N-heteroarylalkyl-2-(heterocyclyl and heterocyclylmethyl)acetamide derivatives as SSTR4 agonists

Abstract

To provide a somatostatin receptor 4 (SSTR4) modulator.SOLUTION: N-heteroarylalkyl-2-(heterocyclyl and heterocyclylmethyl)acetamide derivatives and pharmaceutically acceptable salts thereof are provided. The present invention also provides pharmaceutical compositions comprising N-heteroaryl-2-(heterocyclyl and heterocyclylmethyl)acetamide derivatives, and uses thereof for treating diseases, disorders, and conditions associated with SSTR4, including Alzheimer's disease and other CNS disorders. In one aspect, a compound of Formula 1 is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to N-heteroarylalkyl-2-(heterocyclyl and heterocyclylmethyl)acetamide derivatives that are modulators of somatostatin receptor 4 (SSTR4), pharmaceutical compositions containing them, and their use for treating diseases, disorders, and conditions associated with SSTR4, including Alzheimer's disease. [Background technology]

[0002] Somatostatin receptor 4 (SSTR4) is a G protein-coupled receptor for the peptide somatostatin. SSTR4 couples to the inhibitory G protein Gi, which inhibits the production of cyclic AMP. SSTR4 is abundantly expressed in the central nervous system (CNS) and, to a lesser extent, in the dorsal root ganglia and intestine. M.A. Meyer, "Highly Expressed Genes within Hippocampal Sector CA1: Implications for the Physiology of See, for example, "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 over 87% identity at the amino acid level. These factors (predominant expression in the brain and high sequence homology among different species) suggest that SSTR4 plays an important role in physiological functions.

[0003] Experiments using bacTRAP technology have shown that SSTR4 has strongest expression in pyramidal neurons in the cortex and 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 and See “Unconscious Memory Systems,” Cold Spring Harbor Perspectives in Biology 7:a021667 (2015). Indeed, the CA1 region of the hippocampus is the last stop in a trisynaptic circuit responsible for learning. This circuit starts in the entorhinal cortex (which also contains SSTR4), spans the dentate gyrus of the hippocampus, then CA3, and finally reaches the CA1 region. CA1 projects out of the hippocampus via the subiculum. This circuit encodes all types of information from the outside world to generate memories and learn new knowledge.

[0004] Alzheimer's disease is characterized by degeneration of neurons within this circuit, primarily in the entorhinal cortex and CA1 region of the hippocampus. See A. Serrano-Pozo et al., "Neuropathological Alterations in Alzheimer's Disease," Cold Spring Harbor Perspectives in Medicine 1:a006189 (2011). Additionally, hippocampal SSTR4 receptors appear to selectively control cognitive strategy use by switching from multiple hippocampal-based associations to simple striatal-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 a strong rationale for the use of SSTR4 agonists as a pharmacological approach to improve striatal-based learning. Ibid.

[0005] Furthermore, recent studies have indicated that hippocampal hyperactivity is a major driver of not only cognitive impairment but also disease progression in Alzheimer's disease patients. See MA Busche et al., "Decreased Amyloid-β and Increased Neuronal Hyperactivity by Immunotherapy in Alzheimer's Models," Nature Neuroscience 18(12):1725-27 (2015); also see K. Yamamoto et al., "Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer's Disease," Cell Reports 11(6):859-65 (2015). Activation of the SSTR4 receptor has been shown to play a role in regulating 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 of the receptors may be good pharmacological tools to inhibit and control neuronal activity in the cortex and hippocampus.

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

[0007] The present invention provides N-heteroarylalkyl-2-(heterocyclyl- and heterocyclylmethyl)acetamide derivatives and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing the N-heteroaryl-2-(heterocyclyl- and heterocyclylmethyl)acetamide 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] [ka]

[0010] or a pharmaceutically acceptable salt thereof, (a)X 3 is NR 3N and X is selected from O 4 is a single bond, and X 5 N and CR 5 Selected from; R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring which is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or (b) X 3 is CR 3C and X 4 N and CR 4 Selected from X 5 N and CR 5 mosquito Selected from; R 1 and R 2are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring selected from furan, pyrazole, and benzene, wherein one of the nitrogen atoms of the pyrazole ring is hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); L is O and n is 1; or L is a single bond and n is 0 or 1; R 3N is hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R 3C and R 4 are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 5 is selected from the following: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 6 is hydrogen; or R 5 and R 6 together form ethane-1,2-diyl bridging the carbon atoms to which they are attached; R 7 and R 8 are each independently hydrogen and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo), where R 7 and R 8 At least one of is not hydrogen or R 7 and R 8 C together with the carbon atoms to which they are attached 3-6 forming a cycloalkylidene; R 9 is hydrogen and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); R 10 is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, and heterocyclyl having the formula:

[0011] [ka]

[0012] During the ceremony,

[0013] [ka]

[0014] indicates the attachment point, r is selected from 0 and 1; R 11 is hydrogen and R 12 is hydrogen, as well as C1-4 Alkyl and C 3-6 cycloalkyl (each independently substituted with 0-3 optional substituents selected from halo), with the proviso that R 12 is hydrogen, R 1 and R 2 forms a fused ring; or R 11 and R 12 together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached; R 13 , R 14 , R 15 , and R 16 are each independently hydrogen, halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo), or R 13 and R 16 does not exist, and R 14 and R 15 together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 17 and R 18 are each independently hydrogen, halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo). wherein the compound of formula 1 is: 2-(1-methylpiperidin-2-yl)-N-(1-(m-tolyl)cyclopropyl)acetamide; N-(1-(pyridin-3-yl)pentyl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(6-methylpyridin-2-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide; 2-(1-methylpyrrolidin-2-yl)-N-(1-phenylethyl)acetamide; 2-(1-methylpiperidin-2-yl)-N-(1-phenylethyl)acetamide; N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propanamide; N-(2-phenylpropan-2-yl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(4-methylpyridin-2-yl)propyl)-3-(pyrrolidin-1-yl)propenamide; or N-(1-(naphthalen-1-yl)ethyl)-2-(pyrrolidin-2-yl)acetamide or a pharmaceutically acceptable salt thereof, provided that:

[0015] Another aspect of the present invention provides a compound selected from the group of compounds described in the Examples and pharmaceutically acceptable salts thereof.

[0016] A further aspect of the invention is 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, in combination with a pharmaceutical and an excipient acceptable as such.

[0017] A further 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 paragraphs, for use as a medicament.

[0018] Another aspect of the present invention provides 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 treating a disease, disorder, or condition associated with SSTR4.

[0019] A further aspect of the present 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 treating a disease, disorder, or condition associated with SSTR4.

[0020] An additional aspect of the present invention provides a method for treating a disease, disorder, or condition associated with SSTR4, 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.

[0021] 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 hyperactivity disorder.

[0022] A further aspect of the present 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

[0023] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0024] "Substituted" refers to a chemical substituent or moiety (e.g., C 1-6 When used in connection with an alkyl group, it means that one or more hydrogen atoms of that substituent or moiety are replaced with one or more non-hydrogen atoms or groups, provided that valency requirements are met and the substitution results in a chemically stable compound.

[0025] "About" or "approximately," when used in connection with a measurable, numerical variable, refers to the indicated value of that variable and all values ​​of that variable within experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0026] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally 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, pent-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, 2,2,2-trimethyleth-1- ... Examples include xyl.

[0027] "Alkanediyl" refers to a divalent alkyl group, where alkyl is defined above, generally having a specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6(Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, etc.) Alkanediyl 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.

[0028] "Alkenyl" refers to straight-chain and branched saturated hydrocarbon groups having one or more carbon-carbon double bonds and generally having a specified 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.

[0029] "Alkynyl" refers to a straight-chain or branched saturated hydrocarbon group having one or more carbon-carbon triple bonds and generally having a specified 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.

[0030] "Halo," "halogen," and "halogeno" may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0031] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups, respectively, substituted with one or more halogen atoms and generally having a specified number of carbon atoms, where alkyl, alkenyl, and alkynyl are defined above. 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.

[0032] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms comprising the ring(s) (e.g., C 3-8 Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members. Bicyclic hydrocarbon groups may include separated rings (two rings that share no carbon atoms), spiro rings (two rings that share one carbon atom), fused rings (two rings that share two carbon atoms and a bond between two common carbon atoms), and bridged rings (two rings that share two carbon atoms but do not share a common bond). Cycloalkyl groups may be bonded through any ring atom, provided that such bonding does not violate valence requirements, and, where indicated, may optionally contain one or more non-hydrogen substituents, provided that such substitution does not violate valence requirements.

[0033] 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 ... cyclo[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, and the like. 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, and the like. 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 split bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.

[0034] "Cycloalkanediyl" generally refers to a divalent cycloalkyl group having the specified number of carbon atoms, where cycloalkyl is defined above (e.g., C 3-5 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4, or 5) carbon atoms, C 3-6 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, etc.) Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0035] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group (cycloalkyl is defined above) attached through a single carbon atom of the group and generally having a specified number of carbon atoms comprising the ring (e.g., C 3-6 Cycloalkylidene refers to a cycloalkylidene group having from 3 to 6 carbon atoms as ring members.) Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0036] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms comprising the ring(s). Like cycloalkyl groups, bicyclic cycloalkenyl groups can include separate rings, spirocyclic, fused, or bridged rings. Similarly, cycloalkenyl groups can be bonded via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided such bond or substitution does not violate valence requirements. Examples of cycloalkenyl groups include partially unsaturated analogs of the above cycloalkyl groups, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0037] "Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms constituting their ring members (e.g., C 6-14Aryl refers to an aryl group having 6 to 14 carbon atoms as ring members. The group can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided such attachment or substitution does not violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, and groups derived from a cycloheptatriene cation.

[0038] "Arylene" refers to a divalent aryl group, where aryl is defined above. Examples of arylene groups include o-phenylene (i.e., benzene-1,2-diyl).

[0039] "Heterocycle" and "heterocyclyl" can be used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group containing ring atoms consisting of carbon atoms and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups generally have a specified 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. Like bicyclic cycloalkyl groups, bicyclic heterocyclyl groups can include separate rings, spirocyclic rings, fused rings, and bridged rings. Heterocyclyl groups can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, but only if such attachment or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of heterocyclyl groups 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, Examples include 1,4-oxathiepanyl, 1,4-oxazepanyl, 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.

[0040] "Heterocycle-diyl" refers to heterocyclyl groups (heterocyclyl is defined above) that are attached through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6Heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members.) Examples of heterocycle-diyl groups include polyvalent analogs of the above heterocycle groups, such as morpholin-3,4-diyl, pyrrolidin-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, and the like.

[0041] "Heteroaromatic" and "heteroaryl" can be used interchangeably and refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, each of which has ring atoms consisting of carbon atoms and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C 1-9 Heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members, and may include any bicyclic group in which any of the monocyclic heterocycles listed above is fused to a benzene ring. Heteroaryl groups can be bonded through any ring atom (or ring atom of a fused ring) and, where indicated, can optionally contain one or more non-hydrogen substituents, provided that such bonding or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thienyl, Examples include 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.

[0042] Examples of heteroaryl groups also include bicyclic groups, such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-indolyl, 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-benzo[d]imidazolyl, benzo[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.

[0043] "Heteroarylene" refers to heteroaryl groups (heteroaryl is defined above) that are linked through two ring atoms of the group. They generally have a specified 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 listed above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0044] "Oxo" refers to a double-bonded oxygen (=O).

[0045] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution, elimination, and addition-elimination reactions. A leaving group may be nucleofugal (the leaving group leaves along with the electron pair that originally served as the bond between the leaving group and the molecule). , or electrofugal (the leaving group leaves without an electron pair). The ability of a nucleofugal leaving group to leave depends on the strength of its base, with the strongest bases being the weakest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including 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, such as NH2 - and OH - can be made into a better leaving group by treatment with acid. Common electron-free leaving groups include the proton, CO2, and metals.

[0046] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule and can be obtained by inverting all of the chiral centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Similarly, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0047] "Stereoisomer(s)" of a compound having a given stereochemical configuration refers to the opposite enantiomer of that compound and any diastereoisomers, including geometric isomers (Z / E) of that compound. For example, if a compound has an S,R,Z stereochemical configuration, then the stereoisomers would include its opposite enantiomer having the R,S,Z configuration, as well as its diastereoisomers having the 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 a compound is not specified, then "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0048] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound having a particular stereochemical configuration, wherein said sample comprises at least about 95% of the sample.

[0049] "Pure stereoisomer" and variations thereof refer to a sample containing a compound with a particular stereochemical configuration, which comprises at least about 99.5% of the sample.

[0050] "Subject" refers to a mammal, including a human.

[0051] A "pharmaceutically acceptable" substance refers to a substance that is suitable for administration to a subject.

[0052] "Treating" refers to reversing, alleviating, inhibiting the progression of, or preventing the disease, disorder, or condition to which such term applies, or reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of such disease, disorder, or condition.

[0053] "Treatment" refers to the act of treating, as defined immediately above.

[0054] "Drug," "drug substance," "active pharmaceutical ingredient," and the like refer to compounds (e.g., compounds of Formula 1, including subclasses and compounds specifically named herein) that can be used to treat a subject in need thereof.

[0055] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like refer to the amount of drug that can be used to treat a subject, which amount depends, among other things, on the weight and age of the subject and the dosage. May be route dependent.

[0056] "Excipient" refers to any diluent or vehicle for a drug.

[0057] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0058] The terms "drug product," "pharmaceutical dosage form," "dosage form," "final dosage form," and the like refer to a pharmaceutical composition suitable for treating a subject in need thereof, and may generally be in the form of a tablet, capsule, sachet containing powder or granules, liquid or suspension, patch, film, and the like.

[0059] "SSTR4-associated condition" and similar phrases refer to a disease, disorder, or condition in a subject in which activation of SSTR4 can provide a therapeutic or prophylactic benefit.

[0060] The following abbreviations may be used herein: Ac (acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc (tert-butoxycarbonyl); Cbz (carbobenzyloxy); dba (dibenzylideneacetone); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloroethene). DCM (dichloromethane); DEA (diethylamine); 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); DMP (Dess-Martin periodinane); DMSO (dimethyl sulfoxide); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC 50(effective concentration at half-maximal response); EDA (ethoxylated dodecyl alcohol, Brj® 35); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq (equivalent); Et (ethyl); EtN (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-chloroperbenzoic 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 ), where EC 50 is given in molar (M) units); pIC 50 (-log 10 (I C 50 ), where IC 50are given in moles (M); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP® (bromotripyrrolidinophosphonium hexafluorophosphate); RT (room temperature, approximately 20°C to 25°C); SFC (supercritical fluid chromatography); T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 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).

[0061] As described below, the present disclosure relates to compounds of Formula 1 and pharmaceutically acceptable salts thereof. The present disclosure also relates to materials and methods for preparing compounds of Formula 1, pharmaceutical compositions containing them, and the use of compounds of Formula 1 and pharmaceutically acceptable salts thereof (optionally in combination with other pharmacologically active agents) to treat diseases, disorders, or conditions of the CNS, including Alzheimer's disease, and other diseases, disorders, or conditions associated with SSTR4.

[0062] Compounds of Formula 1 include those that are: (1)(a)X 3 is NR 3N and X is selected from O 4 is a single bond, and X 5 N and CR 5 Selected from; R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring which is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or (b) X 3 is CR 3C and X 4 N and CR 4 Selected from X 5 N and CR 5 Selected from; R 1 and R 2 are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring selected from furan, pyrazole, and benzene, wherein one of the nitrogen atoms of the pyrazole ring is hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); L is O and n is 1; or L is a single bond and n is 0 or 1; R 3N is hydrogen, C 1-4 Alkyl, and C 3-6cycloalkyl; R 3C and R 4 are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 5 is selected from the following: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 6 is hydrogen; or R 5 and R 6 together form ethane-1,2-diyl bridging the carbon atoms to which they are attached; R 7 and R 8 are each independently hydrogen and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo), where R 7 and R 8 of At least one is not hydrogen or R 7 and R 8 C together with the carbon atoms to which they are attached 3-6 forming a cycloalkylidene; R 9 is hydrogen and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); R 10 is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, and heterocyclyl having the formula:

[0063] [ka]

[0064] During the ceremony,

[0065] [ka]

[0066] indicates the attachment point, r is selected from 0 and 1; R 11 is hydrogen and R 12 is hydrogen, as well as C 1-4 Alkyl and C 3-6 cycloalkyl (each independently substituted with 0-3 optional substituents selected from halo), with the proviso that R 12 is hydrogen, R 1 and R 2 forms a fused ring; or R 11 and R 12 together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached; R 13 , R 14 , R 15 , and R 16 are each independently hydrogen, halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo), or R 13 and R 16 does not exist, and R 14 and R 15 together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 17 and R 18 are each independently hydrogen, halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); The compound of formula 1 is: 2-(1-methylpiperidin-2-yl)-N-(1-(m-tolyl)cyclopropyl)acetamide; N-(1-(pyridin-3-yl)pentyl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(6-methylpyridin-2-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide; 2-(1-methylpyrrolidin-2-yl)-N-(1-phenylethyl)acetamide; 2-(1-methylpiperidin-2-yl)-N-(1-phenylethyl)acetamide; N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propanamide; N-(2-phenylpropan-2-yl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(4-methylpyridin-2-yl)propyl)-3-(pyrrolidin-1-yl)propenamide; or N-(1-(naphthalen-1-yl)ethyl)-2-(pyrrolidin-2-yl)acetamide This is provided that:

[0067] In addition to embodiment (1) of the preceding paragraph, compounds of Formula 1 include those in which: (2)X 3 is NR 3N and X is selected from O 4 is a single bond, and X 5 N and CR 5 is selected from.

[0068] In addition to embodiment (2) of the preceding paragraph, compounds of Formula 1 may also include R 1 and R 2 wherein each non-fused carbon atom of the fused ring formed by is unsubstituted or substituted with an optional substituent independently selected from: (3)(i) halo and hydroxy; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (4)(i) halo and hydroxy; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (5) Halo and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); (6) Halo and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (7) C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (8) C 1-3 alkyl; or (9) Methyl.

[0069] In addition to embodiments (2)-(9) of the preceding paragraph, compounds of Formula 1 may also include R 3N is selected from the following: (10) Hydrogen and C 1-4 alkyl; (11) Hydrogen and C 1-3 alkyl; (12) hydrogen and methyl; (13)C 1-3 alkyl; or (14) Methyl.

[0070] In addition to embodiments (2) through (14) of the preceding paragraph, compounds of Formula 1 include those in which: (15)X 3 is O and X 4 is a single bond, and X 5 is N; (16)X 3 is NR 3N and X is selected from O 4 is a single bond, and X 5 is N; or (17)X 3 is NR 3N and X 4 is a single bond, and X 5 is N.

[0071] In addition to embodiments (2) through (17) of the preceding paragraph, compounds of Formula 1 include those in which: (18) L is a single bond and n is 0 or 1; or (19) L is a single bond and n is 0.

[0072] In addition to embodiment (1) above, compounds of Formula 1 include those in which: (20)X 3 is CR 3C and X 4 N and CR 4 Selected from X 5 N and CR 5 is selected from.

[0073] In addition to embodiment (20) of the preceding paragraph, compounds of Formula 1 may also include R 1 and R 2 are each independently selected from: (21) (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (22) (i) hydrogen and halo; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (23) (i) hydrogen and halo; and (ii) C 1-3 Alkyl, C 3-6 Cycloalkyl, and C 1-3 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (24) (i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, and isopropoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (25) (i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, and isopropoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (26) (i) hydrogen and halo; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (27) (i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (28) (i) hydrogen and halo; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from chloro and fluoro); (29) (i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from chloro and fluoro); or (30) (i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from fluoro).

[0074] In addition to embodiment (20) above, compounds of Formula 1 include those in which: (31)R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring selected from furan, pyrazole, and benzene, wherein one of the nitrogen atoms of the pyrazole ring is hydrogen, C 1-4 Alkyl, or C 3-6 substituted with cycloalkyl and fused rings is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 Alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo).

[0075] In addition to embodiment (20) above, compounds of Formula 1 include those in which: (32)R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring that is a furan, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C1-4 Alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo).

[0076] In addition to embodiment (32) of the preceding paragraph, compounds of Formula 1 include those in which: (33)R 1 , R 2 , and R 1 and R 2 The fused ring formed by the carbon atoms to which R is attached is 2 is a furan having an oxygen ring atom attached to a carbon atom directly attached to

[0077] In addition to embodiment (20) above, compounds of Formula 1 include those in which: (34)R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring that is a pyrazole, where one of the nitrogen atoms of the pyrazole ring is hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 Alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo).

[0078] In addition to embodiment (34) of the preceding paragraph, compounds of Formula 1 may also include R 1 , R 2 , and R 1 and R 2 is attached to a carbon atom, the fused ring formed by which is a pyrazole, including pyrazoles where: (35)R 2 or (36) R 2Attached to a carbon atom directly attached to a hydrogen atom, C 1-4 Alkyl or C 3-6 It has a nitrogen ring atom substituted with a cycloalkyl.

[0079] In addition to embodiments (34)-(36) of the preceding paragraph, compounds of Formula 1 may also include R 1 , R 2 , and R 1 and R 2 is a pyrazole, including those in which one of the nitrogen ring atoms is substituted with: (37) Hydrogen, C 1-3 Alkyl or C 3-6 cycloalkyl; (38) Hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl; (39) Hydrogen, methyl, ethyl, isopropyl, or cyclopropyl; (40) hydrogen or methyl; or (41) Methyl.

[0080] In addition to embodiment (20) above, compounds of Formula 1 include those in which: (42)R 1 and R 2 together with the carbon atoms to which they are attached form a fused ring which is benzene, and each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 Alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo).

[0081] In addition to embodiments (31)-(42) of the preceding paragraph, compounds of Formula 1 may also include R 1 and R 2wherein each non-fused carbon atom of the fused ring formed by is unsubstituted or substituted with an optional substituent independently selected from: (43) (i) halo and hydroxy; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (44)(i) halo and hydroxy; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (45) Halo and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); (46) Halo and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (47)C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (48)C 1-3 alkyl; or (49) Methyl.

[0082] In addition to embodiments (20)-(49) of the preceding paragraph, compounds of Formula 1 may also include R 3C and R 4 are each independently selected from: (50) (i) hydrogen, halo, and hydroxy; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (51) (i) hydrogen and halo; and (ii) C 1-4 Alkyl, C3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (52) (i) hydrogen and halo; and (ii) C 1-3 Alkyl, C 3-6 Cycloalkyl, and C 1-3 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (53) (i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, and isopropoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (54)(i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, and isopropoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (55)(i) hydrogen and halo; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (56) (i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (57)(i) hydrogen and halo; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from chloro and fluoro); (58)(i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from chloro and fluoro); or (59) (i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from fluoro).

[0083] In addition to embodiments (20)-(59) of the preceding paragraph, compounds of Formula 1 may also include R 5 is selected from the following: (60)(i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (61) (i) hydrogen, halo, and hydroxy; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (62)(i) hydrogen and halo; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (63)(i) hydrogen and halo; and (ii) C 1-3 Alkyl, C 3-6 Cycloalkyl, and C 1-3 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (64)(i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, and isopropoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (65)(i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, and isopropoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (66)(i) hydrogen and halo; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (67) (i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (68)(i) hydrogen and halo; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from chloro and fluoro); (69)(i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from chloro and fluoro); or (70)(i) hydrogen, chloro, and fluoro; and (ii) methyl, ethyl, cyclopropyl, methoxy, and ethoxy (each independently substituted with 0 to 3 optional substituents selected from fluoro).

[0084] In addition to embodiments (20) through (59) above, compounds of Formula 1 include those in which: (71)R 5 and R 6 Together, R 5 and R 6 Ethane bridging the carbon atom to which it is attached -forming 1,2-diyl;

[0085] In addition to embodiments (20) through (71) of the preceding paragraph, compounds of Formula 1 include those in which: (72)X 3 is CR 3C and X 4 is CR 4 and X 5 N and CR 5 Selected from; (73)X 3 is CR 3C and X 4 is CR 4 and X 5 is CR 5 is; or (74)X 3 is CR 3C and X 4 is N and X 5 is CR 5 is.

[0086] In addition to embodiments (20) through (59) above, compounds of Formula 1 include those in which: (75)X 3 is CR 3C and X 4 is CR 4 and X 5 is N.

[0087] In addition to embodiments (20) through (75) of the preceding paragraph, compounds of Formula 1 include those in which: (76)L is O and n is 1.

[0088] In addition to embodiments (20)-(70) and (72)-(75) above, compounds of Formula 1 include those in which: (77) L is a single bond and n is 0 or 1.

[0089] In addition to embodiments (1) through (77) of the preceding paragraph, compounds of Formula 1 may also include R 7 and R 8 are each independently selected from: (78) Hydrogen and C 1-4alkyl (substituted with 0-3 optional substituents independently selected from halo), where R 7 and R 8 At least one of is not hydrogen; (79) hydrogen and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo), where R 7 and R 8 at least one of is not hydrogen; (80) hydrogen, methyl, ethyl, and isopropyl, each of which is independently substituted with 0 to 3 optional substituents selected from halo, where R 7 and R 8 at least one of which is not hydrogen; (81) Hydrogen and methyl (independently substituted with 0 to 3 optional substituents selected from halo), where R 7 and R 8 at least one of which is not hydrogen; (82) Hydrogen, methyl, fluoromethyl, difluoromethyl, and trifluoromethyl, where R 7 and R 8 at least one of is not hydrogen; or (83) Hydrogen and methyl, where R 7 and R 8 At least one of these is not hydrogen.

[0090] In addition to embodiments (78)-(83) of the preceding paragraph, compounds of Formula 1 include those in which: (84)R 8 is hydrogen; or (85)R 7 and R 8 is the same.

[0091] In addition to the above embodiments (1) to (77), compounds of Formula 1 may also include R 7 and R 8 which, together with the carbon atom to which they are attached, form: (86)C 3-6 cycloalkylidene; (87) Cyclopropylidene, cyclobutylidene, and cyclopentylidene; (88) cyclopropylidene or cyclobutylidene; or (89) Cyclopropylidene.

[0092] In addition to embodiments (1) through (89) of the preceding paragraph, compounds of Formula 1 may also include R 9 is selected from the following: (90) Hydrogen and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (91) hydrogen, methyl, ethyl, and isopropyl, each of which is independently substituted with 0 to 3 optional substituents selected from halo; (92) hydrogen, methyl, ethyl, and isopropyl, each of which is independently substituted with 0 to 3 optional substituents selected from fluoro; or (93) Hydrogen, methyl, ethyl, and isopropyl.

[0093] In addition to embodiments (1)-(93) of the preceding paragraph, compounds of Formula 1 may also include R 10 includes those where: (94) azetidin-1-ylmethyl; or (95) Pyrrolidin-1-ylmethyl.

[0094] In addition to embodiments (1) through (93) above, compounds of Formula 1 include those in which: (96)R 10 is a heterocyclyl having the formula:

[0095] [ka]

[0096] During the ceremony,

[0097] [ka]

[0098] indicates the attachment point, r is selected from 0 and 1; R 11 is hydrogen and R 12 is hydrogen, as well as C 1-4 Alkyl and C 3-6 cycloalkyl (each independently substituted with 0-3 optional substituents selected from halo), with the proviso that R 12 is hydrogen, R 1 and R 2 forms a fused ring; or R 11 and R 12 together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached; R 13 , R 14 , R 15 , and R 16 are each independently hydrogen, halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo), or R 13 and R 16 does not exist, and R 14 and R 15 together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R 17 and R 18 are each independently hydrogen, halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo).

[0099] In addition to embodiment (96) of the preceding paragraph, compounds of Formula 1 may also include R 11 is hydrogen and R 12 is selected from the following: (97)C 1-4 Alkyl and C 3-6 cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo); (98)C 1-3 Alkyl and C 3-6 cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo); (99) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, and cyclopentyl (each independently substituted with 0 to 3 optional substituents selected from halo); (100) methyl, ethyl, isopropyl, and cyclopropyl (each independently substituted with 0 to 3 optional substituents selected from halo); (101) Methyl, ethyl, isopropyl, and cyclopropyl (each substituted with 0 to 3 optional substituents selected from fluoro); (102) methyl, ethyl, and isopropyl (each substituted with 0 to 3 optional substituents selected from fluoro); (103) methyl and ethyl (each substituted with 0 to 3 optional substituents selected from fluoro); (104) Methyl and ethyl; or (105) Methyl.

[0100] In addition to embodiment (96) above, compounds of Formula 1 include those in which: (106)R 11 and R 12 together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached.

[0101] In addition to embodiments (96)-(106) of the preceding paragraph, compounds of Formula 1 may also include R 13 , R 14 , R 15 , and R 16 are each independently selected from: (107) Hydrogen, Halo, and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); (108) Hydrogen and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); (109) Hydrogen and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (110) hydrogen, halo, and methyl (independently substituted with 0 to 3 optional substituents selected from halo); (111) hydrogen, halo, and methyl (substituted with 0 to 3 optional substituents independently selected from fluoro); (112) Hydrogen, halo, and methyl; (113) Hydrogen, fluoro, and methyl; (114) Hydrogen and methyl; or (115)Hydrogen.

[0102] In addition to embodiments (107)-(114) of the preceding paragraph, compounds of Formula 1 include those in which: (116)R 15 and R 16 are each hydrogen.

[0103] In addition to embodiments (96)-(106) above, compounds of Formula 1 include those in which: (117)R 13 and R 16 does not exist, and R 14 and R 15together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 Alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo).

[0104] In addition to embodiment (117) of the preceding paragraph, compounds of Formula 1 may also include R 14 and R 15 wherein each non-fused carbon atom of the fused benzene ring formed by is unsubstituted or substituted independently with an optional substituent selected from: (118)(i) halo and hydroxy; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl, and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (119)(i) halo and hydroxy; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); (120) Halo and C 1-4 alkyl (substituted with 0-3 optional substituents independently selected from halo); (121) Halo and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (122)C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (123)C 1-3 alkyl; or (124) Methyl.

[0105] In addition to embodiment (117) above, compounds of Formula 1 include those in which: (125)R 14 and R 15 Each non-fused carbon atom of the fused benzene ring formed by is unsubstituted.

[0106] In addition to embodiments (96)-(125) of the preceding paragraph, compounds of Formula 1 may also include R 17 and R 18 are each independently selected from: (126) Hydrogen, Halo, and C 1-3 alkyl (substituted with 0-3 optional substituents independently selected from halo); (127) hydrogen, halo, methyl, and ethyl, wherein methyl and ethyl are each independently substituted with 0 to 3 optional substituents selected from halo; (128) Hydrogen, halo, and methyl; (129) Hydrogen, fluoro, and methyl; or (130) Hydrogen and Fluoro.

[0107] In addition to embodiments (126)-(130) of the preceding paragraph, compounds of Formula 1 include those in which: (131)R 17 and R 18 is the same.

[0108] In addition to embodiments (96)-(131) of the preceding paragraph, compounds of Formula 1 include those in which: (132) r is 0; or (133)r is 1.

[0109] Compounds of Formula 1 include embodiments (1) through (133) described in the preceding paragraphs, and compounds specifically named in the Examples, and may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, compounds of Formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0110] The compounds of Formula 1 can form pharmaceutically acceptable complexes, salts, solvates, and hydrates. These salts include acid addition salts (including diacids) 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, as well as non-toxic salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, glucept, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethionate. salts, 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 salts.

[0111] Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as alkali or alkaline earth metal cations, and amines. 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. Also see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and See also Use (2002).

[0112] Pharmaceutically acceptable salts can be prepared using a variety of methods. For example, a compound of Formula 1 can be reacted with an appropriate acid or base to obtain the desired salt. Alternatively, a precursor of the compound of Formula 1 can be reacted with an acid or base to remove acid- or base-labile protecting groups or to open the lactone or lactam group of the precursor. In addition, a salt of the compound of Formula 1 can be converted to another salt (or free form) by treating it with an appropriate acid or base or by contacting it with an ion exchange resin. After the reaction, the salt can be isolated by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

[0113] Compounds of Formula 1 can exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid, depending on temperature. Typically, such materials do not produce distinctive X-ray diffraction patterns and are more formally described as liquids, although they exhibit the properties of a solid. Upon heating, they undergo a change of state, typically second-order (a "glass transition"). A change from solid to liquid properties occurs, characterized by a melting point. The term "crystalline" refers to a solid phase in which the material has an internal structure with regular order at the molecular level, resulting in a distinctive X-ray diffraction pattern with distinct peaks. Such materials, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, typically first order (the "melting point").

[0114] The compound of formula 1 can exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex containing a compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., DO, acetone-d6, DMSO-d6).

[0115] A currently accepted classification system for solvates and hydrates of organic compounds distinguishes between segregation site, channel, and metal ion coordinated solvates and hydrates. See, e.g., KR Morris (HGBrittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site hydrates and solvates are those in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules reside in lattice channels where they are next to other solvent molecules. In metal ion coordination solvates, the solvent molecules are bound to the metal ion.

[0116] When the solvent or water is tightly bound, the complex has a well-defined stoichiometry 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, non-stoichiometry will typically be observed.

[0117] The compounds of Formula 1 may also exist as multicomponent complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes inclusion complexes (drug-host inclusion complexes) and cocrystals. The latter is typically defined as a crystalline complex of neutral molecular components bound together by non-covalent interactions, but may also be a complex of a neutral molecule with a salt. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. See, for example, O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a review of multicomponent complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0118] Compounds of Formula 1 can exist in a mesophase (mesophase or liquid crystal) when subjected to appropriate conditions. The mesophase is intermediate between the true crystalline state and the true liquid state (either melt or dissolve). Liquid crystallinity resulting from a change in temperature is described as "thermotropic," while liquid crystallinity resulting from the addition of a second component, such as water or another solvent, is described as "lyotropic." Compounds with the potential to form lyotropic mesophases are described as "amphiphilic," and include polar ionic moieties (e.g., -COO - Na + , -COO - K + , -SO3 - Na + ) or polar nonionic moiety (-N - N +(CH3)3, etc. See, for example, N.H. Hartshorne and A. Stuart, Crystals and See the Polarizing Microscope (4th ed., 1970).

[0119] Each compound of Formula 1 may exist in the form of polymorphs, stereoisomers, tautomers, or some combination thereof. They may be present in combination, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0120] A "prodrug" refers to a compound that has little or no pharmacological activity but can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared by replacing appropriate functional groups present in a pharmacologically active compound with a "promoiety," as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of the compounds of Formula 1 that contain carboxylic acid, hydroxy, or amino functional groups, respectively. For a detailed discussion of prodrugs, see T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and EB Roche ed., Bioreversible Carriers in Drug Design (1987).

[0121] "Metabolites" refer to compounds formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1, which contain methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amido groups, respectively.

[0122] The compounds of Formula 1 can exist as stereoisomers resulting from the presence of one or more asymmetric centers, one or more double bonds, or both. The stereoisomers can be pure, substantially pure, or mixtures. Such stereoisomers can also result from acid addition or base salts in which the counterion is optically active (e.g., when the counterion is D-lactate or L-lysine).

[0123] Compounds of Formula 1 can exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0124] Compounds of formula 1 may exhibit more than one type of isomerism.

[0125] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography or fractional crystallization.

[0126] Conventional techniques for preparing or isolating compounds of a specific stereochemical configuration include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example, using chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with an appropriate optically active compound, for example, an alcohol, or, if the compound of Formula 1 contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture can be separated by chromatography, fractional crystallization, or the like, and the appropriate diastereoisomer can be converted to a compound with the required stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0127] The compounds of formula 1 have at least one atom having the same atomic number but not normally found in nature. Suitable isotopes for inclusion in compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g., 11 C. 13 C, and 14 C; isotopes of nitrogen, e.g., 13 N and 15 N; isotopes of oxygen, e.g., 15 O. 17 O, and 18 O; isotopes of sulfur, e.g., 35 S; isotopes of fluorine, e.g., 18 F; isotopes of chlorine, e.g., 36 Cl; as well as isotopes of iodine, e.g., 123 I and 125 Isotopic variants (e.g., deuterium, 2 The use of H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to increased metabolic stability. Additionally, certain isotopic variations of the disclosed compounds may be substituted with radioactive isotopes (e.g., tritium, 3 H, or 14 C) can be incorporated, which can be useful for drug and / or substrate tissue distribution studies. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds can be prepared by processes analogous to those described elsewhere in this disclosure, using the appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0128] Compounds of Formula 1 can be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and the like; separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like); 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 several treatises, including Richard Larock's Comprehensive Organic Transformations (1999) and the multivolume series, Compendium of Organic Synthetic Methods (since 1974), edited by Michael B. Smith et al. Starting materials and reagents can be obtained from commercial sources or prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., alcohols from the hydrolysis of esters, CO from the decarboxylation of diacids, and the like). Additionally, in some cases, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0129] In some of the reaction schemes and examples that follow, certain compounds can be prepared using protecting groups that prevent undesired chemical reactions outside of the reactive site. Protecting groups can also be used to enhance the solubility of the compound or otherwise modify its physical properties. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a summary of useful protecting groups for common functional groups such as amines, carboxylic acids, alcohols, ketones, and aldehydes, see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0130] Generally, chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions can benefit from using an excess of one or more reactants. Additionally, although many of the reactions disclosed throughout this specification can be carried out at about room temperature (RT) and ambient pressure, some reactions may be carried out at elevated pressures or using higher (e.g., reflux conditions) or lower temperatures (e.g., −78° C. to 0° C.), depending on reaction kinetics, yield, etc. All references in this disclosure and claims to stoichiometric ranges, temperature ranges, pH ranges, etc., include the indicated endpoints, regardless of whether the word “range” is explicitly used.

[0131] Many chemical transformations may also employ one or more compatible solvents, which can affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylene); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., 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, hexane-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2 ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric acid triamide).

[0132] In the following schemes, the substituent identifiers (L, n, r, R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R10 , R 12 , X 3 , X 4 , and X 5 ) are as defined above for Formula 1. However, as noted above, some of the starting materials and intermediates may contain protecting groups, which are removed prior to the final product. In such cases, the substituent identifiers refer to the moieties as defined in Formula 1 and those moieties that have the appropriate protecting groups. For example, a starting material or intermediate in the scheme may have an R 1 group containing a potentially reactive (secondary) amine. 10 In such cases, R 10 would include, for example, a moiety with or without a Boc or Cbz group attached to the amine.

[0133] Scheme A shows a general method for preparing compounds of Formula 1. According to this method, an aryl or heteroaryl (alkyl or oxyalkyl) amine (A1) is reacted with a carboxylic acid (A2) or a suitable base addition salt (e.g., lithium salt). This reaction is carried out using a standard amide coupling agent, such as HATU, DCC, EDC hydrochloride, T3P, or 2-chloro-1-methylpyridin-1-ium iodide, in the presence of a non-nucleophilic base (e.g., Et3N, DIPEA) and one or more compatible solvents (e.g., ACN, DCM, DMA, DMF, NMP, pyridine, THF). This amide coupling can be carried out at temperatures ranging from room temperature to about 80°C. HOBt may be used to facilitate the reaction.

[0134] [ka]

[0135] Although not shown in Scheme A, carboxylic acid (A2) may be substituted with an R 3 hydroxyl group having a protected (e.g., Boc-substituted) secondary amine. 10In such cases, the amine may be deprotected (e.g., by acid treatment) following amide coupling to reveal a secondary amine, which may then be reacted with an alkyl halide (R 12 Y 1 , where R 12 =C 1-4 Alkyl and C 3-6 cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo); Y 1 =Br, I) to form the required R 12 R with 10 Alternatively, a secondary amine may be reacted with the appropriate alkyl aldehyde under acidic conditions in the presence of a mild reducing agent such as sodium cyanoborohydride or sodium acetoxyborohydride and a compatible solvent (e.g., MeOH, DCM) to give the required R 12 R with 10 The N-alkylation and reductive amination steps may be carried out at room temperature or above.

[0136] Scheme B illustrates the synthesis of compounds of Formula 1 (L=O, X 5 A second general method for preparing hydroxyalkylamines (Y =N) is shown. According to this method, a hydroxyalkylamine (B1) is reacted with a carboxylic acid (A2) to form a hydroxyalkylamide (B2). As in Scheme A, the reaction is carried out using a standard amide coupling agent in one or more compatible solvents at room temperature to about 80°C, optionally with HOBt. The hydroxyalkylamide (B2) is then coupled to an aryl or heteroaryl reactant (B3, Y =N) in the presence of a strong non-nucleophilic base (e.g., NaH) and a compatible polar aprotic solvent (e.g., DMF). 2 =F, Cl, Br) to give the compound of formula 1. N The Ar reaction can be carried out at room temperature or above.

[0137] [ka]

[0138] Scheme C shows the R 10 A third general method for preparing compounds of Formula 1 when s is azetidin-1-ylmethyl or pyrrolidin-1-ylmethyl (Formula 1A, s = 1 or 2) is shown. According to this method, an aryl or heteroaryl (alkyl or oxyalkyl) amine (A1) is reacted with an α,β-unsaturated carboxylic acid (C1). As in Scheme A, the reaction is carried out using a standard amide coupling agent in one or more compatible solvents at room temperature to about 80°C, optionally with HOBt. The resulting amide (C2) is reacted with an azetidine or pyrrolidine (C3) in a protic solvent (MeOH, water) at elevated temperatures (e.g., 50-100°C) to provide compounds of Formula 1A.

[0139] The methods depicted in the schemes can be modified as desired. For example, protecting groups can be added or removed, and the products can be further elaborated, for example, via alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, etc., to obtain the desired final product. Furthermore, any intermediates or final products that contain a mixture of stereoisomers can be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically pure reagents, as described above, to obtain the desired stereoisomer.

[0140] [ka]

[0141] The compounds of Formula 1 (including the compounds named above, as well as pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof) should be evaluated for biopharmaceutical properties such as solubility and solution stability versus pH, permeability, etc. to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, lyophilization, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0142] The compounds of Formula 1 can be administered alone, in combination with each other, or in combination 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 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).

[0143] The compound of formula 1 can be orally administered. Oral administration can include swallowing, in which case the compound enters the bloodstream through the gastrointestinal tract. Alternatively, or additionally, oral administration can include mucosal administration (e.g., buccal, sublingual, supragingual), so that the compound enters the bloodstream through the oral mucosa.

[0144] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, such as tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquids, or powders; lozenges (which may be liquid-filled); chewable tablets; gels; fast-dispersing dosage forms; films; vaginal suppositories; sprays; and Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), and typically contain a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifiers, suspending agents, or both. Liquid formulations may also be prepared by reconstitution of a solid (e.g., from a sachet).

[0145] The compounds of Formula 1 may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0146] For tablet dosage forms, depending on the dosage, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% of the dosage form, or more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets may contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorings, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 Included are alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants will comprise from about 1 wt% to about 25 wt%, or from about 5 wt% to about 20 wt% of the dosage form.

[0147] Binders are generally used to give tablet formulations cohesion.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized 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.

[0148] Tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the surfactants may comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0149] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt%, or from about 0.5 wt% to about 3 wt% of the tablet.

[0150] Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends, or portions of the blends, may alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tableting. If desired, one or more of the components may be sized by sieving or milling, or both, prior to blending. The final dosage form may comprise one or more layers, may be coated or uncoated, or may be encapsulated. An exemplary tablet may 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. Blending, Granulation, Milling, Sieving, Tableting, and Coating Considerations For a description of the techniques for preparing drug products, as well as alternative techniques, 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 (2nd ed., 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0151] Consumable oral films for human or animal use are flexible, water-soluble or water-swellable thin film dosage forms that can be fast-dissolving or mucoadhesive. In addition to the API, typical films contain one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients can include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants, and taste masking agents. Some components of the formulation can perform more than one function.

[0152] In addition to dosage requirements, the amount of API in the film can depend on its solubility. If water-soluble, the API will typically comprise about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film, or about 20 wt% to about 50 wt% of the solutes in the film. Less soluble APIs may comprise a larger proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.

[0153] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film.

[0154] Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating and drying apparatus), a freeze-drying machine, or a vacuum oven.

[0155] 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 dispersions and osmotic and coated particles, see Verma et al., Pharmaceutical Technology Online (2001) 25(2):1-14.

[0156] The compound of formula 1 can also be directly administered into the bloodstream, muscle or internal organs of the subject.The techniques suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.The device suitable for parenteral administration includes needle-type (including microneedle) injector, needle-free injector and infusion device.

[0157] Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffering agents (e.g., pH about 3 to about 9). However, for some applications, the compounds of Formula 1 may be more suitably formulated as sterile, non-aqueous solutions or as a dry form for use with a suitable vehicle, such as sterile, pyrogen-free water. Preparation of parenteral formulations under sterile conditions (eg, by lyophilization) may be readily accomplished using standard pharmaceutical techniques.

[0158] The solubility of compounds used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration may be formulated for immediate release and / 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, semisolid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and semisolids and suspensions containing drug-loaded poly(DL-lactic-co-glycolic acid) (PGLA) microspheres.

[0159] The compounds of Formula 1 may also be administered topically, intradermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0160] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject™ and Bioject™) injection. Formulations for topical administration may be formulated to be immediate and / or modified release, as described above.

[0161] The compound of formula 1 can also be administered intranasally or by inhalation, typically in the form of dry powder, aerosol spray, or nasal drops.An inhaler can be used to administer the dry powder, which includes API only, a powder blend of API and a diluent such as lactose, or mixed-component particles including API and a phospholipid such as phosphatidylcholine.When used intranasally, the powder can also include a bioadhesive agent such as chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate an aerosol spray from a solution or suspension containing the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH, with or without water), one or more solvents that function as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Atomizers that use electrohydrodynamics to generate a fine mist may also be used.

[0162] Prior to use in a dry powder or suspension formulation, the drug product is usually milled to a particle size suitable for delivery by inhalation (typically 90% of the particles by volume have a largest dimension less than 5 microns). This can be achieved by any suitable size reduction method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0163] Capsules, blisters, and cartridges (made from, for example, gelatin or hydroxypropyl methylcellulose) for use in an inhaler or insufflator The formulation may contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0164] Solution formulations suitable for use in atomizers that use electrohydrodynamics to generate a fine mist may contain about 1 μg to about 20 mg of API per actuation, and actuation volumes may 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 in place of propylene glycol include glycerol and polyethylene glycol.

[0165] Formulations for inhaled administration, intranasal administration, or both, may be formulated to be immediate or modified release, using, for example, PGLA. Suitable flavors, such as menthol and levomenthol, or suitable sweeteners, such as saccharin or saccharin sodium, may be added to such formulations intended for inhaled / intranasal administration.

[0166] For dry powder inhalers and aerosols, the dosage unit is determined by utilizing a valve that delivers a metered amount. The unit is typically designed to administer a metered dose or "puff" containing from about 10 μg to about 1000 μg of API. The overall daily dose typically ranges from about 100 μg to about 10 mg, which may be administered in a single dose or, more usually, in divided doses throughout the day.

[0167] The active compound may 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 may be used where appropriate. Preparations for rectal or vaginal administration may be formulated as immediate release and / or modified release, as described above.

[0168] The compound of Formula 1 may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in pH-adjusted, isotonic, sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable implants (e.g., absorbent gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes. The formulation may contain one or more polymers and preservatives, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gellan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or otic administration may be formulated for immediate and / or modified release, as described above.

[0169] The compounds of Formula 1 may be combined with soluble macromolecular entities, such as cyclodextrins and their derivatives, and polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste-masking, bioavailability, or stability. For example, API-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, cyclodextrins may be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. Alpha-, beta-, and gamma-cyclodextrins are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02 518, and WO98 / 55148.

[0170] As noted above, one or more compounds of Formula 1, including those specifically named above, and pharmaceutically active complexes, salts, solvates, and hydrates thereof, can be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions, and disorders. In such cases, the active compounds may be combined in a single dosage form, as described above, or provided in the form of a kit suitable for simultaneous administration of the compositions. A kit includes (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1, and (2) a device for separately holding the two pharmaceutical compositions (e.g., a divided bottle or a divided foil packet). An example of such a kit is a common blister pack used for packaging tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral), or for administering different pharmaceutical compositions at different dosing intervals, or for titrating different pharmaceutical compositions relative to each other. To aid patient compliance, the kit typically includes instructions for administration and may provide a memory aid.

[0171] When administered to a human patient, 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 a total daily dose of only about 0.1 mg to about 300 mg. The total daily dose may be administered in a single dose or in divided doses and, at the physician's discretion, may fall outside the typical ranges set forth above. These dosages are based on an average human subject weighing about 60 kg to about 70 kg, although a physician would be able to determine the appropriate dose for patients (e.g., infants) weighing outside this weight range.

[0172] As described 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 occurrence in a subject for which activation of SSTR4 provides a therapeutic benefit. More specifically, 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 (i.e., severe or mild neurocognitive disorders) associated with one or more medical conditions, such as frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or medication use, HIV infection, prion disease, Parkinson's disease, and Huntington's disease. The compounds of Formula 1 can also be used to treat severe 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 epilepsy.

[0173] The claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases, or conditions for which SSTR4 is indicated. Such combinations may provide significant therapeutic benefits, including reduced side effects, improved therapeutic potential for underserved patient populations, or synergistic activity. For example, compounds of Formula 1, including those specifically named above, and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof, may be administered simultaneously, sequentially, or separately in combination with one or more compounds or therapies for treating Alzheimer's disease. Such compounds or therapies include beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., apazone, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaliplatin ... Specific examples of compounds used to treat Alzheimer's disease include donepezil, rivastigmine, memantine, and galantamine.

[0174] In addition to drugs used to improve cognition, the compounds of Formula 1 may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications used to treat Alzheimer's disease. For example, the compounds of Formula 1 may be combined with one or more drugs for treating depression and / or schizophrenia (antidepressants and / or atypical or typical antipsychotics), including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine ... Examples of antidepressants include phenazine, 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 ziprasidone.

[0175] Similarly, the compounds of Formula 1 may be combined with one or more agents for treating anxiety (antianxiety medications), including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone.

[0176] The compounds of Formula 1 may also be combined with one or more agents for treating epilepsy (antiepileptic or anticonvulsant drugs), including 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.

[0177] biological activity

[0178] The biological activity of the compounds of formula 1 with respect to SSTR4 was determined by the following in vitro and in vivo assays. It can be determined using in vivo methods.

[0179] Inhibition of forskolin-stimulated cAMP in cells overexpressing SSTR4

[0180] This cell-based assay measures the ability of compounds 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 with 10% fetal bovine serum (Hyclone), 1% Pen / Strep (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). The cells are then incubated at room temperature for 30 minutes in 10 μL of compound / stimulation buffer. Cells are then incubated for 30 minutes in 10 μL of compound / stimulation buffer. Cellular cAMP levels are detected using an HTRF LANCE Ultra cAMP kit (Perkin Elmer, Cat. No. TRF0264).

[0181] The assay is performed according to the manufacturer's instructions. 5 μL of diluted Eu-W8044 labeled streptavidin (dilution: 1:50 in cAMP detection buffer) is added to each well. 5 μL of diluted biotin-cAMP (dilution: 1:150 in cAMP detection buffer) is then added to each well. The plate is covered and incubated on a shaker at room temperature for 60 minutes. HTRF (665 nm / 615 nm) is read on a Perkin Elmer ENVISION plate reader. pEC 50 The values ​​are generated using the Activity Base in Screening Data Management.

[0182] SSTR4 I-125 somatostatin competitive binding assay

[0183] This membrane-based assay measures the ability of compounds 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 diluted in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM CaCl2, 0.5% BSA) + 0.2 nM I-125 labeled somatostatin (Perkin Elmer catalog number NEX389). 50 μL of assay buffer containing compound / I-125 somatostatin is added per well to a 96-well polypropylene plate. Then, 50 μL of assay buffer containing 1 μg of SSTR4 membranes is added per well. The plate is incubated at room temperature for 60 minutes. FilterMat A filters (Perkin Elmer Catalog No. 1450-421) are presoaked in 0.5% PEI (Sigma Catalog No. P3143). The contents of the assay plate are transferred to the filters with a TomTech harvester and washed five times with 20 mM HEPES, 100 mM NaCl. The filters are dried in a microwave oven and then transferred to a sample bag containing a scintillator sheet (Perkin Elmer Catalog No. 1450-441). A heat block is used to fuse the scintillator sheet to the filter. The filters are then read in a MicroBeta scintillation counter. Binding K curves are generated using Activity Base in Screening Data Management and results are expressed as pIC 50 Report as.

[0184] SSTR1 I-125 somatostatin competitive binding assay for selectivity against SSTR1

[0185] This membrane-based assay measures the ability of compounds 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 diluted in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl, 1 mM CaCl, 0.5% BSA) + 0.4 nM I-125 labeled somatostatin (Perkin Elmer catalog number NEX389). A 96-well polypropylene plate is filled with assay buffer containing compound / I-125 somatostatin. 50 μL of the solution is added per well. 50 μL of assay buffer containing 10 μg of SSTR1 membranes is then added per well. The plate is incubated at room temperature for 60 minutes. FilterMat A filters (Perkin Elmer Catalog No. 1450-421) are presoaked in 0.5% PEI (Sigma Catalog No. P3143). The contents of the assay plate are transferred to the filters with a TomTech harvester and washed five times with 20 mM HEPES, 100 mM NaCl. The filters are dried in a microwave oven and then transferred to a sample bag containing a scintillator sheet (Perkin Elmer Catalog No. 1450-441). A heat block is used to fuse the scintillator sheet to the filter. The filters are then read in a MicroBeta scintillation counter. Binding Ki curves are generated using Activity Base in Screening Data Management and the results are expressed as pIC 50 Report as.

[0186] In vivo screening using subcutaneous pentylenetetrazole (PTZ)

[0187] Six- to eight-week-old Swiss-Webster mice are used in the subcutaneous PTZ model of seizures. PTZ is a GABAergic agent that blocks GABA receptors, thereby disinhibiting all CNS systems and inducing seizures in animals. Seizures can be assessed and quantified by observing the animals in the study. Thus, this model provides a screening model for testing compounds with anticonvulsant activity in mice (derived from their activity on the inhibitory receptor SSTR4). According to this method, six- to eight-week-old Swiss-Webster mice are acclimated to the testing room one hour prior to the start of the experiment. Animals (n=6 / group) are then blindly dosed with vehicle or test compound, followed 15 minutes later by subcutaneous PTZ administration. Animals are scored based on the time it takes to develop a seizure that impairs the ability to stand. This time is scored as the latency to seizure. The number and severity of seizures are also scored but are not used in the final data. [Example]

[0188] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present invention.

[0189] For many of the compounds in the examples below, 1 H nuclear magnetic resonance (NMR) spectra were obtained. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane using conventional abbreviations for major peak designations, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), CD3OD (deuterated methanol), CD3CN (deuterated acetonitrile), and THF-d8 (deuterated tetrahydrofuran). Mass spectra ([M+H] + The m / z for each compound was recorded using either electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0190] Where indicated, products of certain preparations and examples are purified by mass-triggered HPLC, flash chromatography, preparative TLC, or SFC. Reverse-phase chromatography is typically performed on a column (e.g., Phenomenex Gemini® C18, 5 μm, 30 mm i.d. x 150 mm) under acidic conditions ("acid mode"), eluting with a mobile phase of ACN and water (containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively), or under basic conditions ("basic mode", pH 9.5-10), eluting with a mobile phase of water and 20 / 80 (v / v) water / acetonitrile (both containing 10 mM NH4HCO3). Preparative TLC is typically performed on silica gel 60F. 254 The preparation and examples are carried out on plates. Separation of enantiomers using SFC After chromatographic separation, the product is obtained by removing the solvent and drying in a centrifugal evaporator (e.g., GeneVac™), rotary evaporator, vacuum flask, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0191] Preparation 1: 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine

[0192] [ka]

[0193] Step A: tert-butyl (1-(3-chloro-2-fluorophenyl)-1-hydroxy-2-methylpropan-2-yl)carbamate

[0194] [ka]

[0195] To a solution of 1-chloro-2-fluorobenzene (5.3 g, 40.6 mmol) in THF (60 mL) was added n-BuLi (1.6 M in hexane, 16 mL, 25.6 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. Then, a solution of tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (2.00 g, 10.15 mmol) in THF (10 mL) was added at −78° C. The mixture was stirred at −78° C. for an additional 1 hour, then poured into saturated aqueous NH4Cl (80 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 10:1) to give the title compound as a white solid (3.1 g, 86%). ESI-MS m / z [M+H] + 318.1.

[0196] Step B: tert-butyl (1-(3-chloro-2-fluorophenyl)-2-methyl-1-oxopropan-2-yl)carbamate

[0197] [ka]

[0198] To a solution of tert-butyl (1-(3-chloro-2-fluorophenyl)-1-hydroxy-2-methylpropan-2-yl)carbamate (3.0 g, 8.50 mmol) in DCM (60 mL) was added DMP (3.93 g, 9.26 mmol) at 0° C. The mixture was stirred at 25° C. for 12 hours and then adjusted to pH 8 by adding aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc (150 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 10:1) to give the title compound as a white solid (2.3 g, 81%). ESI-MS m / z [M+H]+ 316.1.

[0199] Step C: tert-butyl (Z)-(1-(3-chloro-2-fluorophenyl)-1-(hydroxyimino)-2-methylpropan-2-yl)carbamate

[0200] [ka]

[0201] To a solution of tert-butyl (1-(3-chloro-2-fluorophenyl)-2-methyl-1-oxopropan-2-yl)carbamate (2.3 g, 6.92 mmol) in EtOH (40 mL) was added NaOAc (2.84 g, 34.6 mmol) and NH2OH.HCl (2.40 g, 34.6 mmol). The mixture was stirred at 90 °C for 12 h, then diluted with water (20 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 5:1) to give the title compound as a white solid (2.1 g, 87%). ESI-MS m / z [M+H] + : 331.1.

[0202] Step D: tert-Butyl (2-(7-chlorobenzo[d]isoxazol-3-yl)propan-2-yl)carbamate

[0203] [ka]

[0204] To a solution of tert-butyl (Z)-(1-(3-chloro-2-fluorophenyl)-1-(hydroxyimino)-2-methylpropan-2-yl)carbamate (500 mg, 1.44 mmol) in THF (160 mL) was added t-BuOK (483 mg, 4.31 mmol). The mixture was stirred at 25° C. for 2 hours. The reaction was repeated using three additional portions of tert-butyl (Z)-(1-(3-chloro-2-fluorophenyl)-1-(hydroxyimino)-2-methylpropan-2-yl)carbamate (30 mg, 300 mg, and 500 mg). The four portions were combined and diluted with EtOAc (300 mL). The organic layer was washed with water (300 mL × 2), then brine (300 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 5:1) to give the title compound as a white solid (900 mg, 64% yield, 94% purity). ESI-MS m / z [M+H] + : 311.1.

[0205] Step E: tert-Butyl (2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)carbamate

[0206] [ka]

[0207] A mixture of tert-butyl (2-(7-chlorobenzo[d]isoxazol-3-yl)propan-2-yl)carbamate (900 mg, 2.72 mmol, 94% purity), methylboronic acid (818 mg, 13.7 mmol), Pd(OAc) (122 mg, 544 μmol), KPO (2.89 g, 13.6 mmol), and SPhos (224 mg, 544 μmol) in toluene (20 mL) was degassed and purged with nitrogen (3×). The mixture was stirred under a nitrogen atmosphere for 12 h at 120 °C and then concentrated in vacuo. The residue was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 3:1) to give the title compound as a white solid (600 mg, 71%). ESI-MS m / z [M+H] + 291.1.

[0208] Step F: 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine

[0209] To a solution of tert-butyl (2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)carbamate (550 mg, 1.78 mmol) in DCM (20 mL) was added TFA (3.76 mL, 50.8 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h and then concentrated in vacuo. The residue was diluted with EtOAc (20 mL) and washed with aqueous NaCO (3×20 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The product was purified by preparative TLC on silica using DCM / MeOH (10:1) as eluent to give the title compound as a yellow oil (203.4 mg, 58%). 1 H NMR (400 MHz, CDCl3) δ ppm 1. 69(s,6H),2.57(s,3H),7.18-7.24(m,1H),7.29-7.33(m,1H),7.69(d,J=8.2Hz,1H),ESI-MS m / z [M+H] + 191.1.

[0210] Preparation 2: 2-(isoquinolin-1-yl)propan-2-amine

[0211] [ka]

[0212] Step A: (R,E)—N-(1-(isoquinolin-1-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0213] [ka]

[0214] To a solution of 1-(1-isoquinolyl)ethanone (9.00 g, 52.6 mmol) in THF (100 mL) was added (R)-2-methylpropane-2-sulfinamide (7.65 g, 63.1 mmol) and Ti(OEt) (17.4 mL, 84.1 mmol) at 15 °C. The mixture was stirred under nitrogen for 8 h at 70 °C, then diluted with EtOAc (100 mL) and quenched with water (5 mL) at 0 °C. The mixture was stirred for 0.5 h, and the resulting brown suspension was filtered through a pad of Celite®. The filtrate was washed with brine (10 mL 3x), dried, filtered, and concentrated in vacuo. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 3:1) to give the title compound (5.7 g, 39%). ESI-MS m / z [M+H] + :275.1.

[0215] Step B: (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-methylpropane-2-sulfinamide

[0216] [ka]

[0217] To a solution of (R,E)-N-(1-(isoquinolin-1-yl)ethylidene)-2-methylpropane-2-sulfinamide (13.5 g, 49.2 mmol) in toluene (260 mL) was added MeMgBr (3 M in EtO, 49.2 mL) at 0 °C. The mixture was stirred under nitrogen for 2 h at 0 °C and then quenched with saturated aqueous NH Cl (150 mL) at 0 °C. The mixture was warmed to 15 °C and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 1:1) to give the title compound (10 g, 70%). ESI-MS [M+H] + : 291.1.

[0218] Step C: 2-(isoquinolin-1-yl)propan-2-amine

[0219] To a solution of (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (5.0 g, 17.2 mmol) in MeOH (100 mL) was added HCl (4 M in dioxane, 25.8 mL) at 15° C. The mixture was stirred at 15° C. for 2 h and then concentrated in vacuo. The crude product was triturated with EtOAc (3×20 mL) at 15° C. for 0.5 h. The resulting suspension was filtered, and the filter cake was dried under vacuum to afford the bis-HCl salt of the title compound as a white solid (3.9 g, 87%). 1 H NMR(400MHz,DMSO-d6)δ ppm 1.94(s,6H),7.71 -7.76(m,1H),7.84(t,J=7.3Hz,1H),7.92(d,J=5.6Hz,1H),8.10(d,J=7.8Hz,1H),8.45-8.52(m,2H),8.66(br s,3H);ESI-MS m / z [M+H] + 187.2 .

[0220] Preparation 3: 3-(azetidin-1-yl)-2-methylpropanoic acid

[0221] [ka]

[0222] Step A: Methyl 3-(azetidin-1-yl)-2-methylpropanoate

[0223] [ka]

[0224] To a round-bottom flask containing methyl 2-methylprop-2-enoate (5.91 g, 59.1 mmol) in MeOH (4 mL) was added azetidine (1.00 g, 17.5 mmol). The reaction mixture was stirred at 15° C. for 16 hours, then quenched with water (100 mL) and extracted with DCM (80 mL). The organic layer was washed with water (2×50 mL) and brine (2×50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography using DCM as eluent to give the title compound as a colorless oil (0.8 g, 29%). ESI-MS m / z [M+H] + : 158.1.

[0225] Step B: 3-(Azetidin-1-yl)-2-methylpropanoic acid

[0226] To a round-bottom flask containing methyl 3-(azetidin-1-yl)-2-methylpropanoate (0.2 g, 1.27 mmol) in THF (5 mL) was added LiOH.HO (2 M aqueous solution, 1.11 mL, 2.22 mmol). The reaction mixture was stirred at 15 °C for 16 h and then diluted with EtOAc (10 mL). The aqueous layer was adjusted to pH 5-6 with HCl (1 M), washed with DCM (2 × 30 mL), and lyophilized to afford the HCl salt of the title compound as a white semi-solid (270 mg). 1 H NMR (400 MHz, CD3OD) δ p pm 1.17(d,J=7.3Hz,3H),2.38-2.54(m,3H),3. 11-3.29(m,2H),4.06-4.24(m,4H);ESI-MS m / z [M+H] + 144.1.

[0227] Preparation 4: 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropan-1-amine

[0228] [ka]

[0229] To a solution of (1-aminocyclopropyl)methanol HCl salt (3.80 g, 30.8 mmol) in dioxane (80 mL) was added NaH (60 wt% in mineral oil, 1.73 g, 43.2 mmol) in small portions at 20 °C. The mixture was stirred for 30 min. Then, 2-fluoro-3-methylpyridine (1.09 mL, 10.8 mmol) was added. The reaction mixture was stirred at 100 °C for 68.5 h, then diluted with water (50 mL) and extracted with DCM (2 × 300 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The product was purified by preparative HPLC (Phenomenex Gemini® C18, 10 μm, 25 mm i.d. × 150 mm) using a gradient of 23% to 53% water in ACN (with 0.04% NHOH and 10 mM NHHCO). The product-containing fractions were concentrated to give the title compound as a pale yellow oil (142 mg, 28%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.53(m,2H),0.54-0.58(m,2H),1.99 (br s,2H),2.17(s,3H),4.15(s,2H),6.85(dd, J=7.2,5.1Hz,1H),7.51(d,J=7.0Hz,1H),7.89-7.97(m,1H);ESI-MS m / z [M+H] + 179.2.

[0230] Preparation 5: 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutan-1-amine

[0231] [ka]

[0232] The title compound was prepared similarly to Preparation 4 using (1-aminocyclobutyl)methanol (1.37 g, 13.5 mmol) and obtained as a pale yellow oil (152.2 mg, 17.5%). 1 H NMR(400MHz,DMSO-d6)δ ppm 1.57-1.74(m,2H),1.77-1.86(m,2H),2.01(br d,J=8.3H z,2H),2.13(s,3H),4.10(s,2H),6.84(dd,J=7.0,5.0Hz,1H),7.49(d,J=6.6Hz,1H),7.93(br d , J = 2.9 Hz, 1H); ESI-MS m / z [M+H] + 193.2.

[0233] Preparation 6: 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentan-1-amine

[0234] [ka]

[0235] The title compound was prepared similarly to preparation 4 using (1-aminocyclopentyl)methanol (1.55 g, 13.5 mmol) and obtained as a pale yellow oil (110 mg, 12%). 1 H NMR(400MHz,DMSO-d6)δ ppm 1.38-1.47(m,2H),1.57(dt,J=8.5,5.8Hz,2H),1.60-1.66(m ,2H),1.72-1.79(m,2H),2.15(s,3H),4.06(s,2H),6.83-6.88(m,1H),7.48-7.53(m,1H),7.94(dd,J=5.0,1.2Hz,1H);ESI-MS m / z [M+H] + 207. 2.

[0236] Preparation 7: (R)-2-(1-methylpyrrolidin-2-yl)acetic acid

[0237] [ka]

[0238] To a solution of (R)-2-(pyrrolidin-2-yl)acetic acid HCl salt (2.5 g, 15.1 mmol) and aqueous formaldehyde (37 wt%, 5.84 mL, 78.5 mmol) in MeOH (40 mL) was added Pd / C (10 wt%, 800 mg). The mixture was stirred under H (50 psi) for 16 h at 30° C. and then filtered. The filtrate was concentrated in vacuo and then dissolved in EtOAc (10 mL). The mixture was stirred for 20 min. The solid was collected by filtration and coevaporated with toluene (2 mL) to give the HCl salt of the title compound as a white solid (2.4 g, 89%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.71(m,1H),1.84-2.00(m,2H),2.20-2. 30(m,1H),2.67-2.78(m,4H),3.05(br dd,J=16 .6,4.5Hz,2H),3.40-3.60(m,2H),10.15-12.66(m,2H);ESI-MS m / z [M+H] + 144.2.

[0239] Preparation 8: (S)-2-(1-methylpyrrolidin-2-yl)acetic acid

[0240] [ka]

[0241] The HCl salt of the title compound was prepared similarly to Preparation 7 using (S)-2-pyrrolidin-2-yl)acetic acid HCl salt (1.68 g, 13.0 mmol), aqueous formaldehyde (37 wt%, 5.04 mL, 67.7 mmol), and Pd / C (10 wt%, 510 mg) in MeOH (30 mL) and obtained as a white solid (1.8 g, 77%). 1 H NMR(400MHz,DMSO-d6)δ ppm ESI-MS m / z [M+H] + 144.2.

[0242] Preparation 9: 2-(3-fluoro-2-methoxyphenyl)propan-2-amine

[0243] [ka]

[0244] Step A: 2-(3-fluoro-2-methoxyphenyl)propan-2-ol

[0245] [ka]

[0246] To a solution of 1-bromo-3-fluoro-2-methoxybenzene (1.00 g, 4.88 mmol) in THF (20 mL) was added i-PrMgCl (2.0 M in THF, 5.37 mL, 10.7 mmol) dropwise at 0 °C under nitrogen. The mixture was stirred at 0 °C for 2 h. Next, acetone (340 mg, 5.85 mmol) in THF (5 mL) was added. The resulting mixture was stirred at 0 °C for an additional 30 min, then quenched with saturated aqueous NH4Cl (50 mL) at 20 °C and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 3:1) to give the title compound (197 mg, 20% yield, 90% purity). ESI-MS m / z [M-OH] + 167.1.

[0247] Step B: 2-(3-fluoro-2-methoxyphenyl)propan-2-amine

[0248] To a mixture of 2-(3-fluoro-2-methoxyphenyl)propan-2-ol (1.50 g, 7.74 mmol) in toluene (20 mL) was added TMSN (1.07 g, 9.29 mmol) and BF·OEt (1.32 g, 9.28 mmol) under nitrogen at 20 °C. The reaction mixture was stirred at 20 °C for 30 min, then quenched with NaHCO (20 mL) at 20 °C and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 30 mL), dried, filtered, and concentrated under reduced pressure to give the azide, which was subsequently dissolved in THF (10 mL) and treated with LiAlH (1 M in THF, 7.74 mL, 7.74 mmol). The reaction mixture was stirred at 20 °C for 2 h and then quenched with water (2 mL). The mixture was treated with aqueous NaOH (2 M, 2 mL) at 20 °C, diluted with brine (50 mL), and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure to give the crude product. A second portion was prepared from 2-(3-fluoro-2-methoxy-phenyl)propan-2-ol (196 mg, 0.958 mmol). The two portions were combined, treated with HCl (4 M in dioxane, 10 mL, 40.0 mmol), stirred at 20 °C for 2 minutes, concentrated to dryness, and washed with EtOAc (2 × 20 mL) to give the HCl salt of the title compound (800 mg, 36%). 1 H NMR(400MHz,CD3OD)δ ppm 1.76(s,6H),4.12(d,J=3.2Hz,3H),7.08-7.18(m,1H),7.18-7.30(m,2H);ESI-MS m / z [M-NH2] + 167.1.

[0249] Preparation 10: 2-(3-chloro-2-methoxyphenyl)propan-2-amine

[0250] [ka]

[0251] Step A: 2-(3-chloro-2-methoxyphenyl)propan-2-ol

[0252] [ka]

[0253] To a solution of methyl 3-chloro-2-methoxybenzoate (2.00 g, 9.97 mmol) in THF (40 mL) was added MeMgBr solution (3.0 M in EtO, 7.31 mL) dropwise under nitrogen at −78° C. After 10 min, the reaction mixture was warmed to 20° C. and stirred at 20° C. for 4 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (50 mL) at 0° C. and extracted with EtOAc (2×30 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 20:1) to afford the title compound as a pale yellow oil (1.75 g, 83% yield, 95% purity). ESI-MS m / z [M-OH] + 183.1.

[0254] Step B: 2-(3-chloro-2-methoxyphenyl)propan-2-amine

[0255] The title compound was prepared similarly to Step B of Preparation 9, in which 2-(3-chloro-2-methoxyphenyl)propan-2-ol (1.84 g, 8.72 mmol), TMSN (1.21 g, 10.5 mmol), and BF.OEt (1.49 g, 10.45 mmol) in toluene (30 mL) were reacted to give the azide, which was subsequently treated with LiAlH (1 M in THF, 8.72 mL) in THF (20 mL). Acid workup (4 M HCl in dioxane, 10 mL) afforded the HCl salt of the title compound as a white solid (1.0 g, 49%). ESI-MS m / z [M-NH] + 183.1 .

[0256] Preparation 11: 2-(2-methoxy-3-methylphenyl)propan-2-amine

[0257] [ka]

[0258] The HCl salt of the title compound was prepared similarly to preparation 10 using methyl 2-methoxy-3-methylbenzoate (1.50 g, 8.32 mmol) and MeMgBr (3.0 M in EtO, 6.10 mL, 18.3 mmol) in THF (10 mL) and obtained as a white solid (600 mg, 33% over two steps). ESI-MS m / z [M-NH] + 163.1.

[0259] Preparation 12: 2-(3-chloro-2-methylphenyl)propan-2-amine

[0260] [ka]

[0261] Step A: 2-(3-chloro-2-methylphenyl)propan-2-ol

[0262] [ka]

[0263] To a solution of 1-bromo-3-chloro-2-methylbenzene (5.00 g, 24.3 mmol) in THF (30 mL) was added n-BuLi (2.5 M in hexanes, 10.7 mL) dropwise under nitrogen at −78° C. The mixture was stirred at −78° C. for 1 h. Next, acetone (1.97 mL, 26.8 mmol) in THF (10 mL) was added, and the mixture was stirred at −78° C. for an additional 30 min and then warmed to 20° C. The reaction mixture was stirred at 20° C. for 12 h, then quenched with saturated aqueous NH4Cl (50 mL) at 20° C. and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 5:1) to afford the title compound as a pale yellow oil (3.0 g, 67% yield, 95% purity). ESI-MS m / z [M-OH] + 167.1.

[0264] Step B: 2-(3-chloro-2-methylphenyl)propan-2-amine

[0265] The title compound was prepared similarly to Step B of Preparation 9, in which 2-(3-chloro-2-methylphenyl)propan-2-ol (1.50 g, 8.12 mmol), TMSN (1.12 g, 9.75 mmol), and BF.OEt (1.38 g, 9.75 mmol) in toluene (20 mL) were reacted to give the azide, which was subsequently treated with LiAlH (1 M in THF, 8.12 mL, 8.12 mmol) in THF (10 mL). Acid workup (4 M HCl in dioxane, 10 mL, 40.0 mmol) afforded the HCl salt of the title compound as a white solid (600 mg, 33%). ESI-MS m / z [M-NH2] + 167.1.

[0266] Preparation 13: 2-(2,3-difluorophenyl)propan-2-amine

[0267] [ka]

[0268] A mixture of CeCl3 (4.25 g, 17.2 mmol) in THF (15 mL) was stirred under nitrogen at 20 °C for 2 hours and then cooled to -78 °C. MeLi (3.1 M in diethoxymethane, 5.54 mL) was added, and the mixture was stirred at -78 °C for 30 minutes. Next, 2,3-difluorobenzonitrile (800 mg, 5.75 mmol) in THF (10 mL) was added. The reaction mixture was stirred at -78 °C for 2 hours. Saturated ammonium chloride solution (2 mL) was added, followed by aqueous ammonia (28%, 4 mL). The mixture was stirred at -78 °C, then warmed to room temperature, filtered through Celite®, and washed with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO3 (100 mL) and extracted with aqueous HCl (2 M, 50 mL). The aqueous phase was washed with EtOAc (5 x 50 mL), adjusted to pH 9 by treatment with NaHCO3, and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried and concentrated in vacuo. The crude product was treated with HCl in dioxane (4 M, 20 mL) and concentrated to dryness. The residue was washed with EtOAc (2 x 50 mL). The solid phase was collected by filtration to give the HCl salt of the title compound as a white solid (600 mg, 50%). 1 H NMR(400MHz,CD3OD)δ ppm 1.80(s,6H),7.19-7.33(m,2H),7.34-7.42(m,1H);ESI-MS m / z [M+H] + 172.2.

[0269] Preparation 14: 2-(3-fluoro-2-methylphenyl)propan-2-amine

[0270] [ka]

[0271] The HCl salt of the title compound was prepared similarly to preparation 13 using 3-fluoro-2-methylbenzonitrile (800 mg, 5.92 mmol), CeCl (4.38 g, 17.8 mmol), and MeLi (3.1 M, 5.7 mL, 17.7 mmol) in THF (25 mL) and obtained as a white solid (400 mg, 32%). ESI-MS m / z [M-NH] + 151.1.

[0272] Preparation 15: 2-(3-chloro-2-fluorophenyl)propan-2-amine

[0273] [ka]

[0274] The HCl salt of the title compound was prepared similarly to preparation 13 using 3-chloro-2-fluorobenzonitrile (800 mg, 5.14 mmol), CeCl (4.30 g, 17.4 mmol), and MeLi (3.1 M, 5.6 mL, 17.4 mmol) in THF (25 mL) and obtained as a white solid (600 mg, 52%). ESI-MS m / z [M+H] + :188.6.

[0275] Preparation 16: 2-(2-chloro-3-methylphenyl)propan-2-amine

[0276] [ka]

[0277] The HCl salt of the title compound was prepared similarly to preparation 13 using 2-chloro-3-methylbenzonitrile (800 mg, 5.28 mmol), CeCl (3.90 g, 15.8 mmol), and MeLi (3.1 M, 5.08 mL, 15.7 mmol) in THF (25 mL) and obtained as a white solid (300 mg, 25%). ESI-MS m / z [M+H] + :184.1.

[0278] Preparation 17: 2-(2,3-dichlorophenyl)propan-2-amine

[0279] [ka]

[0280] The HCl salt of the title compound was prepared similarly to preparation 13 using 2,3-dichlorobenzonitrile (1.00 g, 5.81 mmol), CeCl (3.80 g, 15.3 mmol), and MeLi (3.1 M, 4.95 mL, 15.3 mmol) in THF (25 mL) and obtained as a white solid (650 mg, 46%). ESI-MS m / z [M+H] + :205.1.

[0281] Preparation 18: 2-(1-methylpyrrolidin-2-yl)propanoic acid

[0282] [ka]

[0283] Step A: tert-Butyl 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[0284] [ka]

[0285] Diazomethyl(trimethyl)silane (2 M in hexane, 12 mL, 24 mmol) was added dropwise to a solution of 2-(1-tert-butoxycarbonylpyrrolidin-2-yl)acetic acid (3.00 g, 13.1 mmol) in MeOH (6 mL) and toluene (6 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then concentrated in vacuo. The product was purified by column chromatography eluting with petroleum ether / EtOAc (10:1). Pure fractions were concentrated to give the title compound as a pale yellow oil (3.0 g, 94%). 1H NMR(400MHz,CDCl3)δ ppm 1.47(br s,9H),1.68 -1.92(m,3H),2.05(br s,1H),2.31(br dd,J=15.2,9.8Hz,1H),2.77-3.01(m,1H),3.36(br d,J =5.1Hz,2H),3.68(br s,3H),4.04-4.25(m,1H) .

[0286] Step B: tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0287] [ka]

[0288] To a round-bottom flask containing LiHMDS (1 M in THF, 12.3 mL, 12.3 mmol) in THF (5 mL) was added tert-butyl 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.00 g, 4.11 mmol) in THF (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Then, a solution of MeI (1.23 mL, 19.7 mmol) and HMPA (1.08 mL, 6.17 mmol) in THF (3 mL) was added. The reaction mixture was stirred at −78° C. for an additional 4 h, then diluted with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The product was purified by preparative HPLC (Phenomenex Gemini® C18, 10 μm, 25 mm i.d. × 150 mm) using a gradient of 50–80% water (with 0.05% NHOH) in ACN to afford the title compound as a pale yellow oil (0.40 g, 35%).

[0289] Step C: Methyl 2-(pyrrolidin-2-yl)propanoate

[0290] [ka]

[0291] To a round-bottom flask containing tert-butyl 2-(1-methoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.40 g, 1.55 mmol) in DCM (5 mL) was added TFA (1.23 g, 10.8 mmol). The reaction mixture was stirred at 15 °C for 3 h, then poured into ice water (5 mL) and adjusted to pH 10 by the addition of saturated aqueous Na2CO3. The aqueous phase was extracted with DCM (2 x 50 mL), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a pale yellow oil (330.0 mg). ESI-MS m / z [M+H] + 158.1.

[0292] Step D: Methyl 2-(1-methylpyrrolidin-2-yl)propanoate

[0293] [ka]

[0294] To a round-bottom flask containing methyl 2-(pyrrolidin-2-yl)propanoate (0.120 g, 763 μmol) in DCE (3 mL) was added aqueous formaldehyde (37 wt%, 227 μL, 3.05 mmol) and NaBH(OAc) (647 mg, 3.05 mmol). The reaction mixture was stirred at 15° C. for 2 h, then quenched with water (5 mL) and saturated aqueous NaCO (5 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (3×10 mL), dried over NaSO, filtered, and concentrated in vacuo to give the title compound as a pale yellow oil (90.0 mg, 68%). 1 H NMR(400MHz,CDCl3)δ ppm 1.11(d,J=7.1Hz,1 H),1.18(d,J=7.1Hz,3H),1.58-1.78(m,3H),1.84(q,J=7.7Hz,2H),2.29(s,1H),2.3 4(s,3H),2.36-2.43(m,1H),2.50-2.60(m,1H),2.62-2.74(m,1H),3.01-3.11(m,1H).

[0295] Step E: 2-(1-methylpyrrolidin-2-yl)propanoic acid

[0296] A round-bottom flask was charged with methyl 2-(1-methylpyrrolidin-2-yl)propanoate (90.0 mg, 526 μmol) and aqueous HCl (3 M, 1.02 mL). The material was stirred at 90° C. for 16 hours and then concentrated in vacuo to give the HCl salt of the title compound as a pale yellow gum (142 mg). 1 H NMR(400MHz,CD3OD)δ ppm 1.26-1.35(m,3H),1.82-1.94(m,1H),2.04-2.21(m,3H),2.27-2.41(m,1 H),2.97(s,3H),3.12-3.25(m,2H),3.47-3.56(m,1H),3.65-3.76(m,1H).

[0297] Preparation 19: (S)-2-(Azetidin-1-ylmethyl)butanoic acid

[0298] [ka]

[0299] Step A: Ethyl 2-methylenebutanoate

[0300] [ka]

[0301] To a solution of ethyl 2-ethyl-3-oxo-butanoate (50.0 g, 316 mmol) in tetrahydrofuran (200 mL) was slowly added LiHMDS (1 M in THF, 350 mL) at −78° C. The solution was stirred for 0.5 h. Paraformaldehyde (57.5 g, 633 mmol) was added. The mixture was stirred at 25° C. under a nitrogen atmosphere for 16.5 h and then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica column chromatography eluting with petroleum ether / EtOAc (10:1) to give the title compound as a pale yellow liquid (35 g, 86%). 1 HNMR(400MHz,CDCl3)δ ppm 1.08(t,J=7 .3Hz,3H),1.31(t,J=7.1Hz,3H),2.33(q,J=7.4Hz,2H),4.13-4.26(m,2H),5.52(d,J=1.0Hz,1H),6.13(s,1H).

[0302] Step B: Ethyl 2-(azetidin-1-ylmethyl)butanoate

[0303] [ka]

[0304] To a solution of azetidine HCl (28.1 g, 300 mmol) in ethanol (180 mL) was added EtN (117.8 mL, 846.5 mmol) and ethyl 2-methylenebutanoate (35 g, 273 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was combined with the second portion of the reaction (45 g), poured into water (400 mL), and diluted with DCM (2 × 400 mL). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (10:1 to 1:1) to afford the title compound as a pale yellow liquid (50 g), which was used without further purification. 1H NMR(400MHz,CDCl3)δ ppm 0.88(t,J=7.5Hz ,3H),1.23-1.27(m,3H),1.47-1.60(m,2H),2.01-2.04(m,2H),2.28(tt,J=8.7,5.6Hz,1H),2.40( dd,J=11.5,5.6Hz,1H),2.67(dd,J=11.5,8.8Hz,1H),3.15(sxt,J=6.8Hz,4H),4.11-4.17(m,2H).

[0305] Step C: Lithium 2-(azetidin-1-ylmethyl)butanoate

[0306] [ka]

[0307] To a solution of ethyl 2-(azetidin-1-ylmethyl)butanoate (50 g, 270 mmol) in methanol (200 mL) was added LiOH.HO (11.3 g, 270 mmol) in water (50 mL). The mixture was stirred at 60 °C for 16 h and then concentrated to dryness to give the title compound as a pale yellow solid, which was used without purification (40 g, 91% yield). 1 HNMR(400MHz,DMSO-d6)δ ppm 0.74-0.83(m,3H),1.31-1.45(m,2H),1.76-1.95(m,3H),2.20(dd,J=11.3,6.8Hz,1H),2.41-2.47(m,1H),2.89-3.11(m,4H).

[0308] Step D: (S)-1-Phenylethyl 2-(azetidin-1-ylmethyl)butanoate

[0309] [ka]

[0310] To a mixture of lithium 2-(azetidin-1-ylmethyl)butanoate (38 g, 233 mmol) and (S)-1-phenylethan-1-ol (38.1 g, 312 mmol) in DMF (400 mL) was added EDC (89.3 g, 466 mmol) and DMAP (56.9 g, 466 mmol). The mixture was stirred at 25 °C for 16 h, then poured into water (250 mL) and extracted with EtOAc (2 × 350 mL). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated. The reaction mixture was combined with three additional reactions (24 g and 2 × 1 g) and purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (10:1 to 1:1) to give a colorless oil (90 g, crude product). The oil was further purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 5:1). The resulting colorless liquid (84 g) was purified by 45-74% ACN in water ( Further purification by preparative HPLC (YMC Triart C18, 7 μm, 50 mm id×250 mm) using a gradient of 0.04% NH 4 OH+10 mM NH 4 HCO 3 gave the title compound as a yellow liquid (38 g). 1 HNMR(400MHz,CDCl3)δ ppm 0.75-0.94(m,3H),1.46-1.65(m,5H),1.92-2.03(m,2H),2.27-2.51(m,2H),2.61-2.77(m,1H ),3.01-3.28(m,4H),5.86-6.01(m,1H),5.93(quin,J=6.2Hz,1H),7.19-7.49(m,5H);ESI-MS m / z [M+H] + 262.2.

[0311] Step E: (S)-1-Phenylethyl (R)-2-(azetidin-1-ylmethyl)butanoate and (S)-1-Phenylethyl (S)-2-(azetidin-1-ylmethyl)butanoate

[0312] [ka]

[0313] The title diastereoisomers, (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)butanoate (35 g, 134 mmol), were separated by preparative SFC (Daicel ChiralCel OD, 10 μm, 50 mm i.d. × 250 mm) using a mobile phase of 20% isopropanol (with 0.1% NHOH) in CO. The (S,R)-diastereoisomer was the first peak to elute and was obtained as a colorless oil. The (S,S)-diastereoisomer was the second peak to elute and was obtained as a colorless oil (17.4 g) with some residual (S,R) isomer. The impure (S,S) diastereoisomer (16 g) was further separated by preparative SFC (Daicel ChiralPak IC, 10 μm, 50 mm i.d. × 250 mm) using a mobile phase of 20% isopropanol in CO (with 0.1% NHOH) to give the title (S,S)-diastereoisomer as a pale yellow oil (4.80 g, 95% purity, 99% ee). The crude (S,S)-diastereoisomer was also recovered as a pale yellow oil (8 g, 78% purity). ESI-MS m / z [M+H] + :262.2.

[0314] Step F: (S)-2-(Azetidin-1-ylmethyl)butanoic acid

[0315] To a suspension of Pd(OH)2 on carbon in methanol (100 mL) was added (S)-1-phenylethyl (S)-2-(azetidin-1-ylmethyl)butanoate (4.80 g, 17.4 mmol). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen balloon (15 psi) at 25 °C for 16 hours, then filtered through a pad of Celite®, and the filter cake was washed with methanol (30 mL). The combined washings and filtrate were concentrated to dryness to give the title compound as an off-white solid (2.81 g). The crude product was dissolved in acetonitrile (40 mL) and concentrated to dryness to give the title compound as an off-white solid (2.7 g, 99% purity). 1H NMR (400 MHz, CD 3OD)δ ppm 0.97(t,J=7.5Hz,3H),1.47-1.59(m,1H),1.59-1.72(m,1H),2.26-2.36(m,1H),2.46(quin,J =8.1Hz,2H),3.13(dd,J=12.3,3.8Hz,1H),3.26(d,J=11.0Hz,1H),4.04-4.22(m,4H);ESI-MS m / z [M+H] + 158.0.

[0316] Preparation 20: (S)-2-(Azetidin-1-ylmethyl)-3-methylbutanoic acid

[0317] [ka]

[0318] Step A: Ethyl 3-methyl-2-methylenebutanoate

[0319] [ka]

[0320] To a mixture of ethyl 2-acetyl-3-methylbutanoate (43 g, 250 mmol) in THF (660 mL) was added LiHMDS (1 M in THF, 299.5 mL) at −78° C. The mixture was stirred at −78° C. for 0.5 h. Paraformaldehyde (49.4 g, 549 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h, then filtered through a pad of Celite®, and the filter cake was washed with petroleum ether (50 mL). The combined washings and filtrate were purified by silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 5:1) to give the title compound as a colorless liquid (140 g, 30% purity), which was used without further purification.

[0321] Step B: Ethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0322] [ka]

[0323] To a mixture of ethyl 3-methyl-2-methylenebutanoate (30 g, 63.3 mmol) and azetidine HCl (8.88 g, 94.9 mmol) in ethanol (50 mL) was added EtN (44.0 mL, 316 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was combined with two additional batches of the reaction (8 g and 110 g), diluted with water (1500 mL), and extracted with EtOAc (3 × 500 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by flash silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 2:1) to give the title compound as a colorless liquid (42 g). 1 H NMR (400 MHz, CDCl3 )δ ppm 0.91(dd,J=15.2,6.6Hz,6H),1.22-1.29(m,4H),1.80-1.89(m,1H),1.97-2.06(m,3H),2.14(ddd,J=10.5,7.3, 4.3Hz,1H),2.42(dd,J=11.5,4.4Hz,1H),2.73(dd,J=11.4,10.6Hz,1H),3.06-3.23(m,4H),4.08-4.22(m,2H).

[0324] Step C: Lithium 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0325] [ka]

[0326] To a solution of ethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate (20 g, 100 mmol) in ethanol (200 mL) was added aqueous lithium hydroxide (2 M, 75.3 mL). The mixture was stirred at 70° C. for 36 hours. The reaction mixture was concentrated under reduced pressure and lyophilized to dryness. The title compound was obtained as a white solid (17.8 g, estimated quantitative), which was used without purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.83(dd,J=12.0,6.6Hz,6H),1.67-1.92(m,4H),2.18(dd,J=11.0,4.4Hz ,1H),2.52-2.60(m,1H),2.52-2.60(m,1H),3.00(dt,J=10.1,6.7Hz,4H).

[0327] Step D: (S)-1-Phenylethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0328] [ka]

[0329] To a mixture of lithium 2-(azetidin-1-ylmethyl)-3-methylbutanoate (17.8 g, 100 mmol) and (S)-1-phenylethan-1-ol (16.4 g, 135 mmol) in DMF (180 mL) was added DMAP (14.3 g, 117 mmol), followed by EDC (22.5 g, 117 mmol). The reaction mixture was stirred at 25 °C for 12 h, then diluted with water (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO, concentrated, and purified by flash silica column chromatography using a gradient of petroleum ether / EtOAc (1:0 to 5:1) to give a colorless liquid (15 g). The colorless liquid was purified by preparative HPLC (YMC) using a gradient of 45–77% ACN in water (0.04% NHOH + 10 mM NHHCO). Further purification by Triart C18, 7 μm, id 50 mm×250 mm) gave the title compound as a yellow oil (6.5 g, 23%). 1 HNMR(400MHz,CDCl3)δ ppm 0.76-1.02(m,6H),1.55(dd,J=6.6,4.6Hz,3H),1.79-2.08(m,1H),1.79-2.08(m,4H),2.15-2.27(m,1H),2.44(ddd,J =11.5,4.4,1.7Hz,1H),2.73(td,J=10.9,4.2Hz,1H),2.96-3.25(m,4H),5.89-6.01(m,1H),7.26-7.46(m,5H);ESI-MS m / z [M+H] + 276.2.

[0330] Step E: (S)-1-Phenylethyl (R)-2-(azetidin-1-ylmethyl)-3-methylbutanoate and (S)-1-Phenylethyl (S)-2-(azetidin-1-ylmethyl)-3-methylbutanoate (1-ylmethyl)-3-methylbutanoate

[0331] [ka]

[0332] The title diastereoisomer, (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate (6.5 g, 23.6 mmol), was separated by preparative SFC (Daicel ChiralPak IC, 5 μm, 30 mm i.d. × 250 mm) using a mobile phase of 25% isopropanol (with 0.1% NHOH) in CO. The (S,R)-diastereoisomer was the first to elute and was obtained as a colorless oil (2.8 g, 43%). 1 HNMR (400 MHz, CDCl3) δ ppm 0.78-0.89(m,6H),1.56(d,J=6.8Hz,3H),1.77-1.88(m,1H),1.83(dq,J=13.7,6.8Hz,1H),2.00(quin,J=7.0Hz,2H),2.19(ddd,J=10.5 ESI-MS m / z [M+H] + 276.2. The (S,S)-diastereoisomer is the second to elute and is colorless. was obtained as an oil (2.8 g, 43%). 1 HNMR(400MHz,CDCl3)δ ppm 0.84-1.00(m,6H),1.55(d,J=6.5Hz,3H),1.83-2.00(m,1H),1.83-2.00(m,2H),2.19(ddd,J=10.3,7.3,4.5Hz,1H),2.44( ESI-MS m / z [M+H] + 276.2.

[0333] Step F: (S)-2-(Azetidin-1-ylmethyl)-3-methylbutanoic acid

[0334] To a solution of (S)-1-phenylethyl (S)-2-(azetidin-1-ylmethyl)-3-methylbutanoate (2.8 g, 10.2 mmol) in methanol (60 mL) was added Pd(OH)2 on carbon (20 wt%, 500 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as an off-white solid (1.73 g, 94%). 1HNMR(400MHz,DMSO-d6)δ ppm 3.15-3.33(m,4H),2.60-2.74(m,1H),2.47(br d ,J=4.4Hz,1H),1.91-2.06(m,3H),1.75-1.87(m,1H),0.86(d,J=6.8Hz,6H).

[0335] Preparation 21: (S)-3-(azetidin-1-yl)-2-methylpropanoic acid

[0336] [ka]

[0337] Step A: Benzyl 3-(azetidin-1-yl)-2-methylpropanoate

[0338] [ka]

[0339] To a round-bottom flask containing azetidine hydrochloride (5.31 g, 56.8 mmol) in methanol (10 mL) was added EtN (8.69 mL, 62.4 mmol) and benzyl methacrylate (10.0 g, 56.8 mmol). The reaction mixture was stirred at 15 °C for 16 h, then quenched with water (500 mL) and extracted with EtOAc (2 × 500 mL). The organic layer was washed with aqueous HCl (2 M, 200 mL). The aqueous layer was adjusted to pH 10 with aqueous KCO and then extracted with EtOAc (2 × 500 mL). The organic layer was washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil (6.0 g, 43%, 95% pure). 1 H NMR(4 00MHz, CDCl3)δ ppm 1.16(d,J=7.0Hz,3H),1.98-2.09(m,2H),2.36-2.57(m,2H),2.68-2.77(m,1H),3.11-3.23(m,5H),5.14(s,2H),7.28-7.40(m,5H).

[0340] Step B: Benzyl (R)-3-(azetidin-1-yl)-2-methylpropanoate and Benzyl (S)-3-(azetidin-1-yl)-2-methylpropanoate

[0341] [ka]

[0342] The enantiomers of benzyl 3-(azetidin-1-yl)-2-methylpropanoate (6.0 g, 24.4 mmol) were separated by preparative SFC (Daicel ChiralCel OD, 10 μm, 50 mm i.d. × 250 mm) using a gradient of 5–15% isopropanol (with 0.1% NHOH) in CO to give the title compounds. Stereochemistry was arbitrarily assigned. The (S)-enantiomer (1.8 g, 99% ee) and (R)-enantiomer (2.7 g, 95% purity, 96.3% ee) were both obtained as pale yellow oils. 1 H NMR(400MHz,CDCl3)δ ppm 1.16(d,J=7.1Hz ,3H),2.01-2.09(m,2H),2.43(dd,J=11.4,6.2Hz,1H),2.53(sxt,J=6.9Hz,1H),2.75(d d,J=11.4,7.7Hz,1H),3.19(sxt,J=6.8Hz,4H),5.14(s,2H),7.29-7.40(m,5H);ESI-MS m / z [M+H] + 234 .1.

[0343] Step C: (S)-3-(azetidin-1-yl)-2-methylpropanoic acid

[0344] To benzyl (S)-3-(azetidin-1-yl)-2-methylpropanoate (1.05 g, 4.50 mmol) in methanol (15 mL) was added Pd(OH)2 on carbon (20 wt%, 105 mg, 150 μmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a pale yellow oil (561.3 mg, 86%). 1 H NMR(400MHz,CD3OD)δ ppm 1.16(d, ESI-MS m / z [M+H] + 144.2.

[0345] Preparation 22: (R)-3-(azetidin-1-yl)-2-methylpropanoic acid

[0346] [ka]

[0347] The title compound was prepared similarly to Step C of Preparation 21 using benzyl (R)-3-(azetidin-1-yl)-2-methylpropanoate. ESI-MS m / z [M+H] + 144.2.

[0348] Preparation 23: 2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-amine

[0349] [ka]

[0350] Step A: 1,7-Dimethyl-1H-indazole-3-carbonitrile

[0351] [ka]

[0352] To a solution of 7-methyl-1H-indazole-3-carbonitrile (1.00 g, 6.36 mmol) in DMF (20 mL) was added NaH (60 wt%, 0.280 g, 7.00 mmol). mol) was added at 0°C. The reaction mixture was stirred for 20 minutes and allowed to warm to room temperature. Methyl iodide (0.475 mL, 7.63 mmol) was added, and the mixture was stirred at room temperature overnight, then quenched with water (200 mL). The resulting precipitate was collected by filtration and dried under vacuum to give the title compound as a white solid (1.00 g, 92%). ESI-MS m / z [M+H] + 172.1.

[0353] Step B: 2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-amine

[0354] Anhydrous THF (50 mL) was added to cerium(III) chloride (4.32 g, 17.5 mmol) at 0° C. under N2, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to −78° C. Methyllithium-lithium bromide (1.5 M in THF, 11.68 mL, 17.5 mmol) was added dropwise, and stirring was continued for 30 minutes. A solution of 1,7-dimethyl-1H-indazole-3-carbonitrile (1.00 g, 5.84 mmol) in anhydrous THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 30 minutes and then at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (20 mL). Next, aqueous NaOH (50%) was added until a precipitate formed. The mixture was filtered through Celite®, and the filtrate was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The crude residue was purified by flash silica column chromatography to give the title compound as an off-white solid (0.420 g, 35%). ESI-MS m / z [M-NH] + 187.2.

[0355] Preparation 24: 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine

[0356] [ka]

[0357] In a 125 mL round-bottom flask, 2-amino-2-methylpropan-1-ol (3.45 mL, 36.0 mmol) was dissolved in dioxane (16 mL) to give a colorless solution. The reaction mixture was cooled to 0° C., and sodium hydride (60 wt %, 1.51 g, 37.8 mmol) was added portionwise. After stirring for 20 minutes, 2-fluoro-3-methylpyridine (1.00 g, 9.00 mmol) was added. The mixture was heated at 100° C. for 1 hour. The reaction mixture was then cooled to room temperature, diluted with DCM, washed with water, dried over MgSO4, filtered, and concentrated to give the title compound as a yellow oil (2.06 g, 78% purity), which was used without further purification. ESI-MS m / z [M+H] + 181.1 .

[0358] Preparation 25: 1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-amine

[0359] [ka]

[0360] In a 250 mL round-bottom flask, 2-amino-2-methylpropan-1-ol (2.42 g, 27.2 mmol) was dissolved in dioxane (13.6 mL) to give a colorless solution. The solution was cooled to 0 °C, and sodium hydride (60 wt%, 1.14 g, 28.6 mmol) was added. After 20 min, a solution of 3-(difluoromethyl)-2-fluoropyridine (1.00 g, 6.80 mmol) in dioxane (2 mL) was added dropwise. The mixture was heated at 100 °C for 1 h. After cooling to room temperature, the mixture was diluted with DCM, washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica column chromatography (NH silica 120 g) using a gradient of 0–10% MeOH in DCM. Evaporation of pure fractions afforded the title compound as a colorless oil (1.41 g, 96%).

[0361] Preparation 26: 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine

[0362] [ka]

[0363] Cerium(III) chloride (5.13 g, 20.8 mmol) was added to THF (63.1 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 minutes, allowed to warm to room temperature, and then stirred for 160 minutes. The reaction mixture was then cooled to −78° C. MeLi-LiBr (13.9 mL, 20.8 mmol) was added, and the mixture was stirred at −78° C. for 30 minutes. A solution of furo[3,2-c]pyridine-4-carbonitrile (1.00 g, 6.94 mmol) in THF (6.31 mL) was added dropwise. The reaction mixture was maintained at −78° C. for 30 minutes and then stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with 1 M aqueous NaOH, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was dissolved in DCM and purified by flash column chromatography (NH silica) eluting with a gradient of 20-40% EtOAc in heptane to afford the title compound as a yellow oil (0.459 g, 38%).1 H NMR (400 MHz, DMS O-d6)δ ppm 1.44-1.57(m,6H),7.47(dd,J=2.3,1.1Hz,1H),7.49-7.61(m,1H),8.03(d,J=2.3Hz,1H),8.26-8.42(m,1H).

[0364] Preparation 27: 1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-amine

[0365] [ka]

[0366] To a stirred suspension of NaH (0.444 g, 11.1 mmol) in THF (30 mL) was added 2-amino-2-methylpropan-1-ol (0.976 mL, 10.2 mmol). The mixture was stirred at room temperature for 1 hour. A solution of 3-cyclopropyl-2-fluoropyridine (1.27 g, 9.26 mmol) in THF (10 mL) was added, and the mixture was stirred at room temperature overnight. Water (50 mL) was added, followed by EtOAc (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica column chromatography to give the title compound as a clear oil (1.06 g, 55.5%). ESI-MS m / z [M+H] + 207.2.

[0367] Preparation 28: 1-((3-ethoxypyridin-2-yl)oxy)-2-methylpropan-2-amine

[0368] [ka]

[0369] To a stirred suspension of NaH (60 wt%, 0.170 g, 4.25 mmol) in THF (20 mL) was added 2-amino-2-methylpropan-1-ol (0.373 mL, 3.90 mmol). The mixture was stirred at room temperature for 10 minutes. A solution of 3-ethoxy-2-fluoropyridine (0.500 g, 3.54 mmol) in THF (10 mL) was added, and the mixture was stirred at room temperature overnight. Water (50 mL) was added, followed by EtOAc (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica column chromatography to afford the title compound as a clear oil (0.440 g, 59%). ESI-MS m / z [M+H] + 211.2.

[0370] Preparation 29: 2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-amine

[0371] [ka]

[0372] NaH (60 wt%, 0.243 g, 6.07 mmol) stirred in THF (30 mL) To the suspension was added 2-amino-2-methylpropan-1-ol (0.534 mL, 5.57 mmol). The mixture was stirred at room temperature for 20 minutes. A solution of 2-chloro-3-(trifluoromethoxy)pyridine (1.00 g, 5.06 mmol) in THF (10 mL) was added, and the mixture was stirred at room temperature overnight. Water (100 mL) was added, and then the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica column chromatography to give the title compound as a clear oil (0.550 g, 43%). ESI-MS m / z [M+H] + 251.2.

[0373] Preparation 30: (S)-N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0374] [ka]

[0375] To a solution of (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (500 mg, 3.49 mmol) in DMF (17.5 mL) was added HATU (1328 mg, 3.49 mmol), followed by DIPEA (1.83 mL, 10.5 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Next, 2-amino-2-methylpropan-1-ol (342 mg, 3.84 mmol) was added. The solution was stirred overnight at room temperature and then evacuated to remove the solvent. The residue was purified by automated flash column chromatography (NH silica gel) using a gradient of 0-10% MeOH in DCM to give the title compound as a pale yellow oil (350 mg, 47%). ESI-MS m / z [M+H] + 215.2.

[0376] Preparation 31: 2-(chroman-2-yl)propan-2-amine

[0377] [ka]

[0378] Step A: 2-(chroman-2-yl)propan-2-ol

[0379] [ka]

[0380] Methylmagnesium bromide (1.0 M, 4.0 mL, 4.04 mmol) in THF (9.6 mL) was added dropwise to a stirred solution of methyl chroman-2-carboxylate (370 mg, 1.92 mmol) in anhydrous THF (9.6 mL) under nitrogen at 0°C. Stirring was continued at 0°C for 5 minutes and then at room temperature for 2 hours. The reaction mixture was cooled to 0°C. Saturated aqueous NH4Cl solution, Then EtOAc was added dropwise. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (350 mg, 95%), which was used without further purification. 1 H NMR(400MHz,CD3OD)δ ppm 1.28(s ,3H),1.32(s,3H),1.71-1.86(m,1H),2.05(ddt,J=13.4,5.8,2.0Hz,1H),2.73- 2.95(m,2H),3.79(dd,J=11.5,2.0Hz,1H),6.80-6.89(m,2H),7.00-7.13(m,2H).

[0381] Step B: N-(2-(chroman-2-yl)propan-2-yl)acetamide

[0382] [ka]

[0383] To a stirred solution of 2-(chroman-2-yl)propan-2-ol (190 mg, 0.988 mmol) in anhydrous ACN (9.9 mL) and acetic acid (0.1 mL, 1.76 mmol) was added sulfuric acid (50.0 μL, 0.939 mmol) dropwise at 0° C. Stirring was continued at 0° C. for 5 minutes, then at room temperature overnight. The reaction mixture was treated with 5 M ammonium hydroxide (38.5 μL, 0.988 mmol), followed by EtOAc. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash silica column chromatography using a gradient of 30-60% EtOAc in heptane to give the title compound as a white solid (26 mg, 11%). ESI-MS m / z [M+H] + 234.2.

[0384] Step C: 2-(chroman-2-yl)propan-2-amine

[0385] To a solution of N-(2-(chroman-2-yl)propan-2-yl)acetamide (26 mg, 0.11 mmol) in DME (0.2 mL) and ethylene glycol (0.2 mL) was added potassium hydroxide (50.0 mg, 0.892 mmol). The reaction mixture was heated at 150° C. for 36 h. Water (1.0 mL) and EtOAc (10 mL) were added. The organic layer was washed with brine (2×3 mL) and dried over anhydrous NaSO. The solvent was removed to give the title compound as a brown sticky oil (20 mg, 94%), which was used without further purification. ESI-MS m / z [M+H] + 192.2.

[0386] Preparation 32: 2-(5-methylisoquinolin-1-yl)propan-2-amine

[0387] [ka]

[0388] Anhydrous THF (30.7 mL) was added to anhydrous cerium(III) chloride (3.97 g, 16.1 mmol) at 0° C. under a N atmosphere. The reaction mixture was stirred for 2 hours while gradually warming to room temperature. The stirred mixture was then cooled to −78° C. and a 1.5 M solution of MeLi-LiBr (10.75 mL, 16.12 mmol) in diethyl ether was added. Stirring was continued at −78° C. for 30 minutes, at which point 5-methylisoquinoline-1-carbonitrile (0.9 A solution of 0.04 g (5.37 mmol) in anhydrous THF (5.12 mL) was added. The reaction mixture was stirred at -78 °C for 30 minutes and then at room temperature overnight. Saturated aqueous NH4Cl was added to the mixture. A precipitate formed, and the mixture was made basic with aqueous NH4OH. The reaction mixture was filtered through a pad of Celite®, rinsing with diethyl ether. The organic and aqueous layers were separated, and the organic layer was set aside. The aqueous layer was washed twice with diethyl ether. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol and filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 15–65% water / ACN in water (basic mode). Evaporation of pure fractions afforded the title compound as a reddish-brown oil (260.3 mg, 24%), which was used without further purification. ESI-MS m / z [M+H] + 201.1.

[0389] Preparation 33: 1-((2-methoxypyridin-3-yl)methyl)cyclopropan-1-amine

[0390] [ka]

[0391] To a solution of 2-(2-methoxypyridin-3-yl)acetonitrile (0.325 g, 2.19 mmol) and titanium(IV) isopropoxide (0.707 mL, 2.41 mmol) in THF (11.0 mL) was added dropwise a 3 M solution of ethylmagnesium bromide in diethyl ether (1.46 mL, 4.39 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. BF3.OEt2 (0.556 mL, 4.39 mmol) was then added. The reaction mixture was stirred at room temperature for an additional 30 minutes and then quenched with water (2 mL), followed by aqueous HCl (1 M, 20 mL) and DCM (50 mL). 1 M aqueous NaOH was added until the pH of the mixture was basic. The organic layer was separated, and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by automated flash silica column chromatography using a gradient of 0-20% methanol in DCM. Evaporation of pure fractions afforded the title compound as a pale yellow oil (0.187 g, 48%). ESI-MS m / z [M+H] + 179.1.

[0392] Preparation 34: 2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine

[0393] [ka]

[0394] Anhydrous THF (100 mL) was added to cerium(III) chloride (5.00 g, 20.3 mmol) under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 2 h and then cooled to −78° C. Next, MeLi.LiBr (1.5 M, 13.53 mL, 20.3 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. A solution of 1-methyl-1H-pyrazolo[4,3-c]pyridine-4-carbonitrile (1.07 g, 6.77 mmol) in anhydrous THF (33 mL) was added dropwise. The mixture was stirred at -78 °C for 30 minutes and then at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl, and 1 M aqueous NaOH was added until a precipitate formed. After filtering the mixture through Celite®, the filtrate was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash silica column chromatography using a gradient of 0-10% MeOH in DCM to give the title compound. ESI-MS m / z [M+H] + 191.2.

[0395] Preparation 35: 2-(4-methylisoquinolin-1-yl)propan-2-amine

[0396] [ka]

[0397] Step A: 4-Methylisoquinoline-1-carbonitrile

[0398] [ka]

[0399] To a round-bottom flask equipped with a stir bar, 1-chloro-4-methylisoquinoline (1.85 g, 10.4 mmol) and zinc(II) cyanide (1.834 g, 15.62 mmol) in DMA were added under a nitrogen atmosphere, followed by Pd(dba) (0.572 g, 0.625 mmol) and dppf (0.693 g, 1.25 mmol). The reaction mixture was stirred at 115 °C for 4 h, then cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was collected, filtered over MgSO, and concentrated in vacuo. The residue was purified by automated flash silica column chromatography (220 g column) using a gradient of 10–70% EtOAc in heptane. Evaporation of product-containing fractions afforded the title compound as an off-white / yellow solid (1.554 g, 89%). ESI-MS m / z [M+H] + 169.1.

[0400] Step B: 2-(4-methylisoquinolin-1-yl)propan-2-amine

[0401] The title compound was prepared similarly to preparation 34 using cerium(III) chloride (6.83 g, 27.7 mmol) and MeLi.LiBr (1.5 M, 18.5 mL, 27.7 mmol) in THF (100 mL), followed by 4-methylisoquinoline-1-carbonitrile (1.554 g, 9.24 mmol) in THF (33 mL). The product was purified by flash silica column chromatography using a gradient of 0-30% MeOH in DCM to give the title compound as a yellow oil (60 mg, 3.2%). ESI-MS m / z [M+H] + 201.2.

[0402] Preparation 36: 2-(1-(tert-butoxycarbonyl)-3,3-difluoropyrrolidin-2-yl)acetic acid

[0403] [ka]

[0404] Step A: tert-Butyl 3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[0405] [ka]

[0406] To a stirred solution of tert-butyl 2-(2-methoxy-2-oxoethyl)-3-oxopyrrolidine-1-carboxylate (2.91 mL, 13.6 mmol) in DCM (30.1 mL) at 0° C. was added Deoxo-Fluor® (1.00 g, 4.52 mmol). The solution was stirred at room temperature overnight, and then the reaction was quenched with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (500 mg, 40%), which was used without further purification.

[0407] Step B: 2-(1-(tert-butoxycarbonyl)-3,3-difluoropyrrolidin-2-yl)acetic acid

[0408] To a 100 mL round-bottom flask containing a solution of tert-butyl 3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (500 mg, 1.79 mmol) in dioxane (4.97 mL) was added 1 M aqueous LiOH (7.16 mL, 7.16 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with water, acidified, and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound as an orange oil. ESI-MS m / z [M+H] + 266.1.

[0409] Preparation 37: N-(2-(2-chlorophenyl)propan-2-yl)methacrylamide

[0410] [ka]

[0411] A mixture of 2-(2-chlorophenyl)propan-2-amine hydrochloride (0.863 g, 4.19 mmol) and methacrylic acid (0.360 g, 4.19 mmol) in DMA (14 mL) was treated with DIPEA (2.19 mL, 12.6 mmol) and HATU (2.39 g, 6.28 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (3x). The organic phase was washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography using a gradient of 0-60% EtOAc in heptane. Evaporation of product-containing fractions afforded the title compound as a white solid (875.9 mg, 88%). ESI-MS [M+H] + 238.1.

[0412] Preparation 38: (R)-2,2-Difluoro-1-(2-methoxyphenyl)ethan-1-amine

[0413] [ka]

[0414] Step A: (S,E)-N-(2-methoxybenzylidene)-2-methylpropane-2-sulfinamide

[0415] [ka]

[0416] To a 20 mL microwave vial equipped with a stir bar were added 2-methoxybenzaldehyde (1.634 g, 12.00 mmol), (S)-2-methylpropane-2-sulfinamide (1.454 g, 12.00 mmol), and tetraethoxytitanium (5.03 mL, 24.0 mmol). The vial was sealed and heated in a Biotage® microwave reactor at 70° C. for 15 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc (60 mL) and treated with brine (3.0 mL) with rapid stirring. The resulting suspension was filtered through a pad of Celite® and rinsed with EtOAc. The organic filtrate was dried over Na2SO4, filtered again, and evaporated to give the title compound as a yellow oil (2.42 g, 84%). ESI-MS m / z [M+H] + 240.3.

[0417] Step B: (S)—N-((R)-2,2-difluoro-1-(2-methoxyphenyl)-2-(phenylsulfonyl)ethyl)-2-methylpropane-2-sulfinamine Do

[0418] [ka]

[0419] An oven-dried 500 mL round-bottom flask equipped with a stir bar was charged with (S,E)-N-(2-methoxybenzylidene)-2-methylpropane-2-sulfinamide (2.42 g, 10.1 mmol) and ((difluoromethyl)sulfonyl)benzene (1.767 g, 9.19 mmol) under a nitrogen atmosphere. Tetrahydrofuran (115 mL) was added, and the reaction mixture was cooled to −78 °C in a dry ice / acetone bath. A 1 M solution of LiHMDS in THF (11.03 mL, 11.03 mmol) was added at −78 °C, and the reaction mixture was stirred at −78 °C for 90 minutes. The reaction mixture was removed from the dry ice bath, diluted with isopropyl acetate, and quenched with aqueous NH4Cl. The reaction mixture was transferred to a separatory funnel, diluted with water, partitioned, and extracted with isopropyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dry-loaded onto silica using DCM and purified by automated flash silica column chromatography using a gradient of 0-70% EtOAc in heptane. Evaporation of product-containing fractions afforded the title compound as a pale yellow oil / foam (1.65 g, 42%). ESI-MS m / z [M+H] + 432.3.

[0420] Step C: (S)—N-((R)-2,2-difluoro-1-(2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide

[0421] [ka]

[0422] To a stirred solution of (S)—N-((R)-2,2-difluoro-1-(2-methoxyphenyl)-2-(phenylsulfonyl)ethyl)-2-methylpropane-2-sulfinamide (1.65 g, 3.81 mmol) in DMF (31.8 mL) was added a solution of sodium acetate (3.13 g, 38.1 mmol) in acetic acid (2.18 mL, 38.1 mmol) and water (6.36 mL). The clear solution became slightly cloudy. Magnesium (1.39 g, 57.2 mmol) powder was added portionwise over 20 minutes to the reaction mixture. An increase in temperature and gas evolution in the reaction flask were observed. The reaction mixture was stirred at room temperature for 2 hours, then diluted with isopropyl acetate and extracted with water followed by saturated aqueous NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified using a gradient of 20-100% EtOAc in heptane followed by a gradient of 20-80% EtOAc in heptane. Purification was carried out by automated flash silica column chromatography. Evaporation of product-containing fractions gave the title compound as a white solid (0.553 g, 50%). ESI-MS m / z [M+H] + 292.3.

[0423] Step D: (R)-2,2-Difluoro-1-(2-methoxyphenyl)ethan-1-amine

[0424] To a solution of (S)—N—((R)-2,2-difluoro-1-(2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (0.553 g, 1.90 mmol) in DCM (1.90 mL) was added 4 M HCl in dioxane (1.90 mL, 7.59 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The solid was dispersed in diethyl ether and collected by vacuum filtration to give the HCl salt of the title compound as a white powder (0.337 g, 79%). ESI-MS m / z [M+H] + 188.2.

[0425] Preparation 39: (R)-2,2-Difluoro-1-(3-fluorophenyl)ethan-1-amine

[0426] [ka]

[0427] The HCl salt of the title compound was prepared similarly to preparation 38 using 3-fluorobenzaldehyde (1.489 g, 12.00 mmol), (S)-2-methylpropane-2-sulfinamide (1.454 g, 12.00 mmol), and tetraethoxytitanium (5.03 mL, 24.0 mmol) and obtained as a white solid (0.913 g, approximately 70% pure, 25% yield over 4 steps). ESI-MS m / z [M+H] + 176.2.

[0428] Preparation 40: (R)-2,2-Difluoro-1-(4-fluorophenyl)ethan-1-amine

[0429] [ka]

[0430] The HCl salt of the title compound was prepared similarly to preparation 38 using 4-fluorobenzaldehyde (1.862 g, 15.00 mmol), (S)-2-methylpropane-2-sulfinamide (1.818 g, 15.00 mmol), and tetraethoxytitanium (6.29 mL, 30.0 mmol) and obtained as a white solid (0.743 g, 23% over 4 steps). ESI-MS m / z [M+H] + 176.2.

[0431] Preparation 41: (R)-2,2-Difluoro-1-phenylethan-1-amine

[0432] [ka]

[0433] Step A: (S)—N-((R)-2,2-difluoro-1-phenyl-2-(phenylsulfonyl)ethyl)-2-methylpropane-2-sulfinamide

[0434] [ka]

[0435] A dried, 1000 mL, three-neck flask equipped with a thermocouple and stir bar was evacuated and backfilled with nitrogen. The flask was then charged with ((difluoromethyl)sulfonyl)benzene (4.00 g, 20.8 mmol), (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (4.79 g, 22.9 mmol), and THF (260 mL). The reaction mixture was cooled to −78 °C in a dry ice / acetone bath, and 1 M lithium bis(trimethylsilyl)amide in THF (25.0 mL, 25.0 mmol) was added over 10 min. The reaction mixture was stirred at −78 °C for 90 min, then removed from the dry ice bath, diluted with isopropyl acetate (200 mL), and quenched with saturated aqueous NH₄Cl (100 mL). The reaction mixture was transferred to a separatory funnel, diluted with water (200 mL), and extracted with isopropyl acetate (3 × 400 mL). The organic layers were combined, washed with brine (300 mL), dried over sodium sulfate, and concentrated to an oil that solidified overnight. The product was purified by flash silica column chromatography (220 g silica) using a gradient of 20-85% EtOAc in heptane to give the title compound as a white solid (6.1 g, 73%). ESI-MS m / z [M+H] + 402.4.

[0436] Step B: (S)—N-((R)-2,2-difluoro-1-phenylethyl)-2-methylpropane-2-sulfinamide

[0437] [ka]

[0438] To a stirred solution of (S)-N-((R)-2,2-difluoro-1-phenyl-2-(phenylsulfonyl)ethyl)-2-methylpropane-2-sulfinamide (6.1 g, 15.2 mmol) in DMF (141 mL) was added a prepared solution of sodium acetate (12.46 g, 152 mmol), acetic acid (8.70 mL, 152 mmol), and water (28.1 mL). The reaction temperature rose slightly from 21 to 27°C, and the clear solution became cloudy. Magnesium powder (5.54 g, 228 mmol) was added in small portions over 30 minutes to the stirred reaction mixture. The temperature of the mixture rose from 26 to 45°C during the addition, accompanied by gas evolution and bubbling. The reaction mixture was stirred at room temperature for 1 hour, then diluted with isopropyl acetate (500 mL) and washed with water (2 x 300 mL), followed by brine (300 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to an oil. The product was purified by flash silica column chromatography (120 g silica) using a gradient of 20 to 100% EtOAc in heptane to give the title compound as a semi-solid (2.93 g, 74%). ESI-MS m / z [M+H] + 262.3.

[0439] Step C: (R)-2,2-Difluoro-1-phenylethan-1-amine

[0440] To a solution of (S)—N—((R)-2,2-difluoro-1-phenylethyl)-2-methylpropane-2-sulfinamide (2.9 g, 11.1 mmol) in DCM (10 mL) was added 4 M HCl in dioxane (11.1 mL, 44.4 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The solid was dispersed in diethyl ether (30 mL) and collected by filtration under nitrogen to give the HCl salt of the title compound as a white powder (1.93 g, 90%). ESI-MS m / z [M+H] + 158 .1.

[0441] Preparation 42: (S)-2,2-Difluoro-1-phenylethan-1-amine

[0442] [ka]

[0443] The HCl salt of the title compound was prepared similarly to preparation 41 using ((difluoromethyl)sulfonyl)benzene (1.60 g, 8.33 mmol), (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (1.92 g, 9.16 mmol), and lithium bis(trimethylsilyl)amide solution (1 M in THF, 9.99 mL, 9.99 mmol) in THF (83 mL) and obtained as a white powder (0.60 g, 37% over three steps). ESI-MS m / z [M+H] + 158.1.

[0444] Preparation 43: (R)-2-Fluoro-1-phenylethan-1-amine

[0445] [ka]

[0446] The HCl salt of the title compound was prepared similarly to preparation 41 using ((fluoromethyl)sulfonyl)benzene (1.73 g, 9.95 mmol), (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (2.29 g, 10.9 mmol), and lithium bis(trimethylsilyl)amide (1 M in THF, 11.9 mL, 11.9 mmol) in THF (124 mL) to give a white solid (0.418 g, 24% over three steps) ESI-MS m / z [M+H] + 140.1

[0447] Preparation 44: Lithium 3-(azetidin-1-yl)propanoate

[0448] [ka]

[0449] To a solution of methyl 3-(azetidin-1-yl)propanoate (0.900 g, 6.29 mmol) in MeOH (20 mL) was added 2 M LiOH (3.46 mL, 6.91 mmol). The mixture was stirred at 60° C. overnight and then concentrated to give an oily white solid. Acetonitrile (30 mL) was added, and the resulting precipitate was collected and dried under vacuum at 40° C. overnight to give the title compound as a white solid (0.844 g, 99%).

[0450] Preparation 45: (R)-N-(2-(2-fluorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0451] [ka]

[0452] Step A: tert-Butyl (R)-2-(2-((2-(2-fluorophenyl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0453] [ka]

[0454] A solution of 2-(2-fluorophenyl)propan-2-amine (120 mg, 0.783 mmol), (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (216 mg, 0.940 mmol), HATU (365 mg, 0.940 mmol), and EtN (437 μL, 3.13 mmol) in THF (3.92 mL) was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm Millipore® filter. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% ACN in water (acid mode). Evaporation of product-containing fractions afforded the title compound as a white solid (177 mg, 62%). ESI-MS m / z [M+H] + 365.4.

[0455] Step B: (R)—N-(2-(2-fluorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0456] To a solution of tert-butyl (R)-2-(2-((2-(2-fluorophenyl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (177 mg, 0.486 mmol) in DCM (1.94 mL) and MeOH (0.5 mL) was added 4 M HCl in dioxane (728 μL, 2.91 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm Millipore® filter. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode). Evaporation of product-containing fractions gave the TFA salt of the title compound as a colorless oil (140 mg, 76%). 1 H NMR(400MHz,CDCl3)δ ppm 1.70(d,J=5. 0Hz,6H),1.85-2.04(m,2H),2.07-2.17(m,1H),2.64-2.83(m,2H),3.09-3.26(m,2H),3.82(br d,J=6.0Hz,1H),4.33-4.62(m,1H),6.99(ddd,J=12.7,8.2,1.2Hz,1H),7.03(br s,1H),7.10(t d,J=7.5,1.2Hz,1H),7.23(tdd,J=7.6,5.1,1.8Hz,1H),7.33(td,J=8.2,1.8Hz,1H),9.26(br s ,1H),9.65-9.77(m,1H);ESI-MS m / z [M+H] + 26 5.4.

[0457] Preparation 46: (S)—N-(2-(2-fluorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0458] [ka]

[0459] The TFA salt of the title compound was prepared analogously to preparation 45 using 2-(2-fluorophenyl)propan-2-amine (125 mg, 0.816 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (224 mg, 0.979 mmol), EtN (455 μL, 3.26 mmol), and HATU (380 mg, 0.979 mmol) in THF (4.08 mL) to afford a colorless semi-solid (174 mg, 56% over two steps). 1 H NMR (400 MHz, CDCl3) δ ppm 1 .70(app d,J=2.3Hz,6H),1.84-2.03(m,2H),2. 07-2.16(m,1H),2.63-2.74(m,1H),2.77-2.85(m,1H),3.08-3.23(m,2H),3.80(br d,J=6.5Hz, 1H),6.24-6.42(m,1H),6.99(ddd,J=12.7,8.2,1.0Hz,1H),7.06-7.12(m,1H),7.18-7.25(m,2H),7.32(td,J=8.2,1.8Hz,1H),9.22(br s,1H), 9.46-9.60(m,1H);ESI-MS m / z [M+H] + 265.4.

[0460] Preparation 47: 2-((S)-pyrrolidin-2-yl)-N-(2,2,2-trifluoro-1-(p-tolyl)ethyl)acetamide

[0461] [ka]

[0462] To a vial containing (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (48 mg, 0.20 mmol) in DMF (3 mL) was added 2,2,2-trifluoro-1-(p-tolyl)ethan-1-amine (40 mg, 0.21 mmol), HATU (105 mg, 0.275 mmol), and DIPEA (55 mg, 0.42 mmol). The solution was stirred at room temperature overnight. TFA (2 mL) was then added. The reaction mixture was stirred at room temperature for 3 h, then concentrated under reduced pressure, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) eluting with a gradient of 20–30% ACN in water (acid mode). Pure fractions were combined and evaporated to give the TFA salt of the title compound as a clear oil (17 mg, 27%). 1 H NMR(400MHz,CD3OD)δ ppm 1.61-1.7 5(m,1H),1.88-2.12(m,2H),2.14-2.28(m,1H),2.32-2.36(m,3H),2.69-2.95(m,2H),3.23-3. 30(m,2H),3.74-3.91(m,1H),5.63-5.73(m,1H),7.18-7.25(m,2H),7.32-7.38(m,2H);ESI-MS m / z [M+H] + 301.2.

[0463] Example 1: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0464] [ka]

[0465] Step A: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0466] [ka]

[0467] To a solution of EtN (0.351 mL, 2.52 mmol), 2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-amine (0.171 g, 0.841 mmol), and 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.212 g, 0.925 mmol) in DMF (4.20 mL) was added HATU (0.352 g, 0.925 mmol). The reaction mixture was stirred at room temperature overnight, then ethanol was added. The mixture was diluted with Ac, washed repeatedly with water, dried over Na2SO4, filtered, and concentrated in vacuo. The concentrate was dissolved in dioxane (4.20 mL) and acidified with 4 M HCl in dioxane (4.20 mL, 16.8 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The product was dissolved in DMF and MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode). Evaporation of the product-containing fractions gave the title compound (0.160 g, 60%).

[0468] Step B: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0469] To a solution of aqueous formaldehyde (37 wt%, 0.413 g, 5.09 mmol), acetic acid (0.146 mL, 2.54 mmol), and N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (0.160 g, 0.509 mmol) in MeOH (8.48 mL) was added sodium cyanoborohydride (0.320 g, 5.09 mmol). The mixture was stirred at room temperature for 2 h, then diluted with MeOH and DMF, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode). Evaporation of product-containing fractions gave the title compound as a white solid (0.113 g, 68%). 1 H NMR(400MHz,CD3OD)δ ppm 1.42-1.57(m,1H) ,1.64-1.82(m,9H),1.82-1.96(m,1H),2.12-2.26(m,2H),2.26-2.35(m,3H),2.41-2.52(m,2H),2.73( ESI-MS m / z [M+H] + 329.1.

[0470] Example 2: N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0471] [ka]

[0472] To a solution of pyridine (0.131 mL, 1.62 mmol), 2-(1-methyl-1H-indazol-3-yl)propan-2-amine (0.061 g, 0.324 mmol), and 2-(1-methylpiperidin-2-yl)acetic acid (0.051 g, 0.324 mmol) in ACN (0.433 mL) was added T3P (50 wt% in EtOAc, 0.965 mL, 1.62 mmol). The reaction mixture was stirred at room temperature for 24 h, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a clear semisolid (27 mg, 25%). 1 H NMR(400MHz,CD3OD)δ ppm 1.14-1.38( m,2H),1.48-1.69(m,4H),1.71-1.86(m,6H),2.07-2.26(m,5H),2.29-2 .44(m,1H),2.49-2.63(m,1H),2.73-2.88(m,1H),3.29-3.32(m,5H),3. 35(s,1H),3.94-4.05(m,3H),7.04-7.11(m,1H),7.31-7.39(m,1H),7.42-7.49(m,1H),7.79-7.85(m,1H);ESI-MS m / z [M+H] + 329.1.

[0473] Example 3: (R)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0474] [ka]

[0475] Step A: (R)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0476] [ka]

[0477] To a solution of EtN (0.228 mL, 1.63 mmol), 2-(1-methyl-1H-indazol-3-yl)propan-2-amine (0.103 g, 0.544 mmol), and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.137 g, 0.599 mmol) in DMF (2.72 mL) was added HATU (0.228 g, 0.599 mmol). The reaction mixture was stirred at room temperature for 12 minutes, then diluted with EtOAc, washed repeatedly with water, dried over NaSO, filtered, and concentrated in vacuo. The concentrate was dissolved in dioxane (2.72 mL) and acidified with 4 M HCl in dioxane (2.72 mL, 10.9 mmol). The mixture was stirred at room temperature for 2 hours. MeOH (2 mL) was then added to dissolve the remaining solid. The mixture was stirred at room temperature overnight and concentrated in vacuo. The product was dissolved in MeOH and DMF, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (86 mg, 53%).

[0478] Step B: (R)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0479] To a solution of aqueous formaldehyde (37 wt%, 0.116 g, 1.43 mmol) and (R)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (0.086 g, 0.286 mmol) in MeOH (4.77 mL) was added sodium cyanoborohydride (0.090 g, 1.43 mmol). The reaction mixture was stirred at room temperature for 24 h, then diluted with MeOH and DMF, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d.) using a gradient of 10 to 100% water / ACN in water (basic mode). The product was purified by chromatography (150 mm x 150 mm). The product-containing fractions were evaporated to give the title compound as a white solid (50 mg, 56%). 1 H NMR(400MHz,CD3OD)δ ppm 1.44-1.62(m,1H),1.66-1.79(m,2H),1.78 -1.84(m,6H),1.85-2.01(m,1H),2.16-2.30(m,2H),2.32(s,2H),2.29-2.38(m,1H),2.43-2.60(m,2H),3.01-3.10(m,1H),4.0 1(s,3H),7.10(ddd,J=8.1,6.9,0.9Hz,1H),7.31-7.41(m,1H),7.41-7.51(m,1H),7.45-7.54(m,1H),7.76-7.94(m,1H);ESI-MS m / z [M+H] + 315.1.

[0480] Example 4: (S)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0481] [ka]

[0482] Step A: (S)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0483] [ka]

[0484] To a solution of EtN (0.236 mL, 1.70 mmol), 2-(1-methyl-1H-indazol-3-yl)propan-2-amine (0.107 g, 0.565 mmol), and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.143 g, 0.622 mmol) in DMF (2.83 mL) was added HATU (0.236 g, 0.622 mmol). The reaction mixture was stirred at room temperature for 12 min, then diluted with EtOAc, washed repeatedly with water, dried over NaSO, filtered, and concentrated in vacuo. The concentrate was dissolved in dioxane (2.72 mL) and acidified with 4 M HCl in dioxane (2.72 mL, 10.9 mmol). The mixture was stirred at room temperature for 2 h. MeOH (2 mL) was then added to dissolve the remaining solid. The mixture was stirred at room temperature overnight and then concentrated in vacuo. The product was dissolved in MeOH and DMF, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (80 mg, 47%).

[0485] Step B: (S)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0486] Formaldehyde aqueous solution (37 wt%, 0.108 g, 1.33 mmol) and (S) To a solution of -N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (0.080 g, 0.266 mmol) in MeOH (4.44 mL) was added sodium cyanoborohydride (0.167 g, 2.66 mmol). The mixture was stirred at room temperature for 2 hours, then diluted with MeOH and DMF, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a white solid (44 mg, 52%). 1 H NMR(400MHz,CD3OD)δ ppm 1.43-1.60(m,1 H),1.65-1.77(m,2H),1.81(d,J=4.1Hz,6H),1.86-2.03(m,1H),2.15-2.28(m,2H),2.32(s,3H),2.40-2.56(m,2H),3.04(ddd, ESI-MS m / z [M+H] + 315.1.

[0487] Example 5: N-(2-(isoquinolin-1-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide

[0488] [ka]

[0489] To a mixture of 2-(isoquinolin-1-yl)propan-2-amine (37.5 mg, 0.201 mmol) and 3-(pyrrolidin-1-yl)propanoic acid (31.7 mg, 0.221 mmol) in DMA (1.0 mL) was added DIPEA (105 μL, 0.604 mmol) and HATU (115 mg, 0.302 mmol). The reaction mixture was stirred overnight at room temperature and then filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–65% water / ACN in water (basic mode). Product-containing fractions were evaporated and lyophilized to give the title compound as a white solid (17.2 mg, 27%). 1 H NMR(400MHz,CD3OD)δ ppm 1.74-1.79 (m,4H),1.87(s,6H),2.34-2.41(m,2H),2.47-2.55(m,4H),2.57-2.64(m,2H),7.57(ddd,J=8.6,7.0,1.5H ESI-MS m / z [M+H] + 312.20.

[0490] Example 6: N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0491] [ka]

[0492] The title compound was prepared similarly to Example 5 using 2-(isoquinolin-1-yl)propan-2-amine (36.5 mg, 0.196 mmol), 2-(1-methylpiperidin-2-yl)acetic acid (33.9 mg, 0.216 mmol), DIPEA (103 μL, 0.588 mmol), and HATU (112 mg, 0.294 mmol) in DMA (1.3 mL) and obtained as an off-white solid (41.2 mg, 65%). 1 HN MR(400MHz,CD3OD)δ ppm 1.16-1.30(m,2H),1.42-1.65(m,4H),1.88(s,6H),2.09-2.18(m,2H),2.21(s,3H),2.25-2.34(m,1H),2.55(dd,J=14.3,4.5Hz,1H),2.7 6-2.85(m,1H),7.58(ddd,J=8.6,7.0,1.2Hz,1H),7.63-7.72(m,2H),7.89-7.95(m,1H),8.37(d,J=5.8Hz,1H),8.64-8.71(m,1H);ESI-MS m / z [M+H] + 326.15.

[0493] Example 7: N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0494] [ka]

[0495] To a mixture of 2-(5-methylisoquinolin-1-yl)propan-2-amine (32.2 mg, 0.161 mmol) and 2-(1-methylpiperidin-2-yl)acetic acid (27.8 mg, 0.177 mmol) in DMA (1.07 mL) was added DIPEA (84 μL, 0.48 mmol) and HATU (92 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with methanol using a hydrophilic PTFE 0.45 μm gel. The mixture was filtered through a Millipore® filter. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 70% water / ACN in water (basic mode). The product-containing fractions were evaporated and lyophilized to give the title compound as a white solid (19.9 mg, 36%). 1 H NMR(400MHz,CD3OD)δ ppm 1.16 -1.30(m,2H),1.39-1.68(m,4H),1.88(s,6H),2.14(br dd,J=14.2,8.4Hz,2H),2.21(s,3H),2. 26-2.37(m,1H),2.54(dd,J=14.3,4.5Hz,1H),2.69(s,3H),2.76-2.86(m,1H),7.46(dd,J=8.8,7.0Hz,1H ),7.54(d,J=7.0Hz,1H),7.81(dd,J=5.9,0.9Hz,1H),8.42(d,J=6.0Hz,1H),8.54(d,J=8.8Hz,1H);ESI-MS m / z [M+H] + 340.20.

[0496] Example 8: (R)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0497] [ka]

[0498] Example 9: (S)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0499] [ka]

[0500] The title enantiomers of racemic N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide (505 mg, 1.49 mmol) were separated by preparative SFC (Celluose 2, 5 μm, 30 mm i.d. × 250 mm) using a mobile phase of 40% EtOH (with 0.1% NHOH) in CO. The first-eluting compound was arbitrarily assigned as the (R)-enantiomer (173.6 mg, 34%), and the second-eluting compound was arbitrarily assigned as the (S)-enantiomer (166.2 mg, 33%). 1 H NMR (500 MHz, CD3OD) δ ppm 1.31-1.63(m,4H),1.65-1.80(m,3H),1.90(s,6H),2.56-2.85(m,8H),3.10(br d,J=3.6H ESI-MS m / z [M+H] + 340.20.

[0501] Example 10: N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetamide

[0502] [ka]

[0503] To a solution of pyridine (0.094 mL, 1.16 mmol), 2-(1-methyl-1H-indazol-3-yl)propan-2-amine (0.044 g, 0.232 mmol), and 2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetic acid (0.039 g, 0.232 mmol) in ACN (0.310 mL) was added T3P (50 wt% in EtOAc, 0.691 mL, 1.16 mmol). The reaction mixture was stirred for 24 h, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode). The product was purified by HPLC with HCl in ACN (acid mode). Further purification by preparative HPLC (Xbridge) using a gradient of gave the TFA salt of the title compound (8.0 mg, 10%). 1 H NMR (400 MHz, CD3OD) δppm 1.78-1.92(m,8H),1.94-2.13(m,6H),2.72-2.79(m,2H),3.00-3.11(m,2H),3.38-3.52(m,2H),4.01(s,3 ESI-MS m / z [M+H] + 341.1.

[0504] Example 11: N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0505] [ka]

[0506] To a solution of pyridine (0.069 mL, 0.859 mmol), 2-(3-chlorophenyl)propan-2-amine (0.049 g, 0.286 mmol), and 2-(1-methylpiperidin-2-yl)acetic acid (0.045 g, 0.286 mmol) in ACN (0.382 mL) was added T3P (50 wt% in EtOAc, 0.511 mL, 0.859 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (25 mg, 28%). 1 H NMR (400 MHz, C D3OD)δ ppm 1.27-1.45(m,2H),1.51-1.81(m,10H),2.14-2.26(m,2H),2.27-2.34(m,3H),2.37-2.50(m,1H),2. 52-2.67(m,1H),2.79-2.93(m,1H),7.16-7.23(m,1H),7.25-7.35(m,2H),7.35-7.41(m,1H);ESI-MS m / z [M+H] + 309.1.

[0507] Example 12: N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0508] [ka]

[0509] Step A: N-(2-(3-chlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0510] [ka]

[0511] To a solution of pyridine (0.152 mL, 1.88 mmol), 2-(3-chlorophenyl)propan-2-amine (0.107 g, 0.628 mmol), and 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.144 g, 0.628 mmol) in ACN (0.837 mL) was added T3P (50 wt% in EtOAc, 1.12 mL, 1.88 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with saturated aqueous NH4Cl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The concentrate was dissolved in dioxane (6 mL) and acidified with 4 M HCl in dioxane (2.98 mL, 11.9 mmol). The mixture was stirred at room temperature for 6 hours, then concentrated in vacuo, diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (0.176 g, assumed quantitative).

[0512] Step B: N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0513] To a solution of N-(2-(3-chlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (0.176 g, 0.628 mmol) and aqueous formaldehyde (37 wt%, 0.225 g, 2.77 mmol) in MeOH (2.77 mL) was added sodium cyanoborohydride (0.174 g, 2.77 mmol). The reaction mixture was stirred overnight at room temperature, then sonicated, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a crystalline white solid (41 mg, 22% over two steps). 1 H NMR(4 00MHz,CD3OD)δ ppm 1.53-1.70(m,7H),1.73-1.88(m,2H),1.96-2.09(m,2H),2.19-2.31(m,2H),2.33-2.41(m,3H),2.45-2.61(m,2H),3 .08(ddd,J=9.7,6.8,3.3Hz,1H),7.18-7.23(m,1H),7.26-7.34(m,2H),7.35-7.39(m,1H),7.36-7.44(m,1H);ESI-MS m / z [M+H] + 295.1.

[0514] Example 13: N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0515] [ka]

[0516] Pyridine (0.039 mL, 0.477 mmol), 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine (0.028 g, 0.159 mmol), and 2- To a solution of (1-methylpiperidin-2-yl)acetic acid (0.025 g, 0.159 mmol) in ACN was added T3P (50 wt% in EtOAc, 0.284 mL, 0.477 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (17 mg, 34%). 1 H NMR (400 MHz, C D3OD)δ ppm 0.98-1.18(m,1H),1.20-1.45(m,3H),1.51-1.72(m,5H),1.72-1.80(m,7H),2.15-2.27(m,3H),2.26-2.30(m,3H),2.34-2.50(m ESI-MS m / z [M+H] + 316.1 .

[0517] Example 14: (R)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0518] [ka]

[0519] Example 15: (S)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0520] [ka]

[0521] The title enantiomers of racemic N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide (0.582 g, 1.84 mmol) were separated by preparative SFC. The first-eluting compound was arbitrarily assigned as the (R)-enantiomer and obtained as an off-white solid (265.5 mg, 46%), and the second-eluting compound was arbitrarily assigned as the (S)-enantiomer (251.9 mg, 43%). 1 H NMR (400 MHz, CD3OD) δ ppm 1. 21-1.34(m,2H),1.47-1.68(m,4H),1.70-1.80(m,6H),2.07-2.30(m,5H),2.31-2.45(m,1H),2.59(dd,J=14.4,4.8Hz,1H),2 .75-2.91(m,1H),7.12(dd,J=2.3,1.0Hz,1H),7.44(dd,J=5.8,0.9Hz,1H),7.83(d,J=2.3Hz,1H),8.21-8.39(m,1H);ESI-MS m / z [M+H] + 316.1.

[0522] Example 16: (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0523] [ka]

[0524] Step A: tert-Butyl (R)-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0525] [ka]

[0526] To a solution of 2-(isoquinolin-1-yl)propan-2-amine (60 mg, 0.32 mmol) and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (81 mg, 0.35 mmol) in DMA (2.15 mL) was added DIPEA (169 μL, 0.966 mmol) and HATU (184 mg, 0.483 mmol). The reaction mixture was stirred overnight at room temperature, then quenched with water and saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography using a gradient of 20–80% EtOAc in heptane. Evaporation of product-containing fractions afforded the title compound as a colorless oil (128 mg, estimated quantitative). ESI-MS m / z [M+H] + 398.4.

[0527] Step B: (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0528] [ka]

[0529] To a solution of tert-butyl (R)-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (128 mg, 0.322 mmol) in dioxane (1.61 mL) was added 4 M HCl in dioxane (1.61 mL, 6.44 mmol). The reaction mixture was stirred at room temperature for 1.75 h, then concentrated under reduced pressure and re-evaporated with diethyl ether to give the bis-HCl salt of the title compound (119 mg, assumed quantitative). ESI-MS m / z [M+H] + 298.3.

[0530] Step C: (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)- 2-(1-methylpyrrolidin-2-yl)acetamide

[0531] To a solution of (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide dihydrochloride (119 mg, 0.322 mmol) in methanol (3.22 mL) was added aqueous formaldehyde (37 wt %, 131 mg, 1.61 mmol) and sodium cyanoborohydride (1 M in THF, 1.61 mL, 1.61 mmol). The reaction mixture was stirred overnight at room temperature. Following the reaction, the mixture was concentrated under reduced pressure and dissolved in methanol. The resulting solution was filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of water / ACN in water (basic mode). The product-containing fractions were evaporated and lyophilized to give the title compound as a white solid (43.8 mg, 44% over three steps). 1 H NMR (400 MHz, CD 3OD)δ ppm 1.27-1.40(m,1H),1.52-1.72(m,3H),1.77(2s,6H),1.99-2.13(m,2H),2.17(s,3H) ),2.24-2.34(m,1H),2.34-2.42(m,1H),2.92(ddd,J=9.7,7.2,2.6Hz,1H),7.47(d dd,J=8.6,7.0,1.4Hz,1H),7.53(d,J=5.6Hz,1H),7.58(ddd,J=8.1,6.9,1.1Hz,1H ),7.80(d,J=8.2Hz,1H),8.25(d,J=5.6Hz,1H),8.56(dd,J=8.8,0.9Hz,1H);ESI-MS m / z [M+H] + 312.10.

[0532] Example 17: (R)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0533] [ka]

[0534] The title compound was prepared analogously to Example 16 using 2-(5-methylisoquinolin-1-yl)propan-2-amine (71.3 mg, 0.356 mmol), (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (90 mg, 0.39 mmol), DIPEA (187 μL, 1.07 mmol), and HATU (203 mg, 0.534 mmol) in DMA (2.37 mL) and obtained as a white solid (31.4 mg, 27% over 3 steps). 1 H NMR(400MHz,CD3OD)δ ppm 1.34-1.51(m,1H),1.63-1.82(m,3H),1.87(s ,6H),2.08-2.25(m,2H),2.28(s,3H),2.37-2.53(m,2H),2.68(s,3H),3.03(ddd,J=9.7,7.2,3.0Hz,1H),7.44(dd,J= ESI-MS m / z [M+H] + 326.15.

[0535] Example 18: (S)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0536] [ka]

[0537] The title compound was prepared analogously to Example 16 using 2-(5-methylisoquinolin-1-yl)propan-2-amine (71.3 mg, 0.356 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (90 mg, 0.39 mmol), DIPEA (187 μL, 1.07 mmol), and HATU (203 mg, 0.534 mmol) in DMA (2.37 mL) and obtained as a white solid (26.7 mg, 23% over three steps). 1 H NMR (400 MHz, CD3OD) δ ppm 1.34-1.51(m,1H),1.63-1.82(m,3H),1.87(s, 6H),2.08-2.25(m,2H),2.28(s,3H),2.37-2.53(m,2H),2.68(s,3H),3.03(ddd,J=9.7,7.2,3.0Hz,1H),7.44(dd,J= ESI-MS m / z [M+H] + 326.20.

[0538] Example 19: (R)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0539] [ka]

[0540] The title compound was prepared analogously to Example 16 using 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine (350 mg, 1.84 mmol), (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (422 mg, 1.84 mmol), DIPEA (964 μL, 5.52 mmol), and HATU (1.049 g, 2.76 mmol) in DMA (10 mL) to afford a white solid (290 mg, 50% over three steps). 1 H NMR (400MHz, d4-methanol) )δ ppm 1.50(dddd,J=12.6,10.1,8.5,5.9Hz,1H),1.69-1.78(m,2H),1.80(app d,J=2.8Hz,6H ),1.84-1.97(m,1H),2.19-2.31(m,2H),2.33(s,3H),2.45-2.60(m,5H),3.07(ddd,J=9.8, 7.2,3.1Hz,1H),7.19-7.27(m,1H),7.37(dt,J=7.3,1.0Hz,1H),7.63-7.70(m,1H);ESI-MS m / z [M+H] + 316.20.

[0541] Example 20: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)acetamide

[0542] [ka]

[0543] The title compound was prepared analogously to Example 16 using 2-(isoquinolin-1-yl)propan-2-amine (93 mg, 0.50 mmol), (S)-2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetic acid (146 mg, 0.500 mmol), DIPEA (262 μL, 1.50 mmol), and HATU (285 mg, 0.750 mmol) in DMA (2 mL) to afford the title compound as a white solid (29.5 mg, 16% over three steps). 1 H NMR (400 MHz, CD3OD) )δ ppm 1.89(app d,J=3.6Hz,6H),2.19(dd,J=1 4.3,9.2Hz,1H),2.38(s,3H),2.46-2.62(m,2H),2.65-2.74(m,1H),3.08(ddt,J=9.2,6 .7,4.8Hz,1H),3.63-3.79(m,2H),6.93-6.99(m,1H),7.02-7.08(m,1H),7.10-7.18(m,2 H),7.59(ddd,J=8.6,7.0,1.4Hz,1H),7.66(d,J=5.3Hz,1H),7.72(ddd,J=8.1,6.9,1.1H z,1H),7.94(d,J=8.2Hz,1H),8.38(d,J=5.6Hz,1H),8.67(dd,J=8.7,0.8Hz,1H) m / z [M+H] + 374.20.

[0544] Example 21: (S)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0545] [ka]

[0546] The title compound was prepared analogously to Example 16 using 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine (0.350 g, 1.84 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (422 mg, 1.84 mmol), DIPEA (964 μL, 5.52 mmol), and HATU (1.049 g, 2.76 mmol) in DMA (10 mL) to afford the title compound as a white solid (235.7 mg, 41% over three steps). 1 H NMR (400 MHz, CD3O D)δ ppm 1.50(dddd,J=12.6,10.0,8.4,6.0Hz,1H),1.80(app d,J=2.8Hz,6H),1.84-1.97(m,1H ),2.19-2.30(m,2H),2.33(s,3H),2.45-2.61(m,5H),3.07(ddd,J=9.8,7.1,3.2Hz,1H ),7.20-7.27(m,1H),7.37(dt,J=7.2,1.0Hz,1H),7.67(dt,J=8.0,0.8Hz,1H);ESI-MS m / z [M+H] + 316.2 0.

[0547] Example 22: (S)—N-(2-(3-methylisoquinolin-1-yl)propane-2 -yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0548] [ka]

[0549] The title compound was prepared analogously to Example 16 using 2-(3-methylisoquinolin-1-yl)propan-2-amine (0.300 g, 1.50 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.344 g, 1.50 mmol), DIPEA (1.05 mL, 6.00 mmol), and HATU (0.856 g, 2.25 mmol) in DMA (7.5 mL) and obtained as a white solid (201.4 mg, 41% over three steps). 1 H NMR(400MHz,CD3OD)δ ppm 1.41-1.56(m,1H),1.64-1.86(m,3H),1.89( app d,J=2.3Hz,6H),2.12-2.27(m,2H),2.31(s ,3H),2.41-2.55(m,2H),2.64(d,J=0.6Hz,3H),3.05(ddd,J=9.8,7.2,2.8Hz,1H),7.40-7.51(m, 2H),7.60(ddd,J=8.2,6.9,1.0Hz,1H),7.79(d,J=8.2Hz,1H),8.57(dd,J=8.7,0.8Hz,1H) m / z [M+H] + 326.10.

[0550] Example 23: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0551] [ka]

[0552] Step A: tert-Butyl (S)-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0553] [ka]

[0554] In a three-neck flask equipped with a mechanical stirrer, thermometer, and N2 inlet, 2-(isoquinolin-1-yl)propan-2-amine dihydrochloride (292.3 g, 1.13 mol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (284 g, 1.24 mol) and DMF (5500 mL) were added. The resulting suspension was stirred at 14 °C for 15 min, then EtN (550 mL, 3.95 mol) was added over 1 min, followed by solid HATU (462 g, 1.22 mol) over 2 min at room temperature. The reaction mixture was stirred at room temperature for 15 h, then diluted with iPrOAc (6000 mL) and partitioned with water (3000 mL). The aqueous and organic layers were separated. The aqueous phase was washed with iPrOAc (1500 mL). The organic layers were combined, washed with brine (1500 mL), dried over NaSO, filtered, rinsed with iPrOAc, and concentrated in a rotary evaporator. Some product was detected in the aqueous layer, so each was basified with EtN (5 mL) and washed with iPrOAc (500 mL). The organic phase was washed with brine (250 mL), dried over NaSO, filtered, rinsed with iPrOAc, and concentrated by rotary evaporation. The organic extracts were combined, concentrated, and dried in vacuo to give the crude product as a brown oil. After standing overnight, some of the brown oil solidified to give an oily solid. The oily solid was dispersed in EtOAc and filtered with cold EtOAc (2x) and cold heptane. The resulting solid was dried in vacuo to give pure product (35 g). The filtrate was concentrated by rotary evaporation, diluted with heptane and EtOAc, and purified by silica column chromatography (silica gel 2310 g, RediSep® Rf Gold) using a gradient of 15–70% EtOAc in heptane. The product-containing fractions were combined, concentrated in a rotary evaporator, and dried in vacuo to give the pure product as an off-white solid. The pure fractions were combined with the filtered solid to give the title compound as a white solid (305.8 g, 68.2%). 1 H NMR(400MHz,CD3OD)δ ppm 1.37-1. 54(m,10H),1.63-1.93(m,9H),2.04-2.31(m,1H),2.62-2.77(m,1H),3.22-3.30(m,2H),3.86-4.02(m,1H),7.58(ddd,J=8.6,7 .0,1.2Hz,1H),7.64(d,J=5.8Hz,1H),7.68(ddd,J=8.0,6.9,0.9Hz,1H),7.90(d,J=8.0Hz,1H),8.35(d,J=5.8Hz,1H),8.68(br d,J=8.3Hz,1H);ESI-MS m / z [M+ H] + 398.2.

[0555] Step B: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0556] To a three-neck flask equipped with an overhead stirrer, thermometer, addition funnel, and N2 inlet was added tert-butyl (S)-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (305.7 g, 769 mmol) and DCM (2570 mL) at room temperature. The resulting yellow solution was cooled to 0-5 °C, and 4 M HCl in dioxane (1538 mL, 6.15 mol) was added dropwise at 0-5 °C over 2.25 h. The reaction mixture was stirred at 0-5 °C for 8 h to give a yellow suspension, which was allowed to warm to 15 °C over 1 h. The resulting solid was pressure filtered using nitrogen, rinsed with EtO (4 × 300 mL), and dried in vacuo to give the dihydrochloride salt of the title compound as a hygroscopic off-white solid (282.7 g, 99.2% yield, 96–97% ee). 1 H NMR(400MHz,DMSO-d6)δ ppm 1. 28-1.43(m,1H),1.61-1.86(m,3H),1.93(d,J=7.5Hz,6H),2.64-2.72(m,3H),2.91-3.13(m,2H),3.30-3.46(m,1H),7.88(br t,J=7.8Hz,1H),8 .05(br t,J=7.5Hz,1H),8.25(br d,J=7.8Hz,2H),8.53(d,J=6.3Hz,1H),8.96(d,J=9.0Hz,1H),9.02-9.28(m,2H),9.76(br s,1H);ESI-MS m / z [M+H] + 298.2.

[0557] Example 24: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0558] [ka]

[0559] Step A: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0560] [ka]

[0561] To a three-neck flask equipped with an overhead stirrer, thermometer, addition funnel, and N2 inlet was added (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide dihydrochloride (282.7 g, 763 mmol) and MeOH (7650 mL). The resulting orange solution was cooled to 6 °C, and aqueous formaldehyde (37 wt%, 170.5 mL, 2.29 mol) was added over 3 min. The mixture was stirred at 6 °C for 5 min. Sodium triacetoxyborohydride (485 g, 2.29 mol) was then added in small portions over 25 min. The reaction mixture was stirred at 3–7 °C for 2.5 h. Additional aqueous formaldehyde (37 wt%, 28.4 mL, 382 mmol) was added to the flask, and the reaction mixture was stirred at room temperature for 1 min. Additional sodium triacetoxyborohydride (80.9 g, 382 mmol) was added to the flask in small portions over 5 minutes, and the reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo at 35°C in a rotary evaporator. The resulting yellow suspension was reconstituted with MeOH (1500 mL), concentrated again by rotary evaporation, and then dried in a rotary evaporator at 35°C for 30 minutes. The yellow suspension was suspended in EtOAc (1500 mL) and stirred in a rotary evaporator at 35°C for 15 minutes, then at room temperature for 15 minutes. The solids were filtered, rinsed with EtOAc (3 x 300 mL), and the filtrate was dried in vacuo to give a clear, yellow oil. The oil was dissolved in DCM and purified by silica column chromatography (2240 ​​g of NH 60 μM spherical silica gel, Shoko Scientific Purif-Pack®) using a gradient of 0–5% MeOH in DCM. The pure fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give the crude product, which was dissolved in EtOAc (1000 mL) and partitioned with 2 M aqueous Na2CO3 (500 mL). The aqueous phase was washed with EtOAc (3 x 1000 mL). The organic layers were combined, dried over Na2SO4, filtered, rinsed with EtOAc, concentrated by rotary evaporation, and dried in vacuo to give the title compound as a pale yellow solid (193.8 g, 81.5% yield, 95.6% ee). 1 H NMR (400M Hz,DMSO-d6)δ ppm 1.26-1.38(m,1H),1.48-1.64(m,3H),1.73(s,6H),1.93-2.05(m,2H),2.14(s,3H),2.16-2.24(m,1H),2.30(dd,J=13.7,4.4Hz,1H),2 .83-2.92(m,1H),7.55(ddd,J=8.6,7.0,1.5Hz,1H),7.64(d,J=5.3Hz,1H),7.68(ddd,J=8.2,6.9,1.0Hz,1H),7.92(d,J=7.5Hz,1H),8 .37(d,J=5.8Hz,1H),8.69(dd,J=8.8,0.8Hz,1H),8.74(s,1H);ESI-MS m / z [M+H] + 312.1.

[0562] Step B: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylate

[0563] [ka]

[0564] To a three-neck flask equipped with an overhead stirrer, thermometer, and N2 inlet, D-(+)-camphoric acid (170 g, 849 mmol) and iPrOAc (3526 mL) were added at 40 °C to give a colorless solution. A small portion (2532 mg) of the title compound was added as seed crystals. Next, (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (176.3 g, 566 mmol) was added in small portions over 2 minutes to give a yellow suspension. The mixture was heated to 40 °C with stirring for 5 minutes and then slowly cooled to room temperature without stirring over 2 hours. The resulting solid was filtered, rinsed with iPrOAc (3×584 mL), and dried in vacuo to give the title compound as a white solid (313.6 g, 91%) in a 2:3 molar ratio of (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide:D-(+)-camphoric acid. 1 H NMR (400 MHz,DMSO-d6)δ ppm 0.77(s,4H),1.13(s,4H),1.19(s,4H),1.25-1.43(m,3H),1.48-1.65(m,3H),1.66-1.78(m,8H),1.97-2.10(m,3H),2.16(s,3H),2.25(br d,J=7.8Hz,1H),2.28-2.42(m,3 H),2.73(dd,J=9.8,9.0Hz,2H),2.85-2.94(m,1H),7.55(ddd,J=8.6,7.0,1.5Hz,1H),7.64(d,J=5.3Hz,1H),7.68(ddd ,J=8.1,6.8,1.1Hz,1H),7.89-7.98(m,1H),8.36(d,J=5.5Hz,1H),8.68(dd,J=8.5,0.8Hz,1H),8.75(s,1H),12.17(br s ,3H);ESI-MS m / z [M+H] + 312.2 (early peak), [M+Na ] + 223.1 (late peak).

[0565] Step C: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0566] (S)-N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylate (314 g, 513 mmol) was suspended in iPrOAc (3500 mL) and 2 M aqueous NaCO solution (898 mL) to give a biphasic suspension. Water (175 mL) was added to aid dissolution. The layers were separated. The organic phase was washed with water (3 × 600 mL), concentrated by rotary evaporation, and dried in vacuo at 40 °C. The resulting solid was suspended in iPrOAc (500 mL), mixed in a rotary evaporator at 40 °C for 5 min, and then concentrated by rotary evaporation to azeotropically remove residual water. This process The process was repeated two more times with iPrOAc (2 x 500 mL). The solid was dried in a rotary evaporator at 40 °C and then in a high vacuum oven at 70 °C for 6 h under vacuum to give the title compound as an off-white solid (134.41 g, 84% yield, 99% ee). 1 H NMR(400MHz,DMSO-d6)δ ppm 1.25-1.38( m,1H),1.45-1.64(m,3H),1.73(s,6H),1.93-2.05(m,2H),2.14(s,3H),2.16-2. 24(m,1H),2.30(dd,J=13.7,4.4Hz,1H),2.84-2.91(m,1H),7.55(ddd,J=8.6,7.0 ,1.2Hz,1H),7.64(d,J=5.3Hz,1H),7.68(ddd,J=8.2,6.9,1.0Hz,1H),7.90-7.9 5(m,1H),8.36(d,J=5.8Hz,1H),8.69(dd,J=8.8,0.8Hz,1H),8.74(s,1H);ESI-MS m / z [M+H] + 312.2.

[0567] Example 25: N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0568] [ka]

[0569] To a solution of pyridine (0.413 mL, 5.11 mmol), 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine (0.150 g, 0.851 mmol), and 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.195 g, 0.851 mmol) in ACN (3.87 mL) was added T3P (50 wt% in EtOAc, 3.04 mL, 5.11 mmol). The reaction mixture was stirred at room temperature for 2 days, then diluted with saturated aqueous NH4Cl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The concentrate was dissolved in dioxane (6 mL) and treated with 4 M HCl in dioxane (4.26 mL, 17.0 mmol). The mixture was heated to reflux with a heat gun and then cooled to room temperature. The solution was concentrated in vacuo to give the HCl salt of the title compound, which was dissolved in MeOH (3 mL). Aqueous formaldehyde (37 wt%, 0.691 g, 8.51 mmol) and sodium cyanoborohydride (0.535 g, 8.51 mmol) were then added. The reaction mixture was stirred for 24 hours, then sonicated, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm ID × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a white solid (22 mg, 8.6%). 1 H NMR(400MHz,CD3OD)δ ppm 1.44-1.63(m,1H),1.66-1.88(m,8H),1.90-2.02(m,1H),2.02-2.10(m,1H),2.18-2.31(m,2H),2.32-2.38(m,3H),2.44 -2.62(m,2H),3.02-3.14(m,1H),6.98-7.28(m,1H),7.34-7.60(m,1H),7.71-7.96(m,1H),8.34(d,J=5.9Hz,1H);ESI-MS m / z [M+H] + 302.1.

[0570] Example 26: N-(2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0571] [ka]

[0572] To a vial was added 2-(1-methylpiperidin-2-yl)acetic acid (42.1 mg, 0.268 mmol), 2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine (51 mg, 0.268 mmol), EtN (37.4 μL, 0.268 mmol), HATU (102 mg, 0.268 mmol), and DMF (3 mL). The reaction mixture was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a white solid (15 mg, 17%). 1 H NMR (400 MHz, CD3O D)δppm 1.21-1.37(m,2H),1.53-1.73(m,5H),1.78(d,J=5.6Hz,6H),2.14-2.40(m,7H),2.61(dd,J=14.4,4.7Hz,1 ESI-MS m / z [M+H] + 330 .3.

[0573] Example 27: 2-(1-ethylpyrrolidin-2-yl)-N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)acetamide

[0574] [ka]

[0575] To a solution of EtN (0.137 mL, 0.984 mmol), 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine (0.065 g, 0.369 mmol), and 2-(1-ethylpyrrolidin-2-yl)acetic acid hydrochloride (0.048 g, 0.246 mmol) in DMF (2.46 mL) was added HATU (0.140 g, 0.369 mmol). The reaction mixture was stirred at room temperature for 2 days, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode) to give the title compound as a pale yellow crystalline solid (48 mg, 62%). 1 H NMR(400MHz,CD3OD)δ ppm 1.06-1.19(m,3H),1.41-1.61(m,1H),1.77(d,J=14.9Hz,6H),1.84-2.01(m,1H),2.12-2.32(m,3H),2.44-2.56(m,1H),2.60-2.73 ESI-MS m / z [M+H] + 316.1.

[0576] Example 28: N-(2-methyl-1-((3-(trifluoromethyl)pyridine-2- (1-methyl-2-pyrrolidin-2-yl)acetamide

[0577] [ka]

[0578] Step A: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0579] [ka]

[0580] A solution of 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (23.4 mg, 0.102 mmol), DIPEA (0.060 mL, 0.342 mmol), 2-chloro-1-methylpyridinium iodide (26.2 mg, 0.102 mmol), and NMP (0.5 mL) was stirred for 15 min. Next, 2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (20 mg, 0.085 mmol) was added, and the solution was stirred at 45° C. for 3 days and then concentrated in vacuo. The mixture was treated with 4 M HCl in dioxane (1 mL), shaken for 30 min, and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–90% ACN in water (acid mode). Product-containing fractions were combined and dried in a GeneVac™ evaporator to give the TFA salt of the title compound as a film (4.9 mg, 16.6%). ESI-MS m / z [M+H] + 346.1.

[0581] Step B: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0582] To a vial containing N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (4.9 mg, 0.014 mmol) and formaldehyde (2.1 μL, 0.028 mmol) in MeOH (0.6 mL) was added sodium cyanoborohydride (1 M, 28 μL, 0.028 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, and then MeOH (0.5 mL) was added. The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–90% ACN in water (acid mode). The pure fractions were combined and dried in a GeneVac™ evaporator to give the TFA salt of the title compound as a colorless film (4.1 mg, 80%). ESI-MS m / z [M+H] + 360.2.

[0583] Example 29: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpiperidin-2-yl)aceto amide

[0584] [ka]

[0585] A solution of 2-(1-methylpiperidin-2-yl)acetic acid (16.1 mg, 0.102 mmol), DIPEA (44.1 mg, 0.342 mmol), 2-chloro-1-methylpyridin-1-ium iodide (26.2 mg, 0.102 mmol), and NMP (0.5 mL) was stirred at 45°C for 30 min. Next, 2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (20 mg, 0.085 mmol) was added. The solution was stirred at 45°C for 4 h and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–90% ACN in water (acid mode). The product was subsequently purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 20 to 100% water / ACN in water (basic mode). Product-containing fractions were combined and dried in a GeneVac™ evaporator to give the title compound as a yellow solid (5.4 mg, 17%). 1 H NMR (400MHz,CD3OD)δ ppm 1.28-1.39(m,2H),1.44(s,6H),1.50-1.71(m,4H),2.19-2.28(m,2H),2.31(s,3H),2.45-2.55(m,2H),2.88(br d,J=12. 0Hz,1H),4.60(s,2H),7.10(t,J=6.2Hz,1H),8.00(d,J=7.4Hz,1H),8.35(dt,J=5.0,0.9Hz,1H);ESI-MS m / z [M+H] + 374.2.

[0586] Example 30: N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0587] [ka]

[0588] To a solution of EtN (0.113 mL, 0.809 mmol), 2-(4-chlorophenyl)propan-2-amine hydrochloride (0.050 g, 0.243 mmol), and 2-(1-methylpiperidin-2-yl)acetic acid (0.025 g, 0.162 mmol) in DMF (1.62 mL) was added HATU (0.092 g, 0.243 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a yellowish-orange semisolid (28 mg, 56%). 1 H NMR (40 0MHz,CD3OD)δ ppm 1.22-1.41(m,2H),1.47-1.76(m,11H),2.11-2.23(m,2H),2.23-2.29(m,3H),2.32-2. 45(m,1H),2.48-2.59(m,1H),2.76-2.87(m,1H),4.83(s,2H),7.23-7.29(m,2H),7.32 -7.36(m,1H),7.34-7.34(m,1H);ESI-MS m / z [M+H] + 309.1.

[0589] Example 31: N-((S)-1-(4-chlorophenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide

[0590] [ka]

[0591] To a solution of EtN (0.258 mL, 1.849 mmol), (S)-1-(4-chlorophenyl)ethan-1-amine (0.086 g, 0.555 mmol), and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.106 g, 0.462 mmol) in DMF (4.62 mL) was added HATU (0.211 g, 0.555 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode). The product-containing fractions were combined, dissolved in 4 M HCl / dioxane solution (2.31 mL, 9.25 mmol), and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to give the HCl salt of the title compound, which was dissolved in MeOH (5 mL). Aqueous formaldehyde (37 wt%, 0.231 g, 2.31 mmol) and sodium cyanoborohydride (0.145 g, 2.31 mmol) were then added, and the mixture was stirred overnight. The solution was then sonicated, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a white solid (53 mg, 41%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.37-1.47(m,3H),1.48-1.65(m,1H),1.68-1. 85(m,2H),1.94-2.07(m,1H),2.12-2.27(m,2H),2.28(s,3H),2.47-2.63 (m,2H),2.98-3.12(m,1H),4.92-5.06(m,1H),7.24-7.37(m,4H);ESI-MS m / z [M+H] + 281.1.

[0592] Example 32: N-((S)-1-(4-fluorophenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide

[0593] [ka]

[0594] The title compound was prepared similarly to Example 31 using HATU (0.193 g, 0.508 mmol), EtN (0.236 mL, 1.69 mmol), (S)-1-(4-fluorophenyl)ethan-1-amine (0.071 g, 0.508 mmol), and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.097 g, 0.423 mmol) in DMF (4.23 mL) to give a white solid (39 mg , 35%). 1 H NMR(400MHz,CD3OD)δ ppm 1.37 -1.47(m,3H),1.48-1.65(m,1H),1.70-1.85(m,2H),1.92-2.07(m,1H),2.13-2.27(m,2H),2.27-2.33(m,3H),2.41-2.68(m,2H) ,3.05(ddd,J=9.8,6.2,4.0Hz,1H),3.31(dt,J=3.3,1.6Hz,1H),4.92-5.13(m,1H),6.84-7.14(m,2H),7.19-7.40(m,2H);ESI-MS m / z [M+H] + 265.1.

[0595] Example 33: (S)—N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0596] [ka]

[0597] The title compound was prepared in a similar manner to Example 31 using HATU (0.205 g, 0.539 mmol), EtN (0.250 mL, 1.80 mmol), 2-(2,5-dichlorophenyl)propan-2-amine (0.110 g, 0.539 mmol), and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.103 g, 0.449 mmol) in DMF (4.49 mL) and obtained as a white solid (35 mg, 24%). 1 H NMR(400MHz,CD3OD)δ ppm 1.46-1 .62(m,1H),1.66-1.83(m,8H),1.90-2.07(m,1H),2.10-2.26(m,2H),2.26-2.39(m,3H),2.42-2 .58(m,2H),2.95-3.13(m,1H),7.14-7.25(m,1H),7.26-7.36(m,1H),7.44-7.56(m,1H);ESI-MS m / z [M+H] + 331.0.

[0598] Example 34: (S)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0599] [ka]

[0600] The title compound was prepared in a similar manner to Example 31 using HATU (0.233 g, 0.612 mmol), EtN (0.285 mL, 2.041 mmol), 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine (0.108 g, 0.612 mmol), and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.117 g, 0.510 mmol) in DMF (5.10 mL) and obtained as a white solid (64 mg, 42%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.41-1.56(m,1H),1.62-1.82(m,8H),1.85-2. 01(m,1H),2.13-2.27(m,2H),2.27-2.36(m,3H),2.38-2.60(m,2H),2.9 6-3.09(m,1H),7.06-7.23(m,1H),7.37-7.53(m,1H),7.77-7.93(m,1H) ,8.23-8.39(m,1H);ESI-MS m / z [M+H] + 302.1.

[0601] Example 35: (S)—N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0602] [ka]

[0603] The title compound was prepared in a similar manner to Example 31 using HATU (0.271 g, 0.712 mmol), EtN (0.413 mL, 2.97 mmol), 2-(4-chlorophenyl)propan-2-amine hydrochloride (0.108 g, 0.612 mmol), and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.147 g, 0.712 mmol) in DMF (5.93 mL) and obtained as a clear semi-solid (63 mg, 36%). 1 H NMR(400MHz,CD3OD)δ ppm 1.50- 1.67(m,7H),1.71-1.84(m,2H),1.91-2.07(m,1H),2.11-2.30(m,2H),2.33(s,3H), 2.41-2.61(m,2H),2.98-3.10(m,1H),7.21-7.31(m,2H),7.32-7.42(m,2H);ESI-MS m / z [M+H] + 295.1.

[0604] Example 36: N-((S)-1-(4-chlorophenyl)ethyl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide

[0605] [ka]

[0606] To a solution of EtN (0.292 mL, 2.09 mmol), (S)-1-(4-chlorophenyl)ethan-1-amine (0.098 g, 0.628 mmol), and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.120 g, 0.523 mmol) in DMF (5.23 mL) was added HATU (0.239 g, 0.628 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode). Pure fractions were combined and dissolved in a solution of 4 M HCl in dioxane (2.62 mL, 10.47 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo to give the HCl salt of the title compound, which was dissolved in MeOH (5 mL). Formaldehyde (0.212 g, 2.62 mmol) and sodium cyanoborohydride (1 M in THF, 2.62 mL, 2.62 mmol) were then added. The reaction mixture was stirred for 2 hours, then sonicated, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm ID × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a white solid (83 mg, 56%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.37-1.46(m,3H),1.47-1.58(m,1H),1.65-1. 79(m,2H),1.84-1.99(m,1H),2.13-2.29(m,2H),2.29-2.37(m,3H),2.47-2 .58(m,2H),2.96-3.11(m,1H),4.91-5.04(m,1H),7.20-7.40(m,4H);ESI-MS m / z [M+H] + 281.0.

[0607] Example 37: N-((S)-1-(4-fluorophenyl)ethyl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide

[0608] [ka]

[0609] The title compound was prepared in a similar manner to Example 36 using HATU (0.239 g, 0.628 mmol), EtN (0.292 mL, 2.09 mmol), (S)-1-(4-fluorophenyl)ethan-1-amine (0.087 g, 0.628 mmol), and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.120 g, 0.523 mmol) in DMF (5.23 mL) and obtained as a white solid (92 mg, 66%). 1 H NMR(400MHz,CD3OD)δ ppm 1.38- 1.44(m,3H),1.45-1.57(m,1H),1.65-1.81(m,2H),1.84-1.99(m,1H),2.11-2.29(m,2H),2.29-2.36(m,3H),2.46- 2.59(m,2H),2.94-3.08(m,1H),3.27-3.33(m,1H),4.92-5.07(m,1H),6.90-7.09(m,2H),7.24-7.42(m,2H);ESI-MS m / z [M+H] + 265.1.

[0610] Example 38: (R)—N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0611] [ka]

[0612] The title compound was prepared in a similar manner to Example 36 using HATU (0.239 g, 0.628 mmol), EtN (0.292 mL, 2.09 mmol), 2-(2,5-dichlorophenyl)propan-2-amine (0.128 g, 0.628 mmol), and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.120 g, 0.523 mmol) in DMF (5.23 mL) and obtained as a white solid (93 mg, 54%). 1 H NMR(400MHz,CD3OD)δ ppm 1.47-1 .63(m,1H),1.73(m,8H),1.91-2.06(m,1H),2.12-2.29(m,2H),2.32(s,3H),2.49(s,2 H),2.97-3.10(m,1H),7.12-7.24(m,1H),7.25-7.36(m,1H),7.41-7.56(m,1H);ESI-MS m / z [M+H] + 331. 0.

[0613] Example 39: (R)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0614] [ka]

[0615] The title compound was prepared in a similar manner to Example 36 using HATU (0.239 g, 0.628 mmol), EtN (0.292 mL, 2.09 mmol), 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine (0.111 g, 0.628 mmol), and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.120 g, 0.523 mmol) in DMF (5.23 mL) and obtained as a clear solid (45 mg, 28%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.40-1.60(m,1H),1.75(m,7H),1.85-2.01(m,1H),2.12-2.26(m,2H),2.31(s,3H),2.40-2.60(m,2H),3.04(ddd,J=9.7 ESI-MS m / z [M+H] + 302.1.

[0616] Example 40: (R)—N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0617] [ka]

[0618] The title compound was prepared in the same manner as in Example 36 using HATU (0.239 g, 0.628 mmol), EtN (0.365 mL, 2.62 mmol), 2-(4-chlorophenyl)propan-2-amine hydrochloride (0.129 g, 0.628 mmol), and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.120 g, 0.523 mmol) in DMF (5.23 mL) and obtained as a clear semi-solid (80 mg, 52%). 1 H NMR(400MHz,CD3OD)δ ppm 1.50- 1.66(m,7H),1.70-1.85(m,2H),1.92-2.10(m,1H),2.15-2.31(m,2H),2.31-2.37(m,3H),2.43-2.63(m,2H), 3.06(ddd,J=9.8,6.2,3.9Hz,1H),3.31(dt,J=3.3,1.6Hz,2H),7.22-7.30(m,2H),7.32-7.38(m,2H);ESI-MS m / z [M+H] + 295.1.

[0619] Example 41: N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0620] [ka]

[0621] To a vial was added 2-(1-methylpiperidin-2-yl)acetic acid (30.0 mg, 0.191 mmol), HATU (72.6 mg, 0.191 mmol), 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine (36.3 mg, 0.191 mmol), EtN (26.6 μL, 0.191 mmol), and DMF (1 mL). The reaction mixture was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a light brown solid (27 mg, 43%). 1 H NMR (400 MHz, CD3OD) δppm 1.18-1.35(m,2H),1.50-1.70(m,4H),1.80(d,J=1.5Hz,6H),2.12-2.25(m,5H),2.28-2.42(m,1H),2.52-2.6 2(m,4H),2.77-2.86(m,1H),7.22(t,J=7.6Hz,1H),7.35(dt,J=7.2,0.9Hz,1H),7.66(d,J=7.7Hz,1H);ESI-MS m / z [M+H]+ 3 30.3.

[0622] Example 42: N-(2-(4-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0623] [ka]

[0624] The title compound was prepared similarly to Example 41 using 2-(4-methylisoquinolin-1-yl)propan-2-amine (30.0 mg, 0.150 mmol), 2-(1-methylpiperidin-2-yl)acetic acid (23.6 mg, 0.150 mmol), EtN (20.9 μL, 0.150 mmol), and HATU (57.0 mg, 0.150 mmol) in DMF to give a colorless oil (23 mg, 45%). 1 H NMR (400MH z,CD3OD)δ ppm 1.28-1.35(m,1H),1.37-1.61(m,2H),1.68(br d,J=10.9Hz,2H),,1.73-1.90(m ,1H),2.04-2.08(m,6H),2.62-2.71(m,3H),2.76-2.92(m,5H),3.10-3.17(m,1H),3.13-3.20(m,1H),3.29-3.36(m,2H),8 .02(t,J=7.8Hz,1H),8.22(ddd,J=8.4,7.2,1.0Hz,1H),8.31(s,1H),8.43(d,J=8.5Hz,1H),9.06(d,J=8.8Hz,1H);ESI-MS m / z [M+H] + 340.4.

[0625] Example 43: (R)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0626] [ka]

[0627] Example 44: (S)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0628] [ka]

[0629] The title enantiomers of racemic N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide (728 mg, 2.37 mmol) were separated by preparative SFC (Daicel Chiralpak AD, 5 μm, 30 mm i.d. × 250 mm). The first-eluting compound was arbitrarily assigned as the (R)-enantiomer and obtained as a white solid (324 mg, 45%), and the second-eluting compound was arbitrarily assigned as the (S)-enantiomer and obtained as a white solid (329 mg, 45%). 1 H NMR(400MHz,CD3OD)δ ppm 1.23-1.35(m,2H),1.52-1.69(m,4H),1.80(a pp d,J=1.9Hz,6H),2.17-2.28(m,5H),2.35-2. 45(m,1H),2.53-2.62(m,4H),2.80-2.88(m,1H),7.20-7.25(m,1H),7.36(d,J=7.0Hz,1H),7.66(d,J=7.7Hz,1H);ESI-MS m / z [M+H] + 330.1.

[0630] Example 45: N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0631] [ka]

[0632] To a solution of EtN (0.177 mL, 1.27 mmol), 2-(2,5-dichlorophenyl)propan-2-amine (0.097 g, 0.477 mmol), and 2-(1-methylpiperidin-2-yl)acetic acid (0.050 g, 0.318 mmol) in DMF (3.18 mL) was added HATU (0.181 g, 0.477 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a white solid (23 mg, 21%). 1 H NMR (400 MHz, CD3O D)δ ppm 1.22-1.40(m,2H),1.48-1.77(m,10H),2.09-2.22(m,2H),2.22-2.33(m,3H),2.33-2.4 7(m,1H),2.48-2.63(m,1H),2.76-2.91(m,1H),3.31-3.38(m,4H),7.14-7.25(m,1H),7.25-7.36(m,1H),7.45-7.60(m,1H);ESI-MS m / z [M+H] + 345.0.

[0633] Example 46: (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0634] [ka]

[0635] Step A: tert-Butyl (R)-2-(2-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0636] [ka]

[0637] To a 20 mL vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (78% pure, 0.080 g, 0.346 mmol), (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.079 g, 0.346 mmol), HATU (0.132 g, 0.346 mmol), DIPEA (0.181 mL, 1.039 mmol), and DMF (3 mL). The resulting yellow solution was stirred at room temperature overnight, then treated with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO, filtered, and concentrated to give the title compound as a light brown film (136 mg, estimated quantitative).

[0638] Step B: (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0639] [ka]

[0640] In a 125 mL flask, tert-butyl (R)-2-(2-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (0.136 g) in dioxane (3 mL) was added. , 0.346 mmol) and 4 M HCl in dioxane (0.346 mL, 1.38 mmol) were added. The resulting brown solution was stirred at room temperature overnight and then concentrated to dryness to give the HCl salt of the title compound as a light brown film (113 mg, assumed quantitative).

[0641] Step C: (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0642] To a 125 mL flask was added (R)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide HCl salt (113 mg, 0.346 mmol) and aqueous formaldehyde (37 wt%, 0.053 mL, 0.685 mmol) in methanol (3 mL), followed by sodium cyanoborohydride (43.1 mg, 0.685 mmol). The mixture was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound (51.1 mg, 35% over three steps). 1 H NMR(500MHz,CD3OD)δ ppm 1.45 (d,J=2.7Hz,6H),1.67-1.77(m,1H),1.82-1.94(m,1H),1.98-2.08(m,1H),2.21(s,4H),2.70(br d,J=5.4Hz,2H),2.83-2.93(m,3H),3.03-3.1 4(m,1H),3.51-3.69(m,2H),4.30-4.39(m,1H),4.45-4.56(m,1H),6.79-6.89(m,1H),7.42-7.55(m,1H),7.82-7.95(m,1H);ESI-MS m / z [M+H] + 306.4.

[0643] Example 47: (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0644] [ka]

[0645] Step A: tert-Butyl (S)-2-(2-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0646] [ka]

[0647] A vial was charged with 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (78% pure, 0.070 g, 0.303 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.069 g, 0.3 To the residue was added HCl (0.03 mmol), HATU (0.115 g, 0.303 mmol), DIPEA (0.158 mL, 1.039 mmol), and DMF (3 mL). The resulting yellow solution was stirred at room temperature overnight, then treated with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO, filtered, and concentrated to give the title compound as a light brown film (119 mg, estimated quantitative).

[0648] Step B: (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0649] [ka]

[0650] To a 125 mL flask was added tert-butyl (S)-2-(2-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (0.119 g, 0.303 mmol) in dioxane (3 mL) and 4 M HCl in dioxane (0.346 mL, 1.38 mmol). The resulting brown solution was stirred at room temperature overnight. Additional HCl (4 M in dioxane, 0.346 mL, 1.38 mmol) was added, and the mixture was again stirred at room temperature overnight. The mixture was concentrated to dryness to provide the HCl salt of the title compound as a light brown film (99 mg, assumed quantitative).

[0651] Step C: (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0652] To a 125 mL flask was added (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide HCl salt (99 mg, 0.303 mmol) in methanol (3 mL) and aqueous formaldehyde (37 wt%, 0.053 mL, 0.685 mmol), followed by sodium cyanoborohydride (43.1 mg, 0.685 mmol). The mixture was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound (56.2 mg, 44% over three steps). 1 H NMR(500MHz,CD3OD)δ ppm 1.44- 1.48(m,6H),1.67-1.79(m,1H),1.85-1.97(m,1H),1.98-2.09(m,1H),2.21(s,3H),2.24-2.33(m,1H),2.71(s,2H),2.86-2.93(m,3H),3. 04-3.13(m,1H),3.53-3.70(m,2H),4.32-4.41(m,1H),4.47-4.56(m,1H),6.81-6.89(m,1H),7.47-7.54(m,1H),7.83-7.95(m,1H);ESI-MS m / z [M+H] + 306.4.

[0653] Example 48: (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0654] [ka]

[0655] Step A: tert-Butyl (S)-2-(2-((2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0656] [ka]

[0657] To a solution of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid HCl (50.0 mg, 0.218 mmol) and HATU (71.5 mg, 0.188 mmol) in DMF (0.9 mL) was added DIPEA (0.115 mL, 0.659 mmol) at room temperature. The reaction mixture was stirred for 5-10 minutes. Next, 2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (52.9 mg, 0.226 mmol) was added, and the mixture was stirred at room temperature overnight. The residue was dissolved in methanol and filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to give the TFA salt of the title compound as a colorless oil (96 mg, 91%).

[0658] Step B: (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0659] [ka]

[0660] To a solution of the TFA salt of tert-butyl (S)-2-(2-((2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (96 mg, 0.172 mmol) in DCM (5.0 mL) was added TFA (2.5 mL). The resulting solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the TFA salt of the title compound as a colorless oil, which was used without further purification (79 mg, 100%).

[0661] Step C: (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0662] A mixture of (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide TFA salt (79 mg, 0.172 mmol), paraformaldehyde (12.7 mg, 0.422 mmol), sodium triacetoxyborohydride (179 mg, 0.845 mmol), and DIPEA (148 μL, 0.845 mmol) in DCM (2.1 mL) was stirred at room temperature for 2 days. Next, EtOAc (10 mL) and saturated aqueous NaHCO (10 mL) were added, and the reaction mixture was stirred vigorously for 1 h. The organic layer was washed with brine (2 × 3 mL) and concentrated in vacuo. The concentrate was dissolved in methanol and filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to give a colorless oil, which was dissolved in MeOH and filtered through Agilent Stratospheres SPE (PL-HCO3MP) resin to give the title compound as a colorless oil (23 mg, 37%). 1 H NMR (400MHz, CD3OD)δ ppm 1.46(d,J=2.4Hz,6H),1.73-1.85(m,1H),1.89-2.02(m,1H),2.04-2.17(m,1 H),2.31(dtd,J=13.5,8.2,5.5Hz,1H),2.72(dd,J=5.3,1.2Hz,2H),2.93(s,3 H),3.13(dt,J=11.5,8.3Hz,1H),3.53-3.63(m,1H),3.65-3.75(m,1H),4.52- 4.71(m,2H),7.08-7.15(m,1H),7.97-8.06(m,1H),8.32-8.40(m,1H);ESI-MS m / z [M+H] + 360.1.

[0663] Example 49: (R)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0664] [ka]

[0665] The title compound was prepared by reacting (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (50.0 mg, 0.218 mmol) and 2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (52.9 mg, 0.226 mmol) in Step A and tert-butyl (R)-2-(2-((2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine) in Step B. Prepared analogously to Example 48 using the TFA salt of (R)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (95 mg, 0.170 mmol) and in Step C using the TFA salt of (R)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (97 mg, 0.211 mmol) and formaldehyde (12.68 mg, 0.422 mmol). The title compound was obtained as a colorless oil (19 mg, 25%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.46(d,J=2.6Hz,6H),1.72-1.85(m,1H),1.89-2.01(m,1H),2.04-2.17(m,1H),2.25-2.38(m,1H),2.71(d,J=5.0Hz,2H),2.93( ESI-MS m / z [M+H] + 360.1.

[0666] Example 50: 2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0667] [ka]

[0668] The TFA salt of the title compound was prepared similarly to Example 48 (Step A) using 2-(1-ethylpyrrolidin-2-yl)acetic acid hydrochloride (15 mg, 0.077 mmol) and 2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (20 mg, 0.085 mmol) and obtained as a colorless oil (23 mg, 61%). 1 H NMR(400MHz,CD3OD)δ ppm 1.34(t,J=7 .3Hz,3H),1.46(d,J=1.1Hz,6H),1.72-1.85(m,1H),1.93-2.16(m,2H),2.23-2.37(m,1H),2.70(d,J=5.4Hz,2H),3.04-3.22(m ESI-MS m / z [M+H] + 374.20.

[0669] Example 51: (S)-2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0670] [ka]

[0671] A mixture of (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide TFA salt (40 mg, 0.087 mmol), iodoethane (16.3 mg, 0.104 mmol), and potassium carbonate (60 mg, 0.435 mmol) in DMSO (0.87 mL) was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–70% water / ACN in water (basic mode) to give the title compound as a pale yellow oil (3.3 mg, 10%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.11(t,J=7.2Hz,3H),1.44(d,J=2.0Hz,6 H),1.51-1.61(m,1H),1.71-1.82(m,2H),1.86-2.00(m,1H),2.15-2.26(m,3H),2.40(dd,J=14.3,4.3Hz,1H),2.68(qd,J=7.9,4.3Hz,1 ESI-MS m / z [M+H] + 37 4.1.

[0672] Example 52: (S)-2-(1-(2-fluoroethyl)pyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0673] [ka]

[0674] The title compound was prepared in the same manner as in Example 51 using the TFA salt of (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (40 mg, 0.087 mmol), 1-bromo-2-fluoroethane (13.3 mg, 0.104 mmol), and potassium carbonate (48 mg, 0.348 mmol) in DMSO (0.87 mL) and obtained as a colorless oil (4.5 mg, 13.2%). 1 H NMR (400 MHz, CD3OD) δppm 1.43(s,6H),1.52-1.64(m,1H),1.71-1.86(m,2H),1.89-2.01(m,1H),2.20-2.41(m,3H),2.42-2.59(m,1H),2.76(qd,J=7.6,4.3Hz,1H),3 ESI-MS m / z [M+H] + 392.1.

[0675] Example 53: (S)-2-(1-cyclopropylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0676] [ka]

[0677] (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide TFA salt (40 mg, 0.084 mmol), (1-ethoxycyclopropoxy)trimethylsilane (18.2 mg, 0.104 mmol), sodium triacetoxyborohydride (74 mg, 0.348 mmol), and DIPEA (0.061 mL, 0.348 mmol) were added. A mixture of 1, 4.0 equiv. (H, 4.0 equiv.) in DCM (0.87 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO and then extracted with EtOAc (3 × 4.0 mL). The organic phase was concentrated and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to afford the TFA salt of the title compound as a colorless oil (3.0 mg, 6.9%). 1 H NMR(400MHz,CD3OD)δ ppm 0.83- 1.07(m,4H),1.23-1.39(m,1H),1.44(s,6H),1.71-1.85(m,1H),1.89-2.02(m,1H),2.03-2.16(m,1H),2.22-2.38(m,1H),2.64-2.86(m, ESI-MS m / z [M+H] + 386.10.

[0678] Example 54: (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0679] [ka]

[0680] Step A: (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(pyrrolidin-2-yl)acetamide

[0681] [ka]

[0682] The title compound was prepared analogously to Steps A and B of Example 48, starting from (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (30 mg, 0.131 mmol) and 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropan-1-amine (28 mg, 0.157 mmol). The resulting intermediate, tert-butyl (S)-2-(2-((1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate TFA salt (50 mg, 0.099 mmol), was treated with TFA (1 mL) and concentrated. The colorless residue was dissolved in MeOH and filtered through Agilent Stratospheres SPE (PL-HCO3MP) resin to give the title compound as a white solid (33 mg).

[0683] Step B: (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0684] (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(pyrrolidin-2-yl)acetamide (16 mg, 0.055 mmol A mixture of 4-( ... 1 H NMR (400 MHz, CD3OD) δ ppm 0.84-0.92(m,2H),0.97-1.04(m,2H),1.71-1. 87(m,1H),1.96-2.17(m,2H),2.23(s,3H),2.27-2.40(m,1H),2.69(d,J=5.6Hz,2H),2.95(br s ESI-MS m / z [M+H] + 304.2.

[0685] Example 55: (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0686] [ka]

[0687] The TFA salt of the title compound was prepared similarly to Example 54 using 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutan-1-amine (30 mg, 0.157 mmol) and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (30 mg, 0.131 mmol) to afford a colorless oil (16 mg, 28% over three steps). 1H NMR(400MHz,CD3OD)δ ppm 1.69 -1.84(m,1H),1.94-2.17(m,4H),2.23(s,3H),2.27-2.42(m,5H),2.71(dd,J=5.3,2.7Hz,2H),2.94(s,3H),3.09-3.20(m,1H),3.54-3.6 4(m,1H),3.66-3.76(m,1H),4.52-4.66(m,2H),6.88(dd,J=7.0,5.1Hz,1H),7.48-7.55(m,1H),7.94(ddt,J=5.1,1.2,0.6Hz,1H);ESI-MS m / z [M+H] + 318.1.

[0688] Example 56: (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0689] [ka]

[0690] The TFA salt of the title compound was prepared by rinsing 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentan-1-amine (32 mg, 0.157 mmol) and (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (30 mg, 0.13 mmol). 1 mmol) as in Example 54 to give a colorless oil (14 mg, 24% over 3 steps). 1 H NMR (400 MHz, CD3OD) δ ppm 1.6 5-1.85(m,5H),1.87-2.00(m,3H),2.03-2.16(m,3H),2.23(s,3H),2.24-2.34(m,1H),2.65-2.78(m,2H),2.92(s,3H),3.07-3.16(m,1 ESI-MS m / z [M+H] + 332. 1.

[0691] Example 57: (R)-2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0692] [ka]

[0693] A mixture of the TFA salt of (R)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (40.0 mg, 0.087 mmol), iodoethane (16.3 mg, 0.104 mmol), and potassium carbonate (60 mg, 0.435 mmol) in DMF (0.87 mL) was stirred at room temperature for 1 day. The reaction mixture was dissolved in methanol and filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to afford the TFA salt of the title compound as a colorless oil (13 mg, 31%). 1 H NMR (400 MHz, CD3OD) δ ppm 1 .25(t,J=7.3Hz,3H),1.38(s,6H),1.64-1.75(m,1H),1.85-2.04(m,2H),2.21(dtd,J=13.4,7.9,6.0Hz,1H),2.55-2.69(m,2H),2. 94-3.13(m,2H),3.38(dq,J=12.8,7.3Hz,1H),3.55-3.67(m,2H),4.46-4.59(m,2H),6.98-7.07(m,1H),7.89-7.94(m,1H),7.98(br s,1H),8.25-8.30(m,1H );ESI-MS m / z [M+H] + 374.10.

[0694] Example 58: (R)-2-(1-(2-fluoroethyl)pyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0695] [ka]

[0696] The TFA salt of the title compound was prepared in the same manner as in Example 57 using the TFA salt of (R)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (40.0 mg, 0.087 mmol), 1-bromo-2-fluoroethane (13.3 mg, 0.104 mmol), and potassium carbonate (48 mg, 0.348 mmol) in DMF (0.87 mL) and obtained as a colorless oil (6 mg, 14%). 1 H NMR (400 MHz, CD3O D)δppm 1.46(d,J=0.9Hz,6H),1.74-1.85(m,1H),1.93-2.18(m,2H),2.25-2.41 (m,1H),2.75(d,J=5.4Hz,2H),3.20-3.30(m,1H),3.38-3.54(m,1H),3. 70-3.90(m,3H),4.53-4.59(m,1H),4.62-4.68(m,1H),4.71-4.77(m,1H ),4.87(t,J=4.5Hz,1H),7.07-7.16(m,1H),7.99-8.05(m,1H),8.10(br s,1H),8.33-8.39(m,1H);ESI-MS m / z [M+H] + 392.1.

[0697] Example 59: (R)-2-(1-cyclopropylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0698] [ka]

[0699] A mixture of (R)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide TFA salt (40.0 mg, 0.087 mmol), (1-ethoxycyclopropoxy)trimethylsilane (18.2 mg, 0.104 mmol), sodium triacetoxyborohydride (74 mg, 0.348 mmol), and DIPEA (0.061 mL, 0.348 mmol) in DCM (0.87 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO and extracted with EtOAc (3 × 4.0 mL). The organic phase was concentrated and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–70% water / ACN in water (basic mode) to give the title compound as a colorless oil (3.6 mg, 11%). 1H NMR(400MHz,CD3OD)δ ppm 0.37-0.86(m,4H) ,1.44(s,6H),1.54-1.68(m,1H),1.71-1.92(m,2H),1.96-2.18(m,1H),2.29-2.53(m,1H),2.58-2.80(m,2H),2. 97-3.29(m,2H),4.59(s,2H),7.03-7.16(m,1H),8.01(dt,J=7.5,1.2Hz,1H),8.36(dt,J=5.0,1.2Hz,1H);ESI-MS m / z [M+H] + 386.1.

[0700] Example 60: N-((S)-1-(4-chlorophenyl)ethyl)-2-(1-methylpiperidin-2-yl)acetamide

[0701] [ka]

[0702] To a solution of EtN (0.177 mL, 1.27 mmol), (S)-1-(4-chlorophenyl)ethan-1-amine (0.074 g, 0.477 mmol), and 2-(1-methylpiperidin-2-yl)acetic acid (0.050 g, 0.318 mmol) in DMF (3.18 mL) was added HATU (0.181 g, 0.477 mmol). The mixture was stirred overnight at room temperature, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (74 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ ppm 1.1 9-1.42(m,2H),1.42-1.49(m,3H),1.49-1.75(m,4H),1.75-1.86(m,2H),2.12(tdd,J=11.8,11.8,7.7,2.8Hz,1H),2.17-2.26(m ,2H),2.28(s,2H),2.33(s,2H),2.59-2.80(m,1H),2.88-3.02(m,1H),5.03-5.20(m,1H),7.15-7.38(m,4H),8.80-9.40(m,1H).

[0703] Example 61: N-((S)-1-(4-fluorophenyl)ethyl)-2-(1-methylpiperidin-2-yl)acetamide

[0704] [ka]

[0705] To a solution of EtN (0.177 mL, 1.27 mmol), (S)-1-(4-fluorophenyl)ethan-1-amine (0.066 g, 0.477 mmol), and 2-(1-methylpiperidin-2-yl)acetic acid (0.050 g, 0.318 mmol) in DMF (3.18 mL) was added HATU (0.181 g, 0.477 mmol). The mixture was stirred overnight at room temperature, then diluted with MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound (58 mg, 66%). 1 H NMR (400 MHz, CDCl3) δ ppm 1. 18-1.43(m,2H),1.43-1.50(m,3H),1.50-1.74(m,4H),1.74-1.84(m,2H),2.06-2.17(m,1H),2.17-2.26(m,2H),2.26-2.30(m,2H),2.31 -2.37(m,1H),2.60-2.79(m,1H),2.82-3.04(m,1H),5.13(quin,J=7.2Hz,1H),6.91-7.14(m,2H),7.16-7.34(m,2H),8.80-9.20(m,1H).

[0706] Example 62: 2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0707] [ka]

[0708] To a vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (0.030 g, 0.166 mmol), 2-(1-ethylpyrrolidin-2-yl)acetic acid HCl (0.032 g, 0.166 mmol), HATU (0.063 g, 0.166 mmol), and DIPEA (0.087 mL, 0.499 mmol) in DMF (2 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound as a colorless film (37.2 mg, 52%). 1 H NMR(400MHz,CD3OD)δ ppm 1.31(s,3H),1.46(s,6H),1.66-1.80(m,1H),1.91-2.12(m,2H),2.22(s,4H),2.62-2.77(m,2H),2.99-3.16(m,2H),3. 38-3.49(m,1H),3.60-3.70(m,2H),4.35-4.53(m,2H),6.81-6.88(m,1H),7.46-7.53(m,1H),7.86-7.95(m,1H);ESI-MS m / z [M+H] + 320.3.

[0709] Example 63: 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)acetamide

[0710] [ka]

[0711] To a solution of 2-(1-ethylpyrrolidin-2-yl)acetic acid (15 mg, 0.095 mmol) and HATU (36.3 mg, 0.095 mmol) in DMF (636 μL) was added DIPEA (66.7 μL, 0.382 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropan-1-amine (20.4 mg, 0.114 mmol) was added. The solution was stirred at room temperature for 8 hours and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to give the TFA salt of the title compound as a colorless oil (20 mg, 49%). 1 H NMR(400MHz,CD3OD)δ ppm 0.82-0.90( m,2H),0.95-1.03(m,2H),1.34(t,J=7.3Hz,3H),1.67-1.82(m,1H),1.9 3-2.14(m,2H),2.22(s,3H),2.24-2.35(m,1H),2.58-2.72(m,2H),3.01- 3.22(m,2H),3.43-3.57(m,1H),3.62-3.76(m,2H),4.33-4.50(m,2H),6 .84(dd,J=7.2,5.0Hz,1H),7.45-7.51(m,1H),7.82-7.92(m,1H);ESI-MS m / z [M+H] + 318.0.

[0712] Example 64: 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methyl Pyridin-2-yl)oxy)methyl)cyclobutyl)acetamide

[0713] [ka]

[0714] The TFA salt of the title compound was prepared similarly to Example 63 using 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutan-1-amine (22 mg, 0.114 mmol) and 2-(1-ethylpyrrolidin-2-yl)acetic acid (15 mg, 0.095 mmol) and obtained as a colorless oil (25 mg, 59%). 1 H NMR (400MH z,CD3OD)δ ppm 1.32(t,J=7.2Hz,3H),1.68-1.81(m,1H),1.90-2.10(m,4H),2.21(s,3H),2.27(br dd,J=13.3,5.6Hz,1H),2.34(t,J=7.9Hz,4H ),2.68(d,J=5.6Hz,2H),3.01-3.20(m,2H),3.42-3.53(m,1H),3.61-3.73(m,2H),4.49-4.6 4(m,2H),6.86(dd,J=7.0,5.1Hz,1H),7.50(dd,J=7.1,0.9Hz,1H),7.87-7.96(m,1H);ESI-MS m / z [M+H] + 332.1.

[0715] Example 65: 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentyl)acetamide

[0716] [ka]

[0717] The TFA salt of the title compound was prepared similarly to Example 63 using 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentan-1-amine (23.6 mg, 0.114 mmol) and 2-(1-ethylpyrrolidin-2-yl)acetic acid (15 mg, 0.095 mmol) and obtained as a colorless oil (18 mg, 41%). 1 H NMR (40 0MHz,CD3OD)δ ppm 1.31(t,J=7.3Hz,3H),1.62-1.82(m,5H),1.89-2.14(m,6H),2.21(s,3H),2.23-2.30(m,1H),2.68(d,J=5.5Hz,2H),2.99-3.17(m,2H) ),3.38-3.54(m,2H),3.60-3.71(m,2H),4.37-4.64(m,2H),6.85(dd,J=7.2,5.1Hz,1H),7.43-7.53(m,1H),7.85-7.97(m,1H);ESI-MS m / z [M+H] + 346.1.

[0718] Example 66: (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide and (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)propane amide

[0719] [ka]

[0720] Example 67: (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide and (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide

[0721] [ka]

[0722] To a vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (0.050 g, 0.277 mmol), 2-(1-methylpyrrolidin-2-yl)propanoic acid (0.141 g, 0.277 mmol), HATU (0.105 g, 0.277 mmol), and DIPEA (0.145 mL, 0.832 mmol) in DMF (2 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound. The fast-eluting compound was arbitrarily assigned as a mixture of (S,R)- and (R,S)-enantiomers and was obtained as a colorless film (1.8 mg, 1.5%). 1H NMR(400MHz,CD3OD)δ ppm 1.28-1.35(m ,3H),1.46(s,6H),1.68-1.88(m,2H),1.94-2.04(m,1H),2.22(s,3H),2.24-2.36(m,1H),2.67-2.78(m,1H),2.91(s,3H),3.06-3.17(m, ESI-MS m / z [M+H] + 3 20.3. The slower eluting compound was arbitrarily assigned as a mixture of (S,S)- and (R,R)-enantiomers and was obtained as a colorless film (12.9 mg, 11%). 1 H NMR (400MHz,CD3OD)δ ppm 1.28(dd,J=12.0,7.2Hz,3H),1.43-1.50(m,6H),1.71-2.08(m,3H),2.22(s,4H),2.90(d,J=9.5Hz,4H),3.07-3.16(m,1 ESI-MS m / z [M+H] + 320.3.

[0723] Example 68: 2-(1,5-dimethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0724] [ka]

[0725] Step A: Methyl 2-(1,5-dimethylpyrrolidin-2-yl)acetate

[0726] [ka]

[0727] To a 100 mL round-bottom flask was added methyl 2-(5-methylpyrrolidin-2-yl)acetate HCl (0.250 g, 1.03 mmol) and aqueous formaldehyde (37 wt%, 0.160 mL, 2.06 mmol) in MeOH (6 mL), followed by sodium cyanoborohydride (0.130 g, 2.06 mmol). The mixture was stirred overnight at room temperature and then concentrated to dryness to give the title compound as a white solid (0.177 g, estimated quantitative), which was used without further purification. ESI-MS m / z [M+H] + 172.2.

[0728] Step B: 2-(1,5-Dimethylpyrrolidin-2-yl)acetic acid

[0729] [ka]

[0730] To a 100 mL round-bottom flask was added methyl 2-(1,5-dimethylpyrrolidin-2-yl)acetate (0.177 g, 1.03 mmol) and lithium hydroxide (2 M, 2.07 mL, 4.13 mmol). The resulting brown solution was stirred at room temperature for 5 hours and then filtered. The filtrate was concentrated to dryness to give the title compound as an off-white solid (0.488 g, 33% purity). ESI-MS m / z [M+H] + : 158.2.

[0731] Step C: 2-(1,5-dimethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0732] To a vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (0.100 g, 0.555 mmol), 2-(1,5-dimethylpyrrolidin-2-yl)acetic acid (33%, 0.264 g, 0.183 mmol), HATU (0.211 g, 0.555 mmol), and DIPEA (0.290 mL, 1.66 mmol) in DMF (2 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound (9.3 mg, 11%). 1 H NMR (400M Hz,CD3OD)δ ppm 1.28-1.43(m,4H),1.46(d,J=2.0Hz,6H),1.64-1.88(m,2H),2.10(s,1H),2.22(s,4H),2.63-2.74(m,2H),2.79 (s,3H),3.65-3.93(m,1H),4.33-4.56(m,2H),6.82-6.90(m,1H),7.46-7.53(m,1H),7.85-7.96(m,1H);ESI-MS m / z [M+H] + 320.5.

[0733] Example 69: N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0734] [ka]

[0735] To a vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (68.0 mg, 0.377 mmol), 2-(1-methylpiperidin-2-yl)acetic acid (59.3 mg, 0.377 mmol), HATU (143 mg, 0.377 mmol), and DIPEA (0.197 mL, 1.13 mmol) in DMF (2 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound (31.2 mg, 19%). 1 H NMR (400 MHz, CD3O D)δppm 1.46(d,J=2.9Hz,6H),1.51-1.64(m,2H),1.66-1.77(m,2H),1.82-1.92( m,2H),2.22(s,3H),2.54-2.65(m,1H),2.73-2.80(m,1H),2.85(s,3H),2 .88-3.04(m,1H),3.22-3.28(m,1H),3.38-3.49(m,1H),4.39(s,1H),4.5 5(s,1H),6.80-6.95(m,1H),7.47-7.56(m,1H),7.86-7.95(m,1H);ESI-MS m / z [M+H] + 320.3.

[0736] Example 70: (R)—N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0737] [ka]

[0738] Step A: tert-Butyl (R)-2-(2-((2-(3-methylisoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0739] [ka]

[0740] A mixture of 2-(3-methylisoquinolin-1-yl)propan-2-amine (0.300 g, 1.50 mmol) and (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.344 g, 1.50 mmol) in DMA (7.50 mL) was treated with DIPEA (1.05 mL, 6.00 mmol) and HATU (0.856 g, 2.25 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica column chromatography using a gradient of 10% to 70% EtOAc in heptane. Evaporation of the fractions afforded the title compound (600 mg, 97%). ESI-MS [M+H] + m / z 412.

[0741] Step B: (R)—N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0742] [ka]

[0743] To a round-bottom flask was added 4 M HCl in dioxane (3.64 mL, 14.6 mmol) and a solution of tert-butyl (R)-2-(2-((2-(3-methylisoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (0.600 g, 1.46 mmol) in dioxane (3.6 mL). The reaction mixture was concentrated and the resulting solid was washed with MeOH to give the HCl salt of the title compound (0.452 g), which was used without further purification. ESI-MS m / z [M+H] + 312.3.

[0744] Step C: (R)—N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0745] To a solution of (R)—N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide (0.452 g, 1.45 mmol) and aqueous formaldehyde (37 wt %, 0.108 mL, 1.45 mmol) in MeOH was added acetic acid (0.33 mL, 5.8 mmol). The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.923 g, 4.35 mmol) was added. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was suspended in MeOH and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode) to give the title compound as a white solid (32 mg, 6.8% over two steps). 1 H NMR (400 MHz, CD3OD) δ ppm 1. 38-1.57(m,1H),1.65-1.90(m,9H),2.12-2.24(m,2H),2.29(s,3H),2.39-2.54(m,2H),2.63(s,3H),3.00- 3.07(m,1H),7.42-7.50(m,2H),7.60(t,J=7.5Hz,1H),7.78(d,J=8.2Hz,1H),8.58(d,J=8.6Hz,1H);ESI-MS m / z [M+H] + 326.3.

[0746] Example 71: N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)propanamide

[0747] [ka]

[0748] To a solution of 2-(1-methylpyrrolidin-2-yl)propanoic acid (44.1 mg, 0.084 mmol) and HATU (35.2 mg, 0.093 mmol) in DMF (0.84 mL) was added DIPEA (44.1 μL, 0.252 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropan-1-amine (15 mg, 0.084 mmol) was added. The resulting solution was stirred at room temperature for 16 hours and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to afford the TFA salt of the title compound as a colorless oil (4 mg, 11%). 1 H NMR (400 MHz, CD3OD) δ ppm 0. 83-0.94(m,2H),0.96-1.07(m,2H),1.28(dd,J=14.2,7.2Hz,3H),1.70-1.86(m,1H) ,1.89-2.00(m,1H),2.02-2.15(m,1H),2.24(s,3H),2.27-2.41(m,1H),2.63-2.91(m ,1H),2.95(d,J=5.9Hz,3H),3.10-3.23(m,1H),3.44-3.72(m,2H),4.33-4.55(m,2H) ,6.86(dd,J=7.1,5.1Hz,1H),7.46-7.54(m,1H),7.91(dd,J=5.1,1.2Hz,1H);ESI-MS m / z [M+H] + 318.1.

[0749] Example 72: (S)—N-(2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0750] [ka]

[0751] The TFA salt of the title compound was prepared similarly to Example 71 using 2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-amine (52 mg, 0.210 mmol) and (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (25 mg, 0.175 mmol) and obtained as a white solid (36 mg, 42%). 1 H NMR(400MHz,CD3OD)δ ppm 1.46(d,J=2.6Hz,6 H),1.76-1.87(m,1H),1.89-2.00(m,1H),2.03-2.20(m,1H),2.32(dtd,J= 13.4,8.2,5.5Hz,1H),2.69-2.76(m,2H),2.94(s,3H),3.07-3.19(m,1H),3 .60(tt,J=8.5,5.2Hz,1H),3.65-3.77(m,1H),4.42-4.68(m,2H),7.05(dd ,J=7.8,5.0Hz,1H),7.66-7.75(m,1H),8.12(dd,J=5.0,1.6Hz,1H);ESI-MS m / z [M+H] + 376.2.

[0752] Example 73: (S)—N-(1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0753] [ka]

[0754] The TFA salt of the title compound was prepared similarly to Example 71 using 1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-amine (40 mg, 0.192 mmol) and (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (25 mg, 0.175 mmol) and obtained as a colorless oil (24 mg, 31%). 1 HNM R(400MHz,CD3OD)δ ppm 0.65-0.76(m,2H),0.93-1.02(m,2H),1.50(d,J=2.3Hz,6H),1.71-1.83(m,1H),1.9 2(ddd,J=13.5,8.5,5.2Hz,1H),2.03-2.15(m,2H),2.25-2.36(m,1H),2.72(dd,J=8. 7,5.2Hz,2H),2.93(s,3H),3.06-3.19(m,1H),3.55-3.74(m,2H),4.37-4.63(m,2H) ,6.87(dd,J=7.4,5.0Hz,1H),7.25-7.32(m,1H),7.89(dd,J=5.0,1.8Hz,1H);ESI-MS m / z [M+H] + 332.3.

[0755] Example 74: N-(1-(2-methoxybenzyl)cyclopropyl)-2-(1-methylpiperidin-2-yl)acetamide

[0756] [ka]

[0757] 1-(2-Methoxybenzyl)cyclopropan-1-amine hydrochloride (42.7 mg, 0 To a mixture of DIPEA (105 μL, 0.600 mmol) and 2-(1-methylpiperidin-2-yl)acetic acid (31.4 mg, 0.200 mmol) in DMA (1 mL) was added DIPEA (105 μL, 0.600 mmol) and HATU (114 mg, 0.300 mmol). The reaction mixture was stirred at room temperature for 2 h and then filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex) using a gradient of 20-80% water / ACN in water (basic mode). Purification was performed by Gemini® C18, 5 μm, 30 mm×150 mm. The product-containing fractions were evaporated and lyophilized to give the title compound as an off-white solid (11.0 mg, 17%). 1H NMR(400MHz,CD3OD)δ ppm 0.63-0.74(m,2H),0.76-0.90(m,2H),1.13-1 .41(m,2H),1.43-1.77(m,4H),1.99-2.09(m,1H),2.11-2.27(m,4H),2.35-2.48(m,2H),2.76-2.86(m,1H),2. 96(d,J=2.3Hz,2H),3.81(s,3H),6.88(td,J=7.4,1.1Hz,1H),6.94(d,J=7.9Hz,1H),7.15-7.25(m,2H);ESI-MS m / z [M+H] + 317. 10.

[0758] Example 75: (R)—N-(2-(2-methoxyphenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide

[0759] [ka]

[0760] Example 76: (S)—N-(2-(2-methoxyphenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide

[0761] [ka]

[0762] To a mixture of 2-methyl-3-(pyrrolidin-1-yl)propanoic acid hydrochloride (0.800 g, 4.13 mmol), 2-(2-methoxyphenyl)propan-2-amine (0.683 g, 4.13 mmol), and DIPEA (2.89 mL, 16.5 mmol) in DMF (30 mL) was added HATU (3.14 g, 8.26 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with water (100 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative SFC (ChiralPak IC, 5 μm, 30 mm i.d. × 250 mm) using a mobile phase of iPrOH (with 0.1% NHOH) in CO to give the title enantiomer. The first eluting compound was arbitrarily assigned as the (R)-enantiomer and was obtained as a yellow solid (0.202 g, 16.1%). The second eluting compound was arbitrarily assigned as the (S)-enantiomer and was obtained as a yellow solid (0.219 g, 17.4%). 1 H NMR(400MHz,DMSO-d6)δ ppm 0.98(d,J=6.9Hz,3H),1.61(s,3H),1.65(s, 3H),1.73(br s,4H),2.30-2.42(m,1H),2.50-2 .78(m,6H),6.83(t,J=7.2Hz,1H),6.95(d,J=7.8Hz,1H),7.17(t,J=7.6Hz,1H),7.32(dd,J=7.8,1.6Hz,1H),8.10(s,1H);ESI-MS m / z [M+H] + 3 05.3.

[0763] Example 77: N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetamide

[0764] [ka]

[0765] To a vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (0.060 g, 0.333 mmol), 2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetic acid HCl (0.068 g, 0.333 mmol), HATU (0.127 g, 0.333 mmol), and DIPEA (0.174 mL, 0.999 mmol) in DMF (2 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% water / ACN in water (basic mode). 1 H NMR (400 MHz, CD3OD) δ ppm 1 .45(s,6H),1.60-1.92(m,8H),2.22(d,J=7.1Hz,5H),2.53-2.65(m,2H),2.97(br d,J=10.7Hz, 2H),4.40(s,2H),6.77-6.89(m,1H),7.42-7.52(m,1H),7.85-7.96(m,1H);ESI-MS m / z [M+H] + 332.5.

[0766] Example 78: N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetamide

[0767] [ka]

[0768] The TFA salt of the title compound was prepared in the same manner as in Example 77 using 1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-amine (0.060 g, 0.277 mmol), 2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetic acid HCl (0.057 g, 0.277 mmol), HATU (0.106 g, 0.277 mmol), and DIPEA (0.145 mL, 0.832 mmol) to give a colorless HCl salt. as a semi-solid (68.8 mg, 52%). 1 H NMR (400 MHz, CD3O D)δppm 1.45(s,6H),1.85-2.02(m,6H),2.03-2.15(m,2H),2.68(s,2H),3.08-3.19(m,2H),3.56-3.67(m,2 ESI-MS m / z [M+H] + 368.3.

[0769] Example 79: N-(1-((2-methoxypyridin-3-yl)methyl)cyclopropyl)-2-(1-methylpiperidin-2-yl)acetamide

[0770] [ka]

[0771] To a mixture of 1-((2-methoxypyridin-3-yl)methyl)cyclopropan-1-amine hydrochloride (91.0 mg, 0.511 mmol) and 2-(1-methylpiperidin-2-yl)acetic acid (80.0 mg, 0.511 mmol) in DMA (2.55 mL) was added DIPEA (268 μL, 1.53 mmol) and HATU (291 mg, 0.766 mmol). The reaction mixture was stirred at room temperature for 2 h and then filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, rinsing with methanol. The filtrate was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–60% water / ACN in water (basic mode). The product-containing fractions were evaporated and lyophilized to give the title compound as a pale yellow solid, 58.8 mg, 36%). 1 H NMR (400 MHz, CD 3OD)δ ppm 0.69-0.77(m,2H),0.82-0.90(m,2H),1.13-1.39(m,2H),1.46-1.74(m,4H),1.99-2.10(m,1H),2.21(s,4H),2.37-2.49(m,2H),2.81(br d,J=10.8Hz,1H),2.92(s,2H),3.93(s,3H) ,6.91(dd,J=7.2,5.1Hz,1H),7.57(dd,J=7.2,1.9Hz,1H),8.01(dd,J=5.1,1.9Hz,1H);ESI-MS m / z [M+H] + 318.30.

[0772] Example 80: (S)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0773] [ka]

[0774] Step A: tert-Butyl (S)-2-(2-((2-(2,3-dichlorophenyl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0775] [ka]

[0776] To a vial was added (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.150 g, 0.654 mmol), 2-(2,3-dichlorophenyl)propan-2-amine (0.134 g, 0.654 mmol), HATU (249 mg, 0.654 mmol), and EtN (91 μL, 0.654 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 5 h, then diluted with water (20 mL) and extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated in vacuo to give the title compound (272 mg, estimated quantitative), which was used without further purification. ESI-MS m / z [M+H] + 415.3.

[0777] Step B: (S)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0778] [ka]

[0779] To a vial containing a solution of tert-butyl (S)-2-(2-((2-(2,3-dichlorophenyl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (272 mg, 0.655 mmol) in dioxane (1.64 mL) was added 4 M HCl in dioxane (1.64 mL, 6.55 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The solid was washed with MeOH to give the HCl salt of the title compound (230 mg, assumed quantitative), which was used without further purification. ESI-MS m / z [M+H] + 315.2.

[0780] Step C: (S)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0781] To a solution of (S)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide HCl (230 mg, 0.655 mmol) and formaldehyde (73.0 μL, 0.980 mmol) in MeOH (4 mL) was added acetic acid (150 μL, 2.61 mmol). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (415 mg, 1.96 mmol) was then added. The reaction mixture was stirred overnight at room temperature and then filtered and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% ACN in water (acid mode) to afford the TFA salt of the title compound as a clear oil (4.0 mg, 1.4% over three steps). 1 H NMR (40 0MHz,CD3OD)δ ppm 1.79(d,J=3.8Hz,6H),1.89-2.01(m,1H),2.03-2.19(m,1H),2.27-2.38(m,1H),2.77(d,J=5.4Hz,2H),2.87(s,3H),3.09(dt, ESI-MS m / z [M+H] + 32 9.2.

[0782] Example 81: (S)—N-(1-(3-methylbenzyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0783] [ka]

[0784] The title compound was prepared analogously to Example 80 using 1-(3-methylbenzyl)cyclopropan-1-amine (141 mg, 0.872 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (200 mg, 0.872 mmol), EtN (243 μL, 1.74 mmol), and HATU (332 mg, 0.872 mmol) in DMF. In Step C, the reaction did not proceed to completion at room temperature, so the reaction mixture was heated at 45° C. for 1 h before purification. The title compound was obtained as a white solid (11 mg, 4.4% over three steps). 1 H NMR (400 MHz) ,CD3OD)δ ppm 0.69-0.86(m,3H),1.37-1.49(m,1H),1.62-1.77(m,2H),1.90-2.10(m,2H),2 .18-2.29(m,4H),2.33(s,3H),2.36-2.52(m,2H),2.82-2.93(m,2H),3.00(br t,J=8.4Hz,1H),7.0 0-7.07(m,3H),7.16(t,J=7.0Hz,1H);ESI-MS m / z [M+H] + 287.3.

[0785] Example 82: (S)—N-(2-(2,3-difluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0786] [ka]

[0787] The TFA salt of the title compound was prepared similarly to Example 80 using 2-(2,3-difluorophenyl)propan-2-amine (112 mg, 0.654 mmol) and obtained as a clear oil (16 mg, 6.2% over three steps). 1 H NMR (400 MHz, CD 3OD)δ ppm 1.72-1.85(m,7H),1.89-2.03(m,1H),2.04-2.20(m,1H),2.23-2.39(m,1H),2.68-2.85(m ,2H),2.90(s,3H),3.11(dt,J=11.5,8.3Hz,1H),3.54-3.71(m,2H),7.07-7.23(m,3H);ESI -MS m / z [M+H] + 297.3.

[0788] Example 83: (S)—N-(2-(3-chloro-2-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0789] [ka]

[0790] The TFA salt of the title compound was prepared similarly to Example 80 using 2-(3-chloro-2-fluorophenyl)propan-2-amine (123 mg, 0.654 mmol) and obtained as a clear oil (48 mg, 17% over 3 steps). 1 H NMR (400 MHz, CD3OD)δ ppm 1.71-1.86(m,7H),1.89-2.15(m,2H),2.33(dtd,J=13.3,8.2,8.2,5.6Hz,1H),2.67-2.86(m,2H),2.89(s,3 ESI-MS m / z [M+H] + 313.2.

[0791] Example 84: (R)—N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0792] [ka]

[0793] To a vial was added 1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-amine (0.070 g, 0.324 mmol), (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (0.046 g, 0.324 mmol), HATU (0.123 g, 0.324 mmol), and DIPEA (0.169 mL, 0.971 mmol) in DMF (3 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a colorless film (35.4 mg, 32%). 1 H NMR(400MHz,CD3OD)δ ppm 1.42(s,6H),1 .47-1.58(m,1H),1.64-1.77(m,2H),1.83-2.00(m,1H),2.09-2.25(m,2H),2.28(s,3H),2.39-2.54(m,2H),2.95-3. 07(m,1H),4.52(d,J=0.8Hz,2H),6.75-6.94(m,1H),7.02-7.10(m,1H),7.85-7.94(m,1H),8.18-8.28(m,1H);ESI-MS m / z [M+H] + 342.2.

[0794] Example 85: (S)—N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0795] [ka]

[0796] To a vial was added 1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-amine (0.070 g, 0.324 mmol), (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (0.046 g, 0.324 mmol), HATU (0.123 g, 0.324 mmol), and DIPEA (0.169 mL, 0.971 mmol) in DMF (3 mL). The resulting yellow solution was stirred overnight at room temperature and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–50% ACN in water (acid mode) to give the TFA salt of the title compound as a colorless film (29.5 mg, 20%). 1 H NMR(400MHz,CD3OD)δ ppm 1.44(d,J=0. 6Hz,6H),1.69-1.82(m,1H),1.89-2.10(m,2H),2.21-2.34(m,1H),2.67-2.74(m,2H),2.90(s,3H),3.04-3.16(m,1H),3.52-3.61(m,1H) ESI-MS m / z [M+H] + 3 42.2.

[0797] Example 86: (S)—N-(2-(2-fluoro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0798] [ka]

[0799] To a vial was added (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (30 mg, 0.21 mmol), 2-(2-fluoro-3-methylphenyl)propan-2-amine (35 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), and EtN (29 μL, 0.21 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for several hours, then diluted with water and extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as a clear oil (26 mg, 30%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.72(d,J=2.5Hz,6H),1.88-2.00(m,1H),2 .02-2.18(m,1H),2.24(d,J=2.5Hz,3H),2.69-2.82(m,2H),2.89(s,3H),3.10(dt,J=11.4,8.4Hz,1H) ,3.54-3.70(m,2H),7.00(t,J=7.6Hz,1H),7.12(t,J=6.9Hz,1H),7.22(td,J=7.9,1.4Hz,1H);ESI-MS m / z [M+H] + 293.2.

[0800] Example 87: (R)—N-(2-(2-fluoro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0801] [ka]

[0802] The TFA salt of the title compound was prepared similarly to Example 86 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (30 mg, 0.21 mmol) and obtained as a clear oil (26 mg, 30%). 1 H NMR (400 MHz, CD3OD) δ ppm 1. 72(d,J=2.5Hz,6H),2.03-2.18(m,1H),2.24(d,J=2.5Hz,3H),2.67-2.83(m,2H),2.89(s,3H),3.10(dt,J=11. ESI-MS m / z [M+H] + 293. 2.

[0803] Example 88: (S)—N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0804] [ka]

[0805] The TFA salt of the title compound was prepared similarly to Example 86 using 2-(2-chloro-3-methylphenyl)propan-2-amine (38.5 mg, 0.21 mmol) and obtained as a clear oil (23 mg, 26%). 1 H NMR(400MHz,CD3OD)δ ppm 1.26(d,J=7.0Hz,3H),1.81(s,6H),1.91-2 .17(m,4H),2.38(s,3H),2.88-3.15(m,4H),3.34-3.41(m,1H),3.57(br s,2H),7.16-7.24(m,2 H),7.43(dd,J=7.5,2.1Hz,1H);ESI-MS m / z [M+H] + 309.2.

[0806] Example 89: (S)—N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0807] [ka]

[0808] The TFA salt of the title compound was prepared similarly to Example 86 using 2-(3-fluoro-2-methylphenyl)propan-2-amine (35 mg, 0.21 mmol) and obtained as a clear oil (30 mg, 35%). 1 H NMR(400MHz,CD3OD)δ ppm 1.71-1.84(m,6H),1.94-2.20(m,2H),2.29- 2.44(m,4H),2.69-2.85(m,2H),2.89(s,3H),3.10(dt,J=11.5,8.2Hz,1H),3.53-3.72 (m,2H),6.93(t,J=8.7Hz,1H),7.15(td,J=7.9,6.3Hz,1H),7.21-7.26(m,1H);ESI-MS m / z [M+H] + 293.2 .

[0809] Example 90: (R)—N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0810] [ka]

[0811] The TFA salt of the title compound was prepared similarly to Example 86 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (30 mg, 0.21 mmol) and 2-(3-fluoro-2-methylphenyl)propan-2-amine (35 mg, 0.21 mmol) and obtained as a clear oil (31 mg, 36%). 1 H NMR (400 MHz, CD3OD) δppm 1.71-1.84(m,6H),1.94-2.20(m,2H),2.29-2.44(m,4H),2.69-2.86(m,2H),2.89(s,3H),3.10(dt,J=11.4, 8.3Hz,1H),3.53-3.71(m,2H),6.93(t,J=9.0Hz,1H),7.15(td,J=8.1,6.1Hz,1H),7.21-7.26(m,1H),ESI-MS m / z [M+H] + 293 .2.

[0812] Example 91: (R)—N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0813] [ka]

[0814] The TFA salt of the title compound was prepared similarly to Example 86 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (150 mg, 1.05 mmol), 2-(2-chloro-3-methylphenyl)propan-2-amine (192 mg, 1.05 mmol), HATU (398 mg, 1.05 mmol), and EtN (146 μL, 1.05 mmol) in DMF (2 mL) and obtained as a clear oil (19 mg, 4.3%). 1 HNM R(400MHz,CD3OD)δ ppm 1.79(d,J=2.9Hz,6H),2.03-2.14(m,1H),2.28-2.39(m,4H),2.68-2.83(m,2H),2.86(s,3H),3.09 (dt,J=11.5,8.3Hz,1H),3.52-3.69(m,2H),7.15-7.23(m,2H),7.41(dd,J=7.4,2.1Hz,1H);ESI-MS m / z [M+H] + 309. 2.

[0815] Example 92: (S)—N-(2-(2,3-dimethylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0816] [ka]

[0817] The TFA salt of the title compound was prepared similarly to Example 86 using (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (30 mg, 0.21 mmol), 2-(2,3-dimethylphenyl)propan-2-amine (34.2 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), and EtN (58 μL, 0.42 mmol) in DMF (2 mL) and obtained as a clear oil (40 mg, 47%). 1 H NMR (400M Hz,CD3OD)δ ppm 1.75(d,J=7.2Hz,6H),1.91-2.16(m,2H),2.25-2.40(m,6H),2.67-2.82(m,2H),2.88(s,3H),3. 09(dt,J=11.5,8.3Hz,1H),3.52-3.70(m,2H),7.01-7.08(m,2H),7.28(d,J=6.5Hz,1H);ESI-MS m / z [M+H] + 289.4.

[0818] Example 93: (S)—N-(2-(2-chloro-3-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0819] [ka]

[0820] The TFA salt of the title compound was prepared similarly to Example 86 using 2-(2-chloro-3-fluorophenyl)propan-2-amine (39.3 mg, 0.21 mmol) and obtained as a clear oil (33 mg, 37%). 1 H NMR (400 MHz, CD3OD) δppm 1.78(d,J=4.8Hz,6H),1.90-2.15(m,2H),2.27-2.38(m,1H),2.72-2.90(m,5H),3.10(dt, J=11.5,8.3Hz,1H),3.52-3.70(m,2H),7.13(t,J=8.3Hz,1H),7.27-7.41(m,2H),8.73(br s,1H );ESI-MS m / z [M+H] + 313.3.

[0821] Example 94: (R)—N-(2-(2-chloro-3-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0822] [ka]

[0823] The TFA salt of the title compound was prepared similarly to Example 86 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (30 mg, 0.21 mmol) and 2-(2-chloro-3-fluorophenyl)propan-2-amine (39.3 mg, 0.21 mmol) and obtained as a clear oil (31 mg, 35%). 1 H NMR (400 MHz, CD3O D)δppm 1.78(d,J=4.8Hz,6H),1.91-2.15(m,2H),2.27-2.38(m,1H),2.72-2.90(m,5H),3.10(dt, J=11.5,8.3Hz,1H),3.52-3.70(m,2H),7.13(t,J=8.4Hz,1H),7.27-7.40(m,2H),8.73(br s, 1H);ESI-MS m / z [M+H] + 313.3.

[0824] Example 95: N-((S)-1-(4-fluoro-2-methoxyphenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide

[0825] [ka]

[0826] The TFA salt of the title compound was prepared by addition of (S)-2-(1-methylpyrrolidine) Prepared as in Example 86 using (S)-1-(4-fluoro-2-methoxyphenyl)ethan-1-amine (41.4 mg, 0.244 mmol), (S)-1-(4-fluoro-2-methoxyphenyl)ethan-1-amine (41.4 mg, 0.244 mmol), HATU (93 mg, 0.244 mmol), and EtN (34.1 μL, 0.244 mmol) and obtained as a clear oil (15 mg, 15%). 1 H NMR(400MHz,CD3OD)δ ppm 1.45(d,J=7.0 Hz,3H),1.71-1.88(m,1H),1.91-2.05(m,1H),2.05-2.19(m,1H),2.28-2.41(m,1H),2.69-2.87(m,2H),2.94(s,3 ESI-MS m / z [M+H] + 295.3.

[0827] Example 96: (R)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0828] [ka]

[0829] The TFA salt of the title compound was prepared similarly to Example 86 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (35 mg, 0.244 mmol), 2-(2,3-dichlorophenyl)propan-2-amine (49.9 mg, 0.244 mmol), HATU (93 mg, 0.244 mmol), and EtN (34.1 μL, 0.244 mmol) in DMF (2 mL) and obtained as a clear oil (17 mg, 16%). 1 HNM R(400MHz,CD3OD)δ ppm 1.79(d,J=3.9Hz,6H),1.90-2.15(m,2H),2.33(dtd,J=13.3,8.2,5.4Hz,1H),2.71-2.89(m,5H),3.09(dt,J=11.5,8 ESI-MS m / z [M+H] + 329.3.

[0830] Example 97: 2-(3,3-difluoro-1-methylpyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[0831] [ka]

[0832] Step A: tert-Butyl 3,3-difluoro-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0833] [ka]

[0834] To a vial was added 2-(1-(tert-butoxycarbonyl)-3,3-difluoropyrrolidin-2-yl)acetic acid (150 mg, 0.565 mmol), 2-(isoquinolin-1-yl)propan-2-amine (105 mg, 0.565 mmol), HATU (215 mg, 0.565 mmol), and EtN (158 μL, 1.131 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for several hours and then extracted with EtOAc. The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo to give the title compound (245 mg, estimated quantitative), which was used without further purification.

[0835] Step B: 2-(3,3-Difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[0836] [ka]

[0837] To a vial containing tert-butyl 3,3-difluoro-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (245 mg, 0.565 mmol) in dioxane (1.41 mL) was added 4 M HCl in dioxane (1.41 mL, 5.65 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo to provide the HCl salt of the title compound (209 mg, assumed quantitative), which was used without further purification.

[0838] Step C: 2-(3,3-Difluoro-1-methylpyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[0839] To a solution of 2-(3,3-difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide (209 mg, 0.565 mmol) and formaldehyde (63.0 μL, 0.846 mmol) in MeOH (3.76 mL) was added acetic acid (129 μL, 2.256 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (359 mg, 1.69 mmol) was added. The reaction mixture was stirred overnight at room temperature, then filtered and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a clear oil (5 mg, 2.5% over three steps). 1 H NMR (40 0MHz,CD3OD)δ ppm 2.04(d,J=1.5Hz,6H),2.31-2.50(m,1H),2.51-2.67(m,1H),2.75-2.83(m,3 H),2.88-3.03(m,2H),3.35-3.50(m,1H),3.73(ddd,J=11.8,8.5,3.5Hz,1H),3.91(tt,J=12.3,6.0Hz,1H), 7.91-7.97(m,1H),8.06-8.12(m,1H),8.21-8.27(m,2H),8.42(d,J=6.40Hz,1H),8.91-8.97(m,1H);ESI-MS m / z [M+H] + 348.4.

[0840] Example 98: 2-(3,3-difluoro-1-methylpyrrolidin-2-yl)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)acetamide

[0841] [ka]

[0842] The title compound was prepared analogously to Example 97 using 2-(5-methylisoquinolin-1-yl)propan-2-amine (113 mg, 0.565 mmol) and obtained as a pale beige solid (14 mg, 6.9% over three steps). 1 H NMR (400 MHz, C D3OD)δ ppm 1.89(d,J=3.1Hz,6H),2.14-2.37(m,7H),2.45-2.59(m,1H),2.66-2.79(m,4H),3.00-3.10(m,1H), 7.44-7.56(m,2H),7.81(dd,J=5.9,0.9Hz,1H),8.41(d,J=6.0Hz,1H),8.54(d,J=8.7Hz,1H);ESI-MS m / z [M+H] + 362.4.

[0843] Example 99: 2-(3,3-difluoro-1-methylpyrrolidin-2-yl)-N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)acetamide

[0844] [ka]

[0845] The title compound was prepared analogously to Example 97 using 2-(furo[3,2-c]pyridin-4-yl)propan-2-amine (100 mg, 0.565 mmol) and obtained as an orange solid (8 mg, 4.2% over 3 steps). 1 H NMR (400 MHz, CD3O D)δppm 1.78(d,J=3.9Hz,6H),2.19-2.44(m,7H),2.54-2.66(m,1H),2.83(td,J=11.5,5.6Hz,1H),3.03-3.16(m,1H), 7.16(dd,J=2.4,1.0Hz,1H),7.46(dd,J=5.8,1.0Hz,1H),7.84(d,J=2.3Hz,1H),8.34(d,J=5.8Hz,1H);ESI-MS m / z [M+H] + 338.3.

[0846] Example 100: 2-(3,3-difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[0847] [ka]

[0848] Step A: tert-Butyl 3,3-difluoro-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0849] [ka]

[0850] To a 20 mL vial was added 2-(1-(tert-butoxycarbonyl)-3,3-difluoropyrrolidin-2-yl)acetic acid (75 mg, 0.283 mmol), 2-(isoquinolin-1-yl)propan-2-amine (52.7 mg, 0.283 mmol), HATU (108 mg, 0.283 mmol), and EtN (79 μL, 0.565 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for several hours and then extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated in vacuo to give the title compound (123 mg, 0.284 mmol), which was used without further purification. ESI-MS m / z [M+H] + 434.5.

[0851] Step B: 2-(3,3-Difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[0852] To a 20 mL vial containing tert-butyl 3,3-difluoro-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (123 mg, 0.284 mmol) in dioxane (709 μL) was added 4 M HCl in dioxane (709 μL, 2.84 mmol). The reaction mixture was stirred overnight at room temperature, then washed with MeOH and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm i.d. × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as an orange oil (3 mg, 3.2% over two steps). 1 H NMR (40 0MHz,CD3OD)δ ppm 1.87-1.95(m,6H),2.04-2.28(m,2H),2.36(ddd,J=15.4,8.8,1.1Hz,1H),2.54(dd,J=15.4,4.6Hz,1H),2.89-2.97(m,1H),3.01-3 .18(m,1H),3.26-3.32(m,1H),7.57-7.71(m,3H),7.91(d,J=8.2Hz,1H),8.37(d,J=5.6Hz,1H),8.68(dd,J=8.7,0.8Hz,1H);ESI-MS m / z [M+H] + 334.3.

[0853] Example 101: 2-(3,3-difluoropyrrolidin-2-yl)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)acetamide

[0854] [ka]

[0855] The title compound was prepared analogously to Example 100 using 2-(5-methylisoquinolin-1-yl)propan-2-amine (56.6 mg, 0.283 mmol) and obtained as a white film (4 mg, 4.2% over two steps). 1 H NMR (400 MHz, CD 3OD)δ ppm 2.03-2.09(m,6H),2.41-2.62(m,2H),2.77-2.87(m,4H),2.98(dd,J=17.1,4.3Hz,1H),3.35-3.49(m,2H),3.92- 4.02(m,1H),7.88(dd,J=8.9,7.2Hz,1H),8.01(d,J=7.2Hz,1H),8.46-8.51(m,2H),8.86(d,J=8.7Hz,1H);ESI-MS m / z [M+H] + 348.4.

[0856] Example 102: (S)—N-(2-methyl-1-((4-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0857] [ka]

[0858] To a solution of (S)—N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (25 mg, 0.117 mmol) in DMF (1.17 mL) was added NaH (60 wt%, 7.0 mg, 0.175 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Next, 2-fluoro-4-methylpyridine (14.3 mg, 0.128 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then quenched with 1N aqueous HCl (0.15 mL) and purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm ID × 150 mm) using a gradient of 10–70% water / ACN in water (basic mode). The title compound was obtained as a colorless oil (5.8 mg, 16%). 1 H NMR (400 MHz, CD3 OD)δ ppm 1.43(d,J=3.0Hz,6H),1.50-1.65(m,1H),1.70-1.87(m,2H),1.91-2.01(m, 1H),2.11-2.28(m,2H),2.31(s,3H),2.33(s,3H),2.38-2.45(m,1H),2.51(q d,J=8.0,4.5Hz,1H),3.02(ddd,J=9.6,7.3,2.8Hz,1H),4.27-4.42(m,2H),6 .66(dt,J=1.4,0.7Hz,1H),6.77-6.87(m,1H),7.96(d,J=5.3Hz,1H);ESI-MS m / z [M+H] + 306.2.

[0859] Example 103: (S)—N-(2-methyl-1-((5-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0860] [ka]

[0861] The title compound was prepared in the same manner as in Example 102 using (S)—N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (25 mg, 0.117 mmol) and 2-fluoro-5-methylpyridine (14 mg, 0.128 mmol) and obtained as a colorless oil (6.7 mg, 19%). 1 HN MR(400MHz,CD3OD)δ ppm 1.32(d,J=3.01Hz,6H),1.39-1.52(m,1H),1.60-1.73(m,2H),1.80-1.93(m, 1H),2.07-2.14(m,2H),2.15(s,3H),2.22(s,3H),2.27-2.35(m,1H),2.43(br dd,J=6.3, 1.9Hz,1H),2.88-2.98(m,1H),4.17-4.29(m,2H),6.61(d,J=8.3Hz,1H),7.38-7.47(m,1H),7.81(dt,J=2.5,0.8Hz,1H);ESI-MS m / z [M+H] + 30 6.2.

[0862] Example 104: (S)—N-(2-methyl-1-((6-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0863] [ka]

[0864] The title compound was prepared similarly to Example 102 using (S)—N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (25 mg, 0.117 mmol) and 2-fluoro-6-methylpyridine (14 mg, 0.128 mmol) and obtained as a colorless oil (10 mg, 28%). 1 HNM R(400MHz,CD3OD)δ ppm 1.32(d,J=2.1Hz,6H),1.41-1.51(m,1H),1.56-1.72(m,2H),1.81-1.95(m,1H),2.06-2.21(m,2H),2.24(s,3H),2.29-2.35(m,4H),2.47(br dd,J=10.5,5.1Hz,1H),2. 90-3.00(m,1H),4.25(d,J=1.4Hz,2H),6.43-6.53(m,1H),6.70(d,J=7.1Hz,1H),7.45(dd,J=8.2,7.3Hz,1H);ESI-MS m / z [M+H] + 306.2.

[0865] Example 105: (S)—N-(1-((4-chloro-5-fluoropyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0866] [ka]

[0867] The title compound was prepared similarly to Example 102 using (S)—N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (25 mg, 0.117 mmol) and 4-chloro-2,5-difluoropyridine (19 mg, 0.128 mmol) and obtained as a white solid (8 mg, 20%). 1 HN MR(400MHz,CD3OD)δ ppm 1.42(d,J=2.4Hz,6H),1.52-1.65(m,1H),1.72-1.87(m,2H),1.92-2.05(m,1H),2.18-2.33(m,2H),2.36(s,3H),2.41-2.49(m,1H),2.58(br d,J=2.4Hz,1H),3.08(br t,J=6.2Hz,1H),4.35-4.47(m,2H),6.98(d,J=4.9Hz,1H),8.10(d,J=1.1Hz,1H);ESI-MS m / z [M+H] + 345.10.

[0868] Example 106: (R)—N-(2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0869] [ka]

[0870] To a solution of (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (25 mg, 0.175 mmol) and HATU (66.4 mg, 0.175 mmol) in DMF (1.16 mL) was added DIPEA (122 μL, 0.698 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Next, 2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-amine (48.1 mg, 0.192 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then purified by preparative HPLC (Phenomenex Gemini® C18, 5 μm, 30 mm ID × 150 mm) using a gradient of 10 to 100% water / ACN in water (basic mode) to give the title compound as a colorless oil (18 mg, 28%). 1 H NMR (400 MHz, CD3OD) δppm 1.44(d,J=1.2Hz,6H),1.52-1.62(m,1H),1.68-1.85(m,2H),1.91-2.0 3(m,1H),2.14-2.28(m,2H),2.32(s,3H),2.40-2.46(m,1H),2.47-2.5 6(m,1H),3.04(ddd,J=9.7,7.2,2.9Hz,1H),4.54(s,2H),7.04(dd,J=7.9,5.0Hz,1H),7.65-7.70(m,1H),8.11(dd,J=5.0,1.6Hz,1H);ESI-MS m / z [M+H] + 376.20.

[0871] Example 107: (R)—N-(1-((3-ethoxypyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamine Do

[0872] [ka]

[0873] The title compound was prepared in the same manner as in Example 106 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (25 mg, 0.175 mmol) and 2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-amine (40 mg, 0.192 mmol) and obtained as a colorless oil (24 mg, 41%). 1 HN MR(400MHz,CD3OD)δ ppm 1.42(t,J=7.0Hz,3H),1.45(d,J=3.6Hz,6H),1.51-1.63(m,1H),1.66-1.84(m,2H),1 .89-2.04(m,1H),2.14-2.27(m,2H),2.31(s,3H),2.38-2.45(m,1H),2.47-2.55(m,1H) ),3.01(ddd,J=9.6,7.5,2.6Hz,1H),4.09(q,J=7.0Hz,2H),4.36-4.50(m,2H),6.89(d d,J=7.8,5.0Hz,1H),7.23(dd,J=7.8,1.6Hz,1H),7.65(dd,J=5.1,1.6Hz,1H);ESI-MS m / z [M+H] + 3 36.2.

[0874] Example 108: (R)—N-(1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0875] [ka]

[0876] The title compound was prepared in a similar manner to Example 106 using (R)-2-(1-methylpyrrolidin-2-yl)acetic acid (25 mg, 0.175 mmol) and 1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-amine (39.6 mg, 0.192 mmol) and obtained as a colorless oil (21 mg, 36%). 1 H NMR( 400MHz,CD3OD)δ ppm 0.63-0.74(m,2H),0.90-1.06(m,2H),1.48(d,J=1.6Hz,6H),1.52-1.61(m,1H),1.69-1 .80(m,2H),1.90-2.01(m,1H),2.07-2.25(m,3H),2.31(s,3H),2.41-2.48(m,1H),2.51 (dd,J=8.0,4.5Hz,1H),3.01(ddd,J=9.7,7.1,3.1Hz,1H),4.44(d,J=0.9Hz,2H),6.86( dd,J=7.4,5.0Hz,1H),7.26(dd,J=7.3,1.8Hz,1H),7.89(dd,J=5.0,1.8Hz,1H);ESI-MS m / z [M+H] + 332.2.

[0877] Example 109: (S)—N-(1-((3-ethoxypyridin-2-yl)oxy)- 2-methylpropa...

Claims

1. A compound of formula 1, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, (a) X ３ is NR ３Ｎ and O, and X ４ is a single bond, and X ５ is N and CR ５ Selected from: R １ and R ２ together with the carbon atoms to which they are attached form a fused ring which is benzene, wherein each non-fused carbon atom of said fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or (b) X ３ is CR ３Ｃ and X ４ is N and CR ４ is selected from X ５ is N and CR ５ Selected from: R １ and R ２ are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or R １ and R ２ together with the carbon atoms to which they are attached form a fused ring selected from furan, pyrazole, and benzene, wherein one of the nitrogen atoms of the pyrazole ring is selected from hydrogen, C １－４ Alkyl or C ３－６ cycloalkyl, wherein each non-fused carbon atom of said fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); L is O and n is 1; or L is a single bond and n is 0 or 1; R ３Ｎ is hydrogen, C １－４ Alkyl, and C ３－６ cycloalkyl; R ３Ｃ and R ４ are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R ５ is selected from the following: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R ６ is hydrogen; or R ５ and R ６ together form ethane-1,2-diyl bridging the carbon atoms to which they are attached; R ７ and R ８ are each independently hydrogen and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo), where R ７ and R ８ At least one of is not hydrogen, or R ７ and R ８ together with the carbon atoms to which they are attached. ３－６ forming a cycloalkylidene; R ９ is hydrogen and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo); R １０ is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, and a heterocyclyl having the formula: 【Chemistry 2】 During the ceremony, 【Transformation 3】 indicates the attachment point, r is selected from 0 and 1; R １１ is hydrogen, and R １２ is hydrogen, and C １－４ Alkyl and C ３－６ cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo), with the proviso that R １２ is hydrogen, R １ and R ２ form a fused ring; or R １１ and R １２ together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached; R １３ , R １４ , R １５ , and R １６ are each independently hydrogen, halo, and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo), or R １３ and R １６ does not exist, and R １４ and R １５ together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R １７ and R １８ are each independently hydrogen, halo, and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo). wherein the compound of formula 1 is: 2-(1-methylpiperidin-2-yl)-N-(1-(m-tolyl)cyclopropyl)acetamide; N-(1-(pyridin-3-yl)pentyl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(6-methylpyridin-2-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide; 2-(1-methylpyrrolidin-2-yl)-N-(1-phenylethyl)acetamide; 2-(1-methylpiperidin-2-yl)-N-(1-phenylethyl)acetamide; N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propanamide; N-(2-phenylpropan-2-yl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(4-methylpyridin-2-yl)propyl)-3-(pyrrolidin-1-yl)propenamide; or N-(1-(naphthalen-1-yl)ethyl)-2-(pyrrolidin-2-yl)acetamide A compound of formula 1 or a pharmaceutically acceptable salt thereof, provided that:

2. X ３ NR ３Ｎ and O, and X ４ is a single bond, and X ５ N and CR ５ 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

3. R １ and R ２ each non-fused carbon atom of said fused ring formed by is unsubstituted or independently selected from halo and C １－３ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl (substituted with 0 to 3 optional substituents independently selected from halo).

4. R ３Ｎ is C １－３ 4. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein:

5. X ３ NR ３Ｎ and O, and X ４ is a single bond, and X ５ 5. The compound of claim 2, wherein is N, or a pharmaceutically acceptable salt thereof.

6. 6. The compound of any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein L is a single bond and n is 0.

7. X ３ is CR ３Ｃ and X ４ N and CR ４ is selected from X ５ N and CR ５ 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

8. R １ and R ２ are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof.

9. R １ and R ２ together with the carbon atoms to which they are attached form a fused ring selected from furan, pyrazole, and benzene, wherein one of the nitrogen atoms of the pyrazole ring is hydrogen, C １－４ Alkyl, or C ３－６ cycloalkyl, wherein each non-fused carbon atom of said fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof.

10. R １ and R ２ and each non-fused carbon atom of the fused ring formed by or independently halo and C １－３ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl (substituted with 0 to 3 optional substituents independently selected from halo).

11. R ３Ｃ and R ４ are each independently selected from: (i) hydrogen and halo; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); 11. A compound according to any one of claims 7 to 10, or a pharmaceutically acceptable salt thereof.

12. R ５ is selected from: (i) hydrogen and halo; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); 12. A compound according to any one of claims 7 to 11, or a pharmaceutically acceptable salt thereof.

13. R ７ and R ８ are each independently hydrogen and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo), where R ７ and R ８ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein at least one of is not hydrogen.

14. R ７ and R ８ or a pharmaceutically acceptable salt thereof, wherein together with the carbon atom to which they are attached form a cyclopropylidene, cyclobutylidene, and cyclopentylidene.

15. R ９ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, methyl, ethyl, and isopropyl.

16. R １０ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is azetidin-1-ylmethyl.

17. R １０ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is pyrrolidin-1-ylmethyl.

18. R １０ is a heterocyclyl having the formula 【Chemistry 4】 During the ceremony, 【Transformation 5】 indicates the attachment point, r is selected from 0 and 1; R １１ is hydrogen, and R １２ is hydrogen, and C １－４ Alkyl and C ３－６ cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo), with the proviso that R １２ is hydrogen, R １ and R ２ form a fused ring; or R １１ and R １２ together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached; R １３ , R １４ , R １５ , and R １６ are each independently hydrogen, halo, and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo), or R １３ and R １６ does not exist, and R １４ and R １５ together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R １７ and R １８ are each independently hydrogen, halo, and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo); 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

19. R １１ is hydrogen, and R １２ But C １－４ Alkyl and C ３－６ 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo).

20. R １１ is hydrogen, and R １２ is selected from methyl, ethyl, isopropyl, and cyclopropyl, each independently substituted with 0 to 3 optional substituents selected from halo, or a pharmaceutically acceptable salt thereof.

21. R １３ , R １４ , R １５ , and R １６ 21. The compound of any one of claims 18 to 20, or a pharmaceutically acceptable salt thereof, wherein: are each independently selected from hydrogen and methyl.

22. R １７ and R １８ 22. The compound of any one of claims 18 to 21, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from hydrogen, fluoro, and methyl.

23. The following compounds: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(isoquinolin-1-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide; N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (S)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetamide; N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (S)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)acetamide; (S)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide; (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; 2-(1-ethylpyrrolidin-2-yl)-N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)acetamide; N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-((S)-1-(4-chlorophenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; N-((S)-1-(4-fluorophenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-((S)-1-(4-chlorophenyl)ethyl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide; N-((S)-1-(4-fluorophenyl)ethyl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-(2-(4-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (S)—N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; 2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; (S)-2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; (S)-2-(1-(2-fluoroethyl)pyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; (S)-2-(1-cyclopropylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutyl (1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentyl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)-2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; (R)-2-(1-(2-fluoroethyl)pyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; (R)-2-(1-cyclopropylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide; N-((S)-1-(4-chlorophenyl)ethyl)-2-(1-methylpiperidin-2-yl)acetamide; N-((S)-1-(4-fluorophenyl)ethyl)-2-(1-methylpiperidin-2-yl)acetamide; 2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide; 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)acetamide; 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutyl)acetamide; 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentyl)acetamide; (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide; (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide; (S)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide; (R)—N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide; 2-(1,5-dimethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide; N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)propanamide; (S)—N-(2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(1-(2-methoxybenzyl)cyclopropyl)-2-(1-methylpiperidin-2-yl)acetamide; (R)—N-(2-(2-methoxyphenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide; (S)—N-(2-(2-methoxyphenyl)propan-2-yl)-2-methyl-3- (Pyrrolidin-1-yl)propanamide; N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetamide; N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(tetrahydro-1H-pyrrolidin-7a(5H)-yl)acetamide; N-(1-((2-methoxypyridin-3-yl)methyl)cyclopropyl)-2-(1-methylpiperidin-2-yl)acetamide; (S)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-(3-methylbenzyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2,3-difluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(3-chloro-2-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2-fluoro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(2-fluoro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2,3-dimethylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2-chloro-3-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(2-chloro-3-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-((S)-1-(4-fluoro-2-methoxyphenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; 2-(3,3-difluoro-1-methylpyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide; 2-(3,3-difluoro-1-methylpyrrolidin-2-yl)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)acetamide; 2-(3,3-difluoro-1-methylpyrrolidin-2-yl)-N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)acetamide; 2-(3,3-difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide; 2-(3,3-difluoropyrrolidin-2-yl)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)acetamide; (S)—N-(2-methyl-1-((4-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-methyl-1-((5-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-methyl-1-((6-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-((4-chloro-5-fluoropyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(1-((3-ethoxypyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-((3-ethoxypyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide: (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide; (R)-N-(2-(isoquinolin-1-yl)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide; (S)—N-(2-(isoquinolin-1-yl)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide; (S)—N-(2-(3-chloro-2-methoxyphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(3-chloro-2-methoxyphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(3-fluoro-2-methoxyphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(3-fluoro-2-methoxyphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2-methoxy-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(2-methoxy-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(3-chloro-2-methoxyphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)—N-(2-(3-chloro-2-methoxyphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; 2-(1-methylpiperidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)acetamide; (R)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-(furo[2,3-c]pyridin-7-yloxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-methyl-1-(pyridin-2-yloxy)propan-2-yl)- 2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-((3-chloro-5-methylpyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-(furo[3,2-c]pyridin-4-yloxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide; (R)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide; N-(2-((S)-chroman-2-yl)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; N-(2-((R)-chroman-2-yl)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; N-(2-((R)-chroman-2-yl)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide; N-(2-((S)-chroman-2-yl)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide; 3-(azetidin-1-yl)-N-(2-(2-chlorophenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(2-chlorophenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(2-chlorophenyl)propan-2-yl)-2-methylpropanamide; N-(2-(2-chlorophenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide; (R)—N-(2-(2-chlorophenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide; (S)—N-(2-(2-chlorophenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide; (R)-3-(azetidin-1-yl)-N-(2-(4-methoxyphenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(4-methoxyphenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-2-methyl-N-(2-(o-tolyl)propan-2-yl)propanamide; (S)-3-(azetidin-1-yl)-2-methyl-N-(2-(o-tolyl)propan-2-yl)propanamide; (R)-3-(azetidin-1-yl)-N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(2-methoxy-3-methylphenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(2-methoxy-3-methylphenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-2-methyl-N-(2-(p-tolyl)propanol) (2-phenyl-2-yl)propanamide; (S)-3-(azetidin-1-yl)-2-methyl-N-(2-(p-tolyl)propan-2-yl)propanamide; (R)-3-(azetidin-1-yl)-N-(1-(2-fluorophenyl)cyclopropyl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(1-(2-fluorophenyl)cyclopropyl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(3-fluorophenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(3-fluorophenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(4-chlorophenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(4-chlorophenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(2-fluorophenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(2-fluorophenyl)propan-2-yl)-2-methylpropanamide; 2-((S)-1-methylpyrrolidin-2-yl)-N-(2,2,2-trifluoro-1-(p-tolyl)ethyl)acetamide; (R)—N-(2-(2-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)—N-(2-(2-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; 3-(azetidin-1-yl)-N-(2-(2-chloro-3-methylphenyl)propan-2-yl)propanamide; 3-(azetidin-1-yl)-N-(2-(m-tolyl)propan-2-yl)propanamide; 3-(azetidin-1-yl)-N-(2-(3-fluorophenyl)propan-2-yl)propanamide; 3-(azetidin-1-yl)-N-(2-(3-chlorophenyl)propan-2-yl)propanamide; 3-(azetidin-1-yl)-N-(2-(4-chlorophenyl)propan-2-yl)propanamide; 3-(azetidin-1-yl)-N-(2-(3-fluoro-2-methylphenyl)propan-2-yl)propanamide; 3-(azetidin-1-yl)-N-(1-(2,5-difluorophenyl)-2,2-difluoroethyl)propanamide; (S)-3-(azetidin-1-yl)-N-(1-(2,5-difluorophenyl)-2,2-difluoroethyl)propanamide; (R)-3-(azetidin-1-yl)-N-(1-(2,5-difluorophenyl)-2,2-difluoroethyl)propanamide; 3-(azetidin-1-yl)-N-(2-(3-fluoro-2-methoxyphenyl)propan-2-yl)-2-methylpropanamide; (R)-3-(azetidin-1-yl)-N-(2-(3-fluoro-2-methoxyphenyl)propan-2-yl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2-(3-fluoro-2-methoxyphenyl)propan-2-yl)-2-methylpropanamide; 3-(azetidin-1-yl)-N-(2-fluoro-1-(p-tolyl)ethyl)pro Panamide; (S)-3-(azetidin-1-yl)-N-(2-fluoro-1-(p-tolyl)ethyl)propanamide; (R)-3-(azetidin-1-yl)-N-(2-fluoro-1-(p-tolyl)ethyl)propanamide; (S)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-((S)-1-methylpyrrolidin-2-yl)propanamide; (R)—N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-((R)-1-methylpyrrolidin-2-yl)propanamide; (S)-2-(azetidin-1-ylmethyl)-N-((S)-2,2-difluoro-1-phenylethyl)-3-methylbutanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-phenylethyl)-3-methylbutanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-phenylethyl)butanamide; (R)-3-(azetidin-1-yl)-N-((R)-2,2-difluoro-1-phenylethyl)-2-methylpropanamide; (R)-2-(azetidin-1-ylmethyl)-N-(2-(4-fluorophenyl)propan-2-yl)butanamide; (S)-2-(azetidin-1-ylmethyl)-N-(2-(4-fluorophenyl)propan-2-yl)butanamide; (R)-2-(azetidin-1-ylmethyl)-N-(2-(3-fluorophenyl)propan-2-yl)butanamide; (S)-2-(azetidin-1-ylmethyl)-N-(2-(3-fluorophenyl)propan-2-yl)butanamide; (R)-2-(azetidin-1-ylmethyl)-N-(2-(p-tolyl)propan-2-yl)butanamide; (S)-2-(azetidin-1-ylmethyl)-N-(2-(p-tolyl)propan-2-yl)butanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-(2-methoxyphenyl)ethyl)-3-methylbutanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-(2-methoxyphenyl)ethyl)butanamide; (S)-3-(azetidin-1-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)propanamide; (S)-3-(azetidin-1-yl)-N-(1-(3-chlorophenyl)-2,2,2-trifluoroethyl)propanamide; (R)-3-(azetidin-1-yl)-N-(1-(3-chlorophenyl)-2,2,2-trifluoroethyl)propanamide; (R)-3-(azetidin-1-yl)-N-(2,2,2-trifluoro-1-(3-fluorophenyl)ethyl)propanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-(3-fluorophenyl)ethyl)-3-methylbutanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-(3-fluorophenyl)ethyl)butanamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-(4-fluorophenyl)ethyl)-3-methylbutanamide; (S)—N-(1-(3-chlorophenyl)-2,2-difluoroethyl)-3-(pyrrolidin-1-yl)propanamide; (R)—N-(1-(3-chlorophenyl)-2,2-difluoroethyl)-3-(pyrophenoxyethanol) Lysin-1-yl)propanamide; (R)-2-(azetidin-1-ylmethyl)-N-(2-(2-fluorophenyl)propan-2-yl)butanamide; (S)-2-(azetidin-1-ylmethyl)-N-(2-(2-fluorophenyl)propan-2-yl)butanamide; (R)-3-(azetidin-1-yl)-N-(2,2-difluoro-1-phenylethyl)propanamide; (R)-3-(azetidin-1-yl)-N-(1-(3-chlorophenyl)-2,2-difluoroethyl)propanamide; N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (S)-2-(azetidin-1-ylmethyl)-N-((R)-2,2-difluoro-1-(4-fluorophenyl)ethyl)butanamide; (R)-3-(azetidin-1-yl)-N-((R)-2-fluoro-1-phenylethyl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-((R)-2-fluoro-1-phenylethyl)-2-methylpropanamide; (S)-3-(azetidin-1-yl)-N-(2,2,2-trifluoro-1-(p-tolyl)ethyl)propanamide; (S)-3-(azetidin-1-yl)-N-(2,2,2-trifluoro-1-(3-fluorophenyl)ethyl)propanamide; (S)-3-(azetidin-1-yl)-N-(2,2,2-trifluoro-1-(2-fluorophenyl)ethyl)propanamide; (S)-3-(azetidin-1-yl)-N-(2,2,2-trifluoro-1-(o-tolyl)ethyl)propanamide; and 10. The compound of claim 1 selected from a pharmaceutically acceptable salt of any one of the foregoing compounds.

24. A compound as defined in any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; A pharmaceutical composition comprising:

25. 24. A compound or a pharmaceutically acceptable salt as defined in any one of claims 1 to 23 for use as a pharmaceutical.

26. 24. A compound or a pharmaceutically acceptable salt as defined in any one of claims 1 to 23 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.

27. 24. A method of treating a disease, disorder, or condition in a subject, said method comprising administering to said subject a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 23, wherein said disease, disorder, or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

28. 24. A combination comprising a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 23 and at least one additional pharmacologically active agent.

29. The additional pharmacologically active agent is a beta secretase inhibitor, a gamma secretase inhibitor, 29. The combination of claim 28, wherein the agent is selected from an anti-inflammatory drug, ...

30. A compound of formula 1 for use as a medicament, 【Transformation 6】 or a pharmaceutically acceptable salt thereof, (a) X ３ is NR ３Ｎ and O, and X ４ is a single bond, and X ５ is N and CR ５ Selected from: R １ and R ２ together with the carbon atoms to which they are attached form a fused ring which is benzene, wherein each non-fused carbon atom of said fused ring is unsubstituted or substituted with any substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy, each independently substituted with 0 to 3 optional substituents selected from halo; or (b) X ３ is CR ３Ｃ and X ４ is N and CR ４ is selected from X ５ is N and CR ５ Selected from: R １ and R ２ are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); or R １ and R ２ together with the carbon atoms to which they are attached form a fused ring selected from furan, pyrazole, and benzene, wherein one of the nitrogen atoms of the pyrazole ring is selected from hydrogen, C １－４ Alkyl or C ３－６ cycloalkyl, wherein each non-fused carbon atom of said fused ring is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); L is O and n is 1; or L is a single bond and n is 0 or 1; R ３Ｎ is hydrogen, C １－４ Alkyl, and C ３－６ cycloalkyl; R ３Ｃ and R ４ are each independently selected from: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R ５ is selected from the following: (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－４ Alkyl and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R ６ is hydrogen; or R ５ and R ６ together form ethane-1,2-diyl bridging the carbon atoms to which they are attached; R ７ and R ８ are each independently hydrogen and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo), where R ７ and R ８ At least one of is not hydrogen, or R ７ and R ８ together with the carbon atoms to which they are attached. ３－６ forming a cycloalkylidene; R ９ is hydrogen and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo); R １０ is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, and a heterocyclyl having the formula: 【Transformation 7】 During the ceremony, 【Transformation 8】 indicates the attachment point, r is selected from 0 and 1; R １１ is hydrogen, and R １２ is hydrogen, and C １－４ Alkyl and C ３－６ cycloalkyl (each independently substituted with 0 to 3 optional substituents selected from halo), with the proviso that R １２ is hydrogen, R １ and R ２ form a fused ring; or R １１ and R １２ together form propane-1,3-diyl bridging the carbon and nitrogen atoms to which they are respectively attached; R １３ , R １４ , R １５ , and R １６ are each independently hydrogen, halo, and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo), or R １３ and R １６ does not exist, and R １４ and R １５ together with the carbon atoms to which they are attached form a fused benzene ring, in which each non-fused carbon atom is unsubstituted or substituted with an optional substituent independently selected from: (i) halo, hydroxy, and cyano; and (ii) C １－４ Alkyl, C ３－６ Cycloalkyl, and C １－４ alkoxy (each independently substituted with 0 to 3 optional substituents selected from halo); R １７ and R １８ are each independently hydrogen, halo, and C １－４ alkyl (substituted with 0 to 3 optional substituents independently selected from halo). wherein the compound of formula 1 is: N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propanamide; or N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propanamide 10. A compound of formula 1 or a pharmaceutically acceptable salt thereof for use as said pharmaceutical, provided that:

31. A compound or a pharmaceutically acceptable salt thereof as defined in claim 30; and a pharmaceutically acceptable excipient; A pharmaceutical composition comprising:

32. 31. A compound or pharmaceutically acceptable salt as defined in claim 30 for treating a disease, disorder or condition selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

33. 31. A method of treating a disease, disorder, or condition in a subject, said method comprising administering to said subject a compound or a pharmaceutically acceptable salt thereof as defined in claim 30, wherein said disease, disorder, or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

34. 31. A combination comprising a compound or a pharmaceutically acceptable salt thereof as defined in claim 30 and at least one additional pharmacologically active agent.

35. 35. The combination of claim 34, wherein the additional pharmacologically active agent is selected from a beta secretase inhibitor, a gamma secretase inhibitor, an HMG-CoA reductase inhibitor, a nonsteroidal anti-inflammatory agent, vitamin E, an anti-amyloid antibody, an antidepressant, an antipsychotic, an anxiolytic, and an anticonvulsant.

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