt%, 2.02 g, 50.6 mmol) was added to a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (5.02 g, 38.0 mmol) in DMF (6 mL). After stirring at room temperature for 1 hour, 2-chloro-3-(trifluoromethoxy)pyridine (5.00 g, 25.3 mmol) was added. The mixture was heated at 100 °C overnight and then concentrated to 1 / 3 volume and treated with saturated aqueous NH 4 Cl and then with E It was extracted with tOAc. The organic phase was dried over MgSO 4 and filtered, concentrated to give the crude title compound as a yellowish-brown oil (7.42 g, presumed quantitative), which was used without further purification. ESI-MS [M+H] + C 12 H 14 F 3 NO 4 Calculated for, 294.09; found, 294.3.

[0422] Preparation 66: 2,2-Dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoic acid

[0423]

Chem.

[0424] In a 250 mL round-bottom flask, methyl 2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoate (6.89 g, 23.5 mmol) and lithium hydroxide (2 M, 47.0 mL, 94 mmol) were combined in dioxane (50 mL) to give a brown solution. The reaction mixture was stirred overnight at room temperature, then concentrated to 1 / 3 volume, acidified with 1N aqueous HCl, and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered, concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (120 g column) eluting with a gradient of 0 - 50% EtOAc in heptane. The fractions were evaporated to give the title compound as a colorless oil (3.17 g, 48%). ESI-MS [M+H] + C 11 H 12 F3NO 4 Calculated for, 280.07; found, 280.13.

[0425] Preparation 67: tert-Butyl 4-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate

[0426]

Chem.

[0427] Step A: 1-(tert-Butyl) 4-ethyl 5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate

[0428]

Chem.

[0429] In a 125 mL round-bottom flask, RuPhos Pd G3 (0.143 g, 0.171 mmol), cesium carbonate (2.225 g, 6.83 mmol), 1-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (1.548 g, 3.41 mmol ) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 4.10 mmol) were combined in dioxane (20.09 mL) to give an orange solution. Nitrogen was bubbled through the reaction mixture for 5 minutes and then it was heated at 75 °C overnight. Subsequently, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the resulting residue was purified by automated flash silica column chromatography (40 g column) eluting with a gradient of 0 - 50% EtOAc in heptane. The fractions were evaporated to give the title compound (1.16 g, 91%) as a yellow syrup. ESI-MS [M+H] + C 17 H 23 F 2 N 3 O 4 Calculated for, 372.17; Found, 372.4.

[0430] Step B: cis-1-(tert-Butyl) 4-ethyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl) piperidine-1,4-dicarboxylate

[0431]

Chem.

[0432] A mixture of 1-(tert-butyl) 4-ethyl 5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (1.16 g, 3.12 mmol), palladium dihydroxide on carbon (20 wt%, 0.219 g, 0.312 mmol) and ammonium formate (0.788 g, 12.5 mmol) was combined in ethanol (31.2 mL) to give a black suspension. The reaction mixture was stirred at 90 °C overnight and then filtered. The filtrate was concentrated to give the title compound (1.145 g, 98%). ESI-MS [M+H] + C 17 H 25 F 2 N 3 O 4 Calculated for, 374.19; Found [M-55], 318.2.

[0433] Step C: trans-1-(tert-Butyl) 4-ethyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl) piperidine-1,4-dicarboxylate

[0434]

Chem.

[0435] In a 50 mL round-bottom flask, sodium metal (0.141 g, 6.13 mmol) was stirred in ethanol (18.4 mL) under a nitrogen atmosphere until the metal disappeared. This solution was transferred to a flask containing a solution of cis-1-(tert-butyl) 4-ethyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl) piperidine-1,4-dicarboxylate (1.145 g, 3.07 mmol) in ethanol (12.3 mL). The reaction mixture was stirred at 85 °C overnight and then cooled to room temperature. The mixture was concentrated, and the residue was treated with dilute aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered and concentrated to give the title compound as a brown syrup (1.145 g, presumed quantitative) and used this without further purification. ESI-MS [M+H] + C 17 H 25 F 2 N 3 O 4 Calculated for, 374.19; found [M-55], 318.2.

[0436] Step D: trans-1-(tert-butoxycarbonyl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl) piperidine-4-carboxylic acid

[0437]

Chemical Structure

[0438] To a brown solution of trans-1-(tert-butyl) 4-ethyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl) piperidine-1,4-dicarboxylate (1.145 g, 3.07 mmol) in ethanol (8 mL) was added sodium hydroxide (10 M, 0.737 mL, 7.37 mmol). The reaction mixture was stirred at 90 °C for 1 h and then acidified to pH 5 with 1 N aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4Dry on top, filter, concentrate to obtain the title compound as a yellowish-brown syrup (1.06 g, presumed to be quantitative), and use this without further purification. ESI-MS [M+H] + C 15 H 21 F 2 N 3 O 4 Calculated for, 346. 16; Found, 346.3.

[0439] Step E: trans-tert-Butyl 4-amino-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate

[0440] In a 250 mL round-bottom flask, combine trans-1-(tert-butoxycarbonyl)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)piperidine-4-carboxylic acid (1.06 g, 3.07 mmol), diphenyl phosphorazidite (1.00 mL, 4.91 mmol), and triethylamine (0.642 mL, 4.61 mmol)) in toluene (18 mL) to obtain a brown solution. Heat the reaction mixture at 100 °C for 1 hour, then cool to room temperature. Add sodium hydroxide (10 M, 3.07 mL, 30.7 mmol), and stir the reaction mixture at room temperature for 3 hours. Treat the mixture with water and extract with EtOAc. Wash the organic phase with water and brine, and dry over MgSO 4 Dry on top, filter, and concentrate. Purify the residue by automated flash silica column chromatography (60 g NH column) eluting with a gradient of 0 - 100% EtOAc in heptane. Evaporate the fractions to obtain the title compound as a colorless film (0.56 g, 58%). ESI-MS [M+H + C 14 H 22 F 2 N 4 O 2 Calculated for, 317.18; Found [M-55], 261.2. ​

[0441] Preparation 68: tert-Butyl trans-4-amino-3-ethylpiperidine-1-carboxylate

[0442]

Chem.

[0443] Step A: Ethyl 1-benzyl-3-ethylpiperidine-4-carboxylate

[0444]

Chem.

[0445] In a 250 mL round-bottom flask, a gray suspension of copper(I) iodide (3.14 g, 16.5 mmol) in diethyl ether (15 mL) was cooled to -40 °C (dry ice in acetonitrile). Ethylmagnesium bromide (1 M in THF, 46.9 mL, 46.9 mmol) was added dropwise. After stirring for 30 minutes, a solution of ethyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (2.02 g, 8.23 mmol) in diethyl ether (10 mL) was added dropwise. The reaction mixture was stirred at -40 °C for 6 hours and then quenched with saturated aqueous NH 4 Cl. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The residue was purified by automated flash silica column chromatography (80 g column) eluting with a gradient of 0 - 20% EtOAc in heptane. Fractions were collected to give a colorless syrup which was treated with water and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO 4It was dried, filtered, and concentrated over. The residue was purified by automated flash silica column chromatography (60 g NH column) eluting with a gradient of 0 - 100% EtOAc in heptane. The fractions were evaporated to give the title compound (1.21 g, 53%) as a colorless film. ESI-MS [M+H] + C 17 H 25 NO 2 Calculated for, 276.20; found value, 276.3.

[0446] Step B: Ethyl 3 - ethylpiperidine - 4 - carboxylate

[0447]

Chem.

[0448] A black suspension of ethyl 1 - benzyl - 3 - ethylpiperidine - 4 - carboxylate (1.21 g, 4.39 mmol) and palladium dihydroxide on carbon (20 wt%, 0.309 g, 0.439 mmol) in THF (20 mL) and ethanol (20 mL) was evacuated and refilled three times with hydrogen gas. The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere (balloon). The reaction mixture was filtered and the filtrate was concentrated to give the title compound (0.814 g, presumed quantitative) as a colorless syrup, which was used without further purification. ESI-MS [M+H] + C 10 H 19 NO 2 Calculated for, 186. 15; found value, 186.3.

[0449] Step C: 1 - (tert - butyl) 4 - ethyl 3 - ethylpiperidine - 1,4 - dicarboxylate

[0450]

Chem.

[0451] A colorless solution of ethyl 3-ethylpiperidine-4-carboxylate (0.814 g, 4.39 mmol), di-tert-butyl dicarbonate (1.102 g, 5.05 mmol) and triethylamine (0.918 mL, 6.59 mmol) in DCM (40 mL) was stirred at room temperature for 7 h. The reaction mixture was treated with water and extracted with DCM. The organic matter was washed with brine and dried over MgSO 4 and filtered, concentrated to give the title compound (1.25 g, presumed quantitative) as a colorless syrup and used this without further purification. ESI-MS [M+H] + C 15 H 27 NO 4 Calculated for, 286.20; found [M-Boc], 186.0.

[0452] Step D: 1-(tert-Butyl) trans-4-ethyl 3-ethylpiperidine-1,4-dicarboxylate

[0453]

Chemical formula

[0454] To a colorless solution of 1-(tert-butyl) 4-ethyl 3-ethylpiperidine-1,4-dicarboxylate (1.25 g, 4.39 mmol) in ethanol (17.6 mL) was added a freshly prepared solution of sodium metal (0.202 g, 8.78 mmol) in ethanol (26.3 mL). The reaction mixture was stirred at 85 °C overnight. The reaction mixture was treated with water and extracted with EtOAc. The organic phase was washed with brine and dried over MgSO 4 and filtered, concentrated to give the crude title compound (1.25 g, presumed quantitative) as a yellowish brown syrup and used this without further purification.

[0455] Step E: trans-1-(tert-Butoxycarbonyl)-3-ethylpiperidine-4-carboxylic acid

[0456]

Chem.

[0457] A brown solution of 1-(tert-butyl) trans-4-ethyl 3-ethylpiperidine-1,4-dicarboxylate (1.25 g, 4.39 mmol) and lithium hydroxide (2 M, 8.78 mL, 17.6 mmol) in dioxane (16 mL) was stirred overnight at room temperature. The reaction mixture was acidified to pH 5 with dilute aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered, concentrated to give the title compound (1.05 g, 93%) as a pale brown syrup, which was used without further purification.

[0458] Step F: tert-butyl trans-4-amino-3-ethylpiperidine-1-carboxylate

[0459] A brown solution of trans-1-(tert-butoxycarbonyl)-3-ethylpiperidine-4-carboxylic acid (1.05 g, 4.08 mmol), diphenyl phosphorazidite (1.33 mL, 6.53 mmol) and triethylamine (0.853 mL, 6.12 mmol) in toluene (27.2 mL) was heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and sodium hydroxide (10 M, 4.08 mL, 40.8 mmol) was added. The reaction mixture was stirred at room temperature for 3 h and then extracted with DCM. The organic phase was dried over MgSO 4 and filtered, concentrated to give the title compound (0.622 g, 67%) as a pale brown syrup, which was used without further purification. ESI-MS [M+H] + C 12 H 24 N 2 O 2 Calculated for, 22 9.19; found, 229.2.

[0460] Preparation 69: tert-Butyl 4-amino-2,2-dimethylpiperidine-1-carboxylate

[0461] [Chemical formula]

[0462] A colorless solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (1.00 g, 4.40 mmol) and ammonium formate (1.11 g, 17.6 mmol) in methanol (29.3 mL) was stirred at room temperature for 10 minutes and then treated with palladium on carbon (10 wt%, 0.140 g, 0.132 mmol). The reaction mixture was stirred at 60 °C for 2 hours. Additional ammonium formate (1.11 g, 17.6 mmol) was added and the reaction mixture was stirred at 60 °C for an additional 1 hour. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (1.00 g, presumed quantitative) as a white solid, which was used without further purification. ESI-MS [M+H] + C 12 H 24 N 2 O 2 Calculated for, 229.19; found [M - 55], 173.1.

[0463] Preparation 70: 1,5,5-Trimethylpyrrolidin-3-amine

[0464] [Chemical formula]

[0465] A black suspension of 1,5,5-trimethylpyrrolidin-3-one (1.00 g, 7.86 mmol), ammonium formate (1.983 g, 31.4 mmol), and palladium on carbon (10 wt%, 0.251 g, 0.236 mmol) in methanol (52.4 mL) was stirred at 60 °C for 2 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated to afford the title compound (0.63 g, 62%) as a yellow syrup, which was used without further purification. ESI-MS [M+H] + C 7 H 16 N 2 Calculated for, 129.14; Found, 129.1.

[0466] Preparation 71: 4-Benzyl-4-azaspiro[2.5]octan-7-amine

[0467]

Chem.

[0468] A yellow solution of 4-benzyl-4-azaspiro[2.5]octan-7-one (0.690 g, 3.20 mmol), ammonium acetate (1.235 g, 16.02 mmol), and sodium cyanoborohydride (0.060 g, 0.96 mmol) in methanol (21.4 mL) was heated to reflux for 64 h. The reaction mixture was concentrated. The residue was purified by automated flash silica column chromatography (40 g NH column) eluting with a gradient of 0–50% EtOAc in heptane. The fractions were evaporated to afford the title compound (0.308 g, 44%) as a brown film. ESI-MS [M+H] + C 14 H 20 N 2 Calculated for, 217.17; Found, 217.2.

[0469] Formulation 72: tert-Butyl 3-(o-tolyl)-4-(N,2,2-trimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide)piperidine-1-carboxylate

[0470]

Chem.

[0471] Step A: tert-Butyl 4-oxo-3-(o-tolyl)piperidine-1-carboxylate

[0472]

Chem.

[0473] The glass vial was purged with nitrogen and charged with anhydrous THF (6.3 mL), palladium diacetate (28.2 mg, 0.125 mmol), and sodium tert-butoxide (362 mg, 3.76 mmol). The mixture was stirred for 15 minutes until the sodium tert-butoxide was dissolved. Tri-tert-butylphosphine (1.0 M in toluene, 251 μL, 0.251 mmol), 1-bromo-2-methylbenzene (332 μL, 2.76 mmol), and tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.51 mmol) were added. The reaction mixture was slowly heated at 45 - 50 °C over 4 hours and then poured into a saturated aqueous solution of NaHCO 3 (5 mL) and extracted with EtOAc (8 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure. Purification by flash silica column chromatography eluting with a gradient of 15 - 100% EtOAc in heptane gave the title compound (172 mg, 24%) as a colorless oil.

[0474] Step B: tert-Butyl 4-(methylamino)-3-(o-tolyl)piperidine-1-carboxylate

[0475]

Chem.

[0476] In DCM (4.7 mL), a mixture of tert-butyl 4-oxo-3-(o-tolyl)piperidine-1-carboxylate (270 mg, 0.933 mmol), methanamine (33% in EtOH, 134 μL, 1.07 mmol), and sodium triacetoxyborohydride (989 mg, 4.67 mmol) was stirred at room temperature for 3 days. To the reaction mixture was added EtOAc (15 mL), followed by a saturated aqueous solution of NaHCO 3 The resulting mixture was stirred at room temperature for 1 h. The organic layer was separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 and filtered, concentrated to give the title compound (260 mg, 92%) as a pale yellow oil, which was used directly without further purification.

[0477] Step C: tert-butyl 3-(o-tolyl)-4-(N,2,2-trimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide)piperidine-1-carboxylate

[0478] To a solution of 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (73.5 mg, 0.279 mmol) and HATU (106 mg, 0.279 mmol) in DMF (1.4 mL) was added DIPEA (146 μL, 0.838 mmol). The resulting solution was stirred at room temperature for 10 min. Next, tert-butyl 4-(methylamino)-3-(o-tolyl)piperidine-1-carboxylate (100 mg, 0.279 mmol) was added, and the reaction mixture was stirred at room temperature for 6 h and then heated at 60 °C overnight. The reaction mixture was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (17 mg, 9.2%) as a light brown oil. ESI-MS [M +H]+ C 29 H 38 F 3 N 3 O 4 Calculated value for, 550.28; Measured value, 55 0.1.

[0479] Preparation 73: trans-tert-butyl 4-(2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide)-3-(o-tolyl)piperidine-1-carboxylate

[0480]

Chemical formula

[0481] Step A: tert-butyl 4-amino-3-(o-tolyl)piperidine-1-carboxylate

[0482]

Chemical formula

[0483] Sodium cyanotrihydroborate (36.9 mg, 0.587 mmol) was added in two portions at 10-minute intervals to a solution of tert-butyl 4-oxo-3-(o-tolyl)piperidine-1-carboxylate (170 mg, 0.587 mmol) and ammonium acetate (453 mg, 5.87 mmol) in anhydrous methanol (3.0 mL). Subsequently, the reaction mixture was quenched with saturated aqueous NaHCO 3 (5.0 mL), and then extracted with EtOAc (2 × 10 mL). The organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed to give the title compound as a colorless oil (175 mg, presumed to be quantitative), which was used without further purification.

[0484] Step B: trans-tert-butyl 4-(2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide)-3-(o-tolyl)piperidine-1-carboxylate

[0485] To a solution of HATU (79 mg, 0.21 mmol) and 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (54.4 mg, 0.207 mmol) in DMF (1.0 mL) was added DIPEA (108 μL, 0.620 mmol). The solution was stirred at room temperature for 5 minutes. Next, tert-butyl 4-amino-3-(o-tolyl)piperidine-1-carboxylate (60 mg, 0.21 mmol) was added and the solution was stirred at room temperature for 4 hours. The product was purified by preparative HPLC (Method A) to give the title compound (34 mg, 31%) as a colorless oil. ESI-MS [M+H] + C 28 H 36 F 3 N 3 O 4 Calculated for, 536.27; Found, 536.1 .

[0486] Preparation 74: tert-butyl 4-amino-3-phenylpiperidine-1-carboxylate

[0487]

Chem.

[0488] Step A: tert-butyl (E)-4-(hydroxyimino)-3-phenylpiperidine-1-carboxylate

[0489]

Chem.

[0490] tert-Butyl 4-oxo-3-phenyl-piperidine-1-carboxylate (1.1 g, 4.00 mmol) and NH 2 OH·HCl (420 mg, 6.04 mmol) in EtOH (15 mL), NaOAc (700 mg, 8.53 mmol) was added. The reaction mixture was stirred at room temperature overnight and then poured into water and extracted with EtOAc. The organic phase was washed with a saturated aqueous solution of NaHCO 3 and dried over Na 2 SO 4 . It was filtered and concentrated under reduced pressure to give the title compound (1.1 g, 95%) which was used without further purification. ESI-MS [M+H] + Calculated for C 16 H 22 N 2 O 3 , 291.17; found, 291.2.

[0491] Step B: tert-Butyl 4-amino-3-phenylpiperidine-1-carboxylate

[0492] To a mixture of tert-butyl (E)-4-(hydroxyimino)-3-phenylpiperidine-1-carboxylate (700 mg, 2.41 mmol) in 1:1 THF / EtOH (25 mL), Raney nickel (0.2 g) was added. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred at 70 °C for 24 h under H 2 (60 psi) and then filtered through a pad of Celite® which was rinsed with EtOAc. The filtrate was dried over Na 2 SO 4 and filtered and concentrated under reduced pressure to give the title compound (0.75 g, 87%) which was used without further purification (77% purity). ESI-MS [M+H] + Calculated for C 16 H 24 N 2 O 2 , 277.19; found [M-t-Bu], 221.1.​

[0493] Preparation 75: trans-tert-butyl 4-(2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide)-3-phenylpiperidine-1-carboxylate

[0494]

Chemical formula

[0495] To a mixture of 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (300 mg, 1.14 mmol) and tert-butyl 4-amino-3-phenylpiperidine-1-carboxylate (380 mg, 1.376 mmol) in DMF (10 mL), HATU (650 mg, 1.71 mmol) and DIPEA (442 mg, 3.42 mmol) were added at 25 °C under nitrogen. The reaction mixture was stirred at room temperature overnight and then partitioned between EtOAc and brine. The organic phase was separated, washed with brine, dried, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Phenomenex Gemini 10 μm, 25 mm inner diameter × 150 mm column) eluting with a gradient of 60 - 80% ACN in water (containing 0.05% HCl) to give the title compound (240 mg, 38%) as a pale yellow solid (94% purity). ESI-MS [M+H] + C 27 H 34 F 3 N 3 O 4 Calculated for, 522 .26; Found, 522.0.

[0496] Preparation 76: trans-tert-butyl 3-phenyl-4-(N,2,2-trimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide )piperidine-1-carboxylate

[0497] [Chemistry]

[0498] To a solution of trans-tert-butyl 4-((2,2-dimethyl-3-((3-(trifluoromethyl)-2-pyridyl)oxy)propanoyl)amino)-3-phenyl-piperidine-1-carboxylate (50 mg, 95 μmol) in DMF (2 mL) was added MeI (1.0 g, 7.05 mmol) at room temperature. NaH (60 wt%, 11.4 mg, 285 μmol) was added to the mixture and stirred overnight. The mixture was added to brine and extracted with EtOAc. The organic phase was dried over anhydrous Na 2 SO 4 and filtered, concentrated to give the crude product. The crude product was purified by preparative TLC using 3:1 petroleum ether / EtOAc as eluent to give the title compound (35 mg, 69%) as a colorless oil. ESI-MS [M+H] + C 27 H 34 F 3 N 3 O 4 Calculated for, 53 6.27; found, 536.3.

[0499] Preparation 77: 2,2-Dimethyl-N-(3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0500] [Chemistry]

[0501] Step A: tert-Butyl 4-oxo-3-phenylpiperidine-1-carboxylate

[0502] [Chemistry]

[0503] The glass vial was purged with nitrogen and charged with anhydrous THF (10 mL), palladium diacetate (0.056 g, 0.251 mmol), and sodium tert-butoxide (0.724 g, 7.53 mmol). The mixture was stirred for 15 minutes until the sodium tert-butoxide was dissolved. Tri-tert-butylphosphine (50 wt% in toluene, 0.239 mL, 0.502 mmol), bromobenzene (0.579 mL, 5.27 mmol), and tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) were added. The reaction mixture was slowly heated at 45 - 50 °C for 4 hours and then poured into a saturated aqueous NaHCO 3 solution (5 mL) and extracted with EtOAc ( 8 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by automated flash silica column chromatography eluting with a gradient of 10 - 100% EtOAc in heptane gave the title compound (570 mg, 41%) as a colorless oil. ESI-MS [M+H] + C 16 H 21 NO 3 calculated for, 276.34; found [M - 55], 220.1.

[0504] Step B: tert-Butyl 4-amino-3-phenylpiperidine-1-carboxylate

[0505]

Chemical formula

[0506] Sodium cyanotrihydroborate (103 mg, 1.64 mmol) was added in two portions at 10-minute intervals to a solution of tert-butyl 4-oxo-3-phenylpiperidine-1-carboxylate (430 mg, 1.56 mmol) and ammonium acetate (1204 mg, 15.62 mmol) in anhydrous methanol (7.8 mL). The resulting solution was stirred at room temperature overnight and then NaHCO3 It was quenched with saturated aqueous solution (5.0 mL) and extracted with EtOAc (2×10 mL). The organic layers were combined and dried over anhydrous Na 2 SO 4 . It was dried over anhydrous NaSO4. The solvent was removed to obtain the title compound (420 mg, 97% yield) as a colorless oil, which was used without further purification. ESI-MS [M+H] + C 16 H 24 N 2 O 2 Calculated for, 277.34; Found [M-55], 221.1.

[0507] Step C: tert-Butyl 4-(2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamido)-3-phenylpiperidine-1-carboxylate

[0508]

Chemical formula

[0509] The title compound was prepared in a manner similar to Preparation 75 using a mixture of the cis and trans stereoisomers of tert-butyl 4-amino-3-phenylpiperidine-1-carboxylate (150 mg, 0.543 mmol, 1 equiv). The product was purified by preparative HPLC (Method A) to give the title compound (102 mg, 30%) as a colorless oil. ESI-MS [M+H] + C 27 H 34 F 3 N 3 O 4 Calculated for, 522. 25; Found, 522.1.

[0510] Step D: 2,2-Dimethyl-N-(3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0511] The title compound was prepared in a manner similar to Example 162 using tert-butyl 4-(2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide)-3-phenylpiperidine-1-carboxylate (102 mg, 0.162 mmol, 1 equiv) instead of trans-tert-butyl 3-phenyl-4-(N,2,2-trimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamido)piperidine-1-carboxylate. The solvent was removed to afford the TFA salt of the title compound (87 mg, quantitative), which was used without further purification. ESI-MS [M+H] Calculated for + C 22 H 26 F 3 N 3 O 2 , 422. 20; found, 422.1.

[0512] Preparation 78: tert-butyl cis-4-(2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide)-3-phenylpiperidine-1-carboxylate

[0513] [Chemical Structure]

[0514] Preparation 79: tert-butyl trans-4-(2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide)-3-phenylpiperidine-1-carboxylate

[0515] [Chemical Structure]

[0516] To a solution of 2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoic acid (152 mg, 0.543 mmol) and HATU (206 mg, 0.543 mmol) in DMF (5427 μL) was added DIPEA (284 μL, 1.628 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then tert-butyl 4-amino-3-phenylpiperidine-1-carboxylate (150 mg, 0.543 mmol) was added. The resulting solution was stirred at room temperature for 3 hours and subsequently purified by preparative HPLC (Method A) to afford the title cis and trans stereoisomers as colorless oils. The major peak was arbitrarily assigned to the cis stereoisomer (52 mg, 18%) and the minor peak was arbitrarily assigned to the trans stereoisomer (44 mg, 15%). Major peak: ESI-MS [M+H] + C 27 H 34 N 3 O 5 Calculated for, 538.25; found, 538.1. Minor peak: ESI-MS [M+H] + C 27 H 34 N 3 O 5 Calculated for, 538.25; found, 538.1.

[0517] Preparation 80: trans-1-Methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidin-3-amine

[0518]

Chem.

[0519] Step A: 1-(tert-Butyl) 3-ethyl 4-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate

[0520]

Chem.

[0521] 1-(tert-Butyl) 3-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (45.0 g, 112 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (27.85 g, 133.9 mmol), K 3 PO 4 (59.20 g, 278.9 mmol) and Pd(dppf)Cl 2 (8.16 g, 11.2 mmol) were added to a round-bottom flask containing dioxane (500 mL). The reaction mixture was stirred at 90 °C for 16 h under nitrogen and then concentrated under reduced pressure. The crude product was purified by flash silica column chromatography eluting with petroleum ether / EtOAc to give the title compound (42.7 g, 38%) as a red oil (85% purity). ESI-MS [M+H] + C 17 H 25 N 3 O 4 Calculated for, 336. 19; Found [M-55], 280.0.

[0522]

[0523]

Chemical formula

[0524] Mg (13.05 g, 536.7 mmol) was added to a solution of 1-(tert-butyl) 3-ethyl 4-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (30.0 g, 89.4 mmol) in MeOH (400 mL). The suspension was stirred at 15 °C for 2 h under a nitrogen atmosphere. Then the mixture The substance was diluted with EtOAc and washed with 1 M aqueous HCl and brine. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by automated flash silica column chromatography (120 g column) eluting with a gradient of 0 - 60% EtOAc in petroleum ether to afford the title compound (27 g, 93%, cis:trans = 1.8:1) as a pale yellow rubber. ESI-MS [M+H] + C 17 H 27 N 3 O 4 Calculated for, 338.21; Found [M - 55], 282.0.

[0525] Step C: 1-(tert-Butyl) trans-3-ethyl 4-(1-methyl-1H-pyrazol-4-yl)piperidine-1,3-dicarboxylate

[0526]

Chemical Structure

[0527] A solution of 1-(tert-butyl) 3-ethyl 4-(1-methyl-1H-pyrazol-4-yl)piperidine-1,3-dicarboxylate (a mixture of cis and trans isomers, 10.0 g, 29.6 mmol) in EtOH (10 mL) was stirred at room temperature. A solution of EtONa in ethanol (6.5 M, 10 mL) was added. The mixture was stirred under reflux for 16 h and then diluted with EtOAc and saturated aqueous NH 4 Cl. The organic layer was separated, dried, filtered, and concentrated under reduced pressure. The crude product was purified by automated flash silica column chromatography (120 g column) eluting with a gradient of 0 - 1% methanol in DCM to afford the title compound (3.5 g, 35%) as a pale yellow rubber. ESI-MS [M+H] + C 17 H 27 N 3 O 4 Calculated for, 338.21; Found [M - 55], 282.0.

[0528] Step D: Ethyl trans-4-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate

[0529]

Chemical formula

[0530] To a round-bottom flask containing 1-(tert-butyl) trans-3-ethyl 4-(1-methyl-1H-pyrazol-4-yl)piperidine-1,3-dicarboxylate (3.50 g, 10.4 mmol) in DCM (50 mL) was added TFA (23.10 g, 202.6 mmol). The reaction mixture was stirred at 15 °C for 2 h and then concentrated under reduced pressure. The resulting crude product TFA salt was dissolved in water and washed with EtOAc. The aqueous layer was treated with a saturated aqueous solution of Na 2 CO 3 to adjust the pH to 9 - 10 and then stirred at room temperature for 10 min and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure to give the title compound (1.35 g, 56%) as a pale yellow gum. ESI-MS [M+H] + C 12 H 19 N 3 O 2 Calculated for, 238.16; Found, 238.0.

[0531] Step E: Ethyl trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate

[0532]

Chemical formula

[0533] To a round-bottom flask containing ethyl trans-4-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate (1.35 g, 5.69 mmol) in DCE (10 mL), formaldehyde (40% aqueous solution, 1.71 g, 22.8 mmol) and NaBH(OAc) 3 (4.82 g, 22.8 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then quenched with water and a saturated aqueous solution of Na 2 CO 3 (20 mL), and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (Phenomenex Synergi Max-RP 10 μm, 50 mm inner diameter × 250 mm column) eluting with a gradient of 1 - 30% ACN in water (containing 0.1% TFA). The resulting TFA salt was basified with an aqueous solution of Na 2 CO 3 , extracted with EtOAc, dried, and concentrated to give the title compound (1.0 g, 83%) as a pale yellow oil. ESI-MS [M + H] + C 13 H 21 N 3 O 2 Calculated for, 252.17; found, 252.2.

[0534] Step F: trans-1-Methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylic acid

[0535]

Chemical Structure

[0536] To a solution of ethyl trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate (500 mg, 1.99 mmol) in THF (6 mL) was added lithium hydroxide monohydrate (150.3 mg, 3.58 mmol) and water (2 mL) at room temperature. The mixture was stirred at 60 °C for 24 h and then washed with MTBE (3 × 3 mL). The aqueous phase was acidified to pH 6 - 7 with 1 M aqueous HCl and freeze-dried to give the title compound (as a white solid) (0.135 g) (along with LiCl). ESI-MS [M+H] + C 11 H 17 N 3 O 2 calculated for, 224.14; found , 224.1.

[0537] Step G: Butyl (trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)carbamate

[0538]

Chemical formula

[0539] A mixture of trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylic acid (200 mg, 0.896 mmol), Et 3 N (272 mg, 2.69 mmol) and diphenyl phosphorazidite (493 mg, 1.79 mmol) in n-BuOH (2 mL) was heated at 110 °C for 40 h. Subsequently, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over Na 2 SO 4It was dried over, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Phenomenex Gemini 10 μm, 25 mm i.d. × 150 mm column) eluting with a gradient of 24 - 54% ACN in water (containing 0.05% ammonium hydroxide) to give the title compound as a yellow oil (120 mg, 23%). ESI-MS [M+H] + C 15 H 26 N 4 O 2 Calculated for, 295.21; Found, 295.2.

[0540] Step H: trans-1-Methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidin-3-amine

[0541] To a round-bottomed flask containing butyl (trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)carbamate (100 mg, 0.340 mmol) in ethylene glycol dimethyl ether (1 mL) was added KOH (57.2 mg, 1.02 mmol). The reaction mixture was stirred at 90 °C for 16 h and then filtered. The filtrate was concentrated under reduced pressure and the resulting concentrate was purified by automated flash silica column chromatography (4 g column) eluting with a gradient of 0 - 20% methanol in DCM to give the title compound as a yellow oil (55 mg, 81%). ESI-MS [M+H] + C 10 H 18 N 4 Calculated for, 195.16; Found, 195.2.

[0542] Preparation 81: tert-Butyl 4-amino-2-ethylpiperidine-1-carboxylate

[0543]

Chemical formula

[0544] The title compound was prepared in a manner similar to Preparation 70 using tert-butyl 2-ethyl-4-oxopiperidine-1-carboxylate (1.00 g, 4.40 mmol, 1 equiv) instead of 1,5,5-trimethylpyrrolidin-3-one to afford a white solid (1.005 g, presumed quantitative), which was used without further purification. ESI-MS [M+H] + C 12 H 24 N 2 O 2 Calculated for, 229.19; found value [M-72], 155.7.

[0545] Preparation 82: 2,2-Difluoro-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid

[0546]

Chem.

[0547] To a solution of ethyl 2,2-difluoro-3-hydroxypropanoate (0.336 g, 2.18 mmol) in DMF (8 mL) was added NaH (60 wt%, 0.145 g, 3.63 mmol). The mixture was stirred at room temperature for 30 min. Then 2-fluoro-3-(trifluoromethyl)pyridine (0.300 g, 1.817 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and then treated with dilute aqueous HCl and extracted with EtOAc. The aqueous layer was concentrated and the residue was redissolved in ethanol. The precipitate was removed by filtration and the filtrate was concentrated to afford the title compound (0.407 g, 83%) as a brown syrup, which was used without further purification. ESI-MS [M+H] + C 9 H 6 F 5 NO 3 Calculated for, 272.03; found, 272.1.

[0548] Preparation 83: 3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-difluoropropanoic acid

[0549]

Chem.

[0550] To a solution of ethyl 2,2-difluoro-3-hydroxypropanoate (0.405 g, 2.62 mmol) in DMF (8 mL) was added NaH (60 wt%, 0.131 g, 3.28 mmol). After stirring for 1 h, 3-cyclopropyl-2-fluoropyridine (0.300 g, 2.19 mmol) was added. The mixture was stirred overnight and then treated to pH 5 with dilute aqueous HCl and extracted with EtOAc. The aqueous layer was concentrated, and the residue was redissolved in EtOH / EtOAc (3:1) and filtered. The filtrate was concentrated to give the title compound (0.527 g, 99%) as a brown syrup, which was used without further purification. ESI-MS [M+H] + C 11 H 11 F 2 NO 3 Calculated for, 244 .08; found, 244.2.

[0551] Preparation 84: Ethyl 2,2-difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoate

[0552]

Chem.

[0553] In a 100 mL round-bottom flask, ethyl 2,2-difluoro-3-hydroxypropanoate (0.468 g, 3.04 mmol) was dissolved in DMF (8 mL) to obtain a colorless solution. NaH (60 wt%, 91 mg, 3.8 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Next, 2-chloro-3-(trifluoromethoxy)pyridine (0.500 g, 2.53 mmol) was added. The reaction mixture was stirred at 100 °C overnight, then the heating was removed, and it was treated with dilute aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered and concentrated to give the crude title compound (0.797 g, presumed to be quantitative) as a colorless oil. ESI-MS [M+H] + Calculated for C 11 H 10 F 5 NO 4 , 316.06; found, 316.3.

[0554] Preparation 85: 2,2-Difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoic acid

[0555]

Chem.

[0556] A solution of ethyl 2,2-difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoate (0.797 g, 2.53 mmol) and LiOH (2 M aqueous solution, 5.06 mL, 10.1 mmol) in dioxane (15 mL) was stirred at 50 °C for 2 h. Then the reaction mixture was treated with dilute aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered and concentrated to give the crude title compound (0.726 g, presumed to be quantitative) as a brown syrup, which was used without further purification. ESI-MS [M+H] + Calculated for C 9 H 6 F 5 NO 4Calculated value for, 288.03; Measured value, 288.2.

[0557] Preparation 86: Ethyl 2,2-difluoro-3-((3-methylpyridin-2-yl)oxy)propanoate

[0558] [Chemical formula]

[0559] To a solution of ethyl 2,2-difluoro-3-hydroxypropanoate (0.458 g, 2.97 mmol) in DMF (8 mL) was added sodium hydride (60 wt%, 0.097 g, 4.0 mmol). After stirring at room temperature for 1 hour, 2-fluoro-3-methylpyridine (0.300 g, 2.70 mmol) was added. The mixture was stirred at room temperature overnight and then treated with dilute aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered, concentrated to give the title compound as a colorless oil (0.662 g, presumed quantitative) and used without further purification. ESI-MS [M +H] + C 11 H 13 F 2 NO 3 Calculated value for, 246.09; Measured value, 246 .2.

[0560] Preparation 87: 2,2-Difluoro-3-((3-methylpyridin-2-yl)oxy)propanoic acid

[0561] [Chemical formula]

[0562] A solution of ethyl 2,2-difluoro-3-((3-methylpyridin-2-yl)oxy)propanoate (0.662 g, 2.70 mmol) and LiOH (2 M aqueous solution, 5.40 mL, 10.8 mmol) in dioxane (15 mL) was stirred at 50 °C for 2 h. The reaction mixture was then treated to pH 5 with dilute aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO 4 and filtered, concentrated to afford the crude title compound (0.23 g, 39%) as a colorless oil, which was used without further purification. ESI-MS [M+H] + Calculated for C 9 H 9 F 2 NO 3 , 218.06; found, 218. 2.

[0563] Preparation 88: tert-Butyl (3S,4S)-4-(3-(2-chlorophenoxy)-2,2-dimethylpropanamide)-3-fluoropiperidine-1-carboxylate

[0564] [Chemical formula]

[0565] A solution of 3-(2-chlorophenoxy)-2,2-dimethylpropanoic acid (69 mg, 0.30 mmol), tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate (86 mg, 0.392 mmol), HATU (152 mg, 0.392 mmol) and triethylamine (168 μL, 1.21 mmol) in THF (1.51 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and rinsed with methanol. The filtrate was purified by preparative HPLC (Method A) to afford the title compound as a white solid (95 mg, 73%). ESI-MS [M+H + Calculated for C 21 H 30 ​ClFN 2 O 4 Calculated value for, 429.20; Measured value, 429 .4.

[0566] Preparation 89: tert-Butyl (3S,4S)-4-(3-(2-chlorophenoxy)-2,2-dimethylpropanamide)-3-methylpiperidine-1-carboxylate

[0567]

Chem.

[0568] A solution of 3-(2-chlorophenoxy)-2,2-dimethylpropanoic acid (104 mg, 0.455 mmol), tert-butyl (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate (117 mg, 0.546 mmol), HATU (212 mg, 0.546 mmol) and Et 3 N(254 μL, 1.82 mmol)) in DMA (2.27 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and rinsed with methanol. The filtrate was purified by preparative HPLC (Method A) to give the title compound as a white solid (150 mg, 78%). ESI-MS [M+H + C 22 H 33 ClN 2 O 4 Calculated value for, 425.22; Measured value, 425. 5.

[0569] Preparation 90: tert-Butyl 4-(3-(2-chlorophenoxy)-2,2-dimethylpropanamide)piperidine-1-carboxylate

[0570]

Chem.

[0571] ​ 3-(2-Chlorophenoxy)-2,2-dimethylpropanoic acid (502 mg, 2.20 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (550 mg, 2.63 mmol), HATU (1.02 g, 2.63 mmol) and Et 3 N (1.22 mL, 8.78 mmol) in DMA (11 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and rinsed with methanol. The filtrate was purified by preparative HPLC (Method A) to afford the title compound as a white semi-solid (578 mg, 64%). ESI-MS [M+H] + C 21 H 31 ClN 2 O 4 Calculated for, 411.20; Found, 411.5.

[0572] Preparation 91: Methyl 3-(4-chlorophenoxy)-2,2-dimethylpropanoate

[0573]

Chem.

[0574] A solution of methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (510 mg, 2.43 mmol), 4-chlorophenol (720 μL, 7.28 mmol) and cesium carbonate (2.37 g, 7.28 mmol) in DMA (6.06 mL) was stirred on a hot plate at 100 °C for 12 h. The reaction mixture was suction filtered and the solvent was removed under reduced pressure. The residue was purified by automated flash silica column chromatography (12 g column) eluting with 10% EtOAc in heptane to afford the title compound as a pale yellow liquid (218 mg, 37%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.32 (s, 6 H), 3.70 (s, 3 H), 3.9 4 (s, 2 H), 6.81 - 6.85 (m, 2 H), 7.20 - 7.25 (m, 2 H); ESI-MS [M+H] + C 12 H 15 ClO 3 Calculated value for, 243.08; Measured value 243.2.

[0575] Preparation 92: 3-(4-Chlorophenoxy)-2,2-dimethylpropanoic acid

[0576]

Chem.

[0577] A solution of methyl 3-(4-chlorophenoxy)-2,2-dimethylpropanoate (215 mg, 0.886 mmol) in MeOH (2.22 mL) was treated with 3 M aqueous LiOH (886 μL, 2.66 mmol) at room temperature. The resulting reaction mixture was stirred for 48 h and acidified to pH 2 - 3 by dropwise addition of 1 N aqueous HCl. The acidified solution was extracted with EtOAc and DCM (2×). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the title compound as a white solid (195 mg, 96%) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.20 (s, 6 H), 3.94 (s, 2 H), 6.92 - 6.98 (m, 2 H), 7.27 - 7.34 (m, 2 H), 12.31 (s, 1 H); ESI-MS [M+H] + C 11 H 13 ClO 3 For Calculated value, 229.06; Measured value [M-OH], 211.2.

[0578] Preparation 93: Ethyl 2,2-difluoro-3-(tosyloxy)propanoate

[0579] [Chemical formula]

[0580] A solution of ethyl 2,2-difluoro-3-hydroxypropanoate (250 mg, 1.62 mmol) in DCM (8.11 mL) was treated with triethylamine (452 μL, 3.24 mmol) and 4-methylbenzenesulfonyl chloride (464 mg, 2.43 mmol). The resulting reaction mixture was stirred overnight, then diluted with brine and extracted with DCM. The organic phase was concentrated under reduced pressure, and the residue was purified by automated flash silica column chromatography (24 g column) eluting with a gradient of 0 - 50% EtOAc in heptane to afford the title compound (181 mg, 36%) as a clear oil.

[0581] Preparation 94: Ethyl 3-(2-chlorophenoxy)-2,2-difluoropropanoate

[0582] [Chemical formula]

[0583] Sodium hydride (60 wt%, 35.2 mg, 0.880 mmol) was added to a solution of ethyl 2,2-difluoro-3-(tosyloxy)propanoate (181 mg, 0.587 mmol) in DMF (1.96 mL). The reaction mixture was stirred for 1 hour. Then, 2-chlorophenol (83 mg, 66.9 μL, 0.646 mmol) was added. The reaction mixture was stirred overnight and then concentrated under reduced pressure, and purified by automated flash silica column chromatography (24 g column) eluting with a gradient of 0 - 100% EtOA c in heptane to afford the title compound (97 mg, 62%).

[0584] Preparation 95: 3-(2-Chlorophenoxy)-2,2-difluoropropanoic acid

[0585] [Chemical formula]

[0586] A solution of ethyl 3-(2-chlorophenoxy)-2,2-difluoropropanoate (97 mg, 0.37 mmol) in dioxane (1.10 mL) was treated with 1 M aqueous lithium hydroxide (1.10 mL, 1.100 mmol). The mixture was stirred for 5 minutes and concentrated in vacuo to remove dioxane. The remaining aqueous layer was acidified to pH 1 - 2 and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The resulting oil was diluted with heptane (20 mL) and concentrated under reduced pressure to afford the title compound as a white solid (84 mg, 97%).

[0587] Preparation 96: tert-Butyl (3S,4S)-4-(3-(2-chlorophenoxy)-2,2-difluoropropanamido)-3-methylpiperidine-1-carboxylate

[0588] [Chemical formula]

[0589] To a mixture of 3-(2-chlorophenoxy)-2,2-difluoropropanoic acid (30.0 mg, 0.127 mmol) in DCE (0.5 mL) and DMF (3 drops) was added oxalyl chloride (22 μL, 0.25 mmol). The mixture was stirred at room temperature for 1 hour. Next, a solution of tert-butyl (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate (54.3 mg, 0.254 mmol) in DCE (1 mL) and DIPEA (66 μL, 0.38 mmol) was added. The reaction mixture was heated to 70 °C for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The mixture was partitioned between DCM and brine. The organic phase was concentrated and purified by automated flash silica column chromatography (24 g column) eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (6.0 mg, 11%). ESI-MS [M+H] + C 20 H 27 ClF 2 N 2 O 4 Calculated for, 433.17; found [M - Boc], 333.3.

[0590] Example 1: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide

[0591]

Chem.

[0592] 2,2-Dimethyl-3-((3-methylpyridin-2-yl)oxy) in DMF (2 mL) To a 20 mL vial containing xy)propanoic acid (0.050 g, 0.239 mmol) was added 1-methylpiperidin-4-amine (0.033 g, 0.287 mmol), HATU (0.109 g, 0.287 mmol) and DIPEA (0.077 g, 0.597 mmol). The resulting yellow solution was stirred overnight at room temperature. The reaction mixture was then filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and rinsed with methanol. The filtrate was purified by preparative HPLC (Method C) eluting with a gradient of 5 - 30% ACN in water. The product-containing fractions were evaporated to give the TFA salt of the title compound (64 mg, 64%) as a clear oil. 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.29 - 1.35 (m, 6 H), 1.74 - 1.90 (m, 2 H), 1.99 - 2.10 (m, 2 H), 2.17 (s, 3 H), 2.82 - 2.87 (m, 3 H), 3.02 - 3.15 (m, 2 H), 3.47 - 3.58 (m, 2 H), 3.89 - 4.08 (m, 1 H), 4.29 - 4.39 (m, 2 H), 6.85 - 6.94 (m, 1 H), 7.49 - 7.59 (m, 1 H), 7.90 - 7.98 (m, 1 H); ESI-MS [M+H] + C 17 H 27 N 3 O 2 Calculated for 306.21; found, 306.2.

[0593]

[0594]

Chemical Structure

[0595] The TFA salt of the title compound was prepared in a manner similar to Example 1, using 1-methylpyrrolidin-3-amine (0.029 g, 0.287 mmol, 1.2 eq) instead of 1-methylpiperidin-4-amine. The product was isolated as a pale brown oil (64 mg, 72%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.29 - 1.3 5 (m, 6 H), 2.04 - 2.14 (m, 1 H), 2.17 (s, 3 H ), 2.28 - 2.62 (m, 1 H), 2.92 (br s, 3 H), 3.02 - 3.16 (m, 1 H), 3.32 - 3.43 (m, 1 H), 3.53 - 3.97 (m, 2 H), 4.26 - 4.36 (m, 2 H), 4.44 (br s, 1 H), 6.88 (dd, J = 7.1, 5.0 Hz, 1 H), 7. 48 - 7.56 (m, 1 H), 7.93 (dd, J = 5.0, 1.0 Hz, 1 H); ESI-MS [M+H] + C 16 H 25 N 3 O 2 Calculated for, 29 2.19; Found, 292.2.

[0596] Example 3: 3-((3-Cyanopyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0597]

Chemical Structure

[0598] The title compound was prepared in a manner similar to the above, using 3-((3-cyanopyridin-2-yl)oxy)-2,2-dimethylpropanoic acid instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid Using 273 mg (1.24 mmol) of tilopropanoic acid, it was prepared in a manner similar to Example 1. The product was purified by preparative HPLC (Method A) to obtain the TFA salt (79.3 mg, 15%) of the title compound as a white solid. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.32 (s, 6 H), 1.81 - 1.92 (m, 2 H), 2.09 - 2.17 (m, 2 H), 2.85 (s, 3 H), 3.05 - 3.15 (m, 2 H), 3.50 - 3.59 (m, 2 H), 3.92 - 4.03 (m, 1 H), 4.44 (s, 2 H), 7.07 - 7.14 (m, 1 H), 8.01 - 8.08 (m, 1 H), 8.36 - 8.41 (m, 1 H); ESI-MS [M+H] + C 17 H 24 N 4 O 2 Calculated for, 317.19 ; Found, 317.23.

[0599] Example 4: (R)-3-((5-Cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0600]

Chemical Structure

[0601] The title compound was prepared in a manner similar to Example 1, using 3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethylpropanoic acid (148 mg, 0.626 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and (R)-1-methylpyrrolidin-3-amine (62.7 mg, 0.626 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to give the title compound (40.4 mg, 20%) as a yellowish-brown film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.79 (dd, J = 5.6, 1.7 Hz, 2 H), 0.96 (dd, J = 8.3, 2.0 Hz, 2 H), 1.31 (app d, J = 1.5 Hz, 6 H), 1.64 - 1.73 (m, 1 H), 1.86 - 1.94 (m, 1 H), 2.22 - 2.31 (m, 1 H), 2.35 (s, 3 H), 2.41 - 2.50 (m, 2 H), 2.69 - 2.78 (m, 2 H), 4.36 - 4.42 (m, 1 H), 4.43 (s, 2 H), 8.11 (s, 1 H), 8.52 (s, 1 H); ESI-MS [M+H] + C 17 H26N 4 O 2 for, calculated, 31 8.21; found, 319.38.

[0602] Example 5: 3-((5-Cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0603]

Chemical formula

[0604] The title compound was prepared in a manner similar to Example 1, using 3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethylpropanoic acid (148 mg, 0.626 mmol, 1 equivalent) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid. The product was purified by preparative HPLC (Method B) to give the title compound (49.4 mg, 0.149 mmol) as a yellowish-brown film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.79 (dd, J = 5.4, 2.0 Hz, 2 H), 0.92 - 0.98 (m, 2 H), 1.31 (s, 6 H), 1.51 - 1.61 (m, 2 H), 1.75 - 1.81 (m, 2 H), 1.85 - 1.92 (m, 1 H), 2.05 - 2.12 (m, 2 H), 2.26 (s, 3 H), 2.82 - 2.88 (m, 2 H), 3.65 - 3.74 (m, 1 H), 4.44 (s, 2 H), 8.06 - 8.14 (m, 1 H), 8.50 - 8.53 (m, 1 H); ESI-MS [M+H] + C 18 H 28 N 4 O 2 Calculated for, 333.22; Found, 333.24.

[0605] Example 6: 3-((3-Cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0606]

Chemical Structure

[0607] The title compound was prepared in a manner similar to Example 1, using 3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (131 mg, 0.526 mmol, 1 equivalent) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (106.8 mg, 44%) as a pale blue solid. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.68 (dd, J = 4. 9, 2.0 Hz, 2 H), 0.89 - 0.96 (m, 2 H), 1.32 (s, 6 H), 1.77 - 1.89 (m, 2 H), 1.99 (s, 1 H), 2 .03 (br s, 2 H), 2.20 (s, 3 H), 2.85 (s, 3 H), 3.04 - 3.14 (m, 2 H), 3.50 - 3.58 (m, 2 H), 3 .92 - 4.02 (m, 1 H), 4.31 (s, 2 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.69 - 7.73 (m, 1 H); ESI-MS [M+H] + C 20 H 31 N 3 O 2 Calculated for, 346.24; Found, 346 .4.

[0608] Example 7: (R)-3-((3-Cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0609]

Chem.

[0610] The title compound was prepared in a manner similar to Example 1, using 3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (131 mg, 0.526 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and (R)-1-methylpyrrolidin-3-amine (52.7 mg, 0.526 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (53.8 mg, 0.121 mmol) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.67 (dd, J = 5.4, 2.0 Hz, 2 H), 0 .92 (dd, J = 8.3, 2.0 Hz, 2 H), 1.32 (app d, J = 2.9 Hz, 6 H), 1.93 - 2.02 (m, 1 H), 2.04 - 2.16 (m, 1 H), 2.20 (s, 3 H), 2.46 - 2.58 (m, 1 H), 2.93 (s, 3 H), 3.04 - 3.14 (m, 1 H), 3.33 - 3.38 (m, 1 H), 3.55 - 3.62 (m, 1 H), 3.78 - 3.87 (m, 1 H), 4.25 - 4.33 (m, 2 H), 4.41 - 4.53 (m, 1 H), 7.09 - 7.17 (m, 1 H), 7.65 - 7.73 (m, 1 H); ESI-MS [M+H] + C 19 H 29 N 3 O 2 Calculated for , 332.23; Found, 332.4.

[0611] Example 8: 3-((5-Cyclopropyl-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0612]

Chem.

[0613] The title compound was prepared in a manner similar to Example 1, using 3-((5-cyclopropyl-3-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (108 mg, 0.433 mmol, 1 equiv) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid. The product was purified by preparative HPLC (Method B) to give the title compound (51.9 mg, 35%) as a pale brown film. 1 H N MR (500 MHz, CD 3 OD) δ ppm 0.58 - 0.62 (m, 2 H ), 0.91 (dd, J = 8.5, 1.7 Hz, 2 H), 1.28 (s, 6 H), 1.50 - 1.60 (m, 2 H), 1.79 (dd, J = 14.4, 9.0 Hz, 3 H), 2.04 - 2.11 (m, 2 H), 2.13 (s, 3 H), 2.25 (s, 3 H), 2.78 - 2.85 (m, 2 H), 3.64 - 3.74 (m, 1 H), 4.26 (s, 2 H), 7.13 - 7.18 (m, 1 H), 7.70 - 7.74 (m, 1 H); ESI-MS [M+H] + C 20 H 31 N 3 O 2 Calculated for, 346.24; Found, 346.3.

[0614] Example 9: 3-((3-Cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0615]

Chem.

[0616] The title compound was prepared in a manner similar to Example 1, using 3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (218 mg, 0.876 mmol, 1 equiv) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (78.9 mg, 20%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.62 (dd, J = 5 .4, 2.0 Hz, 2 H), 0.86 - 0.91 (m, 2 H), 1.32 (s, 6 H), 1.77 - 1.87 (m, 2 H), 1.92 - 1.98 (m, 1 H), 2.01 - 2.07 (m, 2 H), 2.39 (s, 3 H), 2. 84 (s, 3 H), 3.03 - 3.13 (m, 2 H), 3.50 - 3.56 (m, 2 H), 3.92 - 4.04 (m, 1 H), 4.36 (s, 2 H) , 6.74 (s, 1 H), 7.11 - 7.21 (m, 1 H); ESI-MS [M+H] + C 20 H 31 N 3 O 2 Calculated for, 346.24; Found, 34 6.5.

[0617] Example 10: (R)-3-((3-Cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0618]

Chemical Structure

[0619] The title compound was prepared in a manner similar to Example 1, using 3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (217 mg, 0.872 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and (R)-1-methylpyrrolidin-3-amine (87 mg, 0.87 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (38.7 mg, 10%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.61 (dd, J = 5.4, 2.0 Hz, 2 H), 0.84 - 0.92 (m, 2 H), 1.32 (app d, J = 2.0 Hz, 6 H), 1.89 - 1.98 (m, 1 H), 2.05 - 2.17 (m, 1 H), 2.35 (s, 3 H), 2.46 - 2.57 (m, 1 H), 2.92 (s, 3 H), 3 .03 - 3.12 (m, 1 H), 3.32 - 3.38 (m, 1 H), 3.52 - 3.63 (m, 1 H), 3.76 - 3.86 (m, 1 H), 4.28 - 4.36 (m, 2 H), 4.40 - 4.48 (m, 1 H), 6.69 (d, J = 7.8 Hz, 1 H), 7.05 - 7.14 (m, 1 H). ESI- MS [M+H] + C 19 H 29 N 3 O 2 Calculated for, 332.23; Found, 332.5.

[0620] Example 11: trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0621]

Chemical formula

[0622] Example 12: cis-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0623]

Chemical formula

[0624] The titled trans stereoisomer and cis stereoisomer were prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.100 g, 0.380 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and 1,3-dimethylpiperidin-4-amine, 2HCl (0.076 g, 0.38 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to obtain the trans stereoisomer (the first elution peak) (29.5 mg, 21%) as a colorless film and the cis stereoisomer (the second elution peak) (19.8 mg, 14%) as a colorless film. Peak 1: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.8 3 (d, J = 5.9 Hz, 3 H), 1.31 (app d, J = 3.9 Hz, 6 H), 1.48 - 1.60 (m, 1 H), 1.71 - 1.80 (m, 3H), 2.00 - 2.11 (m, 1H), 2.26 (s, 3H), 2.80 - 2.94 (m, 2H), 3.38 - 3.47 (m, 1H), 4.45 (d, J = 7.3 Hz, 2H), 7.04 - 7.11 (m, 1H), 7. 92 - 8.02 (m, 1H), 8.30 - 8.38 (m, 1H); ESI- MS [M+H] + C 18 H 26 F 3 N 3 O 2 Calculated value for, 374.20; Measured value, 374.4. Peak 2: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.90 (d, J = 6.8 Hz, 3H), 1.29 - 1.35 (m, 6H ), 1.59 - 1.69 (m, 1H), 1.73 - 1.85 (m, 1H), 2.01 - 2.12 (m, 1H), 2.22 (s, 3H), 2.26 (s, 4H), 3.88 - 4.01 (m, 1H), 4.46 (d, J = 3.9 Hz, 2H), 7.10 (dd, J = 7.3, 4.9 Hz, 1H), 7.94 - 8.04 (m, 1H), 8.30 - 8.38 (m, 1H); ESI-MS [M+H] + C 18 H 26 F 3 N 3 O 2 Calculated value for, 374.20; Measured value, 374.4.

[0625] Example 13: trans-N-(1,3-Dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide

[0626]

Chem.

[0627] Example 14: cis-N-(1,3-Dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide

[0628]

Chem.

[0629] The title trans-stereoisomer and cis-stereoisomer were prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoic acid (0.100 g, 0.272 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and 1,3-dimethylpiperidin-4-amine, 2HCl (0.055 g, 0.27 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to give the trans-stereoisomer (the first elution peak) (21.7 mg, 20%) as a colorless film and the cis-stereoisomer (the second elution peak) (16.7 mg, 16%) as a colorless film. Peak 1: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0. 84 (d, J = 6.4 Hz, 3 H), 1.31 (app d, J = 2.4 Hz, 6 H), 1.51 - 1.62 (m, 1 H), 1.68 - 1.80 (m, 3 H), 2.02 - 2.11 (m, 1 H), 2.26 (s, 3 H), 2. 82 - 2.92 (m, 2 H), 3.38 - 3.49 (m, 1 H), 4.41 (d, J = 2.0 Hz, 2 H), 6.99 - 7.06 (m, 1 H), 7.61 - 7.68 (m, 1 H), 8.05 - 8.14 (m, 1 H); ESI- MS [M+H] + C 18 H 26 F 3 N 3 O 3 Calculated value for, 390.19; Measured value, 390.4. Peak 2: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.90 (d, J = 6.8 Hz, 3 H), 1.28 - 1.34 (m, 6 H) , 1.62 - 1.71 (m, 1 H), 1.75 - 1.85 (m, 1 H), 1.98 - 2.12 (m, 1 H), 2.22 (m, 7 H), 3.93 - 4.03 (m, 1 H), 4.42 (d, J = 1.0 Hz, 2 H), 7.02 - 7.08 (m, 1 H), 7.63 - 7.71 (m, 1 H), 8.07 - 8.16 (m, 1 H); ESI-MS [M+H] + C 18 H 26 F 3 N 3 O 3 Calculated value for, 390.19; Measured value, 390.4.

[0630] Example 15: trans-N-(4-Isopropyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0631]

Chemical Structure

[0632] The title compound was prepared in a manner similar to Example 1, using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.110 g, 0.420 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-isopropyl-1-methylpyrrolidin-3-amine, HCl (0.075 g, 0.42 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to give the title compound (9.9 mg, 6.1%) as a colorless film. The title compound (9.9 mg, 6.1%) was obtained as a colorless film. 1 H NMR (500 MHz , CD 3 OD) δ ppm 0.83 - 0.94 (m, 6 H), 1.29 (ap p d, J = 10.2 Hz, 6 H), 1.52 - 1.60 (m, 1 H), 1.75 - 1.86 (m, 1 H), 2.02 - 2.11 (m, 1 H), 2.33 (s, 3 H), 2.50 - 2.63 (m, 2 H), 2.96 - 3.05 (m, 1 H), 4.13 - 4.21 (m, 1 H), 4.36 - 4.49 (m, 2 H), 7.05 - 7.13 (m, 1 H), 7.94 - 8.03 (m, 1 H), 8.32 - 8.38 (m, 1 H); ESI-MS [M+H] + C 19 H 28 F 3 N 3 O 2 Calculated for, 388.21; Found, 388.4.

[0633] Example 16: trans-N-(4-Isopropyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide

[0634]

Chemical Structure

[0635] The title compound was prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanoic acid (0.117 g, 0.420 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-isopropyl-1-methylpyrrolidin-3-amine, HCl (0.075 g, 0.42 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to give the title compound (8.5 mg, 5.0%) as a colorless film. 1 H NMR (500 MH z, CD 3 OD) δ ppm 0.88 (t, J = 6.1 Hz, 6 H), 1.29 (app d, J = 4.4 Hz, 6 H), 1.50 - 1.63 (m, 1 H), 1.75 - 1.87 (m, 1 H), 2.02 - 2.12 (m, 1 H), 2.33 (s, 3 H), 2.50 - 2.64 (m, 2 H), 2.96 - 3 .04 (m, 1 H), 4.15 - 4.22 (m, 1 H), 4.39 (d, J = 3.4 Hz, 2 H), 6.99 - 7.06 (m, 1 H), 7.58 - 7.72 (m, 1 H), 8.05 - 8.16 (m, 1 H). ESI-MS [M +H] + C 19 H 28 F 3 N 3 O 3 Calculated for, 404.21; Found, 40 4.4.

[0636] Example 17: trans-N-(1,3-Dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide

[0637]

Chem.

[0638] The title compound was prepared in a manner similar to Example 1 using 1,3-dimethylpiperidin-4-amine, HCl (0.049 g, 0.297 mmol, 1 equiv) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to afford the title compound (30.5 mg, 32%) as a colorless film. 1 3 H NMR (500 MHz, CD + OD) δ ppm 0.82 (d, J = 6.4 Hz, 3 H), 1.31 (s, 6 H), 1.49 - 1.59 (m, 1 H), 1.68 - 1 .79 (m, 3 H), 2.00 - 2.10 (m, 1 H), 2.16 (s, 3 H), 2.26 (s, 3 H), 2.80 - 2.91 (m, 2 H), 3.38 - 3.47 (m, 1 H), 4.32 (s, 2 H), 6.84 (dd, J = 7.1, 5.1 Hz, 1 H), 7.42 - 7.50 (m, 1 H), 7.88 - 7.94 (m, 1 H). ); ESI-MS [M+H] + C 18 H 29 N 3 O 2 Calculated for, 320.23; Found, 320.4.

[0639] Example 18: trans-2,2-Dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide

[0640]

Chem.

[0641] The title compound was prepared in a manner similar to Example 1, using trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine, HCl (0.064 g, 0.30 mmol, 1 equiv) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (40.2 mg, 28%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.04 - 1.34 (m, 6 H), 2.02 - 2.15 (m, 3 H), 2.94 - 3.08 (m, 3 H), 3.14 - 3.26 (m, 1 H), 3.54 - 3.72 (m, 2 H), 3.78 (s, 3 H), 3.92 - 4.02 (m, 1 H), 4.13 - 4.19 (m, 1 H), 4.26 - 4.35 (m, 1 H), 4.41 - 4.49 (m, 1 H), 6.85 - 6.92 (m, 1 H), 7.38 - 7.44 (m, 1 H), 7.48 - 7.56 (m, 2 H), 7.90 - 7.95 (m, 1 H); ESI-MS [M+H] + C 20 H 29 N 5 O 2 Calculated for, 372.23; Found, 372.4.

[0642] Example 19: trans-2,2-Dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0643]

Chemical Structure

[0644] The title compound was prepared in a manner similar to Example 1, using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.070 g, 0.27 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine, HCl (0.058 g, 0.27 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (33.4 mg, 23%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.99 - 1. 32 (m, 6 H), 2.98 (br s, 3 H), 3.15 - 3.26 (m, 1 H), 3.53 - 3.73 (m, 2 H), 3.78 - 3.86 (m, 4 H), 3.95 - 4.13 (m, 1 H), 4.21 - 4.31 (m, 1 H), 4.43 (s, 2 H), 7.06 - 7.13 (m, 1 H), 7.37 - 7.45 (m, 1 H), 7.51 - 7.58 (m, 1 H), 7.91 - 8.00 (m, 1 H), 8.30 - 8.39 (m, 1 H); ESI-MS [M+H] + C 20 H 26 F 3 N 5 O 2 Calculated for, 426.20; Found, 426.4.

[0645]

[0646]

Chemical formula

[0647] Example 21: cis-3-((3-Cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide

[0648]

Chem.

[0649] The title trans and cis stereoisomers were prepared in a manner similar to Example 1 using 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (0.084 g, 0.33 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and 1,3-dimethylpiperidin-4-amine, HCl (0.055 g, 0.33 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to give the trans stereoisomer (first elution peak) as a pale brown film (25.7 mg, 22%) and the cis stereoisomer (second elution peak) as a pale brown film (13.3 mg, 12%). Peak 1: 1H NMR (500 MHz, CD 1 OD) δ ppm 0.61 - 0 3 .67 (m, 2 H), 0.82 (d, J = 5.9 Hz, 3 H), 0.88 .67 (m, 2 H), 0.82 (d, J = 5.9 Hz, 3 H), 0.88 - 0.94 (m, 2 H), 1.33 (app d, J = 1.5 Hz, 6 H) , 1.48 - 1.59 (m, 1 H), 1.66 - 1.81 (m, 3 H), 1.99 - 2.10 (m, 2 H), 2.26 (s, 3 H), 2.80 - 2.91 (m, 2 H), 3.39 - 3.48 (m, 1 H), 4.33 (d, J = 2.9 Hz, 2 H), 6.80 - 6.87 (m, 1 H), 7.17 - 7 .26 (m, 1 H), 7.85 - 7.90 (m, 1 H); ESI-MS [M+H] + C 20 H 31 N 3 O 2 Calculated value for, 346.24; Measured value, 346.4 . Peak 2: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.62 - 0 .71 (m, 2 H), 0.83 - 0.99 (m, 5 H), 1.34 (m, 7 H), 1.59 - 1.69 (m, 1 H), 1.73 - 1.82 (m, 1 H ), 1.99 - 2.08 (m, 2 H), 2.18 (s, 3 H), 2.26 (s, 3 H), 3.94 - 4.01 (m, 1 H), 4.37 (m, 2 H), 6.83 - 6.90 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.87 - 7.93 (m, 1 H); ESI-MS [M+H] + C 20 H 31 N 3 O 2 Calculated value for, 346.24; Measured value, 346.4.

[0650] Example 22: trans-3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)propanamide

[0651]

Chemical Structure

[0652] The title compound was prepared in a manner similar to Example 1 using 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (0.080 g, 0.34 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine, HCl (0.074 mg, 0.34 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (15.4 mg, 8.8%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.54 - 0.67 (m, 2 H), 0.79 - 0.86 (m, 2 H), 1.03 - 1.18 (m, 1 H), 1.33 (app d, J = 4.4 Hz, 6 H), 1.80 - 1.97 (m, 1 H), 2.93 - 3.07 (m, 4 H), 3.54 - 3.72 (m, 3 H), 3.77 (s, 3 H), 3.93 - 4.02 (m, 1 H ), 4.32 (d, J = 12.2 Hz, 2 H), 6.86 (dd, J = 6 .8, 5.4 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.40 (s, 1 H), 7.45 - 7.51 (m, 1 H), 7.83 - 7.92 (m, 1 H); ESI-MS [M+H] + C 22 H 31 N 5 O 2 Calculated for, 39 8.25; Found, 398.4.

[0653] Example 23: trans-N-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide

[0654] [Chemical formula]

[0655] The title compound was prepared in a manner similar to Example 1, using trans-4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine (57.3 mg, 0.295 mmol, 1 equivalent) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to obtain the TFA salt of the title compound (92.8 mg, 63%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.30 (app d, J = 3.9 Hz, 6 H), 2.01 (br s, 3 H), 2.12 (s, 3 H), 2.99 (m, 4 H), 3.71 (m, 6 H), 3.91 - 4.02 (m, 1 H), 4.30 (s, 2 H ), 4.48 - 4.61 (m, 1 H), 6.87 (dd, J = 7.1, 5.1 Hz, 1 H), 7.47 - 7.55 (m, 2 H), 7.89 - 7.95 (m, 1 H); ESI-MS [M+H] + C 21 H 31 N 5 O 2 Calculated for, 386.25; Found, 386.4.

[0656] Example 24: trans-3-((3-Cyclopropylpyridin-2-yl)oxy)-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide

[0657] [Chemical formula]

[0658] The title compound was prepared in a manner similar to Example 1 using 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (73.8 mg, 0.295 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-(1,3-dimethyl-1H-pyrazol- 4-yl)-1-methylpyrrolidin-3-amine (57.3 mg, 0.295 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (54.4 mg, 35%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.60 (d, J = 5.4 Hz, 2 H), 0.79 - 0.86 (m, 2 H), 1.32 (app d, J = 3.4 Hz, 6 H), 1.80 - 1.88 (m, 1 H), 2.1 1 (s, 3 H), 2.98 (br s, 3 H), 3.06 - 3.18 (m, 1 H), 3.65 (m, 3 H), 3.72 (br s, 3 H), 3.92 - 4.03 (m, 1 H), 4.25 - 4.35 (m, 2 H), 4.40 - 4.51 (m, 1 H), 6.87 (dd, J = 7.3, 4.9 Hz, 1 H), 7.23 - 7.28 (m, 1 H), 7.48 - 7.53 (m, 1 H), 7.88 (dd, J = 5.1, 1.7 Hz, 1 H); ESI-MS [M+H] + C 23 H 33 N 5 O 2 Calculated for, 412.26; Found, 412.4.

[0659] Example 25: trans-N-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0660] [Chemical formula]

[0661] The title compound was prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (78 mg, 0.295 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine (57.3 mg, 0.295 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to obtain the TFA salt of the title compound (39.3 mg, 24%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.10 (s, 1 H), 1.24 - 1.33 (m, 6 H), 2.15 (s, 3 H), 2.98 (m, 4 H) 3.76 (m, 6 H), 3.93 - 4.01 (m, 1 H), 4.41 (s, 2 H), 7.05 - 7.12 (m, 1 H), 7.48 - 7.55 (m, 1 H), 7.92 - 8.00 (m, 1 H), 8.30 - 8.38 (m, 1 H); ESI-MS [M+H] + C 21 H 28 F 3 N 5 O 2 Calculated value for, 440.22; Measured value, 440.3.

[0662] ​Example 26: trans-N-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide

[0663]

Chem.

[0664] The title compound was prepared in a manner similar to Example 1, using trans-4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine, HCl (131 mg, 0.295 mmol, 1 equiv) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (37.7 mg, 26%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.29 (s, 6 H), 2.01 (br s, 3 H), 2.14 (s, 3 H), 2.98 (br s, 3 H), 3.11 - 3.25 (m, 1 H), 3.70 (m, 6 H), 3.85 - 3.97 (m, 1 H), 4.27 (d, J = 4.4 Hz, 2 H), 4.45 - 4.57 (m, 1 H ), 6.85 - 6.91 (m, 1 H), 7.43 - 7.54 (m, 2 H), 7.88 - 7.95 (m, 1 H); ESI-MS [M+H] + C 21 H 31 N 5 O 2 Calculated for, 386.25; Found, 386.4.

[0665] Example 27: trans-3-((3-Cyclopropylpyridin-2-yl)oxy)-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide

[0666]

Chem.

[0667] The title compound was prepared in a manner similar to Example 1 using 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (73.8 mg, 0.295 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine, HCl (131 mg, 0.295 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (24.4 mg, 16%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.53 - 0. 68 (m, 2 H), 0.79 - 0.88 (m, 2 H), 1.31 (s, 6 H), 1.79 - 1.90 (m, 1 H), 2.12 (s, 3 H), 2.98 (br s, 3 H), 3.12 - 3.23 (m, 1 H), 3.70 (m, 6 H), 3.85 - 3.95 (m, 1 H), 4.29 (s, 2 H), 4.34 - 4.45 (m, 1 H), 6.83 - 6.90 (m, 1 H), 7.23 - 7.32 (m, 1 H), 7.43 - 7.49 (m, 1 H), 7.84 - 7.92 (m, 1 H); ESI-MS [M+H] + C 23 H 33 N 5 O 2 Calculated value for, 412.26; Found, 412.4.

[0668] ​Example 28: trans-N-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0669]

Chemical Structure

[0670] The title compound was prepared in a manner similar to Example 1, using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (78 mg, 0.295 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine, HCl (131 mg, 0.295 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to obtain the TFA salt of the title compound (57.1 mg, 35%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.23 - 1.33 (m, 6 H), 2.21 (s, 3 H), 2.98 (br s, 3 H), 3.16 - 3.26 (m, 1 H), 3.74 (m, 6 H), 3.85 - 4.02 (m, 1 H), 4.40 (s, 3 H), 7.04 - 7.12 (m, 1 H), 7.40 - 7.55 (m, 1 H), 7.93 - 8.02 (m, 1 H), 8.28 - 8.37 (m, 1 H); ESI-MS [M+H] + C 21 H 28 F 3 N 5 O 2 Calculated for, 440.22; Found, 440.3.

[0671] Example 29: trans-N-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide

[0672] [Chemical formula]

[0673] The title compound was prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (82 mg, 0.295 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine (57.3 mg, 0.295 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (25.7 mg, 15%) as a colorless film. H NMR (500 MHz, CD 1 OD) δ ppm 1.30 (s, 6 H), 2.15 (s, 3 H), 2.98 (m, 4 H), 3.66 (m, 3 H), 3.75 (br s, 3 H), 3.98 (br s, 1 H), 4.07 - 3 4.29 (m, 1 H), 4.31 - 4.44 (m, 2 H), 6.97 - 7.08 (m, 1 H), 7.42 - 7.56 (m, 1 H), 7.60 - 7.70 (m, 1 H), 8.01 - 8.13 (m, 1 H); ESI-MS [M+H] (m, 1 H), 8.01 - 8.13 (m, 1 H); ESI-MS [M+H] + C 21 H 28 F 3 N 5 O 3 Calculated for, 456.21; Found, 456.4.

[0674] Example 30: trans-N-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide

[0675]

Chemical formula

[0676] The title compound was prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (82 mg, 0.295 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and trans-4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-amine, HCl (131 mg, 0.295 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (50.5 mg, 30%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.24 - 1.33 (m, 6 H), 2.21 (s, 3 H), 2.99 (br s, 3 H), 3.16 - 3.27 (m, 1 H), 3.74 (m, 6 H), 3.86 - 3.97 (m, 1 H), 4.37 (br s, 3 H), 6.97 - 7.07 (m, 1 H), 7.42 - 7.52 (m, 1 H), 7.61 - 7.71 (m, 1 H), 7.99 - 8.12 (m, 1 H); ESI-MS [M+H] + C 21 H 28 F 3 N 5 O 3 Calculated value for, 456.21; Measured value, 456.4.

[0677] Example 31: trans-N-(1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide

[0678]

Chemical formula

[0679] Example 32: cis-N-(1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide

[0680]

Chemical formula

[0681] The title trans stereoisomer and cis stereoisomer were prepared in a manner similar to Example 1, using 3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanoic acid (0.100 g, 0.448 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and 3-dimethylpiperidin-4-amine (0.057 g, 0.45 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method B) to obtain the trans stereoisomer (the first elution peak) (64.0 mg, 43%) as a light brown film and the cis stereoisomer (the second elution peak) (32.9 mg, 22%) as a pale yellow film. Peak 1: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.82 (d, J = 6. 1 Hz, 3 H), 1.30 (s, 6 H), 1.48 - 1.59 (m, 1 H ), 1.66 - 1.80 (m, 3 H), 1.99 - 2.09 (m, 1 H), 2.13 (s, 3 H), 2.19 (s, 3 H), 2.26 (s, 3 H), 2.81 - 2.90 (m, 2 H), 3.39 - 3.47 (m, 1 H), 4.27 (s, 2 H), 7.28 - 7.34 (m, 1 H), 7.68 - 7.75 (m, 1 H); ESI-MS [M+H] + C 19 H 31 N 3 O 2 Calculated value for , 334.24; Measured value, 334.4. Peak 2: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.87 (d, J = 6.8 Hz, 3 H), 1.31 (m, 7 H), 1.61 - 1.70 (m, 1 H), 1.73 - 1.83 (m, 1 H), 2.00 - 2.08 (m, 1 H), 2.10 - 2.25 (m, 10 H), 2.29 - 2.44 (m, 2 H), 3.92 - 4.01 (m, 1 H ), 4.30 (s, 2 H), 7.32 - 7.37 (m, 1 H), 7.68 - 7.77 (m, 1 H); ESI-MS [M+H] + C 19 H 31 N 3 O 2 for the calculated value, 334.24; Measured value, 334.4.

[0682] Example 33: trans-N-(3-Isopropyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0683]

Chemical Structure

[0684] Example 34: cis-N-(3-Isopropyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0685]

Chemical formula

[0686] The trans and cis stereoisomers of the title compound were prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.060 g, 0.23 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and 3-isopropyl-1-methylpiperidin-4-amine, 2HCl (0.052 g, 0.23 mmol) instead of 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A), evaporated to give the TFA salts of the trans stereoisomer (first elution peak) (1.7 mg, 1.5%) as a colorless film and the cis stereoisomer (second elution peak) (12.1 mg, 10%) as a yellowish-brown film. Peak 1: 1 H NMR (500 MH z, CD 3 OD) δ ppm 0.80 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 7.1 Hz, 3 H), 1.31 (app d, J = 6.4 Hz, 6 H), 1.70 - 1.82 (m, 1 H), 1.89 - 2.08 (m, 3 H), 2.87 (s, 3 H), 2.90 - 2.96 (m, 1 H), 3.04 - 3.11 (m, 1 H), 3.45 - 3.53 (m, 2 H), 3.92 - 4.04 (m, 1 H), 4.38 - 4.55 (m, 2 H), 7.06 - 7.14 (m, 1 H), 7.56 - 7.64 (m, 1 H), 7.95 - 8.03 (m, 1 H), 8.31 - 8.39 (m, 1 H); ESI-MS [M+H] + C 20 H 30 F 3 N 3 O 2 Calculated value for, 402.23; Measured value, 402. 4. Peak 2: 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.80 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 7.1 Hz, 3 H), 1.31 (app d, J = 6.4 Hz, 6 H), 1.70 - 1.82 (m, 1 H), 1.89 - 2.08 (m, 3 H), 2.87 (s, 3 H), 2. 90 - 2.96 (m, 1 H), 3.04 - 3.11 (m, 1 H), 3.45 - 3.53 (m, 2 H), 3.92 - 4.04 (m, 1 H), 4.38 - 4.55 (m, 2 H), 7.06 - 7.14 (m, 1 H), 7.56 - 7.64 (m, 1 H), 7.95 - 8.03 (m, 1 H), 8.31 - 8.39 (m, 1 H); ESI-MS [M+H] + C 20 H 30 F 3 N 3 O 2 Calculated value for 402.23; Measured value, 402.4.

[0687] Example 35: 2,2-Dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,5,5-trimethylpyrrolidin-3-yl)propanamide

[0688]

Chemical Structure

[0689] The title compound was prepared in a manner similar to Example 1, using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.113 g, 0.450 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid, and 1,5,5-trimethylpyrrolidin-3-amine (0.055 g, 0.43 mmol) instead of 1-methylpiperidin-4-amine. The crude product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (19.4 mg, 9.3%) as a brown film. 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.31 (s, 9 H), 1.50 (s, 3 H), 2.06 - 2.17 (m, 1 H), 2.40 - 2.52 (m, 1 H), 2.76 (s, 3 H ), 3.50 - 3.69 (m, 2 H), 4.43 (s, 3 H), 7.05 - 7.13 (m, 1 H), 7.91 - 8.03 (m, 1 H), 8.31 - 8 .39 (m, 1 H); ESI-MS [M+H] + C 18 H 26 F 3 N 3 O 2 Calculated for, 374.20; Found, 374.4.

[0690] Example 36: (R)-2,2-Dimethyl-N-((1-methylpyrrolidin-3-yl)methyl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0691]

Chemical Structure

[0692] The title compound was prepared in a manner similar to Example 1 using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.060 g, 0.23 mmol) and (R)-(1-methylpyrrolidin-3-yl)methanamine (0.026 g, 0.23 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid and 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (71.5 mg, 66%) as a colorless film. 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.31 (app d, J = 1.8 Hz, 6 H), 1.68 - 1. 97 (m, 1 H), 2.06 - 2.34 (m, 1 H), 2.55 - 2.86 (m, 2 H), 2.91 (s, 3 H), 3.01 - 3.17 (m, 1 H) , 3.22 - 3.28 (m, 1 H), 3.33 - 3.49 (m, 1 H), 3.56 - 3.81 (m, 2 H), 4.43 (d, J = 0.9 Hz, 2 H ), 7.00 - 7.16 (m, 1 H), 7.92 - 8.01 (m, 1 H), 8.30 - 8.42 (m, 1 H); ESI-MS [M+H] + C 17 H 24 F 3 N 3 O 2 Calculated for, 360.19; Found, 360.3.

[0693] Example 37: (S)-2,2-Dimethyl-N-((1-methylpyrrolidin-3-yl)methyl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0694]

Chemical Structure

[0695] The title compound was prepared in a manner similar to Example 1, using 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.060 g, 0.23 mmol) and (S)-(1-methylpyrrolidin-3-yl)methanamine (0.026 g, 0.23 mmol) instead of 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanoic acid and 1-methylpiperidin-4-amine. The product was purified by preparative HPLC (Method A) to give the TFA salt of the title compound (86.5 mg, 80%) as a pale brown film. 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.31 (app d, J = 1.8 Hz, 6 H), 1.66 - 1.98 (m, 1 H), 2.05 - 2.31 (m, 1 H), 2.55 - 2.83 (m, 2 H), 2.90 (s, 3 H), 3.03 - 3.28 (m, 2 H) , 3.34 - 3.47 (m, 1 H), 3.55 - 3.76 (m, 2 H), 4.43 (d, J = 1.0 Hz, 2 H), 7.03 - 7.14 (m, 1 H ), 7.94 - 8.02 (m, 1 H), 8.35 (dd, J = 5.0, 1.1 Hz, 1 H); ESI-MS [M+H] + C 17 H 24 F 3 N 3 O 2 for calculated value, 360.19; found value, 360.3.

[0696] Example 38: 3-((3-Chloropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0697] [Chemical formula]

[0698] In a 20 mL vial, 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide (0.138 g, 0.380 mmol) was dissolved in DMF (1.5 mL) to obtain a colorless solution. Sodium hydride (60 wt%, 0.035 g, 0.87 mmol) was added. After stirring at room temperature for 30 minutes, 3-chloro-2-fluoropyridine (0.050 g, 0.38 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and rinsed with methanol. The filtrate was purified by preparative HPLC (Method A). The product-containing fractions were evaporated to give the TFA salt of the title compound (69.0 mg, 41%) as a transparent film. 1 H NMR( 500 MHz, CDCl 3 ) δ ppm 1.28 (s, 6 H), 1.95 - 2 .11 (m, 4 H), 2.83 (m, 5 H), 3.56 - 3.66 (m, 2 H), 3.98 - 4.11 (m, 1 H), 4.25 (s, 2 H), 6.31 - 6.37 (m, 1 H), 6.67 - 6.72 (m, 1 H), 7.50 - 7.58 (m, 1 H), 8.01 - 8.11 (m, 1 H); ESI-MS [M+H] + C 16 H 24 ClN 3 O 2 Calculated for, 326.16; Found, 326.19.

[0699] Example 39: 3-((3-Fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0700] [Chemical formula]

[0701] The title compound was prepared in a manner similar to Example 38, using 2,3-difluoropyridine (0.050 g, 0.43 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (26.1 mg, 19%) as a pale brown film. 1 H NMR (500 MHz, CDC l 3 ) δ ppm 1.30 (s, 6 H), 1.41 - 1.52 (m, 2 H), 1.84 - 1.94 (m, 2 H), 2.10 - 2.16 (m, 2 H), 2 .25 (s, 3 H), 2.65 - 2.77 (m, 2 H), 3.71 - 3.86 (m, 1 H), 4.34 (s, 2 H), 6.16 - 6.26 (m, 1 H ), 6.83 - 6.93 (m, 1 H), 7.29 - 7.38 (m, 1 H), 7.86 - 7.93 (m, 1 H); ESI-MS [M+H] + C 16 H 24 FN 3 O 2 Calculated for, 310.19; Found, 310.5.

[0702] Example 40: 3-((3,5-Difluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0703] [Chemical formula]

[0704] The title compound was prepared in a manner similar to Example 38 using 2,3,5-trifluoropyridine (0.050 g, 0.38 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to afford the title compound (23.7 mg, 19%) as a pale brown film. 1 H NMR (500 MHz, CDCl 3 ) δ ppm 1.26 - 1.32 (m, 6 H), 1.40 - 1.5 2 (m, 2 H), 1.85 - 1.95 (m, 2 H), 2.06 - 2.15 (m, 2 H), 2.21 - 2.30 (m, 3 H), 2.67 - 2.79 (m, 2 H), 3.72 - 3.85 (m, 1 H), 4.30 (s, 2 H), 6 .03 - 6.13 (m, 1 H), 7.16 - 7.24 (m, 1 H), 7.78 - 7.85 (m, 1 H); ESI-MS [M+H] + C 16 H 23 F 2 N 3 O 2 Calculated for, 328.18; Found, 328.4.

[0705] Example 41: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0706]

Chemical Structure

[0707] The title compound was prepared in a manner similar to Example 38, using 2-fluoro-3-(trifluoromethyl)pyridine (0.12 g, 0.73 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (68.7 mg, 26%) as a pale green film. 1 H NMR (500 MHz, CDCl 3 ) δ ppm 1.30 (s, 6 H), 1.45 (dd, J = 12.2, 3.9 Hz, 2 H), 1.83 - 1.92 (m, 2 H) 2.06 (td, J = 11.6, 1.7 Hz, 2 H), 2.25 (s, 3 H), 2.77 (d, J = 11.7 Hz, 2 H), 3.71 - 3.81 (m, 1 H), 4.39 (s, 2 H), 5.98 - 6.08 (m, 1 H), 6.93 - 7.03 (m, 1 H), 7.84 - 7.92 (m, 1 H), 8.23 - 8.36 (m, 1 H); ESI-MS [M+H] + C 17 H 24 F 3 N 3 O 2 for calculated, 360.18; found, 360.5.

[0708] Example 42: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-((4-(trifluoromethyl)pyridin-3-yl)oxy)propanamide

[0709]

Chemical Structure

[0710] The title compound was prepared in a manner similar to Example 38, using 3-fluoro-4-(trifluoromethyl)pyridine (0.12 g, 0.73 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (87.2 mg, 67%) as a pale brown film. 1 H NMR (500 MHz, CDCl 3 ) δ ppm 1.33 (s, 6 H), 1.41 - 1. 54 (m, 2 H), 1.86 - 1.93 (m, 2 H), 2.03 - 2.14 (m, 2 H), 2.26 (s, 3 H), 2.78 (d, J = 11.7 Hz , 2 H), 3.69 - 3.84 (m, 1 H), 4.15 (s, 2 H), 5 .82 - 5.92 (m, 1 H), 7.45 (d, J = 4.9 Hz, 1 H) , 8.37 - 8.42 (m, 1 H), 8.44 - 8.52 (m, 1 H); ESI-MS [M+H] + C 17 H 24 F 3 N 3 O 2 Calculated for, 360.18 ; Found, 360.5.

[0711] Example 43: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-4-yl)oxy)propanamide

[0712]

Chemical Structure

[0713] The title compound was prepared in a manner similar to Example 38 using 4-chloro-3-(trifluoromethyl)pyridine (0.070 g, 0.39 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (39.4 mg, 28%) as a pale brown film. 1 H NMR (500 MHz, CDCl 3 ) δ ppm 1.32 (s, 6 H), 1.41 - 1. 52 (m, 2 H), 1.82 - 1.92 (m, 2 H), 2.04 - 2.07 (m, 2 H), 2.26 (s, 3 H), 2.70 - 2.83 (m, 2 H) , 3.69 - 3.81 (m, 1 H), 4.08 (s, 2 H), 5.76 - 5.86 (m, 1 H), 6.88 - 6.98 (m, 1 H), 8.58 - 8.64 (m, 1 H), 8.65 - 8.70 (m, 1 H); ESI-MS [M+H] + C 17 H 24 F 3 N 3 O 2 Calculated for, 360.18; Found, 360. 5.

[0714] Example 44: 3-((4-Chloro-3-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0715]

Chemical Structure

[0716] The title compound was prepared in a manner similar to Example 38, using 4-chloro-2,3-difluoropyridine (0.12 g, 0.80 mmol, 2 eq) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (66.2 mg, 48%) as a brown film. 1 H NMR (500 MHz , CDCl 3 ) δ ppm 1.30 (s, 6 H), 1.48 (br s, 2 H), 1.86 - 1.95 (m, 2 H), 2.11 (br s, 2 H), 2.27 (s, 3 H), 2.73 (d, J = 9.8 Hz, 2 H), 3.75 - 3.85 (m, 1 H), 4.35 (s, 2 H), 6.01 - 6.09 (m, 1 H), 6.94 (dd, J = 5.4, 4.4 Hz, 1 H), 7.80 (dd , J = 5.4, 1.0 Hz, 1 H); ESI-MS [M+H] + C 16 H 23 ClFN 3 O 2 Calculated for, 344.15; found, 344.4.

[0717] Example 45: 3-((3-Chloro-5-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0718]

Chemical formula

[0719] The title compound was prepared in a manner similar to Example 38 using 3-chloro-2,5-difluoropyridine (0.094 g, 0.63 mmol, 1.7 eq) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound as a peach-colored solid (39.2 mg, 31%). 1 H NMR (500 MH z, CDCl 3 ) δ ppm 1.31 (s, 6 H), 1.39 - 1.52 (m , 2 H), 1.84 - 1.93 (m, 2 H), 2.05 - 2.14 (m, 2 H), 2.25 (s, 3 H), 2.68 - 2.77 (m, 2 H), 3.69 - 3.83 (m, 1 H), 4.03 (s, 2 H), 5.75 - 5.87 (m, 1 H), 6.46 - 6.50 (m, 1 H), 7.81 - 7.90 (m, 1 H); ESI-MS [M+H] + C 16 H 23 ClFN 3 O 2 Calculated for, 344.15; Found, 344.2.

[0720] Example 46: 3-((6-Chloro-2-methylpyridin-3-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0721]

Chem.

[0722] The title compound was prepared in a manner similar to Example 38, using 6-chloro-3-fluoro-2-methylpyridine (0.092 g, 0.63 mmol, 1.7 equiv) instead of 3-chloro-2-fluoropyridine. The reaction mixture was heated at 100 °C and the product was purified by preparative HPLC (Method B) to give the title compound (12.1 mg, 9.6%) as a brown film. 1 H NMR (500 MHz, CDCl 3 ) δ ppm 1.30 (s, 6 H), 1.41 - 1.52 (m, 2 H), 1.87 - 1.95 (m, 2 H), 2.06 - 2.16 (m, 2 H), 2.28 (s, 3 H), 2. 35 (s, 3 H), 2.73 (br s, 2 H), 3.74 - 3.86 (m, 1 H), 3.95 (s, 2 H), 5.77 - 5.86 (m, 1 H), 7. 07 - 7.14 (m, 1 H), 7.85 - 7.93 (m, 1 H); ESI- MS [M+H] + C 17 H 26 ClN 3 O 2 Calculated for, 340.17; found value, 340.3.

[0723] Example 47: 3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0724]

Chemical Structure

[0725] The title compound was prepared in a manner similar to Example 38, using 3-cyclopropyl-2-fluoropyridine (0.050 g, 0.36 mmol, 1 equivalent) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (21.4 mg, 18%) as a pale brown film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.63 - 0.70 (m, 2 H), 0.87 - 0.96 (m, 2 H), 1.29 - 1.34 (m, 6 H), 1.50 - 1.61 (m, 2 H), 1.76 - 1.85 (m, 2 H), 1.97 - 2.05 (m, 1 H), 2.05 - 2.16 (m, 2 H), 2.27 (dd, J = 2.7, 1.7 Hz, 3 H), 2.79 - 2.89 (m, 2 H), 3. 66 - 3.76 (m, 1 H), 4.29 - 4.35 (m, 2 H), 6.80 - 6.88 (m, 1 H), 7.20 - 7.28 (m, 1 H), 7.86 - 7.91 (m, 1 H); ESI-MS [M+H] + C 19 H 29 N 3 O 2 for calculated value, 332.23; found value, 332.40.

[0726] Example 48: 3-((5-Chloro-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0727]

Chemical Structure

[0728] The title compound was prepared in a manner similar to Example 38, using 2,5-dichloro-3-methylpyridine (0.060 g, 0.37 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The reaction mixture was heated at 100 °C and the product was purified by preparative HPLC (Method B) to give the title compound (23.4 mg, 19%) as a brown film . 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.28 (s, 6 H), 1.51 - 1.60 (m, 2 H), 1.75 - 1.81 (m, 2 H), 2 .06 - 2.13 (m, 2 H), 2.15 (s, 3 H), 2.26 (s, 3 H), 2.80 - 2.87 (m, 2 H), 3.65 - 3.74 (m, 1 H ), 4.29 (s, 2 H), 7.48 - 7.52 (m, 1 H), 7.88 - 7.91 (m, 1 H); ESI-MS [M+H] + C 17 H 26 ClN 3 O 2 for, calculated 340.17; found 340.47.

[0729] Example 49: 3-((3-Methoxypyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0730]

Chemical formula

[0731] The title compound was prepared in a manner similar to Example 38, using 2-fluoro-methoxypyridine (0.050 g, 0.39 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The reaction mixture was heated at 100 °C and the product was purified by preparative HPLC (Method B) to give the title compound (43.0 mg, 34%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.27 (s, 6 H), 1. 50 - 1.60 (m, 2 H), 1.79 - 1.85 (m, 2 H), 2.08 - 2.18 (m, 2 H), 2.27 (s, 3 H), 2.79 - 2.86 ( m, 2 H), 3.65 - 3.73 (m, 1 H), 3.84 (s, 3 H), 4.29 (s, 2 H), 6.88 - 6.93 (m, 1 H), 7.21 - 7.26 (m, 1 H), 7.62 - 7.66 (m, 1 H); ESI-MS [M+H] + C 17 H 27 N 3 O 3 Calculated for, 322.21; Found, 322.41 .

[0732] Example 50: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-methylpyridin-4-yl)oxy)propanamide

[0733]

Chemical Structure

[0734] The title compound was prepared in a manner similar to Example 38, using 4-fluoro-3-methylpyridine (0.050 g, 0.45 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (41.2 mg, 30%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.32 (s, 6 H), 1.53 - 1.64 (m, 2 H), 1.74 - 1.85 (m, 2 H), 2.06 - 2.13 (m, 2 H), 2.16 (s, 3 H), 2.27 (s, 3 H), 2.81 - 2.89 (m, 2 H), 3.65 - 3.78 (m, 1 H), 4.09 (s, 2 H), 6. 92 - 7.01 (m, 1 H), 8.12 - 8.18 (m, 1 H), 8.21 - 8.27 (m, 1 H); ESI-MS [M+H] + C 17 H 27 N 3 O 2 For calculated for, 306.21; found, 306.31.

[0735] Example 51: 3-((5-Cyano-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0736]

Chemical Structure

[0737] The title compound was prepared in a manner similar to Example 38, using 6-fluoro-5-methylnicotinonitrile (0.050 g, 0.37 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (27.6 mg, 23%) as a colorless film.1 1H NMR (500 M Hz, CD 3 OD) δ ppm 1.30 (s, 6 H), 1.50 - 1.61 ( m, 2 H), 1.74 - 1.81 (m, 2 H), 2.05 - 2.13 (m, 2 H), 2.19 (s, 3 H), 2.26 (s, 3 H), 2.82 - 2. 88 (m, 2 H), 3.65 - 3.74 (m, 1 H), 4.40 (s, 2 H), 7.76 - 7.80 (m, 1 H), 8.32 - 8.37 (m, 1 H); ESI-MS [M+H] + C 18 H 26 N 4 O 2 Calculated for, 331.21 ; Found, 331.3.

[0738] Example 52: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-((2-(trifluoromethyl)pyridin-3-yl)oxy)propanamide

[0739]

Chem.

[0740] The title compound was prepared in a manner similar to Example 38 using 3-fluoro-2-(trifluoromethyl)pyridine (0.060 g, 0.36 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to afford the title compound (28.0 mg, 21%) as a colorless film. 1 1H NMR (500 MHz, CD 3 OD) δ ppm 1.32 (s, 6 H), 1.53 - 1. 63 (m, 2 H), 1.77 - 1.84 (m, 2 H), 2.06 - 2.15 (m, 2 H), 2.27 (s, 3 H), 2.83 - 2.89 (m, 2 H) , 3.66 - 3.74 (m, 1 H), 4.15 (s, 2 H), 7.61 (dd, J = 8.5, 4.6 Hz, 1 H), 7.67 - 7.72 (m, 1 H) , 8.17 - 8.21 (m, 1 H); ESI-MS [M+H] + C 17 H 24 F 3 N 3 O 2 Calculated for, 360.18; Found, 360.3.

[0741] Example 53: (R)-3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0742]

Chemical Structure

[0743] The title compound was prepared in a similar manner to Example 38, using (R)-3-hydroxy-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide (0.088 g, 0.44 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 3-cyclopropyl-2-fluoropyridine (0.060 g, 0.44 mmol) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (20.3 mg, 15%) as a brown film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.62 - 0.70 (m, 2 H), 0.92 (dd, J = 8.5 , 1.7 Hz, 2 H), 1.31 (app d, J = 1.5 Hz, 6 H), 1.61 - 1.73 (m, 1 H), 1.98 - 2.05 (m, 1 H), 2.20 - 2.30 (m, 1 H), 2.33 (s, 3 H), 2.39 - 2.48 (m, 2 H), 2.73 (s, 2 H), 4.31 (s, 2 H), 4.36 - 4.45 (m, 1 H), 6.81 - 6.87 (m, 1 H), 7.19 - 7.28 (m, 1 H), 7.81 - 7.93 (m, 1 H); ESI-MS [M+H] + C 18 H 27 N 3 O 2 Calculated for, 318.21; Found, 318. 26.

[0744] Example 54: 3-((3-Ethoxypyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0745]

Chem.

[0746] The title compound was prepared in a manner similar to Example 38 using 3-ethoxy-2-fluoropyridine (0.060 g, 0.42 mmol, 1 equiv) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (86.2 mg, 60%) as a colorless foam. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.28 (s, 6 H), 1.35 - 1.43 (m, 3 H), 1.50 - 1.61 (m, 2 H), 1.74 - 1.86 (m, 2 H), 2 .02 - 2.14 (m, 2 H), 2.25 (s, 3 H), 2.76 - 2.85 (m, 2 H), 3.61 - 3.76 (m, 1 H), 4.06 (d, J = 6.8 Hz, 2 H), 4.30 (s, 2 H), 6.82 - 6.90 (m, 1 H), 7.15 - 7.24 (m, 1 H), 7.60 - 7.66 (m, 1 H ); ESI-MS [M+H] + C 18 H 29 N 3 O 3 Calculated for, 336.22; Found, 336.6.

[0747] Example 55: trans-N-(4-(4-Chlorophenyl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide

[0748]

Chemical Structure

[0749] The title compound was prepared in a manner similar to Example 38, using trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-hydroxy-2,2-dimethylpropanamide (0.160 g, 0.360 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 2-fluoro-3-methylpyridine (0.040 g, 0.36 mmol) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (61.0 mg, 42%) as a brown solid. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.27 (app d, J = 3.91 Hz, 6 H), 2.00 (s, 3 H), 2.39 (s, 3 H), 2.51 - 2.59 (m, 1 H), 2.60 - 2.70 (m, 1 H), 2.84 - 2.98 ( m, 1 H), 3.13 - 3.19 (m, 1 H), 4.26 (d, J = 6. 4 Hz, 2 H), 4.45 - 4.53 (m, 1 H), 6.77 - 6.87 (m, 1 H), 7.15 - 7.22 (m, 4 H), 7.39 - 7.47 (m, 1 H), 7.90 (dd, J = 4.4, 2.0 Hz, 1 H); ESI-M S [M+H] + C 22 H 28 ClN 3 O 2 Calculated for, 402.19; found , 402.4.

[0750] Example 56: trans-N-(4-(4-Chlorophenyl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0751]

Chemical Structure

[0752] The title compound was prepared in a manner similar to Example 38, using trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-hydroxy-2,2-dimethylpropanamide (0.147 g, 0.331 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 2-chloro-3-(trifluoromethyl)pyridine (0.060 g, 0.33 mmol) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (59.2 mg, 39%) as a brown film. 1 H NMR (500 MHz, CD 3OD) δ ppm 1.27 (app d, J = 12.7 Hz, 6 H), 2.40 (s, 3 H), 2.55 (s, 1 H), 2 .65 - 2.73 (m, 1 H), 2.86 - 2.96 (m, 1 H), 3.12 - 3.21 (m, 1 H), 3.26 - 3.30 (m, 1 H), 4.34 - 4.44 (m, 2 H), 4.44 - 4.54 (m, 1 H), 7.04 - 7.10 (m, 1 H), 7.22 (d, J = 1.5 Hz, 4 H), 7.90 - 8.01 (m, 1 H), 8.32 (dd, J = 5.1, 1.2 Hz, 1 H), 8.81 - 8.83 (m, 1 H); ESI-MS [M+H] + C 22 H 25 ClF 3 N 3 O 2 Calculated for C H ClF N O, 456.16; Found, 456.4.

[0753] Example 57: trans-2,2-Dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide

[0754]

Chemical Structure

[0755] The TFA salt of the title compound was prepared in a manner similar to Example 38, using trans-3-hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide (0.155 g, 0.450 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 2-fluoro-3-methylpyridine (0.050 g, 0.45 mmol) instead of 3-chloro-2-fluoropyridine. The product was isolated as a colorless film (4.6 mg, 1.8%). 1 H NMR (500 MH z, CD 3 OD) δ ppm 1.29 (s, 6 H), 1.96 - 2.07 (m , 3 H), 3.05 (br s, 3 H), 3.38 - 3.49 (m, 1 H) , 3.61 - 3.70 (m, 1 H), 3.72 - 3.81 (m, 1 H), 3.85 - 3.97 (m, 1 H), 4.03 - 4.14 (m, 1 H), 4.24 - 4.32 (m, 2 H), 4.48 - 4.59 (m, 1 H), 6.80 - 6.90 (m, 1 H), 7.39 - 7.50 (m, 1 H), 7.67 - 7.77 (m, 1 H), 7.87 - 7.93 (m, 1 H), 7.95 - 8.05 (m, 1 H), 8.58 - 8.68 (m, 1 H);ESI-MS [M+H] + C 22 H 27 F 3 N 4 O 2 Calculated for, 437.21; Found, 437. 3.

[0756] Example 58: trans-3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide

[0757] [Chemical]

[0758] The TFA salt of the title compound was prepared in a manner similar to Example 38 using trans-3-hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide (0.151 g, 0.450 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 3-cyclopropyl-2-fluoropyridine (0.060 g, 0.44 mmol) instead of 3-chloro-2-fluoropyridine. The product was isolated as a colorless film (1.4 mg, 0.5%). 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.52 - 0.68 (m, 2 H), 0.7 7 - 0.85 (m, 2 H), 0.88 - 0.93 (m, 1 H), 0.97 - 1.02 (m, 1 H), 1.32 (br s, 6 H), 2.99 - 3.09 (m, 3 H), 3.60 - 3.70 (m, 1 H), 3.75 - 3.83 ( m, 1 H), 3.90 - 4.00 (m, 1 H), 4.08 - 4.16 (m, 1 H), 4.27 - 4.33 (m, 2 H), 4.37 - 4.43 (m, 1 H), 6.79 - 6.90 (m, 1 H), 7.19 - 7.27 (m, 1 H), 7.68 - 7.76 (m, 1 H), 7.83 - 7.90 (m, 1 H), 7.93 - 8.00 (m, 1 H), 8.56 - 8.68 (m, 1 H); ES I-MS [M+H] + C 24 H 29 F 3 N4 O 2 Calculated value for, 463.22; Measured value, 463.4.

[0759] Example 59: trans-2,2-Dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0760]

Chemical formula

[0761] The title compound was prepared in a manner similar to Example 38 using trans-3-hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide (0.152 g, 0.441 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 2-chloro-3-(trifluoromethyl)pyridine (0.080 g, 0.44 mmol) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (16. 9 mg, 7.8%) as a colorless film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.71 - 0.80 (m, 1 H), 0.95 - 1.00 (m, 1 H), 1.28 (app d, J = 5.9 Hz, 6 H), 2.44 (s, 3 H), 2. 66 - 2.73 (m, 1 H), 2.99 - 3.07 (m, 1 H), 3.18 - 3.25 (m, 1 H), 3.38 - 3.45 (m, 1 H) 4.39 (d , J = 2.0 Hz, 1 H), 4.45 - 4.54 (m, 1 H), 7.03 - 7.12 (m, 1 H), 7.66 - 7.75 (m, 1 H), 7.92 - 8.01 (m, 2 H), 8.27 - 8.35 (m, 1 H), 8.51 - 8.63 (m, 1 H); ESI-MS [M+H] + C 22 H 24 F 6 N 4 O 2 for calculated value, 491.18; found value, 491.4.

[0762] Example 60: trans-2,2-Dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide

[0763] [Chemical formula]

[0764] The TFA salt of the title compound was prepared in a manner similar to Example 38, using trans-3-hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide (0.131 g, 0.450 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 2-fluoro-3-methylpyridine (0.050 g, 0.45 mmol) instead of 3-chloro-2-fluoropyridine. The product was isolated as a colorless film (23.1 mg, 10%). 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.29 (s, 6 H), 2.02 - 2.13 (m, 3 H), 2. 65 - 2.76 (m, 3 H), 3.05 (s, 3 H), 3.44 - 3.82 (m, 2 H), 4.01 (d, J = 2.4 Hz, 3 H), 4.26 (d, J = 2.0 Hz, 2 H), 4.75 - 4.84 (m, 1 H), 6.83 - 6.90 (m, 1 H), 7.46 - 7.52 (m, 1 H), 7.76 - 7.84 (m, 1 H), 7.88 - 7.95 (m, 1 H), 8.37 - 8.45 (m, 1 H), 8.69 - 8.73 (m, 1 H); ESI-MS [M+H] + C 22 H 30 N 4 O 2 Calculated value for C, H, N, O, 383.24; Found, 383.4.

[0765] Example 61: trans-3-((3-Cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide

[0766] [Chemical Structure]

[0767] The title compound was prepared in a manner similar to Example 38, using trans-3-hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide (0.124 g, 0.437 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 3-cyclopropyl-2-fluoropyridine (0.060 g, 0.44 mmol) instead of 3-chloro-2-fluoropyridine. The product was purified by preparative HPLC (Method B) to give the title compound (35.2 mg, 20%) as a pale green film. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.58 (d, J = 5.4 Hz, 2 H), 0.76 - 0.83 (m, 2 H), 1.29 (s, 6 H), 1.82 - 1.93 (m, 1 H), 2.40 (s, 3 H), 2.46 (s, 3 H), 2.54 - 2.59 (m, 1 H), 2.62 - 2.69 ( m, 1 H), 2.94 (s, 1 H), 3.11 - 3.19 (m, 1 H), 3.25 - 3.29 (m, 1 H), 4.29 (s, 2 H), 4.45 - 4.53 (m, 1 H), 6.80 - 6.86 (m, 1 H), 7.14 - 7.19 (m, 1 H), 7.20 - 7.23 (m, 1 H), 7.61 - 7.69 ( m, 1 H), 7.83 - 7.91 (m, 1 H), 8.21 - 8.27 (m, 1 H); ESI-MS [M+H] + C 24 H 32 N 4 O 2 Calculated for, 40 9.25; Found, 409.4.

[0768] Example 62: trans-2,2-Dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

[0769]

Chemical formula

[0770] The TFA salt of the title compound was prepared in a manner similar to Example 38, using trans-3-hydroxy-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide (0.127 g, 0.424 mmol) instead of 3-hydroxy-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide, and 2-fluoro-3-(trifluoromethyl)pyridine (0.070 g, 0.42 mmol) instead of 3-chloro-2-fluoropyridine. The product was isolated as a colorless film (2.2 mg, 0.9%). 1 H NMR (500 MH z, CD 3 OD) δ ppm 1.28 (app d, J = 11.7 Hz, 6 H), 2.72 (s, 3 H), 3.05 (s, 3 H), 3.09 - 3.16 (m, 1 H), 3.45 (d, J = 1.5 Hz, 1 H), 3.66 - 3.79 (m, 1 H), 3.87 - 3.97 (m, 1 H), 3.99 - 4.12 (m, 1 H), 4.39 (s, 2 H), 4.59 - 4.71 (m, 1 H), 7 .04 - 7.13 (m, 1 H), 7.75 - 7.82 (m, 1 H), 7.91 - 8.01 (m, 1 H), 8.29 - 8.37 (m, 2 H), 8.62 - 8.68 (m, 1 H); ESI-MS [M+H] + C 22 H 27 F 3 N 4 O 2 Calculated for, 437.21; Found, 437.4.

[0771] Example 63: N-(1-Methylpiperidin-4-yl)-1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropane-1-carboxamide

[0772]

Chemical Structure

[0773] Sodium hydride (60 wt%, 0.067 g, 1.7 mmol) was added to a solution of 2-fluoro-3-methylpyridine (0.124 g, 1.11 mmol) and 1-(hydroxymethyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide (0.118 g, 0.145 mmol) in DMF (2.78 mL). The reaction mixture was stirred at room temperature for 1 h, then diluted with methanol, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified by preparative HPLC (Method B) to give the title compound (0.044 g, 26%) as a clear oil. 1 H NMR (500 MHz, CD 3 OD) δ 0.84 - 0.97 (m, 2 H), 1.15 - 1.28 (m, 2 H), 1.45 - 1.63 (m, 2 H), 1.78 - 1.90 (m, 2 H), 2.06 - 2.14 ( m, 2 H), 2.20 (s, 3 H), 2.25 (s, 3 H), 2.81 (d, J = 11.7 Hz, 2 H), 3.72 (tt, J = 11.0, 4.4 H z, 1 H), 4.50 (s, 2 H), 6.88 (dd, J = 7.3, 4.9 Hz, 1 H), 7.47 - 7.55 (m, 1 H), 7.93 - 7.99 ( m, 1 H); ESI-MS [M+H] + C 17 H 25 N 3 O 2 Calculated for, 304.20; Found, 304.20.

[0774] Example 64: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-(2-(trifluoromethyl)phenoxy)propanamide

[0775] [Chem.]

[0776] A solution of 2,2-dimethyl-3-(2-(trifluoromethyl)phenoxy)propanoic acid (65.6 mg, 0.250 mmol) in DMF (1.25 mL) was treated with triethylamine (34.8 μL, 0.250 mmol) and HATU (95.0 mg, 0.250 mmol). After stirring for 5 minutes, 1-methylpiperidin-4-amine (28.5 mg, 0.250 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and rinsed with MeOH. The filtrate was purified by preparative HPLC (Method A) eluting with a slow gradient of 10 - 50% ACN in water. The product-containing fractions were evaporated, then taken up in MeOH and filtered through a 500 mg basic cartridge. The filtrate was evaporated and dried under vacuum to give the title compound (25.5 mg, 28%) as a colorless oil. filtered through and rinsed with MeOH. The filtrate was purified by preparative HPLC (Method A) eluting with a slow gradient of 10 - 50% ACN in water. The product-containing fractions were evaporated, then taken up in MeOH and filtered through an Agilent PL-HCO 3 500 mg basic cartridge. The filtrate was evaporated and dried under vacuum to give the title compound (25.5 mg, 28%) as a colorless oil. 1 H NMR (500 M Hz, CD 3 OD) δ ppm 1.32 (s, 6 H), 1.59 (qd, J = 12.2, 3.9 Hz, 2 H), 1.78 - 1.88 (m, 2 H), 2.1 2 (td, J = 12.2, 2.4 Hz, 2 H), 2.28 (s, 3 H), 2.87 (d, J = 12.2 Hz, 2 H), 3.72 (tt, J = 11.3, 4.3 Hz, 1 H), 4.09 (s, 2 H), 7.06 (t, J = 7. 6 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 1 H), 7.53 - 7.60 (m, 2 H); ESI-MS [M+H] + C 18 H 25 F3 N 2 O 2 Calculated value for, 359.20; Measured value, 359.7.

[0777] Example 65: (R)-2,2-Dimethyl-N-(1-methylpyrrolidin-3-yl)-3-(2-(trifluoromethyl)phenoxy)propanamide

[0778]

Chemical Structure

[0779] The title compound was prepared in a manner similar to Example 64, using (R)-1-methylpyrrolidin-3-amine (25.0 mg, 0.250 mmol, 1 equiv) instead of 1-methylpiperidin-4-amine. The product was isolated as a colorless oil (25.6 mg, 30%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.20 (d, J = 1.0 Hz, 6 H), 1.56 - 1.65 (m, 1 H), 1.99 - 2.09 (m, 1 H), 2.20 (s, 3 H), 2.26 (dd, J = 9.3, 4.9 Hz, 1 H), 2.33 (td, J = 8.2, 6.6 Hz, 1 H), 2.52 - 2.55 (m, 1 H), 2.57 (dd, J = 9.3, 7.3 Hz, 1 H), 4.07 (s, 2 H), 4.14 - 4.25 (m, 1 H), 7.08 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 8. 3 Hz, 1 H), 7.45 (d, J = 7.3 Hz, 1 H), 7.57 - 7.65 (m, 2 H); ESI-MS [M+H] + C 17 H 23 F 3 N 2 O 2Calculated value for, 345.18; Measured value, 345.6.

[0780] Example 66: 3-(2-Chlorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0781] [Chemical formula]

[0782] A 250 mL round-bottom flask was charged with 3-(2-chlorophenoxy)-2,2-dimethylpropanoic acid (6.50 g, 28.4 mmol), anhydrous EtOH (65 mL), and 1-methylpiperidin-4-amine (3.25 g, 28.4 mmol). The resulting solution was cooled to 8 °C, and 4-(4,6-dimethyl-1,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride hydrate (9.22 g, 31.3 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. Subsequently, the mixture was filtered to remove solids, rinsed with MTBE. The filtrate was concentrated under reduced pressure to give an oil (22.5 g). The oil was dissolved in MTBE (65 mL) and washed twice with 1 M aqueous NaOH solution (30 mL, then 50 mL), then with water (50 mL). The organic phase was concentrated and dried under vacuum to give the title compound in free form (9.23 g, presumed quantitative) as an oil. A portion of the free form (2.00 g, 5.85 mmol) was dissolved in EtOH (10 mL) and transferred to a 100 mL round-bottom flask equipped with a stir bar. A solution of citric acid (1.124 g, 5.85 mmol) in EtOH (6 mL) was added at room temperature, and rinsed with EtOH (4 mL). The reaction mixture was stirred at room temperature for 1.75 h. The resulting precipitate was collected by filtration, washed with EtOH, and dried by suction. The product was further dried in a vacuum oven at 40 °C for 5 h to give the citrate salt of the title compound (2.09 g, 69.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.1 4 - 1.33 (m, 6 H), 1.59 - 1.75 (m, 2 H), 1.76 - 1.89 (m, 2 H), 2.46 - 2.72 (m, 8 H), 2.87 (td, J = 12.1, 2.2 Hz, 2 H), 3.25 (br d, J = 12. 4 Hz, 2 H), 3.59 - 3.64 (m, 1 H), 4.02 (s, 2 H ), 6.88 - 6.99 (m, 1 H), 7.12 (dd, J = 8.2, 1.0 Hz, 1 H), 7.20 - 7.34 (m, 1 H), 7.35 - 7.53 (m, 2 H); ESI-MS [M+H] + C 17 H 25 ClN 2 O 2 Calculated for, 325.17; Found, 325.10.

[0783] Example 67: 3-(2-Bromophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0784]

Chemical Structure

[0785] A solution of 3-(2-bromophenoxy)-2,2-dimethylpropanoic acid (328 mg, 1.2 mmol) in DMF (6 mL) was treated with Et 3 N (167 μL, 1.20 mmol) and HATU (456 mg, 1.20 mmol). After stirring for 5 minutes, 1-methylpiperidin-4-amine (137 mg, 1.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water and saturated aqueous NaCl and extracted with DCM. The organic phase was dried over Na 2 SO 4It was dried over, filtered, and concentrated under reduced pressure. The residue was dry loaded onto silica and purified by automated flash silica column chromatography (ISCO® 40 g column) eluting with a gradient of 0 - 20% MeOH in DCM to give the title compound (327.3 mg, 73.9%) as a colorless oil. (327.3 mg, 74%). 1 H NMR (500 MH z, CD 3 OD) δ ppm 1.34 (s, 6 H), 1.69 - 1.84 (m , 2 H), 1.97 - 2.07 (m, 2 H), 2.64 (s, 3 H), 2 .76 (t, J = 11.7 Hz, 2 H), 3.25 (d, J = 12.2 H z, 2 H), 3.89 (tt, J = 11.2, 4.2 Hz, 1 H), 4.04 (s, 2 H), 6.83 - 6.89 (m, 1 H), 7.03 (dd, J = 8.3, 1.5 Hz, 1 H), 7.27 - 7.33 (m, 1 H), 7.51 (dd, J = 8.0, 1.7 Hz, 1 H); ESI-MS [M+H] + C 17 H 25 BrN 2 O 2 Calculated for, 369.12; Found, 369.10.

[0786] Example 68: (R)-3-(2-Chlorophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0787]

Chem.

[0788] A solution of 3-(2-chlorophenoxy)-2,2-dimethylpropanoic acid (57.2 mg, 0.25 mmol) in DMF (1.25 mL) was treated with Et 3It was treated with N (34.8 μL, 0.250 mmol) and HATU (95 mg, 0.250 mmol). After stirring for 5 minutes, (R)-1-methylpyrrolidin-3-amine (25.04 mg, 0.250 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and rinsed with MeOH. The filtrate was purified by preparative HPLC (Method A and then Method B). The product-containing fractions were evaporated and dried under vacuum to give the title compound (24.4 mg, 31.4%) as a colorless oil. 1 H NMR (500 MHz, CD 3 OD) δ ppm 1.33 (s, 6 H), 1.69 - 1.79 (m, 1 H), 2.24 - 2.33 (m, 1 H), 2.36 (s, 3 H), 2.40 - 2.49 (m, 1 H), 2.53 (dd, J = 9.8, 4.4 Hz, 1 H), 2.70 - 2.81 (m, 2 H), 4.03 (s, 2 H), 4.42 (ddt, J = 9.0, 7.2, 4.6, 4.6 Hz, 1 H), 6.90 - 6.95 (m, 1 H), 7.06 (dd, J = 8.3, 1.0 Hz, 1 H), 7.26 (td, J = 7.8, 1.5 Hz, 1 H), 7.35 (dd, J = 8.0, 1.7 Hz, 1 H) ; ESI-MS [M+H] + C 16 H 23 ClN 2 O 2 Calculated for, 311. 15; Found, 311.10.

[0789] Example 69: (R)-3-(2-Bromophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0790]

Chemical Structure

[0791] A solution of 3-(2-bromophenoxy)-2,2-dimethylpropanoic acid (410 mg, 1.501 mmol) in DMF (7.506 mL) was treated with Et 3 N (152 mg, 1.50 mmol) and HATU (571 mg, 1.50 mmol). After stirring for 10 minutes, (R)-1-methylpyrrolidin-3-amine (150 mg, 1.50 mmol) was added. The reaction mixture was stirred overnight at room temperature, then diluted with water and extracted with DCM. The organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (ISCO® 40 g column) eluting with a gradient of 0 - 20% MeOH in DCM. The product-containing fractions were evaporated to give the title compound (458.4 mg, 86%) as an orange solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.23 (s, 6 H), 1.58 - 1.68 (m, 1 H), 2.01 - 2.11 (m, 1 H), 2 .21 (s, 3 H), 2.28 - 2.36 (m, 2 H), 2.53 - 2.62 (m, 2 H), 4.01 (s, 2 H), 4.21 (dtt, J = 9.5, 7.2, 7.2, 4.9, 4.9 Hz, 1 H), 6.89 (td, J = 7.6, 1.5 Hz, 1 H), 7.09 (dd, J = 8.3, 1.0 Hz, 1 H), 7.34 (td, J = 7.8, 1.5 Hz, 1 H), 7.45 (d, J = 7.3 Hz, 1 H), 7.56 (dd, J = 8.0, 1.7 Hz, 1 H); ESI-MS [M+H] + C 16 H 23 BrN 2 O 2 Calculated for, 35 5.10; Measured value, 355.10.

[0792] Example 70: 3-(2-Cyclopropylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0793]

Chemical Structure

[0794] A 5 mL microwave vial equipped with a stir bar was charged with 3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide (111 mg, 0.300 mmol), potassium cyclopropyltrifluoroborate (53.3 mg, 0.360 mmol), and potassium phosphate (159 mg, 0.750 mmol) in toluene (1.25 mL) and water (0.25 mL). The mixture was degassed under vacuum and refilled three times with nitrogen. RuPhos Pd G3 (25.09 mg, 0.030 mmol) was added, the mixture was degassed under vacuum and refilled two more times with nitrogen, and then the vial was sealed. The reaction mixture was irradiated in a Biotage® microwave reactor at 120 °C for 2 hours, then filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and rinsed with MeOH. The filtrate was concentrated under reduced pressure. The residue was taken up in MeOH and purified by preparative HPLC (Method A) eluting with a slow gradient of 10 - 50% ACN in water. The product-containing fractions were evaporated, then taken up in MeOH and filtered through a 500 mg basic cartridge. The filtrate was evaporated and dried under vacuum to afford the title compound (32.8 mg, 33%) as a colorless oil. 3 Filtered through a 500 mg basic cartridge. The filtrate was evaporated and dried under vacuum to afford the title compound (32.8 mg, 33%) as a colorless oil. 1 H NMR (500 MHz, CD 3 OD) δ ppm 0.55 - 0.64 (m, 2 H), 0.83 - 0.92 (m, 2 H), 1.32 (s, 6 H), 1.55 (qd, J = 12.2, 3.9 Hz, 2 H), 1.76 - 1.86 (m, 2 H), 2.03 - 2.16 ( m, 3 H), 2.25 (s, 3 H), 2.82 (d, J = 11.7 Hz, 2 H), 3.72 (tt, J = 11.4, 4.0 Hz, 1 H), 3.98 (s, 2 H), 6.80 - 6.84 (m, 2 H), 6.86 (d, J = 7. 8 Hz, 1 H), 7.04 - 7.11 (m, 1 H); ESI-MS [M+H] + C 20 H 30 N 2 O 2 Calculated for, 331.24; Found, 331.20.

[0795] Example 71: (R)-3-(2-Cyclopropylphenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide

[0796]

Chemical Structure

[0797] The title compound was prepared in a manner similar to Example 70, using (R)-3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide (107 mg, 0.300 mmol, 1 equiv) instead of 3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide. The product was isolated as a colorless oil (15.3 mg, 16%). H NMR (500 1 MHz, DMSO-d ) δ ppm 0.56 - 0.63 (m, 2 H), 0. 6 ) δ ppm 0.56 - 0.63 (m, 2 H), 0. 81 - 0.89 (m, 2 H), 1.22 (s, 6 H), 1.55 - 1.66 (m, 1 H), 1.98 - 2.13 (m, 2 H), 2.23 - 2.35 ( m, 2 H), 2.57 (dd, J = 9.3, 7.3 Hz, 1 H), 3.94 (s, 2 H), 4.21 (dtt, J = 9.5, 7.0, 7.0, 5.1, 5.1 Hz, 1 H), 6.78 - 6.85 (m, 2 H), 6.88 (d, J = 7.8 Hz, 1 H), 7.09 (ddd, J = 8.3, 6.1, 2.7 Hz, 1 H), 7.47 (d, J = 7.3 Hz, 1 H); ESI-MS [M +H] + C 19 H 28 N 2 O 2 Calculated for, 317.22; Found, 317. 3.

[0798] Example 72: 3-(2-Ethylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0799]

Chemical Structure

[0800] In a 20 mL vial, 3-(2-ethylphenoxy)-2,2-dimethylpropanoic acid (100 mg, 0.450 mmol) and 2-chloro-1-methylpyridin-1-ium iodide (345 mg, 1.35 mmol) were combined in DMF (2 mL) to form an activated intermediate. After 30 minutes, 1-methylpiperidin-4-amine (51.4 mg, 0.450 mmol) and triethylamine (314 μL, 2.25 mmol) were added. The reaction mixture was stirred overnight at room temperature and then purified by preparative HPLC (Method C) eluting with a gradient of 25 - 50% ACN in water to afford the title compound (66 mg, 46%) as a colorless oil. 1 H NMR (400 MHz, CD3 OD) δ ppm 1.2 0 (t, J = 7.6 Hz, 3 H), 1.32 - 1.42 (m, 6 H), 1.79 - 2.02 (m, 2 H), 2.12 (d, J = 14.2 Hz, 2 H ), 2.65 (q, J = 7.5 Hz, 2 H), 2.86 - 2.92 (m, 3 H), 3.14 (td, J = 13.1, 2.4 Hz, 2 H), 3.53 - 3.63 (m, 2 H), 3.94 - 4.11 (m, 3 H), 6.83 - 6 .99 (m, 2 H), 7.09 - 7.22 (m, 2 H); ESI-MS [M+H] + C 19 H 30 N 2 O 2 Calculated values for C, H, N, O, 319.24; Found, 319.5.

[0801] Example 73: 3-(4-Cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0802]

Chemical Structure

[0803] The title compound was prepared in a manner similar to Example 72, using 3-(4-cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethylpropanoic acid (200 mg, 0.696 mmol, 1 equiv) instead of 3-(2-ethylphenoxy)-2,2-dimethylpropanoic acid The product was isolated as a white solid (70 mg, 26%). 1 H NM R (400 MHz, CD 3 OD) δ ppm 1.33 - 1.41 (m, 6 H) , 1.81 - 2.04 (m, 2 H), 2.11 (d, J = 13.9 Hz, 2 H), 2.90 (s, 3 H), 3.14 (td, J = 13.1, 2.6 Hz, 2 H), 3.47 - 3.63 (m, 2 H), 3.94 - 4.12 (m, 1 H), 4.22 - 4.29 (m, 2 H), 7.41 (d, J = 6.7 Hz, 1 H), 7.97 - 8.04 (m, 2 H); ESI-MS [M+H] + C 19 H 24 F 3 N 3 O 2 Calculated for, 384.19; Found, 384.5.

[0804] Example 74: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-phenoxypropanamide

[0805]

Chem.

[0806] The title compound was prepared in a manner similar to Example 72, using 2,2-dimethyl-3-phenoxypropanoic acid (114 mg, 0.587 mmol, 1 equiv) instead of 3-(2-ethylphenoxy)-2,2-dimethylpropanoic acid. The product was isolated as a yellow-orange oil (106 mg, 62%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.29 - 1.39 (m, 6 H), 1.79 - 2.01 (m, 2 H), 2.11 (d, J = 12.9 Hz, 2 H), 2.84 - 2.92 (m, 3 H), 3.13 (t, J = 12.6 Hz, 2 H), 3.36 (br s, 1 H), 3.57 (d, J = 12.6 Hz, 2 H), 3.92 - 4.10 (m, 3 H), 6.89 - 7.01 (m, 3 H), 7.29 (t, J = 7.8 Hz, 2 H); ESI-MS [M+H] + C 17 H 26 N 2 O 2 Calculated value for 291.21; measured value, 291.4.

[0807] Example 75: 3-(3-Cyano-2-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0808]

Chemical formula

[0809] Step A: Methyl 3-(3-cyano-2-methylphenoxy)-2,2-dimethylpropanoate

[0810]

Chemical formula

[0811] A mixture of methyl 2,2-dimethyl-3-(tosyloxy)propanoate (0.300 g, 1.05 mmol), 3-hydroxy-2-methylbenzonitrile (0.209 g, 1.57 mmol) and Cs 2 CO 3 (0.512 g, 1.57 mmol) in DMF (4 mL) was heated at 100 °C overnight. The reaction mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc. The combined organics were dried over MgSO 4 and filtered, and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography eluting with a gradient of 0 - 70% EtOAc in heptane to give the title compound (0.15 g, 58%) as a clear oil. ESI-MS [M+H] + C 14 H17 NO 3 Calculated value for 3 , 248.13; measured value, 248.2.

[0812] Step B: 3-(3-Cyano-2-methylphenoxy)-2,2-dimethylpropanoic acid

[0813]

Chemical formula

[0814] To a solution of methyl 3-(3-cyano-2-methylphenoxy)-2,2-dimethylpropanoate (0.15 g, 0.61 mmol) in methanol (5 mL) was added 2 M aqueous LiOH solution (0.455 mL, 0.910 mmol). The reaction mixture was stirred at 60 °C overnight, then concentrated, diluted with water, and extracted with EtOAc. The aqueous layer was acidified by the addition of 1 M aqueous HCl solution and then extracted with EtOAc. The extracts from the acidic aqueous layer were combined, dried over MgSO 4 and filtered, and concentrated under reduced pressure to obtain the title compound (0.123 g, 87%) as a yellow oil. ESI-MS [M+H] + C 13 H 15 NO 3 Calculated value for 3 , 234.12; measured value, 234.2.

[0815] Step C: 3-(3-Cyano-2-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0816] To a solution of 3-(3-cyano-2-methylphenoxy)-2,2-dimethylpropanoic acid (0.123 g, 0.527 mmol) in DCM (5 mL) were added triethylamine (0.220 mL, 1.58 mmol) and 2-chloro-1-methylpyridin-1-ium iodide (0.269 g, 1.06 mmol). The reaction mixture was stirred at room temperature for 20 minutes. Next, 1-methylpiperidin-4-amine (0.072 mL, 0.63 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water (10 mL) was added. The organic layer and the aqueous layer were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried over MgSO 4 and filtered, and concentrated under reduced pressure. The residue was taken up in MeOH and purified by preparative HPLC (Method B) to afford the title compound as a white solid (0.098 g, 56%). 1 H N MR (400 MHz, CD 3 CN) δ ppm 1.28 (s, 6 H), 1.43 - 1.57 (m, 2 H), 1.71 - 1.80 (m, 2 H), 1.97 ( br d, J = 2.5 Hz, 2 H), 2.15 - 2.21 (m, 3 H), 2.37 - 2.39 (m, 3 H), 2.73 (br d, J = 11.9 Hz, 2 H), 3.59 - 3.70 (m, 1 H), 3.94 - 4.05 (m, 2 H), 6.15 - 6.36 (m, 1 H), 7.18 (dd, J = 8.1, 1.0 Hz, 1 H), 7.24 - 7.27 (m, 1 H), 7.28 - 7.33 (m, 1 H); ESI-MS [M+H] + C 19 H 27 N 3 O 2 Calculated for , 330.22; Found, 330.6.

[0817] Example 76: 2,2-Dimethyl-N-(1-methylpiperidin-4-yl)-3-(o-tolyloxy)propanamide

[0818]

Chemical Structure

[0819] The title compound was prepared in a manner similar to Example 75 using 2-methylphenol instead of 3-hydroxy-2-methylbenzonitrile (Step A). The final product was isolated as a white solid (0.035 g). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.22 - 1.32 (m, 6 H), 1.39 - 1.59 (m, 2 H), 1.73 - 1.81 (m, 2 H), 1.98 - 2.06 (m, 2 H), 2.19 (s, 3 H), 2.21 (s, 3 H), 2.72 (br d, J = 11.9 Hz, 2 H), 3.59 - 3.71 (m, 1 H), 3.95 (s, 2 H), 6.29 (br s, 1 H), 6.81 - 6.95 (m, 2 H), 7.11 - 7.20 (m, 2 H); ESI-MS [M+H] + C 19 H 27 N 3 O 2 Calculated for, 305.23; Found, 306.5.

[0820] Example 77: 3-(2-Cyano-6-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0821]

Chemical Structure

[0822] The title compound was prepared in a manner similar to Example 75 using 2-hydroxy-3-methylbenzonitrile instead of 3-hydroxy-2-methylbenzonitrile (Step A). The final product was isolated as a yellow oil (0.072 g). 1 H NMR (400 MHz, CD 3 CN) δ ppm 1.21 - 1.36 (m, 6 H), 1.44 - 1.61 (m, 2 H), 1.73 - 1.84 (m, 2 H), 1.99 - 2.04 (m, 1 H), 2.16 - 2.20 (m, 3 H), 2.26 - 2.30 (m, 3 H), 2.42 (br s, 2 H), 2.74 (br d, J = 11.9 Hz, 2 H), 3.60 - 3.71 (m, 1 H), 4.01 - 4.11 (m, 2 H), 6.25 - 6.41 (m, 1 H), 7.15 (t, J = 7.7 Hz, 1 H), 7.45 - 7.53 (m, 2 H); ESI-MS M+H] + C 19 H 27 N 3 O 2 Calculated for, 330.21; Found, 331 .5.

[0823] Example 78: 3-(2-Ethoxyphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide

[0824]

Chemical Structure

[0825] The title compound was prepared in a manner similar to Example 75 using 2-ethoxyphenol instead of 3-hydroxy-2-methylbenzonitrile (Step A). The final product was isolated as a yellow oil (0.038 g). 1 H NMR (400 MHz, DMSO-d6 ) δ ppm 1.20 (s, 6 H), 1.31 (t, J = 7.0 Hz, 1 H), 1.42 - 1.54 (m, 2 H), 1.60 - 1.73 (m, 2 H), 1.78 - 1.99 (m, 2 H), 2.02 - 2.18 (m, 3 H), 2.70 (br d, J = 11.9 Hz, 2 H), 3.46 - 3.64 ( m, 1 H), 3.92 (s, 2 H), 4.00 (q, J = 7.1 Hz, 2 H), 6.82 ...

Claims

1. A compound of formula 1, 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, X １ N and CR １ Selected from: X ２ N and CR ２ Selected from: X ３ N and CR ３ Selected from: X ４ N and CR ４ is selected from the following: １ , X ２ , X ３ and X ４ no more than two of are N; X １３ is NR １３ And X １４ is CR １５ R １６ or X １３ is CH ２ And X １４ is NR １４ and L is NR ８ and O; r is selected from 0 and 1; s is selected from 0 and 1; R １ , R ２ and R ３ are, respectively, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; are independently selected from; R ４ teeth, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; Selected from: R ５ teeth, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo, oxo, and phenyl, which is substituted with 0-3 optional substituents independently selected from halo; or R ４ and R ５ together with the carbon atoms to which they are attached form cyclopent-1-ene-1,2-diyl or furan-2,3-diyl; R ６ and R ７ are halo and C, respectively. １－３ alkyl, or R ６ and R ７ together with the carbon atom to which they are attached, C ３－４ Forming a cycloalkane-1,1-diyl; R ８ is H and C １－４ alkyl; R ９ and R １０ are, respectively, (a) hydrogen, halo, hydroxy, and cyano; (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; and (c) Phenyl and C １－５ Heteroaryl (each of which is selected from halo, C １－４ Alkyl, and C １－４ substituted by 0 to 3 optional substituents independently selected from alkoxy; １－５ Heteroaryl substituents are monocyclic rings with 5-6 ring members, of which 1-4 ring members are heteroatoms, each of which is independently selected from N, O and S, with the proviso that not more than one of the ring members is O or S; phenyl and C １－５ The C on the heteroaryl １－４ Alkyl and C １－４ Each optional substituent of the alkoxy is independently substituted with 0 to 3 optional substituents independently selected from halo. or R ９ and R １０ together with the carbon atom to which they are attached, C ３－４ Forming a cycloalkane-1,1-diyl; R １１ and R １２ are, respectively, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; or R １１ and R １２ together with the carbon atom to which they are attached, C ３－４ Forming a cycloalkane-1,1-diyl; R １３ and R １４ are, respectively, (a) hydrogen; and (b) C １－４ alkyl, which is substituted with 0-3 optional substituents independently selected from cyano, oxo, and phenyl, which is substituted with 0-3 optional substituents independently selected from halo; are independently selected from; R １５ and R １６ are, respectively, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; or R １５ and R １６ together with the carbon atom to which they are attached, C ３－４ forming a cycloalkane-1,1-diyl).

2. X １ is CR １ And X ２ is CR ２ And X ３ is CR ３ And X ４ is CR ４ 2. The compound of claim 1, wherein:

3. R １ , R ２ , R ３ and R ４ Each of them, (a) hydrogen, halo, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, independently selected from:

4. R １ , R ２ , R ３ and R ４ Each of them, (a) hydrogen, halo, and cyano; and (b) C １－４ Alkyl and C ３－６ cycloalkyl, each of which is substituted with 0 to 3 optional substituents independently selected from halo; 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, independently selected from:

5. R １ , R ２ , R ３ and R ４ Each of them, (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl, each of which is substituted with 0 to 3 optional substituents independently selected from halo.

3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, independently selected from:

6. R １ , R ２ , R ３ and R ４ 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, wherein each is independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl.

7. X １ is N and X ２ is CR ２ And X ３ is CR ３ And X ４ is CR ４ 2. The compound of claim 1, wherein:

8. R ２ , R ３ and R ４ Each of them, (a) hydrogen, halo, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, independently selected from:

9. R ２ , R ３ and R ４ Each of them, (a) hydrogen, halo, and cyano; and (b) C １－４ Alkyl and C ３－６ cycloalkyl, each of which is substituted with 0 to 3 optional substituents independently selected from halo; 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, independently selected from:

10. R ２ , R ３ and R ４ Each of them, (a) hydrogen, halo, and cyano; and (b) methyl and cyclopropyl, each of which is substituted with 0 to 3 optional substituents independently selected from halo.

8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, independently selected from:

11. R ２ , R ３ and R ４ 8. The compound or pharma- ceutically acceptable salt of claim 7, wherein each is independently selected from hydrogen, halo, cyano, methyl, trifluoromethyl, and cyclopropyl.

12. R ５ but, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo, oxo, and phenyl, which is substituted with 0-3 optional substituents independently selected from halo; 12. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 11, selected from:

13. R ５ but, (a) halo and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; 12. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 11, selected from:

14. R ５ but, (a) fluoro, chloro, bromo, and cyano; and (b) methyl, ethyl, cyclopropyl, methoxy, and ethoxy, each of which is substituted with 0 to 3 optional substituents independently selected from fluoro.

12. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 11, selected from:

15. R ６ and R ７ are each independently selected from fluoro and methyl, or together with the carbon atom to which they are attached form cyclopropane-1,1-diyl or cyclobutane-1,1-diyl; or a pharma-ceutically acceptable salt thereof.

16. R ６ and R ７ or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 14, wherein each of is methyl.

17. L is NR ８ 17. The compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein:

18. R ８ 18. The compound or pharma- ceutically acceptable salt of claim 17, wherein is selected from hydrogen and methyl.

19. R ８ 18. The compound or pharma- ceutically acceptable salt of claim 17, wherein is hydrogen.

20. R ９ and R １０ Each of them, (a) hydrogen, halo, hydroxy, and cyano; (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; and (c) Phenyl and C １－５ Heteroaryl (each of which is selected from halo, C １－４ Alkyl, and C １－４ substituted by 0 to 3 optional substituents independently selected from alkoxy; １－５ Heteroaryl substituents are monocyclic rings with 5-6 ring members, of which 1-4 ring members are heteroatoms, each of which is independently selected from N, O and S, with the proviso that not more than one of the ring members is O or S; phenyl and C １－５ The C on the heteroaryl １－４ Alkyl and C １－４ Each optional substituent of the alkoxy is independently substituted with 0 to 3 optional substituents independently selected from halo.

20. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 19, independently selected from:

21. R ９ and R １０ Each of them, (a) hydrogen and halo; (b) C １－４ Alkyl and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; and (c) Phenyl and C １－５ Heteroaryl (each of which is selected from halo and C １－４ substituted with 0 to 3 optional substituents independently selected from alkyl; １－５ Heteroaryl substituents are monocyclic rings with 5 to 6 ring members, in which 1 or 2 ring members are heteroatoms, each of which is N, and are selected from the group consisting of phenyl and C １－５ The C on the heteroaryl １－４ Each alkyl optional substituent is independently substituted with 0 to 3 optional substituents independently selected from halo.

20. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 19, independently selected from:

22. R ９ and R １０ Each of them, (a) hydrogen and halo; (b) C １－４ Alkyl and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; and (c) phenyl, pyridinyl, and pyrazolyl, each of which is selected from halo and C １－４ alkyl, which is substituted by 0 to 3 optional substituents independently selected from halo; substituted with 0-3 selected optional substituents 20. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 19, independently selected from:

23. R ９ and R １０ is hydrogen, halo, and C １－４ 20. The compound or pharma- ceutically acceptable salt of any one of claims 1 to 19, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates ...

24. R １１ and R １２ Each of them, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; 24. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 23, independently selected from:

25. R １１ and R １２ are each hydrogen and C １－４ 24. The compound or pharma- ceutically acceptable salt of any one of claims 1 to 23, independently selected from alkyl.

26. X １３ is NR １３ And X １４ is CR １５ R １６ 26. The compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein:

27. R １３ but, (a) hydrogen; and (b) C １－４ alkyl, which is substituted with 0-3 optional substituents independently selected from cyano, oxo, and phenyl, which is substituted with 0-3 optional substituents independently selected from halo; 27. The compound of claim 26, or a pharma- ceutically acceptable salt thereof, selected from:

28. R １３ 27. The compound or pharma- ceutically acceptable salt of claim 26, wherein is selected from hydrogen and methyl.

29. R １３ 27. The compound of claim 26, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

30. R １５ and R １６ Each of them, (a) hydrogen, halo, hydroxy, and cyano; and (b) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each of which is substituted with 0-3 optional substituents independently selected from halo; 30. The compound or pharma- ceutically acceptable salt of any one of claims 26 to 29, independently selected from:

31. R １５ and R １６ are each hydrogen and C １－４ 30. The compound of any one of claims 26-29 or a pharma- ceutically acceptable salt thereof, wherein each is independently selected from alkyl, which is substituted with 0-3 optional substituents independently selected from halo.

32. 32. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 31, wherein r is 0.

33. 33. The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 32, wherein s is 0.

34. 33. The compound according to any one of claims 1 to 32, wherein s is 1, or a pharma- ceutically acceptable Salt.

35. The following compound: 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide; 2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)-N-(1-methylpyrrolidin-3-yl)propanamide; 3-((3-cyanopyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; (R)-3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; 3-((5-cyclopropylpyrimidin-4-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; (R)-3-((3-cyclopropyl-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; 3-((5-cyclopropyl-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; (R)-3-((3-cyclopropyl-6-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; cis-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; cis-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(4-isopropyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(4-isopropyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-2,2-dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-2,2-dimethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide; cis-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl ethyl-N-(1-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)propanamide; trans-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide; trans-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide; trans-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; cis-N-(1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; trans-N-(3-isopropyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; cis-N-(3-isopropyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,5,5-trimethylpyrrolidin-3-yl)propanamide; (R)-2,2-dimethyl-N-((1-methylpyrrolidin-3-yl)methyl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; (S)-2,2-dimethyl-N-((1-methylpyrrolidin-3-yl)methyl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 3-((3-chloropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3,5-difluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((4-(trifluoromethyl)pyridin-3-yl)oxy)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-4-yl)oxy)propanamide; 3-((4-chloro-3-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-chloro-5-fluoropyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((6-chloro-2-methylpyridin-3-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((5-chloro-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-methoxypyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-methylpyridin-4-yl)oxy)propanamide; 3-((5-cyano-3-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((2-(trifluoromethyl)pyridin-3-yl)oxy)propanamide; (R)-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; 3-((3-ethoxypyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)propanamide; trans-2,2-dimethyl-N-(1-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)propanamide; trans-2,2-dimethyl-N-(1-methyl-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(1-methylpiperidin-4-yl)-1-(((3-methylpyridin-2-yl) Oxy)methyl)cyclopropane-1-carboxamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-(2-(trifluoromethyl)phenoxy)propanamide; (R)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)-3-(2-(trifluoromethyl)phenoxy)propanamide; 3-(2-chlorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; (R)-3-(2-chlorophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; (R)-3-(2-bromophenoxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; 3-(2-cyclopropylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; (R)-3-(2-cyclopropylphenoxy)-2,2,-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; 3-(2-ethylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-(4-cyano-2-(trifluoromethyl)phenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-phenoxypropanamide; 3-(3-cyano-2-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-(o-tolyloxy)propanamide; 3-(2-cyano-6-methylphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-(2-ethoxyphenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((2,3-dihydro-1H-inden-4-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-cyclopropylpyrazin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 1-((2-chlorophenoxy)methyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide; 3-((3-chloro-5-methylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3,6-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3-ethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; (R)-3-((3-ethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpyrrolidin-3-yl)propanamide; 3-((3-ethylpyrazin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((3,4-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(1 -methylpiperidin-4-yl)propanamide; 1-(((3-cyclopropylpyridin-2-yl)oxy)methyl)-N-(1-methylpiperidin-4-yl)cyclobutane-1-carboxamide; 3-((3-(difluoromethyl)pyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-3-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; trans-N-(4-(4-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; trans-N-(4-ethoxy-1-methylpyrrolidin-3-yl)-3-(2-ethylphenoxy)-2,2-dimethylpropanamide; trans-3-(2-ethylphenoxy)-N-(4-methoxy-1-methylpyrrolidin-3-yl)-2,2-dimethylpropanamide; 3-(2-ethylphenoxy)-2,2-dimethyl-N-(1-methyl-4-phenylpyrrolidin-3-yl)propanamide; 3-((6-chloro-4-(trifluoromethyl)pyridazin-3-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-(furo[3,2-c]pyridin-4-yloxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-3-((5-methyl-3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1-methylpiperidin-4-yl)propanamide; 2,2-dimethyl-N-(1-methylpiperidin-4-yl)-3-(2-(trifluoromethoxy)phenoxy)propanamide; trans-N-(1-(cyanomethyl)-4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(2-ethylphenoxy)-2,2-dimethylpropanamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; cis-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,3,3-trimethylpiperidin-4-yl)propanamide; N-(3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(5-methyl-5-azaspiro[2.5]octan-8-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(trans-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; N-(cis-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(3,3-difluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(5-methyl-5-azaspiro[2.5]octan-8-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; N-(3-chloro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; 3-((3,5-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide; N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; trans-3-((3,5-dimethylpyridin-2-yl)oxy)-N-(3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide; cis-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(4-fluoropyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(4,4-difluoropyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)-N-(1,2,2-trimethylpiperidin-4-yl)propanamide; trans-N-(1,5-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; cis-N-(1,5-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; cis-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; N-(2-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; N-((3R,4R)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; N-((3R,4R)-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3S,4S)-3-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(2-ethyl-1-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide; (R)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N-(2-ethyl-1-methylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; (R)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(5-methyl-5-azaspiro[3.4]octan-8-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((2S,4S)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; (R)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-methylpyridin-2-yl)oxy)propanamide; (R)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)propanamide; N,2,2-trimethyl-N-(trans-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N,2,2-trimethyl-N-(cis-3-(o-tolyl)piperidin-4-yl)- 3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(trans-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3S,4S)-3-fluoropiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(3,3-difluoropiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((3S,4S)-3-fluoropiperidin-4-yl)-N,2,2-trimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(trans-1-methyl-3-(o-tolyl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-N,2,2-trimethyl-N-(3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(cis-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(trans-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(cis-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(trans-1-methyl-3-phenylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; trans-3-(o-tolyl)piperidin-4-yl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate; 2,2-dimethyl-N-(trans-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-3-(2-methylpyridin-3-yl)piperidin-4-yl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate; trans-3-phenylpiperidin-4-yl 2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanoate; N,2,2-trimethyl-N-(trans-3-(2-methylpyridin-3-yl)piperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; (S)-2,2-dimethyl-N-(5-methyl-5-azaspiro[2.4]heptan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(4-methyl-4-azaspiro[2.5]octan-7-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 2,2-dimethyl-N-(4-methyl-4-azaspiro[2.5]octan-7-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((2R,4S)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl- 3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((2S,4S)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethylpropanamide; N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethyl-3-((3-methylpyridin-2-yl)oxy)propanamide; 3-((3,5-dimethylpyridin-2-yl)oxy)-N-(trans-1,4-dimethylpyrrolidin-3-yl)-2,2-dimethylpropanamide; trans-N-(1-(cyanomethyl)-3-methylpiperidin-4-yl)-2,2-dimethyl-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 3-((3-(chlorodifluoromethoxy)pyridin-2-yl)oxy)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide; trans-3-(2-chlorophenoxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide; 3-(2-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)-2,2-dimethylpropanamide; 3-(2-chlorophenoxy)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-2,2-dimethylpropanamide; trans-N-(1,3-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 3-(2-chlorophenoxy)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide; cis-N-(1,2-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; trans-3-((3-cyclopropylpyridin-2-yl)oxy)-N-(1,3-dimethylpiperidin-4-yl)-2,2-difluoropropanamide; 3-(2-chlorophenoxy)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-dimethylpropanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-difluoropropanamide; 3-(2-fluorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-(2-fluorophenoxy)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide; 2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide; N-(trans-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-methylpyridin-2-yl)oxy)propanamide; N-(trans-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-3 -((3-methylpyridin-2-yl)oxy)propanamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-3-(2-fluorophenoxy)-2,2-dimethylpropanamide; 3-(3-fluorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; 3-(4-fluorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-methylpyridin-2-yl)oxy)propanamide; N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-2,2-difluoro-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 3-((3-cyclopropylpyridin-2-yl)oxy)-2,2-difluoro-N-((2R,4R)-2-methylpiperidin-4-yl)propanamide; 2,2-difluoro-N-((2R,4R)-2-methylpiperidin-4-yl)-3-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propanamide; 3-(2-chlorophenoxy)-2,2-dimethyl-N-(piperidin-4-yl)propanamide; 3-((3,5-dimethylpyridin-2-yl)oxy)-N-((3R,4R)-3-fluoropiperidin-4-yl)-2,2-dimethylpropanamide; 3-(2-chlorophenoxy)-2,2-difluoro-N-(1-methylpiperidin-4-yl)propanamide; 3-(2-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide; 3-(4-chlorophenoxy)-2,2-dimethyl-N-(1-methylpiperidin-4-yl)propanamide; N-((2R,4R)-1,2-dimethylpiperidin-4-yl)-3-((3,5-dimethylpyridin-2-yl)oxy)-2,2-dimethylpropanamide; and A pharma- ceutically acceptable salt of any one of the above compounds.

2. The compound of claim 1 , selected from:

36. A compound or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 35; and Pharmaceutically acceptable excipients 13. A pharmaceutical composition comprising:

37. 36. A compound or a pharma- ceutically acceptable salt as defined in any one of claims 1 to 35 for use as a medicament.

38. 36. A compound or a pharma- ceutically acceptable salt as defined in any one of claims 1 to 35 for the treatment of a disease, disorder or condition selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

39. 36. A method of treating a disease, disorder or condition in a subject, comprising administering to the subject a compound or a pharma- ceutically acceptable salt as defined in any one of claims 1 to 35, wherein the disease, disorder or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and hyperactivity disorder.

40. A combination comprising a compound or a pharma- ceutically acceptable salt as defined in any one of claims 1 to 35, and at least one additional pharmacologically active agent.

41. 41. The combination of claim 40, wherein the additional pharmacologically active agent is selected from beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.

Images