N-(pyrrolidin-3-yl or piperidin-4-yl) acetamide derivatives

Abstract

Disclosed are compounds of Formula 1, # imgabs0, and pharmaceutically acceptable salts thereof, wherein L6, n, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, and X1 are defined in the specification. The disclosure also relates to materials and methods for preparing the compounds of Formula 1, pharmaceutical compositions containing the same, and their use for the treatment of diseases, disorders, and conditions associated with SSTR4.

Description

Technical Field

[0001] The present invention relates to N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives as modulators of somatostatin receptor 4 (SSTR4), pharmaceutical compositions containing the same, and their use 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 the production of cyclic AMP. SSTR4 is abundantly expressed in the central nervous system (CNS) and to a lesser extent in the dorsal root ganglia and intestine. 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 between species. For example, human, mouse and rat SSTR4 protein sequences share greater than 87% identity at the amino acid level. These factors, namely, predominant expression in the brain and high sequence homology between species, suggest that SSTR4 plays an important role in physiology.

[0004] Experiments using bacTRAP technology indicate that SSTR4 has the strongest expression in pyramidal neurons in the cortex and in the CA1 region of the hippocampus. This CNS expression is conserved in humans, non-human primates, and mice. The hippocampus is important for learning and memory. See LRSquire and AJDede, "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 starts from the entorhinal cortex, which also contains SSTR4, extends to the dentate gyrus, then enters the CA3, and finally reaches the CA1 region of the hippocampus. The CA1 protrudes from the hippocampus through the subiculum. This circuit encodes all types of information from the outside world to generate memories and learn new knowledge.

[0005] Alzheimer's disease is characterized by the degeneration of neurons within this circuit, mainly in the entorhinal cortex and CA1 region of the hippocampus. See A. Serrano-Pozo et al., "Neuropathological Alterations in Alzheimer Disease", Cold Spring Harbor Perspe ctives 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 Str ategies", Psychopharmacology (Berl) 202 (1-3): 153-63 (2009). This finding provides a strong basis for the use of SSTR4 agonists as a pharmacological approach to improve striatal-based learning. Same as above.

[0006] In addition, recent studies have also pointed out that hippocampal hyperactivity is the main driving factor for disease progression and impaired cognitive ability 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 SSTR4 receptors 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 said 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 the treatment of Alzheimer's disease and other CNS disorders such as epilepsy and depression. Summary of the invention

[0008] The present invention provides N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives, and provides uses thereof 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] X 1 Selected from N and CR 1 ;

[0013] n is selected from 0 and 1;

[0014] R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from

[0015] (i) hydrogen, halo, hydroxy and cyano; and

[0016] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0017] L 6 Selected from -CH2-, -N(R 6 )-、*-N(R 6 )CH2- and -O-, where R 6 Selected from hydrogen and C 1-3 alkyl, and * indicates the point of attachment to a carbon atom of the aromatic ring;

[0018] R 7 and R 8 are each independently selected from halogen and C 1-3 Alkyl, provided that R 7 and R 8 are not all methyl; or R 7 and R 8Together with the carbon atom to which it is attached, it forms a cyclopropylene group;

[0019] R 9 and R 10 Each independently selected from

[0020] (i) hydrogen and halogen; and

[0021] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or

[0022] R 9 and R 10 Together with the carbon atom to which it is attached, it forms a cyclopropylene group;

[0023] R 11 and R 12 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 11 and R 12 not more than one of them is methyl; and

[0024] (a)R 13 Selected from hydrogen and C 1-3 Alkyl; and

[0025] R 14 and R 15 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 14 and R 15 not more than one of them is methyl; or

[0026] (b)R 13 and R 14 together form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached; and

[0027] R 15 is selected from hydrogen, halo, and C 1-3 alkyl;

[0028] The condition is

[0029] (i) If X 1 CR 1 , L 6 is -CH2-, and R 7 and R 8 To form a cyclopropylene group, R 1 , R 2 , R3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 At least one of is not hydrogen;

[0030] (ii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form a cyclopropylene group, and R 9 , R 10 and R 13 Each is a methyl group, then R 3 Not fluorine or hydroxyl;

[0031] (iii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 is fluorine, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 9 , R 10 and R 13 are not all hydrogen and are not all methyl;

[0032] (iv) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R12 , R 13 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 9 Not methyl;

[0033] (v) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 11 Not methyl;

[0034] (vi) If X 1 CR 1 , n is 0, R 1 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form cyclopropylene, R 9 and R 10 Each is a methyl group, and R 13 If L is ethyl 6 Not -O- or -NH-;

[0035] (vii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8To form cyclopropylene, R 9 and R 10 are all methyl groups, and R 13 If R is ethyl 3 Not hydroxyl;

[0036] (viii) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, then R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 At least one of is not hydrogen;

[0037] (ix) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, and R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 Each is hydrogen, then R 1 Not fluorinated; and

[0038] (x) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, and R 1 , R 2 , R 4 , R5 , R 9 , R 10 , R 11 , R 12 and R 15 Each is hydrogen, then R 3 Not fluorine.

[0039] 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.

[0040] Another aspect of the present invention provides a compound or a pharmaceutically acceptable salt as defined in the preceding paragraph for use as a medicament.

[0041] Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

[0042] X 1 Selected from N and CR 1 ;

[0043] n is selected from 0 and 1;

[0044] R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from

[0045] (i) hydrogen, halo, hydroxy and cyano; and

[0046] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0047] L 6 Selected from -CH2-, -N(R 6 )-、*-N(R 6 )CH2- and -O-, where R 6 Selected from hydrogen and C 1-3 alkyl, and * indicates the point of attachment to a carbon atom of the aromatic ring;

[0048] R 7 and R 8 are each independently selected from hydrogen, halogen and C 1-3 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 it is attached, it forms C 3-6 Cycloalkylene;

[0049] R 9 and R 10 Each independently selected from

[0050] (i) hydrogen and halogen; and

[0051] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or

[0052] R 9 and R 10 Together with the carbon atom to which it is attached, it forms a cyclopropylene group;

[0053] R 11 and R 12 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 11 and R 12 not more than one of them is methyl; and

[0054] (a)R 13 Selected from hydrogen and C 1-3 Alkyl; and

[0055] R 14 and R 15 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 14 and R 15 not more than one of them is methyl; or

[0056] (b)R 13 and R 14 together form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached; and

[0057] R 15 is selected from hydrogen, halo, and C 1-3 alkyl;

[0058] The condition is

[0059] (i) If X is CR 1 , n is 1, L 6 For-O-, R 7 is methyl and R 8 is hydrogen, then R 1 , R 2 , R 3 , R 4 , R 5, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 or R 15 At least one of is not hydrogen;

[0060] (ii) If X is CR 1 , n is 1, L 6 For-O-, R 7 and R 8 are all methyl groups, and R 1 , R 2 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen, then R 3 No chlorine; and

[0061] (iii) If X is CR 1 , n is 1, L 6 For-O-, R 7 is methyl or ethyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen, then R 9 It is not an unsubstituted phenyl group.

[0062] 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 paragraphs; and a pharmaceutically acceptable excipient.

[0063] 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 paragraphs, for use in treating a disease, disorder or condition associated with SSTR4.

[0064] Another aspect of the present invention provides a 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 paragraphs, for the manufacture of a medicament for treating a disease, disorder or condition associated with SSTR4.

[0065] Another aspect of the present invention provides a method for treating a disease, disorder or condition associated with SSTR4, the method comprising administering to a subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs.

[0066] Another aspect of the present invention provides a method for treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, wherein the disease, disorder or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and ADHD.

[0067] 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 paragraphs; and at least one additional pharmacologically active agent. DETAILED DESCRIPTION

[0068] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0069] When combined with a chemical substituent or moiety (e.g., C 1-6 When 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 the valence requirements are met and the substitution results in a chemically stable compound.

[0070] 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.

[0071] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C 1-6Alkyl 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.

[0072] "Alkanediyl" refers to a divalent alkyl group, where alkyl is defined above, and typically has the specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, 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.

[0073] "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-propene-1-yl, 1-propene-2-yl, 2-propene-1-yl, 1-butene-1-yl, 1-butene-2-yl, 3-butene-1-yl, 3-butene-2-yl, 2-butene-1-yl, 2-butene-2-yl, 2-methyl-1-propene-1-yl, 2-methyl-2-propene-1-yl, 1,3-butadiene-1-yl, 1,3-butadiene-2-yl, and the like.

[0074] "Alkynyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon triple bonds and typically having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0075] "Alkoxy" refers to straight-chain and branched saturated hydrocarbon groups, usually having the specified number of carbon atoms, attached through an oxygen atom (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (ie, 1, 2, 3 or 4) carbon atoms, C 1-6Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, and so on). Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexyloxy, and the like.

[0076] "Halo," "halogen," and "halo" are used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0077] "Haloalkyl", "haloalkenyl" and "haloalkynyl" refer to alkyl, alkenyl and alkynyl, respectively, substituted with one or more halogen atoms, wherein alkyl, alkenyl and alkynyl are defined above and generally have the specified 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.

[0078] "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 may 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 common carbon atoms), and bridged rings (two rings share two carbon atoms but no common bonds). Cycloalkyl groups may be attached via any ring atom, unless such attachment would violate valence requirements; and, where specified, may optionally include one or more non-hydrogen substituents, unless such substitution would violate valence requirements.

[0079] Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyls 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 cycloalkyl groups include those derived from bis(cyclobutane), cyclobutanecyclopentane, bis(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bis(cyclohexane), and the like.

[0080] "Cycloalkanediyl" refers to a divalent cycloalkyl group, wherein 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 the cycloalkanediyl group include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0081] "Cycloalkylene" refers to a divalent monocyclic cycloalkyl group, wherein cycloalkyl is defined above, attached through a single carbon atom of the group and typically having the specified number of carbon atoms constituting 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.

[0082] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups that generally have a specified number of carbon atoms constituting one or more rings. Like cycloalkyl, bicyclic cycloalkenyls may include isolated rings, spirocycles, fused rings, or bridged rings. Similarly, cycloalkenyls may be connected via any ring atom, and in a given case, may optionally include one or more non-hydrogen substituents, unless such connection or substitution would violate the valence requirement. Examples of cycloalkenyls include partially unsaturated analogs of the cycloalkyls described above, such as cyclobutenyl (i.e., cyclobutene-1-yl and cyclobutene-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, etc.

[0083] "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 constituting their ring members (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 the valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthyl, benzocycloheptanyl, biphenylene, fluorenyl, groups derived from cycloheptatrienyl cations, and the like.

[0084] "Arylene" refers to a divalent aromatic radical, wherein aryl is defined above. Examples of arylene radicals include o-phenylene (ie, benzene-1,2-diyl).

[0085] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic radical having ring atoms consisting of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Both monocyclic and bicyclic radicals typically 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 may include isolated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl 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., aziridine-1-yl and aziridine-2-yl), oxetanyl, thiidine, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiidine, azepanyl, 1,4-dioxanyl, heterocycloheptyl, 1,4-oxathicycloheptyl, 1,4-oxazepanyl, 1,4-dithicycloheptyl, 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.

[0086] "Heterocycle-diyl" refers to a heterocyclic group linked via two ring atoms of the group, wherein heterocyclic groups are defined above. They typically have a specified number of carbon atoms in one or more of their rings (e.g., C 2-6 Heterocyclic-diyl refers to heterocyclic-diyl having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members). Examples of heterocyclic-diyl include polyvalent analogs of the heterocyclic groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

[0087] "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 typically have a specified number of carbon atoms as ring members (e.g., C 1-9Heteroaryl refers to heteroaryl groups having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members), and may include any bicyclic group of any of the monocyclic heterocycles listed above fused to a benzene ring. The heteroaryl group may be attached via any ring atom (or ring atoms of a fused ring), and in a given case, 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), furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0088] 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, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[ 4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[3,4-d]pyrimidinyl, [2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0089] "Heteroarylene" refers to a heteroaryl group linked through two ring atoms of a group, wherein heteroaryl is defined above. They typically have a specified number of carbon atoms in one or more of their rings (e.g., C3-5 Heteroarylene refers to heteroarylene having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members). Examples of heteroarylene 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.

[0090] "Oxo" refers to a double-bonded oxygen (=0).

[0091] "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 nucleofugal, 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 ionizing, in which the group leaves without a pair of electrons. The leaving ability of a nucleofugal leaving group depends on the strength of its base, with the strongest bases being the worst leaving groups. Common nucleofugal 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 made by treating with an acid. Common ionizing leaving groups include protons, CO2, and metals.

[0092] "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 stereochemical configuration, the opposite enantiomer has an R absolute stereochemical configuration. Likewise, if the reference molecule has an S,S absolute stereochemical configuration, the opposite enantiomer has an R,R stereochemical configuration, and so on.

[0093] "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 will include its opposite enantiomer having an R,S,Z configuration, and 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, "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0094] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound having a particular stereochemical configuration and comprising at least about 95% of the sample.

[0095] "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.

[0096] "Subject" refers to mammals, including humans.

[0097] "Pharmaceutically acceptable" materials refer to those materials that are suitable for administration to a subject.

[0098] "Treat," "treat," "treat," or "treating" means to reverse, alleviate, inhibit the progression of, or prevent the disease, disorder, or condition to which such term applies, or to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of such disease, disorder, or condition.

[0099] "Treatment" refers to the act of "treating" as defined immediately above.

[0100] "Drug", "API", "active pharmaceutical ingredient" and the like refer to a compound that can be used to treat a subject in need of treatment (eg, a compound of Formula 1, including subclasses of compounds and compounds specifically named in this specification).

[0101] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like, refers to that amount of a drug that can be used to treat a subject and may depend, among other things, on the weight and age of the subject and the route of administration.

[0102] "Excipient" refers to any diluent or vehicle for a drug.

[0103] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0104] "Drug product", "pharmaceutical dosage form", "dosage form", "final dosage form" and the like refer to a pharmaceutical composition that is suitable for treating a subject in need of treatment and that can typically be in the form of a tablet, capsule, sachet containing powder or granules, liquid solution or suspension, patch, film, and the like.

[0105] "A condition associated with SSTR4" and similar phrases relate to a disease, disorder, or condition in a subject for which activation of SSTR4 may provide a therapeutic or prophylactic benefit.

[0106] The following abbreviations may be used in the present 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 of 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); (bromotripyrrolidinophosphonium hexafluorophosphate); PCy3 (tricyclohexylphosphine); 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).

[0107] 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 the same, and uses of compounds of Formula 1 and pharmaceutically acceptable salts thereof (optionally in combination with other pharmacologically active agents) for treating diseases, disorders or conditions of the CNS (including Alzheimer's disease) and other diseases, disorders or conditions associated with SSTR4 (including pain).

[0108] The compounds of formula 1 include those below, wherein:

[0109] (1)X 1 Selected from N and CR 1 ;

[0110] n is selected from 0 and 1;

[0111] R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from

[0112] (i) hydrogen, halo, hydroxy and cyano; and

[0113] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0114] L 6 Selected from -CH2-, -N(R 6 )-、*-N(R6 )CH2- and -O-, where R 6 Selected from hydrogen and C 1-3 alkyl, and * indicates the point of attachment to a carbon atom of the aromatic ring;

[0115] R 7 and R 8 are each independently selected from halogen and C 1-3 Alkyl, provided that R 7 and R 8 are not all methyl; or R 7 and R 8 Together with the carbon atom to which it is attached, it forms a cyclopropylene group;

[0116] R 9 and R 10 Each independently selected from

[0117] (i) hydrogen and halogen; and

[0118] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or

[0119] R 9 and R 10 Together with the carbon atom to which it is attached, it forms a cyclopropylene group;

[0120] R 11 and R 12 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 11 and R 12 not more than one of them is methyl; and

[0121] (a)R 13 Selected from hydrogen and C 1-3 Alkyl; and

[0122] R 14 and R 15 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 14 and R 15 not more than one of them is methyl; or

[0123] (b)R 13 and R 14 together form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached; and

[0124] R 15is selected from hydrogen, halo, and C 1-3 alkyl;

[0125] The condition is

[0126] (i) If X 1 CR 1 , L 6 is -CH2- and R 7 and R 8 To form a cyclopropylene group, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 At least one of is not hydrogen;

[0127] (ii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form a cyclopropylene group, and R 9 , R 10 and R 13 Each is a methyl group, then R 3 Not fluorine or hydroxyl;

[0128] (iii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 is fluorine, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 9 , R10 and R 13 are not all hydrogen and are not all methyl;

[0129] (iv) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 9 Not methyl;

[0130] (v) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 11 Not methyl;

[0131] (vi) If X 1 CR 1 , n is 0, R 1 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form cyclopropylene, R 9 and R 10 Each is a methyl group, and R 13 If L is ethyl 6 Not -O- or -NH-;

[0132] (vii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form cyclopropylene, R 9 and R 10 are all methyl groups, and R 13 If R is ethyl 3 Not hydroxyl;

[0133] (viii) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, then R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 At least one of is not hydrogen;

[0134] (ix) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, and R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 Each is hydrogen, then R 1 Not fluorinated; and

[0135] (x) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, and R 1 , R 2 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 Each is hydrogen, then R 3 Not fluorine.

[0136] In addition to the embodiment (1) in the preceding paragraph, the compounds of formula 1 also include those wherein:

[0137] (2)X 1 CR 1 .

[0138] In addition to the embodiment (2) in the preceding paragraph, the compounds of formula 1 also include those wherein R 1 Selected from:

[0139] (3)(i) hydrogen, halo and cyano; and

[0140] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0141] (4)(i) hydrogen, halo and cyano; and

[0142] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0143] (5)(i) hydrogen, chlorine, fluorine and cyano; and

[0144] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0145] (6)(i) hydrogen, chlorine, fluorine and cyano; and

[0146] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 fluorines;

[0147] (7)(i) hydrogen, chlorine, fluorine and cyano; and

[0148] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0149] (8)(i) hydrogen, halo and cyano; and

[0150] (ii) methyl, methoxy and cyclopropyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0151] (9)(i) hydrogen, halo and cyano; and

[0152] (ii) methyl, methoxy and cyclopropyl, each of which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0153] (10) hydrogen, halo, cyano, methyl, methoxy and cyclopropyl;

[0154] (11) hydrogen, chlorine, fluorine, cyano, methyl, methoxy and cyclopropyl;

[0155] (12) Hydrogen, chlorine, fluorine, cyano, methyl and methoxy;

[0156] (13) Hydrogen, chlorine and methyl; or

[0157] (14) Hydrogen.

[0158] In addition to the above embodiment (1), the compounds of formula 1 also include those below, wherein:

[0159] (15)X 1 is N.

[0160] In addition to the embodiments (1) to (15) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 2 Selected from:

[0161] (16)(i) hydrogen and halogen; and

[0162] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0163] (17)(i) hydrogen and halogen; and

[0164] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0165] (18)(i) Hydrogen, chlorine and fluorine; and

[0166] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0167] (19)(i) Hydrogen, chlorine and fluorine; and

[0168] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 fluorines;

[0169] (20)(i) Hydrogen, chlorine and fluorine; and

[0170] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0171] (21)(i) hydrogen and halogen; and

[0172] (ii)C 1-3 Alkyl and C 1-3 Alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0173] (22)(i) hydrogen and halogen; and

[0174] (ii) methyl and methoxy, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0175] (23)(i) hydrogen and halogen; and

[0176] (ii) methyl and methoxy, each of which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0177] (24) Hydrogen, halogen, methyl and methoxy;

[0178] (25) Hydrogen, chlorine, fluorine and methyl; or

[0179] (26) Hydrogen, chlorine and methyl.

[0180] In addition to the embodiments (1) to (26) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 3 Selected from:

[0181] (27)(i) hydrogen and halogen; and

[0182] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0183] (28)(i) hydrogen and halogen; and

[0184] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0185] (29)(i) Hydrogen, chlorine and fluorine; and

[0186] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0187] (30)(i) Hydrogen, chlorine and fluorine; and

[0188] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 fluorines;

[0189] (31)(i) Hydrogen, chlorine and fluorine; and

[0190] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0191] (32)(i) hydrogen and halogen; and

[0192] (ii) C is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen 1-3 alkyl;

[0193] (33)(i) hydrogen and halogen; and

[0194] (ii) methyl which is unsubstituted or substituted by 1 to 3 substituents independently selected from halogen;

[0195] (34)(i) hydrogen and halogen; and

[0196] (ii) methyl which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0197] (35) Hydrogen, halogen and methyl;

[0198] (36) Hydrogen, chlorine, fluorine and methyl; or

[0199] (37) Hydrogen and chlorine.

[0200] In addition to the embodiments (1) to (37) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 4 Selected from:

[0201] (38)(i) hydrogen and halogen; and

[0202] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0203] (39)(i) hydrogen and halogen; and

[0204] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0205] (40)(i) Hydrogen, chlorine and fluorine; and

[0206] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0207] (41)(i) Hydrogen, chlorine and fluorine; and

[0208] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 fluorines;

[0209] (42)(i) Hydrogen, chlorine and fluorine; and

[0210] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6Cycloalkyl;

[0211] (43)(i) hydrogen and halogen; and

[0212] (ii)C 1-3 Alkyl and C 1-3 Alkoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0213] (44)(i) hydrogen and halogen; and

[0214] (ii) methyl and methoxy, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0215] (45)(i) hydrogen and halogen; and

[0216] (ii) methyl and methoxy, each of which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0217] (46) Hydrogen, halogen, methyl and methoxy;

[0218] (47) Hydrogen, chlorine, fluorine and methyl;

[0219] (48) Hydrogen, chlorine and fluorine;

[0220] (49) Hydrogen and fluorine; or

[0221] (50) Hydrogen.

[0222] In addition to the embodiments (1) to (50) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 5 Selected from:

[0223] (51)(i) hydrogen, halo and cyano; and

[0224] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0225] (52)(i) hydrogen, halo and cyano; and

[0226] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0227] (53)(i) hydrogen, chlorine, fluorine and cyano; and

[0228] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0229] (54)(i) hydrogen, chlorine, fluorine and cyano; and

[0230] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 fluorines;

[0231] (55)(i) hydrogen, chlorine, fluorine and cyano; and

[0232] (ii) each unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl;

[0233] (56)(i) hydrogen, halo and cyano; and

[0234] (ii) methyl, methoxy and cyclopropyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0235] (57)(i) hydrogen, halo and cyano; and

[0236] (ii) methyl, methoxy and cyclopropyl, each of which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0237] (58) hydrogen, halo, cyano, methyl, methoxy and cyclopropyl;

[0238] (59) hydrogen, chlorine, fluorine, cyano, methyl, methoxy and cyclopropyl;

[0239] (60) Hydrogen, chlorine, fluorine, cyano, methyl and methoxy;

[0240] (61) Hydrogen, chlorine and methyl; or

[0241] (62) Hydrogen.

[0242] In addition to the embodiments (1) to (62) in the preceding paragraphs, the compounds of formula 1 also include those wherein L 6 Selected from:

[0243] (63) -CH2- and -O-;

[0244] (64)-CH2-;

[0245] (65) -O-;

[0246] (66)-N(R 6 )- and *-N(R 6 )CH2-; or

[0247] (67)*-N(R 6 )CH2-.

[0248] In addition to the embodiments (66) to (67) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 6 Selected from:

[0249] (68) Hydrogen and methyl;

[0250] (69) methyl; or

[0251] (70) Hydrogen.

[0252] In addition to the embodiments (1) to (70) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 7 and R 8 Each independently selected from:

[0253] (71) Halogen and C 1-3 Alkyl, provided that R 7 and R 8 Not all are methyl;

[0254] (72) Fluorine and C 1-3 Alkyl, provided that R 7 and R 8 Not all are methyl;

[0255] (73) halo and methyl, provided that R 7 and R 8 Not all are methyl;

[0256] (74) fluorine and methyl, provided that R 7 and R 8 Not all are methyl;

[0257] (75) halogen; or

[0258] (76) Fluorine.

[0259] In addition to the embodiments (1) to (70) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0260] (77)R 7 and R 8 Together with the carbon atom to which it is attached it forms a cyclopropylene group.

[0261] In addition to the embodiments (1) to (77) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 9 and R 10 Each independently selected from:

[0262] (78)(i) hydrogen and halogen; and

[0263] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0264] (79)(i) hydrogen and halogen; and

[0265] (ii) each unsubstituted C 1-3 Alkyl and phenyl groups;

[0266] (80)(i) Hydrogen and fluorine; and

[0267] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0268] (81)(i) Hydrogen and fluorine; and

[0269] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from fluorine;

[0270] (82)(i) Hydrogen and fluorine; and

[0271] (ii) each unsubstituted C 1-3 Alkyl and phenyl groups;

[0272] (83)(i) hydrogen and halogen; and

[0273] (ii) methyl, ethyl, isopropyl and phenyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0274] (84)(i) hydrogen and halogen; and

[0275] (ii) methyl, ethyl, isopropyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from chlorine and fluorine;

[0276] (85)(i) hydrogen and halogen; and

[0277] (ii) methyl, ethyl, isopropyl and phenyl, each of which is unsubstituted or substituted with 1 to 3 fluorine atoms;

[0278] (86) hydrogen, halo, methyl, ethyl, isopropyl and phenyl;

[0279] (87) hydrogen, fluorine, methyl, ethyl, isopropyl and phenyl; or

[0280] (88) Hydrogen, fluorine and methyl.

[0281] In addition to the embodiments (78) to (88) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0282] (89)R 9 and R 10 At least one of them is hydrogen.

[0283] In addition to the embodiments (1) to (77) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0284] (90)R 9 and R 10 are all hydrogen; or

[0285] (91)R 9 and R 10 Together with the carbon atom to which it is attached it forms a cyclopropylene group.

[0286] In addition to the embodiments (1) to (91) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 11 and R 12 Each independently selected from:

[0287] (92) Hydrogen, halogen and unsubstituted C 1-3 alkyl;

[0288] (93) hydrogen, fluorine and C unsubstituted or substituted by 1 to 3 substituents independently selected from halogen 1-3 alkyl;

[0289] (94) hydrogen, halo, and methyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0290] (95) hydrogen, halogen and methyl which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0291] (96) hydrogen, halo and methyl; or

[0292] (97) Hydrogen, fluorine and methyl.

[0293] In addition to the embodiments (92) to (97) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0294] (98)R 11 and R 12 At least one of them is hydrogen.

[0295] In addition to the embodiments (1) to (91) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0296] (99)R 11 and R 12All are hydrogen.

[0297] In addition to the embodiments (1) to (99) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 13 Selected from:

[0298] (100) Hydrogen and C 1-3 Alkyl; or

[0299] (101) Hydrogen and methyl.

[0300] In addition to the embodiments (100) to (101) in the preceding paragraphs, the compounds of Formula 1 also include those wherein R 14 and R 15 No more than one of them is methyl, and each R 14 and R 15 Independently selected from:

[0301] (102) hydrogen, halogen, and C 1-3 alkyl;

[0302] (103) Hydrogen, halogen and unsubstituted C 1-3 alkyl;

[0303] (104) hydrogen, fluorine and C unsubstituted or substituted by 1 to 3 substituents independently selected from halogen 1-3 alkyl;

[0304] (105) hydrogen, halo, and methyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0305] (106) hydrogen, halogen and methyl which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0306] (107) hydrogen, halo and methyl; or

[0307] (108) Hydrogen, fluorine and methyl.

[0308] In addition to the embodiments (102) to (108) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0309] (109)R 14 and R 15 At least one of them is hydrogen.

[0310] In addition to the above embodiments (100) to (101), the compounds of formula 1 also include those wherein:

[0311] (110)R 14 and R 15 All are hydrogen.

[0312] In addition to the embodiments (1) to (99) in the preceding paragraphs, the compounds of Formula 1 also include those wherein:

[0313] (111)R 13 and R 14 Together they form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached.

[0314] In addition to the embodiment (111) in the preceding paragraph, the compounds of formula 1 also include those wherein R 15 Selected from:

[0315] (112) hydrogen, halogen, and C 1-3 alkyl;

[0316] (113) Hydrogen, halogen and unsubstituted C 1-3 alkyl;

[0317] (114) hydrogen, fluorine and C unsubstituted or substituted by 1 to 3 substituents independently selected from halogen 1-3 alkyl;

[0318] (115) hydrogen, halo, and methyl which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0319] (116) hydrogen, halogen and methyl which is unsubstituted or substituted by 1 to 3 fluorine groups;

[0320] (117) hydrogen, halo and methyl; or

[0321] (118) Hydrogen, fluorine and methyl.

[0322] In addition to the embodiments (111) to (118) in the preceding paragraphs, the compounds of formula 1 also include those wherein R 15 for:

[0323] (119) Hydrogen.

[0324] In addition to the embodiments (1) to (119) in the preceding paragraphs, the compounds of Formula 1 also include those wherein n is:

[0325] (120) 0; or

[0326] (121)1.

[0327] Compounds of Formula 1 for use as medicaments may include those below, wherein:

[0328] (122)X 1 Selected from N and CR 1 ;

[0329] n is selected from 0 and 1;

[0330] R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from

[0331] (i) hydrogen, halo, hydroxy and cyano; and

[0332] (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo;

[0333] L 6 Selected from -CH2-, -N(R 6 )-、*-N(R 6 )CH2- and -O-, where R 6 Selected from hydrogen and C 1-3 alkyl, and * indicates the point of attachment to a carbon atom of the aromatic ring;

[0334] R 7 and R 8 are each independently selected from hydrogen, halogen and C 1-3 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 it is attached, it forms C 3-6 Cycloalkylene;

[0335] R 9 and R 10 Each independently selected from

[0336] (i) hydrogen and halogen; and

[0337] (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or

[0338] R 9 and R 10 Together with the carbon atom to which it is attached, it forms a cyclopropylene group;

[0339] R 11 and R 12 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 11 and R12 not more than one of them is methyl; and

[0340] (a)R 13 Selected from hydrogen and C 1-3 Alkyl; and

[0341] R 14 and R 15 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 14 and R 15 not more than one of them is methyl; or

[0342] (b)R 13 and R 14 together form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached; and

[0343] R 15 is selected from hydrogen, halo, and C 1-3 alkyl;

[0344] The condition is

[0345] (i) If X is CR 1 , n is 1, L 6 For-O-, R 7 is methyl and R 8 is hydrogen, then R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 or R 15 At least one of is not hydrogen;

[0346] (ii) If X is CR 1 , n is 1, L 6 For-O-, R 7 and R 8 are all methyl, and R 1 , R 2 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14and R 15 Each is hydrogen, then R 3 No chlorine; and

[0347] (iii) If X is CR 1 , n is 1, L 6 For -O-, R 7 is methyl or ethyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen, then R 9 It is not an unsubstituted phenyl group.

[0348] The compounds of formula 1 include the embodiments (1) to (122) described in the preceding paragraphs and the compounds specifically named 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.

[0349] 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, for example, the following inorganic acids: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid and phosphorous acid; and non-toxic salts derived from, for example, the following organic acids: 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, cyclaminate, edisylate, ethanesulfonate, formate, fumarate, 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, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0350] Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as alkali or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, ethanolamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful 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).

[0351] 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) by treating with an appropriate acid or base or by contacting with an ion exchange resin. After the reaction, if the salt is precipitated 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 completely ionized to almost unionized.

[0352] The compound of formula 1 may exist in a continuous solid form ranging from 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").

[0353] The compounds of formula 1 may 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 may be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0354] 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 so as not to directly contact each other. In channel solvates, solvent molecules are located in lattice channels, and in the lattice channels, the solvent molecules are next to other solvent molecules. In the solvates of metal ion coordination, solvent molecules are bonded to metal ions.

[0355] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry, independent 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 typically be observed.

[0356] Formula 1 compounds may also exist in the form of multi-component complexes (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 typically 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.

[0357] When subjected to suitable conditions, the compounds of Formula 1 may 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). Mesomorphism due to temperature changes is described as "thermotropic", and mesomorphism due to the addition of a second component such as water or another solvent is described as "lyotropic". Compounds that may form lyotropic mesophases are described as "amphiphilic" and include compounds with polar ionic moieties (e.g., -COO - Na + 、-COO - K + 、-SO3 - Na + ) or a polar nonionic part (e.g. -NN + (CH3)3) molecules. See, for example, NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th edition, 1970).

[0358] Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically labeled, may be generated by administration of a prodrug, or may form a metabolite following administration.

[0359] "Prodrug" refers to a compound with little or no pharmacological activity, which can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared by replacing the appropriate functional groups present in the pharmacologically active compound with a "promolar 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 EB Roche, ed., Bioreversible Carriers in Drug Design (1987).

[0360] "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.

[0361] 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. The stereoisomers may be pure, substantially pure, or a mixture. 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.

[0362] 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.

[0363] Compounds of Formula 1 may exhibit more than one type of isomerism.

[0364] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

[0365] Conventional techniques for preparing or separating compounds with specific stereochemical configurations include chiral synthesis from suitable optically pure precursors, or using, for example, chiral high pressure liquid chromatography (HPLC) to split racemates (or racemates of salts or derivatives). Alternatively, racemates (or racemic precursors) can be reacted with suitable optically active compounds, such as alcohols, or with acids or bases such as tartaric acid or 1-phenylethylamine when the compound of formula 1 contains acidic or basic moieties. The resulting diastereoisomer mixture can be separated by chromatography, fractional crystallization, etc., and appropriate diastereomers can be converted into compounds with required stereochemical configurations. For further discussion of the technology for separating stereoisomers, see EL Eliel and SH Wilen, Stereochemistry of Organic Compounds (1994).

[0366] 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 18 F; isotopes of chlorine, such as 36Cl; 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 incorporate radioactive isotopes (e.g., tritium 3 H, or 14 C), which may be useful in drug and / or substrate tissue distribution studies. 11 C. 18 F. 15 O and 13 N substitution may be useful 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.

[0367] Formula 1 compound can be prepared using the technology described below. Some methods and examples 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 Michael B.Smith et al. edited multi-volume series, 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 schemes can omit minor products (for example, alcohol obtained by ester hydrolysis, CO obtained by decarboxylation of diacids, etc.) obtained by chemical transformation. In addition, in some cases, the reaction intermediate can be used in subsequent steps (i.e., in situ) without separation or purification.

[0368] In the methods and embodiments below, some compounds can be prepared using protecting groups, which prevent undesirable chemical reactions from occurring at other reaction sites. Protecting groups can also be used to enhance solubility or otherwise change the physical properties of compounds. Discussions on protecting group strategies, descriptions for placing and removing the materials and methods of protecting groups, and compilations of useful protecting groups for common functional groups (including amines, carboxylic acids, alcohols, ketones, aldehydes, etc.), see TW Greene and PGWuts, Protecting Groups in Organic Chemistry (1999) and P.Kocienski, Protective Groups (2000).

[0369] In general, the chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions may benefit from using an excess of one or more reactants. In addition, many reactions disclosed throughout this specification can be carried out at about room temperature (RT) and ambient pressure, but some reactions may be carried out 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 to stoichiometric ranges, temperature ranges, pH ranges, etc. in the present disclosure and claims, whether or not the word "range" is explicitly used, also includes the indicated endpoints.

[0370] 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 acid triamide).

[0371] In the schemes below, a substituent identifier (e.g., L 6 ,n,R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 ) as defined above for Formula 1. As previously mentioned, some starting materials and intermediates may include protecting groups that are removed prior to the final product. In such cases, the substituent identifier refers to the moieties defined in Formula 1 and to those moieties having appropriate protecting groups. For example, the starting materials or intermediates in the synthesis method may include potentially reactive (secondary) amines. In such cases, the amines will include moieties with or without Boc or Cbz groups attached to the amine.

[0372] Scheme A shows a general method for preparing compounds of formula 1. According to the method, an aryl or heteroaryl (alkyl, oxyalkyl or aminoalkyl) carboxylic acid (A1) is reacted with a primary amine (A2) or a suitable base addition salt (e.g., a lithium salt). In the presence of a non-nucleophilic base (e.g., Et3N, DIPEA) and one or more compatible solvents (e.g., ACN, DCM, DMA, DMF, NMP, pyridine, THF), a standard amide coupling agent such as HATU, DCC, EDC hydrochloride, T3P or iodinated 2-chloro-1-methylpyridin-1-ium is used to react. Amide coupling can be carried out at a temperature in the range of room temperature to about 80°C. HOBt can be used to promote the reaction.

[0373]

[0374] Although not shown in Scheme A, the starting material may include a protected (e.g., Boc-substituted) secondary amine. 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 (e.g., R in the presence of a non-nucleophilic base (e.g., KCO) and a compatible solvent (e.g., DMSO). 13 Y 1 , where R 13 =C 1-3 Alkyl and Y 1 =Br, I). 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 (such as MeOH, DCM) to give the desired R 13 The N-alkylation and reductive amination steps can be carried out at room temperature or at elevated temperatures.

[0375] 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, via 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 be optionally 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.

[0376] The biopharmaceutical properties of the compounds of formula 1 (including the compounds named above) and their pharmaceutically acceptable complexes, salts, solvates and hydrates, such as solubility and solution stability across pH values, permeability, etc., should be evaluated to select appropriate dosage forms and routes of administration. The compounds intended for pharmaceutical use can be administered as crystalline or amorphous products and can be obtained, for example, in the form of solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying or radio frequency drying.

[0377] The compounds of formula 1 can be administered alone or in combination with one another or with one or more pharmacologically active compounds different from the compounds of formula 1. Typically, one or more of these compounds are combined with one or more pharmaceutically acceptable excipients for administration 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. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th edition, 2000).

[0378] 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 via the oral mucosa.

[0379] Formulations suitable for oral administration include solid, semisolid and liquid systems, such as tablets; soft or hard capsules containing multi-particles or nanoparticles, liquids or powders; lozenges that can be filled with liquids; chewables; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucosal adhesive patches. Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations can be used as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose) and typically include carriers (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils) and one or more emulsifiers, suspending agents or both. Liquid preparations can also be prepared by reconstitution of solids (e.g., from medicine bags).

[0380] 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.

[0381] For tablet dosage forms, depending on the dose, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% of the dosage form, or more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, the tablet may also contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavoring agents, preservatives, and taste masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, crospovidone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 Alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch and sodium alginate. Typically, the disintegrant will comprise from about 1 wt % to about 25 wt % or from about 5 wt % to about 20 wt % of the dosage form.

[0382] Binders are generally used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0383] Tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80; and glidants, such as silicon dioxide and talc. When present, surfactants may comprise about 0.2 wt % to about 5 wt % of the tablet, and glidants may comprise about 0.2 wt % to about 1 wt % of the tablet.

[0384] 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. The lubricant may comprise about 0.25 wt % to about 10 wt % or about 0.5 wt % to about 3 wt % of the tablet.

[0385] Tablet blends can be compressed directly or by roller compaction to form tablets. Alternatively, tablet blends or portions of blends can be wet, dry or melt granulated, melt coagulated, or extruded before tableting. Where necessary, one or more components can be graded 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 wt% of API, about 10 wt% to about 90 wt% of binder, about 0 wt% to about 85 wt% of diluent, about 2 wt% to about 10 wt% of disintegrant, and about 0.25 wt% to about 10 wt% of lubricant. For a discussion of blending, granulation, milling, screening, tableting, coating, and description of alternative technologies for preparing drug products, see AR Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); HA Lieberman et al. (eds.), Pharmaceutical Dosage Forms: Tablets, Vols. 1-3 (2nd ed., 1990); and DK Parikh and CK Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0386] Consumable oral films for human or veterinary use are flexible 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 contain one or more film-forming polymers, adhesives, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Other film ingredients may 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 may perform more than one function.

[0387] In addition to dosage requirements, the amount of API in the film may also depend on its solubility. If water-soluble, the API will typically account for about 1 wt% to about 80 wt% of the non-solvent component (solute) in the film or about 20 wt% to about 50 wt% of the solute in the film. APIs with less solubility may account for a larger proportion of the composition, typically up to about 88 wt% of the non-solvent component in the film.

[0388] 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.

[0389] Thin-film dosage forms are typically prepared by evaporative drying of an aqueous film coated onto a peelable backing or paper, which can be carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in a freeze-drying unit, or in a vacuum oven.

[0390] Solid preparations suitable 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 on other useful release technologies, such as high energy dispersions and permeation and coated particles, see Verma et al., Pharmaceutical Technology On-line (2001) 25 (2): 1-14.

[0391] The compound of Formula 1 can also be administered directly into the bloodstream, muscle or internal organs of the 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.

[0392] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (e.g., at a pH of about 3 to about 9). However, for some applications, the compound of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or dry form for use in conjunction with a suitable vehicle such as sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be easily accomplished using standard pharmaceutical techniques.

[0393] The solubility of the compound for preparing a parenteral solution can be increased via appropriate formulation techniques, such as by incorporating a solubility enhancer. 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 semisolids and suspensions of drug-loaded poly (DL-lactic acid-co-glycolic acid) (PGLA) microspheres.

[0394] The compound of formula 1 may 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 may also be used. Typical carriers may include alcohol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88 (10): 955-958 (1999).

[0395] Other ways 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 may be formulated for immediate release or modified release.

[0396] Formula 1 compounds can also be administered intranasally or by inhalation, typically in the form of dry powder, aerosol spray or nasal drops. Inhalers can be used to administer dry powders, which include a single API, a powder blend of an API and a diluent (e.g., lactose) or mixed component particles including API and phospholipids (e.g., phosphatidylcholine). For intranasal use, the powder may include a bioadhesive, such as chitosan or cyclodextrin. A pressurized container, pump, ejector, atomizer or sprayer can be used to produce an aerosol spray from a solution or suspension, the solution or suspension comprising an API, one or more agents for dispersing, dissolving the API or extending the release of the API (e.g., aqueous or non-aqueous EtOH), one or more solvents used as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and optional surfactants, such as sorbitan trioleate, oleic acid or oligolactic acid. An electrohydrodynamic atomizer can be used to produce a fine mist.

[0397] Prior to use in a dry powder or suspension formulation, the drug product is usually 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, fluid bed jet milling, supercritical fluid processing, high pressure homogenization or spray drying.

[0398] Capsules, blisters and cartridges (made, for example, of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator may be formulated to contain a powder mix of the active compound; a suitable powder base such as lactose or starch; and a performance modifier such as L-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0399] Solution formulations suitable for use in atomizers using electrohydrodynamics to produce a fine mist may contain from about 1 μg to about 20 mg of API per actuation, and the actuation volume may vary from about 1 μL to about 100 μL. Typical formulations may include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0400] Formulations for inhaled administration, intranasal administration, or both can be formulated for immediate release or modified release using, for example, PGLA. Suitable flavoring agents (e.g., menthol and levomenthol) or sweeteners (e.g., saccharin or saccharin sodium) can be added to formulations intended for inhaled / intranasal administration.

[0401] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. 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 in a single dose or more often in divided doses throughout the day.

[0402] 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 substitutes can be used as appropriate. As described above, preparations for rectal or vaginal administration can be formulated for immediate release or modified release.

[0403] Formula 1 compound can also be directly applied to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic sterile saline with adjusted pH value. Other preparations suitable for administration through the eye and ear include ointments, gels, biodegradable implants (e.g., absorbable gel sponges, collagen), non-biodegradable implants (e.g., silicones), wafer capsules, lenses, and microparticles or vesicle systems, such as vesicles (niosomes) or liposomes. The preparation may include one or more polymers and preservatives, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose) and heteropolysaccharide polymers (e.g., gellan gum). Such preparations can also be delivered by iontophoresis. As described above, preparations for administration through the eye or ear can be formulated for direct release or modified release.

[0404] To improve its solubility, dissolution rate, taste masking, bioavailability or stability, the compound of formula 1 can be combined with a soluble macromolecular entity, including cyclodextrin and its derivatives and polymers containing polyethylene glycol. For example, API-cyclodextrin complexes are generally suitable for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with API, cyclodextrin can be used as an auxiliary additive, i.e., as a carrier, diluent or solubilizer. Alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin are generally used for these purposes. See, for example, WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0405] As mentioned above, one or more compounds of Formula 1 (including the compounds specifically named above) and their pharmaceutically active complexes, salts, solvates and hydrates 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 comprises (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 familiar blister package for packaging tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral), or for administering different pharmaceutical compositions at independent dosing intervals, or for titrating different pharmaceutical compositions relative to each other. To help patient compliance, the kit typically includes instructions for administration and can be provided with a memory aid.

[0406] For administration to human patients, the total daily dose of the claimed and disclosed compounds is typically 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 an intravenous dose 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 ordinary human subjects with a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for patients (e.g., infants) whose mass falls outside this weight range.

[0407] As mentioned above, the compounds of Formula 1 can be used to treat diseases, disorders and conditions that require SSTR4 activation. Such diseases, disorders and conditions generally relate to any unhealthy or abnormal state of a subject for which SSTR4 activation provides a therapeutic benefit. More specifically, the compounds of Formula 1 can be used to treat CNS diseases, disorders or conditions, including Alzheimer's disease, and other forms of dementia associated with one or more medical conditions (i.e., severe or mild neurocognitive disorders), 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. The compounds of Formula 1 can also be used to treat severe or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder and autism. In addition, the compounds of Formula 1 can be used to treat anxiety disorders and to treat epilepsy. The compounds of Formula 1 can also be used to treat pain.

[0408] 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 requiring SSTR4. Such combinations can provide significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity. For example, the 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 independently 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 ( acid, 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.

[0409] In addition to drugs for improving cognition, the compounds of Formula 1 may 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, 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.

[0410] Likewise, the compounds of Formula 1 may be combined with one or more agents used to treat anxiety disorders (anxiolytics), including benzodiazepines (alprazolam, clozapine, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, The drugs included oxazepam, cyclosporine ...

[0411] The compound of formula 1 may also be combined with one or more agents used to treat epilepsy (anti-epileptic or anticonvulsant agents), including acetazolamide, carbamazepine, clobazam, quinazepine, 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.

[0412] Biological Activity

[0413] The biological activity of compounds of Formula 1 against SSTR4 can be determined using the following in vitro and in vivo methods.

[0414] Inhibition of Forskolin-stimulated cAMP in cells overexpressing SSTR4

[0415] 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 DiscoveRx (product code 95-0059C2). CHO-SSTR4 cells were maintained in F12K medium containing 10% fetal bovine serum (Hyclone), 1% penicillin / streptomycin (Life Technologies) and 800 μg / mL G418 (Life Technologies). For the assay, 3000 cells per well were plated in 50 μL of complete medium in a white 384-well plate (Corning 3570) and the cells were 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 and then removed) with Krebs Ringer Buffer (ZenBio, KRB-1000 mL). Test compounds were suspended in DMSO and diluted in the following stimulation buffer: Krebs-Ringer buffer plus 0.5% BSA (Roche), 300 μM IBMX (Sigma) and 350 nM Forskolin (Sigma). Cells were incubated in 10 μL compound / stimulation buffer for 30 minutes at room temperature. Cellular cAMP levels were detected using the HTRF LANCE Ultra cAMP kit (Perkin Elmer, catalog number TRF0264).

[0416] The assay was performed according to the manufacturer's instructions. 5 μL of diluted Eu-W8044 labeled streptavidin (diluted in cAMP assay buffer: 1:50) was added to each well. Then 5 μL of diluted biotin cAMP (diluted in cAMP assay buffer: 1:150) was added to each well. The plate was covered and incubated on a shaker at room temperature for 60 minutes. HTRF (665nm / 615nm) was read on a Perkin Elmer ENVISION plate reader. pEC was generated using the Activity Base for Screening Data Management. 50 value.

[0417] SSTR4 I-125 somatostatin competition binding assay

[0418] This membrane-based assay measures the ability of a compound to competitively inhibit the binding of I-125 labeled somatostatin to SSTR4 in membranes from CHO-K1 cells overexpressing SSTR4. Membranes from CHO-K1 cells overexpressing SSTR4 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 Catalog No. NEX389). 50 μL of assay buffer containing compound / I-125 somatostatin per well was added to a 96-well polypropylene plate. 50 μL of assay buffer containing 1 μg of SSTR4 membrane was then added per well. The plate was incubated for 60 minutes at room temperature. 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 .

[0419] SSTR1 I-125 Somatostatin Competition Binding Assay Selective for SSTR1

[0420] This membrane-based assay measures the ability of a compound to competitively inhibit the binding of I-125 labeled somatostatin to SSTR1 in membranes from CHO-K1 cells overexpressing SSTR1. Membranes from CHO-K1 cells overexpressing SSTR1 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 assay buffer containing compound / I-125 somatostatin per well was added to a 96-well polypropylene plate. 50 μL of assay buffer containing 10 μg of SSTR1 membrane was then added per well. The plate was incubated for 60 minutes at room temperature. FilterMat A filter (Perkin Elmer catalog number 1450-421) was pre-soaked in 0.5% PEI (Sigma catalog number P3143). The contents of the assay plate were transferred to the filter using a TomTech collector and washed 5 times with 20mM HEPES, 100mM NaCl. The filter was 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 was melted and added to the filter using a heating block. The filter was then read in a MicroBeta scintillation counter. The binding Ki curve was generated using the screening data management activity base station, and the results were reported as pIC 50 .

[0421] The following in vitro assay can be used to evaluate the ability of compounds of Formula 1 to cross the blood-brain barrier and enter the CNS.

[0422] LLC-PK1 assay (reported as apparent permeability and efflux rate)

[0423] Lilly Laboratories & Company porcine kidney cells (LLC-PK1) were transfected with multidrug resistance protein 1 (MDR1) and maintained in Gibco medium 199 (Fisher Scientific catalog number 11150067) according to the supplier's instructions. Medium 199 was supplemented with 10% heat-inactivated fetal bovine serum (Gibco catalog number 16000-044), 0.5 mg / mL geneticin (Gibco number 10131035) and colchicine 200 nM (inducer of P-gp, Sigma catalog number C9754). Cells were plated at 6.25 x 10 per well. 3The density of cells / well was seeded into the top of HTS-Transwell-96 plates (0.4 μm pore size, Corning catalog number 3381), with 75 μL and 250 μL culture medium 199 in the top and basolateral wells, respectively, and incubated at 37°C / 5% CO2. After 72 hours, fresh culture medium 199 culture medium was replaced in the top and basolateral compartments, and the cells were allowed to grow as a monolayer for 144 hours before the experimental incubation was started. Incubation was carried out in culture medium 199 (FisherScientific catalog number 11150067) with 1% fetal bovine serum albumin (Sigma, catalog number A9418) and 10mM HEPES (Fisher Scientific, catalog number 15630080) at pH 7.4. Culture medium 199 was removed and the cells were rinsed with warm (37°C) culture medium 199. The medium 199 containing the test compound of 1 μM substrate concentration (0.1% v / v DMSO) is added to the top or basolateral compartment (respectively 75 μL or 250 μL), and the blank medium 199 is added to the compartment lacking the test compound in duplicate. The cells are incubated at 37°C / 5% CO2 for 120 minutes. At the end of the incubation period, 50 μL samples are taken out from each receiving compartment and diluted to 100 μL acetonitrile (Fisher Scientific, catalog number A996SK4) + 100ng / mL diclofenac (internal standard, Sigma number 15307-79-6). The sample is centrifuged at 4°C with 2000RCF for 10 minutes, and then 75 μL supernatant is transferred to a new microplate and diluted with 75 μL HPLC grade water (Fisher Scientific, catalog number W64). In a coupled to a microplate optimized for use by Kinetix 2.1x50mm C18 The samples were analyzed using multiple reaction monitoring on an ABSciex triple quadrupole mass spectrometer using a HPLC pump instrument with a column (Phenomenex, catalog number 00B-4605-AN) to detect the test article.

[0424] The apparent permeability (P) was calculated using the following equation: app ) value and outflow rate:

[0425]

[0426] Where P app A-B is the apparent permeability from the top pore to the basolateral pore; P app B-A is the apparent permeability from the basal lateral pore to the apical pore; Conc BL is the basolateral pore concentration; Conc APis the top pore concentration; A is the pore surface area (cm 2 ), for the above measurement is 0.143 cm 2 ; t is the incubation time (seconds), which is 7200 seconds for the above assay; and ER is the P-gp-mediated efflux rate.

[0427] Example

[0428] The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the invention.

[0429] In the following examples, many 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).

[0430] 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 50 μm NX-C18, 5 μm, ID 30 mm x 100 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”) with water and 20 / 80 (v / v) water / acetonitrile mobile phases (both containing 10 mM NH4HCO3 (pH 9.5-10)). Typically, the chromatography was performed on silica gel 60F 254 Preparative TLC was performed on a plate. The preparation and examples may employ SFC to separate enantiomers. After separation by chromatography, the solvent was removed and the mixture was evaporated by centrifugal evaporation (e.g., GeneVac TM ), rotary evaporator, vacuum flask, etc. to obtain the product. The reaction is typically carried out at a pressure of about 1 atmosphere (14.7 psi) in an inert (e.g., nitrogen) or reactive (e.g., H2) atmosphere.

[0431] Preparation 1: 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid

[0432]

[0433] Step A: Methyl 4-bromo-2-(2-bromophenoxy)butyrate

[0434]

[0435] A mixture of 2-bromophenol (5.00 g, 28.9 mmol), methyl 2,4-dibromobutyrate (9.01 g, 34.7 mmol) and KCO (7.99 g, 57.8 mmol) in DMF (100 mL) was degassed and purged with nitrogen (3x), and then stirred at 20 ° C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 10: 1) to obtain the title compound (8.3 g, 82%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 2.43-2.52(m,1H),2.56-2.65(m,1H),3.62-3.70(m,1H),3.70-3.76(m, 1H),3.78(s,3H),4.89(dd,J=9.0,3.7Hz,1H),6.79(dd,J=8.3,1.2Hz,1H ),6.89(td,J=7.6,1.3Hz,1H),7.21-7.26(m,1H),7.24(dd,J=7.8,1.2Hz ,1H),7.22-7.26(m,1H),7.22-7.26(m,1H),7.55(dd,J=8.0,1.6Hz,1H).

[0436] Step B: Methyl 1-(2-bromophenoxy)cyclopropane-1-carboxylate

[0437]

[0438] At -78 ° C, LiHMDS (1M in THF, 52 mL, 52 mmol) was added to a solution of 4-bromo-2-(2-bromophenoxy)butyric acid methyl ester (8.3 g, 23.6 mmol) in THF (120 mL). The reaction mixture was stirred at -78 ° C under nitrogen for 2 hours, and then poured into NH4Cl aqueous solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using a gradient of petroleum ether / EtOAc (1: 0 to 10: 1) to give the title compound (5.05 g, 79%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 1.36-1.41(m,2H),1.63-1.69(m,2H),3.73(s,3H),6.84-6.90(m,1H),6. 95(dd,J=8.3,1.0Hz,1H),7.20-7.25(m,1H),7.53(dd,J=7.9,1.4Hz,1H).

[0439] Step C: Methyl 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylate

[0440]

[0441] By 1- (2- bromophenoxy) cyclopropane -1- methyl formate (0.500g, 1.84mmol), cyclopropylboronic acid (238mg, 2.77mmol), Pd (OAc) 2 (41.4mg, 184μmol), PCy 3 (51.7mg, 184μmol) and K 3 PO 4 (1.37g, 6.46mmol) in toluene (10mL) and water (0.5mL) mixture degassed and purged with nitrogen (3x), and then at 100 ℃ under nitrogen atmosphere stirred for 12 hours. The reaction mixture is poured into NH 4 Cl aqueous solution (20mL) and extracted with EtOAc (2x 20mL). The organic layer combined is through Na 2 SO 4 dried and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using a gradient of petroleum ether / EtOAc (1:0 to 20:1) to give the title compound (400 mg, 84% yield, 90% purity) as a light yellow oil. 1H NMR (400MHz, CDCl3) δppm 0.59-0.66(m,2H),0.87-0.94(m,2H),1.30-1.37(m,2H),1.60-1.67(m,2H), 2.07-2.18(m,1H),3.74(s,3H),6.81-6.95(m,3H),7.03-7.11(m,1H); ESI-MS m / z[M+H] + 233.2.

[0442] Step D: 1-(2-Cyclopropylphenoxy)cyclopropane-1-carboxylic acid

[0443] LiOH.H2O aqueous solution (1.5M, 3.15mL, 4.72mmol) is added to a solution of 1-(2-cyclopropylphenoxy)cyclopropane-1-formic acid methyl ester (400mg, 1.55mmol) in THF (5mL). The mixture is stirred at 20°C for 12 hours, and then diluted with water (10mL) and extracted with EtOAc (2x 10mL). The water layer is acidified to pH 4 with 2M HCl, and then extracted with EtOAc (3x 10mL). The combined organic layers are concentrated under reduced pressure to give the title compound (230.2mg, 65% yield, 95% purity) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δppm 0.60-0.67(m,2H),0.87-0.93(m,2H),1.38-1.45(m,2H),1.67-1.75(m,2H),2.0 6-2.16(m,1H),6.82-6.87(m,1H),6.88-6.97(m,2H),7.05-7.13(m,1H); ESI-MS m / z[M+H] + 219.1.

[0444] Preparation 2: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylic acid

[0445]

[0446] Step A: Methyl 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylate

[0447]

[0448] In a 40mL vial, 6-chloro-N-methylpyridine-2-amine (0.100g, 0.701mmol) was dissolved in DMF (3mL) to give a colorless solution. Sodium hydride (60wt%, 0.042g, 1.052mmol) was added, followed by 1-(bromomethyl)cyclopropane-1-methyl carboxylate (0.162g, 0.841mmol). The mixture was stirred at room temperature overnight, and then quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (0.179g) in the form of brown syrup. ESI-MS m / z[M+H] + 255.1.

[0449] Step B: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylic acid

[0450] In a 40 ml vial, crude methyl 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylate (0.179 g, 0.701 mmol) was combined with aqueous lithium hydroxide (2M, 1.40 mL, 2.80 mmol) in dioxane (4 mL) to give a colorless solution. The mixture was stirred at room temperature overnight and then acidified to pH 5 with aqueous HCl and extracted with EtOAc. The organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound (0.118 g, 70%) as a light brown syrup. ESI-MS m / z [M+H] + 241.1.

[0451] Preparation 3: 2-(2-cyclopropylphenoxy)propionic acid

[0452]

[0453] Step A: Methyl 2-(2-cyclopropylphenoxy)propionate

[0454]

[0455] In a 100mL round-bottom flask, 2-cyclopropylphenol (0.200g, 1.491mmol) and potassium carbonate (0.618g, 4.47mmol) are combined in DMF (8mL) to obtain a white suspension. Methyl 2-chloropropionate (0.219g, 1.789mmol) is added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with water and extracted with EtOAc. The organic phase is dried and concentrated in vacuo through MgSO4. The residue is purified by the automatic rapid silica column chromatography (ISCO, 40g RediSep Rf The fractions containing the product were combined and concentrated to give the title compound (307 mg, 94%) as a colorless oil.

[0456] Step B: 2-(2-cyclopropylphenoxy)propionic acid

[0457] In a 125mL pear-shaped flask, methyl 2-(2-cyclopropylphenoxy)propanoate (0.307g, 1.394mmol) and aqueous lithium hydroxide solution (2M, 2.79mL, 5.58mmol) were combined in dioxane (8mL) to give a colorless solution. The reaction mixture was stirred at room temperature overnight, and then acidified with HCl and extracted with EtOAc. The organic extract was dried over MgSO4 and concentrated in vacuo to give the title compound (218g, 76%) as a white solid. ESI-MS m / z[M-CO2H] + 161.2.

[0458] Preparation 4: 1-(2-chlorophenoxy)cyclopropane-1-carboxylic acid

[0459]

[0460] In a 250 mL round-bottom flask, methyl 1-(2-chlorophenoxy)cyclopropane-1-carboxylate (1.00 g, 4.41 mmol) was dissolved in dioxane (16 mL) to give a colorless solution. Aqueous lithium hydroxide solution (2 M, 8.82 mL, 17.65 mmol) was added. The mixture was stirred at room temperature for 4 hours, and then acidified with aqueous HCl and extracted with EtOAc. The organic extract was dried over MgSO4 and concentrated in vacuo to give the title compound (0.66 g, 70%) as a white solid. ESI-MS m / z [M-CO2H] + 166.9.

[0461] Preparation 5: (3S,4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester

[0462]

[0463] Step A: (3S,4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester-(2S,3S)-2,3-bis(benzoyloxy)succinic acid

[0464]

[0465] At room temperature, dibenzoyl-D-tartaric acid (201 g, 560 mmol) in MeOH (600 mL) was added to a solution of trans-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (120 g, 560 mmol) in MeOH (1200 mL). The addition was exothermic (22° C. to 29° C.). Seed crystals (about 1 mg) were added and the mixture was stirred overnight at room temperature. The resulting slurry was filtered and washed with MeOH (360 mL, displacement wash), and then suction dried at room temperature to give the title complex (111 g, 35%, 88.2% ee by derivatization). The material was repeatedly recrystallized from EtOH to give the title complex (73.6 g, 98.4% ee) with increased ee. 1 H NMR(400MHz, DMSO-d6)δppm 0.86(d,J=6.5Hz,3H),1.20-1.57(m,11H),1.86(br dd,J=12.8,3.3Hz,1H),2.23-2.48(m,1H),2.55-2.56(m,1H),2.78(br d,J=3.8Hz,2H),3.66-3.95(m,2H),5.65(s,2H),7.40-7.56(m,4H),7.58-7.69(m,2H),7.95(d,J=7.5Hz,4H).

[0466] Step B: (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate

[0467] Into a 2L flask, (3S, 4S) -4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester - (2S, 3S) -2,3-bis (benzoyloxy) succinic acid (71.0g, 124mmol) and DCM (1000mL) were charged to give a white suspension. Then, Na2CO3 aqueous solution (2M, 1000mL) was added to the suspension under stirring for a period of one minute to give two colorless phases. The two phases were stirred at room temperature for 5 minutes, and then transferred to a 4L separatory funnel, shaken vigorously and separated. Additional H2O (500mL) was added to the aqueous phase to dissolve the salt. The aqueous phase was washed with DCM (2×500mL), and the organic extracts were combined, dried over Na2SO4 (430g), filtered, rinsed with DCM, and dried on a rotary evaporator at 30°C. The oil was dissolved in acetonitrile (150 mL), concentrated via rotary evaporation, and dried on a rotary evaporator in vacuo at 30 °C to give the title compound (26.6 g, quantitative) as a colorless oil. 1H NMR (400MHz, CD3OD) δppm 0.97 (d, J=6.5Hz, 3H), 1.19-1.35 (m, 2H), 1.45 (s, 9H), 1.75-1.83 (m, 1H), 2.32-2.53 (m, 2H), 2.80 (br t,J=12.0Hz,1H),3.89-3.98(m,1H),4.04(ddt,J=13.5,4.6,2.4Hz,1H); ESI-MS m / z[M+Na] + 237.2.

[0468] Preparation 6: 2,2-Difluoro-3-phenylpropionic acid

[0469]

[0470] A solution of (bromomethyl)benzene (324 μL, 2.73mmol), ethyl 2,2-difluoro-2-iodoacetate (568mg, 2.27mmol) and copper (375mg, 5.91mmol) in DMSO (5.98mL) was stirred on a hot plate overnight at 60 ° C. The reaction mixture was then filtered under vacuum and extracted with diethyl ether (2x). The combined extracts were concentrated in vacuo, dissolved in MeOH (4.5mL), treated with lithium hydroxide aqueous solution (3M, 2.27mL, 6.82mmol) and stirred at room temperature overnight. The reaction mixture was acidified to pH 4 by dropping 1N HCl, and then extracted with EtOAc (1x) and DCM (2x). The organic layers were combined, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to obtain a crude title compound (139mg, 33%).

[0471] Preparation 7: 2,2-Difluoro-2-phenoxyacetic acid

[0472]

[0473] At room temperature, sodium hydride (60wt%, 0.59g, 14.8mmol) was added portionwise to a solution of phenol (1.39g, 14.8mmol) in dioxane (24.6mL). The solution was stirred vigorously for 30 minutes. Then, 2-chloro-2,2-difluoroacetic acid sodium (1.50g, 9.84mmol) was added in one portion at room temperature. The reaction mixture was stirred on a hot plate for 16 hours at 110°C, and then cooled to room temperature, quenched with water and acidified to pH 1 by dropping 1N HCl. The solution was extracted with ether (1x 50mL) and EtOAc (2x75mL). The organic layers were combined, concentrated under reduced pressure and purified by using 30% EtOAc / heptane automatic fast silica column chromatography (ISCO, 24g RediSep Rf The title compound (1.25 g, 68%) was obtained as an orange-brown liquid. 1 H NMR (400MHz, CDCl3) δppm 7.24-7.29 (m, 2H), 7.31 (dt, J = 7.4, 1.6Hz, 1H), 7.38-7.44 (m, 2H), 9.48 (br s, 1H); 19 F NMR (376MHz, CDCl3) δppm-76.55 (s, 2F).

[0474] Preparation 8: 2-(2-cyanophenoxy)-2,2-difluoroacetic acid

[0475]

[0476] Step A: Ethyl 2-(2-cyanophenoxy)-2,2-difluoroacetate

[0477]

[0478] At room temperature, 2-hydroxybenzonitrile (2.00 g, 16.8 mmol) was added portionwise to a suspension of sodium hydride (60 wt%, 0.739 g, 18.5 mmol) in DMA (42.0 mL). The reaction mixture was stirred for 10 minutes. At room temperature, ethyl 2-bromo-2,2-difluoroacetate (2.69 mL, 21.0 mmol) was added dropwise via a syringe. The brown reaction mixture was stirred on a hot plate at 100 ° C for 48 hours, and then cooled to room temperature. Diethyl ether (150 mL) was added. The organic layer was washed with water (75 mL) and brine (75 mL), dried over Na2SO4, and filtered under vacuum. The solvent was removed under reduced pressure, and the crude product (orange-brown oil) was purified by automatic fast silica column chromatography (ISCO, 40 g RediSep Rf using 15% EtOAc / heptane, followed by a gradient of 30-100% EtOAc / heptane. The fractions containing the product were combined, concentrated under reduced pressure and purified by preparative HPLC (Phenomenex The product was further purified by NX-C18, 5 μm, ID 30 mm×100 mm). The title compound (307 mg, 7.6%) was obtained as an orange oil. 1HNMR(400MHz,CDCl3)δppm 1.41(t,J=7.2Hz,3H),4.44(q,J=7.2Hz,2H),7.38(td,J=7.6,1.0Hz,1H),7.43-7.47(m,1H),7.59-7.67(m,1H),7.71(dd,J=7.8,1.8Hz,1H); 19 F NMR (376MHz, CDCl3) δppm-76.61 (s, 2F).

[0479] Step B: 2-(2-Cyanophenoxy)-2,2-difluoroacetic acid

[0480] At room temperature, a solution of ethyl 2-(2-cyanophenoxy)-2,2-difluoroacetate (307 mg, 1.28 mmol) in THF (4.26 mL) was treated with an aqueous LiOH solution (3 M, 1.28 mL, 3.83 mmol). The resulting light yellow mixture was stirred at room temperature overnight and then acidified to pH 1 by dropping 1N HCl (10 mL). The solution was transferred to a separatory funnel and extracted with diethyl ether (1 x 50 mL) and EtOAc (2 x 50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by automatic fast silica column chromatography (ISCO, 12 g RediSep 100) using a gradient of 0-100% EtOAc / heptane. Dry loading) gave the title compound (203 mg, 75%) as an orange-brown oil. 1 HNMR (400MHz, CDCl3) δppm 7.29 (br s, 1H), 7.37-7.42 (m, 1H), 7.43-7.51 (m, 1H), 7.62-7.69 (m, 1H), 7.72 (ddd, J = 7.8, 3.0, 1.5Hz, 1H).

[0481] Preparation 9: 2-(2-chlorophenoxy)-2,2-difluoroacetic acid

[0482]

[0483] At ambient temperature, sodium hydride (0.457 g, 11.4 mmol) was added to a solution of 2-chlorophenol (1.08 g, 8.38 mmol) in dioxane (30.5 mL). The solution was stirred for 30 minutes. 2-bromo-2,2-difluoroacetic acid sodium (1.50 g, 7.62 mmol) was added in one portion at ambient temperature. Once the bubbling subsided, the reaction mixture was stirred on a hot plate at 105 ° C for 16 hours. The reaction mixture was cooled to ambient temperature, quenched with water (30 mL), acidified to pH 1 by dropping 6N HCl, and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by automatic fast silica column chromatography (ISCO, 120 g RediSep Rf Column) to give the title compound (1.03 g, 61%) as a yellow oil. 1 HNMR (400MHz, DMSO-d6) δppm 7.33-7.39 (m, 1H) 7.39-7.46 (m, 2H), 7.62 (dt, J = 7.6, 0.9Hz, 1H).

[0484] Preparation 10: 2-(3-chlorophenoxy)-2,2-difluoroacetic acid

[0485]

[0486] At ambient temperature, sodium hydride (0.457 g, 11.4 mmol) was added to a solution of 3-chlorophenol (1.077 g, 8.38 mmol) in dioxane (30.5 mL). The solution was stirred for 30 minutes. 2-bromo-2,2-difluoroacetic acid sodium (1.50 g, 7.62 mmol) was added in one portion. Once the bubbling subsided, the reaction mixture was heated at 105 ° C for 7 hours and then cooled to ambient temperature, quenched with water (30 mL), acidified to pH 1 by dropping 6N HCl and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by automatic fast silica column chromatography (ISCO, 120 g RediSep Rf Column) to give the title compound (0.958 g, 56%) as a brown oil. 1H NMR (400MHz, DMSO-d6) δppm7.21-7.26(m,1H),7.33(t,J=2.0Hz,1H),7.41(ddd,J=8.0,1.9,1.0Hz,1H),7.49(t,J=8.4Hz,1H).

[0487] Preparation 11: 2-(4-chlorophenoxy)-2,2-difluoroacetic acid

[0488]

[0489] At ambient temperature, sodium hydride (0.457 g, 11.4 mmol) was added to a solution of 4-chlorophenol (1.08 g, 8.38 mmol) in dioxane (30.5 mL). The solution was stirred for 30 minutes. 2-bromo-2,2-difluoroacetic acid sodium (1.50 g, 7.62 mmol) was added in one portion. The reaction mixture was stirred at 105 ° C for 7 hours and then cooled to ambient temperature, quenched with water (30 mL), acidified to pH 1 by dropping 6N HCl and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by automatic fast silica column chromatography (ISCO, 120 g RediSep Rf Column) to give the title compound (0.665 g, 39%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δppm 7.27 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H).

[0490] Preparation 12: 2,2-difluoro-2-(p-tolyloxy)acetic acid

[0491]

[0492] At room temperature, p-cresol (0.500g, 4.62mmol) was added portionwise to a solution of sodium hydride (60wt%, 0.493g, 12.3mmol) in dioxane (6.16mL). The solution was stirred at room temperature for 15 minutes. At room temperature, 2-bromo-2,2-difluoroacetic acid sodium (0.607g, 3.08mmol) was added portionwise. After bubbling subsided, the reaction mixture was stirred on a hot plate overnight at 105 °C. The reaction mixture was then slowly quenched with a few drops of water, acidified to pH 1 by dropping 1N HCl, and extracted with EtOAc (1x) and DCM (2x). The organic layers were combined and the solvent was carefully removed under reduced pressure to avoid product loss. The title compound was obtained by using 30% EtOAc / heptane automatic fast silica column chromatography (ISCO, 12g RediSep Rf column, dry loading) (0.925 g, quantitative, 67% purity). 1 H NMR (400MHz, DMSO-d6) δppm 2.24-2.39(m,3H),5.68-5.81(m,1H),7.03-7.18(m,2H),7.18-7.32(m,2H).

[0493] Preparation 13: 2,2-difluoro-2-(4-fluorophenoxy)acetic acid

[0494]

[0495] At room temperature, 4-fluorophenol (427mg, 3.81mmol) was added portionwise to a solution of sodium hydride (60wt%, 203mg, 5.08mmol) in dioxane (5mL). The solution was stirred at RT for 15 minutes. Then, 2-bromo-2,2-difluoroacetic acid sodium (500mg, 2.54mmol) was added portionwise at room temperature. After bubbling stopped, the mixture was heated at 100 ° C overnight. The reaction was then quenched by adding water (20mL) and the mixture was extracted with EtOAc. The water layer was adjusted to pH 2 by adding 1M HCl and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by automatic fast silica column chromatography using a gradient of 0-100% EtOAc / heptane. Purification gave the title compound as an orange oil (262 mg, 50.1%).

[0496] Preparation 14: 2,2-difluoro-2-(2-fluorophenoxy)acetic acid

[0497]

[0498] The title compound was prepared as in Preparation 13 using sodium hydride (254 mg, 5.08 mmol), 2-fluorophenol (427 mg, 3.81 mmol) and sodium 2-bromo-2,2-difluoroacetate (500 mg, 2.54 mmol) and obtained as an orange oil (143 mg, 27.3%). 19 F NMR (376MHz, DMSO-d6) δppm-130.44--128.88(m,1F),-77.03(br s,2F).

[0499] Preparation 15: 2,2-difluoro-2-(3-fluorophenoxy)acetic acid

[0500]

[0501] The title compound was prepared as in Preparation 13 using sodium hydride (60 wt %, 203 mg, 5.08 mmol), 3-fluorophenol (427 mg, 3.81 mmol) and sodium 2-bromo-2,2-difluoroacetate (500 mg, 2.54 mmol) and obtained as an orange oil (93 mg, 18%).

[0502] Preparation 16: 2,2-difluoro-2-(o-tolyloxy)acetic acid

[0503]

[0504] The title compound was prepared as in Preparation 13 using sodium hydride (60 wt %, 254 mg, 6.35 mmol), o-cresol (412 mg, 3.81 mmol) and sodium 2-bromo-2,2-difluoroacetate (500 mg, 2.54 mmol) and obtained as an orange oil (272 mg, 53%).

[0505] Preparation 17: 2,2-difluoro-2-(m-tolyloxy)acetic acid

[0506]

[0507] The title compound was prepared as in Preparation 13 using sodium hydride (60 wt%, 254 mg, 5.08 mmol), m-cresol (412 mg, 3.81 mmol) and sodium 2-bromo-2,2-difluoroacetate (500 mg, 2.54 mmol) and obtained as an orange oil (513 mg).

[0508] Example 1: (R)-1-(3-methylbenzyl)-N-(1-methylpyrrolidin-3-yl)cyclopropane-1-carboxamide

[0509]

[0510] A solution of 1-(3-methylbenzyl)cyclopropanecarboxylic acid (76 mg, 0.40 mmol) in DMF (2 mL) was treated with Et3N (56 μL, 0.40 mmol) and (R)-1-methylpyrrolidin-3-amine (40 mg, 0.40 mmol). After stirring for 5 minutes, HATU (152 mg, 0.400 mmol) was added. The reaction mixture was stirred at room temperature overnight and then filtered through a hydrophilic PTFE 0.45 μm The product was purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS), to give the title compound (51.6 mg, 47%) as a yellow oil. 1 H NMR(500MHz,CD3OD)δppm0.75(s,2H),1.05-1.15(m,2H),1.43-1.54(m,1H),2. 15(dtd,J=13.6,8.4,5.6Hz,1H),2.22-2.29(m,1H),2.30(s,6H),2.35-2.46(m ,1H),2.59-2.69(m,2H),2.88-3.00(m,2H),4.24-4.33(m,1H),7.01(d,J=7.3H z,1H),7.04(d,J=7.8Hz,1H),7.08(s,1H),7.12-7.17(m,1H); ESI-MSm / z[M+H] + 273.3.

[0511] Example 2: N-(1-methyl-4-phenylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0512]

[0513] To a vial containing 1-(3-methylbenzyl)cyclopropanecarboxylic acid (0.075 g, 0.394 mmol) in DMF (3 mL) was added 1-methyl-4-phenylpyrrolidin-3-amine (0.069 g, 0.394 mmol), DIPEA (171 μL, 0.986 mmol) and HATU (0.180 g, 0.473 mmol). The mixture was stirred at room temperature overnight and then filtered through a hydrophilic PTFE 0.45 μm The filter was filtered while rinsing with methanol.The product was purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, ID 30 mm x 150 mm column) using a gradient of 10-100% ACN / water (acidic mode) to give the TFA salt of the title compound (64 mg, 35%) as a light yellow oil. 1 H NMR(400MHz,CD3OD)δppm 3 .08-3.23(m,1H),3.48-3.82(m,2H),3.84-4.38(m,2H),6.80-6.91(m,1H),6.93-7.06(m,2H),7.06-7.21(m,3H),7.24-7.36(m,3H); ESI-MS m / z[M+H] + 349.5.

[0514] Example 3: N-(trans-4-isopropyl-1-methylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0515]

[0516] 1-(3-Methylbenzyl)cyclopropanecarboxylic acid (50.0 mg, 0.263 mmol) and 2-chloro-1-methylpyridin-1-ium iodide (201 mg, 0.788 mmol) were added to a 20 mL vial containing DMF (2 mL). The reaction mixture was stirred for 30 minutes. Then, trans-4-isopropyl-1-methylpyrrolidin-3-amine (37.4 mg, 0.263 mmol) and Et3N (0.183 mL, 1.31 mmol) were added, and the reaction was stirred at room temperature overnight. The product was analyzed by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% water / ACN in water (basic mode) The product was purified by HPLC-MS / MS (HPLC-MS / MS), to give the title compound (8 mg, 11%) as a colorless oil. 1H NMR(400MHz,CD3OD)δppm 0.66-0.75(m,3H),0.85(d,J=6.3Hz,3H),1.55-1.69(m,1H),1.72-1.79(m,6H),2.14-2.22(m,1H),2.77-2.91(m,1H),2.95(br s,3H),3.47-3.71(m,1H),3.73-3.96(m,2H),4.08(s,3H),7.17(t,J=7.5Hz, 1H),7.44(t,J=7.3Hz,1H),7.55(d,J=8.8Hz,1H),7.63-7.78(m,1H),7.88(br s,1H); ESI-MS m / z[M+H] + 315.4.

[0517] Example 4: N-(1,3-dimethylpiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0518]

[0519] To a 20 mL vial filled with DMF (8 mL) was added 1-(3-methylbenzyl)cyclopropanecarboxylic acid (300 mg, 1.58 mmol) and HATU (899 mg, 2.36 mmol), followed by 1,3-dimethylpiperidin-4-amine (202 mg, 1.58 mmol) and Et3N (0.440 mL, 3.15 mmol). The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The product was purified by NX-C18, 5 μm, ID 30 mm×100 mm) to give the TFA salt of the title compound (267 mg, 41%) as a yellow solid. 1 H NMR(400MHz,CD3OD)δppm 0.70-0.96(m,5H),1.09-1.33(m,2H),1.67-2.19(m,3H),2.31-2.38(m,3H ),2.41-2.50(m,1H),2.61(td,J=13.3,3.4Hz,1H),2.77-2.99(m,4H),3.03

[0520] -3.23(m,2H),3.40-3.65(m,2H),4.03-4.16(m,1H),7.03-7.29(m,4H); ESI-MS m / z[M+H] + 301.4.

[0521] Example 5: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0522]

[0523] Step A: tert-Butyl (3S,4S)-3-fluoro-4-(1-(3-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0524]

[0525] To a solution of 1-(3-methylbenzyl)cyclopropane-1-carboxylic acid (150mg, 0.788mmol) in DMA (3.94mL), DIPEA (413μL, 2.36mmol) and HATU (450mg, 1.18mmol) were added. After stirring at room temperature for 5 minutes, (3S, 4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (189mg, 0.867mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with saturated NH4Cl aqueous solution and extracted with DCM (2x). The combined organic layer was washed with saturated NaHCO3 aqueous solution, then washed with saturated NaCl aqueous solution, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (308mg).

[0526] Step B: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0527] To crude (3S, 4S)-3-fluoro-4-(1-(3-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylic acid tert-butyl ester (308 mg, 0.789 mmol) was added TFA (1 mL, 13 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH and filtered through a hydrophilic PTFE 0.45 μm The results were filtered and purified by preparative HPLC (Phenomenex NX-C18, 5 μm, ID 30 mm x 150 mm). The fractions containing the product were lyophilized to give the title compound as a tan semisolid (16.8 mg, 7.3% over two steps). ESI-MS m / z [M+H] + 291.20.

[0528] Example 6: N-(1,4-dimethylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0529]

[0530] To a solution of 1-(3-methylbenzyl)cyclopropane-1-carboxylic acid (150mg, 0.788mmol) in DMA (3.94mL) was added DIPEA (413μL, 2.36mmol) and HATU (450mg, 1.18mmol). After stirring for 5 minutes, 1,4-dimethylpyrrolidin-3-amine (90mg, 0.788mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with saturated NaHCO3 aqueous solution and extracted with DCM (3x). The combined organic layer was washed with saturated NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH and filtered through hydrophilic PTFE 0.45μm The HPLC was performed by filter filtration and preparative HPLC (Phenomenex The title compound was obtained as a yellow oil (46.1 mg, 20%). 1 HNMR(500MHz,CDCl3)δppm 0.55(d,J=7.1Hz,1.8H),0.68-0.84(m,2H),0.95(d,J=6.8Hz,1.2H),1.17-1.37(m,2H),1.65-1.78(m,0.8H),2.00(dd,J=9.3,6.8Hz,0.6H ),2.07(dd,J=9.8,3.7Hz,0.6H),2.21(s,3H),2.31(d,J=1.7Hz,3H),2.39-3.01(m,5H),3.82-3.91(m,0.4H),4.33-4.43(m,0.6H),5.88(br d,J=8.8Hz,0.6H),5.99(br d,J=7.6Hz,0.4H),6.99-7.22(m,4H); ESI-MS m / z[M+H] + 287.20.

[0531] Example 7: 1-(2-chlorophenoxy)-N-(trans-3-ethyl-1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0532]

[0533] 1-(2-Chlorophenoxy)cyclopropane-1-carboxylic acid (0.06 g, 0.282 mmol), trans-3-ethyl-1-methylpiperidin-4-amine (0.040 g, 0.282 mmol), HATU (0.107 g, 0.282 mmol) and DIPEA (0.147 mL, 0.847 mmol) were combined in DMF (2 mL) in an 8 mL vial to give a yellow solution. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% water / ACN in water (basic mode). The product was purified by HPLC-MS / MS (HPLC-MS / MS, ... 1 H NMR(500MHz,CD3OD)δppm 0.74-0.80(m,3H),0.93-1.04(m,1H),1.12-1.26(m,2H),1.34-1.42(m,1H),1.45-1.57(m,3H),1.58-1.65(m,1H),1.74(s,2H),1.9 9-2.10(m,1H),2.27(s,3H),2.79-2.96(m,2H),3.48-3.59(m,1H),6.96-7.09(m,2H),7.21-7.29(m,1H),7.36-7.43(m,1H); ESI-MS m / z[M+H] + 337.3.

[0534] Example 8: 1-(2-chlorophenoxy)-N-(1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0535]

[0536] A solution of 1-(2-chlorophenoxy)cyclopropane-1-carboxylic acid (0.020 g, 0.094 mmol), DIPEA (0.066 mL, 0.376 mmol), 2-chloro-1-methylpyridinium iodide (0.029 g, 0.113 mmol) and NMP (0.5 mL) was stirred at 45 °C for 60 minutes, and then 1,2-dimethylpiperidin-4-amine (0.012 g, 0.094 mmol) was added. The solution was stirred at 45 °C overnight. The sample was purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-60% ACN / water (acidic mode). NX-C18, 5 μm, ID 30 mm x 100 mm). Product-containing fractions were collected and purified by preparative HPLC (Phenomenex NX-C18, 5 μm, ID 30 mm x 150 mm) to give the title compound (6.1 mg, 20%). ESI-MS m / z [M+H] + 323.1.

[0537] Example 9: 1-(2-Chlorophenoxy)-N-(hexahydro-1H-pyrrolazin-1-yl)cyclopropane-1-carboxamide

[0538]

[0539] To a 4 mL vial equipped with a stirring bar and containing a solution of hexahydro-1H-pyrrolazin-1-amine (0.012 g, 0.094 mmol), DIPEA (0.049 mL, 0.282 mmol) and 1-(2-chlorophenoxy)cyclopropane-1-carboxylic acid (20 mg, 0.094 mmol) in DMA (0.5 mL) was added T3P (0.140 mL, 0.235 mmol). The reaction mixture was stirred at 45 ° C for 18 hours. Methanol (0.5 mL) was added and the solution was purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-50% ACN / water (acidic mode) The purified product was purified by NX-C18, 5 μm, ID 30 mm x 100 mm). The pure fractions were lyophilized to give the title compound as a TFA salt (8.9 mg, 22%). 1H NMR(400MHz,CD3OD)δppm 1.14-1.30(m,2H),1.49-1.66(m,2H),1.66-1.75(m,0.4H),1.80-1.92(m,1H),1.95-2.01(m,1H),2 .01-2.13(m,2H),2.15-2.27(m,2H),2.32-2.41(m,0.6H),2.98(ddd,J=11.5,9.6,6.1Hz,0.4H),3.1 5-3.29(m,1.6H),3.45-3.55(m,1H),3.65-3.76(m,1H),4.01-4.08(m,0.6H),4.28-4.39(m,1H),4. 53-4.61(m,0.4H),6.98-7.07(m,2H),7.23-7.29(m,1H),7.40(ddd,J=7.9,4.8,1.5Hz,1H),8.38(br dd,J=19.3,6.0Hz,1H); ESI-MS m / z[M+H] + 321.1.

[0540] Example 10: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide

[0541]

[0542] A solution of 1-(4-fluorobenzyl)cyclopropane-1-carboxylic acid (69 mg, 0.355 mmol), trans-1,3-dimethylpiperidin-4-amine (71.9 mg, 0.533 mmol), HATU (207 mg, 0.533 mmol) and DIPEA (248 μL, 1.42 mmol) in THF (1.78 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm Filter filtered and analyzed by preparative HPLC (Phenomenex The title compound was obtained as an orange solid as a TFA salt (118 mg, 79%). 1H NMR (400MHz, CDCl3) δppm 0.64(d,J=6.5Hz,3H),0.76-0.89(m,2H),1.19-1.28(m,1H),1.32-1.4 1(m,1H),1.71-1.86(m,1H),1.89-2.01(m,2H),2.32-2.43(m,1H),2.6 3-2.73(m,1H),2.76(s,3H),2.84(d,J=16.3Hz,1H),3.05(d,J=16.3Hz ,1H),3.37-3.44(m,1H),3.49-3.56(m,1H),3.58-3.69(m,1H),5.41(br d,J=8.5Hz,1H),6.96-7.05(m,2H),7.26-7.30(m,2H),13.00-13.24(m,1H); ESI-MS m / z[M+H] + 305.3.

[0543] Example 11: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(4-methylbenzyl)cyclopropane-1-carboxamide

[0544]

[0545] The TFA salt of the title compound was prepared as in Example 10 using 1-(4-methylbenzyl)cyclopropane-1-carboxylic acid (57 mg, 0.300 mmol) and obtained as an orange solid (72 mg, 58%). 1 H NMR (400MHz, CDCl3) δppm 0.62(d,J=6.53Hz,3H),0.77-0.83(m,1H),0.84-0.91(m,1H),1.25(ddd,J=9.7,6.1,3.5Hz,1H),1.33-1.40(m, 1H),1.62-1.74(m,1H),1.78-1.89(m,1H),1.94(dq,J=14.1,3.2Hz,1H),2.32(s,3H),2.33-2.40(m,1H),2.64- 2.72(m,1H),2.75(s,3H),2.82(d,J=16.1Hz,1H),3.02(d,J=16.1Hz,1H),3.37-3.44(m,1H),3.48-3.55(m,1H) ,3.55-3.67(m,1H),5.46(brd,J=8.8Hz,1H),7.10-7.16(m,2H),7.18-7.24(m,2H)12.73-12.87(m,1H); ESI-MS m / z[M+H]+ 301.4.

[0546] Example 12: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0547]

[0548] The TFA salt of the title compound was prepared as in Example 10 using 1-(2-methylbenzyl)cyclopropane-1-carboxylic acid (55 mg, 0.289 mmol) and obtained as an orange solid (82 mg, 68%). 1 H NMR (400MHz, CDCl3) δppm 0.71(d,J=6.8Hz,3H),0.73-0.81(m,2H),1.27-1.31(m,1H),1.37-1.43(m,1H),1 .66-1.79(m,1H),1.83-1.94(m,1H),1.98(dq,J=14.1,3.2Hz,1H),2.32(s,3H),2 .33-2.43(m,1H),2.64-2.72(m,1H),2.76(s,3H),2.81(d,J=16.8Hz,1H),3.07(d ,J=16.8Hz,1H),3.38-3.45(m,1H),3.49-3.57(m,1H),3.63-3.73(m,1H),5.42(br d,J=8.3Hz,1H),7.10-7.17(m,2H),7.17-7.21(m,1H),7.30-7.35(m,1H),12.81-12.98(m,1H); ESI-MS m / z[M+H] + 301.4.

[0549] Example 13: 1-(4-Fluorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0550]

[0551] Step A: tert-Butyl (3S,4S)-4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamido)-3-methylpiperidine-1-carboxylate

[0552]

[0553] A solution of 1-(4-fluorobenzyl)cyclopropane-1-carboxylic acid (101 mg, 0.520 mmol), (3S, 4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (145 mg, 0.676 mmol), HATU (262 mg, 0.676 mmol) and Et3N (290 μL, 2.08 mmol) in THF (2.60 mL) was stirred at room temperature for 8 hours. The reaction mixture was then diluted with MeOH, filtered through a Millipore filter and purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) NX-C18, 5 μm, ID 30 mm x 100 mm). Pure fractions were combined and lyophilized to give the title compound as a white solid (170 mg, 84%). ESI-MS m / z [Mt-Bu] + 335.1.

[0554] Step B: 1-(4-Fluorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0555] A solution of (3S,4S)-tert-butyl 4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamido)-3-methylpiperidine-1-carboxylate (170 mg, 0.435 mmol) in MeOH (871 μL) and DCM (871 μL) was treated with HCl (653 μL, 2.61 mmol, 4 M in dioxane) at room temperature. The reaction mixture was stirred at RT for 16 h and then diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex The pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (140 mg, 80%). 1H NMR (400MHz, CDCl3) δppm 0.66(d,J=6.8Hz,3H),0.76-0.91(m,2H),1.24-1.30(m,1H),1.34-1.42(m,1H),1.46-1.58(m,1H),1.61-1.74( m,1H),1.89-1.99(m,1H),2.45-2.59(m,1H),2.77-2.96(m,3H),2.99-3.08(m,1H),3.21-3.28(m,1H),3.33(br d,J=12.3Hz,1H),3.59-3.72(m,1H),5.36(d,J=8.8Hz,1H),6.98-7.05(m,2H),7.27-7.33(m,2H),9.04-9.21(m,1H),9.47-9.59(m,1H); ESI-MS m / z[M+H] + 291.3.

[0556] Example 14: 2,2-Difluoro-2-phenoxy-N-(piperidin-4-yl)acetamide

[0557]

[0558] Step A: tert-Butyl 4-(2,2-difluoro-2-phenoxyacetamido)piperidine-1-carboxylate

[0559]

[0560] The title compound was prepared as in step A of Example 13 using 2,2-difluoro-2-phenoxyacetic acid (200 mg, 1.06 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (319 mg, 1.59 mmol), HATU (606 mg, 1.59 mmol) and Et3N (596 μL, 4.25 mmol) in DMA (5.32 mL) and obtained as a white solid (176 mg, 45%). ESI-MS m / z [Mt-Bu] + 315.3.

[0561] Step B: 2,2-Difluoro-2-phenoxy-N-(piperidin-4-yl)acetamide

[0562] At room temperature, a solution of tert-butyl 4-(2,2-difluoro-2-phenoxyacetamido)piperidine-1-carboxylate (176 mg, 0.475 mmol) in DCM (1.2 mL) was treated dropwise with HCl (4 M, 1.19 mL, 4.75 mmol) in dioxane via a syringe. The resulting mixture was stirred at RT for 16 hours and then diluted with MeOH (1.5 mL) and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex The pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (119 mg, 65%). 1 H NMR (400MHz, DMSO-d6) δppm1.59-1.79(m,2H),1.87(br dd,J=13.4,2.6Hz,2H),2.99(br t,J=11.9Hz,2H),3.29(br d,J=12.8Hz,3H),3.92(dtd,J=11.2,7.3,4.0Hz,1H),7.23-7.28(m,2H),7.29-7.38(m,1H),7.42-7.51(m,2H),9.19(br d,J=7.8Hz,1H); ESI-MS m / z[M+H] + 271.3.

[0563] Example 15: 1-(3-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0564]

[0565] Step A: tert-Butyl (3S,4S)-4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamido)-3-methylpiperidine-1-carboxylate

[0566]

[0567] A solution of 1-(3-chlorobenzyl)cyclopropane-1-carboxylic acid (56 mg, 0.266 mmol, 1 eq), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (68.4 mg, 0.319 mmol, 1.2-1.5 eq), HATU (121 mg, 0.319 mmol, 1.2-1.5 eq) and Et3N (148 μL, 1.06 mmol, 4-6 eq) in THF (1.33 mL, 0.20 M) was stirred at room temperature for 16 h. The reaction mixture was then diluted with MeOH (1 mL) and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex NX-C18, 5 μm, ID 30 mm x 100 mm). Pure fractions were combined and lyophilized to give the title compound (92 mg, 85%) as a white solid. ESI-MS m / z [M+H] + 407.4.

[0568] Step B: 1-(3-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0569] A solution of (3S,4S)-tert-butyl 4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamido)-3-methylpiperidine-1-carboxylate (92 mg, 0.226 mmol, 1 eq) in MeOH (452 ​​μL) and DCM (452 ​​μL) was treated with HCl (4M, 339 μL, 1.36 mmol, 6-10 eq) in dioxane at room temperature. The reaction mixture was stirred at RT for 16 h and then diluted with MeOH (1 mL) and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex The pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (84 mg, 88%). 1HNMR(400MHz,CDCl3)δppm 0.68(d,J=6.8Hz,3H),0.79-0.90(m,2H),1.22-1.31(m,1H),1.34-1.42(m,1H),1. 47-1.60(m,1H),1.63-1.76(m,1H),1.92-2.01(m,1H),2.47-2.59(m,1H),2.85(br d,J=16.3Hz,2H),3.04(d,J=16.6Hz,1H),3.21-3.30(m,1H),3.34(br d,J=12.0Hz,1H),3.62-3.74(m,1H),5.35(d,J=8.8Hz,1H),7.17-7.26(m,3H),7.32-7.35(m,1H),9.05-9.22(m,1H),9.42-9.55(m,1H); ESI-MS m / z[M+H] + 307.3.

[0570] Example 16: 1-(2-methylbenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0571]

[0572] Step A: tert-Butyl (3S,4S)-3-methyl-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0573]

[0574] The title compound was prepared as in step A of Example 15 using 1-(2-methylbenzyl)cyclopropane-1-carboxylic acid (88 mg, 0.346 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (129 mg, 0.601 mmol), HATU (233 mg, 0.601 mmol) and Et3N (258 μL, 1.85 mmol) in THF (2.31 mL) and obtained as a white solid (143 mg, 80%). ESI-MS m / z [Mt-Bu] + 331.2.

[0575] Step B: 1-(2-methylbenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0576] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-3-methyl-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate (143 mg, 0.370 mmol) and obtained as a white solid (127 mg, 86%). 1 H NMR (400MHz, CDCl3) δppm 0.72(d,J=6.5Hz,3H),0.74-0.83(m,2H),1.29-1.36(m,1H),1.39-1.46(m,1H),1.46-1.55(m,1H),1.59-1.72(m,1H),1.99(br dd,J=14.0,2.0Hz,1H),2.31(s,3H),2.47-2.59(m,1H),2.77-2.93(m,2H),3.05(d,J=17.1Hz,1H),3.21-3.28(m,1H),3.33(br d,J=12.8Hz,1H),3.62-3.76(m,1H),4.25-4.45(m,1H),5.41(d,J=8.5Hz,1H),7.12-7.16( m,2H),7.17-7.21(m,1H),7.33-7.39(m,1H),8.93-9.09(m,1H),9.24-9.36(m,1H); ESI-MS m / z[M+H] + 287.4.

[0577] Example 17: 1-(2-chlorobenzyl)-N-(trans-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0578]

[0579] The TFA salt of the title compound was prepared as in step A of Example 15 using 1-(2-chlorobenzyl)cyclopropane-1-carboxylic acid (50.0 mg, 0.237 mmol), trans-1,3-dimethylpiperidin-4-amine (39.6 mg, 0.309 mmol), HATU (120 mg, 0.309 mmol) and Et3N (132 μL, 0.949 mmol) in THF (1.19 mL) and obtained as a white solid (85 mg, 82%). 1H NMR (400MHz, CDCl3) δppm 0.72(d,J=6.5Hz,3H),0.79-0.87(m,2H),1.24-1.30(m,1H),1.37-1.42( m,1H),1.70-1.84(m,1H),1.92-2.00(m,2H),2.32-2.42(m,1H),2.64-2.7 3(m,1H),2.76(s,3H),2.97(d,J=16.8Hz,1H),3.22(d,J=17.1Hz,1H),3. 40-3.47(m,1H),3.54(dt,J=12.2,2.1Hz,1H),3.62-3.73(m,1H),5.53(br d,J=8.8Hz,1H),7.16-7.24(m,2H),7.38-7.46(m,2H); ESI-MS m / z[M+H] + 321.1.

[0580] Example 18: 1-(4-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0581]

[0582] The TFA salt of the title compound was prepared as in Example 15 using 1-(4-chlorobenzyl)cyclopropane-1-carboxylic acid (77 mg, 0.366 mmol) and obtained as a white solid (97 mg, 63% over two steps). 1 H NMR (400MHz, CDCl3) δppm 0.66(d,J=6.5Hz,3H),0.77-0.89(m,2H),1.22-1.30(m,1H),1.37(ddd,J=9.8,5.8,3.5Hz,1H),1.48-1.61(m,1H),1.63-1.77(m,1H),1.91- 1.99(m,1H),2.52(q,J=11.5Hz,1H),2.79-2.92(m,2H),3.00-3.06(m, 1H),3.22-3.30(m,1H),3.30-3.44(m,2H),3.61-3.72(m,1H),5.37(br d,J=8.8Hz,1H),7.24-7.31(m,4H),9.03-9.17(m,1H),9.43-9.56(m,1H); ESI-MS m / z[M+H] + 307.3.

[0583] Example 19: 3-(4-chlorophenyl)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide

[0584]

[0585] The TFA salt of the title compound was prepared as in Example 15 using 3-(4-chlorophenyl)-2,2-dimethylpropanoic acid (65 mg, 0.306 mmol) and obtained as a white solid (92 mg, 71% over two steps). 1 H NMR (400MHz, CDCl3) δppm 0.84(d,J=6.8Hz,3H),1.20(d,J=7.5Hz,6H),1.56-1.69(m,1H),1.80-1.95(m,1H),2.00(br d,J=13.3Hz,1H),2.54-2.68(m,1H),2.82(s,2H),2.87-3.01(m,1H),3.32-3.38(m,1H),3.42(br d,J=12.6Hz,1H),3.69-3.83(m,1H),4.15-4.29(m,1H),5.43(br d,J=8.8Hz,1H),7.05-7.09(m,2H),7.20-7.24(m,2H),9.07-9.24(m,1H),9.27-9.41(m,1H); ESI-MS m / z[M+H] + 309.3.

[0586] Example 20: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(3-fluorobenzyl)cyclopropane-1-carboxamide

[0587]

[0588] The TFA salt of the title compound was prepared as in step A of Example 15 using 1-(3-fluorobenzyl)cyclopropane-1-carboxylic acid (62 mg, 0.319 mmol), trans-1,3-dimethylpiperidin-4-amine (51.7 mg, 0.383 mmol), HATU (150 mg, 0.383 mmol) and Et3N (178 μL, 1.28 mmol) in THF (1.60 mL) and obtained as a white solid (26 mg, 19%). 1H NMR (400MHz, CDCl3) δppm 0.66(d,J=6.8Hz,3H),0.79-0.90(m,2H),1.21-1.28(m,1H),1.35-1.4 1(m,1H),1.69-1.82(m,1H),1.87-1.99(m,2H),2.33-2.44(m,1H),2.6 4-2.74(m,1H),2.77(s,3H),2.86(d,J=16.6Hz,1H),3.07(d,J=16.3Hz ,1H),3.38-3.46(m,1H),3.49-3.56(m,1H),3.59-3.71(m,1H),5.43(br d,J=8.5Hz,1H),6.94(ddd,J=9.2,7.6,1.8Hz,1H),7.03-7.10(m,2H),7.24-7.33(m,1H),12.59-12.75(m,1H); ESI-MS m / z[M+H] + 305.4.

[0589] Example 21: N-(trans-3-ethyl-1-methylpiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0590]

[0591] The TFA salt of the title compound was prepared as in step A of Example 15 using 1-(3-methylbenzyl)cyclopropane-1-carboxylic acid (20 mg, 0.105 mmol), trans-3-ethyl-1-methylpiperidin-4-amine (20.5 mg, 0.137 mmol), HATU (53.6 mg, 0.137 mmol) and Et3N (58.6 μL, 0.421 mmol) in THF (526 μL) and obtained as a white solid (44 mg, 98%). 1H NMR (400MHz, CDCl3) δppm 0.64-0.72(m,3H),0.75-0.85(m,2H),0.86-0.93(m,1H),1.04-1.16(m,1H ),1.24(ddd,J=9.9,6.4,3.8Hz,1H),1.38-1.46(m,1H),1.59-1.75(m,2H) ,1.92-2.00(m,1H),2.29-2.40(m,4H),2.61-2.73(m,1H),2.74-2.82(m,4 H),3.06(d,J=16.6Hz,1H),3.46-3.55(m,2H),3.62-3.73(m,1H),5.45(br d,J=8.3Hz,1H),7.11-7.15(m,2H)7.06(d,J=7.3Hz,1H),7.18-7.23(m,1H),12.55-12.68(m,1H); ESI-MS m / z[M+H] + 315.4.

[0592] Example 22: 1-(4-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0593]

[0594] Step A: tert-Butyl (3S,4S)-3-fluoro-4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0595]

[0596] A solution of 1-(4-fluorobenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.515 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (135 mg, 0.618 mmol), HATU (242 mg, 0.618 mmol) and Et3N (287 μL, 2.06 mmol) in THF (2.575 mL) was stirred at room temperature overnight. The solvent was removed, and the crude material was mixed with silica and purified by automated flash silica column chromatography using 50% EtOAc / heptane (ISCO, 4 g RediSep Rf Column, dry loading) to give the title compound as a light yellow oil (0.203 g, quantitative). ESI-MS m / z [M+H] + 395.4.

[0597] Step B: 1-(4-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0598] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-3-fluoro-4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate (0.203 g, 0.515 mmol) and obtained as a white solid (145 mg, 69%). 1 H NMR (400MHz, CDCl3) δppm 0.83-0.87(m,2H),1.32-1.36(m,2H),1.47-1.59(m,1H),2.14-2.23(m,1H),2.90-3.09(m ,6H),3.29(ddd,J=16.1,13.0,3.5Hz,1H),4.11-4.23(m,1H),4.46-4.65(m,1H),5.61(br d,J=7.0Hz,1H),7.00-7.07(m,2H),7.28-7.34(m,2H); ESI-MS m / z[M+H] + 295.3.

[0599] Example 23: 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0600]

[0601] Step A: (3S,4S)-tert-butyl 4-(1-(4-chlorobenzyl)cyclopropane-1-carboxamido)-3-fluoropiperidine-1-carboxylate

[0602]

[0603] The title compound was prepared as in step A of Example 22 using 1-(4-chlorobenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.475 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (124 mg, 0.570 mmol), HATU (223 mg, 0.570 mmol) and Et3N (265 μL, 1.90 mmol) in THF (2.37 mL) and obtained as a light yellow semisolid (170 mg, 87%). ESI-MS m / z [M+H] + 411.4.

[0604] Step B: 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0605] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-4-(1-(4-chlorobenzyl)cyclopropane-1-carboxamido)-3-fluoropiperidine-1-carboxylate (170 mg, 0.414 mmol) and obtained as an off-white solid (98 mg, 56%). 1 H NMR (400MHz, CDCl3) δppm 0.82-0.87(m,2H),1.31-1.35(m,2H),1.50-1.61(m,1H),2.14-2.23(m,1H),2.92-3.05(m ,4H),3.05-3.13(m,1H),3.24-3.41(m,1H),4.11-4.24(m,1H),4.46-4.68(m,1H),5.65(br d,J=7.3Hz,1H),7.24-7.32(m,4H); ESI-MSm / z[M+H] + 311.3.

[0606] Example 24: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0607]

[0608] Step A: tert-Butyl (3S,4S)-3-fluoro-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0609]

[0610] The title compound was prepared as in step A of Example 22 using 1-(2-methylbenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.526 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (138 mg, 0.631 mmol), HATU (245 mg, 0.631 mmol) and Et3N (293 μL, 2.10 mmol) in THF (2.63 mL) and obtained as a light yellow solid (191 mg, 93%). ESI-MS m / z [M+H] + 391.4.

[0611] Step B: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0612] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-3-fluoro-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate (191 mg, 0.489 mmol) and obtained as a white solid (145 mg, 73%). 1 H NMR (400MHz, CDCl3) δppm 0.79-0.85(m,2H),1.37-1.42(m,2H),1.46-1.56(m,1H),2.15-2.25(m,2H),2.30-2.33(m,3H),2.79-2.89(m,1H),2.90-3.00(m, 3H),3.00-3.18(m,2H),4.11-4.24(m,1H),4.44-4.67(m,1H),5.56(d,J=7.3Hz,1H),7.16-7.24(m,3H),7.35-7.40(m,1H); ESI-MS m / z[M+H] + 291.4.

[0613] Example 25: 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-phenoxyacetamide

[0614]

[0615] Step A: tert-Butyl (3S,4S)-4-(2,2-difluoro-2-phenoxyacetamido)-3-methylpiperidine-1-carboxylate

[0616]

[0617] The title compound was prepared as in step A of Example 15 using 2,2-difluoro-2-phenoxyacetic acid (47 mg, 0.250 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (64.2 mg, 0.300 mmol), HATU (116 mg, 0.300 mmol) and Et3N (139 μL, 0.999 mmol) in DMA (1.25 mL) and obtained as a white solid (41 mg, 43%). ESI-MS m / z [Mt-Bu] + 329.3.

[0618] Step B: 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-phenoxyacetamide

[0619] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-4-(2,2-difluoro-2-phenoxyacetamido)-3-methylpiperidine-1-carboxylate (41 mg, 0.107 mmol) and HCl in dioxane (4 M, 160 μL, 0.640 mmol), DCM (213 μL) and MeOH (0.5 mL) and obtained as a white solid (35 mg, 82%). 1 H NMR (400MHz, CDCl3) δppm 0.96-1.05(m,3H),1.85-2.02(m,1H),2.02-2.16(m,3H),2.64-2.76(m,1H),2.94-3.09(m ,1H),3.40-3.50(m,1H),3.52-3.61(m,1H),3.82-3.91(m,1H),6.43-6.50(m,1H),7.24(br d,J=8.3Hz,2H),7.28-7.32(m,1H),7.36-7.43(m,2H); ESI-MS m / z[M+H] + 285.3.

[0620] Example 26: 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-phenylpropanamide

[0621]

[0622] The TFA salt of the title compound was prepared as in Example 15 using 2,2-difluoro-3-phenylpropanoic acid (50 mg, 0.269 mmol) and obtained as a white solid (15 mg, 52%). 1 HNMR(400MHz,CDCl3)δppm 0.70(d,J=6.3Hz,3H),1.52-1.69(m,1H),1.85-1.92(m,1H),2.48-2.62( m,1H),2.82-3.10(m,3H),3.25-3.49(m,4H),3.58-3.70(m,1H),6.00(br d,J=8.5Hz,1H),7.24-7.33(m,5H),9.14-9.52(m,2H); ESI-MS m / z[M+H] + 283.4.

[0623] Example 27: 1-(3-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0624]

[0625] Step A: (3S,4S)-tert-butyl 4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamido)-3-fluoropiperidine-1-carboxylate

[0626]

[0627] The title compound was prepared as in step A of Example 15 using 1-(3-chlorobenzyl)cyclopropane-1-carboxylic acid (73 mg, 0.347 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (91 mg, 0.416 mmol), HATU (158 mg, 0.416 mmol) and Et3N (193 μL, 1.386 mmol) in DMA (1.73 mL) and obtained as a white solid (74 mg, 52%). ESI-MS m / z [M+H] + 411.5.

[0628] Step B: 1-(3-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0629] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamido)-3-fluoropiperidine-1-carboxylate (74 mg, 0.180 mmol) and HCl in dioxane (4 M, 270 μL, 1.08 mmol) and DCM (0.6 mL) and obtained as a white solid (67 mg, 88%). 1 H NMR (400MHz, CDCl3) δppm 0.85-0.92(m,2H),1.31-1.38(m,2H),1.57-1.69(m,1H),2.12-2.23(m,2H),3.00(d,J=3.8Hz,2H),3.02-3.16(m,3H)3.33(br t,J=14.9Hz,1H),4.20(br d,J=3.8Hz,1H),4.53-4.77(m,1H),5.94(br d,J=7.3Hz,1H),7.19-7.23(m,1H),7.24-7.31(m,2H),7.33(s,1H); ESI-MS m / z[M+H] + 311.3.

[0630] Example 28: 2,2-Difluoro-N-(1-methylpiperidin-4-yl)-2-phenoxyacetamide

[0631]

[0632] The TFA salt of the title compound was prepared as in step A of Example 15 using 2,2-difluoro-2-phenoxyacetic acid (61 mg, 0.324 mmol), 1-methylpiperidin-4-amine (55.5 mg, 0.486 mmol), HATU (189 mg, 0.486 mmol) and DIPEA (231 μL, 1.297 mmol) in DMA (1.62 mL) and obtained as a colorless oil (8 mg, 6%). 1 HNMR(400MHz, CDCl3)δppm 2.17(m,4H),2.80(m,5H),3.63(br d,J=12.0Hz,2H),4.10(br d,J=3.5Hz,1H),7.03(br d,J=6.8Hz,1H),7.22(d,J=7.8Hz,2H),7.25-7.30(m,1H),7.35-7.42(m,2H); ESI-MS m / z[M+H] + 285.3.

[0633] Example 29: 2,2-Difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-2-phenoxyacetamide

[0634]

[0635] Step A: (3S,4S)-tert-butyl 4-(2,2-difluoro-2-phenoxyacetamido)-3-fluoropiperidine-1-carboxylate

[0636]

[0637] The title compound was prepared as in step A of Example 15 using 2,2-difluoro-2-phenoxyacetic acid (133 mg, 0.707 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (185 mg, 0.848 mmol), HATU (329 mg, 0.848 mmol) and DIPEA (494 μL, 2.83 mmol) in DMA (3.54 mL) and obtained as a colorless oil (275 mg).

[0638] Step B: 2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-2-phenoxyacetamide

[0639] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-4-(2,2-difluoro-2-phenoxyacetamido)-3-fluoropiperidine-1-carboxylate (275 mg, 0.707 mmol) and HCl in dioxane (4 M, 1.77 mL, 7.07 mmol) and DCM (2.83 mL) and obtained as a white solid (116 mg, 41% over two steps). 1 HNMR(400MHz,DMSO-d6)δppm 1.69-1.82(m,1H),1.93-2.06(m,1H),3.02-3.11(m,1H),3.12-3.22(m,2H),3.60(ddd,J=12.1,7.6,4.4Hz,1H ),4.13-4.32(m,1H),4.66-4.91(m,1H),7.27(d,J=7.5Hz,2H),7.31-7.36(m,1H),7.43-7.50(m,2H),9.39(br d,J=8.5Hz,1H); ESI-MS m / z[M+H] + 289.3.

[0640] Example 30: 1-(4-Fluoro-2-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0641]

[0642] Step A: tert-Butyl (3S,4S)-3-fluoro-4-(1-(4-fluoro-2-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0643]

[0644] A solution of 1-(4-fluoro-2-methylbenzyl)cyclopropane-1-carboxylic acid (103 mg, 0.495 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.594 mmol), HATU (230 mg, 0.594 mmol) and Et3N (276 μL, 1.98 mmol) in DMA (2.47 mL) was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was purified by automated flash silica column chromatography (ISCO, 40 g RediSep Rf Column, dry loading). Evaporation of the fractions containing the product gave the title compound (202 mg). ESI-MS m / z [M+H] + 409.5.

[0645] Step B: 1-(4-Fluoro-2-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0646] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-3-fluoro-4-(1-(4-fluoro-2-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate (202 mg, 0.495 mmol) and HCl in dioxane (4 M, 1.24 mL, 4.95 mmol), DCM (1.24 mL) and MeOH (1.24 mL) and obtained as a white solid (106 mg, 51% over two steps). 1 H NMR (400MHz, CDCl3) δppm 0.75-0.80(m,2H),1.33-1.39(m,2H),1.55-1.68(m,1H),2.14-2.25(m,1H),2.30(s,3H),2.9 3(s,2H),2.96-3.14(m,3H),3.27-3.40(m,1H),4.16-4.28(m,1H),4.51-4.71(m,1H),5.73(br d,J=7.5Hz,1H),6.85(td,J=8.4,2.8Hz,1H),6.91(dd,J=9.5,2.5Hz,1H),7.24-7.30(m,1H); ESI-MS m / z[M+H] + 309.4.

[0647] Example 31: 1-(4-Fluoro-3-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0648]

[0649] Step A: tert-Butyl (3S,4S)-3-fluoro-4-(1-(4-fluoro-3-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0650]

[0651] The title compound was prepared as in step A of Example 15 using 1-(4-fluoro-3-methylbenzyl)cyclopropane-1-carboxylic acid (155 mg, 0.744 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (205 mg, 0.893 mmol), HATU (375 mg, 0.968 mmol) and Et3N (415 μL, 2.98 mmol) in DMA (3.72 mL) and obtained as a white solid (258 mg, 83%). ESI-MS m / z [M+H] + 409.5.

[0652] Step B: 1-(4-Fluoro-3-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0653] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-3-fluoro-4-(1-(4-fluoro-3-methylbenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate (258 mg, 0.632 mmol) and HCl in dioxane (4 M, 1.58 mL, 6.32 mmol) and DCM (1.58 mL) and obtained as a white solid (207 mg, 78%). 1 HNMR(400MHz,CDCl3)δppm 0.75-0.91(m,2H),1.25-1.39(m,2H),1.46-1.63(m,1H),2.13-2.21(m,1H),2.25(d,J=1.8Hz,3H),2.92(s,2H),2.94-3.10(m,3H),3 .24-3.40(m,1H),4.17(td,J=7.7,4.6Hz,1H),4.44-4.70(m,1H),5.74(d,J=7.5Hz,1H),6.90-7.01(m,1H),7.06-7.18(m,2H); ESI-MS m / z[M+H] + 309.3.

[0654] Example 32: 2-(2-Cyanophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide

[0655]

[0656] Step A: tert-Butyl 4-(2-(2-cyanophenoxy)-2,2-difluoroacetamido)piperidine-1-carboxylate

[0657]

[0658] The title compound was prepared as in step A of Example 15 using 2-(2-cyanophenoxy)-2,2-difluoroacetic acid (50 mg, 0.235 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (48.4 mg, 0.235 mmol), HATU (91 mg, 0.235 mmol) and Et3N (131 μL, 0.938 mmol) in DMA (1.17 mL) and obtained as a colorless oil. ESI-MS m / z [M+Na] + 418.4.

[0659] Step B: 2-(2-Cyanophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide

[0660] The TFA salt of the title compound was prepared as in Example 15, step B, using tert-butyl 4-(2-(2-cyanophenoxy)-2,2-difluoroacetamido)piperidine-1-carboxylate and obtained as a colorless oil (13 mg, 14% over two steps). 1 H NMR (400MHz, DMSO-d6) δppm 1.65-1.81(m,2H),1.90(br dd,J=13.0,2.3Hz,2H),2.93-3.11(m,2H),3.30(br d,J=12.8Hz,2H),3.95(tdt,J=11.1,7.40,4.0Hz,1H),7.47-7.57(m,2H),7.76-7.86(m,1H),7.98(dd,J=7.9,1.6Hz,1H),9.35(br d,J=7.5Hz,1H); ESI-MS m / z[M+H] + 296.3.

[0661] Example 33 (NB011692-080-002): 2-(2-cyanophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0662]

[0663] Step A: tert-Butyl (3S,4S)-4-(2-(2-cyanophenoxy)-2,2-difluoroacetamido)-3-methylpiperidine-1-carboxylate

[0664]

[0665] The title compound was prepared as in step A of Example 15 using 2-(2-cyanophenoxy)-2,2-difluoroacetic acid (99 mg, 0.464 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (119 mg, 0.557 mmol), HATU (216 mg, 0.557 mmol) and Et3N (259 μL, 1.89 mmol) in DMA (2.32 mL) and obtained as a colorless oil (23 mg, 12%). ESI-MS [M+Na] + 432.5.

[0666] Step B: 2-(2-Cyanophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0667] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl (3S,4S)-4-(2-(2-cyanophenoxy)-2,2-difluoroacetamido)-3-methylpiperidine-1-carboxylate (23 mg, 0.056 mmol) and HCl in dioxane (4 M, 140 μL, 0.562 mmol) and DCM (140 μL) and obtained as a colorless oil (18 mg, 76%). 1 HNMR(400MHz,CDCl3)δppm 1.10(br d,J=5.5Hz,3H),1.93-2.05(m,1H),2.21-2.29(m,1H),2.64-2.78(m,3H),2.98 -3.11(m,1H),3.40-3.49(m,1H),3.50-3.61(m,1H),3.80-3.94(m,1H),6.94(br d,J=8.5Hz,1H),7.39-7.45(m,1H),7.50(d,J=8.0Hz,1H),7.64-7.76(m,2H); ESI-MS[M+H] + 310.3.

[0668] Example 34: 2,2-difluoro-N-(piperidin-4-yl)-2-(p-tolyloxy)acetamide

[0669]

[0670] Step A: tert-Butyl 4-(2,2-difluoro-2-(p-tolyloxy)acetamido)piperidine-1-carboxylate

[0671]

[0672] A solution of 2,2-difluoro-2-(p-tolyloxy)acetic acid (261 mg, 1.29 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (404 mg, 1.94 mmol), HATU (751 mg, 1.94 mmol) and Et3N (720 μL, 5.16 mmol) in THF (6.46 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by automated flash silica column chromatography (ISCO, 4 g RediSep Rf Column, dry loading) to give the title compound as a light yellow oil (74 mg, 15%). ESI-MS m / z [M+Na] + 407.5.

[0673] Step B: 2,2-difluoro-N-(piperidin-4-yl)-2-(p-tolyloxy)acetamide

[0674] The TFA salt of the title compound was prepared as in step B of Example 15 using tert-butyl 4-(2,2-difluoro-2-(p-tolyloxy)acetamido)piperidine-1-carboxylate (74 mg, 0.192 mmol) and HCl in dioxane (4 M, 481 μL, 1.92 mmol) and MeOH (642 μL) and obtained as a white solid (46 mg, 60%). 1 H NMR (400MHz, DMSO-d6) δppm 1.63-1.77(m,2H),1.87(br dd,J=13.6,2.3Hz,2H),2.28-2.34(m,3H),2.93-3.06(m,2H),3.29(br d,J=12.8Hz,2H),3.87-3.98(m,1H),7.13(d,J=8.5Hz,2H),7.24(d,J=8.0Hz,2H),8.21-8.36(m,1H),8.49-8.62(m,1H); ESI-MS m / z[M+H] + 285.3.

[0675] Example 35: N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide

[0676]

[0677] A solution of 1-(4-fluorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide TFA salt (122 mg, 0.302 mmol) in MeOH (2.01 mL) was treated with Et3N (105 μL, 0.754 mmol) and aqueous formaldehyde (37 wt%, 67.4 μL, 0.905 mmol) at room temperature. The mixture was stirred for 30 minutes. Then, sodium triacetoxyborohydride (198 mg, 0.905 mmol) was added in one portion and stirring was continued at room temperature for 16 hours. The reaction mixture was then diluted with MeOH (1 mL) and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex The pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (112 mg, 89%). 1 H NMR (400MHz, CDCl3) δppm 0.64(d,J=6.8Hz,3H),0.74-0.90(m,2H),1.19-1.28(m,1H),1.32-1.4 0(m,1H),1.71-1.85(m,1H),1.89-2.01(m,2H),2.31-2.43(m,1H),2.6 3-2.73(m,1H),2.75(s,3H),2.84(d,J=16.3Hz,1H),3.05(d,J=16.3Hz ,1H),3.36-3.46(m,1H),3.48-3.56(m,1H),3.58-3.70(m,1H),5.41(br d,J=8.5Hz,1H),6.97-7.04(m,2H),7.25-7.31(m,2H),13.14-13.26(m,1H); ESI-MS m / z[M+H] + 305.5.

[0678] Example 36: 1-(3-chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0679]

[0680] A solution of 1-(3-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide TFA salt (72 mg, 0.302 mmol) in MeOH (1141 μL) was treated with Et3N (60 μL, 0.428 mmol) and aqueous formaldehyde (37 wt%, 38.2 μL, 0.513 mmol) at room temperature. The solution was stirred for 30 minutes. Then, sodium triacetoxyborohydride (112 mg, 0.513 mmol) was added and stirring was continued at room temperature for 16 hours. The reaction mixture was then diluted with MeOH (1 mL) and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex The pure fractions were combined and lyophilized to give the TFA salt of the title compound as a colorless oil (60 mg, 81%). 1 H NMR (400MHz, CDCl3) δppm 0.68(d,J=6.5Hz,3H),0.78-0.90(m,2H),1.20-1.28(m,1H),1.33-1.40(m,1H),1.71-1.8 5(m,1H),1.89-2.01(m,2H),2.33-2.45(m,1H),2.64-2.73(m,1H),2.77(s,3H),2.85(d,J= 16.6Hz,1H),3.06(d,J=16.3Hz,1H),3.38-3.46(m,1H),3.50-3.57(m,1H),3.60-3.72(m,1 H),5.43-5.52(m,1H),7.15-7.19(m,1H),7.20-7.25(m,2H),7.32(t,J=1.8Hz,1H); ESI-MS m / z[M+H] + 321.4.

[0681] Example 37: 1-(4-chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0682]

[0683] The TFA salt of the title compound was prepared as in Example 36 using 1-(4-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide TFA salt (81 mg, 1.92 mmol) and obtained as a white solid (71 mg, 85%). 1H NMR (400MHz, CDCl3) δppm 0.65(d,J=6.8Hz,3H),0.76-0.88(m,2H),1.18-1.26(m,1H),1.32-1.3 9(m,1H),1.75-1.88(m,1H),1.90-2.03(m,2H),2.33-2.44(m,1H),2.6 4-2.75(m,1H),2.77(s,3H),2.84(d,J=16.3Hz,1H),3.05(d,J=16.3Hz ,1H),3.39-3.46(m,1H),3.49-3.58(m,1H),3.61-3.71(m,1H),5.48(br d,J=8.3Hz,1H),7.22-7.30(m,4H); ESI-MSm / z[M+H] + 321.4.

[0684] Example 38: N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0685]

[0686] The TFA salt of the title compound was prepared as in Example 36 using 1-(2-methylbenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide TFA salt (107 mg, 0.267 mmol) and obtained as a white solid (81 mg, 73%). 1 H NMR (400MHz, CDCl3) δppm 0.71(d,J=6.5Hz,3H),0.74-0.78(m,2H),1.25-1.31(m,1H),1.37-1.42(m,1H),1 .65-1.78(m,1H),1.83-1.94(m,1H),1.94-2.01(m,1H),2.31(s,3H),2.34-2.45( m,1H),2.65-2.73(m,1H),2.76(s,3H),2.82(d,J=16.8Hz,1H),3.07(d,J=16.8Hz ,1H),3.37-3.45(m,1H),3.53(dt,J=12.0,1.8Hz,1H),3.62-3.73(m,1H),5.49(br d,J=8.8Hz,1H),7.10-7.16(m,2H),7.16-7.20(m,1H),7.29-7.35(m,1H),12.71(brd,J=1.0Hz,1H); ESI-MS m / z[M+H] +301.4.

[0687] Example 39: 1-(4-Chlorobenzyl)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0688]

[0689] The TFA salt of the title compound was prepared as in Example 36 using 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide TFA salt (16 mg, 0.038 mmol), Et3N (16 μL, 0.11 mmol), aqueous formaldehyde (37 wt%, 8.4 μL, 0.11 mmol) and sodium triacetoxyborohydride (24.7 mg, 0.113 mmol) in DCM (251 μL) and obtained as a colorless oil (14 mg, 85%). 1 H NMR (400MHz, CDCl3) δppm 0.75-0.87(m,2H),1.24-1.35,(m,2H),1.73-1.86(m,1H),2.06-2.21(m,1H),2.74-2.92(m,5H),2.93-3.05(m,2H),3. 43-3.56(m,1H),3.67-3.82(m,1H),4.10-4.27(m,1H),4.63-4.88(m,1H),5.88-6.02(m,1H),7.19-7.34(m,4H); ESI-MS m / z[M+H] + 325.3.

[0690] Example 40: N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-2-phenoxyacetamide

[0691]

[0692] The TFA salt of the title compound was prepared as in Example 36 using 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-phenoxyacetamide TFA salt and obtained as a white solid (113 mg, 62%). 1H NMR (400MHz, CDCl3) δppm 0.99 (d, J = 6.3Hz, 3H), 2.13-2.19 (m, 3H), 2.29-2.43 (m, 1H), 2.52 (br t, J = 12.0Hz, 1H), 2.82 (s, 3H), 3.53 (br d,J=11.8Hz,1H),3.62(br d,J=12.6Hz,1H),3.77-3.91(m,1H),6.97(br d,J=9.0Hz,1H),7.22-7.26(m,2H),7.27-7.31(m,1H),7.35-7.42(m,2H); ESI-MS m / z[M+H] + 299.3.

[0693] Example 41: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0694]

[0695] Step A: tert-Butyl (2R,4R)-4-(1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxamido)-2-methylpiperidine-1-carboxylate

[0696]

[0697] To a 40 mL vial was added 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylic acid (0.118 g, 0.490 mmol), (2R,4R)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (0.105 g, 0.490 mmol), HATU (0.186 g, 0.490 mmol), DIPEA (0.256 mL, 1.47 mmol) and DMF (3 mL) to give a yellow solution. The mixture was stirred at room temperature overnight and then diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (0.214 g). ESI-MS m / z[M+H] + 437.4.

[0698] Step B: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-2-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0699]

[0700] To a 125 mL pear-shaped flask was added tert-butyl (2R,4R)-4-(1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxamido)-2-methylpiperidine-1-carboxylate (0.214 g, 0.49 mmol), HCl in dioxane (4M, 0.490 mL, 1.96 mmol) and dioxane (3 mL) to give a brown solution. The mixture was stirred at 50 °C for 3 hours and then concentrated in vacuo to give the HCl salt of the title compound as a brown film (0.183 g). ESI-MS m / z [M+H] + 337.3.

[0701] Step C: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0702] In a 125 mL pear-shaped flask, 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-2-methylpiperidin-4-yl)cyclopropane-1-carboxamide HCl (183 mg, 0.49 mmol) and aqueous formaldehyde (37 wt%, 0.076 mL, 0.980 mmol) were dissolved in MeOH (3 mL) to give a brown solution. Next, sodium cyanoborohydride (61.6 mg, 0.980 mmol) was added. The mixture was stirred at room temperature overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The residue was purified by NX-C18, 5 μm, ID 30 mm×100 mm) to afford the title compound as a TFA salt (106.4 mg, 47% over three steps). 1 H NMR(400MHz,CD3OD)δppm 0.87(d,J=2.8Hz,2H),1.17(d,J=2.8Hz,2H),1.34(d,J=6.4Hz,3H),1.38-1.50(m,1H),1.54-1.67(m,1H),1.95-2.04(m,2H),2.84(s, 3H),3.01(s,3H),3.03-3.11(m,1H),3.14-3.23(m,1H),3.46-3.53(m,1H),3.85(s,3H),6.57-6.69(m,2H),7.48-7.57(m,1H); ESI-MS m / z[M+H] + 351.3.

[0703] Example 42: (R)-2,2-difluoro-2-phenoxy-N-(5-azaspiro[2.4]hept-7-yl)acetamide

[0704]

[0705] A solution of 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), (R)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (115 mg, 0.544 mmol), HATU (233 mg, 0.593 mmol) and DIPEA (0.259 mL, 1.483 mmol) in DMF (1.6 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (20 mL) and washed with 1 M HCl and brine. The organic phase was dried over MgSO4, mixed with TFA (1 mL) and stirred for 4 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Phenomenex The pure fractions were combined and lyophilized to give the title compound (21.1 mg, 15%) as a clear oil. 1 H NMR(400MHz,CD3OD)δppm 0.47-0.90(m,4H),2.81-2.95(m,1H),3.08-3.18(m,1H),3.21-3.28(m,1H),3.4 4-3.59(m,1H),4.02-4.24(m,1H),7.20-7.37(m,3H),7.39-7.50(m,2H); ESI-MS m / z[M+H] + 283.3.

[0706] Example 43: 1-(2-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0707]

[0708] The title compound was prepared as in Example 42 using 1-(2-fluorobenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.515 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (135 mg, 0.618 mmol), HATU (242 mg, 0.618 mmol) and DIPEA (0.27 mL, 1.54 mmol) and obtained as a clear oil (32.1 mg, 21%). 1HNMR (400MHz, CDCl3) δppm 0.85 (d, J = 2.4Hz, 2H), 1.32 (br d, J = 2.3Hz, 3H), 1.90 -2.22(m,1H),2.70-2.93(m,3H),3.01(d,J=2.6Hz,2H),3.12-3.30(m,1H),3.36-4.57(m,3H),5.73(br s,1H),7.03-7.16(m,2H),7.28(s,1H),7.37-7.44(m,1H); ESI-MS m / z[M+H] + 295.2.

[0709] Example 44: 1-(3-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0710]

[0711] The title compound was prepared as in Example 42 using 1-(3-fluorobenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.515 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (135 mg, 0.515 mmol), HATU (242 mg, 0.618 mmol) and DIPEA (0.27 mL, 1.54 mmol) and obtained as a light yellow oil (51.9 mg, 34%). 1 HNMR (400MHz, CDCl3) δppm 0.85 (d, J=2.4Hz, 2H), 1.32 (br d,J=2.3Hz,3H),1.90-2.22(m,1H),2.70-2.93(m,3H),3.01(d,J=2.6Hz,2H),3.12-3.30(m,1H),3.36-4.57(m,3H),5.73(br s,1H),7.03-7.16(m,2H),7.28(s,1H),7.37-7.44(m,1H); ESI-MS m / z[M+H] + 297.4.

[0712] Example 45: 1-Benzyl-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0713]

[0714] The title compound was prepared as in Example 42 using 1-benzylcyclopropane-1-carboxylic acid (100 mg, 0.567 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (136 mg, 0.624 mmol), HATU (267 mg, 0.681 mmol) and DIPEA (0.297 mL, 1.70 mmol) and obtained as a clear oil (22.1 mg, 14%). 1 H NMR (400MHz, CDCl3) δppm 0.79-0.87(m,2H),1.04-1.18(m,1H),1.34-1.42(m,2H),1.88-2.01(m,1H),2.60-2.77(m,3H),2.90-3.04(m,1H ),3.00(s,1H),3.92-4.05(m,1H),4.10-4.21(m,1H),5.41-5.65(m,1H),7.25-7.30(m,1H),7.37(s,4H); ESI-MS m / z[M+H] + 277.3.

[0715] Example 46: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methoxybenzyl)cyclopropane-1-carboxamide

[0716]

[0717] The title compound was prepared as in Example 42 using 1-(3-methoxybenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.485 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (116 mg, 0.533 mmol), HATU (228 mg, 0.582 mmol) and DIPEA (0.26 mL, 1.45 mmol) and obtained as a clear oil (21.7 mg, 14.6%). 1 HNMR(400MHz,CDCl3)δppm 0.85(d,J=2.6Hz,2H),1.12-1.28(m,1H),1.38(s,2H),1.92-2.08(m,1H),2.68-2.85(m,3H),2.97(s,3H),3.82(s,3H),3.96-4 .31(m,2H),3.97-4.20(m,2H),4.21-4.31(m,1H),5.54-5.68(m,1H),6.78-6.86(m,1H),6.90-6.99(m,2H),7.28(s,1H); ESI-MS m / z[M+H] + 307.3.

[0718] Example 47: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methoxybenzyl)cyclopropane-1-carboxamide

[0719]

[0720] The title compound was prepared as in Example 42 using 1-(2-methoxybenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.485 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (106 mg, 0.485 mmol), HATU (228 mg, 0.582 mmol) and DIPEA (0.254 mL, 1.455 mmol) and obtained as a clear oil (25.3 mg, 17%). 1 HNMR(400MHz,CDCl3)δppm 0.86(d,J=2.8Hz,2H),1.35(s,3H),1.99-2.15(m,1H),2.72-2.92(m,3H),2.96(d,J=7.0Hz,2H),3.09-3.24(m,1H),3.92(s,3 ESI-MS m / z[M+H] + 307.3.

[0721] Example 48: 2,2-Difluoro-N-((2S,4S)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0722]

[0723] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), (2S,4S)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (117 mg, 0.544 mmol), HATU (233 mg, 0.593 mmol) and DIPEA (0.26 mL, 1.48 mmol) and obtained as a clear film (8.8 mg, 6%). 1H NMR (400MHz, CDCl3) δppm 1.01-1.10(m,1H),1.12-1.16(m,3H),1.28-1.43(m,1H),1.95-2.09(m,2H),2.78(br d,J=2.5Hz,2H),3.05-3.26(m,1H),3.72-4.06(m,1H),6.19-6.33(m,1H),7.21-7.26(m,2H),7.27-7.31(m,1H),7.35-7.45(m,2H); ESI-MS m / z[M+H] + 285.4.

[0724] Example 49: 2,2-Difluoro-2-phenoxy-N-(5-azaspiro[2.5]octan-8-yl)acetamide

[0725]

[0726] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), tert-butyl 8-amino-5-azaspiro[2.5]octane-5-carboxylate (123 mg, 0.544 mmol), HATU (233 mg, 0.593 mmol) and DIPEA (0.26 mL, 1.48 mmol) and obtained as a clear oil (8.8 mg, 6%). 1 H NMR (400MHz, CDCl3) δppm 0.30-1.00(m,4H),2.06-2.26(m,2H),2.81-2.96(m,1H),3.01-3.12(m,1H),3.13-3.44(m,2H),3.79-4.11(m ,1H),6.25-6.46(m,1H),7.18-7.25(m,4H),7.28-7.43(m,1H),7.28-7.44(m,3H),9.26-10.31(m,1H); ESI-MS m / z[M+H] + 297.4.

[0727] Example 50: 2,2-Difluoro-N-(cis-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0728]

[0729] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (87 mg, 0.462 mmol), (2S,4S)-4-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (109 mg, 0.509 mmol), HATU (218 mg, 0.555 mmol) and DIPEA (0.24 mL, 1.39 mmol) and obtained as a clear film (27.8 mg, 21%). ESI-MS m / z [M+H] + 285.3.

[0730] Example 51: 2,2-Difluoro-N-((2R,4R)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0731]

[0732] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (87 mg, 0.462 mmol), (2R,4R)-4-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (109 mg, 0.509 mmol), HATU (218 mg, 0.555 mmol) and DIPEA (0.24 mL, 1.39 mmol) and obtained as a clear oil (18.6 mg, 14%). ESI-MS m / z [M+H] + 285.3.

[0733] Example 52: 2,2-Difluoro-N-((2R,4S)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0734]

[0735] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), (2R,4S)-4-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.544 mmol), HATU (233 mg, 0.593 mmol) and DIPEA (0.26 mL, 1.48 mmol) and obtained as a clear film (14.3 mg, 10%). ESI-MS m / z [M+H] + 285.3.

[0736] Example 53: 2,2-Difluoro-N-((2S,4R)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0737]

[0738] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), (2S,4R)-4-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester hydrochloride (136 mg, 0.544 mmol), HATU (233 mg, 0.593 mmol) and DIPEA (0.34 mL, 1.98 mmol) and obtained as a clear film (47 mg, 33%). ESI-MS m / z [M+H] + 285.3.

[0739] Example 54: 2,2-Difluoro-2-(2-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0740]

[0741] The title compound was prepared as in Example 42 using 2,2-difluoro-2-(2-fluorophenoxy)acetic acid (93 mg, 0.451 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (97 mg, 0.451 mmol), HATU (212 mg, 0.541 mmol) and DIPEA (0.394 mL, 2.25 mmol) and obtained as a clear oil (10 mg, 7.3%). 1 HNMR(400MHz,CD3OD)δppm 0.96(m,3H),1.61-1.95(m,3H),2.48-2.58(m,1H),2.80-2.91(m,1H),3.15-3.30(m,2H),3.60-3.71(m,1H),7.18-7.44(m,4H).

[0742] Example 55: 2,2-Difluoro-2-(3-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0743]

[0744] The title compound was prepared as in Example 42 using 2,2-difluoro-2-(3-fluorophenoxy)acetic acid (82 mg, 0.398 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (85 mg, 0.398 mmol), HATU (187 mg, 0.477 mmol) and DIPEA (0.35 mL, 1.99 mmol) and obtained as a clear oil (21 mg, 17.4%). 1HNMR(400MHz,CD3OD)δppm 0.92(d,J=6.6Hz,3H),1.57-1.74(m,1H),1.76-2.01(m,2H),2.39-2.58(m,1H),2.77-2.92 (m,1H),3.13-3.29(m,2H),3.56-3.72(m,1H),7.04-7.23(m,3H),7.45-7.58(m,1H); ESI-MS m / z[M+H] + 303.3.

[0745] Example 56: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(o-tolyloxy)acetamide

[0746]

[0747] The title compound was prepared as in Example 42 using 2,2-difluoro-2-(o-tolyloxy)acetic acid (93 mg, 0.460 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (128 mg, 0.598 mmol), HATU (216 mg, 0.552 mmol) and DIPEA (0.24 mL, 1.38 mmol) and obtained as a clear oil (19.9 mg, 14%). 1 H NMR(400MHz,CD3OD)δppm 0.97(d,J=6.6Hz,3H),1.75-1.93(m,1H),2.00-2.15(m,2H),2.83(s,1H),3.03 -3.20(m,1H),3.39-3.53(m,2H),3.68-3.87(m,1H),7.07-7.37(m,4H); ESI-MS m / z[M+H] + 299.3.

[0748] Example 57: 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(m-tolyloxy)acetamide

[0749]

[0750] The title compound was prepared as in Example 42 using 2,2-difluoro-2-(m-tolyloxy)acetic acid (93 mg, 0.460 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (128 mg, 0.598 mmol), HATU (216 mg, 0.552 mmol) and DIPEA (0.24 mL, 1.38 mmol) and obtained as a clear oil (25.5 mg, 19%). 1 H NMR(400MHz,CD3OD)δppm 0.94(d,J=6.6Hz,3H),1.71-1.91(m,1H),1.95-2.10(m,2H),2.36(d,J=10.3Hz,4H),2.70-2.9 3(m,1H),3.01-3.20(m,1H),3.36-3.53(m,2H),3.63-3.83(m,1H),6.98-7.33(m,2H),7.13(br d,J=0.8Hz,1H),7.21(d,J=7.8Hz,1H),7.26-7.32(m,1H); ESI-MS m / z[M+H] + 299.3.

[0751] Example 58: 2,2-Difluoro-2-(4-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0752]

[0753] A solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid (87 mg, 0.422 mmol), (3S, 4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.422 mmol), HATU (199 mg, 0.507 mmol) and DIPEA (369 μL, 2.110 mmol) in DMF (1.41 mL) was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine and dried over Na2SO4. Trifluoroacetic acid (1 mL) was added to the organic layer. The mixture was stirred for 4 hours and then purified by preparative HPLC (Phenomenex NX-C18, 5 μm, ID 30 mm x 150 mm). The product was purified by preparative HPLC (Phenomenex Repurification with NX-C18, 5 μm, ID 30 mm×100 mm) gave the TFA salt of the title compound as a clear oil (5.3 mg, 3.0%). 1 H NMR(400MHz,CD3OD)δppm 0.96(d,J=6.6Hz,3H),1.77-1.96(m,1H),1.99-2.13(m,2H),2.75-2.89(m,1H),3.04-3.21 (m,1H),3.36-3.53(m,2H),3.70-3.82(m,1H),7.08-7.22(m,2H),7.24-7.34(m,2H); ESI-MS m / z[M+H] + 303.3.

[0754] Example 59: 1-(3-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0755]

[0756] In a 4 mL vial, 1-(3-chlorophenoxy)cyclopropane-1-carboxylic acid (53.2 mg, 0.250 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (54.6 mg, 0.250 mmol), HATU (95 mg, 0.250 mmol) and DIPEA (87 μL, 0.500 mmol) were dissolved in DMF (2 mL). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine and dried over Na2SO4. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the organic layer. The mixture was stirred overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The product was purified by HPLC-MS / MS (HPLC-MS / MS), to afford the TFA salt of the title compound as an off-white solid (59 mg, 55%). 1H NMR(400MHz,DMSO-d6)δppm 1.08-1.17(m,2H),1.39-1.47(m,2H),1.58-1.68(m,1H),1.81-1.89(m ,1H),2.95-3.03(m,1H),3.06-3.21(m,2H),3.42-3.51(m,1H),4.16-4 .21(m,1H),4.58-4.77(m,1H),6.84-6.95(m,2H),7.01-7.11(m,1H),7.33(t,J=8.2Hz,1H)8.41(d,J=8.3Hz,1H),8.79-9.06(m,1H),9.20(br s,1H); ESI-MS m / z[M+H] + 313.2.

[0757] Example 60: 1-(2-Cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0758]

[0759] To a 4 mL vial was added 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid (54.6 mg, 0.250 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (54.6 mg, 0.250 mmol), HATU (95 mg, 0.250 mmol), DIPEA (87 μL, 0.500 mmol) and DMF (2 mL). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine and dried over Na2SO4. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the organic layer. The mixture was stirred overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The product was purified by HPLC-MS / MS (HPLC-MS / MS), to afford the TFA salt of the title compound as an off-white solid (70 mg, 65%). 1H NMR(400MHz,DMSO-d6)δppm 0.56-0.64(m,2H),0.85-0.92(m,2H),1.00-1.10(m,2H),1.35-1.46(m,2H),1.66-1.78( m,1H),1.88-1.96(m,1H),2.07-2.16(m,1H),2.98-3.07(m,1H),3.08-3.17(m,1H),3.18- 3.25(m,1H),3.51-3.54(m,1H),4.17-4.29(m,1H),4.67-4.88(m,1H),6.79-6.87(m,2H) ,6.88-6.95(m,1H),7.04-7.13(m,1H),8.39(d,J=8.3Hz,1H),8.70-8.97(m,1H),9.12(br s,1H); ESI-MS m / z[M+H] + 319.5.

[0760] Example 61: 2-(2,3-dichlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide

[0761]

[0762] To a 4 mL vial was added 2-(2,3-dichlorophenoxy)propionic acid (58.8 mg, 0.250 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (54.6 mg, 0.250 mmol), HATU (95 mg, 0.250 mmol), DIPEA (87 μL, 0.500 mmol) and DMF (2 mL). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine and dried over Na2SO4. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the organic layer. The mixture was stirred overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The product was purified by HPLC-MS / MS (HPLC-MS / MS), to afford the TFA salt of the title compound as an off-white solid (59 mg, 53%). 1H NMR(400MHz,DMSO-d6)δppm 1.47-1.54(m,3H),1.60-1.76(m,1H),1.93-2.03(m,1H),3.01-3.10(m,1H),3.16-3.27(m,2H),3.4 7-3.54(m,1H),4.07-4.19(m,1H),4.60-4.85(m,2H),6.91-6.97(m,1H),7.20-7.31(m,2H),8.52(br d,J=7.4Hz,1H),9.14(br s,2H); ESI-MS m / z[M+H] + 335.2.

[0763] Example 62: 2-(2-Chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide

[0764]

[0765] To a 4 mL vial was added 2-(2-chlorophenoxy)propionic acid (50.2 mg, 0.250 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (54.6 mg, 0.250 mmol), HATU (95 mg, 0.250 mmol), DIPEA (87 μL, 0.500 mmol) and DMF (2 mL). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine and dried over Na2SO4. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the organic layer. The mixture was stirred overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The product was purified by HPLC-MS / MS (HPLC-MS / MS, ... 1 H NMR(400MHz,CD3OD)δppm 1.67(dd,J=6.6,1.2Hz,3H),1.87-2.04(m,1H),2.22-2.37(m,1H),3.20-3.37(m,2H),3.49-3.68(m,1H),4.24-4. 37(m,1H),4.79-4.86(m,2H),4.90-5.01(m,1H),7.04-7.13(m,2H),7.24-7.39(m,1H),7.43-7.53(m,1H); ESI-MS m / z[M+H] + 301.2.

[0766] Example 63: 2-(2-Cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide

[0767]

[0768] To a 4 ml vial was added 2-(2-cyclopropylphenoxy)propionic acid (51.6 mg, 0.25 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (54.6 mg, 0.250 mmol), HATU (95 mg, 0.250 mmol), DIPEA (87 μL, 0.500 mmol) and DMF (2 mL). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine and dried over Na2SO4. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the organic layer. The mixture was stirred overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% ACN / water (acidic mode) The product was purified by HPLC-MS / MS (HPLC-MS / MS), to afford the TFA salt of the title compound as an off-white solid (64 mg, 61%). 1 H NMR(400MHz,CD3OD)δppm 0.64-0.73(m,1H),0.73-0.82(m,1H),0.95-1.07(m,2H),1.65(dd,J=6.6,2.1Hz ,3H),1.85-2.04(m,1H),2.20-2.39(m,2H),3.20-3.35(m,2H),3.43-3.66(m,1H) ,4.25-4.35(m,1H),4.73-4.79(m,1H),4.79-4.86(m,1H),4.89-5.01(m,1H),6. 87-6.91(m,1H),6.91-6.95(m,1H),6.95-7.01(m,1H),7.09-7.19(m,1H); ESI-MS m / z[M+H] + 307.3.

[0769] Example 64: 2-(2-Chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0770]

[0771] To a solution of 2-(2-chlorophenoxy)-2,2-difluoroacetic acid (100 mg, 0.449 mmol), (3S,4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (96.0 mg, 0.449 mmol) and HATU (205 mg, 0.539 mmol) in DMA (0.899 mL) was added DIPEA (0.172 mL, 0.988 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (3 mL). The aqueous layer was decanted and the oily residue was washed with water (1 mL) and dried under a stream of nitrogen. The resulting oil was treated with 4M HCl (1.12 mL, 4.49 mmol) in dioxane. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo and purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS) to give the title compound (59.0 mg, 41%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 0.67(d,J=6.6Hz,3H),1.38(qd,J=12.2,4.3Hz,1H),1.49-1.61(m,2H),2.08-2.18(m,1H),2.45-2.49(m,1H),2.83-2. 94(m,2H),3.30-3.38(m,1H),7.23-7.31(m,1H),7.32-7.39(m,2H),7.52-7.57(m,1H),8.88(brd,J=8.8Hz,1H); ESI-MS m / z[M+H] + 319.3.

[0772] Example 65: 2-(3-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0773]

[0774] To a solution of 2-(3-chlorophenoxy)-2,2-difluoroacetic acid (100 mg, 0.449 mmol), (3S,4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (96 mg, 0.449 mmol) and HATU (205 mg, 0.539 mmol) in DMA (0.899 mL) was added DIPEA (0.313 mL, 1.80 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (3 mL). The aqueous layer was decanted and the oily residue was washed with water (1 mL) and dried under a stream of nitrogen. The resulting oil was treated with HCl (4 M, 1.12 mL, 4.49 mmol) in dioxane. The mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo and purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / ... 1 H NMR (400MHz, DMSO-d6) δppm 0.69 (d, J=6.5Hz, 3H), 1.40 (qd, J=12.2, 4.3Hz, 1H), 1.50-1.65 (m, 2H), 2.17 (br t,J=11.6Hz,1H),2.34-2.49(m,1H),2.85-3.02(m,2H),3.37-3.48(m,1H),7.23-7.31(m,1H),7.36-7.44(m,2H),7.46-7.52(m,1H),8.93(br d,J=8.7Hz,1H); ESI-MS m / z[M+H] + 319.3.

[0775] Example 66: 2-(4-Chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0776]

[0777] To a solution of 2-(4-chlorophenoxy)-2,2-difluoroacetic acid (100 mg, 0.449 mmol), (3S,4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (96 mg, 0.449 mmol) and HATU (205 mg, 0.539 mmol) in DMA (0.899 mL) was added DIPEA (0.313 mL, 1.80 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (3 mL). The aqueous layer was decanted and the oily residue was washed with water (1 mL) and dried under a stream of nitrogen. The resulting oil was treated with HCl (4 M, 1.12 mL, 4.49 mmol) in dioxane. The mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo and purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS), to give the title compound (65 mg, 45%) as a yellow semisolid. 1 H NMR(400MHz,DMSO-d6)δppm 0.61(d,J=6.5Hz,3H),1.33(qd,J=12.2,4.3Hz,1H),1.41-1.59(m,2H),2.09(t,J=11.7Hz,1H),2.3 6-2.42(m,1H),2.79-2.92(m,2H),3.28-3.33(m,1H),7.18-7.28(m,2H),7.38-7.51(m,2H),8.84(br d,J=8.7Hz,1H); ESI-MS m / z[M+H] + 319.2.

[0778] Example 67: 2-(2-Chlorophenoxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)propanamide

[0779]

[0780] Step A: tert-Butyl (2R,4R)-4-(2-(2-chlorophenoxy)propionamido)-2-methylpiperidine-1-carboxylate

[0781]

[0782] 2-(2-chlorophenoxy)propionic acid (0.040 g, 0.200 mmol), (2R, 4R)-4-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.043 g, 0.200 mmol), HATU (0.076 g, 0.200 mmol), DIPEA (0.139 mL, 0.800 mmol) and DMF (1.600 mL) were added to a 4 mL vial. The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM. The organic layer was washed with 1N HCl and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (79 mg, 0.200 mmol) as an off-white solid. ESI-MS m / z[M+Ht-Bu] + 341.2.

[0783] Step B: 2-(2-Chlorophenoxy)-N-((2R,4R)-2-methylpiperidin-4-yl)propanamide

[0784]

[0785] Crude (2R,4R)-tert-butyl 4-(2-(2-chlorophenoxy)propionamido)-2-methylpiperidine-1-carboxylate (0.079 g, 0.200 mmol) and HCl in dioxane (4M, 0.200 mL, 0.800 mmol) were combined in dioxane (1.227 ml) to give a brown solution. The mixture was stirred at 50 °C for 3 hours. Additional HCl in dioxane (4M, 0.200 mL, 0.800 mmol) was added and the mixture was stirred at 50 °C for another 3 hours. The mixture was concentrated in vacuo to give the title compound (59 mg, 0.200 mmol) as a brown film. ESI-MS m / z [M+H] + 297.3.

[0786] Step C: 2-(2-Chlorophenoxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)propanamide

[0787] Crude 2-(2-chlorophenoxy)-N-((2R,4R)-2-methylpiperidin-4-yl)propanamide (59 mg, 0.200 mmol), formaldehyde (31.2 μL, 0.400 mmol) and MeOH (1.227 mL) were combined in a round bottom flask. To the resulting brown solution was added sodium cyanoborohydride (25.1 mg, 0.400 mmol). The mixture was stirred at room temperature overnight and then purified by preparative HPLC (Phenomenex HPLC) using a gradient of 10-100% water / ACN in water (basic mode). NX-C18, 5 μm, ID 30 mm x 150 mm). The purification step recovered the starting material, which was reacted again under the above conditions and then purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS, ... 1 H NMR(400MHz,CD3OD)δppm 1.36-1.74(m,8H),1.77-1.90(m,1H),2.15-2.24(m,1H),2.24-2.34(m,1H),2.95-3.00(m,3H),3.24-3.32(m,1H),3.6 0-3.66(m,1H),4.09-4.17(m,1H),4.76-4.81(m,1H),7.07-7.12(m,2H),7.31-7.36(m,1H),7.47-7.52(m,1H); ESI-MS m / z[M+H] + 311.3.

[0788] Example 68: 1-(3-Fluoro-5-methoxybenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0789]

[0790] Step A: tert-Butyl (3S,4S)-3-fluoro-4-(1-(3-fluoro-5-methoxybenzyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0791]

[0792] A solution of 1-(3-fluoro-5-methoxybenzyl)cyclopropane-1-carboxylic acid (200 mg, 0.892 mmol), (3S, 4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (246 mg, 1.07 mmol), HATU (415 mg, 1.07 mmol) and Et3N (496 μL, 3.57 mmol) in THF (4.46 mL) was stirred at room temperature for 48 hours. The reaction mixture was diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS) to give the title compound (300 mg, 79%) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 0.80-0.85(m,2H),1.09-1.24(m,1H),1.32-1.37(m,2H),1.46(s,9H),1.92-2.04(m,1H),2.82-3 .09(m,4H),3.66(brd,J=13.6Hz,1H),3.86(s,3H),3.93-4.05(m,2H),4.06-4.24(m,1H),6.20(br s,1H),6.79-6.86(m,1H),6.88-6.98(m,1H),7.08(dd,J=9.0,3.0Hz,1H); 19 F NMR(376MHz, CDCl3)δppm-75.85(s,1F),-122.48(br s,1F); ESI-MS m / z[M+H] + 425.5.

[0793] Step B: 1-(3-Fluoro-5-methoxybenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0794] At room temperature, a solution of (3S, 4S)-3-fluoro-4-(1-(3-fluoro-5-methoxybenzyl)cyclopropane-1-formamido)piperidine-1-formic acid tert-butyl ester (300 mg, 0.707 mmol) in DCM (2 mL) and MeOH (1 mL) was used for HCl (4M, 1.77 μL, 7.07 mmol) in dioxane. The reaction mixture was stirred for 16 hours. The solvent was removed under reduced pressure to obtain a sticky yellow solid, which was treated with ether (3x 25 mL). The solvent was removed under reduced pressure to produce a sticky solid again, so heptane (25 mL) was added. The solvent was removed under reduced pressure to obtain a flowing yellow solid. The yellow solid was divided into two batches, and by using a gradient of 0-100% EtOAc / heptanes, followed by an automatic fast silica column chromatography (ISCO, 4 g RediSep Rf Pure fractions were concentrated under reduced pressure to give the HCl salt of the title compound as a pale yellow solid (194 mg, 76%). 1H NMR(400MHz,DMSO-d6)δppm 0.60-0.67(m,2H),1.00-1.09(m,2H),1.56-1.70(m,1H),1.84(br dd,J=10.0,4.8Hz,1H),2.89-3.02(m,3H),3.02-3.12(m,1H),3.14-3.21(m,1H),3.45(td,J=12.0,4.1Hz,1H ),3.76(s,3H),3.98-4.17(m,1H),4.59-4.84(m,1H),6.89-7.03(m,3H),7.74(dd,J=4.4,1.6Hz,1H); ESI-MS m / z[M+H] + 325.4.

[0795] Example 69: 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(p-tolyloxy)acetamide

[0796]

[0797] Step A: tert-Butyl (3S,4S)-4-(2,2-difluoro-2-(p-tolyloxy)acetamido)-3-methylpiperidine-1-carboxylate

[0798]

[0799] A solution of 2,2-difluoro-2-(p-tolyloxy)acetic acid (150 mg, 0.742 mmol), (3S,4S)-4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl ester (191 mg, 0.890 mmol), HATU (339 mg, 0.890 mmol) and Et3N (414 μL, 2.97 mmol) in DMA (2.99 mL) was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and filtered through a hydrophilic PTFE 0.45 μm The product was filtered and analyzed by preparative HPLC (Phenomenex NX-C18, 5 μm, ID 30 mm x 100 mm) to give the title compound (153 mg, 52%) as a white solid. ESI-MS m / z [M+Na] + 421.5.

[0800] Step B: 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(p-tolyloxy)acetamide

[0801] At room temperature, a solution of (3S, 4S) -4- (2,2- difluoro -2- (p-tolyloxy) acetamido) -3- methylpiperidine -1- carboxylic acid tert-butyl ester (153 mg, 0.384 mmol) in DCM (960 μ L) was treated dropwise with HCl (4M, 960 μ L, 3.84 mmol) in dioxane via a syringe. The reaction mixture was stirred at RT for 16 hours. The solvent was removed under reduced pressure and the product was lyophilized for 3 days to give the HCl salt of the title compound as a white solid (128 mg, quantitative). 1 H NMR(400MHz,DMSO-d6)δppm 0.78(d,J=6.5Hz,3H),1.66-1.86(m,2H),1.92-2.02(m,1H),2.27-2.35(m,3H),2.64-2.76(m,1H),2. 91-3.03(m,1H),3.19-3.28(m,2H),3.60-3.72(m,1H),7.11-7.17(m,2H),7.21-7.27(m,2H),8.88(br s,1H),9.12(br d,J=8.5Hz,1H); ESI-MS m / z[M+H] + 299.3.

[0802] Example 70: 2-(2-Chlorophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide

[0803]

[0804] To a solution of 2-(2-chlorophenoxy)-2,2-difluoroacetic acid (150 mg, 0.674 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (135 mg, 0.674 mmol) and HATU (308 mg, 0.809 mmol) in DMA (1.35 mL) was added DIPEA (0.258 mL, 1.48 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (3 mL). The aqueous layer was decanted, and the oily residue was washed with water (1 mL) and dried under a stream of nitrogen. The resulting oil was treated with HCl (4 M, 1.69 mL, 6.74 mmol) in dioxane. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo, and purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS) to give the title compound (59 mg, 29%) as a white solid. 1H NMR (400MHz, DMSO-d6) δppm 1.34 (qd, J=11.9, 3.6Hz, 2H), 1.55 (br d, J=10.2Hz, 2H), 2.25-2.41 (m, 2H), 2.85 (br d,J=12.3Hz,2H),3.51-3.66(m,1H),7.25-7.31(m,1H),7.31-7.38(m,2H),7.54(dt,J=7.8,1.0Hz,1H),8.88(br d,J=7.6Hz,1H); ESI-MS m / z[M+H] + 305.2.

[0805] Example 71: 2-(2-Chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)acetamide

[0806]

[0807] To a solution of 2-(2-chlorophenoxy)-2,2-difluoroacetic acid (150 mg, 0.674 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (147 mg, 0.674 mmol) and HATU (308 mg, 0.809 mmol) in DMA (1.35 mL) was added DIPEA (0.258 mL, 1.48 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (3 mL). The aqueous layer was decanted and the oily residue was washed with water (1 mL) and dried under a stream of nitrogen. The resulting oil was treated with HCl (4 M, 1.69 mL, 6.74 mmol) in dioxane. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo, and purified by preparative HPLC (Phenomenex The product was purified by HPLC-MS / MS (HPLC-MS / MS) to give the title compound (75 mg, 34%) as a white solid. 1H NMR (400MHz, DMSO-d6) δppm 1.41 (qd, J=12.3, 4.4Hz, 1H), 1.59-1.70 (m, 1H), 2.14-2.29 (m, 1H), 2.30-2.41 (m, 2H), 2.75 (br d,J=12.3Hz,1H),3.08-3.18(m,1H),3.71-3.84(m,1H),4.23-4.50(m,1H) ,7.26-7.32(m,1H),7.36(d,J=3.9Hz,2H),7.55(d,J=7.9Hz,1H),9.18(br d,J=7.9Hz,1H); ESI-MS m / z[M+H] + 323.2.

[0808] Table 1 lists the bioassay data (SSTR4 activity, SSTR4 binding and SSTR1 binding) of some compounds shown in the examples, among which the largest pEC 50 and pIC 50 Values ​​of 0.1% indicate higher activity or potency. The compounds shown in Table 1 were tested according to a cell-based assay that measures inhibition of forskolin-stimulated cAMP in cells overexpressing SSTR4 (reported as pEC 50 Many of the compounds shown in Table 1 were also tested in a membrane-based assay that measures competitive binding of compounds to SSTR4 and SSTR1 (reported as pIC 50 ). These assays are described above in the section entitled Biological Activity.

[0809] Table 1: Bioassay data

[0810]

[0811]

[0812]

[0813] Unless the context clearly indicates otherwise, singular articles such as "a", "an", and "the" as used in this specification and the appended claims may refer to a single object or a plurality of objects. Thus, for example, a reference to a composition containing a "compound" may include a single compound or two or more compounds. The above description is intended to be illustrative and not restrictive. After reading the above description, many embodiments will be apparent to those skilled in the art. Therefore, the scope of the present invention should be determined with reference to the appended claims, and includes the full range of equivalents granted by such claims. The disclosures of all articles and references (including patents, patent applications, and publications) cited in this disclosure are incorporated herein by reference in their entirety and are used for all purposes.

Claims

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein: X 1 Selected from N and CR 1 ; n is selected from 0 and 1; R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from (i) hydrogen, halo, hydroxy and cyano; and (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; L 6 Selected from -CH2-, -N(R 6 )-、*-N(R 6 )CH2- and -O-, where R 6 Selected from hydrogen and C 1-3 alkyl, and * indicates the point of attachment to a carbon atom of the aromatic ring; R 7 and R 8 are each independently selected from halogen and C 1-3 Alkyl, provided that R 7 and R 8 are not all methyl; or R 7 and R 8 Together with the carbon atom to which it is attached, it forms a cyclopropylene group; R 9 and R 10 Each independently selected from (i) hydrogen and halogen; and (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or R 9 and R 10 Together with the carbon atom to which it is attached, it forms a cyclopropylene group; R 11 and R 12 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 11 and R 12 not more than one of them is methyl; and (a)R 13 Selected from hydrogen and C 1-3 Alkyl; and R 14 and R 15 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 14 and R 15 not more than one of them is methyl; or (b)R 13 and R 14 together form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached; and R 15 is selected from hydrogen, halo, and C 1-3 alkyl; The condition is (i) If X 1 CR 1 , L 6 is -CH2- and R 7 and R 8 To form a cyclopropylene group, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 At least one of is not hydrogen; (ii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form a cyclopropylene group, and R 9 , R 10 and R 13 Each is a methyl group, then R 3 Not fluorine or hydroxyl; (iii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 is fluorine, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 9 , R 10 and R 13 are not all hydrogen and are not all methyl; (iv) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 9 Not methyl; (v) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are each hydrogen, and R 7 and R 8 To form a cyclopropylene group, R 11 Not methyl; (vi) If X 1 CR 1 , n is 0, R 1 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form cyclopropylene, R 9 and R 10 Each is a methyl group, and R 13 If L is ethyl 6 Not -O- or -NH-; (vii) If X 1 CR 1 , L 6 is -CH2-, n is 0, R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 Each is hydrogen, R 7 and R 8 To form cyclopropylene, R 9 and R 10 are all methyl groups, and R 13 If R is ethyl 3 Not hydroxyl; (viii) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, then R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 At least one of is not hydrogen; (ix) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, and R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 Each is hydrogen, then R 1 Not fluorinated; and (x) If X 1 CR 1 , L 6 is -CH2-, n is 1, R 7 and R 8 To form a cyclopropylene group, and R 13 and R 14 together to form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached, and R 1 , R 2 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 and R 15 Each is hydrogen, then R 3 Not fluorine.

2. The compound or pharmaceutically acceptable salt according to claim 1, wherein X 1 CR 1 .

3. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein R 1 Selected from (i) hydrogen, halo and cyano; and (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

4. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein R 1 is selected from hydrogen, halo, cyano, methyl, methoxy and cyclopropyl.

5. The compound or pharmaceutically acceptable salt according to claim 1, wherein X 1 is N.

6. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein R 2 Selected from (i) hydrogen and halogen; and (ii)C 1-3 Alkyl and C 1-3 Alkoxy groups are each unsubstituted or substituted with 1 to 3 substituents independently selected from halo.

7. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein R 2 is selected from hydrogen, halo, methyl and methoxy.

8. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein R 3 Selected from (i) hydrogen and halogen; and (ii) C is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen 1-3 alkyl.

9. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein R 3 is selected from hydrogen, halo and methyl.

10. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein R 4 is selected from hydrogen, halo, methyl and methoxy.

11. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein R 4 Selected from hydrogen and fluorine.

12. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R 5 is selected from hydrogen, halo, cyano, methyl, methoxy and cyclopropyl.

13. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R 5 For hydrogen.

14. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein L 6 is selected from -CH2- and -O-.

15. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein R 7 and R 8 Each independently selected from fluorine and C 1-3 Alkyl, provided that R 7 and R 8 Not all are methyl.

16. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein R 7 and R 8 All are fluorine.

17. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein R 7 and R 8 Together with the carbon atom to which it is attached it forms a cyclopropylene group.

18. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein R 9 and R 10 are each independently selected from hydrogen, halogen, C 1-3 Alkyl and phenyl.

19. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein R 9 and R 10 Together with the carbon atom to which it is attached it forms a cyclopropylene group.

20. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein R 11 and R 12 Each is independently selected from hydrogen, halo and methyl.

21. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein R 13 Selected from hydrogen and C 1-3 alkyl.

22. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein R 13 is selected from hydrogen and methyl.

23. A compound or pharmaceutically acceptable salt according to any one of claims 21 and 22, wherein R 14 and R 15 All are hydrogen.

24. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein R 13 and R 14 Together they form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached.

25. The compound or pharmaceutically acceptable salt according to claim 24, wherein R 15 For hydrogen.

26. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein n is 0.

27. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein n is 1.

28. The compound according to claim 1, which is selected from the following compounds: (R)-1-(3-methylbenzyl)-N-(1-methylpyrrolidin-3-yl)cyclopropane-1-carboxamide; N-(1-methyl-4-phenylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(trans-4-isopropyl-1-methylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(1,3-dimethylpiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(1,4-dimethylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; 1-(2-chlorophenoxy)-N-(trans-3-ethyl-1-methylpiperidin-4-yl)cyclopropane-1-carboxamide; 1-(2-chlorophenoxy)-N-(1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide; 1-(2-Chlorophenoxy)-N-(hexahydro-1H-pyrrolizin-1-yl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidin-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidin-4-yl)-1-(4-methylbenzyl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; 1-(4-Fluorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide; 2,2-Difluoro-2-phenoxy-N-(piperidin-4-yl)acetamide; 1-(3-Chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide; 1-(2-methylbenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide; 1-(2-chlorobenzyl)-N-(trans-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide; 1-(4-Chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidin-4-yl)-1-(3-fluorobenzyl)cyclopropane-1-carboxamide; N-(trans-3-ethyl-1-methylpiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; 1-(4-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 1-(4-Chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-phenylpropanamide; 1-(3-Chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 2,2-Difluoro-N-(1-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-2-phenoxyacetamide; 1-(4-Fluoro-2-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 1-(4-Fluoro-3-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 2-(2-Cyanophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide; 2-(2-Cyanophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 2,2-Difluoro-N-(piperidin-4-yl)-2-(p-tolyloxy)acetamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide; 1-(3-Chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide; 1-(4-Chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; 1-(4-Chlorobenzyl)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-2-phenoxyacetamide; 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide; (R)-2,2-difluoro-2-phenoxy-N-(5-azaspiro[2.4]hept-7-yl)acetamide; 1-(2-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 1-(3-Fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 1-Benzyl-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methoxybenzyl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methoxybenzyl)cyclopropane-1-carboxamide; 2,2-difluoro-N-((2S,4S)-2-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-2-phenoxy-N-(5-azaspiro[2.5]octan-8-yl)acetamide; 2,2-Difluoro-N-(cis-2-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-N-((2R,4R)-2-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-N-((2R,4S)-2-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-N-((2S,4R)-2-methylpiperidin-4-yl)-2-phenoxyacetamide; 2,2-Difluoro-2-(2-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 2,2-Difluoro-2-(3-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(o-tolyloxy)acetamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(m-tolyloxy)acetamide; 2,2-difluoro-2-(4-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 1-(3-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 1-(2-Cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 2-(2-Chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 2-(3-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 2-(4-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide; 1-(3-Fluoro-5-methoxybenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide; 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(p-tolyloxy)acetamide; 2-(2-Chlorophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide; 2-(2-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)acetamide; and A pharmaceutically acceptable salt of any one of the above compounds.

29. A compound selected from the group consisting of: 3-(4-chlorophenyl)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide; 2-(2,3-Dichlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide; 2-(2-Chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide; 2-(2-Cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide; 2-(2-chlorophenoxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)propanamide; and A pharmaceutically acceptable salt of any one of the above compounds.

30. A compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 29 for use as a medicament.

31. A compound of formula 1, or a pharmaceutically acceptable salt thereof for use as a medicament, wherein: X 1 Selected from N and CR 1 ; n is selected from 0 and 1; R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from (i) hydrogen, halo, hydroxy and cyano; and (ii)C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; L 6 Selected from -CH2-, -N(R 6 )-、*-N(R 6 )CH2- and -O-, where R 6 Selected from hydrogen and C 1-3 alkyl, and * indicates the point of attachment to a carbon atom of the aromatic ring; R 7 and R 8 are each independently selected from hydrogen, halogen and C 1-3 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 it is attached, it forms C 3-6 Cycloalkylene; R 9 and R 10 Each independently selected from (i) hydrogen and halogen; and (ii)C 1-3 Alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; or R 9 and R 10 Together with the carbon atom to which it is attached, it forms a cyclopropylene group; R 11 and R 12 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 11 and R 12 not more than one of them is methyl; and (a)R 13 Selected from hydrogen and C 1-3 Alkyl; and R 14 and R 15 are each independently selected from hydrogen, halogen, and C 1-3 Alkyl, provided that R 14 and R 15 not more than one of them is methyl; or (b)R 13 and R 14 together form a propane-1,3-diyl group bridging the nitrogen and carbon atoms to which they are respectively attached; and R 15 is selected from hydrogen, halo, and C 1-3 alkyl; The condition is (i) If X is CR 1 , n is 1, L 6 For -O-, R 7 is methyl and R 8 is hydrogen, then R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 or R 15 At least one of is not hydrogen; (ii) If X is CR 1 , n is 1, L 6 For -O-, R 7 and R 8 are all methyl groups, and R 1 , R 2 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen, then R 3 Not for chlorine; as well as (iii) If X is CR 1 , n is 1, L 6 For -O-, R 7 is methyl or ethyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen, then R 9 It is not an unsubstituted phenyl group.

32. The compound according to claim 31 or a pharmaceutically acceptable salt thereof for use as a medicament, wherein R 7 and R 8 are each independently selected from halogen and C 1-3 Alkyl, provided that R 7 and R 8 Not all are methyl.

33. A pharmaceutical composition comprising: A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 32; and Pharmaceutically acceptable excipients.

34. A compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 32 for use in treating a disease, disorder or condition selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and ADHD.

35. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1 to 32, wherein the disease, disorder or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and ADHD.

36. A combination comprising a compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 32, and at least one additional pharmacologically active agent.

37. The combination of claim 36, 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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