N-(Pyrrolidin-3-yl or Piperidin-4-yl)acetamide derivatives

Abstract

Compound of Formula 1 [Formula 1] JPEG2025511255000126.jpg41158 and pharma- ceutical acceptable salts thereof (wherein, 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 , R 15 and X 1 (wherein is defined herein). The disclosure also relates to materials and methods for preparing the compounds of formula 1, pharmaceutical compositions containing them, and their use for treating 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 that are modulators of somatostatin receptor 4 (SSTR4), pharmaceutical compositions containing them, and their use for treating diseases, disorders, and conditions associated with SSTR4, including Alzheimer's disease. [Background technology]

[0002] Somatostatin receptor 4 (SSTR4) is a G protein-coupled receptor for the peptide somatostatin. SSTR4 is coupled 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 among different species. For example, the SSTR4 protein sequences of human, mouse, and rat share more than 87% identity at the amino acid level. These factors (predominant expression in the brain and high sequence homology among different species) suggest that SSTR4 has an important role in physiological functions.

[0003] Experiments using bacTRAP technology have shown that SSTR4 has strongest expression in pyramidal neurons in the cortex and 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 stop of the trisynaptic circuit responsible for learning. This circuit starts in the entorhinal cortex (which also contains SSTR4), spans the dentate gyrus of the hippocampus, then CA3, and finally reaches the CA1 region. CA1 projects out of the hippocampus via the subiculum. This circuit encodes all types of information from the outside world to generate memories and learn new knowledge.

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

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

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

[0007] The present invention provides N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives and pharma- ceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing the N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives and their use for treating diseases, disorders, and conditions associated with SSTR4, including Alzheimer's disease and other CNS disorders.

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

[0009] [ka]

[0010] or a pharma- ceutical acceptable salt thereof, X 1 N and CR 1 Selected from; n is selected from 0 and 1; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo); L 6 -CH2-, -N(R 6 )-, * -N(R 6 ) CH2- and -O- 6 is hydrogen and C 1-3 alkyl, * represents the point of attachment of an aromatic ring carbon atom); R 7 and R 8 are halo and C, respectively. 1-3alkyl (wherein R 7 and R 8 are not both methyl), or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropylidene; R 9 and R 10 are each independently (i) hydrogen and halo; and (ii) C 1-3 alkyl and phenyl, each of which is 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 they are attached form a cyclopropylidene; R 11 and R 12 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 11 and R 12 wherein not more than one of is methyl; (a)R 13 is hydrogen and C 1-3 alkyl; R 14 and R 15 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 14 and R 15 wherein not more than one of is methyl; or (b)R 13 and R 14 together form propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached; R 15 is hydrogen, halo, and C 1-3alkyl (unsubstituted or substituted with 1-3 substituents independently selected from halo); however, (i)X 1 CR 1 And L 6 is -CH2- and R 7 and R 8 When forms a cyclopropylidene, 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) X 1 CR 1 And L 6 is -CH2-, n is 0, and R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8 forms a cyclopropylidene, R 9 , R 10 and R 13 are each methyl, R 3 is not fluoro or hydroxy; (iii)X 1 CR 1 And L 6 is -CH2-, n is 0, and R 1 is fluoro and R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R8 When forms a cyclopropylidene, R 9 , R 10 and R 13 is not all hydrogen, nor is it all methyl; (iv) X 1 CR 1 And L 6 is -CH2-, n is 1, and R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are hydrogen, and R 7 and R 8 When forms a cyclopropylidene, R 9 is not methyl; (v) X 1 CR 1 And L 6 is -CH2-, n is 1, and R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are hydrogen, and R 7 and R 8 When forms a cyclopropylidene, R 11 is not methyl; (vi) X 1 CR 1 where n is 0 and R 1 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8forms a cyclopropylidene, R 9 and R 10 are methyl, and R 13 If is ethyl, L 6 is not -O- or -NH-; (vii)X 1 CR 1 And L 6 is -CH2-, n is 0, and R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8 forms a cyclopropylidene, and R 9 and R 10 are both methyl, and R 13 is ethyl, R 3 is not hydroxy; (viii)X 1 CR 1 And L 6 is -CH2-, n is 1, and R 7 and R 8 forms a cyclopropylidene, and R 13 and R 14 together form a propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached, 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)X 1 CR 1 And L 6 is -CH2-, n is 1, and R 7 and R 8 forms a cyclopropylidene, R 13 and R 14together form a propane-1,3-diyl 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 are each hydrogen, R 1 is not fluoro; (x)X 1 CR 1 And L 6 is -CH2-, n is 1, and R 7 and R 8 forms a cyclopropylidene, R 13 and R 14 together form a propane-1,3-diyl 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 are each hydrogen, R 3 is not fluoro).

[0011] Another aspect of the present invention provides a compound selected from the group of compounds described in the Examples and pharma- ceutically acceptable salts thereof.

[0012] A further aspect of the invention provides a compound or a pharma- ceutically acceptable salt as defined in the preceding paragraph for use as a medicament.

[0013] A further aspect of the invention provides a compound of formula 1 or a pharma- ceutically acceptable salt thereof for use as a medicament. (X 1 N and CR 1 Selected from; n is selected from 0 and 1; R 1 , R2 , R 3 , R 4 , and R 5 are each independently (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo); L 6 -CH2-, -N(R 6 )-, * -N(R 6 ) CH2- and -O- 6 is hydrogen and C 1-3 alkyl, * represents the point of attachment of an aromatic ring carbon atom); R 7 and R 8 are each independently hydrogen, halo, or C 1-3 alkyl; R 7 and R 8 At least one of is not hydrogen or R 7 and R 8 C together with the carbon atom to which they are attached 3-6 Forming a cycloalkylidene; R 9 and R 10 are each independently (i) hydrogen and halo; and (ii) C 1-3 alkyl and phenyl, each of which is 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 they are attached form a cyclopropylidene; R 11 and R 12 are each independently hydrogen, halo, or C 1-3alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 11 and R 12 wherein not more than one of is methyl; (a)R 13 is hydrogen and C 1-3 alkyl; R 14 and R 15 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 14 and R 15 wherein not more than one of is methyl; or (b)R 13 and R 14 together form propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached; R 15 is hydrogen, halo, and C 1-3 alkyl (unsubstituted or substituted with 1-3 substituents independently selected from halo); however, (i) X is CR 1 where n is 1 and L 6 is -O- and R 7 is methyl and R 8 If is hydrogen, 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) X is CR 1 where n is 1 and L 6 is -O- and R 7 and R 8 are both methyl, and R 1 , R 2 , R4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each hydrogen, R 3 is not Chloro; (iii) X is CR 1 where n is 1 and L 6 is -O- and R 7 is methyl or ethyl, and 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 are each hydrogen, R 9 is not unsubstituted phenyl).

[0014] Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula 1 or a pharma- ceutically acceptable salt thereof, or any one of the compounds or pharma- ceutically acceptable salts defined in the preceding paragraph, and a pharma- ceutically acceptable excipient.

[0015] A further aspect of the present invention provides a compound of formula 1 or a pharma- ceutically acceptable salt thereof, or any one of the compounds or pharma- ceutically acceptable salts defined in the preceding paragraph, for treating a disease, disorder, or condition associated with SSTR4.

[0016] An additional aspect of the present invention provides the use of a compound of formula 1 or a pharma- ceutically acceptable salt thereof, or any one of the compounds or pharma- ceutically acceptable salts defined in the preceding paragraph, for the manufacture of a medicament for treating a disease, disorder, or condition associated with SSTR4.

[0017] Another aspect of the present invention provides a method for treating a disease, disorder, or condition associated with SSTR4, comprising administering to a subject an effective amount of a compound of formula 1 or a pharma- ceutically acceptable salt thereof, or any one of the compounds or pharma- ceutically acceptable salts defined in the preceding paragraph.

[0018] A further aspect of the invention provides a method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject an effective amount of a compound of formula 1 or a pharma- ceutically acceptable salt thereof, or any one of the compounds or pharma- ceutically acceptable salts defined in the preceding paragraph, wherein the disease, disorder, or condition is selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

[0019] A further aspect of the present invention provides an effective amount of a compound of formula 1 or a pharma- ceutically acceptable salt thereof, or any one of the compounds or pharma- ceutically acceptable salts defined in the preceding paragraph, and at least one additional pharmacologically active agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0021] "Substituted" refers to a chemical substituent or moiety (e.g., C 1-6 When used in connection with an alkyl group, it means that one or more hydrogen atoms of that substituent or moiety are replaced with one or more non-hydrogen atoms or groups, provided that valency requirements are met and that the substitution results in a chemically stable compound.

[0022] "About" or "approximately," when used in connection with a measurable, numerical variable, refers to the indicated value of that variable and to any value of that variable within experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0023] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally having a specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms; C 1-6 (Alkyl refers to an alkyl group having 1 to 6 carbon atoms, etc.) Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

[0024] "Alkanediyl" refers to a divalent alkyl group, generally having a specified number of carbon atoms, where alkyl is defined above (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms; 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, etc. Alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0025] "Alkenyl" refers to straight-chain and branched saturated hydrocarbon groups having one or more carbon-carbon double bonds and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0026] "Alkynyl" refers to a straight or branched saturated hydrocarbon group having one or more carbon-carbon triple bonds and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0027] "Alkoxy" generally refers to straight-chain and branched saturated hydrocarbon groups attached through an oxygen atom having the specified number of carbon atoms (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms; 1-6 (Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, etc.) Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-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-hexoxy, and the like.

[0028] "Halo", "halogen", and "halogeno" may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0029] "Haloalkyl", "haloalkenyl", and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups, respectively, substituted with one or more halogen atoms and generally having a specified number of carbon atoms, where alkyl, alkenyl, and alkynyl are defined above. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0030] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that constitute the ring(s), e.g., C 3-8 Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members. Bicyclic hydrocarbon groups may include separate rings (two rings that share no carbon atoms), spiro rings (two rings that share one carbon atom), fused rings (two rings that share two carbon atoms and a bond between two common carbon atoms), and bridged rings (two rings that share two carbon atoms but do not share a common bond). Cycloalkyl groups may be bonded through any ring atom, provided such bonding does not violate valence requirements, and, where indicated, may optionally include one or more non-hydrogen substituents, provided such substitution does not violate valence requirements.

[0031] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, and the like. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, etc. Examples of split bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.

[0032] "Cycloalkanediyl" generally refers to a divalent cycloalkyl group having a specified number of carbon atoms, where cycloalkyl is defined above (e.g., C 3-5 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4, or 5) carbon atoms; 3-6Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, etc. Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0033] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group (wherein cycloalkyl is defined above) attached through a single carbon atom of the group and generally having a specified number of carbon atoms that constitute the ring (e.g., C 3-6 Cycloalkylidene refers to a cycloalkylidene group having from 3 to 6 carbon atoms as ring members.) Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0034] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms constituting the ring(s). Like cycloalkyl groups, bicyclic cycloalkenyl groups can include separate rings, spiro rings, fused rings, or bridged rings. Similarly, cycloalkenyl groups can be bonded through any ring atom and, where indicated, can optionally include one or more non-hydrogen substituents, but only if such bond or substitution does not violate valence requirements. Examples of cycloalkenyl groups include partially unsaturated analogs of the above cycloalkyl groups, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0035] "Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic hydrocarbons having at least one aromatic ring, where both monocyclic and polycyclic aryl groups generally have a specified number of carbon atoms constituting their ring members (e.g., C 6-14Aryl refers to an aryl group having 6 to 14 carbon atoms as ring members. The group may be attached via any ring atom and, where indicated, may optionally contain one or more non-hydrogen substituents, provided such attachment or substitution does not violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from a cycloheptatriene cation, and the like.

[0036] "Arylene" refers to a divalent aryl group, where aryl is defined above. Exemplary arylene groups include o-phenylene (i.e., benzene-1,2-diyl).

[0037] "Heterocycle" and "heterocyclyl" may be used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group containing ring atoms of carbon atoms and from one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6Heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members. Like bicyclic cycloalkyl groups, bicyclic heterocyclyl groups can include separate rings, spiro rings, fused rings, and bridged rings. Heterocyclyl groups can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, but only if such attachment or substitution does not violate valence requirements or result in chemically unstable compounds. Examples of heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathiyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathiyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, Examples include 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, and 1,2-dihydropyrazolo[1,5-d][1,2,4]triazinyl.

[0038] "Heterocycle-diyl" refers to a heterocyclyl group (heterocyclyl is defined above) that is attached through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6Heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members.) Examples of heterocycle-diyl groups include polyvalent analogs of the above heterocycle groups, such as morpholine-3,4-diyl, pyrrolidin-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

[0039] "Heteroaromatic" and "heteroaryl" may be used interchangeably and refer to unsaturated monocyclic aromatic groups, each of which has ring atoms consisting of carbon atoms and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and polycyclic groups having at least one aromatic ring. Both monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C 1-9 Heteroaryl refers to heteroaryl groups having 1-9 carbon atoms and 1-4 heteroatoms as ring members, and may include any bicyclic group in which any of the monocyclic heterocycles listed above are fused to a benzene ring. Heteroaryl groups may be attached via any ring atom (or ring atoms of a fused ring) and, where indicated, may optionally contain one or more non-hydrogen substituents, but only if such attachment or substitution does not violate valence requirements or result in chemically unstable compounds. 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.

[0040] Examples of heteroaryl groups also include bicyclic groups, such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-indolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b] Pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0041] "Heteroarylene" refers to heteroaryl groups (heteroaryl being defined above) that are linked through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 3-5 Heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members.) Examples of heteroarylene groups include polyvalent analogs of the above heteroaryl groups, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0042] "Oxo" refers to a double bonded oxygen (=O).

[0043] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups can be nucleofugal (where the leaving group leaves with the electron pair that originally served the bond between the leaving group and the molecule) or electrofugal (where the leaving group leaves without the electron pair). The ability of a nucleofugal leaving group to leave depends on the strength of its base, with the strongest bases being the weakest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylates), fluoroalkylsulfonates (e.g., triflates, hexaflates, nonaflates, and tresylates), and arylsulfonates (e.g., tosylates, brosylates, closylates, and nosylates). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, e.g., NH - and OH - can be made into a better leaving group by treatment with acid. Common electrofugal leaving groups include the proton, CO2, and metals.

[0044] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, and can be obtained by inverting all of the chiral centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Similarly, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0045] A "stereoisomer or stereoisomers" of a compound having a given stereochemical configuration refers to the opposite enantiomer of that compound, and any diastereoisomers, including geometric isomers (Z / E) of that compound. For example, if a compound has an S,R,Z stereochemical configuration, then the stereoisomers would include its opposite enantiomer having the R,S,Z configuration, as well as its diastereoisomers having the S,S,Z configuration, the R,R,Z configuration, the S,R,E configuration, the R,S,E configuration, the S,S,E configuration, and the R,R,E configuration. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0046] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound having a particular stereochemical configuration, where the sample comprises at least about 95% of the sample.

[0047] "Pure stereoisomer" and variations thereof refer to a sample containing a compound with a particular stereochemical configuration, which comprises at least about 99.5% of the sample.

[0048] "Subject" refers to a mammal, including a human.

[0049] A "pharmaceutical acceptable" substance refers to a substance that is suitable for administration to a subject.

[0050] "Treating" refers to reversing, alleviating, inhibiting the progression of, or preventing the disease, disorder, or condition to which such term applies, or reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of such disease, disorder, or condition.

[0051] "Treatment" refers to the act of treating, as defined immediately above.

[0052] "Drug", "drug substance", "active pharmaceutical ingredient", and the like refer to a compound (e.g., a compound of Formula 1, including subgeneric compounds and those specifically named herein) that can be used to treat a subject in need of such treatment.

[0053] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like refer to the amount of a drug that can be used to treat a subject, which amount can depend, inter alia, on the weight and age of the subject and the route of administration.

[0054] "Excipient" refers to any diluent or vehicle for a drug.

[0055] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0056] The terms "drug product," "pharmaceutical dosage form," "dosage form," "final dosage form," and the like refer to a pharmaceutical composition suitable for treating a subject in need thereof and may generally be in the form of a tablet, capsule, a sachet containing powder or granules, a liquid or suspension, a patch, a film, and the like.

[0057] "SSTR4-associated condition" and similar phrases relate to a disease, disorder, or condition in a subject in which activation of SSTR4 can provide a therapeutic or prophylactic benefit.

[0058] The following abbreviations may be used herein: Ac (acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc (tert-butoxycarbonyl); Cbz (carbobenzyloxy); dba (dibenzylideneacetone); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloroethane). ethane;DCM(dichloromethane);DEA(diethylamine);DIAD(diisopropyl azodicarboxylate);DIPEA(N,N-diisopropylethylamine, Hunig's base);DMA(N,N-dimethylacetamide);DMAP(4-dimethylaminopyridine);DME(1,2-dimethoxyethane);DMF(N,N-dimethylformamide);DMP(Dess-Martin periodinane);DMSO(dimethylsulfoxide);dppf(1,1'-bis(diphenylphosphino)ferrocene);DTT(dithiothreitol);EC 50 (effective concentration at half maximum response); EDA (ethoxylated dodecyl alcohol, Brj® 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 at 50% inhibition);IPA (isopropanol);IPAc (isopropyl acetate);IPE (isopropyl ether);LDA (lithium diisopropylamide);LiHMDS (lithium bis(trimethylsilyl)amide);mCPBA (m-chloroperbenzoic acid);Me (methyl);MeOH (methanol);MTBE (methyl tert-butyl ether);mp (melting point);NaOt-Bu (sodium tert-butoxide);NMM (N-methylmorpholine);NMP (N-methyl-pyrrolidone);OTf (triflate);PE (petroleum ether);Ph (phenyl);pEC 50 (-log 10 (EC 50 ), where EC 50 is given in molar (M) units); pIC 50 (-log 10 (I C 50 ), where IC 50 are given in moles (M); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP® (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-trioxatriphosphinane 2,4,6-trioxide); TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMS (trimethylsilyl); and Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer).

[0059] As described below, the present disclosure relates to compounds of formula 1 and pharma- ceutically acceptable salts thereof. The present disclosure also relates to materials and methods for preparing the compounds of formula 1, pharmaceutical compositions containing them, and the use of the compounds of formula 1 and pharma- ceutically acceptable salts thereof (in combination with any other pharmacologically active agent) to treat diseases, disorders, or conditions of the CNS, including Alzheimer's disease, and other diseases, disorders, or conditions associated with SSTR4, including pain.

[0060] Compounds of formula 1 include those which are: (1)X 1 N and CR 1 Selected from; n is selected from 0 and 1; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo); L 6 is -CH2-, -N(R 6 )-, * -N(R 6 ) CH2- and -O- 6 is hydrogen and C 1-3 alkyl, * represents the point of attachment of an aromatic ring carbon atom); R 7 and R 8 are halo and C, respectively. 1-3 alkyl (wherein R 7 and R 8 are not both methyl), or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropylidene; R 9 and R 10 are each independently (i) hydrogen and halo; and (ii) C 1-3 alkyl and phenyl, each of which is 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 they are attached form a cyclopropylidene; R 11 and R 12 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 11 and R 12 wherein not more than one of is methyl; (a)R 13 is hydrogen and C 1-3 alkyl; R 14 and R 15 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 14 and R 15 wherein not more than one of is methyl; or (b)R 13 and R 14 together form propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached; R 15 is hydrogen, halo, and C 1-3 alkyl (unsubstituted or substituted with 1-3 substituents independently selected from halo); however, (i)X 1 CR 1 And L 6 is -CH2- and R 7 and R 8When forms a cyclopropylidene, 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) X 1 CR 1 And L 6 is -CH2-, n is 0, and R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8 forms a cyclopropylidene, R 9 , R 10 and R 13 are each methyl, R 3 is not fluoro or hydroxy; (iii)X 1 CR 1 And L 6 is -CH2-, n is 0, and R 1 is fluoro and R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8 When forms a cyclopropylidene, R 9 , R 10 and R 13 is not all hydrogen, nor is it all methyl; (iv) X 1 CR 1 And L 6is -CH2-, n is 1, and R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are hydrogen, and R 7 and R 8 When forms a cyclopropylidene, R 9 is not methyl; (v) X 1 CR 1 And L 6 is -CH2-, n is 1, and R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are hydrogen, and R 7 and R 8 When forms a cyclopropylidene, R 11 is not methyl; (vi) X 1 CR 1 where n is 0 and R 1 , R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8 forms a cyclopropylidene, R 9 and R 10 are methyl, and R 13 If is ethyl, L 6 is not -O- or -NH-; (vii)X 1 CR 1 And L6 is -CH2-, n is 0, and R 1 , R 2 , R 4 , R 5 , R 11 , R 12 , R 14 and R 15 are hydrogen, and R 7 and R 8 forms a cyclopropylidene, and R 9 and R 10 are both methyl, and R 13 is ethyl, R 3 is not hydroxy; (viii)X 1 CR 1 And L 6 is -CH2-, n is 1, and R 7 and R 8 forms a cyclopropylidene, and R 13 and R 14 together form a propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached, 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)X 1 CR 1 And L 6 is -CH2-, n is 1, and R 7 and R 8 forms a cyclopropylidene, R 13 and R 14 together form a propane-1,3-diyl 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 12and R 15 are each hydrogen, R 1 is not fluoro; (x)X 1 CR 1 And L 6 is -CH2-, n is 1, and R 7 and R 8 forms a cyclopropylidene, R 13 and R 14 together form a propane-1,3-diyl 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 are each hydrogen, R 3 is not fluoro.

[0061] In addition to embodiment (1) of the preceding paragraph, compounds of Formula 1 include those which are: (2)X 1 CR 1 It is.

[0062] In addition to embodiment (2) of the preceding paragraph, the compound of Formula 1 may further comprise R 1 but includes those selected from the following: (3)(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)(i) hydrogen, halo, and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (5)(i) hydrogen, chloro, fluoro, and cyano; and (ii) C1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (6)(i) hydrogen, chloro, fluoro, 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 fluoro); (7)(i) hydrogen, chloro, fluoro, and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (8)(i) hydrogen, halo, and cyano; and (ii) methyl, methoxy, and cyclopropyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (9)(i) hydrogen, halo, and cyano; and (ii) methyl, methoxy, and cyclopropyl (each unsubstituted or substituted with 1 to 3 fluoro); (10) hydrogen, halo, cyano, methyl, methoxy and cyclopropyl; (11) hydrogen, chloro, fluoro, cyano, methyl, methoxy and cyclopropyl; (12) hydrogen, chloro, fluoro, cyano, methyl and methoxy; (13) hydrogen, chloro and methyl; or (14) Hydrogen.

[0063] In addition to embodiment (1) above, compounds of formula 1 include those which are: (15)X 1 is N.

[0064] In addition to embodiments (1)-(15) of the preceding paragraph, the compound of Formula 1 may further comprise R 2is selected from the following: (16)(i) hydrogen and halo; 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); (17)(i) hydrogen and halo; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (18)(i) hydrogen, chloro, and fluoro; 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); (19) (i) hydrogen, chloro, and fluoro; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted or substituted with 1 to 3 fluoro); (20) (i) hydrogen, chloro, and fluoro; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (21)(i) hydrogen and halo; and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (22)(i) hydrogen and halo; and (ii) methyl and methoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (23)(i) hydrogen and halo; and (ii) methyl and methoxy (each unsubstituted or substituted with 1 to 3 fluoro); (24) hydrogen, halo, methyl and methoxy; (25) hydrogen, chloro, fluoro and methyl; or (26) Hydrogen, chloro and methyl.

[0065] In addition to embodiments (1)-(26) of the preceding paragraph, the compound of Formula 1 may further comprise R 3 is selected from the following: (27)(i) hydrogen and halo; 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); (28)(i) hydrogen and halo; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (29) (i) hydrogen, chloro, and fluoro; 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); (30) (i) hydrogen, chloro, and fluoro; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted or substituted with 1 to 3 fluoro); (31) (i) hydrogen, chloro, and fluoro; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (32)(i) hydrogen and halo; and (ii) C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (33)(i) hydrogen and halo; and (ii) methyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (34)(i) hydrogen and halo; and (ii) methyl (unsubstituted or substituted with 1-3 fluoro); (35) hydrogen, halo, and methyl; (36) hydrogen, chloro, fluoro and methyl; or (37) Hydrogen and chloro.

[0066] In addition to embodiments (1)-(37) of the preceding paragraph, the compound of Formula 1 may further comprise R 4 is selected from the following: (38)(i) hydrogen and halo; 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); (39)(i) hydrogen and halo; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (40) (i) hydrogen, chloro, and fluoro; 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); (41) (i) hydrogen, chloro, and fluoro; and (ii) C 1-3 Alkyl, C 1-3Alkoxy and C 3-6 cycloalkyl (each unsubstituted or substituted with 1 to 3 fluoro); (42) (i) hydrogen, chloro, and fluoro; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (43)(i) hydrogen and halo; and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (44)(i) hydrogen and halo; and (ii) methyl and methoxy, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (45)(i) hydrogen and halo; and (ii) methyl and methoxy (each unsubstituted or substituted with 1 to 3 fluoro); (46) Hydrogen, halo, methyl and methoxy; (47) Hydrogen, chloro, fluoro and methyl; (48) Hydrogen, chloro, and fluoro; (49) hydrogen and fluoro; or (50)Hydrogen.

[0067] In addition to embodiments (1)-(50) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 is selected from the following: (51)(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); (52)(i) hydrogen, halo, and cyano; and (ii) C 1-3Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (53)(i) hydrogen, chloro, fluoro 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); (54)(i) hydrogen, chloro, fluoro 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 fluoro); (55)(i) hydrogen, chloro, fluoro and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each unsubstituted); (56)(i) hydrogen, halo, and cyano; and (ii) methyl, methoxy, and cyclopropyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (57)(i) hydrogen, halo, and cyano; and (ii) methyl, methoxy, and cyclopropyl (each unsubstituted or substituted with 1 to 3 fluoro); (58) hydrogen, halo, cyano, methyl, methoxy and cyclopropyl; (59) Hydrogen, chloro, fluoro, cyano, methyl, methoxy and cyclopropyl; (60) Hydrogen, chloro, fluoro, cyano, methyl and methoxy; (61) Hydrogen, chloro and methyl; or (62)Hydrogen.

[0068] In addition to embodiments (1)-(62) of the preceding paragraph, the compound of Formula 1 may further comprise L6 is selected from the following: (63) -CH2- and -O-; (64)-CH2-; (65)-O-; (66)-N(R 6 )-and * -N(R 6 )CH2-; or (67) * -N(R 6 )CH2-.

[0069] In addition to embodiments (66)-(67) of the preceding paragraph, the compound of Formula 1 may further comprise R 6 is selected from the following: (68) Hydrogen and methyl; (69) Methyl; or (70)Hydrogen.

[0070] In addition to embodiments (1)-(70) of the preceding paragraph, the compound of Formula 1 may further comprise R 7 and R 8 are each independently selected from: (71) Halo and C 1-3 Alkyl (where R 7 and R 8 are not both methyl); (72) Fluoro and C 1-3 Alkyl (where R 7 and R 8 are not both methyl); (73) Halo and methyl (where R 7 and R 8 are not both methyl); (74) Fluoro and methyl (where R 7 and R 8 are not both methyl); (75) Halo; or (76) Fluoro.

[0071] In addition to embodiments (1)-(70) of the preceding paragraph, compounds of Formula 1 include those in which: (77)R 7and R 8 together with the carbon atom to which they are attached form a cyclopropylidene.

[0072] In addition to embodiments (1)-(77) of the preceding paragraph, the compound of Formula 1 may further comprise R 9 and R 10 are each independently selected from: (78)(i) hydrogen and halo; and (ii) C 1-3 alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (79)(i) hydrogen and halo; and (ii) C 1-3 alkyl and phenyl (each unsubstituted); (80)(i) hydrogen and fluoro; and (ii) C 1-3 alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (81)(i) hydrogen and fluoro; and (ii) C 1-3 alkyl and phenyl, each unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro; (82)(i) hydrogen and fluoro; and (ii) C 1-3 alkyl and phenyl (each unsubstituted); (83)(i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, and phenyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo; (84)(i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, and phenyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from chloro and fluoro; (85)(i) hydrogen and halo; and (ii) methyl, ethyl, isopropyl, and phenyl (each unsubstituted or substituted with 1 to 3 fluoro); (86) hydrogen, halo, methyl, ethyl, isopropyl and phenyl; (87) Hydrogen, fluoro, methyl, ethyl, isopropyl and phenyl; or (88) Hydrogen, fluoro, and methyl.

[0073] In addition to embodiments (78)-(88) of the preceding paragraph, compounds of Formula 1 include those in which: (89)R 9 and R 10 At least one of is hydrogen.

[0074] In addition to embodiments (1)-(77) of the preceding paragraph, compounds of Formula 1 include those in which: (90)R 9 and R 10 are both hydrogen; or (91)R 9 and R 10 together with the carbon atom to which they are attached form a cyclopropylidene.

[0075] In addition to embodiments (1)-(91) of the preceding paragraph, the compound of Formula 1 may further comprise R 11 and R 12 are each independently selected from: (92) Hydrogen, halo, and C 1-3 Alkyl (unsubstituted); (93) Hydrogen, Fluorine and C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (94) hydrogen, halo, and methyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (95) hydrogen, halo, and methyl (each unsubstituted or substituted with 1 to 3 fluoro); (96) Hydrogen, halo and methyl; or (97) Hydrogen, fluoro and methyl.

[0076] In addition to embodiments (92)-(97) of the preceding paragraphs, compounds of Formula 1 include those in which: (98)R 11 and R 12 At least one of is hydrogen.

[0077] In addition to embodiments (1)-(91) of the preceding paragraph, compounds of Formula 1 include those in which: (99)R 11 and R 12 Both are hydrogen.

[0078] In addition to embodiments (1)-(99) of the preceding paragraph, the compound of Formula 1 may further comprise R 13 is selected from the following: (100) Hydrogen and C 1-3 Alkyl; or (101) Hydrogen and methyl.

[0079] In addition to embodiments (100)-(101) of the preceding paragraph, the compound of formula 1 may further comprise R 14 and R 15 is methyl, and R 14 and R 15 are each independently selected from: (102) Hydrogen, halo and C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (103) Hydrogen, halo, and C 1-3 Alkyl (unsubstituted); (104) Hydrogen, Fluorine and C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (105) hydrogen, halo, and methyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (106) Hydrogen, halo and methyl (unsubstituted or substituted with 1 to 3 fluoro); (107) Hydrogen, halo and methyl; or (108) Hydrogen, fluoro and methyl.

[0080] In addition to embodiments (102)-(108) of the preceding paragraphs, compounds of Formula 1 include those in which: (109)R 14 and R 15 At least one of is hydrogen.

[0081] In addition to the above embodiments (100)-(101), compounds of formula 1 include those in which: (110)R 14 and R 15 Both are hydrogen.

[0082] In addition to embodiments (1)-(99) of the preceding paragraph, compounds of Formula 1 include those in which: (111)R 13 and R 14 together form propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached.

[0083] In addition to embodiment (111) of the preceding paragraph, the compound of Formula 1 may further comprise R 15 but includes those selected from the following: (112) Hydrogen, halo and C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (113) Hydrogen, halo, and C 1-3 Alkyl (unsubstituted); (114) Hydrogen, Fluorine and C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (115) hydrogen, halo, and methyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo); (116) Hydrogen, halo and methyl (unsubstituted or substituted with 1 to 3 fluoro); (117) Hydrogen, halo and methyl; or (118) Hydrogen, fluoro and methyl.

[0084] In addition to embodiments (111)-(118) of the preceding paragraph, the compound of Formula 1 may further comprise R 15 Includes those where: (119)Hydrogen.

[0085] In addition to embodiments (1)-(119) of the preceding paragraph, compounds of Formula 1 include those where n is: (120)0; or (121)1.

[0086] Compounds of formula 1 for use as pharmaceuticals may include those which are: (122)X 1 N and CR 1 Selected from; n is selected from 0 and 1; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently (i) hydrogen, halo, hydroxy, and cyano; and (ii) C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl (each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from halo); L 6 -CH2-, -N(R 6 )-, * -N(R 6 ) CH2- and -O- 6 is hydrogen and C 1-3 alkyl, * represents the point of attachment of an aromatic ring carbon atom); R 7 and R 8 are each independently hydrogen, halo, or C 1-3 alkyl; R 7 and R 8At least one of is not hydrogen or R 7 and R 8 C together with the carbon atom to which they are attached 3-6 Forming a cycloalkylidene; R 9 and R 10 are each independently (i) hydrogen and halo; and (ii) C 1-3 alkyl and phenyl, each of which is 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 they are attached form a cyclopropylidene; R 11 and R 12 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 11 and R 12 wherein not more than one of is methyl; (a)R 13 is hydrogen and C 1-3 alkyl; R 14 and R 15 are each independently hydrogen, halo, or C 1-3 alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halo, provided that R 14 and R 15 wherein not more than one of is methyl; or (b)R 13 and R 14 together form propane-1,3-diyl bridging the nitrogen and carbon atoms to which they are respectively attached; R 15 is hydrogen, halo, and C 1-3 alkyl (unsubstituted or substituted with 1-3 substituents independently selected from halo); however, (i) X is CR 1 where n is 1 and L 6 is -O- and R 7 is methyl and R 8 If is hydrogen, 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) X is CR 1 where n is 1 and L 6 is -O- and R 7 and R 8 are both methyl, and R 1 , R 2 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each hydrogen, R 3 is not Chloro; (iii) X is CR 1 where n is 1 and L 6 is -O- and R 7 is methyl or ethyl, and 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 are each hydrogen, R 9 is not unsubstituted phenyl.

[0087] Compounds of formula 1, including those compounds specifically named in the embodiments (1) through (122) described in the preceding paragraphs and in the Examples, may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, compounds of formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0088] The compounds of formula 1 may form pharma- ceutically acceptable complexes, salts, solvates, and hydrates. These salts include acid addition salts (including diacids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, and non-toxic salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, glucept, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate. Salts include, for example, salts of the following acids: lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0089] Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as alkali or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see S.M. Berge et al., J.Pharm.Sci.(1977)66:1-19. See also Stahl and Wermuth, Handbook of Pharmaceutical Salts:Properties, Selection, and Use(2002).

[0090] 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, a precursor of the compound of formula 1 can be reacted with an acid or base to remove acid- or base-labile protecting groups or to open the lactone or lactam group of the precursor. In addition, the salt of the compound of formula 1 can be converted to another salt (or free form) by treating with an appropriate acid or base or by contacting with an ion exchange resin. After the reaction, the salt can be isolated by filtration if it precipitates from the solution, or by evaporating to recover the salt. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

[0091] Compounds of formula 1 may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term "amorphous" refers to a state in which a substance does not have long-range order at the molecular level and may exhibit the physical properties of a solid or a liquid depending on the temperature. Typically, such substances do not result in a distinctive X-ray diffraction pattern and are more formally described as liquids, although they exhibit the properties of a solid. Upon heating, a change from solid to liquid properties occurs, characterized by a state change, typically of second order ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has an internal structure with regular order at the molecular level, resulting in a distinctive X-ray diffraction pattern with well-defined peaks. Such substances, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, typically of first order ("melting point").

[0092] The compound of formula 1 can exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex that includes a compound and one or more pharma- ceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., DO, acetone-d6, DMSO-d6).

[0093] A currently accepted classification system for solvates and hydrates of organic compounds distinguishes between isolated site, channel, and metal ion coordinated solvates and hydrates. See, for example, KR Morris (HG Brittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site hydrates and solvates are those in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules lie in lattice channels where they are next to other solvent molecules. In metal ion coordinated solvates, the solvent molecules are bonded to the metal ion.

[0094] If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, as in the case of channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will typically be observed.

[0095] The compounds of formula 1 may also exist as multicomponent complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes inclusion complexes (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, but may also be complexes of neutral molecules and salts. Cocrystals can be prepared by melt crystallization, recrystallization from solvents, or by physically grinding the components together. See, for example, O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17: 1889-1896. For a review of multicomponent complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8): 1269-88.

[0096] Compounds of formula 1 may exist in a mesophase (mesophase or liquid crystal) when subjected to appropriate conditions. A mesophase is intermediate between a true crystalline state and a true liquid state (either melted or dissolved). Liquid crystallinity resulting from a change in temperature is described as "thermotropic" and liquid crystallinity resulting from the addition of a second component such as water or another solvent is described as "lyotropic". Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and can be characterized as having polar ionic moieties (e.g., -COO - Na + , -COO - K + , -SO3 - Na + ) or polar non-ionic moiety (-N - N +(CH3)3, etc. See, for example, N. H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

[0097] Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0098] A "prodrug" refers to a compound that has little or no pharmacological activity, but can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared by replacing the appropriate functional group present in a pharmacologically active compound with a "promoiety", for example, as described in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of the compounds of formula 1 that have carboxylic acid, hydroxy, or amino functional groups, respectively. For a detailed discussion of prodrugs, see 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).

[0099] "Metabolite" refers to a compound formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of the compound of formula 1, which have methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amido groups, respectively.

[0100] The compounds of formula 1 may exist as stereoisomers resulting from the presence of one or more asymmetric centers, one or more double bonds, or both.The stereoisomers may be pure, substantially pure, or mixtures.Such stereoisomers may also result from acid addition or base salts in which the counterion is optically active (e.g., when the counterion is D-lactate or L-lysine).

[0101] Compounds of formula 1 can exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0102] Compounds of formula 1 may exhibit more than one type of isomerism.

[0103] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography or fractional crystallization.

[0104] Conventional techniques for preparing or isolating compounds with a particular stereochemical configuration include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example using chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, if the compound of formula 1 contains an acidic or basic moiety, with an acid or base, such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture may be separated by chromatography, fractional crystallization, or the like, and the appropriate diastereoisomer may be converted to a compound with the required stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see EL Eliel and SH Wilen, Stereochemistry of Organic Compounds (1994).

[0105] 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 compounds of formula 1 include, for example, isotopes of hydrogen, e.g., 2 H and 3 H; isotopes of carbon, e.g. 11 C. 13 C, and 14 C; isotopes of nitrogen, e.g. 13 N and 15 N; isotopes of oxygen, e.g. 15 O. 17 O, and 18 O; isotopes of sulfur, e.g. 35 S; isotopes of fluorine, e.g. 18 F; isotopes of chlorine, e.g. 36 Cl; and isotopes of iodine, e.g. 123 I and 125 I. Isotopic variants (e.g., deuterium, 2 The use of H) can provide certain therapeutic advantages (e.g., increased half-life in vivo or reduced dosage requirements) due to increased metabolic stability. In addition, certain isotopic variations of the disclosed compounds can be radioisotopes (e.g., tritium, 3 H, or 14 C) can be incorporated, which can be useful for drug and / or substrate tissue distribution studies. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds can be prepared by processes similar to those described elsewhere in this disclosure using the appropriate isotopically labeled reagent in place of a non-labeled reagent.

[0106] Compounds of formula 1 can be prepared using the techniques described below. Some of the methods and examples may omit details of common reactions, including oxidation, reduction, and the like, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures that are known to those skilled in the art of organic chemistry. Details of such reactions and techniques can be found in several treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series, Compendium of Organic Synthetic Methods (since 1974), edited by Michael B. Smith et al. Starting materials and reagents can be obtained from commercial sources or prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., alcohols from hydrolysis of esters, CO2 from decarboxylation of diacids, and the like). In addition, in some cases, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0107] In the methods and examples that follow, certain compounds can be prepared using protecting groups that prevent undesired chemical reactions outside of the reactive sites. Protecting groups can also be used to enhance the solubility of the compounds or otherwise modify their physical properties. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a summary of useful protecting groups for common functional groups such as amines, carboxylic acids, alcohols, ketones, and aldehydes, see TW Greene and PG Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0108] In general, the chemical transformations described throughout the specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions can benefit from using an excess of one or more reactants. In addition, although many of the reactions disclosed throughout the specification can be carried out at about room temperature (RT) and ambient pressure, some reactions may be carried out at elevated pressures or may use higher (e.g., reflux conditions) or lower temperatures (e.g., −78° C. to 0° C.), depending on reaction kinetics, yields, etc. All references in the present disclosure and claims to stoichiometric ranges, temperature ranges, pH ranges, etc., include the indicated endpoints, whether or not the word “range” is explicitly used.

[0109] Many of the chemical transformations may also employ one or more compatible solvents, which may affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, 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., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexane-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-methoxy ... 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).

[0110] In the following schemes, the substituent identifiers (e.g., L 6 , n, R 2 , R 3 , R 4 , R 5 , R 7 , R8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 ) are as defined above for Formula 1. As noted above, some of the starting materials and intermediates may contain protecting groups, which are removed prior to the final product. In such cases, the substituent identifiers refer to the moieties as defined in Formula 1 and those moieties that have the appropriate protecting groups. For example, a starting material or intermediate in a synthetic method may contain a potentially reactive (secondary) amine. In such cases, the amine will include the moiety with or without a group attached to the amine, e.g., a Boc or Cbz group.

[0111] Scheme A shows a general method for preparing compounds of formula 1. According to this 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., lithium salt). This reaction is carried out using a standard amide coupling agent, such as HATU, DCC, EDC hydrochloride, T3P, or 2-chloro-1-methylpyridin-1-ium iodide, in the presence of a non-nucleophilic base (e.g., Et3N, DIPEA) and one or more compatible solvents (e.g., ACN, DCM, DMA, DMF, NMP, pyridine, THF). This amide coupling can be carried out at temperatures ranging from room temperature to about 80° C. HOBt may be used to facilitate the reaction.

[0112] [ka]

[0113] Although not shown in Scheme A, the starting material may contain a protected (e.g., Boc-substituted) secondary amine. In such a case, the amine may be deprotected (e.g., by acid treatment) following amide coupling to reveal the secondary amine. This can be accomplished, for example, by deprotection with a non-nucleophilic base (e.g., KCO 3 ) and a compatible solvent (e.g., DMSO) in the presence of an alkyl halide (e.g., R 13 Y 1 , where R 13 =C 1-3 Alternatively, secondary amines can be reacted with the appropriate alkyl aldehyde under acidic conditions in the presence of a mild reducing agent such as sodium cyanoborohydride or sodium acetoxyborohydride and a compatible solvent (e.g., MeOH, DCM) to give the required R 13 The N-alkylation and reductive amination steps may be carried out at room temperature or above.

[0114] The methods depicted in the schemes can be modified as desired. For example, protecting groups can be added or removed, and the products can be further elaborated, for example, by alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, etc., to obtain the desired final product. Additionally, any intermediates or final products that contain a mixture of stereoisomers can optionally be purified by chiral column chromatography (e.g., supercritical fluid chromatography) as described above, or derivatization with optically pure reagents to obtain the desired stereoisomer.

[0115] Compounds of formula 1, including those named above, and their pharma- ceutically acceptable complexes, salts, solvates and hydrates, should be evaluated for biopharmaceutical properties, such as solubility and solution stability over pH, permeability, etc., in order to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0116] The compounds of formula 1 can be administered alone or in combination with each other, or in combination with one or more pharmacologically active compounds different from the compounds of formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharma- ceutical acceptable excipients. The choice of excipient depends, inter alia, on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and their preparation methods can be found, for example, in AR Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0117] The compound of formula 1 can be orally administered. Oral administration can include swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively, or in addition, oral administration can include mucosal administration (e.g., buccal, sublingual, supragingual administration), in which the compound enters the bloodstream through the oral mucosa.

[0118] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, such as tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquids, or powders; lozenges (may be filled with liquid); chewables; gels; fast dispersing dosage forms; films; vaginal suppositories; sprays; and buccal / mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules (e.g., those made from gelatin or hydroxypropylmethylcellulose), and typically include a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils) and one or more emulsifiers, suspending agents, or both. Liquid formulations may also be prepared by the reconstitution of a solid (e.g., from a sachet).

[0119] 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.

[0120] 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, tablets may contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorings, preservatives, and taste masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 Examples include alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants will comprise from about 1 wt% to about 25 wt%, or from about 5 wt% to about 20 wt% of the dosage form.

[0121] Binders are generally used to provide cohesion to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0122] The tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. If present, the surfactants may comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0123] The tablet may also contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricant may comprise from about 0.25 wt% to about 10 wt%, or from about 0.5 wt% to about 3 wt% of the tablet.

[0124] Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends or portions of the blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded prior to tableting. If desired, one or more of the components may be sized by sieving or milling, or both, prior to blending. The final dosage form may include one or more layers, may be coated or uncoated, or may be encapsulated. An exemplary tablet may contain up to about 80 wt% API, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant. For a discussion of blending, granulating, milling, sieving, tabletting, coating, and descriptions of alternative techniques for preparing drug products, see A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H. A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2d ed., 1990); and D. K. Parikh & C. K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0125] Consumable oral films for human or animal use are flexible water-soluble or water-swellable thin film dosage forms that can be fast-dissolving or mucoadhesive. In addition to the API, typical films contain one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients can include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), softeners, bulking agents, antifoaming agents, surfactants, and flavor masking agents. Some ingredients of the formulation can perform more than one function.

[0126] In addition to dosage requirements, the amount of API in the film may depend on its solubility. If water soluble, the API will typically comprise about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film, or about 20 wt% to about 50 wt% of the solutes in the film. Less soluble APIs may comprise a larger percentage of the composition, typically up to about 88 wt% of the non-solvent components in the film.

[0127] 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.

[0128] Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating and drying apparatus), in a freeze-drying machine, or in a vacuum oven.

[0129] Solid formulations useful for oral administration can include immediate release formulations and modified release formulations. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. For a general description of suitable modified release formulations, see U.S. Patent No. 6,106,864. For details of other useful release technologies, such as high energy dispersions and osmotic and coated particles, see Verma et al, Pharmaceutical Technology On-line (2001) 25(2):1-14.

[0130] Compound of formula 1 may also be directly administered into the bloodstream, muscle or internal organs of subject.The techniques suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.The devices suitable for parenteral administration include needle (including microneedle) injector, needleless injector and infusion device.

[0131] Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., pH of about 3 to about 9). However, for some applications, the compounds of formula 1 may be more suitably formulated as sterile nonaqueous solutions or as a dry form for use with a suitable vehicle, such as sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques.

[0132] The solubility of the compounds used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration may be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compound of formula 1 can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents, and semi-solids and suspensions that contain drug-loaded poly(DL-lactic-co-glycolic acid) (PGLA) microspheres.

[0133] The compound of formula 1 may also be administered topically, intradermally, or transdermally to skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J.Pharm.Sci.88(10):955-958(1999).

[0134] Other means of local administration include delivery by electroporation, iontophoresis, sonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject™ and Bioject™) injection. Formulations for topical administration may be formulated to be immediate or modified release, as described above.

[0135] The compound of formula 1 can also be administered intranasally or by inhalation, typically in the form of dry powder, aerosol spray, or nasal drops.An inhaler can be used to administer dry powder, which includes API only, a powder blend of API and diluent such as lactose, or mixed component particles including API and phospholipid such as phosphatidylcholine.When used intranasally, the powder can also include a bioadhesive agent, such as chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate an aerosol spray from a solution or suspension that contains the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH with or without water), one or more solvents that function as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Atomizers that use electrohydrodynamics to generate a fine mist may also be used.

[0136] Prior to use in a dry powder or suspension formulation, the drug product is usually milled to a particle size suitable for delivery by inhalation (typically 90% of the particles by volume have a maximum dimension less than 5 microns). This can be accomplished by any suitable size reduction method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0137] Capsules, blisters, and cartridges (made, for example, from 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. The lactose may be anhydrous or monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0138] A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to generate a fine mist may contain about 1 μg to about 20 mg of API per actuation, and actuation volumes may vary from about 1 μL to about 100 μL. A typical formulation may include one or more compounds of formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0139] Formulations for inhaled or intranasal administration, or both, may be formulated to be immediate or modified release, for example using PGLA. Suitable flavours, such as menthol and levomenthol, or suitable sweeteners, such as saccharin or saccharin sodium, may be added to such formulations intended for inhaled / intranasal administration.

[0140] For dry powder inhalers and aerosols, the dosage unit is determined by utilizing a valve that delivers a metered amount. The unit is typically designed to administer a metered dose or "puff" containing about 10 μg to about 1000 μg of API. The total daily dose typically ranges from about 100 μg to about 10 mg, which may be administered in a single dose or, more usually, in divided doses throughout the day.

[0141] The active compound may be administered rectally or vaginally, for example, in the form of suppository, pessary or enema.Cocoa butter is a conventional suppository base, but various alternatives may be used where appropriate.The preparation for rectal or vaginal administration may be formulated to be immediate release or modified release as described above.

[0142] The compound of formula 1 may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in a pH-adjusted, isotonic, sterile saline solution. Other formulations suitable for administration to the eye and ear include ointments, gels, biodegradable implants (e.g., absorbent gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes. The formulation may include one or more polymers and preservatives, such as benzalkonium chloride. Exemplary polymers include crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gellan gum). Such formulations may also be delivered by iontophoresis. Formulations for administration to the eye or ear may be formulated to be immediate release or modified release, as described above.

[0143] The compounds of formula 1 may be combined with soluble macromolecular entities, such as cyclodextrin and its derivatives, and polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability, or stability. For example, API-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, cyclodextrins may be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. Alpha-, beta-, and gamma-cyclodextrins are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0144] As mentioned above, one or more compounds of formula 1, including those specifically named above, and pharma- cetically active complexes, salts, solvates, and hydrates thereof, can be combined with each other or with one or more other active pharma- cetically active compounds to treat various diseases, conditions, and disorders. In such cases, the active compounds may be combined in a single dosage form as described above, or provided in the form of a kit suitable for simultaneous administration of the compositions. The kit includes (1) two or more different pharmaceutical compositions, at least one of which contains a compound of formula 1, and (2) a device (e.g., a divided bottle or a divided foil packet) for separately holding the two pharmaceutical compositions. An example of such a kit is a common blister pack used to package tablets and capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral), or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating different pharmaceutical compositions relative to each other. To aid in patient compliance, the kit typically includes instructions for administration and may provide a memory aid.

[0145] When administered to a human patient, the total daily dose of the claimed and disclosed compounds typically ranges from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require only a total daily dose of about 0.1 mg to about 300 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside the typical ranges given above. These dosages are based on an average human subject weighing about 60 kg to about 70 kg, although a physician would be able to determine the appropriate dose for patients (e.g., infants) whose weight falls outside this weight range.

[0146] As mentioned above, the compounds of formula 1 can be used to treat diseases, disorders, and conditions for which activation of SSTR4 is indicated. Such diseases, disorders, and conditions generally relate to any unhealthy or abnormal occurrence in a subject for which activation of SSTR4 provides therapeutic benefit. More specifically, the compounds of formula 1 can be used to treat diseases, disorders, or conditions of the CNS, including Alzheimer's disease and other forms of dementia (i.e., severe or mild neurocognitive disorders) associated with one or more medical conditions, such as frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or 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 and treat epilepsy. The compounds of formula 1 can also be used to treat pain.

[0147] The claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases or conditions for which SSTR4 is indicated. Such combinations may provide significant therapeutic benefits, including reduced side effects, improved therapeutic potential for underserved patient populations, or synergistic activity. For example, the compounds of formula 1, including those specifically named above, and their pharmacologic acceptable complexes, salts, solvates and hydrates may be administered simultaneously, sequentially, or separately in combination with one or more compounds or therapies for treating Alzheimer's disease. Such compounds or therapies include beta secretase inhibitors, gamma secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., apazone, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, sodium meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylates, 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.

[0148] In addition to drugs used to improve cognition, the compounds of formula 1 may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications used to treat Alzheimer's disease. For example, the compounds of formula 1 may be combined with one or more drugs (antidepressants and / or atypical or typical antipsychotics) for treating depression and / or schizophrenia, including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine ... Examples of such antidepressants include phenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and ziprasidone.

[0149] Similarly, the compounds of formula 1 may be combined with one or more agents for treating anxiety (antianxiety drugs), including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone.

[0150] The compounds of formula 1 may also be combined with one or more agents for treating epilepsy (antiepileptic or anticonvulsant drugs), including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0151] biological activity

[0152] The biological activity of the compounds of formula 1 with respect to SSTR4 can be determined using the following in vitro and in vivo methods.

[0153] Inhibition of forskolin-stimulated cAMP in cells overexpressing SSTR4

[0154] This cell-based assay measures the ability of compounds to inhibit forskolin-stimulated cAMP in CHO-K1 cells overexpressing SSTR4. CHO-K1 cells overexpressing SSTR4 (CHO-SSTR4) are purchased from DiscoveRx (product code 95-0059C2). CHO-SSTR4 cells are maintained in F12K medium with 10% fetal bovine serum (Hyclone), 1% Pen / Strep (Life Technologies), and 800 μg / mL G418 (Life Technologies). To perform the assay, 3000 cells per well are plated in 50 μL of complete medium in a white 384-well plate (Corning 3570) and the cells are allowed to attach for 16 hours in a 37° C., 5% CO2 incubator. The next day, the medium is removed from the cells and the cells are washed (added and then removed) with Krebs-Ringer buffer (ZenBio, KRB-1000 mL). Test compounds are suspended in DMSO and diluted in stimulation buffer (Krebs-Ringer buffer + 0.5% BSA (Roche), 300 μM IBMX (Sigma), and 350 nM Forskolin (Sigma)). Cells are incubated in 10 μL of compound / stimulation buffer for 30 minutes at room temperature. Cellular cAMP levels are detected with the HTRF LANCE Ultra cAMP kit (Perkin Elmer, Cat. No. TRF0264).

[0155] The assay is performed according to the manufacturer's instructions. 5 μL of diluted Eu-W8044 labeled streptavidin (dilution: 1:50 in cAMP detection buffer) is added to each well. Then 5 μL of diluted biotin cAMP (dilution: 1:150 in cAMP detection buffer) is added to each well. The plate is covered and incubated at room temperature for 60 minutes on a shaker. HTRF (665 nm / 615 nm) is read on a Perkin Elmer ENVISION plate reader. pEC 50 Values ​​are generated using Screening Data Management's Activity Base.

[0156] SSTR4 I-125 somatostatin competitive binding assay

[0157] This membrane-based assay measures the ability of compounds to competitively inhibit the binding of I-125 labeled somatostatin to SSTR4 in membranes from CHO-K1 cells overexpressing SSTR4. Membranes from CHO-K1 cells overexpressing SSTR4 are purchased from Perkin Elmer (catalog number ES-524-M400UA). Test compounds are suspended in DMSO and then diluted in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM CaCl2, 0.5% BSA) + 0.2 nM I-125 labeled somatostatin (Perkin Elmer catalog number NEX389). 50 μL of assay buffer containing compound / I-125 somatostatin is added per well to a 96-well polypropylene plate. 50 μL of assay buffer containing 1 μg SSTR4 membrane is then added per well. The plate is incubated at room temperature for 60 minutes. FilterMat A filters (Perkin Elmer Catalog No. 1450-421) are presoaked in 0.5% PEI (Sigma Catalog No. P3143). The contents of the assay plate are transferred to the filters with a TomTech harvester and washed five times with 20 mM HEPES, 100 mM NaCl. The filters are dried in a microwave oven and then transferred to a sample bag containing a scintillator sheet (Perkin Elmer Catalog No. 1450-441). A heat block is used to fuse the scintillator sheet to the filter. The filters are then read in a MicroBeta scintillation counter. Binding Ki curves are generated using Activity Base in Screening Data Management and results are expressed as pIC 50 Report as.

[0158] SSTR1 I-125 somatostatin competitive binding assay for selectivity against SSTR1

[0159] This membrane-based assay measures the ability of compounds to competitively inhibit the binding of I-125 labeled somatostatin to SSTR1 in membranes from CHO-K1 cells overexpressing SSTR1. Membranes from CHO-K1 cells overexpressing SSTR1 are purchased from Perkin Elmer (catalog number ES-520-M400UA). Test compounds are suspended in DMSO and then diluted in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, 1 mM CaCl2, 0.5% BSA) + 0.4 nM I-125 labeled somatostatin (Perkin Elmer catalog number NEX389). 50 μL of assay buffer containing compound / I-125 somatostatin is added per well to a 96-well polypropylene plate. 50 μL of assay buffer containing 10 μg SSTR1 membranes is then added per well. The plate is incubated at room temperature for 60 minutes. FilterMat A filters (Perkin Elmer Catalog No. 1450-421) are presoaked in 0.5% PEI (Sigma Catalog No. P3143). The contents of the assay plate are transferred to the filters with a TomTech harvester and washed five times with 20 mM HEPES, 100 mM NaCl. The filters are dried in a microwave oven and then transferred to a sample bag containing a scintillator sheet (Perkin Elmer Catalog No. 1450-441). A heat block is used to fuse the scintillator sheet to the filter. The filters are then read in a MicroBeta scintillation counter. Binding Ki curves are generated using Activity Base in Screening Data Management and results are expressed as pIC 50 Report as.

[0160] The following in vitro assay can be used to assess the ability of compounds of formula 1 to cross the blood-brain barrier and enter the CNS.

[0161] LLC-PK1 assay (reported as apparent permeability and efflux ratio)

[0162] Lilly Laboratories & Company porcine kidney cells (LLC-PK1) are transfected with multidrug resistance protein 1 (MDR1) and maintained in Gibco Media 199 (Fisher Scientific catalogue no. 11150067) according to the supplier's instructions. Medium 199 is supplemented with 10% heat-inactivated fetal bovine serum (Gibco catalogue no. 16000-044), 0.5 mg / mL Geneticin (Gibco no. 10131035) and 200 nM colchicine (an inducer of P-gp, Sigma catalogue no. C9754). Cells are plated at 6.25 x 10 per well on the apical side of HTS-Transwell-96 plates (0.4 μm pore size, Corning catalogue no. 3381) with 75 μL and 250 μL of Media 199 in the apical and basolateral wells, respectively. 3Cells are seeded at a density of 100x and incubated at 37°C / 5% CO2. Fresh Medium 199 medium in the apical and basolateral compartments is replaced after 72 hours and cells are allowed to grow into a monolayer for 144 hours before experimental incubation begins. Incubations are performed in Media 199 (Fisher Scientific Catalog No. 11150067) containing 1% bovine serum albumin (Sigma, Catalog No. A9418) and 10 mM HEPES (Fisher Scientific, Catalog No. 15630080) at pH 7.4. Media 199 is removed and cells are rinsed with warm (37°C) Media 199. Media 199 containing test compound at a substrate concentration of 1 μM (0.1% v / v DMSO) is added to either the apical or basolateral compartment (75 μL or 250 μL, respectively), and blank Media 199 is added in single samples to compartments lacking test compound. Cells are incubated for 120 min at 37 °C / 5% CO2. At the end of the incubation period, 50 μL samples are removed from each receiver compartment and diluted with 100 μL acetonitrile (Fisher Scientific, Cat. No. A996SK4) + 100 ng / mL diclofenac (internal standard, Sigma No. 15307-79-6). Samples are centrifuged at 2000 RCF for 10 min at 4 °C, after which 75 μL of the supernatant is transferred to a new microplate and diluted with 75 μL HPLC grade water (Fisher Scientific, Cat. No. W64). Samples are analyzed using multiple reaction monitoring on an ABSciex triple quadrupole mass spectrometer coupled to a high performance liquid chromatography pump instrument optimized for detection of analytes through a Kinetix 2.1×50 mm C18 100 Å column (Phenomenex, catalog no. 00B-4605-AN).

[0163] Apparent Permeability (P app ) values ​​and emission ratios are calculated using the following formulas:

[0164]

number

[0165] In the formula, P appA-B is the apparent permeability from the apical well to the basolateral well, and P appB-A is the apparent permeability from the basolateral well to the apical well, and Conc BL is the basolateral well concentration, Conc AP is the apical well concentration and A is the well surface area (cm 2 ) and in the above assay, 0.143 cm 2 where t is the incubation time (sec), which is 7200 sec in the above assay, and ER is the efflux rate by P-gp. EXAMPLES

[0166] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present invention.

[0167] For many of the compounds in the examples below, 1 H nuclear magnetic resonance (NMR) spectra were obtained. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane using conventional abbreviations for major peak designations, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethylsulfoxide), CD3OD (deuterated methanol), CD3CN (deuterated acetonitrile), and THF-d8 (deuterated tetrahydrofuran). Mass spectra ([M+H] + The m / z for were recorded using either electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0168] Where indicated, the products of certain preparations and examples are purified by mass-triggered HPLC, flash chromatography, preparative TLC or SFC. Reverse phase chromatography is typically performed on a column (e.g., Phenomenex Gemini® NX-C18, 5 μm, 30 mm×100 mm ID) under acidic conditions ("acid mode"), eluting with a mobile phase of ACN and water (containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively), or under basic conditions ("basic mode"), eluting with a mobile phase of water and 20 / 80 (v / v) water / acetonitrile (both containing 10 mM NH4HCO3 (pH 9.5-10). Preparative TLC is typically performed on silica gel 60F. 254 The reaction is carried out on a plate. Preparations and examples may use SFC to separate the enantiomers. After chromatographic separation, the product is obtained by removing the solvent and drying in a centrifugal evaporator (e.g., GeneVac™), a rotary evaporator, a vacuum flask, or the like. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H2) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0169] Preparation 1: 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid

[0170] [ka]

[0171] Step A: Methyl 4-bromo-2-(2-bromophenoxy)butanoate

[0172] [ka]

[0173] A mixture of 2-bromophenol (5.00 g, 28.9 mmol), methyl 2,4-dibromobutanoate (9.01 g, 34.7 mmol), and K2CO3 (7.99 g, 57.8 mmol) in DMF (100 mL) was degassed and purged with nitrogen (three times), then stirred under nitrogen atmosphere at 20 °C for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 10:1) to give the title compound as a colorless oil (8.3 g, 82%). 1 H NMR (400 MHz, CDCl3) δ ppm 2.43 - 2.52 (m, 1 H), 2.56 - 2.65 (m, 1 H), 3.62 - 3.70 (m, 1 H), 3.70 - 3.76 (m, 1 H), 3.78 (s, 3 H), 4.89 (dd, J = 9.0, 3.7 Hz, 1 H), 6.79 (dd, J = 8.3, 1.2 Hz, 1 H), 6.89 (td, J = 7.6, 1.3 Hz, 1 H), 7.21 - 7.26 (m, 1 H), 7.24 (dd, J = 7.8, 1.2 Hz, 1 H), 7.22 - 7.26 (m, 1 H), 7.22 - 7.26 (m, 1 H), 7.55 (dd, J = 8.0, 1.6 Hz, 1 H).

[0174] Step B: Methyl 1-(2-bromophenoxy)cyclopropane-1-carboxylate

[0175] [ka]

[0176] To a solution of methyl 4-bromo-2-(2-bromophenoxy)butanoate (8.3 g, 23.6 mmol) in THF (120 mL) was added LiHMDS (1 M in THF, 52 mL, 52 mmol) at -78 °C. The reaction mixture was stirred under nitrogen at -78 °C for 2 h, then poured into aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 10:1) to give the title compound as a colorless oil (5.05 g, 79%). 1 H NMR (400 MHz, CDCl3) δ ppm 1.36 - 1.41 (m, 2 H), 1.63 - 1.69 (m, 2 H), 3.73 (s, 3 H), 6.84 - 6.90 (m, 1 H), 6.95 (dd, J = 8.3, 1.0 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.53 (dd, J = 7.9, 1.4 Hz, 1 H).

[0177] Step C: Methyl 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylate

[0178] [ka]

[0179] A mixture of methyl 1-(2-bromophenoxy)cyclopropane-1-carboxylate (0.500 g, 1.84 mmol), cyclopropylboronic acid (238 mg, 2.77 mmol), Pd(OAc)2 (41.4 mg, 184 μmol), PCy3 (51.7 mg, 184 μmol) and K3PO4 (1.37 g, 6.46 mmol) in toluene (10 mL) and water (0.5 mL) was degassed and purged with nitrogen (3 times) and then stirred at 100 °C under nitrogen atmosphere for 12 h. The reaction mixture was poured into aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using a petroleum ether / EtOAc gradient (1:0 to 20:1) to afford the title compound as a pale yellow oil (400 mg, 84% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.59 - 0.66 (m, 2 H), 0.87 - 0.94 (m, 2 H), 1.30 - 1.37 (m, 2 H), 1.60 - 1.67 (m, 2 H), 2.07 - 2.18 (m, 1 H), 3.74 (s, 3 H), 6.81 - 6.95 (m, 3 H), 7.03 - 7.11 (m, 1 H);ESI-MS m / z [M+H] + 233.2.

[0180] Step D: 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid

[0181] To a solution of methyl 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylate (400 mg, 1.55 mmol) in THF (5 mL) was added aqueous LiOH.H2O (1.5 M, 3.15 mL, 4.72 mmol). The mixture was stirred at 20° C. for 12 h, then diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The aqueous layer was acidified to pH 4 with 2 M HCl, then extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under reduced pressure to give the title compound as a pale yellow solid (230.2 mg, 65% yield, 95% purity).1 H NMR (400 MHz, CDCl3) δ ppm 0.60 - 0.67 (m, 2 H), 0.87 - 0.93 (m, 2 H), 1.38 - 1.45 (m, 2 H), 1.67 - 1.75 (m, 2 H), 2.06 - 2.16 (m, 1 H), 6.82 - 6.87 (m, 1 H), 6.88 - 6.97 (m, 2 H), 7.05 - 7.13 (m, 1 H);ESI-MS m / z [M+H] + 219.1.

[0182] Preparation 2: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylic acid

[0183] [ka]

[0184] Step A: Methyl 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylate

[0185] [ka]

[0186] In a 40 mL vial, 6-chloro-N-methylpyridin-2-amine (0.100 g, 0.701 mmol) was dissolved in DMF (3 mL) to give a colorless solution. Sodium hydride (60 wt%, 0.042 g, 1.052 mmol) was added, followed by methyl 1-(bromomethyl)cyclopropane-1-carboxylate (0.162 g, 0.841 mmol). The mixture was stirred at room temperature overnight, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a brown syrup (0.179 g). ESI-MS m / z [M+H] + 255.1.

[0187] Step B: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxylic acid

[0188] 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 mixed with aqueous lithium hydroxide (2 M, 1.40 mL, 2.80 mmol) in dioxane (4 mL) to give a colorless solution. The mixture was stirred at room temperature overnight, then acidified to pH 5 with aqueous HCl and extracted with EtOAc. The organic extract was dried over MgSO4 and concentrated in vacuo to give the title compound as a light brown syrup (0.118 g, 70%). ESI-MS m / z [M+H] + 241.1.

[0189] Preparation 3: 2-(2-cyclopropylphenoxy)propanoic acid

[0190] [ka]

[0191] Step A: Methyl 2-(2-cyclopropylphenoxy)propanoate

[0192] [ka]

[0193] In a 100 mL round bottom flask, 2-cyclopropylphenol (0.200 g, 1.491 mmol) and potassium carbonate (0.618 g, 4.47 mmol) were mixed in DMF (8 mL) to give a white suspension. Methyl 2-chloropropanoate (0.219 g, 1.789 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by automated flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 0-20% EtOAc in heptane. The product-containing fractions were combined and concentrated to give the title compound as a colorless oil (307 mg, 94%).

[0194] Step B: 2-(2-cyclopropylphenoxy)propanoic acid

[0195] In a 125 mL pear-shaped flask, methyl 2-(2-cyclopropylphenoxy)propanoate (0.307 g, 1.394 mmol) and aqueous lithium hydroxide (2 M, 2.79 mL, 5.58 mmol) were mixed in dioxane (8 mL) to give a colorless solution. The reaction mixture was stirred at room temperature overnight, 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 as a white solid (218 mg, 76%). ESI-MS m / z [M-CO2H] + 161.2.

[0196] Preparation 4: 1-(2-chlorophenoxy)cyclopropane-1-carboxylic acid

[0197] [ka]

[0198] 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 (2 M, 8.82 mL, 17.65 mmol) was added. The mixture was stirred at room temperature for 4 h, 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 as a white solid (0.66 g, 70%). ESI-MS m / z [M-CO2H] + 166.9.

[0199] Preparation 5: (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate tert-butyl

[0200] [ka]

[0201] Step A: tert-Butyl (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate (2S,3S)-2,3-bis(benzoyloxy)succinic acid

[0202] [ka]

[0203] To a solution of tert-butyl trans-4-amino-3-methylpiperidine-1-carboxylate (120 g, 560 mmol) in MeOH (1200 mL) at room temperature was added dibenzoyl-D-tartaric acid (201 g, 560 mmol) in MeOH (600 mL). The addition was exothermic (22° C. to 29° C.). Seed crystals (ca. 1 mg) were added and the mixture was stirred at room temperature overnight. The resulting slurry was filtered, washed with MeOH (360 mL, displacement wash) and then sucked dry 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 with increasing ee (73.6 g, 98.4% ee). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (d, J = 6.5 Hz, 3 H), 1.20 - 1.57 (m, 11 H), 1.86 (br dd, J = 12.8, 3.3 Hz, 1 H), 2.23 - 2.48 (m, 1 H), 2.55 - 2.56 (m, 1 H), 2.78 (br d, J = 3.8 Hz, 2 H), 3.66 - 3.95 (m, 2 H), 5.65 (s, 2 H), 7.40 - 7.56 (m, 4 H), 7.58 - 7.69 (m, 2 H), 7.95 (d, J = 7.5Hz, 4H).

[0204] Step B: (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate

[0205] A 2 L flask was charged with tert-butyl (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate (2S,3S)-2,3-bis(benzoyloxy)succinic acid (71.0 g, 124 mmol) and DCM (1000 mL) to give a white suspension. Aqueous Na2CO3 (2 M, 1000 mL) was then added to the suspension with stirring over 1 min to give two colorless phases. The two phases were stirred at room temperature for 5 min before being transferred to a 4 L separatory funnel, shaken vigorously and separated. Additional H2O (500 mL) was added to the aqueous phase to solubilize the salts. The aqueous phase was washed with DCM (2 x 500 mL) and the organic extracts were combined, dried over Na2SO4 (430 g), filtered, rinsed with DCM and dried on a rotary evaporator at 30 °C. The oil was dissolved in acetonitrile (150 mL), concentrated by rotary evaporation, and dried in vacuum on a rotary evaporator at 30° C. to give the title compound as a colorless oil (26.6 g, quantitative). 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (d, J = 6.5 Hz, 3 H), 1.19 - 1.35 (m, 2 H), 1.45 (s, 9 H), 1.75 - 1.83 (m, 1 H), 2.32 - 2.53 (m, 2 H), 2.80 (br t, J = 12.0 Hz, 1 H), 3.89 - 3.98 (m, 1 H), 4.04 (ddt, J = 13.5, 4.6, 2.4 Hz, 1 H);ESI-MS m / z [M+Na] + 237.2.

[0206] Preparation 6: 2,2-Difluoro-3-phenylpropanoic acid

[0207] [ka]

[0208] A solution of (bromomethyl)benzene (324 μL, 2.73 mmol), ethyl 2,2-difluoro-2-iodoacetate (568 mg, 2.27 mmol) and copper (375 mg, 5.91 mmol) in DMSO (5.98 mL) was stirred overnight on a hot plate at 60° C. The reaction mixture was then filtered under vacuum and extracted with diethyl ether (2×). The combined extracts were concentrated in vacuo, dissolved in MeOH (4.5 mL), treated with aqueous lithium hydroxide (3 M, 2.27 mL, 6.82 mmol) and stirred overnight at room temperature. The reaction mixture was acidified to pH 4 by dropwise addition of 1N HCl and then extracted with EtOAc (1×) and DCM (2×). The organic layers were combined, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the crude title compound (139 mg, 33%).

[0209] Preparation 7: 2,2-Difluoro-2-phenoxyacetic acid

[0210] [ka]

[0211] To a solution of phenol (1.39 g, 14.8 mmol) in dioxane (24.6 mL) was added sodium hydride (60 wt%, 0.59 g, 14.8 mmol) in portions at room temperature. The solution was stirred vigorously for 30 min. Sodium 2-chloro-2,2-difluoroacetate (1.50 g, 9.84 mmol) was then added in one portion at room temperature. The reaction mixture was stirred on a 110° C. hotplate for 16 h, then cooled to room temperature, quenched with water, and acidified to pH 1 by dropwise addition of 1N HCl. The solution was extracted with ether (1×50 mL) and EtOAc (2×75 mL). The organic layers were combined, concentrated under reduced pressure, and purified by automated flash silica column chromatography (ISCO, 24 g RediSep Rf Gold® column) using 30% EtOAc in heptane. The title compound was obtained as an orange-brown liquid (1.25 g, 68%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.24 - 7.29 (m, 2 H), 7.31 (dt, J = 7.4, 1.6 Hz, 1 H), 7.38 - 7.44 (m, 2 H), 9.48 (br s, 1 H); 19 F NMR (376 MHz, CDCl3) δ ppm -76.55 (s, 2 F).

[0212] Preparation 8: 2-(2-cyanophenoxy)-2,2-difluoroacetic acid

[0213] [ka]

[0214] Step A: Ethyl 2-(2-cyanophenoxy)-2,2-difluoroacetate

[0215] [ka]

[0216] To a suspension of sodium hydride (60 wt%, 0.739 g, 18.5 mmol) in DMA (42.0 mL) was added 2-hydroxybenzonitrile (2.00 g, 16.8 mmol) in portions at room temperature. The reaction mixture was stirred for 10 min. Ethyl 2-bromo-2,2-difluoroacetate (2.69 mL, 21.0 mmol) was added dropwise via syringe at room temperature. The brown reaction mixture was stirred on a 100° C. hotplate for 48 h 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 automated flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column, dry loading) using 15% EtOAc in heptane followed by a gradient of 30-100% EtOAc in heptane. The product-containing fractions were combined, concentrated under reduced pressure and further purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). The title compound was obtained as an orange oil (307 mg, 7.6%). 1 H NMR (400 MHz, CDCl3) δ ppm 1.41 (t, J = 7.2 Hz, 3 H), 4.44 (q, J = 7.2 Hz, 2 H), 7.38 (td, J = 7.6, 1.0 Hz, 1 H), 7.43 - 7.47 (m, 1 H), 7.59 - 7.67 (m, 1 H), 7.71 (dd, J = 7.8, 1.8 Hz, 1 H); 19 F NMR (376 MHz, CDCl3) δ ppm -76.61 (s, 2 F).

[0217] Step B: 2-(2-cyanophenoxy)-2,2-difluoroacetic acid

[0218] A solution of ethyl 2-(2-cyanophenoxy)-2,2-difluoroacetate (307 mg, 1.28 mmol) in THF (4.26 mL) was treated with aqueous LiOH (3 M, 1.28 mL, 3.83 mmol) at room temperature. The resulting pale yellow mixture was stirred at room temperature overnight and then acidified to pH 1 by dropwise addition of 1N HCl (10 mL). The solution was transferred to a separatory funnel and extracted with diethyl ether (1×50 mL) and EtOAc (2×50 mL). The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The product was purified by automated flash silica column chromatography (ISCO, 12 g RediSep Rf Gold® column, dry loading) using a gradient of 0-100% EtOAc in heptane to give the title compound as an orange-brown oil (203 mg, 75%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 (br s, 1 H), 7.37 - 7.42 (m, 1 H), 7.43 - 7.51 (m, 1 H), 7.62 - 7.69 (m, 1 H), 7.72 (ddd, J = 7.8, 3.0, 1.5 Hz, 1H).

[0219] Preparation 9: 2-(2-chlorophenoxy)-2,2-difluoroacetic acid

[0220] [ka]

[0221] To a solution of 2-chlorophenol (1.08 g, 8.38 mmol) in dioxane (30.5 mL) was added sodium hydride (0.457 g, 11.4 mmol) at ambient temperature. The solution was stirred for 30 min. Sodium 2-bromo-2,2-difluoroacetate (1.50 g, 7.62 mmol) was added in one portion at ambient temperature. Once bubbling subsided, the reaction mixture was stirred on a 105° C. hotplate for 16 h. The reaction mixture was cooled to ambient temperature, quenched with water (30 mL), acidified to pH 1 by dropwise addition of 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 automated flash silica column chromatography (ISCO, 120 g RediSep Rf Gold® column) using a gradient of 10 to 100% EtOAc in heptane to afford the title compound as a yellow oil (1.03 g, 61%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.33 - 7.39 (m, 1 H) 7.39 - 7.46 (m, 2 H), 7.62 (dt, J = 7.6, 0.9 Hz, 1 H).

[0222] Preparation 10: 2-(3-chlorophenoxy)-2,2-difluoroacetic acid

[0223] [ka]

[0224] To a solution of 3-chlorophenol (1.077 g, 8.38 mmol) in dioxane (30.5 mL) was added sodium hydride (0.457 g, 11.4 mmol) at ambient temperature. The solution was stirred for 30 min. Sodium 2-bromo-2,2-difluoroacetate (1.50 g, 7.62 mmol) was added in one portion. Once bubbling had subsided, the reaction mixture was heated at 105° C. for 7 h, then cooled to ambient temperature, quenched with water (30 mL), acidified to pH 1 by dropwise addition of 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 automated flash silica column chromatography (ISCO, 120 g RediSep Rf Gold® column) using a gradient of 10-80% EtOAc in heptane to afford the title compound as a brown oil (0.958 g, 56%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.21 - 7.26 (m, 1 H), 7.33 (t, J = 2.0 Hz, 1 H), 7.41 (ddd, J = 8.0, 1.9, 1.0 Hz, 1 H), 7.49 (t, J = 8.4 Hz, 1 H).

[0225] Preparation 11: 2-(4-chlorophenoxy)-2,2-difluoroacetic acid

[0226] [ka]

[0227] To a solution of 4-chlorophenol (1.08 g, 8.38 mmol) in dioxane (30.5 mL) was added sodium hydride (0.457 g, 11.4 mmol) at ambient temperature. The solution was stirred for 30 min. Sodium 2-bromo-2,2-difluoroacetate (1.50 g, 7.62 mmol) was added in one portion. The reaction mixture was stirred at 105° C. for 7 h, then cooled to ambient temperature, quenched with water (30 mL), acidified to pH 1 by dropwise addition of 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 automated flash silica column chromatography (ISCO, 120 g RediSep Rf Gold® column) using a gradient of 10-80% EtOAc in heptane to afford the title compound as a yellow oil (0.665 g, 39%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H).

[0228] Preparation 12: 2,2-Difluoro-2-(p-tolyloxy)acetic acid

[0229] [ka]

[0230] To a solution of sodium hydride (60 wt%, 0.493 g, 12.3 mmol) in dioxane (6.16 mL) was added p-cresol (0.500 g, 4.62 mmol) portionwise at room temperature. The solution was stirred for 15 min. Sodium 2-bromo-2,2-difluoroacetate (0.607 g, 3.08 mmol) was added portionwise at room temperature. After the bubbling subsided, the reaction mixture was stirred overnight on a hot plate at 105 °C. The reaction mixture was then slowly quenched with a few drops of water and acidified to pH 1 by dropwise addition of 1N HCl, followed by extraction with EtOAc (1x) and DCM (2x). The organic layers were combined and the solvent was carefully removed under reduced pressure to avoid loss of product. The title compound was purified by automated flash silica column chromatography (ISCO, 12 g RediSep Rf Gold® column, dry loading) using 30% EtOAc in heptane (0.925 g, quantitative, 67% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.24 - 2.39 (m, 3 H), 5.68 - 5.81 (m, 1 H), 7.03 - 7.18 (m, 2 H), 7.18 - 7.32 (m, 2 H).

[0231] Preparation 13: 2,2-Difluoro-2-(4-fluorophenoxy)acetic acid

[0232] [ka]

[0233] To a solution of sodium hydride (60 wt%, 203 mg, 5.08 mmol) in dioxane (5 mL) was added 4-fluorophenol (427 mg, 3.81 mmol) portionwise at room temperature. The solution was stirred at room temperature for 15 min. Sodium 2-bromo-2,2-difluoroacetate (500 mg, 2.54 mmol) was then added portionwise at room temperature. After the bubbling ceased, the mixture was heated at 100° C. overnight. The reaction was then quenched by the addition of water (20 mL) and the mixture was extracted with EtOAc. The aqueous layer was adjusted to pH 2 by the addition of 1 M HCl and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography (ISCO®) using a gradient of 0-100% EtOAc in heptane to give the title compound as an orange oil (262 mg, 50.1%).

[0234] Preparation 14: 2,2-Difluoro-2-(2-fluorophenoxy)acetic acid

[0235] [ka]

[0236] 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 (376 MHz, DMSO-d6) δ ppm -130.44 - -128.88 (m, 1 F), -77.03 (br s, 2 F).

[0237] Preparation 15: 2,2-Difluoro-2-(3-fluorophenoxy)acetic acid

[0238] [ka]

[0239] 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%).

[0240] Preparation 16: 2,2-Difluoro-2-(o-tolyloxy)acetic acid

[0241] [ka]

[0242] 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%).

[0243] Preparation 17: 2,2-Difluoro-2-(m-tolyloxy)acetic acid

[0244] [ka]

[0245] 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).

[0246] Example 1: (R)-1-(3-methylbenzyl)-N-(1-methylpyrrolidin-3-yl)cyclopropane-1-carboxamide

[0247] [ka]

[0248] 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 min, HATU (152 mg, 0.400 mmol) was added. The reaction mixture was stirred overnight at room temperature and then filtered through a hydrophilic PTFE 0.45 μm Millipore® filter rinsing with MeOH. The product was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-100% water / ACN in water (basic mode) to give the title compound as a yellow oil (51.6 mg, 47%). 1 H NMR (500 MHz, CD3OD) δ ppm 0.75 (s, 2 H), 1.05 - 1.15 (m, 2 H), 1.43 - 1.54 (m, 1 H), 2.15 (dtd, J = 13.6, 8.4, 5.6 Hz, 1 H), 2.22 - 2.29 (m, 1 H), 2.30 (s, 6 H), 2.35 - 2.46 (m, 1 H), 2.59 - 2.69 (m, 2 H), 2.88 - 3.00 (m, 2 H), 4.24 - 4.33 (m, 1 H), 7.01 (d, J = 7.3 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 7.12 - 7.17 (m, 1 H);ESI-MS m / z [M+H] + 273.3.

[0249] Example 2: N-(1-methyl-4-phenylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0250] [ka]

[0251] 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 Millipore® filter rinsing with methanol. The product was purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, ID 30 mm×150 mm column) using a gradient of 10-100% ACN in water (acid mode) to give the TFA salt of the title compound as a pale yellow oil (64 mg, 35%). 1 H NMR (400 MHz, CD3OD) δ ppm 0.45 - 0.62 (m, 2 H), 0.75 - 0.83 (m, 1 H), 1.13 (d, J = 2.0 Hz, 1 H), 1.30 - 1.44 (m, 1 H), 2.22 - 2.33 (m, 3 H), 2.55 - 2.94 (m, 2 H), 2.95 - 3.08 (m, 3 H), 3.08 - 3.23 (m, 1 H), 3.48 - 3.82 (m, 2 H), 3.84 - 4.38 (m, 2 H), 6.80 - 6.91 (m, 1 H), 6.93 - 7.06 (m, 2H), 7.06 - 7.21 (m, 3 H), 7.24 - 7.36 (m, 3 H);ESI-MS m / z [M+H] + 349.5.

[0252] Example 3: N-(trans-4-isopropyl-1-methylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0253] [ka]

[0254] To a 20 mL vial containing DMF (2 mL) was added 1-(3-methylbenzyl)cyclopropanecarboxylic acid (50.0 mg, 0.263 mmol) and 2-chloro-1-methylpyridin-1-ium iodide (201 mg, 0.788 mmol). The reaction mixture was stirred for 30 min. 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 overnight at room temperature. The product was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-100% water / ACN in water (basic mode) to give the title compound as a colorless oil (8 mg, 11%). 1 H NMR (400 MHz, CD3OD) δ ppm 0.66 - 0.75 (m, 3 H), 0.85 (d, J = 6.3 Hz, 3 H), 1.55 - 1.69 (m, 1 H), 1.72 - 1.79 (m, 6 H), 2.14 - 2.22 (m, 1 H), 2.77 - 2.91 (m, 1 H), 2.95 (br s, 3 H), 3.47 - 3.71 (m, 1 H), 3.73 - 3.96 (m, 2 H), 4.08 (s, 3 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.3 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.63 - 7.78 (m, 1 H), 7.88 (br s, 1 H);ESI-MS m / z [M+H] + 315.4.

[0255] Example 4: N-(1,3-dimethylpiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0256] [ka]

[0257] To a 20 mL vial containing 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 Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode) to give the TFA salt of the title compound as a yellow solid (267 mg, 41%). 1 H NMR (400 MHz, CD3OD) δ ppm 0.70 - 0.96 (m, 5 H), 1.09 - 1.33 (m, 2 H), 1.67 - 2.19 (m, 3 H), 2.31 - 2.38 (m, 3 H), 2.41 - 2.50 (m, 1 H), 2.61 (td, J = 13.3, 3.4 Hz, 1 H), 2.77 - 2.99 (m, 4 H), 3.03 - 3.23 (m, 2 H), 3.40 - 3.65 (m, 2 H), 4.03 - 4.16 (m, 1 H), 7.03 - 7.29 (m, 4 H);ESI-MS m / z [M+H] + 301.4.

[0258] Example 5: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0259] [ka]

[0260] Step A: (3S,4S)-tert-butyl 3-fluoro-4-(1-(3-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate

[0261] [ka]

[0262] To a solution of 1-(3-methylbenzyl)cyclopropane-1-carboxylic acid (150 mg, 0.788 mmol) in DMA (3.94 mL) was added DIPEA (413 μL, 2.36 mmol) and HATU (450 mg, 1.18 mmol). After stirring at room temperature for 5 min, (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (189 mg, 0.867 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with saturated aqueous NH4Cl and extracted with DCM (2 times). The combined organic layers were washed with saturated aqueous NaHCO3, followed by saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (308 mg).

[0263] Step B: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0264] To the crude (3S,4S)-tert-butyl 3-fluoro-4-(1-(3-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate (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, filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-70% water / ACN in water (basic mode). The product-containing fractions were lyophilized to give the title compound as a tan semi-solid (16.8 mg, 7.3% for two steps). ESI-MS m / z [M+H] + 291.20.

[0265] Example 6: N-(1,4-dimethylpyrrolidin-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0266] [ka]

[0267] To a solution of 1-(3-methylbenzyl)cyclopropane-1-carboxylic acid (150 mg, 0.788 mmol) in DMA (3.94 mL) was added DIPEA (413 μL, 2.36 mmol) and HATU (450 mg, 1.18 mmol). After stirring for 5 min, 1,4-dimethylpyrrolidin-3-amine (90 mg, 0.788 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with saturated aqueous NaHCO3 and extracted with DCM (3 times). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in MeOH, filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 30-80% water / ACN in water (basic mode) to give the title compound as a yellow oil (46.1 mg, 20%). 1H NMR (500 MHz, CDCl3) δ ppm 0.55 (d, J = 7.1 Hz, 1.8 H), 0.68 - 0.84 (m, 2 H), 0.95 (d, J = 6.8 Hz, 1.2 H), 1.17 - 1.37 (m, 2 H), 1.65 - 1.78 (m, 0.8 H), 2.00 (dd, J = 9.3, 6.8 Hz, 0.6 H), 2.07 (dd, J = 9.8, 3.7 Hz, 0.6 H), 2.21 (s, 3 H), 2.31 (d, J = 1.7 Hz, 3 H), 2.39 - 3.01 (m, 5 H), 3.82 - 3.91 (m, 0.4 H), 4.33 - 4.43 (m, 0.6 H), 5.88 (br d, J = 8.8 Hz, 0.6 H), 5.99 (br d, J = 7.6 Hz, 0.4 H), 6.99 - 7.22 (m, 4 H);ESI-MS m / z [M+H] + 287.20.

[0268] Example 7: 1-(2-chlorophenoxy)-N-(trans-3-ethyl-1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0269] [ka]

[0270] In an 8 mL vial, 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 mixed in DMF (2 mL) to give a yellow solution. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10 to 100% water / ACN in water (base mode) to give the title compound as a light brown film (58.8 mg, 62%). 1 H NMR (500 MHz, CD3OD) δ ppm 0.74 - 0.80 (m, 3 H), 0.93 - 1.04 (m, 1 H), 1.12 - 1.26 (m, 2 H), 1.34 - 1.42 (m, 1 H), 1.45 - 1.57 (m, 3 H), 1.58 - 1.65 (m, 1 H), 1.74 (s, 2 H), 1.99 - 2.10 (m, 1 H), 2.27 (s, 3 H), 2.79 - 2.96 (m, 2 H), 3.48 - 3.59 (m, 1 H), 6.96 - 7.09 (m, 2 H), 7.21 - 7.29 (m, 1 H), 7.36 - 7.43 (m, 1 H);ESI-MS m / z [M+H] + 337.3.

[0271] Example 8: 1-(2-chlorophenoxy)-N-(1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0272] [ka]

[0273] 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 min, after which 1,2-dimethylpiperidin-4-amine (0.012 g, 0.094 mmol) was added. The solution was stirred overnight at 45 °C. The sample was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm × 100 mm) using a gradient of 10-60% ACN in water (acid mode). The product-containing fractions were collected and re-purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-90% water / ACN in water (basic mode) to give the title compound (6.1 mg, 20%). ESI-MS m / z [M+H] + 323.1.

[0274] Example 9: 1-(2-chlorophenoxy)-N-(hexahydro-1H-pyrrolidin-1-yl)cyclopropane-1-carboxamide

[0275] [ka]

[0276] To a 4 mL vial equipped with a stir bar and containing a solution of hexahydro-1H-pyrrolidin-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 h. Methanol (0.5 mL) was added and the solution was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-50% ACN in water (acid mode). Lyophilization of the pure fractions afforded the TFA salt of the title compound (8.9 mg, 22%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.14 - 1.30 (m, 2 H), 1.49 - 1.66 (m, 2 H), 1.66 - 1.75 (m, 0.4 H), 1.80 - 1.92 (m, 1 H), 1.95 - 2.01 (m, 1 H), 2.01 - 2.13 (m, 2 H), 2.15 - 2.27 (m, 2 H), 2.32 - 2.41 (m, 0.6 H), 2.98 (ddd, J = 11.5, 9.6, 6.1 Hz, 0.4 H), 3.15 - 3.29 (m, 1.6 H), 3.45 - 3.55 (m, 1 H), 3.65 - 3.76 (m, 1 H), 4.01 - 4.08 (m, 0.6 H), 4.28 - 4.39 (m, 1 H), 4.53 - 4.61 (m, 0.4 H), 6.98 - 7.07 (m, 2 H), 7.23 - 7.29 (m, 1 H), 7.40 (ddd, J = 7.9, 4.8, 1.5 Hz, 1 H), 8.38 (br dd, J = 19.3, 6.0 Hz, 1 H);ESI-MS m / z [M+H] + 321.1.

[0277] Example 10: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide

[0278] [ka]

[0279] 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, filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-100% water / ACN in water (basic mode). The TFA salt of the title compound was obtained as an orange solid (118 mg, 79%). 1H NMR (400 MHz, CDCl3) δ ppm 0.64 (d, J = 6.5 Hz, 3 H), 0.76 - 0.89 (m, 2 H), 1.19 - 1.28 (m, 1 H), 1.32 - 1.41 (m, 1 H), 1.71 - 1.86 (m, 1 H), 1.89 - 2.01 (m, 2 H), 2.32 - 2.43 (m, 1 H), 2.63 - 2.73 (m, 1 H), 2.76 (s, 3 H), 2.84 (d, J = 16.3 Hz, 1 H), 3.05 (d, J = 16.3 Hz, 1 H), 3.37 - 3.44 (m, 1 H), 3.49 - 3.56 (m, 1 H), 3.58 - 3.69 (m, 1 H), 5.41 (br d, J = 8.5 Hz, 1 H), 6.96 - 7.05 (m, 2 H), 7.26 - 7.30 (m, 2 H), 13.00 - 13.24 (m, 1 H);ESI-MS m / z [M+H] + 305.3.

[0280] Example 11: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(4-methylbenzyl)cyclopropane-1-carboxamide

[0281] [ka]

[0282] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.62 (d, J=6.53 Hz, 3 H), 0.77 - 0.83 (m, 1 H), 0.84 - 0.91 (m, 1 H), 1.25 (ddd, J = 9.7, 6.1, 3.5 Hz, 1 H), 1.33 - 1.40 (m, 1 H), 1.62 - 1.74 (m, 1 H), 1.78 - 1.89 (m, 1 H), 1.94 (dq, J = 14.1, 3.2 Hz, 1 H), 2.32 (s, 3 H), 2.33 - 2.40 (m, 1 H), 2.64 - 2.72 (m, 1 H), 2.75 (s, 3 d, J = 8.8 Hz, 1 H), 7.10 - 7.16 (m, 2 H), 7.18 - 7.24 (m, 2 H) 12.73 - 12.87 (m, 1 H);ESI-MS m / z [M+H] + 301.4.

[0283] Example 12: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0284] [ka]

[0285] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.71 (d, J = 6.8 Hz, 3 H), 0.73 - 0.81 (m, 2 H), 1.27 - 1.31 (m, 1 H), 1.37 - 1.43 (m, 1 H), 1.66 - 1.79 (m, 1 H), 1.83 - 1.94 (m, 1 H), 1.98 (dq, J = 14.1, 3.2 Hz, 1 H), 2.32 (s, 3 H), 2.33 - 2.43 (m, 1 H), 2.64 - 2.72 (m, 1 H), 2.76 (s, 3 H), 2.81 (d, J = 16.8 Hz, 1 H), 3.07 (d, J = 16.8 Hz, 1 H), 3.38 - 3.45 (m, 1 H), 3.49 - 3.57 (m, 1 H), 3.63 - 3.73 (m, 1 H), 5.42 (br d, J = 8.3 Hz, 1 H), 7.10 - 7.17 (m, 2 H), 7.17 - 7.21 (m, 1 H), 7.30 - 7.35 (m, 1 H), 12.81 - 12.98 (m, 1 H);ESI-MS m / z [M+H] + 301.4.

[0286] Example 13: 1-(4-Fluorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0287] [ka]

[0288] Step A: (3S,4S)-tert-butyl 4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamido)-3-methylpiperidine-1-carboxylate

[0289] [ka]

[0290] A solution of 1-(4-fluorobenzyl)cyclopropane-1-carboxylic acid (101 mg, 0.520 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (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 h. The reaction mixture was then diluted with MeOH, filtered through a Millipore filter and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). 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.

[0291] Step B: 1-(4-Fluorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0292] A solution of (3S,4S)-tert-butyl 4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamide)-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, 4M in dioxane) at room temperature. The reaction mixture was stirred at room temperature for 16 h, then diluted with MeOH, filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). Pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (140 mg, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 0.66 (d, J = 6.8 Hz, 3 H), 0.76 - 0.91 (m, 2 H), 1.24 - 1.30 (m, 1 H), 1.34 - 1.42 (m, 1 H), 1.46 - 1.58 (m, 1 H), 1.61 - 1.74 (m, 1 H), 1.89 - 1.99 (m, 1 H), 2.45 - 2.59 (m, 1 H), 2.77 - 2.96 (m, 3 H), 2.99 - 3.08 (m, 1 H), 3.21 - 3.28 (m, 1 H), 3.33 (br d, J = 12.3 Hz, 1 H), 3.59 - 3.72 (m, 1 H), 5.36 (d, J = 8.8 Hz, 1 H), 6.98 - 7.05 (m, 2 H), 7.27 - 7.33 (m, 2 H), 9.04 - 9.21 (m, 1 H), 9.47 - 9.59 (m, 1 H);ESI-MS m / z [M+H] + 291.3.

[0293] Example 14: 2,2-Difluoro-2-phenoxy-N-(piperidin-4-yl)acetamide

[0294] [ka]

[0295] Step A: tert-Butyl 4-(2,2-difluoro-2-phenoxyacetamido)piperidine-1-carboxylate

[0296] [ka]

[0297] The title compound was prepared as in Example 13, Step A, 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.

[0298] Step B: 2,2-Difluoro-2-phenoxy-N-(piperidin-4-yl)acetamide

[0299] 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 with a drop of HCl in dioxane (4 M, 1.19 mL, 4.75 mmol) via syringe at room temperature. The resulting mixture was stirred at room temperature for 16 h, then diluted with MeOH (1.5 mL), filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). Pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (119 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 - 1.79 (m, 2 H), 1.87 (br dd, J = 13.4, 2.6 Hz, 2 H), 2.99 (br t, J = 11.9 Hz, 2 H), 3.29 (br d, J = 12.8 Hz, 3 H), 3.92 (dtd, J = 11.2, 7.3, 4.0 Hz, 1 H), 7.23 - 7.28 (m, 2 H), 7.29 - 7.38 (m, 1 H), 7.42 - 7.51 (m, 2 H), 9.19 (br d, J = 7.8 Hz, 1 H);ESI-MS m / z [M+H] + 271.3.

[0300] Example 15: 1-(3-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0301] [ka]

[0302] Step A: (3S,4S)-tert-butyl 4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamido)-3-methylpiperidine-1-carboxylate

[0303] [ka]

[0304] A solution of 1-(3-chlorobenzyl)cyclopropane-1-carboxylic acid (56 mg, 0.266 mmol, 1 equiv.), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (68.4 mg, 0.319 mmol, 1.2-1.5 equiv.), HATU (121 mg, 0.319 mmol, 1.2-1.5 equiv.) and EtN (148 μL, 1.06 mmol, 4-6 equiv.) 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), filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). Pure fractions were combined and lyophilized to give the title compound as a white solid (92 mg, 85%). ESI-MS m / z [M+H] + 407.4.

[0305] Step B: 1-(3-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0306] A solution of (3S,4S)-tert-butyl 4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamide)-3-methylpiperidine-1-carboxylate (92 mg, 0.226 mmol, 1 equiv) in MeOH (452 ​​μL) and DCM (452 ​​μL) was treated with HCl in dioxane (4 M, 339 μL, 1.36 mmol, 6-10 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16 h, then diluted with MeOH (1 mL), filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). The pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (84 mg, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.68 (d, J = 6.8 Hz, 3 H), 0.79 - 0.90 (m, 2 H), 1.22 - 1.31 (m, 1 H), 1.34 - 1.42 (m, 1 H), 1.47 - 1.60 (m, 1 H), 1.63 - 1.76 (m, 1 H), 1.92 - 2.01 (m, 1 H), 2.47 - 2.59 (m, 1 H), 2.85 (br d, J = 16.3 Hz, 2 H), 3.04 (d, J = 16.6 Hz, 1 H), 3.21 - 3.30 (m, 1 H), 3.34 (br d, J = 12.0 Hz, 1 H), 3.62 - 3.74 (m, 1 H), 5.35 (d, J = 8.8 Hz, 1 H), 7.17 - 7.26 (m, 3 H), 7.32 - 7.35 (m, 1 H), 9.05 - 9.22 (m, 1 H), 9.42 - 9.55 (m, 1 H);ESI-MS m / z [M+H] + 307.3.

[0307] Example 16: 1-(2-Methylbenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0308] [ka]

[0309] Step A: (3S,4S)-tert-butyl 3-methyl-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate

[0310] [ka]

[0311] The title compound was prepared as in Example 15, Step A, using 1-(2-methylbenzyl)cyclopropane-1-carboxylic acid (88 mg, 0.346 mmol), (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate tert-butyl (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.

[0312] Step B: 1-(2-Methylbenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0313] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-3-methyl-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate tert-butyl (143 mg, 0.370 mmol) and obtained as a white solid (127 mg, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 0.72 (d, J = 6.5 Hz, 3 H), 0.74 - 0.83 (m, 2 H), 1.29 - 1.36 (m, 1 H), 1.39-1.46 (m, 1 H), 1.46 - 1.55 (m, 1 H), 1.59 - 1.72 (m, 1 H), 1.99 (br dd, J = 14.0, 2.0 Hz, 1 H), 2.31 (s, 3 H), 2.47 - 2.59 (m, 1 H), 2.77 - 2.93 (m, 2 H), 3.05 (d, J = 17.1 Hz, 1 H), 3.21 - 3.28 (m, 1 H), 3.33 (br d, J = 12.8 Hz, 1 H), 3.62 - 3.76 (m, 1 H), 4.25 - 4.45 (m, 1 H), 5.41 (d, J = 8.5 Hz, 1 H), 7.12 - 7.16 (m, 2 H), 7.17 - 7.21 (m, 1 H), 7.33 - 7.39 (m, 1 H), 8.93 - 9.09 (m, 1 H), 9.24 - 9.36 (m, 1 H);ESI-MS m / z [M+H] + 287.4.

[0314] Example 17: 1-(2-chlorobenzyl)-N-(trans-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0315] [ka]

[0316] The TFA salt of the title compound was prepared as in Example 15, Step A, 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 EtN (132 μL, 0.949 mmol) in THF (1.19 mL) and obtained as a white solid (85 mg, 82%).1 H NMR (400 MHz, CDCl3) δ ppm 0.72 (d, J = 6.5 Hz, 3 H), 0.79 - 0.87 (m, 2 H), 1.24 - 1.30 (m, 1 H), 1.37 - 1.42 (m, 1 H), 1.70 - 1.84 (m, 1 H), 1.92 - 2.00 (m, 2 H), 2.32 - 2.42 (m, 1 H), 2.64 - 2.73 (m, 1 H), 2.76 (s, 3 H), 2.97 (d, J = 16.8 Hz, 1 H), 3.22 (d, J = 17.1 Hz, 1 H), 3.40 - 3.47 (m, 1H), 3.54 ESI-MS m / z [M+H] + 321.1.

[0317] Example 18: 1-(4-chlorobenzyl)-N-((3S,4S)-3-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0318] [ka]

[0319] 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 afforded as a white solid (97 mg, 63% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 0.66 (d, J = 6.5 Hz, 3 H), 0.77 - 0.89 (m, 2 H), 1.22 - 1.30 (m, 1 H), 1.37 (ddd, J = 9.8, 5.8, 3.5 Hz, 1 H), 1.48 - 1.61 (m, 1 H), 1.63 - 1.77 (m, 1 H), 1.91 - 1.99 (m, 1 H), 2.52 (q, J = 11.5 Hz, 1 H), 2.79 - 2.92 (m, 2 H), 3.00 - 3.06 (m, 1 H), 3.22 - 3.30 (m, 1 H), 3.30 - 3.44 (m, 2 H), 3.61 - 3.72 (m, 1 H), 5.37 (br d, J = 8.8 Hz, 1 H), 7.24 - 7.31 (m, 4 H), 9.03 - 9.17 (m, 1 H), 9.43 - 9.56 (m, 1 H); m / z [M+H] + 307.3.

[0320] Example 19: 3-(4-chlorophenyl)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidin-4-yl)propanamide

[0321] [ka]

[0322] 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). 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (d, J = 6.8 Hz, 3 H), 1.20 (d, J = 7.5 Hz, 6 H), 1.56 - 1.69 (m, 1 H), 1.80 - 1.95 (m, 1 H), 2.00 (br d, J = 13.3 Hz, 1 H), 2.54 - 2.68 (m, 1 H), 2.82 (s, 2 H), 2.87 - 3.01 (m, 1 H), 3.32 - 3.38 (m, 1 H), 3.42 (br d, J = 12.6 Hz, 1 H), 3.69 - 3.83 (m, 1 H), 4.15 - 4.29 (m, 1 H), 5.43 (br d, J = 8.8 Hz, 1 H), 7.05 - 7.09 (m, 2 H), 7.20 - 7.24 (m, 2 H), 9.07 - 9.24 (m, 1 H), 9.27 - 9.41 (m, 1 H);ESI-MS m / z [M+H] + 309.3.

[0323] Example 20: N-(trans-1,3-dimethylpiperidin-4-yl)-1-(3-fluorobenzyl)cyclopropane-1-carboxamide

[0324] [ka]

[0325] The TFA salt of the title compound was prepared as in Example 15, Step A, 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 EtN (178 μL, 1.28 mmol) in THF (1.60 mL) and obtained as a white solid (26 mg, 19%). 1H NMR (400 MHz, CDCl3) δ ppm 0.66 (d, J = 6.8 Hz, 3 H), 0.79 - 0.90 (m, 2 H), 1.21 - 1.28 (m, 1 H), 1.35 - 1.41 (m, 1 H), 1.69 - 1.82 (m, 1 H), 1.87 - 1.99 (m, 2 H), 2.33 - 2.44 (m, 1 H), 2.64 - 2.74 (m, 1 H), 2.77 (s, 3 H), 2.86 (d, J = 16.6 Hz, 1 H), 3.07 (d, J = 16.3 Hz, 1 H), 3.38 - 3.46 (m, 1 H), 3.49 - 3.56 (m, 1 H), 3.59 - 3.71 (m, 1 H), 5.43 (br d, J = 8.5 Hz, 1 H), 6.94 (ddd, J = 9.2, 7.6, 1.8 Hz, 1 H), 7.03 - 7.10 (m, 2 H), 7.24 - 7.33 (m, 1 H), 12.59 - 12.75 (m, 1 H);ESI-MS m / z [M+H] + 305.4.

[0326] Example 21: N-(trans-3-ethyl-1-methylpiperidin-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide

[0327] [ka]

[0328] The TFA salt of the title compound was prepared as in Example 15, Step A, 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 EtN (58.6 μL, 0.421 mmol) in THF (526 μL) and obtained as a white solid (44 mg, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 0.64 - 0.72 (m, 3 H), 0.75 - 0.85 (m, 2 H), 0.86 - 0.93 (m, 1 H), 1.04 - 1.16 (m, 1 H), 1.24 (ddd, J = 9.9, 6.4, 3.8 Hz, 1 H), 1.38 - 1.46 (m, 1 H), 1.59 - 1.75 (m, 2 H), 1.92 - 2.00 (m, 1 H), 2.29 - 2.40 (m, 4 H), 2.61 - 2.73 (m, 1 H), 2.74 - 2.82 (m, 4 H), 3.06 (d, J = 16.6 Hz, 1 H), 3.46 - 3.55 (m, 2 H), 3.62 - 3.73 (m, 1 H), 5.45 (br d, J = 8.3 Hz, 1 H), 7.11 - 7.15 (m, 2 H) 7.06 (d, J = 7.3 Hz, 1 H), 7.18 - 7.23 (m, 1 H), 12.55 - 12.68 (m, 1 H);ESI-MS m / z [M+H] + 315.4.

[0329] Example 22: 1-(4-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0330] [ka]

[0331] Step A: (3S,4S)-tert-butyl 3-fluoro-4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate

[0332] [ka]

[0333] 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 (ISCO, 4 g RediSep Rf Gold® column, dry loading) using 50% EtOAc in heptane to give the title compound as a pale yellow oil (0.203 g, quantitative). ESI-MS m / z [M+H] + 395.4.

[0334] Step B: 1-(4-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0335] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-3-fluoro-4-(1-(4-fluorobenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate tert-butyl (0.203 g, 0.515 mmol) and obtained as a white solid (145 mg, 69%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.83 - 0.87 (m, 2 H), 1.32 - 1.36 (m, 2 H), 1.47 - 1.59 (m, 1 H), 2.14 - 2.23 (m, 1 H), 2.90 - 3.09 (m, 6 H), 3.29 (ddd, J = 16.1, 13.0, 3.5 Hz, 1 H), 4.11 - 4.23 (m, 1 H), 4.46 - 4.65 (m, 1 H), 5.61 (br d, J = 7.0 Hz, 1 H), 7.00 - 7.07 (m, 2 H), 7.28 - 7.34 (m, 2 H);ESI-MS m / z [M+H] + 295.3.

[0336] Example 23: 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0337] [ka]

[0338] Step A: (3S,4S)-tert-butyl 4-(1-(4-chlorobenzyl)cyclopropane-1-carboxamide)-3-fluoropiperidine-1-carboxylate

[0339] [ka]

[0340] The title compound was prepared as in Example 22, Step A, using 1-(4-chlorobenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.475 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate tert-butyl (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 pale yellow semi-solid (170 mg, 87%). ESI-MS m / z [M+H] + 411.4.

[0341] Step B: 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0342] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-4-(1-(4-chlorobenzyl)cyclopropane-1-carboxamide)-3-fluoropiperidine-1-carboxylate tert-butyl (170 mg, 0.414 mmol) and obtained as a pale white solid (98 mg, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 0.82 - 0.87 (m, 2 H), 1.31 - 1.35 (m, 2 H), 1.50 - 1.61 (m, 1 H), 2.14 - 2.23 (m, 1 H), 2.92 - 3.05 (m, 4 H), 3.05 - 3.13 (m, 1 H), 3.24 - 3.41 (m, 1 H), 4.11 - 4.24 (m, 1 H), 4.46 - 4.68 (m, 1 H), 5.65 (br d, J = 7.3 Hz, 1 H), 7.24 - 7.32 (m, 4 H);ESI-MS m / z [M+H] + 311.3.

[0343] Example 24: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0344] [ka]

[0345] Step A: (3S,4S)-3-fluoro-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate tert-butyl

[0346] [ka]

[0347] The title compound was prepared as in Example 22, Step A, using 1-(2-methylbenzyl)cyclopropane-1-carboxylic acid (100 mg, 0.526 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate tert-butyl (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 pale yellow solid (191 mg, 93%). ESI-MS m / z [M+H] +391.4.

[0348] Step B: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0349] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-3-fluoro-4-(1-(2-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate tert-butyl (191 mg, 0.489 mmol) and obtained as a white solid (145 mg, 73%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.79 - 0.85 (m, 2 H), 1.37 - 1.42 (m, 2 H), 1.46 - 1.56 (m, 1 H), 2.15 - 2.25 (m, 2 H), 2.30 - 2.33 (m, 3 H), 2.79 - 2.89 (m, 1 H), 2.90 - 3.00 (m, 3 H), 3.00 - 3.18 (m, 2 H), 4.11 - 4.24 (m, 1 H), 4.44 - 4.67 (m, 1 H), 5.56 (d, J = 7.3 Hz, 1 H), 7.16 - 7.24 (m, 3H), 7.35 - 7.40 (m, 1 H);ESI-MS m / z [M+H] + 291.4.

[0350] Example 25: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-phenoxyacetamide

[0351] [ka]

[0352] Step A: (3S,4S)-tert-butyl 4-(2,2-difluoro-2-phenoxyacetamido)-3-methylpiperidine-1-carboxylate

[0353] [ka]

[0354] The title compound was prepared as in Example 15, Step A, using 2,2-difluoro-2-phenoxyacetic acid (47 mg, 0.250 mmol), (3S,4S)-4-amino-3-methylpiperidine-1-carboxylate tert-butyl (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.

[0355] Step B: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-phenoxyacetamide

[0356] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-tert-butyl 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 (400 MHz, CDCl3) δ ppm 0.96 - 1.05 (m, 3 H), 1.85 - 2.02 (m, 1 H), 2.02 - 2.16 (m, 3 H), 2.64 - 2.76 (m, 1 H), 2.94 - 3.09 (m, 1 H), 3.40 - 3.50 (m, 1 H), 3.52 - 3.61 (m, 1 H), 3.82 - 3.91 (m, 1 H), 6.43 - 6.50 (m, 1 H), 7.24 (br d, J = 8.3 Hz, 2 H), 7.28 - 7.32 (m, 1 H), 7.36 - 7.43 (m, 2 H);ESI-MS m / z [M+H] +285.3.

[0357] Example 26: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-3-phenylpropanamide

[0358] [ka]

[0359] 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 H NMR (400 MHz, CDCl3) δ ppm 0.70 (d, J = 6.3 Hz, 3 H), 1.52 - 1.69 (m, 1 H), 1.85 - 1.92 (m, 1 H), 2.48 - 2.62 (m, 1 H), 2.82 - 3.10 (m, 3 H), 3.25 - 3.49 (m, 4 H), 3.58 - 3.70 (m, 1 H), 6.00 (br d, J = 8.5 Hz, 1 H), 7.24 - 7.33 (m, 5 H), 9.14 - 9.52 (m, 2 H);ESI-MS m / z [M+H] + 283.4.

[0360] Example 27: 1-(3-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0361] [ka]

[0362] Step A: (3S,4S)-tert-butyl 4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamide)-3-fluoropiperidine-1-carboxylate

[0363] [ka]

[0364] The title compound was prepared as in Example 15, Step A, using 1-(3-chlorobenzyl)cyclopropane-1-carboxylic acid (73 mg, 0.347 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate tert-butyl (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.

[0365] Step B: 1-(3-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0366] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-tert-butyl 4-(1-(3-chlorobenzyl)cyclopropane-1-carboxamide)-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 was obtained as a white solid (67 mg, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.85 - 0.92 (m, 2 H), 1.31 - 1.38 (m, 2 H), 1.57 - 1.69 (m, 1 H), 2.12 - 2.23 (m, 2 H), 3.00 (d, J = 3.8 Hz, 2 H), 3.02 - 3.16 (m, 3 H) 3.33 (br t, J = 14.9 Hz, 1 H), 4.20 (br d, J = 3.8 Hz, 1 H), 4.53 - 4.77 (m, 1 H), 5.94 (br d, J = 7.3 Hz, 1 H), 7.19 - 7.23 (m, 1 H), 7.24 - 7.31 (m, 2 H), 7.33 (s, 1 H);ESI-MS m / z [M+H] + 311.3.

[0367] Example 28: 2,2-Difluoro-N-(1-methylpiperidin-4-yl)-2-phenoxyacetamide

[0368] [ka]

[0369] The TFA salt of the title compound was prepared as in Example 15, Step A, 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%). 1H NMR (400 MHz, CDCl3) δ ppm 2.17 (m, 4 H), 2.80 (m, 5 H), 3.63 (br d, J = 12.0 Hz, 2 H), 4.10 (br d, J = 3.5 Hz, 1 H), 7.03 (br d, J = 6.8 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 2 H), 7.25 - 7.30 (m, 1 H), 7.35 - 7.42 (m, 2 H);ESI-MS m / z [M+H] + 285.3.

[0370] Example 29: 2,2-Difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-2-phenoxyacetamide

[0371] [ka]

[0372] Step A: (3S,4S)-tert-butyl 4-(2,2-difluoro-2-phenoxyacetamido)-3-fluoropiperidine-1-carboxylate

[0373] [ka]

[0374] The title compound was prepared as in Example 15, Step A, 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) to give the title compound (275 mg) as a colorless oil.

[0375] Step B: 2,2-Difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)-2-phenoxyacetamide

[0376] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-tert-butyl 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) to give a white solid (116 mg, 41% for two steps). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.69 - 1.82 (m, 1 H), 1.93 - 2.06 (m, 1 H), 3.02 - 3.11 (m, 1 H), 3.12 - 3.22 (m, 2 H), 3.60 (ddd, J = 12.1, 7.6, 4.4 Hz, 1 H), 4.13 - 4.32 (m, 1 H), 4.66 - 4.91 (m, 1 H), 7.27 (d, J = 7.5 Hz, 2 H), 7.31 - 7.36 (m, 1 H), 7.43 - 7.50 (m, 2 H), 9.39 (br d, J = 8.5 Hz, 1 H);ESI-MS m / z [M+H] + 289.3.

[0377] Example 30: 1-(4-fluoro-2-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0378] [ka]

[0379] Step A: (3S,4S)-tert-butyl 3-fluoro-4-(1-(4-fluoro-2-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate

[0380] [ka]

[0381] A solution of 1-(4-fluoro-2-methylbenzyl)cyclopropane-1-carboxylic acid (103 mg, 0.495 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 h. The solvent was removed under reduced pressure and the residue was purified by automated flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column, dry loading) using a gradient of 20-100% EtOAc in heptane. Evaporation of product-containing fractions gave the title compound (202 mg). ESI-MS m / z [M+H] + 409.5.

[0382] Step B: 1-(4-fluoro-2-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0383] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-tert-butyl 3-fluoro-4-(1-(4-fluoro-2-methylbenzyl)cyclopropane-1-carboxamide)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) to give a white solid (106 mg, 51% for two steps). 1H NMR (400 MHz, CDCl3) δ ppm 0.75 - 0.80 (m, 2 H), 1.33 - 1.39 (m, 2 H), 1.55 - 1.68 (m, 1 H), 2.14 - 2.25 (m, 1 H), 2.30 (s, 3 H), 2.93 (s, 2 H), 2.96 - 3.14 (m, 3 H), 3.27 - 3.40 (m, 1 H), 4.16 - 4.28 (m, 1 H), 4.51 - 4.71 (m, 1 H), 5.73 (br d, J = 7.5 Hz, 1 H), 6.85 (td, J = 8.4, 2.8 Hz, 1 H), 6.91 (dd, J = 9.5, 2.5 Hz, 1 H), 7.24 - 7.30 (m, 1 H);ESI-MS m / z [M+H] + 309.4.

[0384] Example 31: 1-(4-fluoro-3-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0385] [ka]

[0386] Step A: (3S,4S)-tert-butyl 3-fluoro-4-(1-(4-fluoro-3-methylbenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate

[0387] [ka]

[0388] The title compound was prepared as in Example 15, Step A, using 1-(4-fluoro-3-methylbenzyl)cyclopropane-1-carboxylic acid (155 mg, 0.744 mmol), (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate tert-butyl (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.

[0389] Step B: 1-(4-fluoro-3-methylbenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0390] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-tert-butyl 3-fluoro-4-(1-(4-fluoro-3-methylbenzyl)cyclopropane-1-carboxamide)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 H NMR (400 MHz, CDCl3) δ ppm 0.75 - 0.91 (m, 2 H), 1.25 - 1.39 (m, 2 H), 1.46 - 1.63 (m, 1 H), 2.13 - 2.21 (m, 1 H), 2.25 (d, J = 1.8 Hz, 3 H), 2.92 (s, 2 H), 2.94 - 3.10 (m, 3 H), 3.24 - 3.40 (m, 1 H), 4.17 (td, J = 7.7, 4.6 Hz, 1 H), 4.44 - 4.70 (m, 1 H), 5.74 (d, J = 7.5 Hz, 1 H), 6.90 - 7.01 (m, 1 H), 7.06 - 7.18 (m, 2 H);ESI-MS m / z [M+H] + 309.3.

[0391] Example 32: 2-(2-cyanophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide

[0392] [ka]

[0393] Step A: tert-butyl 4-(2-(2-cyanophenoxy)-2,2-difluoroacetamido)piperidine-1-carboxylate

[0394] [ka]

[0395] The title compound was prepared as in Example 15, Step A, 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.

[0396] Step B: 2-(2-cyanophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide

[0397] 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 to give a colorless oil (13 mg, 14% for two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 - 1.81 (m, 2 H), 1.90 (br dd, J = 13.0, 2.3 Hz, 2 H), 2.93 - 3.11 (m, 2 H), 3.30 (br d, J = 12.8 Hz, 2 H), 3.95 (tdt, J = 11.1, 7.40, 4.0 Hz, 1 H), 7.47 - 7.57 (m, 2 H), 7.76 - 7.86 (m, 1 H), 7.98 (dd, J = 7.9, 1.6 Hz, 1 H), 9.35 (br d, J = 7.5 Hz, 1 H);ESI-MS m / z [M+H] + 296.3.

[0398] Example 33 (NB011692-080-002): 2-(2-cyanophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0399] [ka]

[0400] Step A: (3S,4S)-tert-butyl 4-(2-(2-cyanophenoxy)-2,2-difluoroacetamido)-3-methylpiperidine-1-carboxylate

[0401] [ka]

[0402] The title compound was prepared as in Example 15, Step A, 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.

[0403] Step B: 2-(2-cyanophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0404] The TFA salt of the title compound was prepared as in Example 15, Step B using (3S,4S)-tert-butyl 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) to give a colorless oil (18 mg, 76%). 1 H NMR (400 MHz, CDCl3) δ ppm 1.10 (br d, J = 5.5 Hz, 3 H), 1.93 - 2.05 (m, 1 H), 2.21 - 2.29 (m, 1 H), 2.64 - 2.78 (m, 3 H), 2.98 - 3.11 (m, 1 H), 3.40 - 3.49 (m, 1 H), 3.50 - 3.61 (m, 1 H), 3.80 - 3.94 (m, 1 H), 6.94 (br d, J = 8.5 Hz, 1 H), 7.39 - 7.45 (m, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.64 - 7.76 (m, 2 H);ESI-MS [M+H] + 310.3.

[0405] Example 34: 2,2-Difluoro-N-(piperidin-4-yl)-2-(p-tolyloxy)acetamide

[0406] [ka]

[0407] Step A: tert-Butyl 4-(2,2-difluoro-2-(p-tolyloxy)acetamido)piperidine-1-carboxylate

[0408] [ka]

[0409] 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 Gold® column, dry loading) using a gradient of 0-100% EtOAc in heptane to give the title compound as a pale yellow oil (74 mg, 15%). ESI-MS m / z [M+Na] + 407.5.

[0410] Step B: 2,2-Difluoro-N-(piperidin-4-yl)-2-(p-tolyloxy)acetamide

[0411] The TFA salt of the title compound was prepared as in Example 15, Step B, 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%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63 - 1.77 (m, 2 H), 1.87 (br dd, J = 13.6, 2.3 Hz, 2 H), 2.28 - 2.34 (m, 3 H), 2.93 - 3.06 (m, 2 H), 3.29 (br d, J = 12.8 Hz, 2 H), 3.87 - 3.98 (m, 1 H), 7.13 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 8.21 - 8.36 (m, 1 H), 8.49 - 8.62 (m, 1 H);ESI-MS m / z [M+H] + 285.3.

[0412] Example 35: N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide

[0413] [ka]

[0414] 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 EtN (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 min. Sodium triacetoxyborohydride (198 mg, 0.905 mmol) was then added in one portion and stirring was continued at room temperature for 16 h. The reaction mixture was then diluted with MeOH (1 mL), filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). 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 (400 MHz, CDCl3) δ ppm 0.64 (d, J = 6.8 Hz, 3 H), 0.74 - 0.90 (m, 2 H), 1.19 - 1.28 (m, 1 H), 1.32 - 1.40 (m, 1 H), 1.71 - 1.85 (m, 1 H), 1.89 - 2.01 (m, 2 H), 2.31 - 2.43 (m, 1 H), 2.63 - 2.73 (m, 1 H), 2.75 (s, 3 H), 2.84 (d, J = 16.3 Hz, 1 H), 3.05 (d, J = 16.3 Hz, 1 H), 3.36 - 3.46 (m, 1 H), 3.48 - 3.56 (m, 1 H), 3.58 - 3.70 (m, 1 H), 5.41 (br d, J = 8.5 Hz, 1 H), 6.97 - 7.04 (m, 2 H), 7.25 - 7.31 (m, 2 H), 13.14 - 13.26 (m, 1 H);ESI-MS m / z [M+H] + 305.5.

[0415] Example 36: 1-(3-chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0416] [ka]

[0417] 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 EtN (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 min. Sodium triacetoxyborohydride (112 mg, 0.513 mmol) was then added and stirring was continued at room temperature for 16 h. The reaction mixture was then diluted with MeOH (1 mL), filtered through a hydrophilic PTFE 0.45 μm Millipore® filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode). Pure fractions were combined and lyophilized to give the TFA salt of the title compound as a colorless oil (60 mg, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 0.68 (d, J = 6.5 Hz, 3 H), 0.78 - 0.90 (m, 2 H), 1.20 - 1.28 (m, 1 H), 1.33 - 1.40 (m, 1 H), 1.71 - 1.85 (m, 1 H), 1.89 - 2.01 (m, 2 H), 2.33 - 2.45 (m, 1 H), 2.64 - 2.73 (m, 1 H), 2.77 (s, 3 H), 2.85 (d, J = 16.6 Hz, 1 H), 3.06 (d, J = 16.3 Hz, 1 H), 3.38 - 3.46 (m, 1 H), 3.50 - 3.57 (m, 1 H), 3.60 - 3.72 (m, 1 H), 5.43 - 5.52 (m, 1 H), 7.15 - 7.19 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.32 (t, J = 1.8 Hz, 1 H);ESI-MS m / z [M+H] + 321.4.

[0418] Example 37: 1-(4-chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0419] [ka]

[0420] 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 (400 MHz, CDCl3) δ ppm 0.65 (d, J = 6.8 Hz, 3 H), 0.76 - 0.88 (m, 2 H), 1.18 - 1.26 (m, 1 H), 1.32 - 1.39 (m, 1 H), 1.75 - 1.88 (m, 1 H), 1.90 - 2.03 (m, 2 H), 2.33 - 2.44 (m, 1 H), 2.64 - 2.75 (m, 1 H), 2.77 (s, 3 H), 2.84 (d, J = 16.3 Hz, 1 H), 3.05 (d, J = 16.3 Hz, 1 H), 3.39 - 3.46 (m, 1 H), 3.49 - 3.58 (m, 1 H), 3.61 - 3.71 (m, 1 H), 5.48 (br d, J = 8.3 Hz, 1 H), 7.22 - 7.30 (m, 4 H);ESI-MS m / z [M+H] + 321.4.

[0421] Example 38: N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide

[0422] [ka]

[0423] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.71 (d, J = 6.5 Hz, 3 H), 0.74 - 0.78 (m, 2 H), 1.25 - 1.31 (m, 1 H), 1.37 - 1.42 (m, 1 H), 1.65 - 1.78 (m, 1 H), 1.83 - 1.94 (m, 1 H), 1.94 - 2.01 (m, 1 H), 2.31 (s, 3 H), 2.34 - 2.45 (m, 1 H), 2.65 - 2.73 (m, 1 H), 2.76 (s, 3 H), 2.82 (d, J = 16.8 Hz, 1 H), 3.07 (d, J = 16.8 Hz, 1 H), 3.37 - 3.45 (m, 1 H), 3.53 (dt, J = 12.0, 1.8 Hz, 1 H), 3.62 - 3.73 (m, 1 H), 5.49 (br d, J = 8.8 Hz, 1 H), 7.10 - 7.16 (m, 2 H), 7.16 - 7.20 (m, 1 H), 7.29 - 7.35 (m, 1 H), 12.71 (br d, J = 1.0 Hz, 1 H);ESI-MS m / z [M+H] + 301.4.

[0424] Example 39: 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0425] [ka]

[0426] 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), EtN (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 (400 MHz, CDCl3) δ ppm 0.75 - 0.87 (m, 2 H), 1.24 - 1.35, (m, 2 H), 1.73 - 1.86 (m, 1 H), 2.06 - 2.21 (m, 1 H), 2.74 - 2.92 (m, 5 H), 2.93 - 3.05 (m, 2 H), 3.43 - 3.56 (m, 1 H), 3.67 - 3.82 (m, 1 H), 4.10 - 4.27 (m, 1 H), 4.63 - 4.88 (m, 1 H), 5.88 - 6.02 (m, 1 H), 7.19 - 7.34 (m, 4 H);ESI-MS m / z [M+H] + 325.3.

[0427] Example 40: N-((3S,4S)-1,3-dimethylpiperidin-4-yl)-2,2-difluoro-2-phenoxyacetamide

[0428] [ka]

[0429] 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 (400 MHz, CDCl3) δ ppm 0.99 (d, J = 6.3 Hz, 3 H), 2.13 - 2.19 (m, 3 H), 2.29 - 2.43 (m, 1 H), 2.52 (br t, J = 12.0 Hz, 1 H), 2.82 (s, 3 H), 3.53 (br d, J = 11.8 Hz, 1 H), 3.62 (br d, J = 12.6 Hz, 1 H), 3.77 - 3.91 (m, 1 H), 6.97 (br d, J = 9.0 Hz, 1 H), 7.22 - 7.26 (m, 2 H), 7.27 - 7.31 (m, 1H), 7.35 - 7.42 (m, 2H); ESI-MS m / z [M+H] + 299.3.

[0430] Example 41: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0431] [ka]

[0432] Step A: (2R,4R)-4-(1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)cyclopropane-1-carboxamido)-2-methylpiperidine-1-carboxylate tert-butyl

[0433] [ka]

[0434] 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, 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.

[0435] Step B: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-2-methylpiperidin-4-yl)cyclopropane-1-carboxamide

[0436] [ka]

[0437] To a 125 mL pear-shaped flask was added (2R,4R)-tert-butyl 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 (4 M, 0.490 mL, 1.96 mmol) and dioxane (3 mL) to give a brown solution. The mixture was stirred at 50° C. for 3 h 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.

[0438] Step C: 1-(((6-chloropyridin-2-yl)(methyl)amino)methyl)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)cyclopropane-1-carboxamide

[0439] 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. Sodium cyanoborohydride (61.6 mg, 0.980 mmol) was then added. The mixture was stirred at room temperature overnight and then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode) to give the TFA salt of the title compound (106.4 mg, 47% for three steps). 1 H NMR (400 MHz, CD3OD) δ ppm 0.87 (d, J = 2.8 Hz, 2 H), 1.17 (d, J = 2.8 Hz, 2 H), 1.34 (d, J = 6.4 Hz, 3 H), 1.38 - 1.50 (m, 1 H), 1.54 - 1.67 (m, 1 H), 1.95 - 2.04 (m, 2 H), 2.84 (s, 3 H), 3.01 (s, 3 H), 3.03 - 3.11 (m, 1 H), 3.14 - 3.23 (m, 1 H), 3.46 - 3.53 (m, 1 H), 3.85 (s, 3 H), 6.57 - 6.69 (m, 2 H), 7.48 - 7.57 (m, 1 H);ESI-MS m / z [M+H] + 351.3.

[0440] Example 42: (R)-2,2-difluoro-2-phenoxy-N-(5-azaspiro[2.4]heptan-7-yl)acetamide

[0441] [ka]

[0442] A solution of 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), (R)-tert-butyl 7-amino-5-azaspiro[2.4]heptane-5-carboxylate (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 overnight at room temperature. 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 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-100% water / ACN in water (basic mode). Pure fractions were combined and lyophilized to give the title compound as a clear oil (21.1 mg, 15%). 1 H NMR (400 MHz, CD3OD) δ ppm 0.47 - 0.90 (m, 4 H), 2.81 - 2.95 (m, 1 H), 3.08 - 3.18 (m, 1 H), 3.21 - 3.28 (m, 1 H), 3.44 - 3.59 (m, 1 H), 4.02 - 4.24 (m, 1 H), 7.20 - 7.37 (m, 3 H), 7.39 - 7.50 (m, 2 H);ESI-MS m / z [M+H] + 283.3.

[0443] Example 43: 1-(2-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0444] [ka]

[0445] 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%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.85 (d, J = 2.4 Hz, 2 H), 1.32 (br d, J = 2.3 Hz, 3 H), 1.90 -2.22 (m, 1 H), 2.70 - 2.93 (m, 3 H), 3.01 (d, J = 2.6 ESI-MS m / z [M+H] + 295.2.

[0446] Example 44: 1-(3-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0447] [ka]

[0448] 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) to give a pale yellow oil (51.9 mg, 34%). 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (d, J = 2.4 Hz, 2 H), 1.32 (br d, J = 2.3 Hz, 3 H), 1.90 - 2.22 (m, 1 H), 2.70 - 2.93 (m, 3 H), 3.01 (d, J = 2.6 ESI-MS m / z [M+H] + 297.4.

[0449] Example 45: 1-benzyl-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0450] [ka]

[0451] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.79 - 0.87 (m, 2 H), 1.04 - 1.18 (m, 1 H), 1.34 - 1.42 (m, 2 H), 1.88 - 2.01 (m, 1 H), 2.60 - 2.77 (m, 3 H), 2.90 - 3.04 (m, 1 H), 3.00 (s, 1 H), 3.92 - 4.05 (m, 1 H), 4.10 - 4.21 (m, 1 H), 5.41 - 5.65 (m, 1 H), 7.25 - 7.30 (m, 1 H), 7.37 (s, 4 H);ESI-MS m / z [M+H] + 277.3.

[0452] Example 46: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(3-methoxybenzyl)cyclopropane-1-carboxamide

[0453] [ka]

[0454] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (d, J = 2.6 Hz, 2 H), 1.12 - 1.28 (m, 1 H), 1.38 (s, 2 H), 1.92 - 2.08 (m, 1 H), 2.68 - 2.85 (m, 3 H), 2.97 (s, 3 H), 3.82 (s, 3 H), 3.96 - 4.31 (m, 2 H), 3.97 - 4.20 (m, 2 H), 4.21 - 4.31 (m, 1 H), 5.54 - 5.68 (m, 1 H), 6.78 - 6.86 (m, 1 H), 6.90 - 6.99 (m, 2 H), 7.28 (s, 1 H); ESI-MS m / z [M+H] + 307.3.

[0455] Example 47: N-((3S,4S)-3-fluoropiperidin-4-yl)-1-(2-methoxybenzyl)cyclopropane-1-carboxamide

[0456] [ka]

[0457] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.86 (d, J = 2.8 Hz, 2 H), 1.35 (s, 3 H), 1.99 - 2.15 (m, 1 H), 2.72 - 2.92 (m, 3 H), 2.96 (d, J = 7.0 Hz, 2 H), 3.09 - 3.24 (m, 1 H), 3.92 (s, 3 H), 3.99 - 4.13 (m, 1 H), 4.20 - 4.49 (m, 1 H), 6.26 - 6.36 (m, 1 H), 6.90 - 7.00 (m, 2 H), 7.21 - 7.28 (m, 1 H), 7.34 - 7.41 (m, 1 H); ESI-MS m / z [M+H] + 307.3.

[0458] Example 48: 2,2-Difluoro-N-((2S,4S)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0459] [ka]

[0460] 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 (400 MHz, CDCl3) δ ppm 1.01 - 1.10 (m, 1 H), 1.12 - 1.16 (m, 3 H), 1.28 - 1.43 (m, 1 H), 1.95 - 2.09 (m, 2 H), 2.78 (br d, J = 2.5 Hz, 2 H), 3.05 - 3.26 (m, 1 H), 3.72 - 4.06 (m, 1 H), 6.19 - 6.33 (m, 1 H), 7.21 - 7.26 (m, 2 H), 7.27 - 7.31 (m, 1 H), 7.35 - 7.45 (m, 2 H);ESI-MS m / z [M+H] + 285.4.

[0461] Example 49: 2,2-Difluoro-2-phenoxy-N-(5-azaspiro[2.5]octan-8-yl)acetamide

[0462] [ka]

[0463] 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%). 1H NMR (400 MHz, CDCl3) δ ppm 0.30 - 1.00 (m, 4 H), 2.06 - 2.26 (m, 2 H), 2.81 - 2.96 (m, 1 H), 3.01 - 3.12 (m, 1 H), 3.13 - 3.44 (m, 2 H), 3.79 - 4.11 (m, 1 H), 6.25 - 6.46 (m, 1 H), 7.18 - 7.25 (m, 4 H), 7.28 - 7.43 (m, 1 H), 7.28 - 7.44 (m, 3 H), 9.26 - 10.31 (m, 1 H);ESI-MS m / z [M+H] + 297.4.

[0464] Example 50: 2,2-Difluoro-N-(cis-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0465] [ka]

[0466] 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-carboxylate tert-butyl (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.

[0467] Example 51: 2,2-Difluoro-N-((2R,4R)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0468] [ka]

[0469] 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-carboxylate tert-butyl (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.

[0470] Example 52: 2,2-Difluoro-N-((2R,4S)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0471] [ka]

[0472] The title compound was prepared as in Example 42 using 2,2-difluoro-2-phenoxyacetic acid (93 mg, 0.494 mmol), (2R,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 (14.3 mg, 10%). ESI-MS m / z [M+H] + 285.3.

[0473] Example 53: 2,2-Difluoro-N-((2S,4R)-2-methylpiperidin-4-yl)-2-phenoxyacetamide

[0474] [ka]

[0475] 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-carboxylate tert-butyl 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.

[0476] Example 54: 2,2-Difluoro-2-(2-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0477] [ka]

[0478] 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 H NMR (400 MHz, CD3OD) δ ppm 0.96 (m, 3 H), 1.61 - 1.95 (m, 3 H), 2.48 - 2.58 (m, 1 H), 2.80 - 2.91 (m, 1 H), 3.15 - 3.30 (m, 2 H), 3.60 - 3.71 (m, 1H), 7.18 - 7.44 (m, 4H).

[0479] Example 55: 2,2-Difluoro-2-(3-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0480] [ka]

[0481] 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%). 1 H NMR (400 MHz, CD3OD) δ ppm 0.92 (d, J = 6.6 Hz, 3 H), 1.57 - 1.74 (m, 1 H), 1.76 - 2.01 (m, 2 H), 2.39 - 2.58 (m, 1 H), 2.77 - 2.92 (m, 1 H), 3.13 - 3.29 (m, 2 H), 3.56 - 3.72 (m, 1 H), 7.04 - 7.23 (m, 3 H), 7.45 - 7.58 (m, 1 H);ESI-MS m / z [M+H] + 303.3.

[0482] Example 56: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(o-tolyloxy)acetamide

[0483] [ka]

[0484] 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%). 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (d, J = 6.6 Hz, 3 H), 1.75 - 1.93 (m, 1 H), 2.00 - 2.15 (m, 2 H), 2.83 (s, 1 H), 3.03 - 3.20 (m, 1 H), 3.39 - 3.53 (m, 2 H), 3.68 - 3.87 (m, 1 H), 7.07 - 7.37 (m, 4 H);ESI-MS m / z [M+H] + 299.3.

[0485] Example 57: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(m-tolyloxy)acetamide

[0486] [ka]

[0487] 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%). 1H NMR (400 MHz, CD3OD) δ ppm 0.94 (d, J = 6.6 Hz, 3 H), 1.71 - 1.91 (m, 1 H), 1.95 - 2.10 (m, 2 H), 2.36 (d, J = 10.3 Hz, 4 H), 2.70 - 2.93 (m, 1 H), 3.01 - 3.20 (m, 1 H), 3.36 - 3.53 (m, 2 H), 3.63 - 3.83 (m, 1 H), 6.98 - 7.33 (m, 2 H), 7.13 (br d, J = 0.8 Hz, 1 H), 7.21 (d, J = 7.8 Hz, 1 H), 7.26 - 7.32 (m, 1 H); ESI-MS m / z [M+H] + 299.3.

[0488] Example 58: 2,2-Difluoro-2-(4-fluorophenoxy)-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0489] [ka]

[0490] A solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid (87 mg, 0.422 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (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 h and then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10-100% water / ACN in water (basic mode). The product was repurified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10 to 100% ACN in water (acid mode) to give the TFA salt of the title compound as a clear oil (5.3 mg, 3.0%). 1 H NMR (400 MHz, CD3OD) δ ppm 0.96 (d, J = 6.6 Hz, 3 H), 1.77 - 1.96 (m, 1 H), 1.99 - 2.13 (m, 2 H), 2.75 - 2.89 (m, 1 H), 3.04 - 3.21 (m, 1 H), 3.36 - 3.53 (m, 2 H), 3.70 - 3.82 (m, 1 H), 7.08 - 7.22 (m, 2 H), 7.24 - 7.34 (m, 2 H);ESI-MS m / z [M+H] + 303.3.

[0491] Example 59: 1-(3-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0492] [ka]

[0493] In a 4 mL vial, 1-(3-chlorophenoxy)cyclopropane-1-carboxylic acid (53.2 mg, 0.250 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as an off-white solid (59 mg, 55%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.08 - 1.17 (m, 2 H), 1.39 - 1.47 (m, 2 H), 1.58 - 1.68 (m, 1 H), 1.81 - 1.89 (m, 1 H), 2.95 - 3.03 (m, 1 H), 3.06 - 3.21 (m, 2 H), 3.42 - 3.51 (m, 1 H), 4.16 - 4.21 (m, 1 H), 4.58 - 4.77 (m, 1 H), 6.84 - 6.95 (m, 2 H), 7.01 - 7.11 (m, 1 H), 7.33 (t, J = 8.2 Hz, 1 H) 8.41 (d, J = 8.3 Hz, 1 H), 8.79 - 9.06 (m, 1 H), 9.20 (br s, 1 H);ESI-MS m / z [M+H] + 313.2.

[0494] Example 60: 1-(2-cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0495] [ka]

[0496] To a 4 mL vial was added 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid (54.6 mg, 0.250 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as an off-white solid (70 mg, 65%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.56 - 0.64 (m, 2 H), 0.85 - 0.92 (m, 2 H), 1.00 - 1.10 (m, 2 H), 1.35 - 1.46 (m, 2 H), 1.66 - 1.78 (m, 1 H), 1.88 - 1.96 (m, 1 H), 2.07 - 2.16 (m, 1 H), 2.98 - 3.07 (m, 1 H), 3.08 - 3.17 (m, 1 H), 3.18 - 3.25 (m, 1 H), 3.51 - 3.54 (m, 1 H), 4.17 - 4.29 (m, 1 H), 4.67 - 4.88 (m, 1 H), 6.79 - 6.87 (m, 2 H), 6.88 - 6.95 (m, 1 H), 7.04 - 7.13 (m, 1 H), 8.39 (d, J = 8.3 Hz, 1 H), 8.70 - 8.97 (m, 1 H), 9.12 (br s, 1 H);ESI-MS m / z [M+H]+ 319.5.

[0497] Example 61: 2-(2,3-dichlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide

[0498] [ka]

[0499] To a 4 ml vial was added 2-(2,3-dichlorophenoxy)propanoic acid (58.8 mg, 0.250 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as an off-white solid (59 mg, 53%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.47 - 1.54 (m, 3 H), 1.60 - 1.76 (m, 1 H), 1.93 - 2.03 (m, 1 H), 3.01 - 3.10 (m, 1 H), 3.16 - 3.27 (m, 2 H), 3.47 - 3.54 (m, 1 H), 4.07 - 4.19 (m, 1 H), 4.60 - 4.85 (m, 2 H), 6.91 - 6.97 (m, 1 H), 7.20 - 7.31 (m, 2 H), 8.52 (br d, J = 7.4 Hz, 1 H), 9.14 (br s, 2 H);ESI-MS m / z [M+H] +335.2.

[0500] Example 62: 2-(2-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide

[0501] [ka]

[0502] To a 4 mL vial was added 2-(2-chlorophenoxy)propanoic acid (50.2 mg, 0.250 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 at room temperature overnight and then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as an off-white semi-solid (68 mg, 65%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.67 (dd, J = 6.6, 1.2 Hz, 3 H), 1.87 - 2.04 (m, 1 H), 2.22 - 2.37 (m, 1 H), 3.20 - 3.37 (m, 2 H), 3.49 - 3.68 (m, 1 H), 4.24 - 4.37 (m, 1 H), 4.79 - 4.86 (m, 2 H), 4.90 - 5.01 (m, 1 H), 7.04 - 7.13 (m, 2 H), 7.24 - 7.39 (m, 1 H), 7.43 - 7.53 (m, 1 H);ESI-MS m / z [M+H] + 301.2.

[0503] Example 63: 2-(2-cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidin-4-yl)propanamide

[0504] [ka]

[0505] To a 4 ml vial was added 2-(2-cyclopropylphenoxy)propanoic acid (51.6 mg, 0.25 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as an off-white solid (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ ppm 0.64 - 0.73 (m, 1 H), 0.73 - 0.82 (m, 1 H), 0.95 - 1.07 (m, 2 H), 1.65 (dd, J = 6.6, 2.1 Hz, 3 H), 1.85 - 2.04 (m, 1 H), 2.20 - 2.39 (m, 2 H), 3.20 - 3.35 (m, 2 H), 3.43 - 3.66 (m, 1 H), 4.25 - 4.35 (m, 1 H), 4.73 - 4.79 (m, 1 H), 4.79 - 4.86 (m, 1 H), 4.89 - 5.01 (m, 1 H), 6.87 - 6.91 (m, 1 H), 6.91 - 6.95 (m, 1 H), 6.95 - 7.01 (m, 1 H), 7.09 - 7.19 (m, 1 H);ESI-MS m / z [M+H] + 307.3.

[0506] Example 64: 2-(2-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0507] [ka]

[0508] To a solution of 2-(2-chlorophenoxy)-2,2-difluoroacetic acid (100 mg, 0.449 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (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 h 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 4 M HCl in dioxane (1.12 mL, 4.49 mmol). The mixture was stirred at room temperature for 2 h, then concentrated in vacuo and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 20 to 60% water / ACN in water (base mode) to give the title compound as a white solid (59.0 mg, 41%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.67 (d, J = 6.6 Hz, 3 H), 1.38 (qd, J = 12.2, 4.3 Hz, 1 H), 1.49 - 1.61 (m, 2 H), 2.08 - 2.18 (m, 1 H), 2.45 - 2.49 (m, 1 H), 2.83 - 2.94 (m, 2 H), 3.30 - 3.38 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.32 - 7.39 (m, 2 H), 7.52 - 7.57 (m, 1 H), 8.88 (br d, J = 8.8 Hz, 1 H);ESI-MS m / z [M+H] + 319.3.

[0509] Example 65: 2-(3-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0510] [ka]

[0511] To a solution of 2-(3-chlorophenoxy)-2,2-difluoroacetic acid (100 mg, 0.449 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (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 h 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 in dioxane (4 M, 1.12 mL, 4.49 mmol). The mixture was stirred at ambient temperature for 2 h, then concentrated in vacuo and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 20 to 80% water / ACN in water (base mode) to give the title compound as a yellow semi-solid (55 mg, 38%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (d, J = 6.5 Hz, 3 H), 1.40 (qd, J = 12.2, 4.3 Hz, 1 H), 1.50 - 1.65 (m, 2 H), 2.17 (br t, J = 11.6 Hz, 1 H), 2.34 - 2.49 (m, 1 H), 2.85 - 3.02 (m, 2 H), 3.37 - 3.48 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.36 - 7.44 (m, 2 H), 7.46 - 7.52 (m, 1 H), 8.93 (br d, J = 8.7 Hz, 1 H);ESI-MS m / z [M+H] + 319.3.

[0512] Example 66: 2-(4-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)acetamide

[0513] [ka]

[0514] To a solution of 2-(4-chlorophenoxy)-2,2-difluoroacetic acid (100 mg, 0.449 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (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 h 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 in dioxane (4 M, 1.12 mL, 4.49 mmol). The mixture was stirred at ambient temperature for 2 h, then concentrated in vacuo and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 20 to 60% water / ACN in water (base mode) to give the title compound as a yellow semi-solid (65 mg, 45%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.61 (d, J = 6.5 Hz, 3 H), 1.33 (qd, J = 12.2, 4.3 Hz, 1 H), 1.41 - 1.59 (m, 2 H), 2.09 (t, J = 11.7 Hz, 1 H), 2.36 - 2.42 (m, 1 H), 2.79 - 2.92 (m, 2 H), 3.28 - 3.33 (m, 1 H), 7.18 - 7.28 (m, 2 H), 7.38 - 7.51 (m, 2 H), 8.84 (br d, J = 8.7 Hz, 1 H);ESI-MS m / z [M+H] + 319.2.

[0515] Example 67: 2-(2-chlorophenoxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)propanamide

[0516] [ka]

[0517] Step A: (2R,4R)-tert-butyl 4-(2-(2-chlorophenoxy)propanamido)-2-methylpiperidine-1-carboxylate

[0518] [ka]

[0519] To a 4 mL vial was added 2-(2-chlorophenoxy)propanoic acid (0.040 g, 0.200 mmol), (2R,4R)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (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). 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 as an off-white solid (79 mg, 0.200 mmol). ESI-MS m / z [M+Ht-Bu] + 341.2.

[0520] Step B: 2-(2-chlorophenoxy)-N-((2R,4R)-2-methylpiperidin-4-yl)propanamide

[0521] [ka]

[0522] Crude (2R,4R)-tert-butyl 4-(2-(2-chlorophenoxy)propanamido)-2-methylpiperidine-1-carboxylate (0.079 g, 0.200 mmol) and HCl in dioxane (4 M, 0.200 mL, 0.800 mmol) were mixed in dioxane (1.227 ml) to give a brown solution. The mixture was stirred at 50° C. for 3 h. Additional HCl in dioxane (4 M, 0.200 mL, 0.800 mmol) was added and the mixture was stirred at 50° C. for an additional 3 h. The mixture was concentrated in vacuo to give the title compound as a brown film (59 mg, 0.200 mmol). ESI-MS m / z [M+H] + 297.3.

[0523] Step C: 2-(2-chlorophenoxy)-N-((2R,4R)-1,2-dimethylpiperidin-4-yl)propanamide

[0524] In a round bottom flask, 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 mixed. 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 Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 10 to 100% water / ACN in water (base mode). In the purification step, the starting material was recovered, which was reacted again under the above conditions and then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10–100% ACN in water (acid mode) to give the TFA salt of the title compound as a clear oil (26 mg, 31%). 1H NMR (400 MHz, CD3OD) δ ppm 1.36 - 1.74 (m, 8 H), 1.77 - 1.90 (m, 1 H), 2.15 - 2.24 (m, 1 H), 2.24 - 2.34 (m, 1 H), 2.95 - 3.00 (m, 3 H), 3.24 - 3.32 (m, 1 H), 3.60 - 3.66 (m, 1 H), 4.09 - 4.17 (m, 1 H), 4.76 - 4.81 (m, 1 H), 7.07 - 7.12 (m, 2 H), 7.31 - 7.36 (m, 1 H), 7.47 - 7.52 (m, 1 H);ESI-MS m / z [M+H] + 311.3.

[0525] Example 68: 1-(3-fluoro-5-methoxybenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0526] [ka]

[0527] Step A: (3S,4S)-3-fluoro-4-(1-(3-fluoro-5-methoxybenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate tert-butyl

[0528] [ka]

[0529] A solution of 1-(3-fluoro-5-methoxybenzyl)cyclopropane-1-carboxylic acid (200 mg, 0.892 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 h. The reaction mixture was diluted with MeOH, filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode) to give the title compound as a white solid (300 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.80 - 0.85 (m, 2 H), 1.09 - 1.24 (m, 1 H), 1.32 - 1.37 (m, 2 H), 1.46 (s, 9 H), 1.92 - 2.04 (m, 1 H), 2.82 - 3.09 (m, 4 H), 3.66 (br d, J = 13.6 Hz, 1 H), 3.86 (s, 3 H), 3.93 - 4.05 (m, 2 H), 4.06 - 4.24 (m, 1 H), 6.20 (br s, 1 H), 6.79 - 6.86 (m, 1 H), 6.88 - 6.98 (m, 1 H), 7.08 (dd, J = 9.0, 3.0 Hz, 1 H); 19 F NMR (376 MHz, CDCl3) δ ppm -75.85 (s, 1 F), -122.48 (br s, 1 F);ESI-MS m / z [M+H] + 425.5.

[0530] Step B: 1-(3-fluoro-5-methoxybenzyl)-N-((3S,4S)-3-fluoropiperidin-4-yl)cyclopropane-1-carboxamide

[0531] A solution of tert-butyl (3S,4S)-3-fluoro-4-(1-(3-fluoro-5-methoxybenzyl)cyclopropane-1-carboxamide)piperidine-1-carboxylate (300 mg, 0.707 mmol) in DCM (2 mL) and MeOH (1 mL) was treated with HCl in dioxane (4 M, 1.77 μL, 7.07 mmol) at room temperature. The reaction mixture was stirred for 16 h. The solvent was removed under reduced pressure to give a sticky yellow solid which was treated with ether (3×25 mL). The solvent was removed under reduced pressure to give a sticky solid again so heptane (25 mL) was added. The solvent was removed under reduced pressure to give a mobile yellow solid. The yellow solid was separated into two batches and purified by automated flash silica column chromatography (ISCO, 4 g RediSep Rf Gold® column, dry loading) using a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-30% MeOH in DCM. Pure fractions were concentrated under reduced pressure to give the HCl salt of the title compound as a pale yellow solid (194 mg, 76%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.60 - 0.67 (m, 2 H), 1.00 - 1.09 (m, 2 H), 1.56 - 1.70 (m, 1 H), 1.84 (br dd, J = 10.0, 4.8 Hz, 1 H), 2.89 - 3.02 (m, 3 H), 3.02 - 3.12 (m, 1 H), 3.14 - 3.21 (m, 1 H), 3.45 (td, J = 12.0, 4.1 Hz, 1 H), 3.76 (s, 3 H), 3.98 - 4.17 (m, 1 H), 4.59 - 4.84 (m, 1H), 6.89 - 7.03 (m, 3 H), 7.74 (dd, J = 4.4, 1.6 Hz, 1 H);ESI-MS m / z [M+H] + 325.4.

[0532] Example 69: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(p-tolyloxy)acetamide

[0533] [ka]

[0534] Step A: (3S,4S)-tert-butyl 4-(2,2-difluoro-2-(p-tolyloxy)acetamido)-3-methylpiperidine-1-carboxylate

[0535] [ka]

[0536] A solution of 2,2-difluoro-2-(p-tolyloxy)acetic acid (150 mg, 0.742 mmol), (3S,4S)-tert-butyl 4-amino-3-methylpiperidine-1-carboxylate (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, filtered through a hydrophilic PTFE 0.45 μm Millipore® filter and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×100 mm) using a gradient of 10-100% ACN in water (acid mode) to give the title compound as a white solid (153 mg, 52%). ESI-MS m / z [M+Na] + 421.5.

[0537] Step B: 2,2-Difluoro-N-((3S,4S)-3-methylpiperidin-4-yl)-2-(p-tolyloxy)acetamide

[0538] A solution of tert-butyl (3S,4S)-4-(2,2-difluoro-2-(p-tolyloxy)acetamido)-3-methylpiperidine-1-carboxylate (153 mg, 0.384 mmol) in DCM (960 μL) was treated with a drop of HCl in dioxane (4 M, 960 μL, 3.84 mmol) via syringe at room temperature. The reaction mixture was stirred at room temperature 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 (400 MHz, DMSO-d6) δ ppm 0.78 (d, J = 6.5 Hz, 3 H), 1.66 - 1.86 (m, 2 H), 1.92 - 2.02 (m, 1 H), 2.27 - 2.35 (m, 3 H), 2.64 - 2.76 (m, 1 H), 2.91 - 3.03 (m, 1 H), 3.19 - 3.28 (m, 2 H), 3.60 - 3.72 (m, 1 H), 7.11 - 7.17 (m, 2 H), 7.21 - 7.27 (m, 2 H), 8.88 (br s, 1 H), 9.12 (br d, J = 8.5 Hz, 1 H);ESI-MS m / z [M+H] + 299.3.

[0539] Example 70: 2-(2-chlorophenoxy)-2,2-difluoro-N-(piperidin-4-yl)acetamide

[0540] [ka]

[0541] 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 h 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 in dioxane (4 M, 1.69 mL, 6.74 mmol). The mixture was stirred at room temperature for 2 h, then concentrated in vacuo and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 20-60% water / ACN in water (base mode) to give the title compound as a white solid (59 mg, 29%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (qd, J = 11.9, 3.6 Hz, 2 H), 1.55 (br d, J = 10.2 Hz, 2 H), 2.25 - 2.41 (m, 2 H), 2.85 (br d, J = 12.3 Hz, 2 H), 3.51 - 3.66 (m, 1 H), 7.25 - 7.31 (m, 1 H), 7.31 - 7.38 (m, 2 H), 7.54 (dt, J = 7.8, 1.0 Hz, 1 H), 8.88 (br d, J = 7.6 Hz, 1 H);ESI-MS m / z [M+H] + 305.2.

[0542] Example 71: 2-(2-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-fluoropiperidin-4-yl)acetamide

[0543] [ka]

[0544] To a solution of 2-(2-chlorophenoxy)-2,2-difluoroacetic acid (150 mg, 0.674 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (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 h 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 in dioxane (4 M, 1.69 mL, 6.74 mmol). The mixture was stirred at room temperature for 2 h, then concentrated in vacuo and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 μm, ID 30 mm×150 mm) using a gradient of 20-60% water / ACN in water (base mode) to give the title compound as a white solid (75 mg, 34%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (qd, J = 12.3, 4.4 Hz, 1 H), 1.59 - 1.70 (m, 1 H), 2.14 - 2.29 (m, 1 H), 2.30 - 2.41 (m, 2 H), 2.75 (br d, J = 12.3 Hz, 1 H), 3.08 - 3.18 (m, 1 H), 3.71 - 3.84 (m, 1 H), 4.23 - 4.50 (m, 1 H), 7.26 - 7.32 (m, 1 H), 7.36 (d, J = 3.9 Hz, 2 H), 7.55 (d, J = 7.9 Hz, 1 H), 9.18 (br d, J = 7.9 Hz, 1 H);ESI-MS m / z [M+H] + 323.2.

[0545] Table 1 lists biological assay data (SSTR4 activity, SSTR4 binding, and SSTR1 binding) for some of the compounds shown in the examples. 50 and pIC 50Higher values ​​represent greater 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 (pEC 50 Many of the compounds shown in Table 1 were also tested according to a membrane-based assay that measures the competitive binding of compounds to SSTR4 and SSTR1 (pIC 50 (The assays are reported as mean ± SEM.) These assays are described above in the section entitled Biological Activity.

[0546] [Table 1-1]

[0547] [Table 1-2]

[0548] As used herein and in the appended claims, singular articles such as "a," "an," and "the" may refer to a single or multiple referents unless the context clearly dictates otherwise. 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 non-limiting. Many embodiments will be apparent to those of skill in the art upon reading the above description. Thus, the scope of the present invention is to be determined with reference to the appended claims, including the full scope of equivalents to such claims. The disclosures of all articles and references cited in this disclosure, including patents, patent applications, and publications, are incorporated herein by reference in their entirety for all purposes.

Claims

1. Compound of formula 1, 【Chemistry 1】 or its salts that are pharmaceutically acceptable (in the formula, X １ N and CR １ Selected from; n is selected from 0 and 1; R １ , R ２ , R ３ , and R4 are independent of each other. (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－３ Alkyl, C １－３ Alkoxy and C ３－６ Selected from cycloalkyl groups (each either unsubstituted or substituted with 1 to 3 substituents independently selected from halos); R5 is hydrogen; L ６ is selected from -CH ２ -, *-N(R ６ )CH ２ - and -O- (R ６ is selected from hydrogen and C １－３ alkyl, and ＊ represents the bonding point of an aromatic ring carbon atom); R ７ and R ８ These are Halo and C, respectively. １－３ Is it independently selected from alkyl (however, R ７ and R ８ (Neither of them is methyl), or R ７ and R ８ They form cyclopropylidene together with the carbon atoms to which they are bonded; R10 is hydrogen, and R9 is, (i) Hydrogen and halos; and (ii) C １－３ Selected from alkyl and phenyl (each either unsubstituted or independently substituted with 1 to 3 substituents selected from halos); R12 is hydrogen, and R11 is hydrogen, halo, and C １－３ Selected from alkyl groups (unsubstituted or substituted with 1 to 3 substituents independently selected from halos); (a) R １３ is hydrogen and C １－３ Selected from alkyl groups; R １４ and R １５ Each of them is either hydrogen; or (b) R １３ and R １４ Together, they form propane-1,3-diyl, which bridges the nitrogen and carbon atoms to which they are bonded; R １５ These are hydrogen, halo, and C １－３ Selected from alkyl groups (unsubstituted or substituted with 1 to 3 substituents independently selected from halos); however, (i) X １ CR １ And L ６ ga-CH ２ - and R ７ and R ８ However, when cyclopropylidene is formed, 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 them is not hydrogen; (ii) X １ CR １ And L ６ ga-CH ２ -, n is 0, R １ , R ２ , R ４ , R ５ , R １１ , R １２ , R １４ and R １５ Each of these is hydrogen, and R ７ and R ８ However, it forms cyclopropylidene, R ９ , R １０ and R １３ If each of them is methyl, then R ３ is not fluoro or hydroxy; (iii)X １ CR １ And L ６ ga-CH ２ -, n is 0, R １ is fluoro, R ２ , R ３ , R ４ , R ５ , R １１ , R １２ , R １４ and R １５ Each of them is hydrogen, and R ７ and R ８ However, when cyclopropylidene is formed, R ９ , R １０ and R １３ Not all are hydrogen, nor are all are methyl; (iv) X １ is CR １ and L ６ is -CH ２ -, n is 1, and 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 when R ７ and R ８ form cyclopropylidene, R ９ is not methyl; (v) X １ CR １ And L ６ ga-CH ２ - and 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 Each of these is hydrogen, and R ７ and R ８ However, when cyclopropylidene is formed, R １１ It is not methyl; (vi)X １ CR １ And n is 0, R １ , R ２ , R ３ , R ４ , R ５ , R １１ , R １２ , R １４ and R １５ Each of these is hydrogen, and R ７ and R ８ However, it forms cyclopropylidene, R ９ and R １０ Each of these is methyl, and R １３ If L is ethyl, ６ It is not -O-; (vii)X １ CR １ And L ６ ga-CH ２ -, n is 0, R １ , R ２ , R ４ , R ５ , R １１ , R １２ , R １４ and R １５ Each of these is hydrogen, and R ７ and R ８ , forms cyclopropylidene, R ９ and R １０ Both are methyl, R １３ If R is ethyl, ３ It is not hydroxyl; (viiii)X １ CR １ And L ６ ga-CH ２ - and n is 1, R ７ and R ８ , forms cyclopropylidene, R １３ and R １４ When they together form propane-1,3-diyl that bridges the nitrogen and carbon atoms to which they are each bonded, 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 them is not hydrogen; (ix)X １ CR １ And L ６ ga-CH ２ - and n is 1, R ７ and R ８ However, it forms cyclopropylidene, R １３ and R １４ Together, they form propane-1,3-diyl, which bridges the nitrogen and carbon atoms to which they are bonded, R ２ , R ３ , R ４ , R ５ , R ９ , R １０ , R １１ , R １２ and R １５ If each of them is hydrogen, then R １ It is not fluoro; (x)X １ CR １ And L ６ ga-CH ２ - and n is 1, R ７ and R ８ However, it forms cyclopropylidene, R １３ and R １４ Together, they form propane-1,3-diyl, which bridges the nitrogen and carbon atoms to which they are bonded, R １ , R ２ , R ４ , R ５ , R ９ , R １０ , R １１ , R １２ and R １５ If each of them is hydrogen, then R ３ (This is not fluoro).

2. X １ CR １ And here R 1 is, (i) hydrogen, halo, and cyano; and (ii) Selected from C1-3 alkyl, C1-3 alkoxy, and C3-6 cycloalkyl (each either unsubstituted or substituted with 1 to 3 substituents independently selected from halos), or R1 is selected from hydrogen, halo, cyano, methyl, methoxy, and cyclopropyl. A compound or pharmaceutically acceptable salt according to claim 1.

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

4. R ２ And R3 are independent of each other. (i) Hydrogen and halos; and (ii) C １－３ Alkyl and C １－３ Selected from alkoxys (each either unsubstituted or substituted with 1 to 3 substituents independently selected from halos), R2 and R3 are each independently selected from hydrogen, halo, methyl, and methoxy. A compound or pharmaceutically acceptable salt according to claim 1.

5. R ４ is selected from hydrogen, halo, methyl and methoxy, or R4 is selected from hydrogen and fluoro. A compound or pharmaceutically acceptable salt according to claim 1.

6. L ６ is, -CH ２ A compound or pharmaceutically acceptable salt according to claim 1, selected from - and -O-.

7. R ７ and R ８ These are independently fluoro and C １－３ Selected from alkyl groups (however, R ７ and R ８ (Neither of them is methyl) or R7 and R8 are both fluoro, or R7 and R8, together with the carbon atoms to which they are bonded, form cyclopropylidene. A compound or pharmaceutically acceptable salt according to claim 1.

8. R ９ is hydrogen, halo, C １－３ Selected from alkyl and phenyl, Optionally, R11 is selected from hydrogen, halo, and methyl. A compound or pharmaceutically acceptable salt according to claim 1.

9. R １３ is hydrogen and C １－３ Selected from alkyl groups, or R 13 is selected from hydrogen and methyl. A compound or pharmaceutically acceptable salt according to claim 1.

10. A compound or pharmaceutically acceptable salt according to claim 1, wherein n is 1.

11. The following compounds: (R)-1-(3-methylbenzyl)-N-(1-methylpyrrolidine-3-yl)cyclopropane-1-carboxamide; N-(1-methyl-4-phenylpyrrolidine-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(trans-4-isopropyl-1-methylpyrrolidine-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(1,3-dimethylpiperidine-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidine-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(1,4-dimethylpyrrolidine-3-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; 1-(2-chlorophenoxy)-N-(trans-3-ethyl-1-methylpiperidine-4-yl)cyclopropane-1-carboxamide; 1-(2-chlorophenoxy)-N-(1,2-dimethylpiperidine-4-yl)cyclopropane-1-carboxamide; 1-(2-chlorophenoxy)-N-(hexahydro-1H-pyrrolidine-1-yl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidine-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidine-4-yl)-1-(4-methylbenzyl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidine-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; 1-(4-fluorobenzyl)-N-((3S,4S)-3-methylpiperidine-4-yl)cyclopropane-1-carboxamide; 2,2-difluoro-2-phenoxy-N-(piperidine-4-yl)acetamide; 1-(3-chlorobenzyl)-N-((3S,4S)-3-methylpiperidine-4-yl)cyclopropane-1-carboxamide; 1-(2-methylbenzyl)-N-((3S,4S)-3-methylpiperidine-4-yl)cyclopropane-1-carboxamide; 1-(2-chlorobenzyl)-N-(trans-1,3-dimethylpiperidine-4-yl)cyclopropane-1-carboxamide; 1-(4-chlorobenzyl)-N-((3S,4S)-3-methylpiperidine-4-yl)cyclopropane-1-carboxamide; N-(trans-1,3-dimethylpiperidine-4-yl)-1-(3-fluorobenzyl)cyclopropane-1-carboxamide; N-(trans-3-ethyl-1-methylpiperidine-4-yl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; 1-(4-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidine-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)-3-phenylpropanamide; 1-(3-chlorobenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 2,2-difluoro-N-(1-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-N-((3S,4S)-3-fluoropiperidine-4-yl)-2-phenoxyacetamide; 1-(4-fluoro-2-methylbenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 1-(4-fluoro-3-methylbenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 2-(2-cyanophenoxy)-2,2-difluoro-N-(piperidine-4-yl)acetamide; 2-(2-cyanophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 2,2-difluoro-N-(piperidine-4-yl)-2-(p-tolyloxy)acetamide; N-((3S,4S)-1,3-dimethylpiperidine-4-yl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide; 1-(3-chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidine-4-yl)cyclopropane-1-carboxamide; 1-(4-chlorobenzyl)-N-((3S,4S)-1,3-dimethylpiperidine-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-1,3-dimethylpiperidine-4-yl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; 1-(4-chlorobenzyl)-N-((3S,4S)-3-fluoro-1-methylpiperidine-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-1,3-dimethylpiperidine-4-yl)-2,2-difluoro-2-phenoxyacetamide; 1-(((6-chloropyridine-2-yl)(methyl)amino)methyl)-N-((2R,4R)-1,2-dimethylpiperidine-4-yl)cyclopropane-1-carboxamide; (R)-2,2-difluoro-2-phenoxy-N-(5-azaspiro[2.4]heptan-7-yl)acetamide; 1-(2-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 1-(3-fluorobenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 1-benzyl-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidine-4-yl)-1-(3-methoxybenzyl)cyclopropane-1-carboxamide; N-((3S,4S)-3-fluoropiperidine-4-yl)-1-(2-methoxybenzyl)cyclopropane-1-carboxamide; 2,2-difluoro-N-((2S,4S)-2-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-2-phenoxy-N-(5-azaspiro[2.5]octan-8-yl)acetamide; 2,2-difluoro-N-(cis-2-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-N-((2R,4R)-2-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-N-((2R,4S)-2-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-N-((2S,4R)-2-methylpiperidine-4-yl)-2-phenoxyacetamide; 2,2-difluoro-2-(2-fluorophenoxy)-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 2,2-difluoro-2-(3-fluorophenoxy)-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)-2-(o-tolyloxy)acetamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)-2-(m-tolyloxy)acetamide; 2,2-difluoro-2-(4-fluorophenoxy)-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 1-(3-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 1-(2-cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 2-(2-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 2-(3-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 2-(4-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)acetamide; 1-(3-fluoro-5-methoxybenzyl)-N-((3S,4S)-3-fluoropiperidine-4-yl)cyclopropane-1-carboxamide; 2,2-difluoro-N-((3S,4S)-3-methylpiperidine-4-yl)-2-(p-tolyloxy)acetamide; 2-(2-chlorophenoxy)-2,2-difluoro-N-(piperidine-4-yl)acetamide; 2-(2-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-fluoropiperidine-4-yl)acetamide; and The compound according to claim 1, selected from any one pharmaceutically acceptable salt of the aforementioned compounds.

12. The following compounds: 3-(4-chlorophenyl)-2,2-dimethyl-N-((3S,4S)-3-methylpiperidine-4-yl)propanamide; 2-(2,3-dichlorophenoxy)-N-((3S,4S)-3-fluoropiperidine-4-yl)propanamide; 2-(2-chlorophenoxy)-N-((3S,4S)-3-fluoropiperidine-4-yl)propanamide; 2-(2-cyclopropylphenoxy)-N-((3S,4S)-3-fluoropiperidine-4-yl)propanamide; 2-(2-chlorophenoxy)-N-((2R,4R)-1,2-dimethylpiperidine-4-yl)propanamide; and A compound selected from any one of the pharmaceutically acceptable salts of the aforementioned compounds.

13. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 12, for use as a pharmaceutical agent.

14. A compound of formula 1 for use as a pharmaceutical agent, 【Chemistry 2】 or its salts that are pharmaceutically acceptable (in the formula, X １ N and CR １ Selected from; n is selected from 0 and 1; R １ , R ２ , R ３ , R ４ , and R ５ Each of them is independent, (i) hydrogen, halo, hydroxy, and cyano; and (ii) C １－３ Alkyl, C １－３ Alkoxy, and C ３－６ Selected from cycloalkyl groups (each either unsubstituted or substituted with 1 to 3 substituents independently selected from halos); L ６ is, -CH ２ -, -N(R ６ ) - ＊ -N(R) ６ )CH ２ - and -O- are selected (R ６ is hydrogen and C １－３ Selected from alkyl groups, ＊ (This represents the bond point of an aromatic ring carbon atom); R ７ and R ８ These are, independently, hydrogen, halo, and C. １－３ Selected from alkyl groups, R ７ and R ８ At least one of them is not hydrogen, or R ７ and R ８ C ３－６ Forming cycloalkylidenes; R ９ and R １０ Each of them is independent, (i) Hydrogen and halos; and (ii) C １－３ Selected from alkyl and phenyl (each either unsubstituted or independently substituted with 1 to 3 substituents selected from halos), R ９ and R １０ Together with the carbon atoms to which they are bonded, they form cyclopropylidene; R １１ and R １２ These are, independently, hydrogen, halo, and C. １－３ Alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halos, provided R １１ and R １２ Selected from (where one or less of the molecules are methyl); (a) R １３ is hydrogen and C １－３ Selected from alkyl groups; R １４ and R １５ These are, independently, hydrogen, halo, and C. １－３ Alkyl (unsubstituted or substituted with 1 to 3 substituents independently selected from halos, provided R １４ and R １５ Selected from (where one or less of them are methyl); or (b) R １３ and R １４ Together, they form propane-1,3-diyl, which bridges the nitrogen and carbon atoms to which they are bonded; R １５ These are hydrogen, halo, and C １－３ Selected from alkyl groups (unsubstituted or substituted with 1 to 3 substituents independently selected from halos); however, (i) X is CR １ And n is 1, L ６ is -O-, R ７ is methyl, R ８ If R is hydrogen, 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 them is not hydrogen; (ii) X is CR １ And n is 1, L ６ is -O-, R ７ and R ８ Both are methyl, R １ , R ２ , R ４ , R ５ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ and R １５ If each of them is hydrogen, then R ３ It is not chloro; (iii) X is CR １ And n is 1, L ６ is -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 If each of them is hydrogen, then R ９ It is not an unsubstituted phenyl, Optionally, R7 and R8 are each independently selected from halo and C1-3 alkyl groups, provided that neither R7 nor R8 is methyl.

15. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 12 for use in treating a disease, disorder or condition selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and attention deficit hyperactivity disorder.

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