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

Abstract

Disclosed are compounds of formula 1 and pharmaceutically acceptable salts thereof, wherein L, n, R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , X 3 , X 4 and X 5 The present disclosure also relates to materials and methods for preparing compounds of Formula 1, pharmaceutical compositions containing compounds of Formula 1, and uses of compounds of Formula 1 for treating diseases, disorders and conditions associated with SSTR4.

Description

Field of the Invention

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

[0003] Somatostatin receptor 4 (SSTR4) is a G protein-coupled receptor for the peptide somatostatin. SSTR4 couples to the inhibitory G protein Gi, which inhibits cyclic AMP production. SSTR4 is abundantly expressed in the central nervous system (CNS) and to a lesser extent in the dorsal root ganglia and intestine. See MA Meyer, "Highly Expressed Genes within Hippocampal Sector CA1: Implications for the Physiology of Memory," Neurology International 6(2):5388 (2014). SSTR4 is highly conserved across species. For example, human, mouse, and rat SSTR4 protein sequences share greater than 87% identity at the amino acid level. These factors—primary expression in the brain and high sequence homology across species—suggest that SSTR4 plays an important role in physiology.

[0004] Experiments using bacTRAP technology indicate that SSTR4 is most strongly expressed 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. See L. R. Squire and A. J. Dede, "Conscious and Unconscious Memory Systems," Cold Spring Harbor Perspectives in Biology 7:a021667 (2015). In fact, the CA1 region of the hippocampus is the last site in the trisynaptic circuit that governs learning. This circuit begins in the entorhinal cortex, which also contains SSTR4, extends to the dentate gyrus, then into the CA3, and finally to the CA1 region of the hippocampus. The CA1 protrudes from the hippocampus via its inferior peduncles. This circuit encodes all types of information from the external world to form memories and learn new knowledge.

[0005] Alzheimer's disease is characterized by the 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 Disease", Cold Spring Harbor Perspectives in Medicine 1: a006189 (2011). In addition, hippocampal SST4 appears to selectively control the use of cognitive strategies 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 discovery provides a strong basis for using SSTR4 agonists as a pharmacological approach to improve striatal-based learning. Ibid.

[0006] In addition, recent studies have also pointed out that hippocampal hyperactivity is the main driving force for disease progression and cognitive impairment in patients with Alzheimer's disease. 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); see also K. Yamamoto et al., "Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease", Cell Reports 11(6):859-65(2015). Activation of the SSTR4 receptor has been shown to play a role in controlling 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 these receptors would likely represent good pharmacological tools to inhibit and control neuronal activity in the cortex and hippocampus.

[0007] SSTR4 agonists are expected to be useful in treating Alzheimer's disease and other CNS disorders, such as epilepsy and depression. Summary of the Invention

[0008] 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-heteroarylalkyl-2-(heterocyclyl and heterocyclylmethyl)acetamide derivatives, and provides the use of the pharmaceutical compositions for treating diseases, disorders, and conditions associated with SSTR4, including Alzheimer's disease and other CNS disorders.

[0009] One aspect of the present invention provides a compound of formula 1:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] (a)X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 Selected from N and CR 5 ;and

[0013] R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring that is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0014] (i) halo, hydroxy and cyano; and

[0015] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or

[0016] (b)X 3 It's CR 3C , X 4 Selected from N and CR 4 , and X 5 Selected from N and CR 5 ;and

[0017] R 1 and R 2 Each independently selected from:

[0018] (i) hydrogen, halo, hydroxy and cyano; and

[0019] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or

[0020] R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring selected from furan, pyrazole and benzene, wherein one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The fused ring is substituted with a cycloalkyl radical, and each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0021] (i) halo, hydroxy and cyano; and

[0022] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0023] L is O and n is 1; or

[0024] L is a single bond and n is 0 or 1;

[0025] R 3N Selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;

[0026] R 3C and R 4 Each independently selected from:

[0027] (i) hydrogen, halo, hydroxy and cyano; and

[0028] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0029] R 5 Selected from:

[0030] (i) hydrogen, halo, hydroxy and cyano; and

[0031] (ii)C 1-4 Alkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and

[0032] R 6 is hydrogen; or

[0033] R 5 and R 6 together forming an ethane-1,2-diyl radical bridging the carbon atoms to which they are attached;

[0034] R 7 and R 8 are each independently selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 Alkyl, where R 7 and R 8 At least one of is not hydrogen, or R 7 and R 8 Together with the carbon atom to which they are attached, they form C 3-6 cycloalkylene;

[0035] R 9 is selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0036] R 10 is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl and a heterocyclic group having the formula:

[0037]

[0038] in Indicates the connection point, and

[0039] r is selected from 0 and 1;

[0040] R 11 is hydrogen, and R 12 selected from hydrogen and selected from C each substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl and C 3-6 Cycloalkyl, provided that if R 12 is hydrogen, then R 1 and R 2 forming a fused ring; or

[0041] R 11 and R 12 Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached;

[0042] R 13 、R 14 、R 15 and R 16 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, or R 13 and R 16 does not exist and R14 and R 15 Together with the carbon atoms to which they are attached, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a substituent independently selected from:

[0043] (i) halo, hydroxy and cyano; and

[0044] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and

[0045] R 17 and R 18 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl;

[0046] The prerequisite is that the compound of formula 1 is not:

[0047] 2-(1-methylpiperidin-2-yl)-N-(1-(m-tolyl)cyclopropyl)acetamide;

[0048] N-(1-(pyridin-3-yl)pentyl)-3-(pyrrolidin-1-yl)propanamide;

[0049] N-(1-(6-methylpyridin-2-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide;

[0050] 2-(1-methylpyrrolidin-2-yl)-N-(1-phenylethyl)acetamide;

[0051] 2-(1-methylpiperidin-2-yl)-N-(1-phenylethyl)acetamide;

[0052] N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propionamide;

[0053] N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propionamide;

[0054] N-(2-phenylpropan-2-yl)-3-(pyrrolidin-1-yl)propionamide;

[0055] N-(1-(4-methylpyridin-2-yl)propyl)-3-(pyrrolidin-1-yl)acrylamide; or

[0056] N-(1-(naphthalen-1-yl)ethyl)-2-(pyrrolidin-2-yl)acetamide.

[0057] Another aspect of the present invention provides a compound selected from the group consisting of the compounds described in the Examples and pharmaceutically acceptable salts thereof.

[0058] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph; and a pharmaceutically acceptable excipient.

[0059] Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds and pharmaceutically acceptable salts defined in the preceding paragraph, for use as a medicament.

[0060] Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for use in treating a disease, condition or disorder associated with SSTR4.

[0061] Another aspect of the present invention provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for the manufacture of a medicament for treating a disease, condition or disorder associated with SSTR4.

[0062] Another aspect of the present invention provides a method for treating a disease, condition or disorder 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 of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0063] Another aspect of the present invention provides a method of treating a disease, condition or disorder in a subject, comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, condition or disorder is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and ADHD.

[0064] Another aspect of the present invention provides an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph; and at least one additional pharmacologically active agent. DETAILED DESCRIPTION

[0065] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0066] When combined with a chemical substituent or moiety (e.g., C 1-6When used in conjunction with an alkyl group, "substituted" means that one or more hydrogen atoms of the substituent or moiety are replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and the substitution results in a chemically stable compound.

[0067] When used in connection with a measurable numerical variable, "about" or "approximately" refers to the indicated value of the variable and all values ​​of the variable that are within the experimental error of the indicated value or within ±10% of the indicated value, whichever is greater.

[0068] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally having the specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (ie, 1, 2, 3, or 4) carbon atoms, C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, and so on. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentan-1-yl, pentan-2-yl, pentan-3-yl, 3-methylbutan-1-yl, 3-methylbutan-2-yl, 2-methylbutan-2-yl, 2,2,2-trimethylethan-1-yl, n-hexyl, and the like.

[0069] "Alkanediyl" refers to a divalent alkyl group where alkyl is defined above and generally has the specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (ie, 1, 2, 3 or 4) carbon atoms, C 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, and so on. Examples of 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.

[0070] "Alkenyl" refers to straight and branched 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.

[0071] "Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and generally having the 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.

[0072] "Halo," "halogen," and "halo" are used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0073] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl, respectively, substituted with one or more halogen atoms, wherein alkyl, alkenyl, and alkynyl are as defined above and generally have the indicated number of carbon atoms. Examples of haloalkyl 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.

[0074] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups (e.g., C 3-8 Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members. Bicyclic hydrocarbon groups can include isolated rings (two rings share no carbon atoms), spiro rings (two rings share one carbon atom), fused rings (two rings share two carbon atoms and a bond between the two shared carbon atoms), and bridged rings (two rings share two carbon atoms but no common bond). Cycloalkyl groups can be attached via any ring atom, unless such attachment would violate valence requirements, and, where specified, can optionally include one or more non-hydrogen substituents, unless such substitution would violate valence requirements.

[0075] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, etc. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, etc. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, etc. Examples of isolated bicyclic cycloalkyls include those derived from bis(cyclobutane), cyclobutanecyclopentane, bis(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bis(cyclohexane), and the like.

[0076] "Cycloalkanediyl" refers to a divalent cycloalkyl group, where cycloalkyl is defined above and generally has the specified number of carbon atoms (e.g., C 3-5 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (ie, 3, 4 or 5) carbon atoms, C 3-6 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, and so on. Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0077] "Cycloalkylene" refers to a divalent monocyclic cycloalkyl group, where cycloalkyl is defined above, attached through a single carbon atom of the group and generally having the specified number of carbon atoms forming the ring (e.g., C 3-6 Cycloalkylene refers to a cycloalkylene group having 3 to 6 carbon atoms as ring members. Examples include cyclopropylene, cyclobutylene, cyclohexylene, and cyclohexylene.

[0078] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon radicals, generally having a specified number of carbon atoms constituting one or more rings. Like cycloalkyl, bicyclic cycloalkenyl can include isolated rings, spirocycles, fused rings or bridged rings. Similarly, cycloalkenyl can be connected through any ring atom, and in specified cases, can optionally include one or more non-hydrogen substituents, unless such connection or replacement would violate the valence requirement. Examples of cycloalkenyl include partially unsaturated analogs of the cycloalkyl described above, such as cyclobutenyl (i.e., cyclobutene-1-yl and cyclobutene-3-yl), cyclopentenyl, cyclohexenyl, bicyclo [2.2.1] hept-2-enyl etc.

[0079] "Aryl" refers to a fully unsaturated monocyclic aromatic hydrocarbon and to a polycyclic hydrocarbon having at least one aromatic ring. Both monocyclic and polycyclic aromatic groups generally have a specified number of carbon atoms (e.g., C 6-14 Aryl refers to an aromatic group having 6 to 14 carbon atoms as ring members. The group may be attached via any ring atom and, where specified, may optionally include one or more non-hydrogen substituents, unless such attachment or substitution would violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthyl, benzocycloheptanyl, biphenylene, fluorenyl, groups derived from cycloheptatrienyl cations, and the like.

[0080] "Arylene" refers to a divalent aromatic radical, wherein aryl is as defined above. Examples of arylene radicals include o-phenylene (ie, benzene-1,2-diyl).

[0081] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group having ring atoms consisting of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups generally have a specified number of carbon atoms in one or more of their rings (e.g., C 2-6Heterocyclyl refers to a heterocyclyl having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members. Like bicyclic cycloalkyls, bicyclic heterocyclyls can include isolated rings, spirocycles, fused rings, and bridged rings. The heterocyclyl group may be attached via any ring atom and, where specified, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heterocyclic groups include oxirane, thiirane, azirane (e.g., aziridan-1-yl and aziridan-2-yl), oxetanyl, thiirane, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxanyl, heterocycloheptyl, 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.

[0082] "Heterocycle-diyl" refers to a heterocycle group connected via two ring atoms of the group, wherein the heterocycle is as defined above. Heterocycle-diyl groups generally have the specified number of carbon atoms in one or more of their rings (e.g., C 2-6 Heterocycle-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 heterocycle groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridyl-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.

[0083] "Heteroaromatic" and "heteroaryl" are used interchangeably and refer to unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each group having ring atoms consisting of carbon atoms and 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 1-9Heteroaryl 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. The heteroaryl group may be attached via any ring atom (or ring atoms of a fused ring), and in given cases, may optionally include one or more non-hydrogen substituents, unless such attachment or substitution would 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), furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0084] Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindololinyl, 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[1,2-c]pyrimidinyl, [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-pyrrole [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.

[0085] "Heteroarylene" refers to a heteroaryl group linked through two ring atoms of the group, wherein heteroaryl is as defined above. Heteroarylene groups generally have a specified number of carbon atoms in one or more of their rings (e.g., C3-5 Heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members. Examples of heteroarylene groups include polyvalent analogs of the heteroaryl groups described above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0086] "Oxo" refers to a double-bonded oxygen (=0).

[0087] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. A leaving group can be nuclear free, in which the group leaves with a pair of electrons that originally served as a bond between the leaving group and the molecule; or it can be ionized, in which the group leaves without a pair of electrons. The ability of a nuclear free leaving group to leave depends on the strength of its base, with the strongest base being the worst leaving group. Common nuclear free leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., methanesulfonates), fluoroalkyl sulfonates (e.g., trifluoromethanesulfonates, hexafluoropropanesulfonates, nonafluorobutanesulfonates, and trifluoroethanesulfonates), and aryl sulfonates (e.g., toluenesulfonates, bromobenzenesulfonates, chlorobenzenesulfonates, and nitrobenzenesulfonates). Others include carbonates, halides, carboxylate anions, phenolates, and alkoxides. Some stronger bases, such as NH2 - and OH - Better leaving groups can be prepared by treating with acid. Common ionizing leaving groups include protons, CO2 and metals.

[0088] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by inverting all stereogenic centers of the reference molecule. For example, if the reference molecule has an S absolute stereochemistry, the opposite enantiomer has an R absolute stereochemistry. Similarly, if the reference molecule has an S,S absolute stereochemistry, the opposite enantiomer has an R,R stereochemistry, and so on.

[0089] "A stereoisomer" and "stereoisomers" of a compound having a given stereochemical configuration refer to the opposite enantiomer of the compound and to any diastereomer of the compound, including geometric isomers (Z / E). For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having an R,S,Z configuration, as well as its diastereomers having an S,S,Z configuration, an R,R,Z configuration, an S,R,E configuration, an R,S,E configuration, an S,S,E configuration, and an R,R,E configuration. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0090] "Substantially pure stereoisomer" and variations thereof refers to a sample containing a compound having a particular stereochemical configuration and comprising at least about 95% of the sample.

[0091] "Pure stereoisomer" and variations thereof refer to a sample containing a compound having a specific stereochemical configuration and comprising at least about 99.5% of the sample.

[0092] "Subject" refers to mammals, including humans.

[0093] "Pharmaceutically acceptable" substances refer to those substances that are suitable for administration to a subject.

[0094] "Treat," "treat," "treat," or "treating" refers to reversing, alleviating, inhibiting the progress of, or preventing the disease, condition, or disorder to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disease, condition, or disorder.

[0095] "Therapeutic treatment" means the act of "treating" as defined just above.

[0096] "Drug," "drug substance," "active pharmaceutical ingredient," etc., refers to a compound (e.g., a compound of Formula 1, including subclasses and compounds specifically named herein) that can be used to treat a subject in need of treatment.

[0097] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like, refers to the amount of the drug that can be used to treat a subject and may depend, among other things, on the weight and age of the subject, the route of administration, and the like.

[0098] "Excipient" refers to any diluent or vehicle for a drug.

[0099] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0100] "Drug product," "drug dosage form," "dosage form," "final dosage form," etc., refers to a pharmaceutical composition suitable for treating a subject in need of treatment and which can generally be in the form of a tablet, capsule, sachet containing powder or granules, liquid solution or suspension, patch, film, etc.

[0101] "A condition associated with SSTR4" and similar phrases refer to a disease, disorder, or condition in a subject for which activation of SSTR4 may provide a therapeutic or prophylactic benefit.

[0102] The following abbreviations may be used in this specification: Ac (acetyl); ACN (acetonitrile); AIBN (azobisisobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc (tert-butyloxycarbonyl); Cbz (benzyloxycarbonyl); dba (dibenzylideneacetone); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloroethane); DCM (dichloromethane); DEA (diethylamine); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine, Hünig's base) 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 to achieve half the maximum response); EDA (ethoxylated dodecanol, 35); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq (equivalent); Et (ethyl); Et3N (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 to achieve 50% inhibition); IPA (isopropyl alcohol); 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 (trifluoromethanesulfonate); PE (petroleum ether); Ph (phenyl); pEC 50 (-log 10 (EC 50 ), where EC 50 Given in molar concentration (M) units); pIC 50(-log 10 (IC 50 ), where IC 50 Given in molar concentration (M) units); Pr (propyl); c-Pr (cyclopropyl); i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); (bromotripyrrolidinylphosphonium 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-trioxatriphosphine 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).

[0103] 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 compounds of Formula 1, and the use of compounds of Formula 1 and pharmaceutically acceptable salts thereof (optionally in combination with other pharmacologically active agents) for treating CNS diseases, disorders, or conditions (including Alzheimer's disease) and other diseases, disorders, or conditions associated with SSTR4.

[0104] Compounds of Formula 1 include those wherein:

[0105] (1)(a)X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 Selected from N and CR 5 ;and

[0106] R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring that is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0107] (i) halo, hydroxy and cyano; and

[0108] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or

[0109] (b)X 3 It's CR 3C , X4 Selected from N and CR 4 , and X 5 Selected from N and CR 5 ;and

[0110] R 1 and R 2 Each independently selected from:

[0111] (i) hydrogen, halo, hydroxy and cyano; and

[0112] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or

[0113] R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring selected from furan, pyrazole and benzene, wherein one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The fused ring is substituted with a cycloalkyl radical, and each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0114] (i) halo, hydroxy and cyano; and

[0115] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0116] L is O and n is 1; or

[0117] L is a single bond and n is 0 or 1;

[0118] R 3N Selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;

[0119] R 3C and R 4 Each independently selected from:

[0120] (i) hydrogen, halo, hydroxy and cyano; and

[0121] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0122] R5 Selected from:

[0123] (i) hydrogen, halo, hydroxy and cyano; and

[0124] (ii)C 1-4 Alkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and

[0125] R 6 is hydrogen; or

[0126] R 5 and R 6 together forming an ethane-1,2-diyl radical bridging the carbon atoms to which they are attached;

[0127] R 7 and R 8 are each independently selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 Alkyl, where R 7 and R 8 At least one of is not hydrogen, or R 7 and R 8 Together with the carbon atom to which they are attached, they form C 3-6 cycloalkylene;

[0128] R 9 is selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0129] R 10 is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl and a heterocyclic group having the formula:

[0130]

[0131] in Indicates the connection point, and

[0132] r is selected from 0 and 1;

[0133] R 11 is hydrogen, and R 12 selected from hydrogen and selected from C each substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl and C 3-6 Cycloalkyl, provided that if R 12 is hydrogen, then R 1 and R 2 forming a fused ring; or

[0134] R 11 and R 12Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached;

[0135] R 13 、R 14 、R 15 and R 16 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, 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, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a substituent independently selected from:

[0136] (i) halo, hydroxy and cyano; and

[0137] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and

[0138] R 17 and R 18 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl;

[0139] The prerequisite is that the compound of formula 1 is not:

[0140] 2-(1-methylpiperidin-2-yl)-N-(1-(m-tolyl)cyclopropyl)acetamide;

[0141] N-(1-(pyridin-3-yl)pentyl)-3-(pyrrolidin-1-yl)propanamide;

[0142] N-(1-(6-methylpyridin-2-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide;

[0143] 2-(1-methylpyrrolidin-2-yl)-N-(1-phenylethyl)acetamide;

[0144] 2-(1-methylpiperidin-2-yl)-N-(1-phenylethyl)acetamide;

[0145] N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propionamide;

[0146] N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propionamide;

[0147] N-(2-phenylpropan-2-yl)-3-(pyrrolidin-1-yl)propionamide;

[0148] N-(1-(4-methylpyridin-2-yl)propyl)-3-(pyrrolidin-1-yl)acrylamide; or

[0149] N-(1-(naphthalen-1-yl)ethyl)-2-(pyrrolidin-2-yl)acetamide.

[0150] In addition to embodiment (1) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein:

[0151] (2)X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 Selected from N and CR 5 .

[0152] In addition to embodiment (2) in the preceding paragraph, compounds of formula 1 include those compounds wherein R 1 and R 2 Each non-fused carbon atom forming the fused ring is unsubstituted or optionally substituted with a substituent independently selected from:

[0153] (3)(i) halo and hydroxy; and

[0154] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0155] (4)(i) halo and hydroxy; and

[0156] (ii)C 1-4 Alkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0157] (5) halogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0158] (6) halogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0159] (7) C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0160] (8)C 1-3 alkyl; or

[0161] (9) Methyl.

[0162] In addition to embodiments (2) to (9) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein R 3N Selected from:

[0163] (10) Hydrogen and C 1-4 alkyl;

[0164] (11) Hydrogen and C 1-3 alkyl;

[0165] (12) Hydrogen and methyl;

[0166] (13)C 1-3 alkyl; or

[0167] (14) Methyl.

[0168] In addition to embodiments (2) to (14) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein:

[0169] (15)X 3 It's O, X 4 is a single bond, and X 5 It is N;

[0170] (16)X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 is N; or

[0171] (17)X 3 It is NR 3N , X 4 is a single bond, and X 5 It's N.

[0172] In addition to embodiments (2) to (17) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein:

[0173] (18) L is a single bond and n is 0 or 1; or

[0174] (19) L is a single bond and n is 0.

[0175] In addition to the above embodiment (1), compounds of formula 1 also include those compounds wherein:

[0176] (20)X 3 It's CR 3C , X 4 Selected from N and CR 4 , and X 5 Selected from N and CR 5.

[0177] In addition to embodiment (20) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 1 and R 2 Each independently selected from:

[0178] (21)(i) hydrogen, halo, hydroxy and cyano; and

[0179] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0180] (22)(i) hydrogen and halogen; and

[0181] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0182] (23)(i) hydrogen and halogen; and

[0183] (ii)C 1-3 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0184] (24)(i) hydrogen and halogen; and

[0185] (ii) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy and isopropoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0186] (25)(i) hydrogen and halogen; and

[0187] (ii) methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and isopropoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0188] (26)(i) hydrogen and halogen; and

[0189] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0190] (27)(i) Hydrogen, chlorine and fluorine; and

[0191] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0192] (28)(i) hydrogen and halogen; and

[0193] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from chlorine and fluorine;

[0194] (29)(i) Hydrogen, chlorine and fluorine; and

[0195] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from chlorine and fluorine; or

[0196] (30)(i) Hydrogen, chlorine and fluorine; and

[0197] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from fluorine.

[0198] In addition to the above embodiment (20), compounds of Formula 1 also include those compounds wherein:

[0199] (31)R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring selected from furan, pyrazole and benzene, wherein one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The fused ring is substituted with a cycloalkyl radical, and each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0200] (i) halo, hydroxy and cyano; and

[0201] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are each substituted with 0 to 3 optional substituents independently selected from halo.

[0202] In addition to the above embodiment (20), compounds of Formula 1 also include those compounds wherein:

[0203] (32)R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring that is furan, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0204] (i) halo, hydroxy and cyano; and

[0205] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are each substituted with 0 to 3 optional substituents independently selected from halo.

[0206] In addition to embodiment (32) in the preceding paragraph, compounds of Formula 1 include those compounds wherein:

[0207] (33) By R 1 、R 2 With R 1 and R 2 The fused ring formed by the carbon atoms to which it is attached is a ring having a bond directly connected to R 2 The carbon atom is the oxygen ring atom of furan.

[0208] In addition to the above embodiment (20), compounds of Formula 1 also include those compounds wherein:

[0209] (34)R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring as a pyrazole, in which one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The fused ring is substituted with a cycloalkyl radical, and each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0210] (i) halo, hydroxy and cyano; and

[0211] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are each substituted with 0 to 3 optional substituents independently selected from halo.

[0212] In addition to the embodiment (34) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 1 、R 2 With R 1 and R 2 The fused ring formed by the attached carbon atoms is a pyrazole:

[0213] (35) has a bond directly connected to R 2 a nitrogen ring atom of a carbon atom of

[0214] (36) has a bond directly connected to R 2 The carbon atoms and hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl substituted nitrogen ring atom.

[0215] In addition to embodiments (34) to (36) in the preceding paragraph, compounds of Formula 1 include those wherein R 1 、R 2 With R 1 and R 2 The fused ring formed by the attached carbon atoms is a pyrazole in which one of the nitrogen ring atoms is substituted with:

[0216] (37) Hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0217] (38) hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl;

[0218] (39) hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0219] (40) hydrogen or methyl; or

[0220] (41) Methyl.

[0221] In addition to the above embodiment (20), compounds of Formula 1 also include those compounds wherein:

[0222] (42)R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring that is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted substituent independently selected from:

[0223] (i) halo, hydroxy and cyano; and

[0224] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are each substituted with 0 to 3 optional substituents independently selected from halo.

[0225] In addition to the embodiments (31) to (42) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein R 1 and R 2 Each non-fused carbon atom forming the fused ring is unsubstituted or optionally substituted with a substituent independently selected from:

[0226] (43)(i) halogen and hydroxy; and

[0227] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0228] (44)(i) halo and hydroxy; and

[0229] (ii)C 1-4 Alkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0230] (45) halogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0231] (46) halogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0232] (47) C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0233] (48)C 1-3 alkyl; or

[0234] (49) Methyl.

[0235] In addition to embodiments (20) to (49) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein R 3C and R 4 Each independently selected from:

[0236] (50)(i) hydrogen, halo and hydroxy; and

[0237] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0238] (51)(i) hydrogen and halogen; and

[0239] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0240] (52)(i) hydrogen and halogen; and

[0241] (ii)C 1-3 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0242] (53)(i) hydrogen and halogen; and

[0243] (ii) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy and isopropoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0244] (54)(i) hydrogen and halogen; and

[0245] (ii) methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and isopropoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0246] (55)(i) hydrogen and halogen; and

[0247] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0248] (56)(i) Hydrogen, chlorine and fluorine; and

[0249] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0250] (57)(i) hydrogen and halogen; and

[0251] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from chlorine and fluorine;

[0252] (58)(i) Hydrogen, chlorine and fluorine; and

[0253] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from chlorine and fluorine; or

[0254] (59)(i) Hydrogen, chlorine and fluorine; and

[0255] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from fluorine.

[0256] In addition to embodiments (20) to (59) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein R 5 Selected from:

[0257] (60)(i) hydrogen, halo, hydroxy and cyano; and

[0258] (ii)C 1-4 Alkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0259] (61)(i) hydrogen, halo and hydroxy; and

[0260] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0261] (62)(i) hydrogen and halogen; and

[0262] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0263] (63)(i) hydrogen and halogen; and

[0264] (ii)C 1-3 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0265] (64)(i) hydrogen and halogen; and

[0266] (ii) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy and isopropoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0267] (65)(i) hydrogen and halogen; and

[0268] (ii) methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and isopropoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0269] (66)(i) hydrogen and halogen; and

[0270] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0271] (67)(i) Hydrogen, chlorine and fluorine; and

[0272] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0273] (68)(i) hydrogen and halogen; and

[0274] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from chlorine and fluorine;

[0275] (69)(i) Hydrogen, chlorine and fluorine; and

[0276] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from chlorine and fluorine; or

[0277] (70)(i) Hydrogen, chlorine and fluorine; and

[0278] (ii) methyl, ethyl, cyclopropyl, methoxy and ethoxy, each substituted with 0 to 3 optional substituents independently selected from fluorine.

[0279] In addition to the above embodiments (20) to (59), compounds of Formula 1 also include those compounds wherein:

[0280] (71)R 5 and R 6 Together they form a bridge R 5 and R 6 The attached carbon atom is ethane-1,2-diyl.

[0281] In addition to embodiments (20) to (71) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein:

[0282] (72)X 3 It's CR 3C , X 4 It's CR 4 , and X 5 Selected from N and CR 5 ;

[0283] (73)X 3 It's CR 3C , X 4 It's CR 4 , and X 5 It's CR 5 ;or

[0284] (74)X 3 It's CR 3C , X 4 is N, and X 5 It's CR 5 .

[0285] In addition to the above embodiments (20) to (59), compounds of Formula 1 also include those compounds wherein:

[0286] (75)X 3 It's CR 3C , X4 It's CR 4 , and X 5 It's N.

[0287] In addition to embodiments (20) to (75) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein:

[0288] (76)L is O and n is 1.

[0289] In addition to the above embodiments (20) to (70) and (72) to (75), compounds of Formula 1 also include those compounds wherein:

[0290] (77) L is a single bond and n is 0 or 1.

[0291] In addition to embodiments (1) to (77) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 7 and R 8 Each independently selected from:

[0292] (78) hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 Alkyl, where R 7 and R 8 At least one of is not hydrogen;

[0293] (79) hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 Alkyl, where R 7 and R 8 At least one of is not hydrogen;

[0294] (80) hydrogen, methyl, ethyl and isopropyl, wherein each methyl, ethyl and isopropyl is substituted with 0 to 3 substituents optionally independently selected from halo, wherein R 7 and R 8 At least one of is not hydrogen;

[0295] (81) hydrogen and methyl substituted with 0 to 3 optional substituents independently selected from halo, wherein R 7 and R 8 At least one of is not hydrogen;

[0296] (82) hydrogen, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, wherein R 7 and R 8 At least one of is not hydrogen; or

[0297] (83) hydrogen and methyl, where R 7 and R 8 At least one of is not hydrogen.

[0298] In addition to embodiments (78) to (83) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0299] (84)R 8 is hydrogen; or

[0300] (85)R 7 With R 8 same.

[0301] In addition to the above embodiments (1) to (77), compounds of formula 1 also include those compounds wherein R 7 and R 8 Together with the carbon atoms to which they are attached, they form:

[0302] (86)C 3-6 cycloalkylene;

[0303] (87) Cyclopropylene, cyclobutylene and cyclopentylene;

[0304] (88) cyclopropylene or cyclobutylene; or

[0305] (89) Cyclopropylene.

[0306] In addition to embodiments (1) to (89) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 9 Selected from:

[0307] (90) hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0308] (91) hydrogen, methyl, ethyl and isopropyl, wherein each methyl, ethyl and isopropyl is substituted with 0 to 3 substituents optionally independently selected from halo;

[0309] (92) hydrogen, methyl, ethyl and isopropyl, wherein each methyl, ethyl and isopropyl is substituted with 0 to 3 substituents optionally selected from fluorine; or

[0310] (93) Hydrogen, methyl, ethyl and isopropyl.

[0311] In addition to embodiments (1) to (93) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 10 yes:

[0312] (94) azetidin-1-ylmethyl; or

[0313] (95) Pyrrolidin-1-ylmethyl.

[0314] In addition to the above embodiments (1) to (93), compounds of Formula 1 also include those compounds wherein:

[0315] (96)R 10 is a heterocyclic group having the formula:

[0316]

[0317] in Indicates the connection point, and

[0318] r is selected from 0 and 1;

[0319] R 11 is hydrogen, and R 12 selected from hydrogen and selected from C each substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl and C 3-6 Cycloalkyl, provided that if R 12 is hydrogen, then R 1 and R 2 forming a fused ring; or

[0320] R 11 and R 12 Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached;

[0321] R 13 、R 14 、R 15 and R 16 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, 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, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a substituent independently selected from:

[0322] (i) halo, hydroxy and cyano; and

[0323] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and

[0324] R 17 and R 18 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl.

[0325] In addition to embodiment (96) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R11 is hydrogen and R 12 Selected from:

[0326] (97)C 1-4 Alkyl and C 3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo;

[0327] (98)C 1-3 Alkyl and C 3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo;

[0328] (99) methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, each substituted with 0 to 3 substituents optionally independently selected from halo;

[0329] (100) methyl, ethyl, isopropyl and cyclopropyl, each substituted with 0 to 3 substituents optionally independently selected from halo;

[0330] (101) methyl, ethyl, isopropyl and cyclopropyl, each substituted with 0 to 3 substituents optionally selected from fluorine;

[0331] (102) methyl, ethyl and isopropyl, each substituted with 0 to 3 substituents optionally selected from fluorine;

[0332] (103) methyl and ethyl, each substituted with 0 to 3 substituents optionally selected from fluorine;

[0333] (104) methyl and ethyl; or

[0334] (105) Methyl.

[0335] In addition to the above embodiment (96), compounds of Formula 1 also include those compounds wherein:

[0336] (106)R 11 and R 12 Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached.

[0337] In addition to embodiments (96) to (106) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 13 、R 14 、R 15 and R 16 Each independently selected from:

[0338] (107) hydrogen, halogen, and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0339] (108) hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0340] (109) hydrogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0341] (110) hydrogen, halo, and methyl substituted with 0 to 3 optional substituents independently selected from halo;

[0342] (111) hydrogen, halo, and methyl substituted with 0 to 3 optional substituents independently selected from fluoro;

[0343] (112) Hydrogen, halogen and methyl;

[0344] (113) Hydrogen, fluorine and methyl;

[0345] (114) hydrogen and methyl; or

[0346] (115) Hydrogen.

[0347] In addition to embodiments (107) to (114) in the preceding paragraph, compounds of Formula 1 also include those compounds wherein:

[0348] (116)R 15 and R 16 Each is hydrogen.

[0349] In addition to the above embodiments (96) to (106), compounds of Formula 1 also include those compounds wherein:

[0350] (117)R 13 and R 16 does not exist and R 14 and R 15 Together with the carbon atoms to which they are attached, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a substituent independently selected from:

[0351] (i) halo, hydroxy and cyano; and

[0352] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are each substituted with 0 to 3 optional substituents independently selected from halo.

[0353] In addition to the embodiment (117) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 14 and R 15 Each non-fused carbon atom forming the fused ring is unsubstituted or optionally substituted with a substituent independently selected from:

[0354] (118) (i) halo and hydroxy; and

[0355] (ii)C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0356] (119)(i) halo and hydroxy; and

[0357] (ii)C 1-4 Alkyl and C 1-4 Alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

[0358] (120) halogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-4 alkyl;

[0359] (121) halogen and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0360] (122) C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0361] (123)C 1-3 alkyl; or

[0362] (124) Methyl.

[0363] In addition to the above embodiment (117), compounds of Formula 1 include those compounds wherein:

[0364] (125) By R 14 and R 15 Each non-fused carbon atom of the resulting fused benzene ring is unsubstituted.

[0365] In addition to embodiments (96) to (125) in the preceding paragraph, compounds of Formula 1 include those compounds wherein R 17 and R 18 Each independently selected from:

[0366] (126) hydrogen, halogen, and C substituted with 0 to 3 optional substituents independently selected from halogen 1-3 alkyl;

[0367] (127) hydrogen, halo, methyl and ethyl, wherein methyl and ethyl are each substituted with 0 to 3 optional substituents independently selected from halo;

[0368] (128) Hydrogen, halo and methyl;

[0369] (129) Hydrogen, fluorine and methyl; or

[0370] (130) Hydrogen and fluorine.

[0371] In addition to embodiments (126) to (130) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0372] (131)R 17 With R 18 same.

[0373] In addition to embodiments (96) to (131) in the preceding paragraph, compounds of Formula 1 include those compounds wherein:

[0374] (132) r is 0; or

[0375] (133)r is 1.

[0376] The compounds of Formula 1 include the compounds specifically named in the embodiments (1) to (133) described in the preceding paragraph and in the examples, which may exist in the form of salts, complexes, solvates, hydrates, and liquid crystals. Similarly, the compounds of Formula 1 as salts may exist in the form of complexes, solvates, hydrates, and liquid crystals.

[0377] 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 the following inorganic acids: such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid; and non-toxic salts derived from the following organic acids: such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Such salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, pyroglutamate, sucrose, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0378] 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'-diphenylmethylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, ethanolamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of available acid addition salts and base salts, see SM Berge et al., J. Pharm. Sci. (1977) 66: 1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0379] Pharmaceutically acceptable salts can be prepared using various methods. For example, the compound of formula 1 can be reacted with an appropriate acid or base to obtain the desired salt. Alternatively, the precursor of the compound of formula 1 can be reacted with an acid or base to remove a protective group that is unstable to an acid or base or to open a lactone or lactam group of the precursor. In addition, the salt of the compound of formula 1 can be converted into another salt (or free form) via treatment with an appropriate acid or base or via contact with an ion exchange resin. After the reaction, if the salt precipitates from the solution, the salt can be separated by filtration, or the salt can be recovered by evaporation. The degree of ionization of the salt can vary between complete ionization and almost non-ionization.

[0380] Formula 1 compound can exist in a continuous solid form within the range of completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and may exhibit the physical properties of a solid or liquid depending on the temperature. Typically, such materials do not produce a unique X-ray diffraction pattern, and although they exhibit the properties of a solid, they are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, characterized by a change in state, typically secondary ("glass transition"). The term "crystallization" refers to a solid phase in which a material has a regular, ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with a specified peak. Such materials will also exhibit the properties of a liquid when fully heated, but the change from solid to liquid is characterized by a phase transition, typically primary ("melting point").

[0381] The compound of formula 1 can also exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent can be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0382] The currently recognized classification system for the solvates and hydrates of organic compounds is a system that distinguishes the solvates and hydrates of independent sites, channels and metal ion coordination.See, for example, KR Morris (HG Rittain ed.) Polymorphism in Pharmaceutical Solids (1995). Independent site solvates and hydrates are solvates and hydrates in which solvent (e.g., water) molecules are independent by intervening in the molecules of organic compounds in order to avoid direct contact with each other. In channel solvates, solvent molecules are located in lattice channels, and in the channels, the solvent molecules are next to other solvent molecules. In the solvates of metal ion coordination, solvent molecules are bonded to the metal ion.

[0383] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry, regardless of humidity. However, when the solvent or water is weakly bound (such as in channel solvates and hygroscopic compounds), the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will generally be observed.

[0384] Formula 1 compound can also exist in the form of a multi-component complex (except salts and solvates), wherein the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components bound together via non-covalent interactions, but may also be a complex of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. See, for example, O.Almarsson and MJZaworotko, Chem.Commun. (2004) 17: 1889-1896. For a general review of multi-component complexes, see JKHaleblian, J.Pharm.Sci. (1975) 64 (8): 1269-88.

[0385] When subjected to suitable conditions, the compound of formula 1 can exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state is between a true crystalline state and a true liquid state (melt or solution). The mesomorphicity produced by temperature changes is described as "thermotropic", and the mesomorphicity produced by adding a second component such as water or another solvent is described as "lyotropic". Compounds that may form a lyotropic mesophase are described as "amphiphilic" and include compounds with polar ionic moieties (e.g., -COO - Na + 、-COO - K + 、-SO3 - Na + ) or a polar nonionic moiety (such as -N - N + (CH3)3) molecules. See, for example, NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0386] Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically labeled, may be produced by administration of a prodrug, or may form a metabolite after administration.

[0387] "Prodrug" refers to a compound with little or no pharmacological activity that can be converted into a compound with the desired pharmacological activity when metabolized in the body. Prodrugs can be prepared by replacing the appropriate functional groups present in the pharmacologically active compound with a "promote moiety" such as described in H.Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or amide derivatives of compounds of formula 1 having carboxylic acid, hydroxyl or amino functional groups, respectively. For further discussion of prodrugs, see, for example, T.Higuchi and V.Stella "Pro-drugs as Novel Delivery Systems", ACS Symposium Series 14 (1975) and E.B.Roche, ed., Bioreversible Carriers in Drug Design (1987).

[0388] "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 having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

[0389] The compounds of Formula 1 may exist as stereoisomers, which are due to the presence of one or more stereogenic centers, one or more double bonds, or both. Stereoisomers may be pure, substantially pure, or mixtures. Such stereoisomers may also be produced by acid addition salts or base salts in which the counterion is optically active, for example, when the counterion is D-lactic acid or L-lysine.

[0390] The compounds of Formula 1 may exist as tautomers, which are isomers resulting from tautomerism. Tautomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0391] Compounds of Formula 1 may exhibit more than one type of isomerism.

[0392] Geometric (cis / trans) isomers can be separated by conventional techniques, such as chromatography and fractional crystallization.

[0393] The conventional techniques for preparing or separating the compound with specific stereochemical configuration include carrying out chiral synthesis from an applicable optically pure precursor, or using, for example, chiral high pressure liquid chromatography (HPLC) to split racemate (or the racemate of salt or derivative). Alternatively, racemate (or racemic precursor) and applicable optically active compound, for example alcohol reaction, or in the case where formula 1 compound contains acidic or basic part with acid or alkali, such as tartaric acid or 1-phenylethylamine reaction. Gained diastereomeric mixture can be separated by chromatography, fractional crystallization etc., and suitable diastereomer is converted into the compound with required stereochemical configuration. For further discussion of the technology of separating stereoisomers, referring to E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0394] The compounds of Formula 1 may have isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Suitable isotopes for inclusion in the compounds of Formula 1 include, for example, isotopes of hydrogen such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18F; isotopes of chlorine, such as 36 Cl; and isotopes of iodine, such as 123 I and 125 I. Isotopic variation (e.g., deuterium 2 The use of H) may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations of the disclosed compounds may be incorporated with radioactive isotopes (e.g., tritium). 3 H, or 14 C), which can be used for drug and / or substrate tissue distribution studies. Using positron emitting isotopes, such as 11 C. 18 F. 15 O and 13 N substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.Isotopically labeled compounds can be prepared by procedures analogous to those described elsewhere in this disclosure, using an appropriate isotopically labeled reagent in place of the unlabeled reagent.

[0395] Formula 1 compound can be prepared using the technology described below. Some processes and embodiments can omit the details of common reactions (including oxidation, reduction, etc.), separation techniques (extraction, evaporation, precipitation, chromatography, filtration, wet grinding, crystallization, etc.) and analytical procedures, which are known to those of ordinary skill in the field of organic chemistry. The details of such reactions and techniques can be found in several papers, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B.Smith, Compendium of Organic Synthetic Methods (1974 and subsequent). Starting materials and reagents can be obtained from commercial sources or can be prepared using literature methods. Some reaction processes can omit the minor products obtained by chemical conversion (for example, alcohol obtained by ester hydrolysis, CO obtained by diacid decarboxylation, etc.). In addition, in some cases, the reaction intermediates can be used in subsequent steps (that is, in situ) without separation or purification.

[0396] In some reaction processes and embodiments hereinafter, some compound can be prepared using a protecting group, which prevents undesirable chemical reactions from occurring at other reaction sites. Protecting group can also be used to enhance solubility or otherwise change the physical properties of compound. For discussion of protecting group strategies, for arranging and removing the description of the materials and methods of protecting group and for the compilation of available protecting groups for common functional groups (including amine, carboxylic acid, alcohol, ketone, aldehyde etc.), see TW Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P.Kocienski, Protective Groups (2000).

[0397] In general, the chemical transformations described throughout this specification can be performed using substantially stoichiometric amounts of reactants, although certain reactions may benefit from using an excess of one or more reactants. In addition, many of the reactions disclosed throughout this specification can be performed at approximately room temperature (RT) and ambient pressure, but some reactions may be performed at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C) depending on reaction kinetics, yields, etc. Any reference in this disclosure and claims to stoichiometric ranges, temperature ranges, pH ranges, etc., whether or not the word "range" is explicitly used, also includes the indicated endpoints.

[0398] Many chemical transformations may also employ one or more compatible solvents, which may affect 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, non-polar 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., dichloromethane, 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, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (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 triamide).

[0399] In the following schemes, the substituent identifiers (L, n, r, R 1 、R 2 、R 6 、R 7 、R 8 、R 9 、R 10 、R 12 、X 3 、X 4 and X 5 ) are as defined above for Formula 1. However, as mentioned earlier, some starting materials and intermediates may include protecting groups that are removed prior to the final product. In such cases, the substituent identifiers refer to the moieties defined in Formula 1 and to those moieties having appropriate protecting groups. For example, a starting material or intermediate in the scheme may include R having a potentially reactive (secondary) amine. 10 In such cases, R 10 Moieties with or without a Boc or Cbz group attached to the amine will be included.

[0400] Flow A shows the general method for preparing the compound of formula 1. According to the method, aryl or heteroaryl (alkyl or oxyalkyl) amine (A1) is reacted with carboxylic acid (A2) or a suitable base addition salt (for example, lithium salt). In the presence of non-nucleophilic base (for example, Et3N, DIPEA) and one or more compatible solvents (for example, ACN, DCM, DMA, DMF, NMP, pyridine, THF), standard amide coupling agents such as HATU, DCC, EDC hydrochloride, T3P or iodide 2-chloro-1-methylpyridin-1-ium are reacted. Amide coupling can be carried out at a temperature within the range of room temperature to about 80 DEG C. HOBt can be used to promote the reaction.

[0401]

[0402] Although not shown in Scheme A, the carboxylic acid (A2) may include an R having a protected (eg, Boc-substituted) secondary amine. 10 In such cases, following amide coupling, the amine is subsequently deprotected (e.g., by acid treatment) to reveal the secondary amine, which can be alkylated, for example, via reaction with an alkyl halide (R) in the presence of a non-nucleophilic base (e.g., KCO) and a compatible solvent (e.g., DMSO). 12 Y 1 , where R 12 =C 1-4 Alkyl and C 3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo, and Y 1 =Br, I) reaction to obtain the desired R 12 R 10 Alternatively, the secondary amine can be reacted with an 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 afford the desired R 12 R 10 The N-alkylation and reductive amination steps can be carried out at room temperature or higher.

[0403] Scheme B shows the process for preparing compounds of formula 1 (L=O, X 5 =N). According to the 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 in one or more compatible solvents at room temperature to about 80°C using a standard amide coupling agent, optionally with HOBt. The hydroxyalkylamide (B2) is then reacted with an aryl or heteroaryl reactant (B3, Y) 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 obtain a compound of formula 1. N The Ar reaction can be carried out at room temperature or higher.

[0404]

[0405] Scheme C shows a third general method for preparing compounds of Formula 1, where R 10 is azetidin-1-ylmethyl or pyrrolidin-1-ylmethyl (Formula 1A, s = 1 or 2). According to the method, an aryl or heteroaryl (alkyl or oxyalkyl) amine (A1) is reacted with an α,β-unsaturated carboxylic acid (C1). As in Process A, the reaction is carried out in one or more compatible solvents at room temperature to about 80°C using a standard amide coupling reagent, optionally with HOBt. The resulting amide (C2) is reacted with an azetidine or pyrrolidine (C3) at an elevated temperature (e.g., 50-100°C) in a protic solvent (MeOH, water) to provide a compound of Formula 1A.

[0406] The methods depicted in the schemes can be varied as desired. For example, protecting groups can be added or removed, and the product can be further refined, for example, by alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynylation, etc., to obtain the desired final product. In addition, any intermediate or final product comprising a mixture of stereoisomers can optionally be purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with an optically pure reagent as described above to obtain the desired stereoisomer.

[0407]

[0408] The biopharmaceutical properties of the compound of formula 1 (including the compounds named above) and pharmaceutically acceptable complexes, salts, solvates and hydrates thereof, such as solubility and solution stability across pH, permeability, etc., should be evaluated to select an appropriate dosage form and route of administration. The compound intended for pharmaceutical use can be administered as a crystalline or amorphous product and can be obtained, for example, in the form of a solid plug, powder or film by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying or radio frequency drying.

[0409] The compounds of formula 1 can be administered alone or in combination with one another or with one or more pharmacologically active compounds other than the compounds of formula 1. Generally, one or more of these compounds are administered in combination with one or more pharmaceutically acceptable excipients as a pharmaceutical composition (formulation). The choice of excipient depends on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Available 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 edition, 2000).

[0410] The compound of formula 1 can be administered orally. Oral administration may involve swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or in addition, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) so that the compound enters the bloodstream through the oral mucosa.

[0411] Formulations suitable for oral administration include solid, semisolid, and liquid systems, such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids, or powders; lozenges that can be filled with liquids; chewables; gels; rapidly dispersing dosage forms; films; ovules; sprays; and buccal or mucosal adhesive patches. Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropyl methylcellulose) 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 can also be prepared by reconstitution of a solid (e.g., from a pouch).

[0412] 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.

[0413] For tablet dosage forms, the active pharmaceutical ingredient (API) may comprise from about 1% to about 80% by weight of the dosage form, or more typically from about 5% to about 60% by weight of the dosage form, depending on the dose. In addition to the API, the tablet may also 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, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6Alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from about 1% to about 25% or from about 5% to about 20% by weight of the dosage form.

[0414] Binder is generally used for giving cohesive quality to tablet formulations.Suitable binder includes microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gum, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Tablet can also contain diluent, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and calcium hydrogen phosphate dihydrate.

[0415] The tablets may also contain surfactants, such as sodium lauryl sulfate and polysorbate 80; and glidants, such as silicon dioxide and talc. When present, the surfactant may comprise from about 0.2% to about 5% by weight of the tablet, and the glidant may comprise from about 0.2% to about 1% by weight of the tablet.

[0416] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants may comprise from about 0.25% to about 10% by weight or from about 0.5% to about 3% by weight of the tablet.

[0417] Tablet blends can be compressed directly or by roller compaction to form tablets. Alternatively, tablet blends or portions of blends can be subjected to wet, dry or melt granulation, melt coagulation, or extrusion before tableting. If necessary, one or more components can be fractionated by screening or grinding or both before blending. The final dosage form can comprise one or more layers and can be coated, uncoated, or encapsulated. Exemplary tablets can contain up to about 80% by weight of API, about 10% by weight to about 90% by weight of binder, about 0% by weight to about 85% by weight of diluent, about 2% by weight to about 10% by weight of disintegrant, and about 0.25% by weight to about 10% by weight of lubricant. For a discussion of blending, granulation, milling, screening, tableting, coating, and description of alternative techniques for preparing drug products, see A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H.A. Lieberman et al. (eds.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and D.K. Parikh and C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0418] Consumable oral films for human or veterinary use are soft, water-soluble or water-swellable film dosage forms that can dissolve quickly or adhere to the mucosa. In addition to the API, typical films also include one or more film-forming polymers, adhesives, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients can include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, defoamers, surfactants, and taste masking agents. Some components of the formulation can perform more than one function.

[0419] In addition to dosage requirements, the amount of API in the film may also depend on its solubility. If it is water-soluble, the API will generally comprise from about 1% to about 80% by weight of the non-solvent component (solute) in the film or from about 20% to about 50% by weight of the solute in the film. APIs with lower solubility can comprise a larger proportion of the composition, typically up to about 88% by weight of the non-solvent component in the film.

[0420] 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.

[0421] Thin-film dosage forms are typically prepared by evaporative drying of an aqueous film coated onto a peelable backing or paper, which can be performed in a drying oven or tunnel (e.g., in a combined coating-drying device), in a freeze-drying apparatus, or in a vacuum oven.

[0422] Solid preparations that can be used for oral administration may include direct 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 available release technologies, such as high-energy dispersions and osmotic and coated particles, see Verma et al., Pharmaceutical Technology On-line (2001) 25 (2): 1-14.

[0423] The compound of Formula 1 can also be administered directly into the bloodstream, muscle, or internal organs of a subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include syringes, including microneedle injectors, needle-free injectors, and infusion devices.

[0424] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (e.g., pH of about 3 to about 9). However, for some applications, the compound of Formula 1 may be more suitably formulated into sterile non-aqueous solutions or dry forms, to be used in conjunction with suitable vehicles such as sterile pyrogen-free water. Preparation of parenteral formulations under aseptic conditions (e.g., by lyophilization) may be easily accomplished using standard pharmaceutical techniques.

[0425] The solubility of the compound for preparing parenteral solution can be increased by appropriate formulation technology, such as by incorporating solubility enhancers. Preparations for parenteral administration can be formulated for direct release or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Therefore, the compound of Formula 1 can be formulated into a suspension, solid, semisolid, or thixotropic liquid for use as an implanted reservoir, thereby providing a modified release of the active compound. Examples of such preparations include drug-coated stents and semisolid and suspensions comprising drug-loaded poly (DL-lactic acid-co-glycolic acid) (PGLA) microspheres.

[0426] The compound of Formula 1 can also be applied topically, intradermally, or transdermally to the skin or mucous membranes. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers can include ethanol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol, and propylene glycol. Topical formulations can also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88 (10): 955-958 (1999).

[0427] Other means of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject TM and Bioject TM ) injection for delivery. As described above, formulations for topical administration can be formulated for immediate release or modified release.

[0428] Formula 1 compound can also be administered intranasally or by inhalation, usually in the form of dry powder, aerosol spray or nasal drops. Inhaler can be used to administer dry powder, the dry powder comprising a powder blend of a single API, API and a diluent (such as lactose) or a mixed component particle comprising API and phospholipids (such as phosphatidylcholine). For intranasal use, the powder can include a bioadhesive, for example, chitosan or cyclodextrin. Pressurized container, pump, ejector, atomizer or sprayer can be used to produce aerosol spray from a solution or suspension, the solution or suspension comprising API, one or more agents (for example, aqueous or non-aqueous EtOH) for dispersing, dissolving API or extending the release of API, one or more solvents (for example, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) as a propellant, and optional surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid. Atomizer using electrohydrodynamics can be used to produce a fine mist.

[0429] Prior to use in a dry powder or suspension formulation, the drug product is typically comminuted to a particle size suitable for delivery by inhalation (typically, 90% of the particles by volume have a maximum 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.

[0430] Capsules, blisters, and cartridges (made, for example, of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator can be formulated to contain a powder mix of the active compound; a suitable powder base such as lactose or starch; and a performance enhancer such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0431] Suitable for use in a solution formulation for use in an atomizer using electrohydrodynamics to generate a fine mist can contain about 1 μg to about 20 mg of API per actuation, and the actuation volume can vary between about 1 μL to about 100 μL. Typical formulations can include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0432] Formulations for inhaled administration, intranasal administration, or both can be formulated for direct release or modified release using, for example, PGLA. Suitable flavorings (such as menthol and levomenthol) or sweeteners (such as saccharin or saccharin sodium) can be added to formulations intended for inhaled / intranasal administration.

[0433] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered dose. The unit is typically arranged to administer a metered dose or "bolus" containing from about 10 μg to about 1000 μg of the API. The total daily dose will typically be in the range of from about 100 μg to about 10 mg, which can be administered as a single dose or, more often, as divided doses throughout the day.

[0434] The active compound can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. Formulations for rectal or vaginal administration can be formulated for immediate release or modified release, as described above.

[0435] Formula 1 compound can also be directly applied to the eye or ear, usually in the form of drops of micronized suspension or solution in pH-adjusted isotonic sterile saline. Suitable for other preparations used through the eye and ear include ointment, gel, biodegradable implant (for example, absorbable gel sponge, collagen), non-biodegradable implant (for example, silicone), wafer, lens and microparticle or vesicle system, such as vesicle (niosome) or liposome. Preparation can include one or more polymers and preservatives, such as benzalkonium chloride (benzalkonium chloride). Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer (for example, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose) and heteropolysaccharide polymer (for example, gellan gum (gelan gum)). Such preparations can also be delivered by iontophoresis. As described above, for the preparation used through the eye or through the ear, it can be formulated for direct release or modified release.

[0436] To improve their solubility, dissolution rate, taste masking, bioavailability or stability, the compounds of Formula 1 can be combined with soluble macromolecular entities, including cyclodextrins and their derivatives and polymers containing polyethylene glycol. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusive and non-inclusive complexes can be used. As an alternative to direct compounding with the API, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents or solubilizers. Alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin are commonly used to achieve these purposes. See, for example, WO91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0437] As mentioned above, one or more compounds of Formula 1 (including the compounds 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, disorders and conditions. In such cases, the active compounds can be combined into a single dosage form as described above or can be provided in a kit form suitable for co-administration of the composition. The 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 independently retaining the two pharmaceutical compositions, such as a separate bottle or a separate foil package. An example of such a kit is a well-known blister package for encapsulating 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 independent dosing time intervals, or for titrating different pharmaceutical compositions relative to each other. To help patients comply, the kit typically includes instructions for administration and can be provided with a memory aid.

[0438] For administration to human patients, the total daily dose of the claimed and disclosed compounds is generally in the range of 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 only require a total daily dose of about 0.1 mg to about 300 mg. The total daily dose can be administered in single or divided doses and, at the physician's discretion, may be outside the typical range given above. Although these doses are based on an average human subject with a mass of about 60 kg to about 70 kg, the physician will be able to determine an appropriate dose for a patient (e.g., infant) whose mass is outside this weight range.

[0439] As mentioned above, compounds of Formula 1 can be used to treat diseases, conditions, and disorders for which activation of SSTR4 is indicated. Such diseases, conditions, and disorders generally relate to any unhealthy or abnormal condition in a subject for which activation of SSTR4 provides a therapeutic benefit. More specifically, compounds of Formula 1 can be used to treat CNS diseases, conditions, or disorders, including Alzheimer's disease, as well as other forms of dementia (i.e., severe or mild neurocognitive disorders) associated with one or more medical conditions, including frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or drug use, HIV infection, prion disease, Parkinson's disease, and Huntington's disease. Compounds of Formula 1 can also be used to treat severe or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism. Additionally, compounds of Formula 1 can be used to treat anxiety and epilepsy.

[0440] The claimed and disclosed compounds can be combined with one or more other pharmacologically active compounds or therapies to treat one or more conditions, diseases, or disorders for which SSTR4 is indicated. Such combinations can provide significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity. For example, compounds of Formula 1 (including the compounds specifically named above) and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof can be administered simultaneously, sequentially, or separately with one or more compounds or therapies for treating Alzheimer's disease, including β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, such as apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid,

[0014] Examples of the compounds used to treat Alzheimer's disease include salbutazone, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate and sulindac), vitamin E, and anti-amyloid antibodies. Specific examples of compounds used to treat Alzheimer's disease include donepezil, rivastigmine, memantine, and galantamine.

[0441] In addition to drugs for improving cognition, the compounds of Formula 1 can also be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers and other drugs used to treat Alzheimer's disease. For example, the compounds of Formula 1 can be combined with one or more agents used to treat depression (antidepressants) and / or schizophrenia (atypical or typical antipsychotics), including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, dapoxetine ... boxazid), lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, vortioxetine, and ziprasidone.

[0442] Likewise, the compounds of Formula 1 can be combined with one or more agents used to treat anxiety (anxiolytics), including benzodiazepines (alprazolam, clodiazepine, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, phentermine, benzodiazepines (e.g., benzodiazepines), ... azolam), oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), nonbenzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone.

[0443] The compound of formula 1 may also be combined with one or more agents used to treat epilepsy (antiepileptic or anticonvulsant agents), including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0444] Biological activity

[0445] The biological activity of compounds of Formula 1 against SSTR4 can be determined using the following in vitro and in vivo methods.

[0446] Inhibition of Forskolin-stimulated cAMP in cells overexpressing SSTR4

[0447] 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) were purchased from DiscoverRx (product code 95-0059C2). CHO-SSTR4 cells were maintained in F12K medium containing 10% fetal bovine serum (Hyclone), 1% Pen / Strep (Life Technologies), and 800 μg / mL G418 (Life Technologies). For the assay, 3,000 cells per well were plated in 50 μL of complete medium in a white 384-well plate (Corning 3570) and allowed to attach for 16 hours in a 37°C, 5% CO2 incubator. The next day, the medium was removed from the cells, and the cells were washed (added, then removed) with Krebs Ringer Buffer (ZenBio, KRB - 1000 mL). Test compounds were suspended in DMSO and diluted in stimulation buffer: Klein-Lin buffer plus 0.5% BSA (Roche), 300 μM IBMX (Sigma), and 350 nM Forskolin (Sigma). Cells were incubated in 10 μL of compound / stimulation buffer for 30 minutes at room temperature. Cellular cAMP levels were measured using the HTRF LANCE Ultra cAMP kit (Perkin Elmer, catalog number TRF0264).

[0448] The assay was performed according to the manufacturer's instructions. 5 μL of diluted Eu-W8044-labeled streptavidin (dilution: 1:50 in cAMP assay buffer) was added to each well. 5 μL of diluted biotin-cAMP (dilution: 1:150 in cAMP assay buffer) was then added to each well. The plate was sealed and incubated on a shaker at room temperature for 60 minutes. HTRF was read on a Perkin Elmer ENVISION plate reader (665 nm / 615 nm). pEC was generated using the Activity Base for Screening Data Management. 50 value.

[0449] SSTR4 I-125 somatostatin competition binding assay

[0450] This membrane-based assay measures the ability of compounds to competitively inhibit the binding of I-125-labeled somatostatin to SSTR4 in membranes from SSTR4-overexpressing CHO-K1 cells. Membranes from SSTR4-overexpressing CHO-K1 cells were purchased from Perkin Elmer (Cat. No. ES-524-M400UA). Test compounds were suspended in DMSO and then diluted in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM CaCl2, 0.5% BSA) plus 0.2 nM I-125-labeled somatostatin (Perkin Elmer Cat. No. NEX389). 50 μL of compound / I-125 somatostatin assay buffer was added to each well of a 96-well polypropylene plate. Then, 50 μL of assay buffer containing 1 μg of SSTR4 membrane was added to each well. The plates were incubated at room temperature for 60 minutes. FilterMat A filter (Perkin Elmer catalog number 1450-421) is pre-soaked in 0.5% PEI (Sigma catalog number P3143). The contents of the assay plate are transferred to the filter with a TomTech collector and washed 5 times with 20mM HEPES, 100mM NaCl. The filter is dried in a microwave oven and then transferred to a sample bag containing a scintillator sheet (Perkin Elmer catalog number 1450-441). The scintillator sheet is melted and added to the filter using a heating block. The filter is then read in a MicroBeta scintillation counter. The active base station for screening data management is used to generate a binding Ki curve, and the results are reported as pIC 50 .

[0451] SSTR1 I-125 Somatostatin Competition Binding Assay Selective for SSTR1

[0452] This membrane-based assay measures the ability of compounds to competitively inhibit the binding of I-125-labeled somatostatin to SSTR1 in membranes from SSTR1-overexpressing CHO-K1 cells. Membranes from SSTR1-overexpressing CHO-K1 cells were purchased from Perkin Elmer (Cat. No. ES-520-M400UA). Test compounds were suspended in DMSO and then diluted in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM CaCl2, 0.5% BSA) plus 0.4 nM I-125-labeled somatostatin (Perkin Elmer Cat. No. NEX389). 50 μL of compound / I-125 somatostatin assay buffer was added to each well of a 96-well polypropylene plate. Then, 50 μL of assay buffer containing 10 μg of SSTR1 membrane was added to each well. The plates were incubated at room temperature for 60 minutes. FilterMat A filter (Perkin Elmer catalog number 1450-421) is pre-soaked in 0.5% PEI (Sigma catalog number P3143). The contents of the assay plate are transferred to the filter with a TomTech collector and washed 5 times with 20mM HEPES, 100mM NaCl. The filter is dried in a microwave oven and then transferred to a sample bag containing a scintillator sheet (Perkin Elmer catalog number 1450-441). The scintillator sheet is melted and added to the filter using a heating block. The filter is then read in a MicroBeta scintillation counter. The active base station for screening data management is used to generate a binding Ki curve, and the results are reported as pIC 50 .

[0453] In vivo screening using subcutaneous pentylene tetrazolium (PTZ)

[0454] Swiss-Webster mice, 6-8 weeks old, were used in the subcutaneous PTZ seizure model. PTZ is a GABA agonist that blocks GABA receptors, thereby disinhibiting all CNS systems and inducing seizures in animals. Seizures can be assessed and quantified by observing the animals under study. Therefore, this model provides a screening model for testing compounds with anticonvulsant activity in mice, which is derived from the compound's activity on the inhibitory receptor SSTR4. According to the method, 6- to 8-week-old Swiss-Webster mice were acclimated to the research room before the start of the experiment (1 hour). The animals (n=6 / group) were then blindly administered with vehicle or test compound, and PTZ was administered subcutaneously 15 minutes later. The animals were scored based on the time it took for the animal to have a seizure and weaken its ability to stand. This time was calculated as the latency to seizure. The number and severity of seizures were also scored, but were not used in the final data.

[0455] Example

[0456] The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the invention.

[0457] In the following examples, a number of compounds were obtained 1 H nuclear magnetic resonance (NMR) spectroscopy. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, using conventional abbreviations for designating major peaks, 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] + m / z).

[0458] Where indicated, the products of certain preparations and examples were purified by mass-triggered HPLC, flash chromatography, preparative TLC, or SFC. Reverse phase chromatography was performed on a C18, 5 μm, ID 30 mm x 150 mm) under acidic conditions (“acidic mode”) with ACN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or under basic conditions (“basic mode”, pH 9.5-10) with water and a 20 / 80 (v / v) water / acetonitrile mobile phase (both containing 10 mM NH4HCO3). Typically, the chromatography was performed on silica gel 60F 254 Preparative TLC was performed on the plate. The preparation and examples may employ SFC to separate the enantiomers. After separation by chromatography, the solvent was removed and the mixture was concentrated by centrifugal evaporation (e.g., GeneVac TM ), rotary evaporator, vacuum flask, etc. to obtain the product. The reaction is usually carried out at a pressure of about 1 atmosphere (14.7 psi) in an inert (e.g., nitrogen) or reactive (e.g., H2) atmosphere.

[0459] Preparation 1: 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine

[0460]

[0461] Step A: tert-Butyl (1-(3-chloro-2-fluorophenyl)-1-hydroxy-2-methylpropan-2-yl)carbamate

[0462]

[0463] At -78 ° C, to a solution of 1-chloro-2-fluorobenzene (5.3 g, 40.6 mmol) in THF (60 mL) was added dropwise n-BuLi (1.6 M in hexane, 16 mL, 25.6 mmol). The 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 for another hour at -78 ° C, then poured into a saturated NH4Cl aqueous solution (80 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using a gradient of petroleum ether / EtOAc (1:0 to 10:1) to give the title compound (3.1 g, 86%) as a white solid. ESI-MS m / z [M+H] + 318.1.

[0464] Step B: tert-Butyl (1-(3-chloro-2-fluorophenyl)-2-methyl-1-oxopropan-2-yl)carbamate

[0465]

[0466] To a solution of tert-butyl (1-(3-chloro-2-fluorophenyl)-1-hydroxy-2-methylprop-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 NaHCO3 aqueous solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (150 mL x2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 10: 1) to give the title compound (2.3 g, 81%) as a white solid. ESI-MS m / z[M+H] + 316.1.

[0467] Step C: tert-Butyl (Z)-(1-(3-chloro-2-fluorophenyl)-1-(hydroxyimino)-2-methylpropan-2-yl)carbamate

[0468]

[0469] 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 hours, then diluted with water (20 mL) and extracted with EtOAc (100 mL x2). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 5: 1) to give the title compound (2.1 g, 87%) as a white solid. ESI-MS m / z [M + H] + 331.1.

[0470] Step D: tert-Butyl (2-(7-chlorobenzo[d]isoxazol-3-yl)propan-2-yl)carbamate

[0471]

[0472] To (Z)-(1-(3-chloro-2-fluorophenyl)-1-(hydroxyimino)-2-methylprop-2-yl) t-butyl carbamate (500mg, 1.44mmol) in THF (160mL) solution, add t-BuOK (483mg, 4.31mmol).The mixture was stirred at 25 ℃ for 2 hours.Use other three batches of (Z)-(1-(3-chloro-2-fluorophenyl)-1-(hydroxyimino)-2-methylprop-2-yl) t-butyl carbamate (30mg, 300mg and 500mg) to repeat the reaction.Four batches are merged and diluted with EtOAc (300mL).Wash organic layer with water (300mL x2), then wash with salt solution (300mL x2), through Na SO Drying, filter, and concentrate in a vacuum. The residue was purified by flash column chromatography on silica gel using a gradient of petroleum ether / EtOAc (1:0 to 5:1) to give the title compound (900 mg, 64% yield, 94% purity) as a white solid. ESI-MS m / z [M+H] + 311.1.

[0473] Step E: tert-Butyl (2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)carbamate

[0474]

[0475] 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) 2 (122 mg, 544 μmol), K 3 PO 4 (2.89 g, 13.6 mmol) and SPhos (224 mg, 544 μmol) in toluene (20 mL) was degassed and purged with nitrogen (3x). The mixture was stirred at 120 ° C under a nitrogen atmosphere for 12 hours and then concentrated in vacuo. The residue was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 3: 1) to give the title compound (600 mg, 71%) as a white solid. ESI-MS m / z [M + H] + 291.1.

[0476] Step F: 2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-amine

[0477] To a solution of tert-butyl (2- (7- methylbenzo [d] isoxazole -3- bases) 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 hours and then concentrated in vacuo. The residue was diluted with EtOAc (20 mL) and washed with Na2CO3 aqueous solution (3x20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel preparative TLC using DCM / MeOH (10: 1) as eluent to give the title compound (203.4 mg, 58%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 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.

[0478] Preparation 2: 2-(Isoquinolin-1-yl)propan-2-amine

[0479]

[0480] Step A: (R,E)-N-(1-(Isoquinolin-1-yl)ethylidene)-2-methylpropane-2-sulfenamide

[0481]

[0482] To a solution of 1-(1-isoquinolinyl)ethanone (9.00 g, 52.6 mmol) in THF (100 mL) was added (R)-2-methylpropane-2-sulfenamide (7.65 g, 63.1 mmol) and Ti(OEt)4 (17.4 mL, 84.1 mmol) at 15°C. The mixture was stirred at 70°C under nitrogen for 8 hours, then diluted with EtOAc (100 mL) and quenched with water (5 mL) at 0°C. The mixture was stirred for 0.5 hours and allowed to stand for 1 hour. The resulting brown suspension was filtered through a pad. The filtrate was washed with brine (10 mL 3x), dried, filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1:0 to 3:1) to give the title compound (5.7 g, 39%). ESI-MS m / z [M+H] + 275.1.

[0483] Step B: (R)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-methylpropane-2-sulfenamide

[0484]

[0485] To a solution of (R,E)-N-(1-(isoquinolin-1-yl)ethylidene)-2-methylpropane-2-sulfenamide (13.5 g, 49.2 mmol) in toluene (260 mL) was added MeMgBr (3 M in Et2O, 49.2 mL) at 0°C. The mixture was stirred under nitrogen at 0°C for 2 hours and then quenched with saturated aqueous NH4Cl solution (150 mL) at 0°C. The mixture was warmed to 15°C and extracted with EtOAc (3x200 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1:0 to 1:1) to give the title compound (10 g, 70%). ESI-MS m / z[M+H] + 291.1.

[0486] Step C: 2-(Isoquinolin-1-yl)propan-2-amine

[0487] 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 hours and then concentrated in vacuo. The crude product was triturated with EtOAc (3 x 20 mL) at 15°C for 0.5 hours. The resulting suspension was filtered and the filter cake was dried under vacuum to give the dihydrochloride salt of the title compound (3.9 g, 87%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 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.

[0488] Preparation 3: 3-(azetidin-1-yl)-2-methylpropanoic acid

[0489]

[0490] Step A: Methyl 3-(azetidin-1-yl)-2-methylpropanoate

[0491]

[0492] To a round-bottom flask containing MeOH (4mL) containing methyl 2-methylprop-2-enoate (5.91g, 59.1mmol) was added azetidine (1.00g, 17.5mmol). The reaction mixture was stirred at 15°C for 16 hours, then quenched with water (100mL) and extracted with DCM (80mL). The organic layer was washed with water (2x50mL) and brine (2x50mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using DCM as eluent to give the title compound (0.8g, 29%) as a colorless oil. ESI-MS m / z[M+H] + 158.1.

[0493] Step B: 3-(azetidin-1-yl)-2-methylpropanoic acid

[0494] To a round-bottom flask containing THF (5 mL) containing methyl 3- (azetidine -1- bases) -2-methylpropanoate (0.2 g, 1.27 mmol) was added LiOH.HO (2M aqueous solution, 1.11 mL, 2.22 mmol). The reaction mixture was stirred at 15 ° C for 16 hours and then diluted with EtOAc (10 mL). The aqueous layer was adjusted to pH 5-6 with HCl (1 M), washed with DCM (2x30 mL) and lyophilized to give the hydrochloride (270 mg) of the title compound as a white semi-solid. 1 H NMR (400MHz, CD3OD) δppm 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.

[0495] Preparation 4: 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropan-1-amine

[0496]

[0497] To a solution of (1-aminocyclopropyl)methanol hydrochloride (3.80 g, 30.8 mmol) in dioxane (80 mL) was added portionwise NaH (60 wt %, in mineral oil, 1.73 g, 43.2 mmol) at 20 ° C. The mixture was stirred for 30 minutes. Then, 2-fluoro-3-methylpyridine (1.09 mL, 10.8 mmol) was added. The reaction mixture was stirred at 100 ° C for 68.5 hours, then diluted with water (50 mL) and extracted with DCM (2x300 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative HPLC (Phenomenex C18, 10 μm, ID 25 mm×150 mm) and purified using a gradient of 23-53% water (containing 0.04% NH 4 OH and 10 mM NH 4 HCO 3 ) in ACN. The fractions containing product were concentrated to give the title compound (142 mg, 28%) as a light yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 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.

[0498] Preparation 5: 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutan-1-amine

[0499]

[0500] The title compound was prepared in analogy to Preparation 4 using (1-aminocyclobutyl)methanol (1.37 g, 13.5 mmol) and obtained as a light yellow oil (152.2 mg, 17.5%). 1 H NMR(400MHz,DMSO-d6)δppm 1.57-1.74(m,2H),1.77-1.86(m,2H),2.01(br d,J=8.3Hz,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=2.9Hz,1H); ESI-MS m / z[M+H] + 193.2.

[0501] Preparation 6: 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentan-1-amine

[0502]

[0503] The title compound was prepared in analogy to Preparation 4 using (1-aminocyclopentyl)methanol (1.55 g, 13.5 mmol) and obtained as a light yellow oil (110 mg, 12%). 1 H NMR(400MHz,DMSO-d6)δppm 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.

[0504] Preparation 7: (R)-2-(1-methylpyrrolidin-2-yl)acetic acid

[0505]

[0506] Pd / C (10 wt %, 800 mg) was added to MeOH (40 mL) containing (R)-2-(pyrrolidin-2-yl)acetic acid hydrochloride (2.5 g, 15.1 mmol) and formaldehyde (37 wt %, 5.84 mL, 78.5 mmol). The mixture was stirred at 30 ° C under H (50 psi) for 16 hours and then filtered. The filtrate was concentrated in vacuo and then dissolved in EtOAc (10 mL). The mixture was stirred for 20 minutes. The solid was collected by filtration and co-evaporated with toluene (2 mL) to give the hydrochloride (2.4 g, 89%) of the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 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.

[0507] Preparation 8: (S)-2-(1-methylpyrrolidin-2-yl)acetic acid

[0508]

[0509] The hydrochloride salt of the title compound was prepared in analogy to Preparation 7 using (S)-2-(pyrrolidin-2-yl)acetic acid hydrochloride (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)δppm ESI-MS m / z[M+H] + 144.2.

[0510] Preparation 9: 2-(3-fluoro-2-methoxyphenyl)propan-2-amine

[0511]

[0512] Step A: 2-(3-Fluoro-2-methoxyphenyl)propan-2-ol

[0513]

[0514] To a solution of 1-bromo-3-fluoro-2-methoxybenzene (1.00 g, 4.88 mmol) in THF (20 mL) was added dropwise i-PrMgCl (2.0 M in THF, 5.37 mL, 10.7 mmol) at 0 ° C under nitrogen. The mixture was stirred for 2 hours at 0 ° C. Then, THF (5 mL) containing acetone (340 mg, 5.85 mmol) was added. The reaction mixture was stirred for another 30 minutes at 0 ° C., then quenched with saturated NH4Cl aqueous solution (50 mL) at 20 ° C. and extracted with EtOAc (2x50 mL). The combined organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 3: 1) to give the title compound (197 mg, 20% yield, 90% purity). ESI-MS m / z [M-OH] + 167.1.

[0515] Step B: 2-(3-Fluoro-2-methoxyphenyl)propan-2-amine

[0516] 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) at 20°C under nitrogen. The reaction mixture was stirred at 20°C for 30 minutes, then quenched with NaHCO (20 mL) at 20°C and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 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 hours, then quenched with water (2 mL). The mixture was treated with an aqueous NaOH solution (2M, 2mL) at 20°C, diluted with brine (50mL) and extracted with EtOAc (2x30mL). The combined organic layer was dried, filtered, and concentrated under reduced pressure to give a crude product. A second batch was prepared from 2-(3-fluoro-2-methoxy-phenyl)propan-2-ol (196mg, 0.958mmol). Two batches were combined and treated with HCl (4M in dioxane, 10mL, 40.0mmol), stirred at 20°C for 2 minutes, concentrated to dryness and washed with EtOAc (2x20mL) to give the hydrochloride (800mg, 36%) of the title compound. 1H NMR (400MHz, CD3OD) δppm1.76 (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.

[0517] Preparation 10: 2-(3-chloro-2-methoxyphenyl)propan-2-amine

[0518]

[0519] Step A: 2-(3-chloro-2-methoxyphenyl)propan-2-ol

[0520]

[0521] To a solution of methyl 3-chloro-2-methoxybenzoate (2.00 g, 9.97 mmol) in THF (40 mL) was added dropwise MeMgBr solution (3.0 M in Et2O, 7.31 mL) at -78 ° C under nitrogen. After 10 minutes, the reaction mixture was warmed to 20 ° C and stirred at 20 ° C for 4 hours. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (50 mL) at 0 ° C and extracted with EtOAc (2x30 mL). The combined organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 20: 1) to give the title compound (1.75 g, 83% yield, 95% purity) as a light yellow oil. ESI-MS m / z [M-OH] + 183.1.

[0522] Step B: 2-(3-chloro-2-methoxyphenyl)propan-2-amine

[0523] The title compound was prepared analogously to step B of Preparation 9, where 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) were reacted in toluene (30 mL) to give the azide, which was subsequently treated with LiAlH (1 M in THF, 8.72 mL) in THF (20 mL). Acid treatment (4 M HCl in dioxane, 10 mL) gave the hydrochloride salt of the title compound as a white solid (1.0 g, 49%). ESI-MS m / z [M-NH] + 183.1.

[0524] Preparation 11: 2-(2-methoxy-3-methylphenyl)propan-2-amine

[0525]

[0526] The hydrochloride salt of the title compound was prepared in analogy to Preparation 10 using methyl 2-methoxy-3-methylbenzoate (1.50 g, 8.32 mmol) and MeMgBr (3.0 M in Et2O, 6.10 mL, 18.3 mmol) in THF (10 mL) to obtain a white solid (600 mg, 33% over two steps). ESI-MS m / z [M-NH2] + 163.1.

[0527] Preparation 12: 2-(3-chloro-2-methylphenyl)propan-2-amine

[0528]

[0529] Step A: 2-(3-chloro-2-methylphenyl)propan-2-ol

[0530]

[0531] To a solution of 1- bromo -3- chloro -2- methylbenzene (5.00g, 24.3mmol) in THF (30mL) was added dropwise n-BuLi (2.5M, in hexane, 10.7mL) at -78°C under nitrogen. The mixture was stirred for 1 hour at -78°C. Then, THF (10mL) containing acetone (1.97mL, 26.8mmol) was added and the mixture was stirred for another 30 minutes at -78°C, then warmed to 20°C. The reaction mixture was stirred at 20°C for 12 hours, then quenched with saturated NH4Cl aqueous solution (50mL) at 20°C and extracted with EtOAc (2x50mL). The combined organic layer was dried, filtered and concentrated under reduced pressure. By flash silica gel column chromatography, the crude product was purified using the gradient of petroleum ether / EtOAc (1:0 to 5:1) to obtain the title compound (3.0g, 67% yield, 95% purity) as a light yellow oil. ESI-MS m / z[M-OH] + 167.1.

[0532] Step B: 2-(3-chloro-2-methylphenyl)propan-2-amine

[0533] The title compound was prepared analogously to step B of Preparation 9, where 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) were reacted in toluene (20 mL) to give the azide, which was then treated with LiAlH (1 M in THF, 8.12 mL, 8.12 mmol) in THF (10 mL). Acid treatment (4 M HCl in dioxane, 10 mL, 40.0 mmol) gave the hydrochloride salt of the title compound (600 mg, 33%) as a white solid. ESI-MS m / z [M-NH] + 167.1.

[0534] Preparation 13: 2-(2,3-difluorophenyl)propan-2-amine

[0535]

[0536] A mixture of CeCl3 (4.25 g, 17.2 mmol) in THF (15 mL) was stirred at 20 ° C under nitrogen 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. Then, THF (10 mL) containing 2,3-difluorobenzonitrile (800 mg, 5.75 mmol) 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 and dried over 40 ° C. In the mixture of 4-nitro- 4-nitro-2-oxo-2-oxo-4-oxo-5-nitro-2-oxo-3 ... 1 H NMR (400MHz, CD3OD) δppm 1.80 (s, 6H), 7.19-7.33 (m, 2H), 7.34-7.42 (m, 1H); ESI-MS m / z [M+H] + 172.2.

[0537] Preparation 14: 2-(3-fluoro-2-methylphenyl)propan-2-amine

[0538]

[0539] The hydrochloride salt of the title compound was prepared similarly to Preparation 13 using 3-fluoro-2-methylbenzonitrile (800 mg, 5.92 mmol), CeCl 3 (4.38 g, 17.8 mmol) and MeLi (3.1 M, 5.7 mL, 17.7 mmol) in THF (25 mL) to obtain a white solid (400 mg, 32%). ESI-MS m / z [M-NH 2] + 151.1.

[0540] Preparation 15: 2-(3-chloro-2-fluorophenyl)propan-2-amine

[0541]

[0542] The hydrochloride salt of the title compound was prepared similarly to Preparation 13 using 3-chloro-2-fluorobenzonitrile (800 mg, 5.14 mmol), CeCl3 (4.30 g, 17.4 mmol) and MeLi (3.1 M, 5.6 mL, 17.4 mmol) in THF (25 mL) to obtain a white solid (600 mg, 52%). ESI-MS m / z [M+H] + 188.6.

[0543] Preparation 16: 2-(2-chloro-3-methylphenyl)propan-2-amine

[0544]

[0545] The hydrochloride salt of the title compound was prepared in analogy 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) to obtain a white solid (300 mg, 25%). ESI-MS m / z [M+H] + 184.1.

[0546] Preparation 17: 2-(2,3-dichlorophenyl)propan-2-amine

[0547]

[0548] The hydrochloride salt of the title compound was prepared similarly to Preparation 13 using 2,3-dichlorobenzonitrile (1.00 g, 5.81 mmol), CeCl3 (3.80 g, 15.3 mmol) and MeLi (3.1 M, 4.95 mL, 15.3 mmol) in THF (25 mL) to obtain a white solid (650 mg, 46%). ESI-MS m / z [M+H] + 205.1.

[0549] Preparation 18: 2-(1-methylpyrrolidin-2-yl)propanoic acid

[0550]

[0551] Step A: tert-Butyl 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[0552]

[0553] Diazomethyl(trimethyl)silane (2M 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 hours and then concentrated under vacuum. The product was purified by column chromatography eluting with petroleum ether / EtOAc (10: 1). The pure fraction was concentrated to give the title compound (3.0 g, 94%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δppm 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).

[0554] Step B: tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0555]

[0556] To a round-bottom flask containing THF (5mL) containing LiHMDS (1M, in THF, 12.3mL, 12.3mmol) was added THF (2mL) containing tert-butyl 2-(2-methoxy-2-oxoethyl) pyrrolidine-1-carboxylate (1.00g, 4.11mmol) at -78°C. The reaction mixture was stirred for 1 hour at -78°C. A solution of MeI (1.23mL, 19.7mmol) and HMPA (1.08mL, 6.17mmol) in THF (3mL) was then added. The reaction mixture was stirred for another 4 hours at -78°C, then diluted with saturated NH4Cl aqueous solution (30mL) and extracted with EtOAc (2x50mL). The combined organic layer was washed with brine (20mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative HPLC (Phenomenex C18, 10 μm, ID 25 mm×150 mm) and the product was purified using a gradient of 50-80% water (with 0.05% NH 4 OH) in ACN to give the title compound (0.40 g, 35%) as a light yellow oil.

[0557] Step C: Methyl 2-(pyrrolidin-2-yl)propanoate

[0558]

[0559] To a round-bottom flask containing DCM (5 mL) containing tert-butyl 2-(1-methoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.40 g, 1.55 mmol) was added TFA (1.23 g, 10.8 mmol). The reaction mixture was stirred at 15 ° C for 3 hours, then poured into ice water (5 mL) and adjusted to pH 10 by adding saturated Na2CO3 aqueous solution. The aqueous phase was extracted with DCM (2x50 mL), and the combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (330.0 mg) as a light yellow oil. ESI-MS m / z[M+H] + 158.1.

[0560] Step D: Methyl 2-(1-methylpyrrolidin-2-yl)propanoate

[0561]

[0562] To the round-bottom flask containing DCE (3mL) of 2-(pyrrolidin-2-yl) methyl propionate (0.120g, 763μmol), formaldehyde solution (37 weight %, 227μL, 3.05mmol) and NaBH (OAc) (647mg, 3.05mmol) are added. The reaction mixture is stirred at 15°C for 2 hours, then quenched with water (5mL) and saturated NaCO aqueous solution (5mL) and extracted with DCM (2x20mL). The combined organic layer is washed with salt water (3x10mL), through NaSO dry, filtered and concentrated in vacuo to obtain the title compound (90.0mg, 68%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δppm1.11(d,J=7.1Hz,1H),1.18(d,J=7.1Hz,3H),1.58-1.78(m,3H),1.84(q,J=7.7Hz, 2H),2.29(s,1H),2.34(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).

[0563] Step E: 2-(1-methylpyrrolidin-2-yl)propanoic acid

[0564] 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 mixture was stirred at 90° C. for 16 hours and then concentrated in vacuo to give the hydrochloride salt of the title compound (142 mg) as a light yellow gum. 1 H NMR(400MHz,CD3OD)δppm 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).

[0565] Preparation 19: (S)-2-(azetidin-1-ylmethyl)butanoic acid

[0566]

[0567] Step A: Ethyl 2-methylenebutyrate

[0568]

[0569] To a solution of ethyl 2-ethyl-3-oxo-butyrate (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 hours. Paraformaldehyde (57.5 g, 633 mmol) was added. The mixture was stirred at 25°C under nitrogen atmosphere for 16.5 hours and then The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with petroleum ether / EtOAc (10:1) to give the title compound (35 g, 86%) as a pale yellow liquid. 1 HNMR (400MHz, CDCl3) δppm 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).

[0570] Step B: Ethyl 2-(azetidin-1-ylmethyl)butanoate

[0571]

[0572] To a solution of azetidine hydrochloride (28.1g, 300mmol) in ethanol (180mL) is added EtN (117.8mL, 846.5mmol) and ethyl 2-methylenebutanoate (35g, 273mmol). The mixture is stirred at 25°C for 16 hours. The reaction mixture is merged with the second batch (45g) of reactants and poured into water (400mL) and extracted with DCM (2x400mL). The combined organic layer is washed with brine (400mL), dried over sodium sulfate and concentrated. By flash silica gel column chromatography, the crude product is purified using the gradient of petroleum ether / EtOAc (10: 1 to 1: 1) to obtain the title compound (50g) as a light yellow liquid, which is used without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 0.88 (t, J = 7.5 Hz, 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, 5.6 Hz, 1H), 2.40 (dd, J = 11.5, 5.6 Hz, 1H), 2.67 (dd, J = 11.5, 8.8 Hz, 1H), 3.15 (sextet, J = 6.8 Hz, 4H), 4.11-4.17 (m, 2H).

[0573] Step C: Lithium 2-(azetidin-1-ylmethyl)butyrate

[0574]

[0575] 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 hours and then concentrated to dryness to give the title compound as a light yellow solid, which was used without purification (40 g, 91% yield). 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0576] Step D: (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)butanoate

[0577]

[0578] To the mixture of 2- (azetidine -1- ylmethyl) butyrate lithium (38g, 233mmol) and (S) -1- phenyl ethyl -1- alcohol (38.1g, 312mmol) in DMF (400mL), EDC (89.3g, 466mmol) and DMAP (56.9g, 466mmol) are added. The mixture is stirred at 25 DEG C for 16 hours, then poured into water (250mL) and extracted with EtOAc (2x350mL). The combined organic layer is washed with brine (400mL), dried over sodium sulfate and concentrated. Reactant mixture is merged with other three batches of (24g and 2x1g) reactants and passed through flash silica gel column chromatography, purified using the gradient of petroleum ether / EtOAc (10: 1 to 1: 1) to obtain colorless oil (90g, crude material). The oil was further purified by flash column chromatography on silica gel using a gradient of petroleum ether / EtOAc (1:0 to 5:1). The resulting colorless liquid (84 g) was further purified by preparative HPLC (YMC Triart C18, 7 μm, ID 50 mm x 250 mm) using a gradient of 45-74% ACN (containing 0.04% NH 4 OH + 10 mM NH 4 HCO 3 ) in water to give the title compound (38 g) as a yellow liquid. 1HNMR (400 MHz, 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 (quintet, J = 6.2 Hz, 1H), 7.19-7.49 (m, 5H); ESI-MS m / z [M+H] + 262.2.

[0579] Step E: (R)-(S)-1-phenylethyl 2-(azetidin-1-ylmethyl)butanoate and (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)butanoate

[0580]

[0581] The title diastereomer of (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)butanoate (35 g, 134 mmol) was separated by preparative SFC (Daicel ChiralCel OD, 10 μm, ID 50 mm x 250 mm) using a mobile phase of 20% isopropanol (containing 0.1% NH₄OH) in CO₂. The (S,R)-diastereomer was the first to elute as a colorless oil. The (S,S)-diastereomer was the second to elute as a colorless oil (17.4 g), with some (S,R) isomer remaining. The impure (S,S) diastereomer (16 g) was further separated by preparative SFC (Daicel ChiralPak IC, 10 μm, ID 50 mm x 250 mm) using a mobile phase of 20% isopropanol (containing 0.1% NH 4 OH) in CO 2 to afford the title (S,S)-diastereomer (4.80 g, 95% purity, 99% ee) as a pale yellow oil. The crude (S,S)-diastereomer (8 g, 78% purity) was also recovered as a pale yellow oil. ESI-MS m / z [M+H] + 262.2.

[0582] Step F: (S)-2-(azetidin-1-ylmethyl)butanoic acid

[0583] To a suspension of Pd(OH)2 / carbon (20 wt%, 1.44 g, 2.05 mmol) in methanol (100 mL) was added (S)-1-phenylethyl 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 at 25°C under a hydrogen balloon (15 psi) for 16 hours and then filtered. The mixture was stirred for 2 hours at room temperature for 3 hours.The pad was filtered and the filter cake was washed with methanol (30 mL).The combined washings and filtrate were concentrated to dryness to give the title compound (2.81 g) as an off-white solid. The crude product was dissolved in acetonitrile (40 mL) and concentrated to dryness to give the title compound (2.7 g, 99% purity) as an off-white solid. 1 H NMR (400 MHz, CD3OD) δ ppm 0.97 (t, J = 7.5 Hz, 3H), 1.47-1.59 (m, 1H), 1.59-1.72 (m, 1H), 2.26-2.36 (m, 1H), 2.46 (quintet, J = 8.1 Hz, 2H), 3.13 (dd, J = 12.3, 3.8 Hz, 1H), 3.26 (d, J = 11.0 Hz, 1H), 4.04-4.22 (m, 4H); ESI-MS m / z [M+H] + 158.0.

[0584] Preparation 20: (S)-2-(azetidin-1-ylmethyl)-3-methylbutanoic acid

[0585]

[0586] Step A: Ethyl 3-methyl-2-methylenebutanoate

[0587]

[0588] To a mixture of ethyl 2-acetyl-3-methyl-butyrate (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 hours. Paraformaldehyde (49.4 g, 549 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours and then The mixture was filtered through a pad of Celite® while washing the filter cake with petroleum ether (50 mL). The combined washings and filtrate were purified by silica gel column chromatography using a gradient of petroleum ether / EtOAc (1:0 to 5:1) to give the title compound (140 g, 30% purity) as a colorless liquid which was used without additional purification.

[0589] Step B: Ethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0590]

[0591] To a mixture of ethyl 3-methyl-2-methylenebutanoate (30g, 63.3mmol) and azetidine hydrochloride (8.88g, 94.9mmol) in ethanol (50mL) is added EtN (44.0mL, 316mmol). The mixture is stirred at 25 DEG C for 16 hours. The reaction mixture is merged with two other batches of (8g and 110g) reactants, and diluted with water (1500mL) and extracted with EtOAc (3x500mL). The combined organic layer is dried over sodium sulfate and concentrated. By flash silica gel column chromatography, the crude product is purified using the gradient of petroleum ether / EtOAc (1:0 to 2:1) to obtain the title compound (42g) as a colorless liquid. 1 H NMR (400MHz, CDCl3) δppm 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),

[0592] 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).

[0593] Step C: Lithium 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0594]

[0595] To a solution of ethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate (20 g, 100 mmol) in ethanol (200 mL) was added aqueous lithium hydroxide solution (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 (17.8 g, assumed to be quantitative) was obtained as a white solid and used without purification. 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0596] Step D: (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0597]

[0598] To a mixture of 2- (azetidine -1- ylmethyl) -3- methylbutanoic acid lithium (17.8g, 100mmol) and (S) -1- phenyl ethyl -1- alcohol (16.4g, 135mmol) in DMF (180mL) DMAP (14.3g, 117mmol) was added, followed by EDC (22.5g, 117mmol). The reaction mixture was stirred at 25 ° C for 12 hours, then diluted with water (150mL) and extracted with EtOAc (3x100mL). Over Na SO The combined organic layer was dried, concentrated, and purified using a gradient of petroleum ether / EtOAc (1: 0 to 5: 1) on a flash silica gel column chromatography to give a colorless liquid (15g). The colorless liquid was further purified by preparative HPLC (YMC Triart C18, 7 μm, ID 50 mm×250 mm) using a gradient of 45-77% ACN (0.04% NH 4 OH+10 mM NH 4 HCO 3 ) in water to give the title compound (6.5 g, 23%) as a yellow oil. 1 HNMR(400MHz,CDCl3)δppm 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.

[0599] Step E: (R)-(S)-1-phenylethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate and (S)-1-phenylethyl 2-(azetidin-1-ylmethyl)-3-methylbutanoate

[0600]

[0601] The title diastereomer of (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, ID 30 mm x 250 mm) using a mobile phase of 25% isopropanol (containing 0.1% NH OH) in CO . The (S,R)-diastereomer 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 = 6.8 Hz, 3H), 1.77-1.88 (m, 1H), 1.83 (dq, J = 13.7, 6.8 Hz, 1H), 2.00 (quintet, J = 7.0 Hz, 2H), 2.19 (ddd, J = 10.5, 7.2, 4.4 Hz, 1H), 2.43 (dd, J = 11.4, 4.4 Hz, 1H), 2.66-2.79 (m, 1H), 3.05-3.26 (m, 4H), 5.94 (q, J = 6.5 Hz, 1H), 7.19-7.44 (m, 6H); ESI-MS m / z [M+H] + 276.2. The (S,S)-diastereomer was the second to elute and was obtained as a colorless oil (2.8 g, 43%). 1 HNMR(400MHz,CDCl3)δppm 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.

[0602] Step F: (S)-2-(azetidin-1-ylmethyl)-3-methylbutanoic acid

[0603] To a solution of (S)-2-(azetidin-1-ylmethyl)-3-methylbutanoate (2.8 g, 10.2 mmol) in methanol (60 mL) was added Pd(OH)2 / carbon (20 wt%, 500 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 25 ° C under hydrogen (15 psi) for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (1.73 g, 94%) as an off-white solid. 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0604] Preparation 21: (S)-3-(azetidin-1-yl)-2-methylpropanoic acid

[0605]

[0606] Step A: Benzyl 3-(azetidin-1-yl)-2-methylpropanoate

[0607]

[0608] To the round-bottom flask containing the methanol (10mL) of azetidine hydrochloride (5.31g, 56.8mmol), Et is added N (8.69mL, 62.4mmol) and benzyl methacrylate (10.0g, 56.8mmol). The reaction mixture is stirred at 15 DEG C for 16 hours, then quenched with water (500mL) and extracted with EtOAc (2x500mL). The organic layer is washed with the HCl aqueous solution (2M, 200mL). With KCOThe aqueous layer is adjusted to pH 10 by the aqueous solution, then extracted with EtOAc (2x500mL). The organic layer is washed with salt water (2x100mL), through NaSODry, filtered and concentrated under reduced pressure to obtain the title compound (6.0g, 43%, 95% purity) in a light yellow oil. 1 H NMR (400MHz, CDCl3) δppm 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).

[0609] Step B: (R)-Benzyl 3-(azetidin-1-yl)-2-methylpropanoate and (S)-Benzyl 3-(azetidin-1-yl)-2-methylpropanoate

[0610]

[0611] 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, ID 50 mm x 250 mm) using a gradient of 5-15% isopropanol (containing 0.1% NH OH) in CO to provide the title compound. Stereochemistry was arbitrarily assigned. Both the (S)-enantiomer (1.8 g, 99% ee) and the (R)-enantiomer (2.7 g, 95% purity, 96.3% ee) were obtained as light yellow oils. 1 H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J = 7.1 Hz, 3H), 2.01-2.09 (m, 2H), 2.43 (dd, J = 11.4, 6.2 Hz, 1H), 2.53 (sextet, J = 6.9 Hz, 1H), 2.75 (dd, J = 11.4, 7.7 Hz, 1H), 3.19 (sextet, J = 6.8 Hz, 4H), 5.14 (s, 2H), 7.29-7.40 (m, 5H); ESI-MS m / z [M+H] + 234.1.

[0612] Step C: (S)-3-(azetidin-1-yl)-2-methylpropanoic acid

[0613] To methanol (15 mL) containing (S)-3-(azetidin-1-yl)-2-methylpropanoate (1.05 g, 4.50 mmol) was added Pd(OH)2 / 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 at 25 ° C under hydrogen (15 psi) for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (561.3 mg, 86%) as a light yellow oil. 1 H NMR (400MHz, CD3OD) δppm1.16 (d, J = 7.3Hz, 3H), 2.40-2.52 (m, 3H), 3.08-3.14 (m, 1H), 3.20-3.28 (m, 1H), 4.07-4.22 (m, 4H); ESI-MS m / z [M+H] + 144.2.

[0614] Preparation 22: (R)-3-(azetidin-1-yl)-2-methylpropanoic acid

[0615]

[0616] The title compound was prepared in analogy to step C of Preparation 21 using (R)-benzyl 3-(azetidin-1-yl)-2-methylpropanoate. ESI-MS m / z [M+H] + 144.2.

[0617] Preparation 23: 2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-amine

[0618]

[0619] Step A: 1,7-Dimethyl-1H-indazole-3-carbonitrile

[0620]

[0621] 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) at 0 ° C. The reaction mixture was stirred for 20 minutes while warming to room temperature. Iodomethane (0.475 mL, 7.63 mmol) was added and the mixture was stirred at room temperature overnight and then quenched with water (200 mL). The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (1.00 g, 92%) as a white solid. ESI-MS m / z [M + H] + 172.1.

[0622] Step B: 2-(1,7-Dimethyl-1H-indazol-3-yl)propan-2-amine

[0623] 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. Methyl lithium-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 stirred at room temperature overnight. The reactants were quenched with saturated NH4Cl aqueous solution (20 mL). Subsequently, NaOH aqueous solution (50%) was added until a precipitate was formed. The mixture was filtered 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 gel column chromatography to give the title compound (0.420 g, 35%) as an off-white solid. ESI-MS m / z [M-NH2] + 187.2.

[0624] Preparation 24: 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine

[0625]

[0626] In a 125mL round-bottom flask, 2-amino-2-methylpropan-1-ol (3.45mL, 36.0mmol) was dissolved in dioxane (16mL) to give a colorless solution. The reaction mixture was cooled to 0°C and sodium hydride (60% by weight, 1.51g, 37.8mmol) was added portionwise. After stirring for 20 minutes, 2-fluoro-3-methylpyridine (1.00g, 9.00mmol) 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 (2.06g, 78% purity) as a yellow oil, which was used without further purification. ESI-MS m / z[M+H] + 181.1.

[0627] Preparation 25: 1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-amine

[0628]

[0629] In a 250mL round-bottom flask, 2-amino-2-methylpropan-1-ol (2.42g, 27.2mmol) was dissolved in dioxane (13.6mL) to give a colorless solution. The solution was cooled to 0°C and sodium hydride (60% by weight, 1.14g, 28.6mmol) was added. After 20 minutes, a solution of 3-(difluoromethyl)-2-fluoropyridine (1.00g, 6.80mmol) in dioxane (2mL) was added dropwise. The mixture was heated at 100°C for 1 hour. 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 gel column chromatography (120g NH silica gel) using a gradient of 0-10% MeOH in DCM. The pure portion was evaporated to give the title compound (1.41g, 96%) as a colorless oil.

[0630] Preparation 26: 2-(Furo[3,2-c]pyridin-4-yl)propan-2-amine

[0631]

[0632] Cerium (III) chloride (5.13g, 20.8mmol) is added to THF (63.1mL) under nitrogen at 0°C. The mixture is stirred at 0°C for 30 minutes, allowed to warm to room temperature, and then stirred for 160 minutes. Immediately thereafter, the reaction mixture is cooled to -78°C. MeLi-LiBr (13.9mL, 20.8mmol) is added and the mixture is stirred at -78°C for 30 minutes. A solution of furano[3,2-c]pyridine-4-carbonitrile (1.00g, 6.94mmol) in THF (6.31mL) is added dropwise. The reaction mixture is kept at -78°C for 30 minutes and then stirred at room temperature overnight. The reaction mixture is quenched with saturated NH4Cl aqueous solution, diluted with 1M NaOH aqueous solution, 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 gel) eluting with a gradient of 20-40% EtOAc in heptane to give the title compound (0.459 g, 38%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δppm 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).

[0633] Preparation 27: 1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-amine

[0634]

[0635] 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 gel column chromatography to give the title compound (1.06 g, 55.5%) as a clear oil. ESI-MS m / z[M+H] + 207.2.

[0636] Preparation 28: 1-((3-ethoxypyridin-2-yl)oxy)-2-methylpropan-2-amine

[0637]

[0638] 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 gel column chromatography to give the title compound (0.440 g, 59%) as a clear oil. ESI-MS m / z[M+H] + 211.2.

[0639] Preparation 29: 2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-amine

[0640]

[0641] To a stirred suspension of NaH (60 wt %, 0.243 g, 6.07 mmol) in THF (30 mL) 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 the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography to give the title compound (0.550 g, 43%) as a clear oil. ESI-MS m / z[M+H] + 251.2.

[0642] Preparation 30: (S)-N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0643]

[0644] 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. 2-amino-2-methylpropan-1-ol (342 mg, 3.84 mmol) was then added. The solution was stirred at room temperature overnight and then vacuumed 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 (350 mg, 47%) as a light yellow oil. ESI-MS m / z[M+H] + 215.2.

[0645] Preparation 31: 2-(Chroman-2-yl)propan-2-amine

[0646]

[0647] Step A: 2-(Chroman-2-yl)propan-2-ol

[0648]

[0649] 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 chromane-2-carboxylate (370 mg, 1.92 mmol) in anhydrous THF (9.6 mL) at 0°C under nitrogen. 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 was added dropwise, followed by EtOAc. 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)δppm 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).

[0650] Step B: N-(2-(Chroman-2-yl)propan-2-yl)acetamide

[0651]

[0652] 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 and then stirred at room temperature overnight. The reaction mixture was treated with 5M ammonium hydroxide (38.5 μL, 0.988 mmol) and then treated with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using a gradient of 30-60% EtOAc in heptane to give the title compound (26 mg, 11%) as a white solid. ESI-MS m / z [M + H] + 234.2.

[0653] Step C: 2-(Chroman-2-yl)propan-2-amine

[0654] 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 hours. Water (1.0 mL) and EtOAc (10 mL) were added. The organic layer was washed with brine (2×3 mL) and dried over anhydrous Na 2 SO 4. The solvent was removed to give the title compound (20 mg, 94%) as a brown viscous oil, which was used without further purification. ESI-MS m / z [M + H] + 192.2.

[0655] Preparation 32: 2-(5-methylisoquinolin-1-yl)propan-2-amine

[0656]

[0657] Anhydrous THF (30.7 mL) was added to anhydrous cerium (III) chloride (3.97 g, 16.1 mmol) at 0 ° C under N2 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 solution of 1.5M MeLi-LiBr (10.75 mL, 16.12 mmol) in diethyl ether was added. Stirring was continued at -78 ° C for 30 minutes, at which time a solution of 5-methylisoquinoline-1-carbonitrile (0.904 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 stirred at room temperature overnight. Saturated NH4Cl aqueous solution was added to the mixture. A precipitate was formed, and the mixture was made alkaline with NH4OH aqueous solution. The reaction mixture was filtered through a pad of Celite® while rinsing with ether. The organic layer and the aqueous layer were separated, and the organic layer was allowed to stand. The aqueous layer was washed twice with ether. The organic layers were combined and washed with a saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol and filtered through a hydrophilic PTFE 0.45 μm The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm x 150 mm) and the filtrate was purified using a 15-65% water / ACN gradient in water (basic mode). Pure fractions were evaporated to give the title compound (260.3 mg, 24%) as a reddish-brown oil, which was used without additional purification. ESI-MS m / z [M+H] + 201.1.

[0658] Preparation 33: 1-((2-methoxypyridin-3-yl)methyl)cyclopropan-1-amine

[0659]

[0660] 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 solution of 3M 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. Subsequently, BF3.OEt2 (0.556 ml, 4.39 mmol) was added. The reaction mixture was stirred at room temperature for another 30 minutes, then quenched with water (2 mL), followed by HCl aqueous solution (1 M, 20 mL) and DCM (50 mL). A 1M NaOH aqueous solution was added until the pH of the mixture was alkaline. 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 automatic rapid silica gel column chromatography using a gradient of 0-20% methanol in DCM. Evaporation of the pure fractions gave the title compound as a pale yellow oil (0.187 g, 48%). ESI-MS m / z [M+H] + 179.1.

[0661] Preparation 34: 2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine

[0662]

[0663] Anhydrous THF (100 mL) was added to cerium (III) chloride (5.00 g, 20.3 mmol) at 0 ° C under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then cooled to -78 ° C. Subsequently, 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 stirred at room temperature overnight. The reactants were quenched with saturated NH4Cl aqueous solution and 1M NaOH aqueous solution was added until a precipitate was formed. The mixture was filtered and the filtrate was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash silica gel column chromatography using a gradient of 0-10% MeOH in DCM to give the title compound. ESI-MS m / z [M+H] + 191.2.

[0664] Preparation 35: 2-(4-methylisoquinolin-1-yl)propan-2-amine

[0665]

[0666] Step A: 4-Methylisoquinoline-1-carbonitrile

[0667]

[0668] To a round-bottom flask equipped with a stir bar under a nitrogen atmosphere was added DMA containing 1-chloro-4-methylisoquinoline (1.85 g, 10.4 mmol) and zinc (II) cyanide (1.834 g, 15.62 mmol), followed by Pd2(dba)3 (0.572 g, 0.625 mmol) and dppf (0.693 g, 1.25 mmol). The reaction mixture was stirred at 115 ° C for 4 hours, then cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was collected, filtered over MgSO4, and concentrated in vacuo. The residue was purified by automated flash silica gel column chromatography (220 g column) using a gradient of 10-70% EtOAc in heptane. The fraction containing the product was evaporated to give the title compound (1.554 g, 89%) as an off-white / yellow solid. ESI-MS m / z [M+H] + 169.1.

[0669] Step B: 2-(4-methylisoquinolin-1-yl)propan-2-amine

[0670] The title compound was prepared analogously 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 gel 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.

[0671] Preparation 36: 2-(1-(tert-Butyloxycarbonyl)-3,3-difluoropyrrolidin-2-yl)acetic acid

[0672]

[0673] Step A: tert-Butyl 3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[0674]

[0675] 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) was added (1.00 g, 4.52 mmol). The solution was stirred at room temperature overnight and then quenched with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (500 mg, 40%), which was used without further purification.

[0676] Step B: 2-(1-(tert-Butyloxycarbonyl)-3,3-difluoropyrrolidin-2-yl)acetic acid

[0677] 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.

[0678] Preparation 37: N-(2-(2-chlorophenyl)propan-2-yl)methacrylamide

[0679]

[0680] 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 (3×). The organic phase was washed with water and a saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by automatic flash silica gel column chromatography using a gradient of 0-60% EtOAc in heptane. The portion containing the product was evaporated to give the title compound (875.9 mg, 88%) as a white solid. ESI-MS [M+H] + 238.1.

[0681] Preparation 38: (R)-2,2-difluoro-1-(2-methoxyphenyl)ethan-1-amine

[0682]

[0683] Step A: (S,E)-N-(2-methoxybenzylidene)-2-methylpropane-2-sulfenamide

[0684]

[0685] To a 20 mL microwave vial equipped with a stir bar was added 2-methoxybenzaldehyde (1.634 g, 12.00 mmol), (S)-2-methylpropane-2-sulfenamide (1.454 g, 12.00 mmol) and tetraethoxytitanium (5.03 mL, 24.0 mmol). The vial was sealed and heated at 70 °C. The mixture was heated in a microwave reactor 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 Celite pad 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.

[0686] Step B: (S)-N-((R)-2,2-difluoro-1-(2-methoxyphenyl)-2-(phenylsulfonyl)ethyl)-2-methylpropane-2-sulfenamide

[0687]

[0688] Under nitrogen atmosphere, (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) were loaded into an oven-dried 500 mL round-bottom flask equipped with a stirring bar. Tetrahydrofuran (115 mL) was added and the reaction mixture was cooled to -78 ° C in a dry ice / acetone bath. A solution of 1 M 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 NH4Cl aqueous solution. The reaction mixture was transferred to a separating funnel, diluted with water, distributed, and extracted with isopropyl acetate. The combined organic layer was washed with a saturated NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dry loaded onto silica gel with DCM and purified by automated flash silica gel column chromatography using a gradient of 0-70% EtOAc in heptane. The fractions containing the product were evaporated to give the title compound (1.65 g, 42%) as a light yellow oil / foam. ESI-MS m / z [M+H] + 432.3.

[0689] Step C: (S)-N-((R)-2,2-difluoro-1-(2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfenamide

[0690]

[0691] 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 prepared 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 turbid. Magnesium (1.39 g, 57.2 mmol) powder was added portionwise to the reaction mixture over a period of 20 minutes. The reaction flask warmed up and gas evolution was observed. The reaction mixture was stirred at room temperature for 2 hours, then diluted with isopropyl acetate and extracted with water, followed by extraction with saturated aqueous NaCl solution. The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by automated flash column chromatography on silica gel using a gradient of 20-100% EtOAc in heptane, followed by a gradient of 20-80% EtOAc in heptane. The product-containing fractions were evaporated to give the title compound (0.553 g, 50%) as a white solid. ESI-MS m / z [M+H] + 292.3.

[0692] Step D: (R)-2,2-difluoro-1-(2-methoxyphenyl)ethan-1-amine

[0693] To a solution of (S)-N-((R)-2,2-difluoro-1-(2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfenamide (0.553 g, 1.90 mmol) in DCM (1.90 mL) was added 4M 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 hydrochloride salt of the title compound as a white powder (0.337 g, 79%). ESI-MS m / z [M+H] + 188.2.

[0694] Preparation 39: (R)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-amine

[0695]

[0696] The hydrochloride salt of the title compound was prepared similarly to Preparation 38 using 3-fluorobenzaldehyde (1.489 g, 12.00 mmol), (S)-2-methylpropane-2-sulfenamide (1.454 g, 12.00 mmol) and tetraethoxytitanium (5.03 mL, 24.0 mmol) to obtain a white solid (0.913 g, approximately 70% purity, 25% yield over 4 steps). ESI-MS m / z [M+H] + 176.2.

[0697] Preparation 40: (R)-2,2-difluoro-1-(4-fluorophenyl)ethan-1-amine

[0698]

[0699] The hydrochloride salt of the title compound was prepared in analogy to Preparation 38 using 4-fluorobenzaldehyde (1.862 g, 15.00 mmol), (S)-2-methylpropane-2-sulfenamide (1.818 g, 15.00 mmol) and tetraethoxytitanium (6.29 mL, 30.0 mmol) to obtain a white solid (0.743 g, 23% over 4 steps). ESI-MS m / z [M+H] + 176.2.

[0700] Preparation 41: (R)-2,2-difluoro-1-phenylethan-1-amine

[0701]

[0702] Step A: (S)-N-((R)-2,2-difluoro-1-phenyl-2-(phenylsulfonyl)ethyl)-2-methylpropane-2-sulfenamide

[0703]

[0704] The 1000mL three-necked flask of the heat drying that is equipped with thermocouple and stirring rod is evacuated and backfilled with nitrogen.Immediately afterwards, into flask, ((difluoromethyl) sulfonyl) benzene (4.00g, 20.8mmol), (S, E)-N-benzylidene-2-methylpropane-2-sulfinamide (4.79g, 22.9mmol) and THF (260mL) are packed into.Reactant mixture is cooled to-78 ℃ in dry ice / acetone bath and in the period of 10 minutes, adds the THF (25.0mL, 25.0mmol) containing 1M bis (trimethylsilyl) lithium amide.Reactant mixture is stirred 90 minutes at-78 ℃, then from dry ice bath, shifted out, with isopropyl acetate (200mL) dilution and use saturated NH the cancellation of the Cl aqueous solution (100mL).Reactant mixture is transferred to separating funnel, diluted with water (200mL) and extracted with isopropyl acetate (3x400mL). 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 gel column chromatography (220 g silica gel) using a gradient of 20-85% EtOAc in heptane to give the title compound (6.1 g, 73%) as a white solid. ESI-MS m / z [M+H] + 402.4.

[0705] Step B: (S)-N-((R)-2,2-difluoro-1-phenylethyl)-2-methylpropane-2-sulfenamide

[0706]

[0707] 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 was slightly warmed from 21 ° C to 27 ° C and the clear solution became turbid. Magnesium powder (5.54 g, 228 mmol) was added portionwise to the stirred reaction mixture over a period of 30 minutes. The temperature of the mixture was raised from 26 ° C to 45 ° C, during which gas evolved and foam was produced. The reaction mixture was stirred at room temperature for 1 hour, then diluted with isopropyl acetate (500 mL) and washed with water (2x300 mL), followed by washing with brine (300 mL). The organic layer was collected, dried over sodium sulfate and concentrated to an oil. The product was purified by flash column chromatography on silica gel (120 g silica gel) using a gradient of 20-100% EtOAc in heptane to give the title compound as a semi-solid (2.93 g, 74%). ESI-MS m / z [M+H]+ 262.3.

[0708] Step C: (R)-2,2-difluoro-1-phenylethan-1-amine

[0709] To a solution of (S)-N-((R)-2,2-difluoro-1-phenylethyl)-2-methylpropane-2-sulfenamide (2.9 g, 11.1 mmol) in DCM (10 mL) was added 4M 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 hydrochloride salt of the title compound as a white powder (1.93 g, 90%). ESI-MS m / z [M+H] + 158.1.

[0710] Preparation 42: (S)-2,2-Difluoro-1-phenylethan-1-amine

[0711]

[0712] The hydrochloride salt of the title compound was prepared in analogy to Preparation 41 using ((difluoromethyl)sulfonyl)benzene (1.60 g, 8.33 mmol), (R,E)-N-benzylidene-2-methylpropane-2-sulfenamide (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) to give a white powder (0.60 g, 37% over three steps). ESI-MS m / z [M+H] + 158.1.

[0713] Preparation 43: (R)-2-Fluoro-1-phenylethan-1-amine

[0714]

[0715] The hydrochloride salt of the title compound was prepared in analogy to Preparation 41 using ((fluoromethyl)sulfonyl)benzene (1.73 g, 9.95 mmol), (S,E)-N-benzylidene-2-methylpropane-2-sulfenamide (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 obtain a white solid (0.418 g, 24% over 3 steps). ESI-MS m / z [M+H] + 140.1.

[0716] Preparation 44: Lithium 3-(azetidin-1-yl)propionate

[0717]

[0718] To a solution of methyl 3-(azetidin-1-yl)propanoate (0.900 g, 6.29 mmol) in MeOH (20 mL) was added 2M 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 (0.844 g, 99%) as a white solid.

[0719] Preparation 45: (R)-N-(2-(2-fluorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0720]

[0721] Step A: (R)-tert-Butyl 2-(2-((2-(2-fluorophenyl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0722]

[0723] 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 overnight at room temperature. The reaction mixture was diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm Filtered by filter. C18, 5 μm, ID 30 mm x 150 mm) and the filtrate was purified using a gradient of 10-100% ACN in water (acidic mode). The fractions containing the product were evaporated to give the title compound as a white solid (177 mg, 62%). ESI-MS m / z [M+H] + 365.4.

[0724] Step B: (R)-N-(2-(2-fluorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0725] To a solution of (R)-tert-butyl 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 at room temperature overnight, then diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm Filtered by filter. C18, 5 μm, ID 30 mm×150 mm) and the filtrate was purified using a gradient of 10-100% ACN in water (acidic mode). Product containing fractions were evaporated to give the trifluoroacetic acid salt of the title compound as a colorless oil (140 mg, 76%). 1 H NMR (400MHz, CDCl3) δppm 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(td,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] + 265.4.

[0726] Preparation 46: (S)-N-(2-(2-fluorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0727]

[0728] The trifluoroacetate salt of the title compound was prepared in analogy 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), Et3N (455 μL, 3.26 mmol) and HATU (380 mg, 0.979 mmol) in THF (4.08 mL) and obtained as a colorless semisolid (174 mg, 56% over two steps). 1H NMR (400MHz, CDCl3) δppm 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(brd,J=6.5Hz,1 H),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.

[0729] Preparation 47: 2-((S)-Pyrrolidin-2-yl)-N-(2,2,2-trifluoro-1-(p-tolyl)ethyl)acetamide

[0730]

[0731] 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)ethyl-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. Subsequently, TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 20-30% ACN in water (acidic mode). Pure fractions were combined and evaporated to afford the trifluoroacetic acid salt of the title compound as a clear oil (17 mg, 27%). 1 HNMR(400MHz,CD3OD)δppm 1.61-1.75(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),3.2 3-3.30(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.

[0732] Example 1: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0733]

[0734] Step A: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0735]

[0736] 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 diluted with EtOAc, washed repeatedly with water, dried over NaSO, filtered, and concentrated in vacuo. The concentrate was dissolved in dioxane (4.20 mL) and acidified with dioxane (4.20 mL, 16.8 mmol) containing 4M HCl. The mixture was stirred at room temperature overnight, then concentrated in vacuo. The product was dissolved in DMF and MeOH, filtered, and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode). Product containing fractions were evaporated to give the title compound (0.160 g, 60%).

[0737] Step B: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0738] 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 hours, then diluted with MeOH and DMF, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode). Product containing fractions were evaporated to give the title compound (0.113 g, 68%) as a white solid. 1 H NMR (400MHz, CD3OD) δppm1.42-1.57(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),2.4 1-2.52(m,2H),2.73(s,3H),2.97-3.06(m,1H),4.24(s,3H),6.83-6.99(m,1H),7.00-7.12(m,1H),7.57-7.71(m,1H); ESI-MS m / z[M+H] + 329.1.

[0739] Example 2: N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0740]

[0741] 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 C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (27 mg, 25%) as a clear semisolid. 1H NMR(400MHz,CD3OD)δppm 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), ESI-MS m / z[M+H] + 329.1.

[0742] Example 3: (R)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0743]

[0744] Step A: (R)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0745]

[0746] To a solution of EtN (0.228 mL, 1.63 mmol), 2-(1-methyl-1H-indazole-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 dioxane (2.72 mL, 10.9 mmol) containing 4M HCl. The mixture was stirred at room temperature for two hours. Then, MeOH (2 mL) was added and the residual solid was dissolved. 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 C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (86 mg, 53%).

[0747] Step B: (R)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0748] 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 C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode). Product containing fractions were evaporated to give the title compound (50 mg, 56%) as a white solid. 1 H NMR (400 MHz, 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),4.01(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.

[0749] Example 4: (S)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0750]

[0751] Step A: (S)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0752]

[0753] To a solution of EtN (0.236 mL, 1.70 mmol), 2-(1-methyl-1H-indazole-3-yl)propan-2-amine (0.107 g, 0.565 mmol) and (S)-2-(1-(tert-butyloxycarbonyl)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 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 dioxane (2.72 mL, 10.9 mmol) containing 4M HCl. The mixture was stirred at room temperature for two hours. Then, MeOH (2 mL) was added and the residual solid was dissolved. The mixture was stirred at room temperature overnight, then concentrated in vacuo. The product was dissolved in MeOH and DMF, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (80 mg, 47%).

[0754] Step B: (S)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0755] To a solution of aqueous formaldehyde (37 wt%, 0.108 g, 1.33 mmol) and (S)-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 two hours, then diluted with MeOH and DMF, filtered, and analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (44 mg, 52%) as a white solid. 1H NMR(400MHz,CD3OD)δppm 1.43-1.60(m,1H),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,J=9.7,7.3,2.8Hz,1H),3.96-4.06(m,3H),7.02-7.18(m,1H),7.30-7.43(m,1H),7.44-7.52(m,1H),7.78-7.90(m,1H); ESI-MS m / z[M+H] + 315.1.

[0756] Example 5: N-(2-(Isoquinolin-1-yl)propan-2-yl)-3-(pyrrolidin-1-yl)propanamide

[0757]

[0758] 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 at room temperature overnight and then filtered through a hydrophilic PTFE 0.45 μm The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm×150 mm) and the filtrate was purified using a gradient of 10-65% water / ACN in water (basic mode). Product containing fractions were evaporated and lyophilized to give the title compound (17.2 mg, 27%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 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, 1.5Hz,1H),7.61-7.72(m,2H),7.90(d,J=8.0Hz,1H),8.35(d,J=5.5Hz,1H),8.66(dd,J=8.8,0.8Hz,1H); ESI-MS m / z[M+H] + 312.20.

[0759] Example 6: N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0760]

[0761] The title compound was prepared in analogy to Example 5 using DMA (1.3 mL) containing 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) and obtained as an off-white solid (41.2 mg, 65%). 1 H NMR(400MHz,CD3OD)δppm 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.

[0762] Example 7: N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0763]

[0764] 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 hours and then filtered through a hydrophilic PTFE 0.45 μm The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm x 150 mm) and the filtrate was purified using a gradient of 10-70% water / ACN in water (basic mode). Product containing fractions were evaporated and lyophilized to give the title compound (19.9 mg, 36%) as a white solid. 1 H NMR (400MHz, CD3OD) δppm 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(d d,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.

[0765] Example 8: (R)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0766] and

[0767] Example 9: (S)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0768]

[0769] Racemic N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide (505 mg, 1.49 mmol) was separated by preparative SFC (Celluose 2, 5 μm, ID 30 mm x 250 mm) using a mobile phase of 40% EtOH (containing 0.1% NH OH) in CO . The first eluting compound was arbitrarily designated as the (R)-enantiomer (173.6 mg, 34%) and the second eluting compound was arbitrarily designated as the (S)-enantiomer (166.2 mg, 33%). 1H NMR (500MHz, CD3OD) δppm1.31-1.63(m,4H),1.65-1.80(m,3H),1.90(s,6H),2.56-2.85(m,8H),3.10(br d,J=3.6Hz,1H),3.13-3.23(m,1H),7.45-7.52(m,1H),7.53-7.59(m,1H),7.8 2(dd,J=6.0,1.0Hz,1H),8.43(d,J=6.0Hz,1H),8.52(d,J=8.7Hz,1H); ESI-MS m / z[M+H] + 340.20.

[0770] Example 10: N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-2-(tetrahydro-1H-pyrrolazin-7a(5H)-yl)acetamide

[0771]

[0772] 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-pyrrolizin-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 C18, 5 μm, ID 30 mm x 150 mm) was purified using a gradient of 10-100% water / ACN in water (basic mode). The product was further purified by preparative HPLC (Xbridge) using a gradient of ACN in water (acidic mode) to give the title compound as a trifluoroacetic acid salt (8.0 mg, 10%). 1 H NMR(400MHz,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 H),7.07-7.17(m,1H),7.35-7.44(m,1H),7.46-7.53(m,1H),7.82-7.90(m,1H),8.71-8.88(m,1H); m / z[M+H] + 341.1.

[0773] Example 11: N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0774]

[0775] 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 C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (25 mg, 28%). 1 H NMR(400MHz,CD3OD)δppm 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.

[0776] Example 12: N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0777]

[0778] Step A: N-(2-(3-chlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0779]

[0780] 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 solution, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The concentrate was dissolved in dioxane (6 mL) and acidified with 4M 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 C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (0.176 g, assumed quantitative).

[0781] Step B: N-(2-(3-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0782] 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 at room temperature overnight, then sonicated, filtered, and analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound as a crystalline white solid (41 mg, 22% over two steps). 1H NMR(400MHz,CD3OD)δppm 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.

[0783] Example 13: N-(2-(Furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0784]

[0785] To a solution of 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-(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 analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (17 mg, 34%). 1 HNMR(400MHz,CD3OD)δppm 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 ,1H),2.55-2.68(m,1H),2.77-2.93(m,1H),7.09-7.22(m,1H),7.37-7.57(m,1H),7.78-7.92(m,1H),8.25-8.43(m,1H); ESI-MS m / z[M+H] + 316.1.

[0786] Example 14: (R)-N-(2-(Furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0787] and

[0788] Example 15: (S)-N-(2-(Furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0789]

[0790] The title enantiomer 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) was separated by preparative SFC. The first eluting compound was arbitrarily designated as the (R)-enantiomer and obtained as an off-white solid (265.5 mg, 46%), and the second eluting compound was arbitrarily designated as the (S)-enantiomer (251.9 mg, 43%). 1 H NMR(400MHz,CD3OD)δppm 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.

[0791] Example 16: (R)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0792]

[0793] Step A: (R)-tert-Butyl 2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0794]

[0795] 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 at room temperature overnight, then quenched with water and saturated aqueous NHCl and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by automated flash column chromatography on silica gel using a gradient of 20-80% EtOAc in heptane. The fractions containing the product were evaporated to give the title compound (128 mg, assumed quantitative) as a colorless oil. ESI-MS m / z [M+H] + 398.4.

[0796] Step B: (R)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0797]

[0798] To a solution of (R)-tert-butyl 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 4M HCl in dioxane (1.61 mL, 6.44 mmol). The reaction mixture was stirred at room temperature for 1.75 hours, then concentrated under reduced pressure and re-evaporated with diethyl ether to give the title compound as a bis-hydrochloride salt (119 mg, assumed quantitative). ESI-MS m / z [M+H] + 298.3.

[0799] Step C: (R)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0800] 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 solution (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 at room temperature overnight. After the reaction, the mixture was concentrated under reduced pressure and then dissolved in methanol. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter. The resulting solution was filtered and rinsed with methanol. C18, 5 μm, ID 30 mm×150 mm) and the filtrate was purified using a water / ACN gradient in water (basic mode). Product-containing fractions were evaporated and lyophilized to give the title compound (43.8 mg, 44% over three steps) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 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.

[0801] Example 17: (R)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0802]

[0803] The title compound was prepared in analogy to Example 16 using DMA (2.37 mL) containing 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) and obtained as a white solid (31.4 mg, 27% over three steps). 1H NMR(400MHz,CD3OD)δppm 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=8.8,7.0Hz,1H),7.50-7.55(m,1H),7.79(dd,J=6.0,0.9Hz,1H),8.40(d,J=5.9Hz,1H),8.53(d,J=8.8Hz,1H); ESI-MS m / z[M+H] + 326.15.

[0804] Example 18: (S)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0805]

[0806] The title compound was prepared in analogy to Example 16 using DMA (2.37 mL) containing 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) and obtained as a white solid (26.7 mg, 23% over three steps). 1 H NMR(400MHz,CD3OD)δppm 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=8.8,7.0Hz,1H),7.50-7.55(m,1H),7.79(dd,J=6.0,0.9Hz,1H),8.40(d,J=5.9Hz,1H),8.53(d,J=8.8Hz,1H); ESI-MS m / z[M+H] + 326.20.

[0807] Example 19: (R)-N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0808]

[0809] The title compound was prepared in analogy 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) and obtained as a white solid (290 mg, 50% over three steps). 1 H NMR (400 MHz, d4-methanol) δ ppm 1.50 (dddd, J = 12.6, 10.1, 8.5, 5.9 Hz, 1H), 1.69-1.78 (m, 2H), 1.80 (app d, J = 2.8 Hz, 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, 3.1 Hz, 1H), 7.19-7.27 (m, 1H), 7.37 (dt, J = 7.3, 1.0 Hz, 1H), 7.63-7.70 (m, 1H); ESI-MS m / z [M+H] + 316.20.

[0810] Example 20: (S)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)acetamide

[0811]

[0812] The title compound was prepared in analogy 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) and obtained as a white solid (29.5 mg, 16% over three steps). 1H NMR(400MHz,CD3OD)δppm 1.89(app d,J=3.6Hz,6H),2.19(dd,J=14.3,9.2Hz,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,2H),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. 9,1.1Hz,1H),7.94(d,J=8.2Hz,1H),8.38(d,J=5.6Hz,1H),8.67(dd,J=8.7,0.8Hz,1H); ESI-MS m / z[M+H] + 374.20.

[0813] Example 21: (S)-N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0814]

[0815] The title compound was prepared in analogy to Example 16 using DMA (10 mL) containing 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) and obtained as a white solid (235.7 mg, 41% over three steps). 1 H NMR (400MHz, CD3OD) δppm 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] + 316.20.

[0816] Example 22: (S)-N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0817]

[0818] The title compound was prepared in analogy to Example 16 using DMA (7.5 mL) containing 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) and obtained as a white solid (201.4 mg, 41% over three steps). 1 H NMR(400MHz,CD3OD)δppm 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=9.8,7.2,2.8H z,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); ESI-MS m / z[M+H] + 326.10.

[0819] Example 23: (S)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0820]

[0821] Step A: (S)-tert-Butyl 2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0822]

[0823] To a three-necked flask equipped with a mechanical stirrer, thermometer, and N inlet was added 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). The resulting suspension was stirred at 14° C. for 15 minutes, then EtN (550 mL, 3.95 mol) was added over a period of 1 minute, followed by solid HATU (462 g, 1.22 mol) over a period of 2 minutes at room temperature. The reaction mixture was stirred at room temperature for 15 hours, 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 Na2SO4, filtered, rinsed with iPrOAc and concentrated in a rotary evaporator. Some products were detected in the aqueous layer, so each product was alkalized with Et3N (5 mL) and washed with iPrOAc (500 mL). The organic phase was washed with brine (250 mL), dried over Na2SO4, filtered, rinsed with iPrOAc and concentrated via rotary evaporation. The organic extracts were combined, concentrated and dried in a vacuum to obtain a crude product in the form of a brown oil. After standing overnight, a portion of the brown oil solidified to form an oily solid. The oily solid was dispersed in EtOAc and filtered with cold EtOAc (2×) and cold heptane. The resulting solid was dried in a vacuum to obtain a pure product (35 g). The filtrate was concentrated via rotary evaporation, diluted with heptane and EtOAc, and purified by silica gel column chromatography using a gradient of 15-70% EtOAc in heptane (2310 g silica gel, Rf Gold). The fractions containing product were combined, concentrated on 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 (305.8 g, 68.2%) as a white solid. 1H NMR(400MHz,CD3OD)δppm 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.

[0824] Step B: (S)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0825] To a three-necked flask equipped with an overhead stirrer, thermometer, addition funnel, and N inlet was added (S)-tert-butyl 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 4M HCl in dioxane (1538 mL, 6.15 mol) was added dropwise at 0-5°C over a period of 2.25 hours. The reaction mixture was stirred at 0-5°C for 8 hours to give a yellow suspension, which was warmed to 15°C over a period of 1 hour. The resulting solid was filtered under nitrogen pressure, rinsed with EtO (4 x 300 mL), and dried in vacuo to give the dihydrochloride salt of the title compound (282.7 g, 99.2% yield, 96-97% ee) as a hygroscopic off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 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-MSm / z[M+H] + 298.2.

[0826] Example 24: (S)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0827]

[0828] Step A: (S)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0829]

[0830] To a three-necked 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 a period of 3 minutes. The mixture was stirred at 6°C for 5 minutes. Subsequently, sodium triacetoxyborohydride (485 g, 2.29 mol) was added portionwise over a period of 25 minutes. The reaction mixture was stirred at 3-7°C for 2.5 hours. More 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 minute. Over a period of 5 minutes, additional sodium triacetoxyborohydride (80.9 g, 382 mmol) was added portionwise to the flask, and the reaction mixture was stirred at room temperature for 2 hours, then concentrated in a vacuum on a rotary evaporator at 35 ° C. The resulting yellow suspension was reconstructed in MeOH (1500 mL), concentrated again via rotary evaporation, and then dried in a rotary evaporator at 35 ° C for 30 minutes. The yellow suspension was suspended in EtOAc (1500 mL), stirred at 35 ° C for 15 minutes in a rotary evaporator, and then stirred at room temperature for 15 minutes. The solid was filtered, rinsed with EtOAc (3x300 mL), and the filtrate was dried in a vacuum to give a clear yellow oil. The oil was dissolved in DCM and purified by silica gel column chromatography using a gradient of 0-5% MeOH in DCM (2240 ​​g NH 60 μM spherical silica gel, Shoko Scientific ). The pure fractions were combined, concentrated via rotary evaporation, and dried in vacuo to give a crude product, which was dissolved in EtOAc (1000 mL) and partitioned with a 2M Na2CO3 aqueous solution (500 mL). The aqueous phase was washed with EtOAc (3x1000 mL). The organic layers were combined, dried over Na2SO4, filtered, rinsed with EtOAc, concentrated via rotary evaporation, and dried in vacuo to give the title compound (193.8 g, 81.5% yield, 95.6% ee) as a light yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 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.

[0831] 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

[0832]

[0833] To a three-necked reaction flask equipped with an overhead stirrer, thermometer, and N2 inlet was added D-(+)-camphoric acid (170 g, 849 mmol) and iPrOAc (3526 mL) at 40°C to give a colorless solution. A small portion of the title compound (2532 mg) was added as a seed crystal. This was followed by the addition of (S)-N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide (176.3 g, 566 mmol) portionwise over a 2-minute period to give a yellow suspension. The mixture was heated at 40°C with stirring for 5 minutes, then slowly cooled to room temperature over a 2-hour period without stirring. The resulting solid was filtered, rinsed with iPrOAc (3 x 584 mL), and dried in vacuo to give the title compound (313.6 g, 91%) as a white solid wherein the molar ratio of (S)-N-(2-(isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide:D-(+)-camphoric acid was 2:3. 1 H NMR(400MHz,DMSO-d6)δppm 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,3H),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=5.3H z,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).

[0834] Step C: (S)-N-(2-(Isoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0835] (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 2M Na2CO3 aqueous solution (898 mL) to give a two-phase suspension. Water (175 mL) was added to aid dissolution. The layers were separated. The organic phase was washed with water (3x600 mL), concentrated via 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 minutes, and then concentrated via rotary evaporation to remove residual water azeotropically. This process was repeated twice more with iPrOAc (2x500 mL). The solid was dried in vacuo on a rotary evaporator at 40 °C, then dried in a high vacuum oven at 70 °C for 6 hours to give the title compound (134.41 g, 84% yield, 99% ee) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 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 .95(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.

[0836] Example 25: N-(2-(Furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0837]

[0838] 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 4M HCl in dioxane (4.26 mL, 17.0 mmol). The mixture was heated to reflux with a heat gun and then allowed to cool to room temperature. The solution was concentrated in vacuo to give the hydrochloride salt of the title compound, which was dissolved in MeOH (3 mL). Next, aqueous formaldehyde (37 wt%, 0.691 g, 8.51 mmol) and sodium cyanoborohydride (0.535 g, 8.51 mmol) were added. The reaction mixture was stirred for 24 hours, then sonicated, filtered, and analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (22 mg, 8.6%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 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.

[0839] Example 26: N-(2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0840]

[0841] 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), Et3N (37.4 μL, 0.268 mmol), HATU (102 mg, 0.268 mmol) and DMF (3 mL). The reaction mixture was stirred at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (15 mg, 17%) as a white solid. 1 H NMR(400MHz,CD3OD)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 H),2.80-2.87(m,1H),4.07(s,3H),7.45(dd,J=6.2,1.0Hz,1H),8.26(d,J=6.0Hz,1H),8.32(s,1H); ESI-MS m / z[M+H] + 330.3.

[0842] Example 27: 2-(1-ethylpyrrolidin-2-yl)-N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)acetamide

[0843]

[0844] To a solution of Et3N (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 C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (48 mg, 62%) as a light yellow crystalline solid. 1H NMR(400MHz,CD3OD)δppm 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 (m,1H),2.85-2.97(m,1H),3.12-3.22(m,1H),7.07-7.24(m,1H),7.37-7.53(m,1H),7.78-7.92(m,1H),8.27-8.42(m,1H); ESI-MS m / z[M+H] + 316.1.

[0845] Example 28: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0846]

[0847] Step A: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0848]

[0849] 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 minutes. 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, then concentrated in vacuo. The mixture was treated with 4M HCl in dioxane (1 mL), shaken for 30 minutes, and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-90% ACN in water (acidic mode). Fractions containing product were pooled and purified in GeneVac TM The mixture was dried in an evaporator to give the trifluoroacetic acid salt of the title compound (4.9 mg, 16.6%) as a thin film. ESI-MS m / z [M+H] + 346.1.

[0850] Step B: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0851] To a solution of 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, then MeOH (0.5 mL) was added. The residue was purified by preparative HPLC (Phenomenex The reaction mixture was purified using a gradient of 10-90% ACN in water (acidic mode) using a C18, 5 μm, ID 30 mm x 150 mm). Pure fractions were pooled and purified in a GeneVac TM The mixture was dried in an evaporator to give the trifluoroacetic acid salt of the title compound (4.1 mg, 80%) as a colorless film. ESI-MS m / z [M+H] + 360.2.

[0852] Example 29: N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0853]

[0854] 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 minutes. 2-Methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (20 mg, 0.085 mmol) was then added. The solution was stirred at 45° C. for 4 hours and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-90% ACN in water (acidic mode). C18, 5 μm, ID 30 mm x 150 mm) and the product was repurified using a gradient of 20-100% water / ACN in water (basic mode). Fractions containing product were pooled and purified in GeneVac TMDrying on an evaporator gave the title compound (5.4 mg, 17%) as a yellow solid. 1 H NMR (400MHz, CD3OD) δppm 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.

[0855] Example 30: N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0856]

[0857] To a solution of Et3N (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 at room temperature overnight, then diluted with MeOH, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (28 mg, 56%) as a yellow-orange semisolid. 1 H NMR(400MHz,CD3OD)δppm 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),2.48-2.5 9(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.

[0858] Example 31: N-((S)-1-(4-chlorophenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide

[0859]

[0860] 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 at room temperature overnight, then diluted with MeOH, filtered and purified by preparative HPLC (Phenomenex C18, 5 μ m, ID 30mm x150mm), a gradient of 10-100% water / ACN in water (alkaline mode) was used for purification. The product-containing fractions were combined, dissolved in 4M HCl / dioxane solution (2.31 mL, 9.25 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give the hydrochloride salt of the title compound, which was dissolved in MeOH (5 mL). Subsequently, formaldehyde solution (37 wt %, 0.231 g, 2.31 mmol) and sodium cyanoborohydride (0.145 g, 2.31 mmol) were added and the mixture was stirred overnight. The solution was then ultrasonicated, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (53 mg, 41%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 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.

[0861] Example 32: N-((S)-1-(4-fluorophenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide

[0862]

[0863] The title compound was prepared in analogy to Example 31 using DMF (4.23 mL) containing HATU (0.193 g, 0.508 mmol), Et3N (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) and obtained as a white solid (39 mg, 35%). 1 H NMR(400MHz,CD3OD)δppm 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,2 H),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.

[0864] Example 33: (S)-N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0865]

[0866] The title compound was prepared in analogy to Example 31 using DMF (4.49 mL) containing HATU (0.205 g, 0.539 mmol), Et3N (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) and obtained as a white solid (35 mg, 24%). 1H NMR(400MHz,CD3OD)δppm 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),2.4 2-2.58(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.

[0867] Example 34: (S)-N-(2-(Furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0868]

[0869] The title compound was prepared in analogy to Example 31 using DMF (5.10 mL) containing HATU (0.233 g, 0.612 mmol), Et3N (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) and obtained as a white solid (64 mg, 42%). 1 H NMR(400MHz,CD3OD)δppm 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),2.96-3.09(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.

[0870] Example 35: (S)-N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0871]

[0872] The title compound was prepared in analogy to Example 31 using HATU (0.271 g, 0.712 mmol), Et3N (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 semisolid (63 mg, 36%). 1 H NMR(400MHz,CD3OD)δppm 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,3 H),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.

[0873] Example 36: N-((S)-1-(4-chlorophenyl)ethyl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide

[0874]

[0875] To a solution of Et3N (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 at room temperature overnight, then diluted with MeOH, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30mm x150mm), purified using a gradient of 10-100% water / ACN in water (basic mode). Pure fractions were combined and dissolved in a solution of 4M HCl in dioxane (2.62 mL, 10.47 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo to give the hydrochloride 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 C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (83 mg, 56%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 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),2.2 9-2.37(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.

[0876] Example 37: N-((S)-1-(4-fluorophenyl)ethyl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide

[0877]

[0878] The title compound was prepared in analogy to Example 36 using DMF (5.23 mL) containing HATU (0.239 g, 0.628 mmol), Et3N (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) and obtained as a white solid (92 mg, 66%). 1 H NMR(400MHz,CD3OD)δppm 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-MSm / z[M+H] + 265.1.

[0879] Example 38: (R)-N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0880]

[0881] The title compound was prepared in analogy to Example 36 using DMF (5.23 mL) containing HATU (0.239 g, 0.628 mmol), Et3N (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) and obtained as a white solid (93 mg, 54%). 1 H NMR(400MHz,CD3OD)δppm 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,2H),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.

[0882] Example 39: (R)-N-(2-(Furo[3,2-c]pyridin-4-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0883]

[0884] The title compound was prepared in analogy to Example 36 using HATU (0.239 g, 0.628 mmol), Et3N (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%). 1H NMR(400MHz,CD3OD)δppm 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 ,7.2,2.9Hz,1H),3.26-3.32(m,2H),7.04-7.22(m,1H),7.34-7.53(m,1H),7.76-7.88(m,1H),8.24-8.41(m,1H); ESI-MS m / z[M+H] + 302.1.

[0885] Example 40: (R)-N-(2-(4-chlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0886]

[0887] The title compound was prepared in analogy to Example 36 using HATU (0.239 g, 0.628 mmol), Et3N (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 semisolid (80 mg, 52%). 1 H NMR(400MHz,CD3OD)δppm 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,2 H),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.

[0888] Example 41: N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0889]

[0890] 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), Et3N (26.6 μL, 0.191 mmol) and DMF (1 mL). The reaction mixture was stirred at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (27 mg, 43%) as a light brown solid. 1 H NMR (400MHz, CD3OD) δppm1.18-1.35(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) ),2.52-2.62(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] + 330.3.

[0891] Example 42: N-(2-(4-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0892]

[0893] The title compound was prepared in analogy 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), Et3N (20.9 μL, 0.150 mmol) and HATU (57.0 mg, 0.150 mmol) in DMF to give a colorless oil (23 mg, 45%). 1H NMR(400MHz,CD3OD)δppm 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.

[0894] Example 43: (R)-N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0895] and

[0896] Example 44: (S)-N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0897]

[0898] The title enantiomer of racemic N-(2-(7-methylbenzo[d]isoxazol-3-yl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide (728 mg, 2.37 mmol) was separated by preparative SFC (Daicel Chiralpak AD, 5 μm, ID 30 mm x 250 mm). The first eluting compound was arbitrarily designated as the (R)-enantiomer and obtained as a white solid (324 mg, 45%), and the second eluting compound was arbitrarily designated as the (S)-enantiomer and obtained as a white solid (329 mg, 45%). 1HNMR(400MHz,CD3OD)δppm 1.23-1.35(m,2H),1.52-1.69(m,4H),1.80(app 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.

[0899] Example 45: N-(2-(2,5-dichlorophenyl)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[0900]

[0901] To a solution of Et3N (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 C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (23 mg, 21%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 1.22-1.40(m,2H),1.48-1.77(m,10H),2.09-2.22(m,2H),2.22-2.33(m,3H),2.33-2.47(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.

[0902] Example 46: (R)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0903]

[0904] Step A: (R)-tert-Butyl 2-(2-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0905]

[0906] To a 20 mL vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (78% purity, 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 (136 mg, assumed quantitative) as a light brown film.

[0907] Step B: (R)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0908]

[0909] To a 125 mL flask was added 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, 0.346 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 and then concentrated to dryness to afford the hydrochloride salt of the title compound (113 mg, assumed quantitative) as a light brown film.

[0910] Step C: (R)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0911] 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 hydrochloride (113 mg, 0.346 mmol) and formaldehyde solution (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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% ACN in water (acidic mode) to afford the title compound as a trifluoroacetic acid salt (51.1 mg, 35% over three steps). 1 H NMR (500MHz, CD3OD) δppm 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),3.03-3.14(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.

[0912] Example 47: (S)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0913]

[0914] Step A: (S)-tert-Butyl 2-(2-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0915]

[0916] To a vial was added 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine (78% purity, 0.070 g, 0.303 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (0.069 g, 0.303 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 (119 mg, assumed quantitative) as a light brown film.

[0917] Step B: (S)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0918]

[0919] 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. More HCl (4 M in dioxane, 0.346 mL, 1.38 mmol) was added and the mixture was stirred at room temperature for an additional overnight. The mixture was concentrated to dryness to give the hydrochloride salt of the title compound (99 mg, assumed quantitative) as a light brown film.

[0920] Step C: (S)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0921] 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 hydrochloride (99 mg, 0.303 mmol) and formaldehyde solution (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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% ACN in water (acidic mode) to afford the title compound as a trifluoroacetic acid salt (56.2 mg, 44% over three steps). 1 H NMR(500MHz,CD3OD)δppm 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.

[0922] Example 48: (S)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0923]

[0924] Step A: (S)-tert-Butyl 2-(2-((2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[0925]

[0926] To a solution of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid hydrochloride (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. 2-Methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine (52.9 mg, 0.226 mmol) was then 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 column. The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm×150 mm) and the filtrate was purified using a gradient of 10-50% ACN in water (acidic mode) to give the trifluoroacetic acid salt of the title compound as a colorless oil (96 mg, 91%).

[0927] Step B: (S)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[0928]

[0929] To a solution of (S)-tert-butyl 2-(2-((2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate trifluoroacetate (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 under vacuum to give the trifluoroacetate salt of the title compound as a colorless oil, which was used without further purification (79 mg, 100%).

[0930] Step C: (S)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0931] At room temperature by (S)-N-(2-methyl isophthalic acid-((3-(trifluoromethyl) pyridin-2-yl) oxygen base) propan-2-yl)-2-(pyrrolidin-2-yl) acetamide trifluoroacetate (79mg, 0.172mmol), paraformaldehyde (12.7mg, 0.422mmol), sodium triacetoxyborohydride (179mg, 0.845mmol) and DIPEA (148 μ L, 0.845mmol) in DCM (2.1mL) mixture is stirred 2 days. Then, EtOAc (10mL) and saturated NaHCO aqueous solution (10mL) are added, and the reaction mixture is stirred vigorously for 1 hour. The organic layer is washed with salt water (2x3mL) and concentrated under vacuum. The concentrate is dissolved in methanol and filtered through hydrophilic PTFE 0.45 μm The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm×150 mm) and the filtrate was purified using a gradient of 10-50% ACN in water (acidic mode) to give a colorless oil, which was dissolved in MeOH and filtered through Agilent Stratospheres SPE (PL-HCO 3 MP) resin to give the title compound (23 mg, 37%) as a colorless oil. 1 H NMR (400MHz, CD3OD) δppm1.46 (d, J=2.4Hz, 6H), 1.73-1.85 (m, 1H), 1.89-2.02 (m, 1H ),2.04-2.17(m,1H),2.31(dtd,J=13.5,8.2,5.5Hz,1H),2.72(dd,J=5.3,1.2Hz,2H ),2.93(s,3H),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.

[0932] Example 49: (R)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0933]

[0934] In analogy to Example 48, (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) were used in step A, and (R)-2-(2-((2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-amine was used in step B. To the mixture was added tert-butyl ((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (97 mg, 0.211 mmol) and formaldehyde (12.68 mg, 0.422 mmol) to prepare the title compound. The title compound was obtained as a colorless oil (19 mg, 25%). 1H NMR(400MHz,CD3OD)δppm 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( s,3H),3.08-3.19(m,1H),3.54-3.75(m,2H),4.52-4.72(m,2H),7.07-7.15(m,1H),7.99-8.09(m,1H),8.31-8.40(m,1H); ESI-MS m / z[M+H] + 360.1.

[0935] Example 50: 2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0936]

[0937] The trifluoroacetic acid salt of the title compound was prepared in analogy 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 a colorless oil was obtained (23 mg, 61%). 1 H NMR (400MHz, CD3OD) δppm1.34(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,2H),3.41-3.56(m,1H),3.62-3.74(m,2H),4.53-4.68 (m,2H),7.06-7.16(m,1H),7.95-8.05(m,1H),8.32-8.40(m,1H); ESI-MS m / z[M+H] + 374.20.

[0938] Example 51: (S)-2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0939]

[0940] A mixture of (S)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (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 overnight at room temperature. The product was purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and the reaction mixture was purified using a gradient of 10-70% water / ACN in water (basic mode) to give the title compound (3.3 mg, 10%) as a light yellow oil. 1 H NMR (400MHz, CD3OD) δppm1.11(t,J=7.2Hz,3H),1.44(d,J=2.0Hz,6H),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=14.3,4.3 Hz,1H),2.68(qd,J=7.9,4.3Hz,1H),2.90(dq,J=12.1,7.4Hz,1H),3.11-3.20(m,1H) ,4.50-4.65(m,2H),7.06-7.14(m,1H),7.97-8.04(m,1H),8.30-8.39(m,1H); ESI-MS m / z[M+H] + 374.1.

[0941] Example 52: (S)-2-(1-(2-fluoroethyl)pyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0942]

[0943] The title compound was prepared in analogy to Example 51 using DMSO (0.87 mL) containing (S)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (40 mg, 0.087 mmol), 1-bromo-2-fluoroethane (13.3 mg, 0.104 mmol) and potassium carbonate (48 mg, 0.348 mmol), and a colorless oil was obtained (4.5 mg, 13.2%). 1H NMR(400MHz,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 .05-3.18(m,1H),3.20-3.27(m,1H),4.40-4.53(m,1H),4.56-4.68(m,3H),7.05-7.14(m,1H),7.96-8.04(m,1H),8.29-8.38(m,1H); ESI-MS m / z[M+H] + 392.1.

[0944] Example 53: (S)-2-(1-cyclopropylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0945]

[0946] At room temperature by (S)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propyl-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (40mg, 0.084mmol), (1-ethoxycyclopropyloxy)trimethylsilane (18.2mg, 0.104mmol), sodium triacetoxyborohydride (74mg, 0.348mmol) and DIPEA (0.061mL, 0.348mmol, 4.0 equivalents) in DCM (0.87mL) mixture is stirred overnight.With saturated NaHCOthe reaction mixture is quenched with aqueous solution, then extracted with EtOAc (3x4.0mL).Concentrate organic phase and by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-50% ACN in water (acidic mode) to give the title compound as a colorless oil (3.0 mg, 6.9%) as the trifluoroacetic acid salt. 1H NMR(400MHz,CD3OD)δppm 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,3H),3.69(ddd,J=12.0,7.9,4.6Hz,1H),3.81-3.92(m,1H),4.59(s,2H),7.06-7.14(m,1H),7.96-8.02(m,1H),8.30-8.36(m,1H); ESI-MS m / z[M+H] + 386.10.

[0947] Example 54: (S)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0948]

[0949] Step A: (S)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(pyrrolidin-2-yl)acetamide

[0950]

[0951] The title compound was prepared analogously to steps A and B of Example 48 from (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (30 mg, 0.131 mmol) and 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl-1-amine (28 mg, 0.157 mmol). The resulting intermediate (S)-tert-butyl 2-(2-((1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate trifluoroacetate (50 mg, 0.099 mmol) was treated with TFA (10 mL) and concentrated. The colorless residue was dissolved in MeOH and filtered through an Agilent Stratospheres SPE (PL-HCO MP) resin to give the title compound (33 mg) as a white solid.

[0952] Step B: (S)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0953] A mixture of (S)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(pyrrolidin-2-yl)acetamide (16 mg, 0.055 mmol), paraformaldehyde (3.3 mg, 0.11 mmol) and sodium triacetoxyborohydride (46.9 mg, 0.221 mmol) in DCM (553 μL) was stirred at room temperature for 16 hours and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-50% ACN in water (acidic mode) gave the title compound as a white oil as a trifluoroacetic acid salt (4.2 mg, 18%). 1 H NMR(400MHz,CD3OD)δppm 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,3H),3.11-3.23(m,1H),3.60-3.77(m,2H),4.34-4.54(m,2H),6.85(dd,J=7.1,5.1Hz,1H),7.44-7.54(m,1H),7.86-7.96(m,1H); ESI-MS m / z[M+H] + 304.2.

[0954] Example 55: (S)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0955]

[0956] In analogy to Example 54, the trifluoroacetate salt of the title compound was prepared 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), and a colorless oil was obtained (16 mg, 28% over three steps). 1H NMR(400MHz,CD3OD)δppm 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 .64(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.

[0957] Example 56: (S)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[0958]

[0959] In analogy to Example 54, the trifluoroacetate salt of the title compound was prepared using 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, 0.131 mmol), and a colorless oil was obtained (14 mg, 24% over three steps). 1 H NMR(400MHz,CD3OD)δppm 1.65-1.85(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, 1H),3.52-3.62(m,1H),3.64-3.73(m,1H),4.41-4.65(m,2H),6.87(dd,J=7.2,5.1Hz,1H),7.49-7.54(m,1H),7.87-7.95(m,1H); ESI-MS m / z[M+H] + 332.1.

[0960] Example 57: (R)-2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0961]

[0962] A mixture of (R)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (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 The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm×150 mm) and the reaction mixture was purified using a gradient of 10-50% ACN in water (acidic mode) to give the trifluoroacetic acid salt of the title compound as a colorless oil (13 mg, 31%). 1 H NMR(400MHz,CD3OD)δppm 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.

[0963] Example 58: (R)-2-(1-(2-fluoroethyl)pyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0964]

[0965] The trifluoroacetate salt of the title compound was prepared in analogy to Example 57 using (R)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (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 a colorless oil was obtained (6 mg, 14%). 1 H NMR(400MHz,CD3OD)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.

[0966] Example 59: (R)-2-(1-cyclopropylpyrrolidin-2-yl)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)acetamide

[0967]

[0968] At room temperature by (R)-N-(2-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)oxy)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide trifluoroacetate (40.0mg, 0.087mmol), (1-ethoxycyclopropyloxy)trimethylsilane (18.2mg, 0.104mmol), sodium triacetoxyborohydride (74mg, 0.348mmol) and DIPEA (0.061mL, 0.348mmol) in DCM (0.87mL) mixture is stirred overnight.With saturated NaHCOthe reaction mixture is quenched with aqueous solution and extracted with EtOAc (3x4.0mL).The organic phase is concentrated and the product is purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-70% water / ACN in water (basic mode) gave the title compound as a colorless oil (3.6 mg, 11%). 1 H NMR (400MHz, CD3OD) δppm0.37-0.86(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.

[0969] Example 60: N-((S)-1-(4-chlorophenyl)ethyl)-2-(1-methylpiperidin-2-yl)acetamide

[0970]

[0971] To a solution of Et3N (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 at room temperature overnight, then diluted with MeOH, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford the title compound (74 mg, 79%). 1H NMR (400MHz, CDCl3) δppm1.19-1.42(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).

[0972] Example 61: N-((S)-1-(4-fluorophenyl)ethyl)-2-(1-methylpiperidin-2-yl)acetamide

[0973]

[0974] To a solution of Et3N (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 at room temperature overnight, then diluted with MeOH, filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode) to afford 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 (quintet, J = 7.2 Hz, 1H), 6.91-7.14 (m, 2H), 7.16-7.34 (m, 2H), 8.80-9.20 (m, 1H).

[0975] Example 62: 2-(1-ethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0976]

[0977] 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 hydrochloride (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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% ACN in water (acidic mode) gave the title compound as a colorless film as a trifluoroacetic acid salt (37.2 mg, 52%). 1 H NMR(400MHz,CD3OD)δppm 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.

[0978] Example 63: 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)acetamide

[0979]

[0980] 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, 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, then the product was purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-50% ACN in water (acidic mode) to give the title compound as a colorless oil (20 mg, 49%) as the trifluoroacetic acid salt. 1 H NMR (400 MHz, 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),1.93-2.14(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.

[0981] Example 64: 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclobutyl)acetamide

[0982]

[0983] In analogy to Example 63, the trifluoroacetate salt of the title compound was prepared 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 a colorless oil was obtained (25 mg, 59%). 1 H NMR (400MHz, CD3OD) δppm 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),4.49-4.64(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.

[0984] Example 65: 2-(1-ethylpyrrolidin-2-yl)-N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopentyl)acetamide

[0985]

[0986] In analogy to Example 63, the trifluoroacetate salt of the title compound was prepared 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 a colorless oil was obtained (18 mg, 41%). 1 H NMR(400MHz,CD3OD)δppm 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.

[0987] 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)propanamide

[0988]

[0989] 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

[0990]

[0991] 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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm), purified using a gradient of 10-100% ACN in water (acidic mode) to give the title compound as a trifluoroacetic acid salt. The earlier eluting compound was arbitrarily designated as a mixture of the (S, R)-enantiomer and the (R, S)-enantiomer and obtained as a colorless film (1.8 mg, 1.5%). 1 H NMR(400MHz,CD3OD)δppm 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,1H),3.49-3.59(m,2H),4.33-4.44(m,1H),4.52-4.58(m,1H),6. 86(dd,J=7.1,5.1Hz,1H),7.40-7.55(m,1H),7.78-7.96(m,1H); ESI-MS m / z[M+H] + 320.3 The later eluting compound was arbitrarily designated as a mixture of the (S,S)- and (R,R)-enantiomers and was obtained as a colorless film (12.9 mg, 11%). 1 H NMR(400MHz,CD3OD)δppm1.28(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,1H),3.40-3.66(m,2H),4.40(s,1H),4.47-4.61(m,1H),6.81-6.90(m,1H),7.47-7.55(m,1H),7.82-7.95(m,1H); ESI-MS m / z[M+H] + 320.3.

[0992] Example 68: 2-(1,5-dimethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[0993]

[0994] Step A: Methyl 2-(1,5-dimethylpyrrolidin-2-yl)acetate

[0995]

[0996] To a 100 mL round-bottom flask was added methyl 2-(5-methylpyrrolidin-2-yl)acetate hydrochloride (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 at room temperature overnight and then concentrated to dryness to give the title compound (0.177 g, assumed quantitative) as a white solid, which was used without further purification. ESI-MS m / z [M+H] + 172.2.

[0997] Step B: 2-(1,5-dimethylpyrrolidin-2-yl)acetic acid

[0998]

[0999] 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 (0.488 g, 33% purity) as an off-white solid. ESI-MS m / z [M+H] + 158.2.

[1000] Step C: 2-(1,5-dimethylpyrrolidin-2-yl)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)acetamide

[1001] 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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% ACN in water (acidic mode) to afford the title compound as a trifluoroacetic acid salt (9.3 mg, 11%). 1 HNMR(400MHz,CD3OD)δppm 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.

[1002] Example 69: N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpiperidin-2-yl)acetamide

[1003]

[1004] 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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified using a gradient of 10-100% ACN in water (acidic mode) to afford the title compound as a trifluoroacetic acid salt (31.2 mg, 19%). 1H NMR(400MHz,CD3OD)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.

[1005] Example 70: (R)-N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1006]

[1007] Step A: (R)-tert-Butyl 2-(2-((2-(3-methylisoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[1008]

[1009] 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 solution and extracted twice with EtOAc. The organics were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using a gradient of 10% to 70% EtOAc in heptane. The evaporated fractions gave the title compound (600 mg, 97%). ESI-MS [M+H] + m / z 412.

[1010] Step B: (R)-N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[1011]

[1012] To a round-bottom flask was added 4M HCl in dioxane (3.64 mL, 14.6 mmol) and a solution of (R)-tert-butyl 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 hydrochloride salt of the title compound (0.452 g), which was used without further purification. ESI-MS m / z [M+H] + 312.3.

[1013] Step C: (R)-N-(2-(3-methylisoquinolin-1-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1014] 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, 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 C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound as a white solid (32 mg, 6.8% over 2 steps). 1 HNMR(400MHz,CD3OD)δppm 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.

[1015] Example 71: N-(1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)propanamide

[1016]

[1017] 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, then 1-(((3-methylpyridin-2-yl)oxy)methyl)cyclopropyl-1-amine (15 mg, 0.084 mmol) was added. The resulting solution was stirred at room temperature for 16 hours, then purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-50% ACN in water (acidic mode) gave the title compound as a colorless oil as a trifluoroacetic acid salt (4 mg, 11%). 1 H NMR(400MHz,CD3OD)δppm 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.

[1018] Example 72: (S)-N-(2-methyl-1-((3-(trifluoromethoxy)pyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1019]

[1020] In analogy to Example 71, the trifluoroacetate salt of the title compound was prepared 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 (400 MHz, CD3OD) δ ppm 1.46(d,J=2.6Hz,6H),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),7.0 5(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.

[1021] Example 73: (S)-N-(1-((3-cyclopropylpyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1022]

[1023] In analogy to Example 71, the trifluoroacetate salt of the title compound was prepared 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 a colorless oil was obtained (24 mg, 31%). 1H NMR(400MHz,CD3OD)δppm 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.

[1024] Example 74: N-(1-(2-methoxybenzyl)cyclopropyl)-2-(1-methylpiperidin-2-yl)acetamide

[1025]

[1026] To a mixture of 1-(2-methoxybenzyl)cyclopropan-1-amine hydrochloride (42.7 mg, 0.200 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 hours and then filtered through a hydrophilic PTFE 0.45 μm The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm x 150 mm) and the filtrate was purified using a gradient of 20-80% water / ACN in water (basic mode). 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)δppm 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.

[1027] Example 75: (R)-N-(2-(2-methoxyphenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide

[1028] and

[1029] Example 76: (S)-N-(2-(2-methoxyphenyl)propan-2-yl)-2-methyl-3-(pyrrolidin-1-yl)propanamide

[1030]

[1031] 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 at room temperature overnight, then diluted with water (100 mL) and extracted with EtOAc (3 x 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, ID 30 mm x 250 mm) using a mobile phase of iPrOH (containing 0.1% NH OH) in CO to give the title enantiomer. The first eluting compound was arbitrarily designated as the (R)-enantiomer and obtained as a yellow solid (0.202 g, 16.1%), and the second eluting compound was arbitrarily designated as the (S)-enantiomer and obtained as a yellow solid (0.219 g, 17.4%). 1H NMR (400MHz, DMSO-d6) δppm 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] + 305.3.

[1032] Example 77: N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-2-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)acetamide

[1033]

[1034] 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-pyrrolizin-7a(5H)-yl)acetic acid hydrochloride (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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm x 150 mm) and purified using a gradient of 10-100% water / ACN in water (basic mode). 1 H NMR (400MHz, CD3OD) δppm 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.

[1035] Example 78: N-(1-((3-(Difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(tetrahydro-1H-pyrrolazin-7a(5H)-yl)acetamide

[1036]

[1037] The trifluoroacetic acid salt of the title compound was prepared in analogy to Example 77 using 1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-amine (0.060 g, 0.277 mmol), 2-(tetrahydro-1H-pyrrolazin-7a(5H)-yl)acetic acid hydrochloride (0.057 g, 0.277 mmol), HATU (0.106 g, 0.277 mmol) and DIPEA (0.145 mL, 0.832 mmol) and a colorless semisolid was obtained (68.8 mg, 52%). 1 H NMR(400MHz,CD3OD)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 H),4.57(s,2H),6.73-6.96(m,1H),7.01-7.12(m,1H),7.81-7.97(m,1H),8.17-8.29(m,1H); ESI-MS m / z[M+H] + 368.3.

[1038] Example 79: N-(1-((2-methoxypyridin-3-yl)methyl)cyclopropyl)-2-(1-methylpiperidin-2-yl)acetamide

[1039]

[1040] 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 hours and then filtered through a hydrophilic PTFE 0.45 μm The product was filtered through a filter and rinsed with methanol. C18, 5 μm, ID 30 mm×150 mm) and the filtrate was purified using a gradient of 10-60% water / ACN in water (basic mode). Product containing fractions were evaporated and lyophilized to give the title compound (58.8 mg, 36%) as a pale yellow solid. 1H NMR(400MHz,CD3OD)δppm 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.

[1041] Example 80: (S)-N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1042]

[1043] Step A: (S)-tert-Butyl 2-(2-((2-(2,3-dichlorophenyl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[1044]

[1045] 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 hours, 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, assumed quantitative), which was used without further purification. ESI-MS m / z [M+H] + 415.3.

[1046] Step B: (S)-N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide

[1047]

[1048] To a vial containing a solution of (S)-tert-butyl 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 4M 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 hydrochloride salt of the title compound (230 mg, assumed quantitative) which was used without further purification. ESI-MS m / z [M+H] + 315.2.

[1049] Step C: (S)-N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1050] To a solution of (S)-N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(pyrrolidin-2-yl)acetamide hydrochloride (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 hour. Immediately thereafter, sodium triacetoxyborohydride (415 mg, 1.96 mmol) was added. The reaction mixture was stirred at room temperature overnight, then filtered and purified by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% ACN in water (acidic mode) gave the title compound as a clear oil (4.0 mg, 1.4% over three steps) as the trifluoroacetic acid salt. 1 H NMR(400MHz,CD3OD)δppm 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, J=11.5,8.3Hz,1H),3.50-3.68(m,2H),7.28(t,J=8.0Hz,1H),7.45(dd,J=8.0,1.5Hz,1H),7.54(dd,J=8.0,1.5Hz,1H); ESI-MS m / z[M+H] + 329.2.

[1051] Example 81: (S)-N-(1-(3-methylbenzyl)cyclopropyl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1052]

[1053] The title compound was prepared in analogy 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 hour before purification. The title compound was obtained as a white solid (11 mg, 4.4% over three steps). 1 H NMR(400MHz,CD3OD)δppm 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),7.00-7.07(m,3H),7.16(t,J=7.0Hz,1H); ESI-MS m / z[M+H] + 287.3.

[1054] Example 82: (S)-N-(2-(2,3-difluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1055]

[1056] The trifluoroacetic acid salt of the title compound was prepared in analogy 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(400MHz,CD3OD)δppm 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,2 H),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.

[1057] Example 83: (S)-N-(2-(3-chloro-2-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1058]

[1059] The trifluoroacetic acid salt of the title compound was prepared in analogy 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 three steps). 1 H NMR(400MHz,CD3OD)δppm 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 H),3.10(dt,J=11.5,8.3Hz,1H),3.54-3.71(m,2H),7.12(td,J=8.0,1.1Hz,1H),7.32-7.40(m,2H); ESI-MS m / z[M+H] + 313.2.

[1060] Example 84: (R)-N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1061]

[1062] 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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound (35.4 mg, 32%) as a colorless film. 1H NMR(400MHz,CD3OD)δppm 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.

[1063] Example 85: (S)-N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1064]

[1065] 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 at room temperature overnight and then analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-50% ACN in water (acidic mode) gave the title compound as a colorless film as a trifluoroacetic acid salt (29.5 mg, 20%). 1 H NMR(400MHz,CD3OD)δppm 1.44(d,J=0.6Hz,6H),1.69-1.82(m,1H),1.89-2.10(m,2H),2.21-2.3 4(m,1H),2.67-2.74(m,2H),2.90(s,3H),3.04-3.16(m,1H),3.52-3.61 (m,1H),3.62-3.75(m,1H),4.51(s,1H),4.56-4.63(m,1H),6.75-6.97( m,1H),7.02-7.11(m,1H),7.85-7.94(m,1H),8.20-8.28(m,1H); ESI-MS m / z[M+H]+ 342.2.

[1066] Example 86: (S)-N-(2-(2-Fluoro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1067]

[1068] 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 C18, 5 μm, ID 30 mm×150 mm) and the residue was purified using a gradient of 10-100% ACN in water (acidic mode) to give the trifluoroacetic acid salt of the title compound as a clear oil (26 mg, 30%). 1 H NMR(400MHz,CD3OD)δppm 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(d t,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.

[1069] Example 87: (R)-N-(2-(2-Fluoro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1070]

[1071] The trifluoroacetic acid salt of the title compound was prepared in analogy 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%). 1H NMR (400MHz, CD3OD) δppm1.72(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=11.5,8.3Hz,1H),3.53-3.70(m,2H),6.97-7.03(m,1H),7.11(t,J=6.9Hz,1H),7.22(td,J=7.9,1.3Hz,1H); ESI-MS m / z[M+H] + 293.2.

[1072] Example 88: (S)-N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1073]

[1074] The trifluoroacetic acid salt of the title compound was prepared in analogy 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) δppm1.26 (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,2H),7.43(dd,J=7.5,2.1Hz,1H); ESI-MSm / z[M+H] + 309.2.

[1075] Example 89: (S)-N-(2-(3-Fluoro-2-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1076]

[1077] The trifluoroacetic acid salt of the title compound was prepared in analogy 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%). 1H NMR (400MHz, CD3OD) δppm1.71-1.84(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.

[1078] Example 90: (R)-N-(2-(3-Fluoro-2-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1079]

[1080] The trifluoroacetic acid salt of the title compound was prepared in analogy 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 (400MHz, CD3OD) δppm1.71-1.84(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.

[1081] Example 91: (R)-N-(2-(2-chloro-3-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1082]

[1083] The trifluoroacetate salt of the title compound was prepared in analogy 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 Et3N (146 μL, 1.05 mmol) in DMF (2 mL) to obtain a clear oil (19 mg, 4.3%). 1 HNMR(400MHz,CD3OD)δppm 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.

[1084] Example 92: (S)-N-(2-(2,3-dimethylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1085]

[1086] The trifluoroacetate salt of the title compound was prepared in analogy 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 Et3N (58 μL, 0.42 mmol) in DMF (2 mL) to obtain a clear oil (40 mg, 47%). 1 H NMR (400MHz, CD3OD) δppm1.75 (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.

[1087] Example 93: (S)-N-(2-(2-chloro-3-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1088]

[1089] The trifluoroacetic acid salt of the title compound was prepared in analogy 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(400MHz,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.

[1090] Example 94: (R)-N-(2-(2-chloro-3-fluorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1091]

[1092] The trifluoroacetic acid salt of the title compound was prepared in analogy 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 (400MHz, CD3OD) δppm1.78 (d, J=4.8Hz, 6H), 1.91-2.15 (m, 2H), 2.27-2.38 (m, 1H), 2.72-2.90 (m, 5 H),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.

[1093] Example 95: N-((S)-1-(4-fluoro-2-methoxyphenyl)ethyl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide

[1094]

[1095] The trifluoroacetate salt of the title compound was prepared in analogy to Example 86 using (S)-2-(1-methylpyrrolidin-2-yl)acetic acid (35 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 Et3N (34.1 μL, 0.244 mmol) in DMF (2 mL) to obtain a clear oil (15 mg, 15%). 1 H NMR(400MHz,CD3OD)δppm 1.45(d,J=7.0Hz,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,3H),3.14(dt,J=11.5,8.2Hz,1H),3.59-3.76(m,2H),3.86(s,3H),4.98(q,J=7.0Hz,1H),7.03-7.12(m,3H); ESI-MS m / z[M+H] + 295.3.

[1096] Example 96: (R)-N-(2-(2,3-dichlorophenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1097]

[1098] The trifluoroacetate salt of the title compound was prepared in analogy 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 Et3N (34.1 μL, 0.244 mmol) in DMF (2 mL) to obtain a clear oil (17 mg, 16%). 1HNMR(400MHz,CD3OD)δppm 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 .3Hz,1H),3.52-3.69(m,2H),7.28(t,J=8.0Hz,1H),7.45(dd,J=8.0,1.5Hz,1H),7.53(dd,J=8.0,1.5Hz,1H); ESI-MS m / z[M+H] + 329.3.

[1099] Example 97: 2-(3,3-Difluoro-1-methylpyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[1100]

[1101] Step A: tert-Butyl 3,3-difluoro-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[1102]

[1103] 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, assumed quantitative), which was used without further purification.

[1104] Step B: 2-(3,3-Difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[1105]

[1106] 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 4M 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 hydrochloride salt of the title compound (209 mg, assumed quantitative) which was used without further purification.

[1107] Step C: 2-(3,3-Difluoro-1-methylpyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[1108] 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, then sodium triacetoxyborohydride (359 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature overnight, then filtered and analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound as a clear oil (5 mg, 2.5% over three steps). 1 H NMR(400MHz,CD3OD)δppm 2.04(d,J=1.5Hz,6H),2.31-2.50(m,1H),2.51-2.67(m,1H),2.75-2.83( m,3H),2.88-3.03(m,2H),3.35-3.50(m,1H),3.73(ddd,J=11.8,8.5,3.5 Hz,1H),3.91(tt,J=12.3,6.0Hz,1H),7.91-7.97(m,1H),8.06-8.12(m,1 H),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.

[1109] Example 98: 2-(3,3-Difluoro-1-methylpyrrolidin-2-yl)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)acetamide

[1110]

[1111] The title compound was prepared in analogy to Example 97 using 2-(5-methylisoquinolin-1-yl)propan-2-amine (113 mg, 0.565 mmol) and obtained as a light beige solid (14 mg, 6.9% over three steps). 1 H NMR (400MHz, CD3OD) δppm1.89 (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.

[1112] Example 99: 2-(3,3-Difluoro-1-methylpyrrolidin-2-yl)-N-(2-(furo[3,2-c]pyridin-4-yl)propan-2-yl)acetamide

[1113]

[1114] The title compound was prepared in analogy 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 three steps). 1 H NMR (400MHz, CD3OD) δppm1.78(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.

[1115] Example 100: 2-(3,3-Difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[1116]

[1117] Step A: tert-Butyl 3,3-difluoro-2-(2-((2-(isoquinolin-1-yl)propan-2-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate

[1118]

[1119] 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 Et3N (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 NaSO4, 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.

[1120] Step B: 2-(3,3-Difluoropyrrolidin-2-yl)-N-(2-(isoquinolin-1-yl)propan-2-yl)acetamide

[1121] 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 at room temperature overnight, then washed with MeOH and analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purification using a gradient of 10-100% water / ACN in water (basic mode) gave the title compound as an orange oil (3 mg, 3.2% over two steps). 1HNMR(400MHz,CD3OD)δppm 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.

[1122] Example 101: 2-(3,3-difluoropyrrolidin-2-yl)-N-(2-(5-methylisoquinolin-1-yl)propan-2-yl)acetamide

[1123]

[1124] The title compound was prepared in analogy 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 (400MHz, CD3OD) δppm2.03-2.09(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.

[1125] Example 102: (S)-N-(2-methyl-1-((4-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1126]

[1127] 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. 2-Fluoro-4-methylpyridine (14.3 mg, 0.128 mmol) was then added. The reaction mixture was stirred at room temperature for 16 hours, then quenched with 1N aqueous HCl (0.15 mL) and analyzed by preparative HPLC (Phenomenex C18, 5 μm, ID 30 mm×150 mm) and purified 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, CD3OD) 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.

[1128] Example 103: (S)-N-(2-methyl-1-((5-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide

[1129]

[1130] The title compound was prepared in analogy 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-5-methylpyridine (14 mg, 0.128 mmol), and a colorless oil was obtained (6.7 mg, 19%). 1H NMR(400MHz,CD3OD)δppm 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] + 306.2.

[1131] Example 104: (S)-N-(2-methyl-1-((6-methylpyridin-2-yl)o...

Claims

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein: (a) X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 Selected from N and CR 5 ;and R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring which is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted 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 substituted with 0 to 3 optional substituents independently selected from halo; or (b) X 3 Yes CR 3C , X 4 Selected from N and CR 4 , and X 5 Selected from N and CR 5 ;and R 1 and R 2 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 substituted with 0 to 3 optional substituents independently selected from halo; or R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring selected from furan, pyrazole and benzene, wherein one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The cycloalkyl group is substituted, 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 substituted with 0 to 3 optional substituents independently selected from halo; L is O and n is 1; or L is a single bond and n is 0 or 1; R 3N Selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl; R 3C and R 4 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 substituted with 0 to 3 optional substituents independently selected from halo; R 5 Selected from: (i) hydrogen, halo, hydroxy and cyano; and (ii) C 1-4 Alkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R 6 is hydrogen; or R 5 and R 6 Together they form an ethane-1,2-diyl radical bridging the carbon atoms to which they are attached; R 7 and R 8 are each independently selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, where R 7 and R 8 At least one of is not hydrogen, or R 7 and R 8 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkylene; R 9 is selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl; R 10 is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl and a heterocyclic group having the formula: in Indicates the connection point, and r is selected from 0 and 1; R 11 is hydrogen, and R 12 is selected from hydrogen and is selected from C each substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl and C 3-6 Cycloalkyl, provided that if R 12 is hydrogen, then R 1 and R 2 forming a fused ring; or R 11 and R 12 Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached; R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, 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, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a 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 substituted with 0 to 3 optional substituents independently selected from halo; and R 17 and R 18 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl; The prerequisite is that the compound of formula 1 is not: 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)propionamide; N-(2-phenylpropan-2-yl)-3-(pyrrolidin-1-yl)propanamide; N-(1-(4-methylpyridin-2-yl)propyl)-3-(pyrrolidin-1-yl)acrylamide; or N-(1-(Naphth-1-yl)ethyl)-2-(pyrrolidin-2-yl)acetamide.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 Selected from N and CR 5 .

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each non-fused carbon atom of the fused ring formed is unsubstituted or substituted with a substituent selected from the group consisting of halo and C substituted with 0 to 3 substituents selected from the group consisting of halo. 1-3 alkyl.

4. The compound according to any one of claims 2 and 3 or a pharmaceutically acceptable salt thereof, wherein R 3N It is C 1-3 alkyl.

5. The compound according to any one of claims 2 to 3 or a pharmaceutically acceptable salt thereof, wherein X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 It is N. 6 . The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein L is a single bond and n is 0.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 Yes CR 3C , X 4 Selected from N and CR 4 , and X 5 Selected from N and CR 5 .

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 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 groups are each substituted with 0 to 3 substituents optionally independently selected from halo.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring selected from furan, pyrazole and benzene, wherein one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The cycloalkyl group is substituted, 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 groups are each substituted with 0 to 3 substituents optionally independently selected from halo.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each non-fused carbon atom of the fused ring formed is unsubstituted or substituted with a substituent selected from the group consisting of halo and C substituted with 0 to 3 substituents selected from the group consisting of halo. 1-3 alkyl.

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

12. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from: (i) hydrogen and halogen; and (ii) C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-4 Alkoxy groups are each substituted with 0 to 3 substituents optionally independently selected from halo.

13. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are each independently selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, where R 7 and R 8 At least one of the is not hydrogen.

14. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Together with the carbon atoms to which they are attached they form cyclopropylene, cyclobutylene and cyclopentylene.

15. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from the group consisting of hydrogen, methyl, ethyl and isopropyl.

16. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 10 It is azetidin-1-ylmethyl.

17. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 10 It is pyrrolidin-1-ylmethyl.

18. A compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein R 10 is a heterocyclic group having the formula: in Indicates the connection point, and r is selected from 0 and 1; R 11 is hydrogen, and R 12 is selected from hydrogen and is selected from C each substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl and C 3-6 Cycloalkyl, provided that if R 12 is hydrogen, then R 1 and R 2 forming a fused ring; or R 11 and R 12 Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached; R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, 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, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a 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 substituted with 0 to 3 optional substituents independently selected from halo; and R 17 and R 18 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen, and R 12 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo.

20. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen, and R 12 is selected from methyl, ethyl, isopropyl and cyclopropyl, each substituted with 0 to 3 substituents optionally independently selected from halo.

21. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl.

22. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 17 and R 18 are each independently selected from hydrogen, fluorine and methyl.

23. The compound according to claim 1, which is selected from the following compounds: N-(2-(1,7-dimethyl-1H-indazol-3-yl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; N-(2-(1-methyl1H-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-pyrrolizin-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)-2-(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-pyrrolizin-7a(5H)-yl)acetamide; N-(1-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-2-(tetrahydro-1H-pyrrolizin-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-methylphenyl)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide; (R)-N-(2-(3-chloro-2-methylphenyl)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)-Chromane-2-yl)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; N-(2-((R)-Chromane-2-yl)propan-2-yl)-2-((S)-1-methylpyrrolidin-2-yl)acetamide; N-(2-((R)-Chromane-2-yl)propan-2-yl)-2-((R)-1-methylpyrrolidin-2-yl)acetamide; N-(2-((S)-Chromane-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)propan-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)propanamide; (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-(pyrrolidin-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 A pharmaceutically acceptable salt of any one of the above compounds.

24. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 23; and a pharmaceutically acceptable excipient.

25. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 23 in the preparation of a medicament for treating a disease, disorder or condition selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and ADHD.

26. A combination comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 23 and at least one additional pharmacologically active agent.

27. The combination according to claim 26, wherein the additional pharmacologically active agent is selected from the group consisting of β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, antianxiety agents and anticonvulsants.

28. Use of a compound of formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease, disorder or condition selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and hyperactivity disorder, in: (a) X 3 Selected from NR 3N and O, X 4 is a single bond, and X 5 Selected from N and CR 5 ;and R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring which is benzene, wherein each non-fused carbon atom of the fused ring is unsubstituted or substituted with an optionally substituted 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 substituted with 0 to 3 optional substituents independently selected from halo; or (b) X 3 Yes CR 3C , X 4 Selected from N and CR 4 , and X 5 Selected from N and CR 5 ;and R 1 and R 2 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 substituted with 0 to 3 optional substituents independently selected from halo; or R 1 and R 2 Together with the carbon atoms to which they are attached, they form a fused ring selected from furan, pyrazole and benzene, wherein one nitrogen atom of the pyrazole ring is connected via hydrogen, C 1-4 Alkyl or C 3-6 The cycloalkyl group is substituted, 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 substituted with 0 to 3 optional substituents independently selected from halo; L is O and n is 1; or L is a single bond and n is 0 or 1; R 3N Selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl; R 3C and R 4 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 substituted with 0 to 3 optional substituents independently selected from halo; R 5 Selected from: (i) hydrogen, halo, hydroxy and cyano; and (ii) C 1-4 Alkyl and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R 6 is hydrogen; or R 5 and R 6 Together they form an ethane-1,2-diyl radical bridging the carbon atoms to which they are attached; R 7 and R 8 are each independently selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, where R 7 and R 8 At least one of is not hydrogen, or R 7 and R 8 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkylene; R 9 is selected from hydrogen and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl; R 10 is selected from azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl and a heterocyclic group having the formula: in Indicates the connection point, and r is selected from 0 and 1; R 11 is hydrogen, and R 12 is selected from hydrogen and is selected from C each substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl and C 3-6 Cycloalkyl, provided that if R 12 is hydrogen, then R 1 and R 2 forming a fused ring; or R 11 and R 12 Together they form a propane-1,3-diyl group bridging the carbon and nitrogen atoms to which they are respectively attached; R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 Alkyl, 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, they form a fused benzene ring, wherein each non-fused carbon atom is unsubstituted or substituted with a 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 substituted with 0 to 3 optional substituents independently selected from halo; and R 17 and R 18 are each independently selected from hydrogen, halo, and C substituted with 0 to 3 optional substituents independently selected from halo 1-4 alkyl; The prerequisite is that the compound of formula 1 is not: N-(1-phenylethyl)-3-(pyrrolidin-1-yl)propionamide; or N-(1-(3,4-dichlorophenyl)propyl)-3-(pyrrolidin-1-yl)propanamide.

29. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt as defined in claim 28; and a pharmaceutically acceptable excipient.

30. A combination comprising a compound or a pharmaceutically acceptable salt as defined in claim 28 and at least one additional pharmacologically active agent.

31. The combination of claim 30, wherein the additional pharmacologically active agent is selected from the group consisting of β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, antianxiety agents, and anticonvulsants.

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