N-(1-(aminomethyl)cyclopropyl)(ARYL or heteroaryl) carboxamide derivatives

Abstract

Disclosed are compounds of Formula (1), and pharmaceutically acceptable salts thereof, wherein G, m, n, R8, R9, R10, R11, and R12 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula (1), to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with SSTR4.

Description

N-(1-(AMINOMETHYL)CYCLOPROPYL)(ARYL OR HETEROARYL) CARBOXAMIDE DERIVATIVES FIELD OF THE INVENTION

[0001] This invention relates to N-(1-(aminomethyl)cyclopropyl)(aryl or heteroaryl) carboxamide derivatives which are modulators of somatostatin receptor 4 (SSTR4), to pharmaceutical compositions which contain them, and to their use to treat diseases, disorders, and conditions associated with SSTR4, including Alzheimer’s disease. BACKGROUND OF THE INVENTION

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

[0003] Experiments using bacTRAP technology indicate SSTR4 has its strongest expression in the 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 L.R. Squire and A.J. Dede, “Conscious and Unconscious Memory Systems,” Cold Spring Harbor Perspectives in Biology 7:a021667 (2015). Indeed, the CA1 region of the hippocampus is the last station in the trisynaptic circuit that governs learning. This circuit starts in the entorhinal cortex, which also contains SSTR4, extends into the dentate gyrus, then into CA3, and finally reaches the CA1 region of the hippocampus. CA1 projects out of the hippocampus through the subiculum. This circuit encodes all types of information from the external world in order to generate memories and to learn new knowledge.

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

[0005] Moreover, recent studies also point to hyperactivity of the hippocampus as a main driver for disease progression as well as impairment of cognitive abilities in Alzheimer’s patients. See M.A. Busche et al., “Decreased Amyloid-β and Increased Neuronal Hyperactivity by Immunotherapy in Alzheimer’s Models,” Nature Neuroscience 18(12):1725-27 (2015); see also K. Yamamoto et al., “Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease,” Cell Reports 11(6):859- 65 (2015). Activation of SSTR4 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 for the receptor will likely represent good pharmacological tools to inhibit and control neuronal activity in the cortex and hippocampus.

[0006] SSTR4 agonists are expected to be useful for treating Alzheimer’s disease and other CNS and neurological disorders such as epilepsy, depression and pain. SUMMARY OF THE INVENTION

[0007] This invention provides N-(1-(aminomethyl)cyclopropyl)(aryl or heteroaryl) carboxamide derivatives and pharmaceutically acceptable salts thereof. This invention also provides pharmaceutical compositions that contain the N-(1-(aminomethyl)cyclopropyl)(aryl or heteroaryl) carboxamide derivatives and provides for their use to treat diseases, disorders and conditions associated with SSTR4, including Alzheimer’s disease and other neurological disorders.

[0008] One aspect of the invention provides a compound of Formula 1: or a pharmaceuticallyG is a cyclic group represented by Formula G-1, G-2, G-3 or G-4: R2X1,X1is from CR1and N; X3is selected from CR3and N; n is selected from 0, 1, 2, 3 and 4; R1, R2, R3and R4are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4alkyl, C3-6cycloalkyl, and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and (a) when G is represented by G-1: m is 1; L1is selected from CR6R7, O and a bond; R5is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R6and R7are each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo, or R6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (b) when G is represented by G-2: m is 1; andX5ais selected from NR5aand O, wherein R5ais selected from hydrogen, C1-4 alkyl, and C3-6cycloalkyl; (c) when G is represented by G-3: m is 1; X6ais selected from CR6aand N, wherein R6ais selected from hydrogen and C1-4 alkyl; and R5bis selected from: (i) hydrogen, halo, and (ii) C1-4 alkyl and C3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo; and (d) when G is represented by G-4: m is 0; p is selected from 0 and 1; X5cis selected from CH2, NR5cand O, wherein R5cis selected from hydrogen, C1-4alkyl, and C3-6 cycloalkyl; and R9ais selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, and C1-4 alkoxy; R8and R9are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4alkyl and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-4 alkoxy, or R8and R9, together with the carbon atom to which they are attached, form a C3-5oxacycloalkylidene, which is unsubstituted, or a C3-6 cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; R10at each occurrence is independently selected from halo; and R11and R12are each independently selected from C1-4alkyl, or R11and R12, together with the nitrogen atom to which they are attached, form a C3-5 heterocyclyl group selected from azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-4alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

[0009] Another aspect of the invention provides a compound which is selected from the group of compounds described in the examples and their pharmaceutically acceptable salts.

[0010] A further aspect of the invention provides a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs for use as a medicament.

[0011] An additional aspect of the invention provides a pharmaceutical composition which includes a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs; and a pharmaceutically acceptable excipient.

[0012] Another aspect of the invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, for treatment of a disease, disorder or condition associated with SSTR4.

[0013] A further aspect of the invention provides a use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with SSTR4.

[0014] An additional aspect of the invention provides a method of treating a disease, disorder or condition associated with SSTR4, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs.

[0015] Another aspect of the invention provides a method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs, wherein the disease, disorder or condition is selected from Alzheimer’s disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

[0016] A further aspect of the invention provides an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraphs; and at least one additional pharmacologically active agent. DETAILED DESCRIPTION OF THE INVENTION

[0017] Unless otherwise indicated, this disclosure uses definitions provided below.

[0018] “Substituted,” when used in connection with a chemical substituent or moiety (e.g., a C1-6alkyl group), means that one or more hydrogen atoms of the substituent or moiety havebeen replaced with one or more non-hydrogen atoms or groups, provided valence requirements are met and a chemically stable compound results from the substitution.

[0019] “About” or “approximately,” when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0020] “Alkyl” refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (e.g., C1-4alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, and so on). Examples of alkyl groups include methyl, ethyl, n-propyl, 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.

[0021] “Alkanediyl” refers to divalent alkyl groups, where alkyl is defined above, and generally having a specified number of carbon atoms (e.g., C1-4alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6 alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, and so on). Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane- 1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0022] “Alkenyl” refers to straight chain and branched hydrocarbon groups having one or more carbon-carbon double bonds, and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1- buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1- propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0023] “Alkynyl” refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon 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.

[0024] “Alkoxy” refers to straight chain and branched saturated hydrocarbon groups attached through an oxygen atom, generally having a specified number of carbon atoms (e.g., C1-4alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, C1-6alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, and so on). 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.

[0025] “Halo,” “halogen” and “halogeno” may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0026] “Haloalkyl,” “haloalkenyl,” and “haloalkynyl,” refer, respectively, to alkyl, alkenyl, and alkynyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, and alkynyl are defined above, and generally having a specified number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1- chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0027] “Cycloalkyl” refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings (e.g., C3-8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members). Bicyclic hydrocarbon groups may include isolated rings (two rings sharing no carbon atoms), spiro rings (two rings sharing one carbon atom), fused rings (two rings sharing two carbon atoms and the bond between the two common carbon atoms), and bridged rings (two rings sharing two carbon atoms, but not a common bond). The cycloalkyl group may be attached through any ring atom unless such attachment would violate valence requirements, and where indicated, may optionally include one or more non-hydrogen substituents unless such substitution would violate valence requirements.

[0028] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. 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 spiro cycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, and the like. Examples of isolated bicyclic cycloalkyl groups include those derived from bi(cyclobutane),cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.

[0029] “Cycloalkanediyl” refers to divalent cycloalkyl groups, where cycloalkyl is defined above, and generally having a specified number of carbon atoms (e.g., C3-5cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4 or 5) carbon atoms, C3-6 cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, and so on). Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0030] “Cycloalkylidene” refers to divalent monocyclic cycloalkyl groups, where cycloalkyl is defined above, which are attached through a single carbon atom of the group, and generally having a specified number of carbon atoms that comprise the ring (e.g., C3-6 cycloalkylidene refers to a cycloalkylidene group having 3 to 6 carbon atoms as ring members). Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0031] “Oxacycloalkylidene” refers to a cycloalkylidene group as defined above, where one of the carbon ring atoms is replaced with an oxygen atom, and generally having a specified number of carbon atoms that comprise the ring (e.g., C3-5 oxacycloalkylidene refers to a cycloalkylidene group having 3 to 5 carbon atoms and one oxygen atom as ring members). Examples include 2-oxacyclobutylidene, 3-oxacyclobutylidene, 2- oxacyclopentylidene, 3-oxacyclopentylidene, 2-oxacyclohexylidene, 3-oxacyclohexylidene, and 4-oxacyclohexylidene.

[0032] “Cycloalkenyl” refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings. As with cycloalkyl groups, the bicyclic cycloalkenyl groups may include isolated, spiro, fused, or bridged rings. Similarly, the cycloalkenyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of cycloalkenyl groups include the partially unsaturated analogs of the cycloalkyl groups described above, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0033] “Aryl” refers to fully unsaturated monocyclic aromatic hydrocarbons and to polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ringmembers (e.g., C6-14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members). The group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from cycloheptatriene cation, and the like.

[0034] “Arylene” refers to divalent aryl groups, where aryl is defined above. Examples of arylene groups include o-phenylene (i.e., benzene-1,2-diyl).

[0035] “Heterocycle” and “heterocyclyl” may be used interchangeably and refer to saturated or partially unsaturated monocyclic or bicyclic groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C2-6 heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members). As with bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4- oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4- thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6- dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, and 1,2-dihydropyrazolo[1,5- d][1,2,4]triazinyl.

[0036] “Heterocycle-diyl” refers to heterocyclyl groups which are attached through two ring atoms of the group, where heterocyclyl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C2-6 heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members). Examples of heterocycle-diyl groups include the multivalent analogs of the heterocycle groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene, 3- oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

[0037] “Heteroaromatic” and “heteroaryl” may be used interchangeably and refer to unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each of the groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C1-9heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members) and may include any bicyclic group in which any of the above- listed monocyclic heterocycles are fused to a benzene ring. The heteroaryl group may be attached through any ring atom (or ring atoms for fused rings), and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5- diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0038] Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H- isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2- c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5- c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4- c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2- c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6- naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4- b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5- d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-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.

[0039] “Heteroarylene” refers to heteroaryl groups which are attached through two ring atoms of the group, where heteroaryl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C3-5 heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members). Examples of heteroarylene groups include the multivalent analogs of the heteroaryl groups described above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4- diyl, and the like.

[0040] “Oxo” refers to a double bonded oxygen (=O).

[0041] “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 may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH2- and OH- can be made better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO2, and metals.

[0042] “Opposite enantiomer” refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all the stereogenic 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. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0043] “Stereoisomer” and “stereoisomers” of a compound with given stereochemical configuration refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (Z / E) of the compound. For example, if a compound has S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and 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.

[0044] “Substantially pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.

[0045] “Pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample.

[0046] “Subject” refers to a mammal, including a human.

[0047] “Pharmaceutically acceptable” substances refer to those substances which are suitable for administration to subjects.

[0048] “Treating” refers to reversing, alleviating, inhibiting the progress of, or preventing a disease, disorder or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disease, disorder or condition.

[0049] “Treatment” refers to the act of “treating,” as defined immediately above.

[0050] “Drug,” “drug substance,” “active pharmaceutical ingredient,” and the like, refer to a compound (e.g., compounds of Formula 1, including subgeneric compounds and compounds specifically named in the specification) that may be used for treating a subject in need of treatment.

[0051] “Effective amount” of a drug, “therapeutically effective amount” of a drug, and the like, refer to the quantity of the drug that may be used for treating a subject and may depend on the weight and age of the subject and the route of administration, among other things.

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

[0053] “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients.

[0054] “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 of treatment and generally may be in the form of tablets, capsules, sachets containing powder or granules, liquid solutions or suspensions, patches, films, and the like.

[0055] “Condition associated with SSTR4” and similar phrases relate to a disease, disorder or condition in a subject for which activation of SSTR4 may provide a therapeutic or prophylactic benefit.

[0056] The following abbreviations may be used in the specification: Ac (acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); Boc (tert-butoxycarbonyl); Cbz (carbobenzyloxy); DAST (diethylaminosulfur trifluoride); dba (dibenzylideneacetone); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1- dichloroethane); DCM (dichloromethane); DEA (diethylamine); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine, Hünig’s Base); 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); EC50 (effective concentration at half maximal response); EDA (ethoxylated dodecyl alcohol, Brj®35); EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq (equivalents); 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); IC50(concentration at 50% inhibition); IPA (isopropanol); IPAc (isopropyl acetate); IPE (isopropylether); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperoxybenzoic acid); Me (methyl); MeOH (methanol); MTBE (methyl tert-butyl ether); mp (melting point); NaOt-Bu (sodium tertiary butoxide); NMM (N-methylmorpholine); NMP (N-methyl-pyrrolidone); OTf (triflate); PE (petroleum ether); Ph (phenyl); pEC50(-log10(EC50), where EC50is given in molar (M) units); pIC50 (-log10(IC50), where IC50 is given in molar (M) units); Pr (propyl); c-Pr (cyclopropyl), i- Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP® (bromotripyrrolidino- phosphonium 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)phos- phine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMS (trimethylsilyl); TMU (tetramethylurea); and Tris buffer (2-amino-2- hydroxymethyl-propane-1,3-diol buffer).

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

[0058] The compounds of Formula 1 include those in which: (1) G is a cyclic group represented by Formula G-1, G-2, G-3 or G-4: ,X1is from CR1and N; X3is selected from CR3and N; n is selected from 0, 1, 2, 3 and 4; R1, R2, R3and R4are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and (a) when G is represented by G-1: m is 1; L1is selected from CR6R7, O and a bond; R5is selected from: (i) hydrogen, halo, hydroxy, cyano, and(ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R6and R7are each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo, or R6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected from hydrogen, halo, and C1-4alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (b) when G is represented by G-2: m is 1; and X5ais selected from NR5aand O, wherein R5ais selected from hydrogen, C1-4 alkyl, and C3-6cycloalkyl; (c) when G is represented by G-3: m is 1; X6ais selected from CR6aand N, wherein R6ais selected from hydrogen and C1-4 alkyl; and R5bis selected from: (i) hydrogen, halo, and (ii) C1-4alkyl and C3-6cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo; and (d) when G is represented by G-4: m is 0; p is selected from 0 and 1; X5cis selected from CH2, NR5cand O, wherein R5cis selected from hydrogen, C1-4 alkyl, and C3-6cycloalkyl; and R9ais selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, and C1-4 alkoxy; R8and R9are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4alkyl and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-4 alkoxy, orR8and R9, together with the carbon atom to which they are attached, form a C3-5 oxacycloalkylidene, which is unsubstituted, or a C3-6cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; R10at each occurrence is independently selected from halo; and R11and R12are each independently selected from C1-4 alkyl, or R11and R12, together with the nitrogen atom to which they are attached, form a C3-5heterocyclyl group selected from azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

[0059] In addition to embodiment (1) in the preceding paragraph, the compounds of Formula 1 include those in which: (2) X1is CR1.

[0060] In addition to embodiment (2) in the preceding paragraph, the compounds of Formula 1 include those in which R1is selected from: (3) (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (4) (i) hydrogen, halo, and (ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (5) (i) hydrogen, halo, and (ii) C1-3alkyl, C3-6cycloalkyl, and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (6) (i) hydrogen, halo, hydroxy, cyano, and (ii) methyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (7) (i) hydrogen, halo, and (ii) methyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (8) hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, and cyclopropyl; (9) hydrogen, halo and methyl; or(10) hydrogen.

[0061] In addition to embodiment (1) above, the compounds of Formula 1 include those in which: (11) X1is N.

[0062] In addition to embodiments (1) to (11) in the preceding paragraphs, the compounds of Formula 1 include those in which: (12) X3is CR3.

[0063] In addition to embodiment (12) in the preceding paragraph, the compounds of Formula 1 include those in which R3is selected from: (13) (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (14) (i) hydrogen, halo, cyano, and (ii) C1-4alkyl, C3-6cycloalkyl, and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (15) (i) hydrogen, halo, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (16) (i) hydrogen, halo, hydroxy, cyano, and (ii) methyl, ethyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (17) (i) hydrogen, halo, cyano, and (ii) methyl, ethyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (18) (i) hydrogen, halo, cyano, and (ii) methyl, ethyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (19) hydrogen, fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy; (20) hydrogen, fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, and methoxy; (21) hydrogen, halo, methyl, and methoxy; or (22) hydrogen.

[0064] In addition to embodiments (1) to (11) in the preceding paragraphs, the compounds of Formula 1 include those in which: (23) X3is N.

[0065] In addition to embodiments (1) to (23) in the preceding paragraphs, the compounds of Formula 1 include those in which R2is selected from: (24) (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (25) (i) hydrogen, halo, cyano, and (ii) C1-4alkyl, C3-6cycloalkyl, and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (26) (i) hydrogen, halo, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (27) (i) hydrogen, halo, hydroxy, cyano, and (ii) methyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (28) (i) hydrogen, halo, cyano, and (ii) methyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (29) (i) hydrogen, halo, cyano, and (ii) methyl and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (30) hydrogen, fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, and cyclopropyl; (31) hydrogen, fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, and trifluoromethoxy; (32) hydrogen, halo, methyl, and methoxy; or (33) hydrogen.

[0066] In addition to embodiments (1) to (33) in the preceding paragraphs, the compounds of Formula 1 include those in which R4is selected from: (34) (i) hydrogen, halo, hydroxy, cyano, and(ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (35) (i) hydrogen, halo, and (ii) C1-4alkyl, C3-6cycloalkyl, and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (36) (i) hydrogen, halo, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (37) (i) hydrogen, halo, hydroxy, cyano, and (ii) methyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (38) (i) hydrogen, halo, and (ii) methyl, cyclopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (39) (i) hydrogen, halo, and (ii) methyl and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (40) hydrogen, fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, and cyclopropyl; (41) hydrogen, halo, methyl, and methoxy; (42) hydrogen, fluoro, chloro, methyl, and methoxy; or (43) hydrogen.

[0067] In addition to embodiments (1) to (43) in the preceding paragraphs, the compounds of Formula 1 include those in which: (44) G is a cyclic group represented by Formula G-1, , L1is selected from CR6R7, O andR5is selected from: (i) hydrogen, halo, hydroxy, cyano, and(ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R6and R7are each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo, or R6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

[0068] In addition to embodiment (44) in the preceding paragraph, the compounds of Formula 1 include those in which: (45) L1is CR6R7.

[0069] In addition to embodiment (45) in the preceding paragraph, the compounds of Formula 1 include those in which R6and R7are each independently selected from: (46) hydrogen, halo, and C1-4alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (47) hydrogen, halo, and C1-3 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (48) hydrogen, halo, and C1-3 alkyl; (49) hydrogen, halo, and methyl; (50) hydrogen, fluoro, and methyl; or (51) hydrogen.

[0070] In addition to embodiment (45) above, the compounds of Formula 1 include those in which R6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected from: (52) hydrogen, halo, and C1-4alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (53) hydrogen, halo, and C1-3alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (54) hydrogen, halo, and methyl which is substituted with 0 to 3 optional substituents independently selected from halo; (55) hydrogen, halo, and methyl; (56) hydrogen, fluoro, and methyl; or (57) hydrogen.

[0071] In addition to embodiments (52) to (56) in the preceding paragraph, the compounds of Formula 1 include those in which: (58) R7aand R8aare the same.

[0072] In addition to embodiment (44) above, the compounds of Formula 1 include those in which: (59) L1is O; or (60) L1is a bond.

[0073] In addition to embodiments (44) to (60) above, the compounds of Formula 1 include those in which R5is selected from: (61) (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (62) (i) hydrogen, halo, and (ii) C1-4alkyl, C3-6cycloalkyl, and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (63) (i) hydrogen, halo, and (ii) C1-4 alkyl and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (64) (i) hydrogen, halo, and (ii) C1-3 alkyl and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; (65) hydrogen, halo, C1-4 alkyl, and C1-4 alkoxy; (66) hydrogen, halo, C1-3alkyl, and C1-3alkoxy; (67) hydrogen, halo, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, and trifluoromethoxy; (68) hydrogen, halo, methyl, and methoxy; (69) hydrogen, chloro, fluoro, methyl, and methoxy; or (70) hydrogen.

[0074] In addition to embodiments (1) to (43) above, the compounds of Formula 1 include those in which: (71) G is a cyclic group represented by Formula G-2,R2X1N , X5ais selected from NR5aand O; 5aR is selected from hydrogen, C1-4 6

[0075] In addition to embodiment (71) in the preceding paragraph, the compounds of Formula 1 include those in which: (72) X5ais NR5a.

[0076] In addition to embodiment (72) in the preceding paragraph, the compounds of Formula 1 include those in which R5ais selected from: (73) hydrogen, C1-3alkyl, and C3-6cycloalkyl; (74) C1-4 alkyl and C3-6 cycloalkyl; (75) C1-3alkyl and C3-6cycloalkyl; (76) C1-3 alkyl; (77) methyl and cyclopropyl; or (78) methyl.

[0077] In addition to embodiment (71) above, the compounds of Formula 1 include those in which: (79) X5ais O.

[0078] In addition to embodiments (1) to (43) above, the compounds of Formula 1 include those in which: (80) G is a cyclic group represented by Formula G-3, , X6ais selected from CR6aand N;R6ais selected from hydrogen and C1-4alkyl; and R5bis selected from:(i) hydrogen, halo, and (ii) C1-4alkyl and C3-6cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo.

[0079] In addition to embodiment (80) in the preceding paragraph, the compounds of Formula 1 include those in which: (81) X6ais CR6a.

[0080] In addition to embodiment (81) in the preceding paragraph, the compounds of Formula 1 include those in which R6ais selected from: (82) hydrogen and C1-3 alkyl; (83) hydrogen and methyl; or (84) hydrogen.

[0081] In addition to embodiment (80) above, the compounds of Formula 1 include those in which: (85) X6ais N.

[0082] In addition to embodiments (80) to (85) in the preceding paragraphs, the compounds of Formula 1 include those in which R5bis selected from: (86) (i) hydrogen, halo, and (ii) C1-3 alkyl and C3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo; (87) hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (88) hydrogen, halo, and C1-3 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (89) hydrogen, halo, and methyl which is substituted with 0 to 3 optional substituents independently selected from halo; (90) hydrogen, halo, methyl and trifluoromethyl; (91) hydrogen, chloro, methyl and trifluoromethyl; (92) hydrogen and methyl; or (93) hydrogen.

[0083] In addition to embodiments (1) to (43) above, the compounds of Formula 1 include those in which: (94) G is a cyclic group represented by Formula G-4,, p is selected from 0 and 1; X5cis selected from CH2, NR5cand O; R5cis selected from hydrogen, C1-4alkyl, and C3-6cycloalkyl; and R9ais selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, and C1-4 alkoxy.

[0084] In addition to embodiment (94) in the preceding paragraph, the compounds of Formula 1 include those in which: (95) X5cis NR5c.

[0085] In addition to embodiment (95) in the preceding paragraph, the compounds of Formula 1 include those in which R5cis selected from: (96) hydrogen, C1-3alkyl, and C3-6cycloalkyl; (97) hydrogen and C1-4 alkyl; (98) hydrogen and C1-3alkyl; (99) hydrogen and methyl; or (100) methyl.

[0086] In addition to embodiment (94) above, the compounds of Formula 1 include those in which: (101) X5cis CH2; or (102) X5cis O.

[0087] In addition to embodiments (94) to (102) above, the compounds of Formula 1 include those in which: (103) p is 0; or (104) p is 1.

[0088] In addition to embodiments (94) to (104) above, the compounds of Formula 1 include those in which R9ais selected from: (105) hydrogen, halo, hydroxy, cyano, C1-3 alkyl, and C1-3 alkoxy; (106) hydrogen, hydroxy, and C1-4 alkyl; (107) hydrogen, hydroxy, and methyl; or(108) hydrogen.

[0089] In addition to embodiments (1) to (108) above, the compounds of Formula 1 include those in which R8and R9are each independently selected from: (109) (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4 alkyl and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-4alkoxy; (110) (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3alkyl and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-3 alkoxy; (111) (i) hydrogen, halo, hydroxy, and (ii) C1-4 alkyl and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-4alkoxy; (112) (i) hydrogen, halo, hydroxy, and (ii) C1-3alkyl and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-3 alkoxy; (113) (i) hydrogen, halo, hydroxy, and (ii) methyl, ethyl, isopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-3 alkoxy; (114) (i) hydrogen, halo, hydroxy, and (ii) methyl, ethyl, isopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from halo and methoxy; (115) (i) hydrogen, halo, hydroxy, and (ii) methyl, ethyl, isopropyl, and methoxy, each substituted with 0 to 3 optional substituents independently selected from fluoro and methoxy; or (116) hydrogen, chloro, fluoro, hydroxy, methyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, methoxy, and methoxymethyl.

[0090] In addition to embodiments (1) to (108) above, the compounds of Formula 1 include those in which R8and R9, together with the carbon atom to which they are attached, form: (117) a C3-5oxacycloalkylidene, which is unsubstituted, or a C3-6cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; (118) a C3-4oxacycloalkylidene, which is unsubstituted, or a C3-6cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo;(119) a C3 oxacycloalkylidene, which is unsubstituted, or a C3-6 cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; (120) a C3 oxacycloalkylidene, which is unsubstituted, or a C3-5 cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; (121) a C3 oxacycloalkylidene, which is unsubstituted, or a C3-4 cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; (122) 3-oxacyclobutylidene, which is unsubstituted, or a C3-4 cycloalkylidene, which is substituted with 0 to 2 optional substituents independently selected from halo; (123) 3-oxacyclobutylidene, which is unsubstituted, or a C3-4 cycloalkylidene, which is substituted with 0 to 4 optional substituents selected from fluoro; (124) 3-oxacyclobutylidene, which is unsubstituted, or a C3-4 cycloalkylidene, which is substituted with 0 to 2 optional substituents selected from fluoro; or (125) 3-oxacyclobutylidene, cyclopropylidene, 2,2-difluorocyclopropylidene, cyclobutylidene, and 3,3-difluorocyclobutylidene.

[0091] In addition to embodiments (1) to (125) above, the compounds of Formula 1 include those in which: (126) R10at each occurrence is fluoro; or (127) n is 0.

[0092] In addition to embodiments (1) to (127) above, the compounds of Formula 1 include those in which R11and R12are each independently selected from: (128) C1-4alkyl; (129) C1-3 alkyl; (130) methyl and ethyl; or (131) methyl.

[0093] In addition to embodiments (128) to (130) in the preceding paragraph, the compounds of Formula 1 include those in which: (132) R11and R12are both the same.

[0094] In addition to embodiments (1) to (127) above, the compounds of Formula 1 include those in which R11and R12, together with the nitrogen atom to which they are attached, form a C3-5 heterocyclyl group selected from: (133) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo;(134) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-3alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (135) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (136) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from C1-3alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (137) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-4 alkyl; (138) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from C1-4 alkyl; (139) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from C1-3 alkyl; or (140) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from methyl.

[0095] In addition to embodiments (133) to (140) in the preceding paragraph, the compounds of Formula 1 include those in which R11and R12, together with the nitrogen atom to which they are attached, form a C3-5 heterocyclyl group selected from: (141) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 3 optional substituents; (142) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 2 optional substituents; or (143) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 1 optional substituents.

[0096] In addition to embodiment (133) above, the compounds of Formula 1 include those in which R11and R12, together with the nitrogen atom to which they are attached, form a C3-5 heterocyclyl group selected from: (144) azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each unsubstituted.

[0097] In addition to embodiments (133) to (144) above, the compounds of Formula 1 include those in which R11and R12, together with the nitrogen atom to which they are attached, form a C3-5heterocyclyl group which is:(145) substituted or unsubstituted azetidin-1-yl; (146) substituted or unsubstituted pyrrolidin-1-yl; or (147) substituted or unsubstituted piperidin-1-yl.

[0098] Compounds of Formula 1 include embodiments (1) through (147) described in the preceding paragraphs and compounds specifically named in the examples, may exist as salts, complexes, solvates, hydrates, and liquid crystals. Likewise, compounds of Formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0099] Compounds of Formula 1 may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including di-acids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0100] Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as 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 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).

[0101] Pharmaceutically acceptable salts may be prepared using various methods. For example, a compound of Formula 1 may be reacted with an appropriate acid or base to givethe desired salt. Alternatively, a precursor of the compound of Formula 1 may be reacted with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, a salt of the compound of Formula 1 may be converted to another salt (or free form) through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, the salt may be isolated by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

[0102] 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 the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”). The term “crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).

[0103] Compounds of Formula 1 may also exist in unsolvated and solvated forms. The term “solvate” describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term “hydrate” is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0104] A currently accepted classification system for solvates and hydrates of organic compounds is one that distinguishes between isolated site, channel, and metal-ion coordinated solvates and hydrates. See, e.g., K. R. Morris (H. G. Brittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are ones 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.

[0105] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will typically be observed.

[0106] Compounds of Formula 1 may also exist as multi-component 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. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions but could also be a complex of a neutral molecule with a salt. Co- crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson and M. J. Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0107] When subjected to suitable conditions, compounds of Formula 1 may exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state lies between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as “thermotropic” and mesomorphism resulting from the addition of a second component, such as water or another solvent, is described as “lyotropic.” Compounds that have the potential to form lyotropic mesophases are described as “amphiphilic” and include molecules which possess a polar ionic moiety (e.g., -COOˉNa+, -COOˉK+, -SO3ˉNa+) or polar non-ionic moiety (such as -NˉN+(CH3)3). See, e.g., N. H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

[0108] Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically-labeled, may result from the administration of a prodrug, or form a metabolite following administration.

[0109] “Prodrugs” refer to compounds having little or no pharmacological activity that can, when metabolized in vivo, undergo conversion to compounds having desired pharmacological activity. Prodrugs may be prepared by replacing appropriate functionalities present in pharmacologically active compounds with “pro-moieties” as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or amide derivatives of compounds of Formula 1 having carboxylic acid, hydroxy, or amino functionalgroups, respectively. For further discussions of prodrugs, see e.g., T. Higuchi and V. Stella “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series 14 (1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design (1987).

[0110] “Metabolites” refer to compounds formed in vivo upon administration of pharmacologically active compounds. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

[0111] Compounds of Formula 1 may exist as stereoisomers that result from the presence of one or more stereogenic 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 counter-ion is optically active, for example, when the counter-ion is D-lactate or L-lysine.

[0112] Compounds of Formula 1 may 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.

[0113] Compounds of Formula 1 may exhibit more than one type of isomerism.

[0114] Geometrical (cis / trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

[0115] Conventional techniques for preparing or isolating a compound having a specific stereochemical configuration include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula 1 contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, etc., and the appropriate diastereoisomer converted to the compound having the requisite stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds (1994).

[0116] Compounds of Formula 1 may possess 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. Isotopes suitable for inclusion in compoundsof Formula 1 include, for example, isotopes of hydrogen, such as2H and3H; isotopes of carbon, such as11C,13C and14C; isotopes of nitrogen, such as13N and15N; isotopes of oxygen, such as15O,17O and18O; isotopes of sulfur, such as35S; isotopes of fluorine, such as18F; isotopes of chlorine, such as36Cl, and isotopes of iodine, such as123I and125I. Use of isotopic variations (e.g., deuterium,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium,3H, or14C), which may be useful in drug and / or substrate tissue distribution studies. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds may be prepared by processes analogous to those described elsewhere in the disclosure using an appropriate isotopically-labeled reagent in place of a non-labeled reagent.

[0117] The compounds of Formula 1 may be prepared using the techniques described in the specification, including Schemes A-O in the examples and general Scheme P, below. Some of the methods and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in several treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Starting materials and reagents may be obtained from commercial sources or may be prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO2from the decarboxylation of a di-acid, etc.). In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0118] In the methods and examples below, certain compounds may be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids,alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0119] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C). Any reference in the disclosure and claims to a stoichiometric range, a temperature range, a pH range, etc., whether expressly using the word “range,” also includes the indicated endpoints.

[0120] Many of the chemical transformations may also employ one or more compatible solvents, which may influence 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, xylenes); 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, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2- ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy- ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1,-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

[0121] In the scheme, below, substituent identifiers (e.g., G, m, n, R8, R9, R10, R11and R12) are as defined above for Formula 1. As mentioned earlier, some of the starting materials and intermediates may include protecting groups, which are removed prior to the final product. In such cases, the substituent identifier refers to moieties defined in Formula 1 and to thosemoieties with appropriate protecting groups. For example, a starting material or intermediate in the synthetic methods may include a potentially reactive (secondary) amine. In such cases, the amine would include the moiety with or without, say, a Boc or Cbz group attached to the amine.

[0122] Scheme P shows a general method for preparing compounds of Formula 1. In accordance with the method, an aryl or heteroaryl(alkyl or oxyalkyl)carboxylic acid (P1) is reacted with a primary amine (P2) or suitable base addition salt (e.g., lithium salt). The reaction is carried out using standard amide coupling agents, 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). The amide coupling may be carried out at temperatures which range from room temperature to about 80°C. HOBt may be used to facilitate the reaction.

[0123] The methods described throughout the specification may be varied as desired. For example, protecting groups may be added or removed and products may be further elaborated via, for example, alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, and the like to give the desired final product. Furthermore, any intermediate or final product which comprises mixture of stereoisomers may be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically-pure reagents as described above to give a desired stereoisomer.

[0124] Compounds of Formula 1, which include compounds named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, should be assessed for their biopharmaceutical properties, such as solubility and solution stability across pH, permeability, and the like, to select an appropriate dosage form and route of administration. Compounds that are intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films bymethods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0125] Compounds of Formula 1 may be administered alone or in combination with one another or with one or more pharmacologically active compounds which are different than the compounds of Formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (a formulation) in association with one or more pharmaceutically acceptable excipients. The choice of excipients depends on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things. Useful pharmaceutical compositions and methods for their preparation may be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0126] Compounds of Formula 1 may be administered orally. Oral administration may involve swallowing in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively, or additionally, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.

[0127] Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges which may be liquid-filled; chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, e.g., from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifying agents, suspending agents or both. Liquid formulations may also be prepared by the reconstitution of a solid (e.g., from a sachet).

[0128] 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.

[0129] For tablet dosage forms, depending on 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 include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, anti-oxidants, colorants, flavoring agents, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, C1-6alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.

[0130] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0131] Tablets may also include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0132] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt% or from about 0.5 wt% to about 3 wt% of the tablet.

[0133] Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. If desired, prior to blending one or more of the components may be sized by screening or milling or both. The final dosage form may comprise one or more layers and may be coated, uncoated, or encapsulated. Exemplary tablets may contain up to about 80 wt% of API, from about 10 wt% to about 90 wt% of binder, from about 0 wt% to about 85 wt% of diluent, from about 2 wt% to about 10 wt% of disintegrant, and from about 0.25 wt% to about 10 wt% of lubricant. For a discussion of blending, granulation, milling, screening, tableting, coating, as well as a description of alternative techniques for preparing drug products, see A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H. A. Lieberman et al. (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).

[0134] Consumable oral films for human or veterinary use are pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive. In addition to the API, a typical film includes one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity-modifying agents, and solvents. Other film ingredients may include anti-oxidants, colorants, flavorants and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste-masking agents. Some components of the formulation may perform more than one function.

[0135] In addition to dosing requirements, the amount of API in the film may depend on its solubility. If water soluble, the API would typically comprise from about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film or from about 20 wt% to about 50 wt% of the solutes in the film. A less soluble API may comprise a greater proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.

[0136] 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.

[0137] 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-drying apparatus), in lyophilization equipment, or in a vacuum oven.

[0138] Useful solid formulations for oral administration may include immediate release formulations and modified release formulations. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. For a general description of suitable modified release formulations, see US 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.

[0139] Compounds of Formula 1 may also be administered directly into the blood stream, muscle, or an internal organ of the subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.

[0140] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (e.g., pH of from about 3 to about 9). For some applications, however, compounds of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) may be readily accomplished using standard pharmaceutical techniques.

[0141] The solubility of compounds which are used in the preparation of parenteral solutions may be increased through appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Thus, compounds of Formula 1 may be formulated as a suspension, a solid, a semi-solid, or a thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic)acid (PGLA) microspheres.

[0142] Compounds of Formula 1 may also be administered topically, intradermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers may include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Topical formulations may also include penetration enhancers. See, e.g., Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0143] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTMand BiojectTM) injection. Formulations for topical administration may be formulated to be immediate or modified release as described above.

[0144] Compounds of Formula 1 may also be administered intranasally or by inhalation, typically in the form of a dry powder, an aerosol spray, or nasal drops. An inhaler may be used to administer the dry powder, which comprises the API alone, a powder blend of theAPI and a diluent, such as lactose, or a mixed component particle that includes the API and a phospholipid, such as phosphatidylcholine. For intranasal use, the powder may include a bioadhesive agent, e.g., chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer, may be used to generate the aerosol spray from a solution or suspension comprising 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 (e.g., 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) which serve as a propellant, and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. An atomizer using electrohydrodynamics may be used to produce a fine mist.

[0145] Prior to use in a dry powder or suspension formulation, the drug product is usually comminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles, based on volume, having a largest dimension less than 5 microns). This may be achieved by any appropriate size reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0146] Capsules, blisters and cartridges (made, for example, from gelatin or hydroxypropylmethyl cellulose) for use in an inhaler or insufflator may be formulated to contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0147] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from about 1 μg to about 20 mg of the API per actuation and the actuation volume may vary from about 1 μL to about 100 μL. A typical formulation may comprise one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents, which may be used instead of propylene glycol, include glycerol and polyethylene glycol.

[0148] Formulations for inhaled administration, intranasal administration, or both, may be formulated to be immediate or modified release using, for example, PGLA. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to formulations intended for inhaled / intranasal administration.

[0149] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units are typically arranged to administer a metered dose or “puff” containing from about 10 μg to about 1000 μg of the API. The overalldaily dose will typically range from about 100 μg to about 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

[0150] The active compounds may be administered rectally or vaginally, e.g., in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration may be formulated to be immediate or modified release as described above.

[0151] Compounds of Formula 1 may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable implants (e.g. absorbable gel sponges, collagen), non- biodegradable implants (e.g. silicone), wafers, lenses, and particulate or vesicular systems, such as niosomes or liposomes. The formulation may include one or more polymers and a preservative, such as benzalkonium chloride. Typical polymers include crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose), and heteropolysaccharide polymers (e.g., gelan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or aural administration may be formulated to be immediate or modified release as described above.

[0152] To improve their solubility, dissolution rate, taste-masking, bioavailability, or stability, compounds of Formula 1 may be combined with soluble macromolecular entities, including cyclodextrin and its derivatives and polyethylene glycol-containing polymers. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Alpha-, beta- and gamma-cyclodextrins are commonly used for these purposes. See, e.g., WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0153] As noted above, one or more compounds of Formula 1, including compounds specifically named above, and their pharmaceutically active complexes, salts, solvates and hydrates, may be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions and disorders. In such cases, the active compounds may be combined in a single dosage form as described above or may be provided in the form of a kit which is suitable for coadministration of thecompositions. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device for separately retaining the two pharmaceutical compositions, such as a divided bottle or a divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating the different pharmaceutical compositions against one another. To assist with patient compliance, the kit typically comprises directions for administration and may be provided with a memory aid.

[0154] For administration to human patients, the total daily dose of the claimed and disclosed compounds is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration. For example, oral administration may require a total daily dose of from about 1 mg to about 3000 mg, while an intravenous dose may only require a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in single or divided doses and, at the physician’s discretion, may fall outside of the typical ranges given above. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.

[0155] As noted above, the compounds of Formula 1 may 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 state in a subject for which the activation of SSTR4 provides a therapeutic benefit. More particularly, the compounds of Formula 1 may be used to treat CNS diseases, disorders or conditions, including Alzheimer’s disease, and other forms of dementia (i.e., major or mild neurocognitive disorders) associated with one or more medical conditions, including frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or medication use, HIV infection, prion disease, Parkinson’s disease, and Huntington’s disease. The compounds of Formula 1 may also be used to treat major or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism. In addition, the compounds of Formula 1 may be used to treat anxiety and to treat epilepsy. The compounds of Formula 1 may be also used to treat pain.

[0156] 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 orconditions for which SSTR4 is indicated. Such combinations may offer significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity. For example, compounds of Formula 1, which include compounds specifically named above, and their pharmaceutically 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, including beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, such as apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, 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.

[0157] 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 that are used in the treatment of Alzheimer’s disease. For example, the compounds of Formula 1 may be combined with one or more agents for treating depression (antidepressants) and / or schizophrenia (atypical or typical antipsychotics) including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and ziprasidone.

[0158] Likewise, the compounds of Formula 1 may be combined with one or more agents for treating anxiety (anxiolytics) including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone) and buspirone.

[0159] The compounds of Formula 1 may also be combined with one or more agents for treating epilepsy (antiepileptics or anticonvulsants) 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.

[0160] BIOLOGICAL ACTIVITY

[0161] The biological activity of the compound of Formula 1 with respect to SSTR4 may be determined using the following in vitro and in vivo methods.

[0162] Inhibition of Forskolin Stimulated cAMP in Cells Overexpressing SSTR4

[0163] 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). The CHO- SSTR4 cells are maintained in F12K media with 10% Fetal Bovine Serum (Hyclone), 1% Pen / Strep (Life Technologies), and 800 µg / mL G418 (Life Technologies). To perform the assay, 3000 cells are plated per well in white 384-well plate (Corning 3570) in 50 µL complete media and the cells are allowed to attach for 16 hours in a 37°C, 5% CO2 incubator. The next day, the culture media is removed from the cells and the cells are washed (added then removed) with Krebs Ringer Buffer (ZenBio, KRB-1000mL). Test compounds are suspended in DMSO and diluted in stimulation buffer: Krebs Ringer Buffer plus 0.5% BSA (Roche), 300 µM IBMX (Sigma), and 350 nM forskolin (Sigma). The cells are incubated in 10 µL compound / stimulation buffer for 30 minutes at room temperature. Cellular cAMP levels are detected with a HTRF LANCE Ultra cAMP kit (Perkin Elmer, catalog number TRF0264).

[0164] The assay is performed in accordance with the manufacturer’s instructions. Five 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 plates are covered and allowed to incubate for 60 minutes at room temperature on a shaker. HTRF (665 nm / 615 nm) is read on a Perkin Elmer ENVISION plate reader. The pEC50 values are generated using Activity Base for Screening Data Management.

[0165] SSTR4 I-125 Somatostatin Competition Binding Assay

[0166] This membrane-based assay measures the ability of compounds to competitively inhibit binding of I-125 labeled somatostatin to SSTR4 in membranes from CHO-K1 thatoverexpress 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) plus 0.2 nM I-125 labeled somatostatin (Perkin Elmer catalog number NEX389). Fifty μL of compound / I-125 somatostatin in assay buffer are added per well to 96- well poly-propylene plate. Then 1 µg of SSTR4 membranes in 50 μL assay buffer are added per well. The Plate is incubated for 60 minutes at room temperature. FilterMat A filters (Perkin Elmer catalog number 1450-421) are pre-soaked in 0.5% PEI (Sigma catalog number P3143). The contents of the assay plate are transferred to filters with a TomTech harvester and washed 5 times with 20 mM HEPES, 100 mM NaCl. The filters are dried in a microwave oven then transferred to sample bag containing a scintillator sheet (Perkin Elmer catalog number 1450-441). The scintillator sheets are melted to filters using a heat block. The filters are then read in a MicroBeta scintillation counter. Binding Ki curves are generated using Activity Base for Screening Data Management and the results are reported as pIC50.

[0167] SSTR1 I-125 Somatostatin Competition Binding Assay for Selectivity Versus SSTR1

[0168] This membrane-based assay measures the ability of compounds to competitively inhibit binding of I-125 labeled somatostatin to SSTR1 in membranes from CHO-K1 that overexpress 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) plus 0.4 nM I-125 labeled somatostatin (Perkin Elmer catalog number NEX389). Fifty μL of compound / I-125 somatostatin in assay buffer are added per well to 96- well poly-propylene plate. Then 10 µg of SSTR1 membranes in 50 μL assay buffer are added per well. The plate is incubated for 60 minutes at room temperature. FilterMat A filters (Perkin Elmer catalog number 1450-421) are pre-soaked in 0.5% PEI (Sigma catalog number P3143). The contents of the assay plate are transferred to filters with a TomTech harvester and washed 5 times with 20 mM HEPES, 100 mM NaCl. The filters are dried in a microwave oven then transferred to sample bag containing a scintillator sheet (Perkin Elmer catalog number 1450-441). The scintillator sheets are melted to the filters using a heat block. The filters are then read in a MicroBeta scintillation counter. Binding Ki curves are generated using Activity Base for Screening Data Management and the results are reported as pIC50.

[0169] The following in vitro assay may be used to assess the ability of a compound of Formula 1 to enter the CNS through the blood-brain barrier.

[0170] LLC-PK1 Assay (Reported as Apparent Permeability and Efflux Ratio)

[0171] Lilly Laboratories & Company porcine kidney cells (LLC-PK1) are transfected with Multidrug resistance protein 1 (MDR1) and are maintained in accordance with the provider’s instructions in Gibco Medium 199 (Fisher Scientific Cat # 11150067). Medium 199 is supplemented with 10% heat-inactivated fetal bovine serum (Gibco Cat # 16000-044), 0.5 mg / mL Geneticin (Gibco #10131035) and colchicine 200 nM (an inducer of P-gp, Sigma Cat# C9754). The cells are seeded onto the apical side of HTS-Transwell-96 Plates (0.4 µm pore size, Corning Cat# 3381) at a density of 6.25 x 103cells per well with 75 µL and 250 µL of Medium 199 in apical and basolateral wells, respectively, and are incubated at 37°C / 5% CO2. Fresh Medium 199 media is exchanged in the apical and basolateral compartments after 72 hours and cells are allowed to grow into a monolayer for 144 hours before beginning the experimental incubation. Incubations are performed in Media 199 (Fisher Scientific Cat # 11150067) at pH 7.4 with 1% bovine serum albumin (Sigma, Cat# A9418) and 10 mM HEPES (Fisher Scientific, Cat# 15630080). Media 199 is removed and cells are rinsed with warm (37°C) Media 199. Media 199 with test compound at 1 µM substrate concentration (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 to compartment which lacks test compound in singlicate. The cells are incubated for 120 minutes at 37°C / 5% CO2. At the end of the incubation period, a 50 µL sample is removed from each receiver compartment and diluted into 100 µL of acetonitrile (Fisher Scientific, Cat# A996SK4) + 100 ng / mL diclofenac (internal standard, Sigma# 15307-79-6). The samples are centrifuged at 2000 RCF, for 10 minutes at 4°C, after which 75 µL of supernatant is transferred to a new microplate and diluted with 75 µL of HPLC grade water (Fisher Scientific, Cat# W64). Samples are analyzed using Multiple Reaction Monitoring on an ABSciex triple quadrupole mass spectrometer coupled to high performance liquid chromatography pump instrumentation optimized for the detection of test articles through a Kinetix 2.1 x 50 mm C18100 Å column (Phenomenex, Cat# 00B-4605-AN).

[0172] Apparent permeability (Papp) values and efflux ratio are calculated using the following equations: P^nm ൈି^^Conc^^ ൈ 0.25 ൈ 10000ୟ୮୮ ^ି^ sec ൌA ൈ t ൈ 10 ;P ^nm ൈ secି^^Conc^^ ൈ 0.075 ൈ 10000ୟ୮୮ ^ି^ ൌA ൈ t ൈ 10 ;P ER ൌୟ୮୮ ^ି^P ; ୟ୮୮ ^ି^where P A-B is the apparent well to basolateral well; Papp B-Athe apparent permeability from the the apical well; ConcBLis the basolateral well concentration; ConcAP is the apical well concentration; A is the well surface area (cm2), which for the above assay is 0.143 cm2; t is the incubation time (seconds), which for the above assay is 7200 seconds; and ER is the P-gp mediated efflux ratio. EXAMPLES

[0173] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present invention.

[0174] 1H Nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (δ) are given in parts- per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3(deuterochloroform), DMSO-d6(deuterodimethylsulfoxide), CD3OD (deuteromethanol), CD3CN (deuteroacetonitrile), and THF-d8 (deuterotetrahydrofuran). The mass spectra (m / z for [M+H]+) were recorded using either electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0175] Where indicated, products of certain preparations and examples are purified by mass-triggered HPLC, flash chromatography, preparative TLC or SFC. Reverse phase chromatography is typically carried out on a column (e.g., Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) under acidic conditions (“Acid Mode”) eluting with ACN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or under basic conditions (“Basic Mode”) eluting with water and 20 / 80 (v / v) water / acetonitrile mobile phases, both containing 10 mM NH4HCO3(pH 9.5-10). Preparative TLC is typically carried out on silica gel 60 F254 plates. The preparations and examples may employ SFC to separate enantiomers. After isolation by chromatography, the solvent is removed and the product is obtained by drying in a centrifugal evaporator (e.g., GeneVac™),rotary evaporator, evacuated flask, etc. 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).

[0176] PREPARATION 1: 1-(azetidin-1-ylmethyl)cyclopropan-1-amine

[0177] STEP A: (1-((tert- methyl methanesulfonate

[0178] To an ice-cooled cyclopropylcarbamate (15g, 80 mmol) in EtOAc (350 mL, 104 mmol) and methanesulfonyl chloride (8.09 mL, 104 mmol). After 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated aqueous NaHCO3. Brine was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine once more, and then dried over MgSO4, filtered, and concentrated to a volume of about 150 mL. The residue was left at 0°C for crystallization. Filtration using a fritted glass funnel under nitrogen gave the title compound as a colorless crystalline solid (14.8 g, 70%).1H NMR (400 MHz, CDCl3) δ ppm 0.83 - 1.05 (m, 4 H), 1.37 - 1.55 (m, 9 H), 2.95 - 3.11 (m, 3 H), 4.14 - 4.33 (m, 2 H), 4.92 - 5.15 (m, 1 H).

[0179] STEP B: tert-butyl (1-(azetidin-1-ylmethyl)cyclopropyl)carbamate

[0180] To a solution of (1-(cyclopropyl)methyl methanesulfonate (11.2 g, 42.2 mmol) in THF (145 mL) was added azetidine (9.96 mL, 148 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered on a glass fritted funnel under nitrogen to remove precipitated byproduct. Cold EtOAc was used to rinse the solid, and the combined filtrate was concentrated in vacuo to remove as much volatiles as possible, including excess azetidine. After drying on the vacuum pump overnight, the title compound was obtained as a white solid (9.46 g, 99%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.44 - 0.54 (m, 4 H), 1.27 - 1.48 (m, 9 H), 1.86 - 2.01 (m, 2 H), 2.34 - 2.42 (m, 2 H), 3.06 - 3.20 (m, 4 H), 6.78 - 6.94 (m, 1 H).

[0181] STEP C: 1-(azetidin-1-ylmethyl)cyclopropan-1-amine

[0182] To a stirring solution of hydrogen chloride (4 M in dioxane, 96 mL, 386 mmol) was added tert-butyl (1-(azetidin-1-ylmethyl)cyclopropyl)carbamate (9.7 g, 42.9 mmol) as a solid in small portions at room temperature. The mixture was vigorously stirred with occasional sonication to ensure even dispersion of starting material. After 18 h, the mixture was then filtered with a fritted glass funnel under nitrogen to collect the solid product. The solid was washed with ether and dried under nitrogen overnight to give the bis-hydrochloride salt of the title compound as a fine white hygroscopic powder (7.4 g, 87%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 - 1.21 (m, 4 H), 2.17 - 2.45 (m, 2 H), 3.47 - 3.55 (m, 2 H), 4.04 - 4.29 (m, 4 H), 8.76 - 9.30 (m, 3 H), 10.83- 11.88 (m, 1 H);13C NMR (100 MHz, DMSO-d6) δ ppm 9.5, 17.0, 30.9, 55.2, 58.1.

[0183] PREPARATION 2: 2-(3-chlorophenyl)-N-(1-formylcyclopropyl)-2- methylpropanamide

[0184] STEP A: 2-(3- cyclopropyl)-2-methylpropanamide

[0185] To a 20 mL vial with-2-methylpropanoic acid (500 mg, 2.52 mmol) in DMF (10 mL) followed by (1-aminocyclopropyl)methanol hydrochloride (311 mg, 2.52 mmol), DIPEA (2.198 mL, 12.59 mmol) and HATU (1.24 g, 3.27 mmol) at room temperature under nitrogen. The solution was stirred for 2 h then extracted with EtOAc (2 x 50 mL) and brine (50 mL). The organics were combined, dried with MgSO4, and concentrated with silica gel. Purification by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 75-95% EtOAc in heptanes gave the title compound as a white solid (529 mg, 78%).1H NMR (400 MHz, CDCl3) δ ppm 0.60 - 0.73 (m, 2 H), 0.82 - 0.91 (m, 2 H), 1.50 (s, 6 H), 3.54-3.57 (m, 2 H), 5.61 (br s, 1 H), 7.17 - 7.36 (m, 4 H); ESI-MS m / z [M+H]+268.1.

[0186] STEP B: 2-(3-chlorophenyl)-N-(1-formylcyclopropyl)-2-methylpropanamide

[0187] To a 20 mL vial with a stir bar was added 2-(3-chlorophenyl)-N-(1- (hydroxymethyl)cyclopropyl)-2-methylpropanamide (200 mg, 0.747 mmol) in DCM (7 mL)and cooled to 0°C in an ice bath under nitrogen. Dess-Martin periodinane (444 mg, 1.05 mmol) was added and the solution was warmed to room temperature and stirred for 4 h. In a 100 mL Erlenmeyer flask, a solution of 3.5 g of anhydrous sodium thiosulfate was dissolved in 30 mL of saturated sodium bicarbonate and was stirred for 30 minutes. The resulting sodium thiosulfate solution (10 mL) was added to the reaction mixture and allowed to stir at room temperature for 30 minutes. The mixture was extracted with EtOAc (2 x 50 mL) and water (50 mL). The organics were combined and dried with MgSO4, filtered, and concentrated to give the crude title compound, which was used without additional purification (208 mg, assumed quantitative, 96% content).1H NMR (400 MHz, CDCl3) δ ppm 1.16 - 1.25 (m, 2 H), 1.45 - 1.52 (m, 2 H), 1.50 (s, 6 H), 5.64 (br s, 1 H), 7.25 - 7.33 (m, 3 H), 7.40 (s, 1 H) 9.00 (s, 1 H); ESI-MS m / z [M+H]+266.0.

[0188] PREPARATION 3: 1-(3-(trifluoromethyl)phenoxy)cyclopropane-1-carboxylic acid

[0189] STEP A: methyl 4- phenoxy)butanoate

[0190] To a solution of 3-g, 6.17 mmol) and methyl 2,4- dibromobutanoate (2.26 g, 7.40 mmol) in DMF (16 mL) was added K2CO3 (1.71 g, 12.34 mmol). The mixture was stirred at 15°C for 16 h. The reaction mixture was extracted with EtOAc (3 x 30mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated to give a crude product. The residue was purified by flash silica column chromatography to give the title compound as a colorless oil (1.05 g, 41%, 82% purity).

[0191] STEP B: methyl 1-(3-(trifluoromethyl)phenoxy)cyclopropane-1-carboxylate

[0192] To a solution ofphenoxy]butanoate (800 mg, 2.35 mmol) in THF (30 mL) was added LiHMDS (1 M in THF, 5.16 mL) at -78°C. The mixture was stirred at -78°C for 2 h. The mixture was quenched with saturated aqueousNH4Cl (15 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over Na2SO4and concentrated. The residue was purified by flash silica column chromatography using 100:1 to 1:1 petroleum ether in EtOAc as eluent to give the title compound as a colorless oil (240 mg, 38%, 96% purity).1H NMR (400 MHz, CDCl3) δ ppm 1.31 - 1.38 (m, 2 H), 1.63 - 1.71 (m, 2 H), 3.74 (s, 3 H), 7.09 (br d, J = 8.31 Hz, 1 H), 7.15 (s, 1 H), 7.22 - 7.30 (m, 1 H), 7.39 (t, J = 8.0 Hz, 1 H); ESI-MS m / z [M+H]+261.1.

[0193] STEP C: 1-(3-(trifluoromethyl)phenoxy)cyclopropane-1-carboxylic acid

[0194] To a solution of methyl 1-[3-(trifluoromethyl) phenoxy]cyclopropanecarboxylate (360 mg, 1.38 mmol) in THF (8 mL) and water (3 mL) was added LiOH ^H2O (174 mg, 4.15 mmol). The mixture was stirred at 15°C for 12 h. The mixture was diluted with DCM (20 mL) and washed with water (20 mL). The aqueous layer was acidified with 3 M HCl to pH 2- 3. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a red solid (249.0 mg, 73%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 - 1.33 (m, 2 H), 1.52 - 1.60 (m, 2 H), 7.15 (s, 1 H), 7.24 (dd, J = 8.3, 2.0 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.50 - 7.58 (m, 1 H), 13.08 (br s, 1 H); ESI-MS m / z [M+H]+247.1.

[0195] PREPARATION 4: 1-(3-chlorophenoxy)cyclopropane-1-carboxylic acid

[0196] The title compound wasstep procedure in PREPARATION 3, using 3-chlorophenol (3.00 g, 23.34 mmol), and was purified by preparative HPLC (Agela ASB, 5 µm, ID 25 mm x 150 mm) using a gradient of 35-65% ACN in water (w / 0.05% HCl). The title compound was obtained as a white solid (209.5 mg).1H NMR (400 MHz, DMSO- d6) δ ppm 1.18 - 1.34 (m, 2 H), 1.44 - 1.60 (m, 2 H), 6.85 - 6.96 (m, 2 H), 7.03 (dd, J = 7.9, 1.1 Hz, 1 H), 7.31 (t, J = 8.2 Hz, 1 H).

[0197] PREPARATION 5: 1-(3-(trifluoromethoxy)phenoxy)cyclopropane-1-carboxylic acid

[0198] The title compoundprocedure in PREPARATION 3, using 3-(trifluoromethoxy)phenol (1.00 g, 5.61 mmol), and was obtained as a white solid (104.5 mg, 7% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 - 1.33 (m, 2 H),1.49 - 1.61 (m, 2 H), 6.85 (s, 1 H), 6.97 (dd, J = 8.3, 1.7 Hz, 2 H), 7.42 (t, J = 8.3 Hz, 1 H), 13.04 (br s, 1 H).

[0199] PREPARATION 6: 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid

[0200] STEP A: methyl 4-bromo- butanoate

[0201] A mixture of 2- , methyl 2,4-dibromobutanoate(9.01 g, 34.7 mmol), and K2CO3g, DMF (100 mL) was degassed and purged with nitrogen three times, and the mixture was stirred at 20°C for 12 h under nitrogen atmosphere. 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 1:0 to 10:1 petroleum ether : EtOAc as eluent to give the title compound as a colorless oil (8.3 g, 82%).1H 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).

[0202] STEP B: methyl 1-(2-bromophenoxy)cyclopropanecarboxylate

[0203] To a solution of methylbutanoate (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 at -78°C for 2 h under nitrogen. The reaction mixture was poured into aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using 1:0 to 10:1 petroleum ether : EtOAc as eluent to give the title compound as a colorless oil (5.05 g, 79%).1H 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).

[0204] STEP C: methyl 1-(2-cyclopropylphenoxy)cyclopropanecarboxylate

[0205] A mixture of methyl 1- (0.500 g, 1.84 mmol), cyclopropylboronic acid, (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 three times, and then the mixture was stirred at 100°C for 12 h under nitrogen atmosphere. 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 1:0 to 20:1 petroleum ether : EtOAc as eluent to give the title compound as a light yellow oil (400 mg, 84%, 90% purity).1H 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.

[0206] STEP D: 1-(2-cyclopropylphenoxy)cyclopropane-1-carboxylic acid

[0207] To a solution of methyl 1-(2-cyclopropylphenoxy)cyclopropanecarboxylate (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. The reaction mixture was diluted with water (10 mL), and then extracted with EtOAc (2 x 10 mL). The aqueous layer was acidified with 2 M HCl to pH = 4, and then extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated under reduced pressure to give the title compound as a light yellow solid (230.2 mg, 65%, 95% purity).1H 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.

[0208] PREPARATION 7: 3,3-difluoro-2-phenoxypropanoic acid

[0209] STEP A: ((1,1-difluoro-3-benzene

[0210] (Bromo(difluoro)methyl)tr mg, 4.50 mmol), PPh3 (944 mg, 3.60 mmol), and DMPU (769 mg, 6.00 mmo ) were added successively to a solution of ((E)-2- nitrovinyl)benzene (447 mg, 3.00 mmol) in ACN (3 mL) at 0°C. The reaction mixture was warmed to 20°C and stirred for 0.5 h. The mixture was cooled to -20°C, and TMSCl (65.2 mg, 600 µmol) and MeOH (607 µL, 15.0 mmol) were added, and the resulting mixture was stirred for 15 minutes, then warmed to 20°C and quenched with water (3 mL) and pyridine (291 µL, 3.60 mmol). Then, the mixture was vigorously stirred at 80°C for 1.5 h. The reaction mixture was partitioned between water (20 mL) and MTBE (3 x 20 mL). The organics were separated, dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica column chromatography using 1:0 to 10:1 petroleum ether : EtOAc as eluent to give the title compound as a yellow oil (460 mg, 76%).1H NMR (400 MHz, CDCl3) δ ppm 3.93 - 4.08 (m, 1 H), 4.78 (dd, J = 13.7, 8.8 Hz, 1 H), 4.94 (dd, J = 13.7, 5.9 Hz, 1 H), 5.85 - 6.19 (m, 1 H), 7.25 - 7.31 (m, 2 H), 7.34 - 7.42 (m, 3 H).

[0211] STEP B: 3,3-difluoro-2-phenoxypropanoic acid

[0212] A solution of ((1,1-difluoro-3-nitropropan-2-yl)oxy)benzene (2.50 g, 12.4 mmol) in 6 N HCl (10 mL) was prepared at 20°C under nitrogen. The mixture was stirred at 100°C for 72 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic phase was separated, dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Synergi® C18, 4 µm, ID 21 mm x 250 mm) using a gradient of 20-50% ACN in water (w / 0.225% FA). The mixture was concentrated to remove ACN, then extracted with DCM (2 x 50 mL). The organics were then dried and concentrated to give the title compound as a light yellow solid (1.3 g, 56%).1H NMR (400 MHz, CDCl3) δ ppm 4.07 (ddd, J = 11.9, 10.2, 6.7 Hz, 1 H), 6.06 - 6.44 (m, 1 H), 7.35 - 7.46 (m, 5 H).

[0213] PREPARATION 8: 1-(2-chlorophenoxy)cyclopropane-1-carboxylic acid

[0214] In a 250 mL round-(2-chlorophenoxy)cyclopropane-1- carboxylate (1.00 g, 4.41 mmol) was dissolved in dioxane (16 mL) to give a colorlesssolution. Aqueous lithium hydroxide (2 M, 8.82 mL, 17.6 mmol) was added. The mixture was stirred at room temperature for 4 h. The mixture was treated with 1 N HCl, then extracted with EtOAc. The organics were dried over MgSO4 and concentrated to give the title compound as a white solid, which was used without additional purification (0.66 g, 70%). ESI-MS m / z [M+H]+213.0.

[0215] PREPARATION 9: 2-methyl-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid

[0216] STEP A: methyl 2-(6- b]pyridin-1-yl)propanoate

[0217] In a 250 mL round- pyrrolo[2,3-b]pyridine (2.00 g,15.13 mmol) was dissolved in DMF (30.9 mL) to give a brown solution. Sodium hydride (60 wt %, 0.787 g, 19.67 mmol) was added. After 30 minutes, methyl 2-chloropropanoate (2.84 g, 23.15 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extracts were washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 80 g RediSep Rf Gold® column) using a gradient of 0-20% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a colorless syrup (2.57 g, 78%). ESI-MS m / z [M+H]+219.2.

[0218] STEP B: methyl 2-methyl-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoate

[0219] In a 250 mL round-methyl-1H-pyrrolo[2,3-b]pyridin-1- yl)propanoate (2.57 g, 11.78 mmol) was dissolved in THF (16 mL) to give a colorless solution. The reaction mixture was cooled to -78°C and lithium diisopropylamide (2 M, 7.07 mL, 14.13 mmol) was added dropwise. After 1 h, iodomethane (1.393 mL, 22.37 mmol) wasadded. After 15 minutes, the mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 80 g RediSep Rf Gold® column) using a gradient of 0-20% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a brown syrup (1.30 g, 48%). ESI-MS m / z [M+H]+233.3.

[0220] STEP C: 2-methyl-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid

[0221] In a 250 mL round-bottomed flask, methyl 2-methyl-2-(6-methyl-1H-pyrrolo[2,3- b]pyridin-1-yl)propanoate (1.30 g, 5.60 mmol) and lithium hydroxide (2 M aqueous, 11.19 mL, 22.39 mmol) were dissolved in dioxane (25 mL) to give a colorless solution. The mixture was stirred at room temperature overnight. The mixture was acidified with aqueous HCl to pH 5 and extracted with EtOAc. The organic extracts were dried over MgSO4and concentrated in vacuo to give the crude title compound as a brown syrup, which was used without additional purification (1.7 g, assumed quantitative, maximum content 71%). ESI- MS m / z [M+H]+219.2.

[0222] PREPARATION 10: 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2- methylpropanoic acid

[0223] The title compound wasstep procedure in PREPARATION 9, using 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.11 mmol) to give a brown syrup (1.96 g, maximum content 76%). ESI-MS m / z [M+H]+239.2.

[0224] PREPARATION 11: 2-(6-chloro-1H-indol-1-yl)-2-methylpropanoic acid

[0225] The title compound wasstep procedure in PREPARATION 9, using 6-chloro-1H-indole (0.300 g, 1.98 mmol), sodium hydride (60 wt %, 0.119 g, 2.97 mmol) and methyl 2-chloropropanoate (0.388 g, 3.17 mmol) in DMF (8 mL) to give a tan syrup (0.290 g, 62% over three steps). ESI-MS m / z [M+H]+238.2.

[0226] PREPARATION 12: 2-(4-chloro-7-fluoro-1H-indol-1-yl)-2-methylpropanoic acid

[0227] The title compound was e-step procedure in PREPARATION 9, using 4-chloro-7-fluoro-1H-indoe (0.3 5 g, . mmol), sodium hydride (60 wt %, 0.133 g, 3.32 mmol) and methyl 2-chloropropanoate (0.542 g, 4.42 mmol) in DMF (8 mL) to give a brown syrup (0.418 g, 74% over three steps). ESI-MS m / z [M+H]+256.2.

[0228] PREPARATION 13: 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2- methylpropanoic acid and 2-(5-chloro-7H-pyrrolo[2,3-b]pyridin-7-yl)-2-methylpropanoic acid

[0229] STEP A: methylpropanoate andethyl 2-(5-chloro-7H-pyrrolo[2,3-b]pyridin-7-yl)-2-methylpropanoate

[0230] In a(0.500 g, 3.28 mmol) and potassium carbonate (0.906 g, 6.55 mmol) were combined in DMA (6 mL) to give a brown suspension. Ethyl 2-bromo-2-methylpropanoate (0.736 mL, 5.01 mmol) was added and the mixture was stirred at 90°C overnight. Additional potassium carbonate (0.906 g, 6.55 mmol) and ethyl 2-bromo-2-methylpropanoate (0.736 mL, 5.01 mmol) were added and stirring was continued at 90°C for 3 days. The mixture was quenched with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 0-10% EtOAc in heptanes. Fractions were combined and concentrated to give a mixture of the title compounds as a light brown syrup (0.286 g, 33%). ESI-MS m / z [M+H]+267.2, 267.2.

[0231] STEP B: 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylpropanoic acid and 2- (5-chloro-7H-pyrrolo[2,3-b]pyridin-7-yl)-2-methylpropanoic acid

[0232] In a 250 mL round-bottomed flask, a mixture of ethyl 2-(5-chloro-1H-pyrrolo[2,3- b]pyridin-1-yl)-2-methylpropanoate and ethyl 2-(5-chloro-7H-pyrrolo[2,3-b]pyridin-7-yl)-2- methylpropanoate (0.286 g, 1.07 mmol) and aqueous lithium hydroxide (2 M, 2.14 mL, 4.29 mmol) were dissolved in dioxane (6 mL) to give a colorless solution. The mixture was stirred at room temperature overnight. The mixture was acidified with aqueous HCl to pH 5 and extracted with EtOAc. The organic extracts were dried over MgSO4and concentrated in vacuo to give a crude mixture of title compounds as a light brown syrup, which was used without additional purification (0.311 g, assumed quantitative, maximum content 82%). ESI- MS m / z [M+H]+239.2, 239.2.

[0233] PREPARATION 14: 2-methyl-2-(6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1- yl)propanoic acid and 2-methyl-2-(6-(trifluoromethyl)-7H-pyrrolo[2,3-b]pyridin-7- yl)propanoic acid

[0234] A mixture of step procedure inPREPARATION 13, using 6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.500 g, 2.69 mmol), ethyl 2-bromo-2-methylpropanoate (two additions of 0.788 mL, 5.37 mmol), and potassium carbonate (two additions of 0.742 g, 5.37 mmol) to give an off-white solid (0.478 g, 65% over two steps). ESI-MS m / z [M+H]+273.3 (one peak observed).

[0235] PREPARATION 15: 2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2- methylpropanoic acid and 2-(6-chloro-7H-pyrrolo[2,3-b]pyridin-7-yl)-2-methylpropanoic acid

[0236] A mixture ofstep procedure in PREPARATION 13, using 6-chloro-1H-pyrrolo[2,3-b]pyridine (0.500 g, 3.28 mmol), ethyl 2-bromo-2-methylpropanoate (0.962 mL, 6.55 mmol), and potassium carbonate (1.36 g, 9.83 mmol) to give a light solid (0.465 g, 59% over two steps). ESI-MS m / z [M+H]+239.2, 239.2.

[0237] PREPARATION 16: 2-(6-chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1- yl)-2-methylpropanoic acid and 2-(6-chloro-3-(trifluoromethyl)-7H-pyrrolo[2,3-b]pyridin-7- yl)-2-methylpropanoic acid

[0238] A mixture of step procedure inPREPARATION 13, - [2,3-b]pyridine (0.500 g, 2.27 mmol), ethyl 2-bromo-2-methylpropanoate (0.665 mL, 4.53 mmol), and potassium carbonate (0.940 g, 6.80 mmol) to give a white solid (0.361 g, 43% yield, 82% content). ESI- MS m / z [M+H]+307.1 (one peak).

[0239] PREPARATION 17: 2-(4-chloro-1H-indol-1-yl)-2-methylpropanoic acid

[0240] STEP A: ethyl 2-(4-Cl O N

[0241] In a 100 mL round-(0.500 g, 3.30 mmol) was dissolved in DMF (6 mL) to give a tan solution. Potassium carbonate (0.912 g, 6.60 mmol) was added. After 30 minutes, ethyl 2-bromo-2-methylpropanoate (0.741 mL, 5.05 mmol) was added. The mixture was stirred at 85°C overnight. The mixture was quenched with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 10-20% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a brown syrup (0.33 g, 38%). ESI-MS m / z [M+H]+266.1.

[0242] STEP B: 2-(4-chloro-1H-indol-1-yl)-2-methylpropanoic acid

[0243] In a 250 mL round-bottomed flask, ethyl 2-(4-chloro-1H-indol-1-yl)-2- methylpropanoate (0.33 g, 1.24 mmol) and aqueous lithium hydroxide (2 M, 2.48 mL, 4.97 mmol) were dissolved in dioxane (6 mL) to give a brown solution. The mixture was stirred atroom temperature for 6 h. The mixture was acidified with aqueous HCl and extracted with EtOAc. The organic extracts were dried over MgSO4and concentrated in vacuo to give the crude title compound as a tan oil, which was used without additional purification (0.295 g, assumed quantitative). ESI-MS m / z [M+H]+238.1.

[0244] PREPARATION 18: 2-(7-chloro-1H-indol-1-yl)-2-methylpropanoic acid

[0245] The title compound was step procedure in PREPARATION17, using 7-chloro-1H-indole , 2-bromo-2-methylpropanoate (0.969 mL, 6.60 mmol), and potassium carbonate (1.37 g, 9.89 mmol) at 90°C to give a light solid (0.200 g, 25% over two steps). ESI-MS m / z [M+H]+238.2.

[0246] PREPARATION 19: 2-(3-chloro-1H-indol-1-yl)-2-methylpropanoic acid

[0247] The title compound was step procedure in PREPARATION17, using 3-chloro-1H-indole (0.500 g, 3.30 mmol), ethyl 2-bromo-2-methylpropanoate (0.969 mL, 6.60 mmol), and potassium carbonate (1.37 g, 9.89 mmol) at 90°C to give a tan solid (0.395 g, 50% over two steps). ESI-MS m / z [M+H]+238.2.

[0248] PREPARATION 20: 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)butanoic acid

[0249] STEP A: methyl 2-(4-pyridin-1-yl)butanoate

[0250] In a 125 mL round-pyrrolo[2,3-b]pyridine (0.500 g, 3.28 mmol) was dissolved in DMF (8 mL) to give a colorless solution. Sodium hydride (60 wt %, 0.170 g, 4.26 mmol) was added. After 30 minutes, methyl 2-bromobutanoate (0.577 mL, 5.01 mmol) was added. The mixture was stirred at room temperature overnight. Themixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extracts were washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 80 g RediSep Rf Gold® column) using a gradient of 0-20% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a colorless syrup (0.80 g, 97%). ESI-MS m / z [M+H]+253.1.

[0251] STEP B: 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)butanoic acid

[0252] In a 250 mL round-bottomed flask, methyl 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1- yl)butanoate (0.80 g, 3.17 mmol) and aqueous lithium hydroxide (2 M, 6.33 mL, 12.66 mmol) were dissolved in dioxane (18 mL) to give a colorless solution. The mixture was stirred at room temperature overnight. The mixture was acidified with aqueous HCl to pH 5 and extracted with EtOAc. The organic extracts were dried over MgSO4 and concentrated in vacuo to give the crude title compound as a colorless syrup, which was used without additional purification (0.774 g, 97% content). ESI-MS m / z [M+H]+239.2.

[0253] PREPARATION 21: 2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methylbutanoic acid

[0254] The title compound wasstep procedure in PREPARATION 20, using 6-chloro-1H-pyrrolo[2,3-b]pyridine (0.200 g, 1.31 mmol) and ethyl 2-bromo-3- methylbutanoate (0.419 g, 2.00 mmol) in STEP A and stirring at 50°C for 1 h in STEP B to give a colorless syrup (0.232 g, 70% over two steps). ESI-MS m / z [M+H]+253.2.

[0255] PREPARATION 22: 2-(4-fluoro-1H-indol-1-yl)propanoic acid

[0256] The title compound was prepared like the two two-step procedure in PREPARATION 20, using 4-fluoro-1H-indole (0.250 g, 1.85 mmol) and methyl 2- chloropropanoate (0.347 g, 2.83 mmol) in STEP A and stirring at 50°C for 4 h in STEP B to give a brown syrup (0.467 g, 82% content). ESI-MS m / z [M+H]+208.1.

[0257] PREPARATION 23: 2-(4-fluoro-1H-indol-1-yl)acetic acid

[0258] The title compound was prepared like the two-step procedure in PREPARATION 20, using 4-fluoro-1H-indole (0.250 g, 1.85 mmol) and ethyl 2-bromoacetate (0.473 g, 2.83 mmol) in STEP A and stirring at 50°C for 4 h in STEP B to give a brown syrup (0.596 g, 60% content). ESI-MS m / z [M+H]+194.1.

[0259] PREPARATION 24: 2-(4-chloro-7-fluoro-1H-indol-1-yl)propanoic acid

[0260] The title compound was step procedure in PREPARATION20, using 4-chloro-7-fluoro-1H- , methyl 2-chloropropanoate (0.217 g, 1.77 mmol), and sodium hydride (60 wt %, 0.053 g, 1.33 mmol) in DMF (8 mL) to give a tan syrup (0.214 g, assumed quantitative). ESI-MS m / z [M+H]+242.2.

[0261] PREPARATION 25: 2-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)propanoic acid

[0262] The title compound was step procedure in PREPARATION20, using 4-chloro-1H-pyrrolo[3,2-c]pyridine (0.400 g, 2.62 mmol), methyl 2- chloropropanoate (0.492 g, 4.01 mmol), and sodium hydride (60 wt %, 0.147 g, 3.67 mmol) in DMF (8 mL) to give a white solid (0.648 g, 78% yield, 70% content). ESI-MS m / z [M+H]+225.1.

[0263] PREPARATION 26: 2-(4-fluoro-7-methyl-1H-indol-1-yl)propanoic acid

[0264] The title compound wasstep procedure in PREPARATION 20, using 4-fluoro-7-methyl-1H-indole (0.310 g, 2.08 mmol), methyl 2-chloropropanoate (0.509 g, 4.16 mmol), and sodium hydride (60 wt %, 0.125 g, 3.12 mmol) in DMF (8 mL) to give a white solid (0.243 g, 53% over two steps). ESI-MS m / z [M+H]+222.2.

[0265] PREPARATION 27: 2-(7-fluoro-4-methyl-1H-indol-1-yl)propanoic acid

[0266] The title compound was prepared like the two-step procedure in PREPARATION 20, using 7-fluoro-4-methyl-1H-indole (0.350 g, 2.35 mmol), methyl 2-chloropropanoate (0.440 g, 3.59 mmol), and sodium hydride (60 wt %, 0.141 g, 3.52 mmol) in DMF (8 mL) to give a white solid (0.337 g, 65% over two steps). ESI-MS m / z [M+H]+222.3.

[0267] PREPARATION 28: 2-(2-chlorophenoxy)butanoic acid

[0268] STEP A: methyl 2-(2-

[0269] In a 100 mL round- (0.250 mL, 2.41 mmol), methyl2-bromobutanoate (0.333 mL, , carbonate (1.00 g, 7.24 mmol) were combined in DMF (8.04 mL) to give a white suspension. The mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 0-10% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a colorless syrup (0.552 g, assumed quantitative).

[0270] STEP B: 2-(2-chlorophenoxy)butanoic acid

[0271] In a 100 mL round-bottomed flask, crude methyl 2-(2-chlorophenoxy)butanoate (0.552 g, 2.41 mmol) and aqueous lithium hydroxide (2 M, 4.83 mL, 9.65 mmol) were dissolved in dioxane (12 mL) to give a colorless solution. The mixture was stirred at room temperature overnight. The mixture was acidified with aqueous HCl and extracted with EtOAc. The organic extracts were dried over MgSO4 and concentrated in vacuo to give the crude title compound as a white solid, which was used without additional purification (0.73 g, 70% content). ESI-MS m / z [M-CO2H]+169.1.

[0272] PREPARATION 29: 2-(2-cyclopropylphenoxy)propanoic acid

[0273] The title compound was prepared like the two-step procedure in PREPARATION 28, using 2-cyclopropylphenol (0.200 g, 1.49 mmol) and methyl 2-chloropropanoate (0.219 g, 1.79 mmol) to give a white solid (0.218 g, 71% over two steps). ESI-MS m / z [M-CO2H]+161.1.

[0274] PREPARATION 30: 2-(2,3-dichlorophenoxy)propanoic acid

[0275] The title compound was step procedure in PREPARATION28, using 2,3-dichlorophenol methyl 2-chloropropanoate (0.180 g, 1.47 mmol) to give a white solid (0.237 g, 81% over two steps).

[0276] PREPARATION 31: 1-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclopropane-1- carboxylic acid

[0277] STEP A: methyl 1-(4- pyridin-1-yl)cyclopropane-1-carboxylate

[0278] In a 100 mL round-pyrrolo[2,3-b]pyridine (0.240 g, 1.57 mmol) was dissolved in DMF (8 mL) to give a colorless solution. Sodium hydride (60 wt %, 0.126 g, 3.15 mmol) was added, followed by methyl 2,4-dibromobutanoate (0.626 g, 2.41 mmol). The mixture was stirred at room temperature overnight. Additional sodium hydride (60 wt %, 0.126 g, 3.15 mmol) was added, followed by additional methyl 2,4- dibromobutanoate (0.626 g, 2.41 mmol) and the mixture was stirred at room temperature overnight again. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 10-33% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a colorless syrup (0.108 g, 27%). ESI-MS m / z [M+H]+251.2.

[0279] STEP B: 1-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclopropane-1-carboxylic acid

[0280] In a 125 mL pear-shaped flask, methyl 1-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1- yl)cyclopropane-1-carboxylate (0.108 g, 0.431 mmol) and aqueous lithium hydroxide (2 M, 0.862 mL, 1.72 mmol) were dissolved in dioxane (3 mL) to give a colorless solution. The mixture was stirred at 50°C for 1 h. The mixture was acidified with aqueous HCl and extracted with EtOAc. The organic extracts were dried over MgSO4 and concentrated in vacuo to give the crude title compound as a colorless film, which was used without additional purification (0.102 g, assumed quantitative). ESI-MS m / z [M+H]+237.1.

[0281] PREPARATION 32: 2-(4-methyl-1H-indol-1-yl)propanoic acid

[0282] STEP A: ethyl 2-(4-

[0283] In a 100 mL round- (0.360 g, 2.74 mmol) andethyl propiolate (0.269 g, 2.74 mmol) were dissolved in DCM (8 mL) to give a tan solution. The mixture was cooled to 0°C and a solution of triphenylphosphine (0.720 g, 2.74 mmol) in DCM (3 mL) was added dropwise. The mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The residue was purified via flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 0-10% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a colorless syrup (0.678 g, 92% content). ESI-MS m / z [M+H]+230.2.

[0284] STEP B: ethyl 2-(4-methyl-1H-indol-1-yl)propanoate

[0285] In a 200 mL round-1H-indol-1-yl)acrylate (0.300 g, 92% content, 1.20 mmol) and platinum(IV) oxide (0.014 g, 0.060 mmol) were combined in MeOH (30 mL) to give a brown suspension. The mixture was evacuated and back filled with hydrogen 3 times, then stirred at room temperature under hydrogen (balloon) for 2 days. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column)using 10% EtOAc in heptanes. Fractions were combined and concentrated to give the title compound as a colorless syrup (80 mg, 29% yield). ESI-MS m / z [M+H]+232.2.

[0286] STEP C: 2-(4-methyl-1H-indol-1-yl)propanoic acid

[0287] In a 125 mL pear-shaped flask, ethyl 2-(4-methyl-1H-indol-1-yl)propanoate (0.080 g, 0.346 mmol) and aqueous lithium hydroxide (2 M, 0.692 mL, 1.38 mmol) were dissolved in dioxane (3 mL) to give a colorless solution. The mixture was stirred at room temperature overnight. The mixture was acidified with aqueous HCl and extracted with EtOAc. The organic extracts were dried over MgSO4and concentrated in vacuo to give the crude title compound, which was used without additional purification (70 mg, assumed quantitative). ESI-MS m / z [M+H]+204.2.

[0288] PREPARATION 33: 2-(2,4-difluorophenyl)-2-fluoropropanoic acid

[0289] STEP A: methyl 2-(2,4-

[0290] To a cold (0°C bath)propanoic acid (5.00 g, 26.9 mmol) in MeOH (53.7 mL) was added thionyl chloride (3.92 mL, 53.7 mmol), and the mixture was stirred at 0°C for 2 h. The mixture was then concentrated in vacuo and the residue was diluted with heptanes (10 mL). The solution was washed with water (7 mL) and brine (5 mL), dried over MgSO4, and concentrated in vacuo to give the title compound as a clear oil (5.14 g, 96%).1H NMR (400 MHz, CD3OD) δ ppm 1.48 (d, J = 7.3 Hz, 3 H), 3.68 (s, 3 H), 4.01 (q, J = 7.3 Hz, 1 H), 6.90 - 6.98 (m, 2 H), 7.36 (td, J = 8.8, 6.3 Hz, 1 H).

[0291] STEP B: methyl 2-(2,4-difluorophenyl)-2-fluoropropanoate

[0292] BuLi (2.5 M in hexanes,was added in small portions to a cold (-78°C) solution of diisopropylamine (4.32 mL, 30.8 mmol) in THF (40 mL). The mixture was warmed to 0°C for 10 minutes and cooled back to -78°C. To the resulting solution was added methyl 2-(2,4-difluorophenyl)propanoate (5.14 g, 25.7 mmol) dropwise at-78°C. A small amount of anhydrous THF was used to complete the transfer. The mixture was stirred for 30 minutes. To this mixture was added a solution of N-fluoro-N- (phenylsulfonyl)benzenesulfonamide (10.53 g, 33.4 mmol) in THF (40 mL) in about 2 mL portions over 5 minutes. Upon completion of the addition, the mixture was warmed to 0°C over about 10 minutes and stirred for 10 min. The mixture was diluted with heptanes (50 mL) and quenched with water (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude oil was purified by flash silica column chromatography (ISCO, 220 g RediSep Rf Gold® column) using a gradient of 10-40% EtOAc in heptanes to afford the title compound as a clear oil (1.99 g, 35%).1H NMR (400 MHz, CD3OD) δ ppm 1.94 (d, J = 22.5 Hz, 3 H), 3.79 (s, 3 H), 6.99 - 7.09 (m, 2 H), 7.62 (td, J = 8.8, 6.6 Hz, 1 H).

[0293] STEP C: 2-(2,4-difluorophenyl)-2-fluoropropanoic acid

[0294] A solution of methyl 2-(2,4-difluorophenyl)-2-fluoropropanoate (1.98 g, 9.08 mmol) in dioxane (27.3 mL) was treated with aqueous lithium hydroxide (1 M, 27.2 mL, 27.2 mmol). The mixture was stirred for 5 minutes and concentrated in vacuo to remove dioxane. The residual aqueous layer was acidified to pH 1-2 with 6 M HCl and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford an oil. The oil was diluted with heptane (20 mL) and concentrated in vacuo to afford the title compound as a white solid (1.81 g, 98 ).1H NMR (400 MHz, DMSO-d6) δ ppm 1.87 (d, J = 22.2 Hz, 1 H), 7.11 - 7.22 (m, 1 H), 7.28 - 7.37 (m, 1 H), 7.65 (tdd, J = 8.8, 6.5, 1.1 Hz, 1 H), 13.56 (br s, 1 H).

[0295] PREPARATION 34: 2-(3-chlorophenyl)-2-fluoropropanoic acid

[0296] Starting from methyl 2-(500 mg, 2.52 mmol), the title compound (130 mg, 25% over two steps) was obtained following STEP B and STEP C of PREPARATION 33.1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J = 22.6 Hz, 3 H), 7.41 - 7.54 (m, 4 H), 13.65 (br s, 1 H).

[0297] PREPARATION 35: 2-fluoro-2-(m-tolyl)propanoic acid

[0298] The title compound was prepared like the three-step procedure in PREPARATION 33, using 2-(m-tolyl)propanoic acid (2.50 g, 15.2 mmol), and was obtained as a white solid (2.25 g, 84% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (d, J = 22.0 Hz, 3 H), 2.34 (s, 3 H), 7.20 (br d, J = 7.2 Hz, 1 H), 7.23 - 7.28 (m, 1 H), 7.28 - 7.35 (m, 2 H), 13.36 (br s, 1 H).

[0299] PREPARATION 36: 2-fluoro-2-phenylpropanoic acid

[0300] The title compound was three-step procedure inPREPARATION 33, using 2- g, 33.3 mmol), and was obtained as a white solid (3.96 g, 71% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J = 22.5 Hz, 3 H), 7.37 - 7.46 (m, 3 H), 7.46 - 7.52 (m, 2 H), 13.41 (br s, 1 H).

[0301] PREPARATION 37: 2-(4-chlorophenyl)-2-fluoropropanoic acid

[0302] The title compound wasstep procedure in PREPARATION 33, using 2-(4-chlorophenyl)propanoic acid (3.00 g, 16.2 mmol), and was obtained as a white solid (2.65 g, 80% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J = 22.0 Hz, 3 H), 7.50 (s, 4 H), 13.55 (br s, 1 H).

[0303] PREPARATION 38: 2-fluoro-2-(2-fluorophenyl)propanoic acid

[0304] The title compound was prepared like the three-step procedure in PREPARATION 33, using 2-(2-fluorophenyl)propanoic acid (1.00 g, 5.95 mmol), and was obtained as a white solid (0.703 g, 64% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (d, J = 22.5 Hz, 3 H), 7.21 - 7.33 (m, 2 H), 7.48 (q, J = 6.8 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 13.49 (br s, 1 H).

[0305] PREPARATION 39: 2-(2-chlorophenyl)-2-fluoropropanoic acid

[0306] The title compound was prepared like the three-step procedure in PREPARATION 33, using 2-(2-chlorophenyl)propanoic acid (1.08 g, 5.85 mmol), and was obtained as a white solid (0.379 g, 32% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (d, J = 24.2 Hz, 3 H), 7.45 (s, 2 H), 7.47 - 7.54 (m, 1 H), 7.62 - 7.70 (m, 1 H), 13.49 (br s, 1 H).

[0307] PREPARATION 40: 2-fluoro-2-(3-fluorophenyl)propanoic acid

[0308] The title compound was step procedure in PREPARATION33, using 2-(3-fluorophenyl) mmol), and was obtained as a yellow oil (7.41 g, 67% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.87 (d, J = 22.3 Hz, 3 H), 7.17 - 7.37 (m, 3 H), 7.49 (td, J = 7.9, 6.2 Hz, 1 H), 13.58 (br s, 1 H).

[0309] PREPARATION 41: 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)-2- methylpropanoic acid

[0310] STEP A: 6-fluoro-4-2-one

[0311] To a solution of 1-(5-ethan-1-one (3.30 g, 19.6 mmol) in toluene (59.5 mL) was added sodium hydride (60 wt %, 3.92 g, 98 mmol) and the mixture was stirred for 5 minutes (no further gas evolution was observed). The mixture was treated with diethyl carbonate (3.33 mL, 27.5 mmol) and stirred at reflux in a 160°C oil bath for 24 h. The mixture was cooled and quenched with a mixture of ice and saturated aqueous NH4Cl (75 mL). The resulting suspension was diluted with water (200 mL) and washed with EtOAc / heptane (2:1, 75 mL). The aqueous layer was acidified with 6 M HCl to pH 1-2 and the resulting precipitate was filtered and vacuum dried at 50°C for 3 days to afford the title compound as a light tan solid (3.80 g, quantitative).1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3 H), 5.63 (s, 1 H), 7.37 (dd, J = 8.6, 3.1 Hz, 1 H), 7.41 - 7.48 (m, 1 H), 12.62 (br s, 1 H); ESI-MS m / z [M+H]+195.0.

[0312] STEP B: 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)acetic acid

[0313] A solution of 6-fluoro- chromen-2-one (3.80 g, 19.6 mmol), hydroxylamine hydrochloride, acetate (5.68 g, 68.5 mmol) in MeOH (39.1 mL) was stirred on a hot plate at 70°C for 16 h. Additional hydroxylamine hydrochloride (1.5 g) and sodium acetate (1.6 g) were added and stirring was continued at 70°C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (1 x 150 mL) and DCM (2 x 150 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give crude title compound, which was utilized directly for the next step without purification. ESI-MS m / z [M+H]+210.2.

[0314] STEP C: methyl 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)acetate

[0315] A solution of 2-(5-3-yl)acetic acid (4.09 g, 19.6 mmol) in MeOH (48.9 mL) at 0°C was treated with thionyl chloride (2.86 mL, 39.1 mmol) dropwise via syringe. The resulting reaction mixture was stirred at 0°C for 1 h and then at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was purified by flash silica column chromatography (ISCO) using 20% EtOAc in heptanes. The title compound was obtained as a white solid (1.97 g, 45%). ESI-MS m / z [M+H]+224.2.

[0316] STEP D: methyl 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)-2-methylpropanoate

[0317] A solution of sodiummmol) in THF (24 mL) at 0°C was treated with a solution of methyl 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)acetate (1.97 g, 8.83 mmol) in THF (20 mL) dropwise via syringe. The ice bath was removed and stirring was continued at room temperature for 30 minutes. The solution was cooled again to 0°C followed by the dropwise addition of MeI (1.932 mL, 30.9 mmol) via syringe. Theresulting reaction mixture was allowed to warm up slowly to room temperature and was stirred for 16 h. The reaction mixture was quenched at 0°C by the dropwise addition of saturated aqueous NH4Cl (25 mL). The quenched solution was transferred into a separatory funnel and extracted with EtOAc (2 x 100 mL) and DCM (1 x 100 mL). The organic layers were combined, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash silica column chromatography (ISCO) using 10% EtOAc in heptanes to give the title compound as a pale yellow oil (1.66 g, 75%).1H NMR (400 MHz, CDCl3) δ ppm 1.77 (s, 6 H), 2.56 (t, J = 0.8 Hz, 3 H), 3.70 (s, 3 H), 7.06 - 7.08 (m, 1 H), 7.08 - 7.10 (m, 1 H); ESI-MS m / z [M+H]+252.2.

[0318] STEP E: 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0319] A solution of methyl 2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)-2- methylpropanoate (1.66 g, 6.61 mmol) in MeOH (8.26 mL) and THF (8.26 mL) was treated with aqueous LiOH (3 M, 6.61 mL, 19.8 mmol) at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction mixture was acidified to pH 2-3 by the dropwise addition of 1 N HCl. The acidified solution was extracted with EtOAc (2 x 100 mL) and DCM (2 x 100 mL). The organic layers were collected and the solvent removed under reduced pressure. The residue was purified by flash silica column chromatography (ISCO) using 25% EtOAc in heptanes to give the title compound as a white solid (1.42 g, 91%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.66 (s, 6 H), 2.51 (s, 3 H), 7.34 (dd, J = 8.3, 2.5 Hz, 1 H), 7.40 (dt, J = 9.7, 1.2 Hz, 1 H), 13.00 (s, 1 H); ESI-MS m / z [M+H]+238.2.

[0320] PREPARATION 42: 2-(5,6-dimethylbenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0321] STEP A: 2-(5,6-acetic acid

[0322] A solution of 4-2-one (1.00 g, 5.26 mmol), hydroxylamine hydrochloride (1.544 g, 21.56 mmol) and DIPEA (3.95 mL, 22.6 mmol) in MeOH (8.76 mL) was stirred at 70°C for 16 h. The solvent was removed under reducedpressure and the orange residue was diluted with diethyl ether (100 mL) and treated with saturated aqueous NaHCO3(100 mL). The basic solution was transferred to a separatory funnel and the layers were allowed to separate. The aqueous layer was collected and acidified by the slow addition of 6 N HCl. The precipitate that formed was filtered by suction, collected and lyophilized overnight. The title compound was obtained as an ivory solid (770 mg, 71%) and utilized directly for the next step without further purification. ESI-MS m / z [M+H]+206.1.

[0323] STEP B: methyl 2-(5,6-dimethylbenzo[d]isoxazol-3-yl)acetate

[0324] The title compound PREPARATION 41, using 2-(5,6-dimethylbenzo[d]isoxazol-3- mg, , and was obtained as a white solid (698 mg, 85%).1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3 H), 2.38 (s, 3 H), 3.67 (s, 3 H), 4.15 (s, 2 H), 7.54 (s, 1 H), 7.55 (s, 1 H); ESI-MS m / z [M+H]+220.1.

[0325] STEP C: methyl 2-(5,6-dimethylbenzo[d]isoxazol-3-yl)-2-methylpropanoate

[0326] The title compoundPREPARATION 41, using methyl 2-(5,6-dimethylbenzo[d]isoxazol-3-yl)acetate (220 mg, 1.00 mmol), sodium hydride (60 wt %, 201 mg, 5.02 mmol) and MeI (0.31 mL, 5.02 mmol) in DMA (3.35 mL). The residue was purified by flash silica column chromatography (ISCO) using 15% EtOAc in heptanes to yield the title compound as a colorless oil (212 mg, 85%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (s, 6 H), 2.32 (s, 3 H), 2.36 (s, 3 H), 3.63 (s, 3 H), 7.45 (s, 1 H), 7.54 (s, 1 H); ESI- MS m / z [M+H]+248.3.

[0327] STEP D: 2-(5,6-dimethylbenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0328] The title compound was prepared like STEP E of PREPARATION 41, using methyl 2-(5,6-dimethylbenzo[d]isoxazol-3-yl)-2-methylpropanoate (320 mg, 1.29 mmol), and was obtained as a white solid (203 mg, 67%). ESI-MS m / z [M+H]+234.2.

[0329] PREPARATION 43: 2-(7-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0330] STEP A: 2-(7-chloroben etic acid

[0331] A solution of sodium 8- 4-olate (1.40 g, 6.55 mmol),hydroxylamine hydrochloride acetate (1.90 g, 22.9 mmol) in MeOH (13.1 mL) was stirred on a hot plate at 70°C overnight. The solvent was removed under reduced pressure and the residue obtained was treated with saturated aqueous NaHCO3 (100 mL) and diluted with diethyl ether (100 mL). The solution was transferred to a separatory funnel and the layers allowed to separate. The aqueous layer was collected and acidified with 6 N HCl. The precipitate that formed was filtered by suction, collected and lyophilized overnight. The title compound was obtained as a pale beige solid (867 mg, 63%) and utilized directly for the next step without further purification. ESI-MS m / z [M+H]+212.1.

[0332] STEP B: methyl 2-(7-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoate

[0333] A solution of 2-(7-acetic acid (1.21 g, 5.72 mmol) in DMA (19.06 mL) at 0°C was treated with sodium hydride (60 wt %, 1.144 g, 28.6 mmol) portion-wise and the solution was stirred at room temperature for 30 minutes. The solution was cooled to 0°C, followed by the dropwise addition of MeI (1.788 mL, 28.6 mmol) via syringe. The resulting reaction mixture was allowed to warm up slowly to room temperature and was stirred for 16 h. The reaction mixture was quenched slowly with water and extracted with EtOAc (2 x 125 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography (ISCO) using 10% EtOAc in heptanes to give the title compound as a yellow oil (637 mg, 44%). ESI-MS m / z [M+H]+254.2.

[0334] STEP C: 2-(7-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0335] A solution of methyl 2-(7-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoate (637 mg, 2.51 mmol) in MeOH (6.28 mL) was treated with aqueous LiOH (3 M, 2.51 mL, 7.53mmol) at room temperature and the resulting reaction mixture was stirred for 48 h. The reaction mixture was acidified to pH 2 by the dropwise addition of 6 N HCl. The acidified solution was transferred to a separatory funnel and extracted with EtOAc (1 x 50 mL) and DCM (2 x 50 mL). The organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography (ISCO) using a gradient of 10-100% EtOAc in heptanes to give the title compound as a white solid (564 mg, 94%).1H NMR (400 MHz, DMSO-d6) δ 1.69 (s, 6 H), 7.42 (t, J = 7.9 Hz, 1 H), 7.74 - 7.80 (m, 2 H), 13.09 (s, 1 H). ESI-MS m / z [M+H]+240.1.

[0336] PREPARATION 44: 2-(4-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0337] STEP A: 2-(4- acid

[0338] The title compound was of PREPARATION 43, using 5-chloro-4-hydroxy-2H-chromen-2-one (2.30 g, 11.7 mmol), and was obtained as a white solid (1.5 g, 61%).1H NMR (400 MHz, DMSO-d6) δ ppm 4.16 (s, 2 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.62 - 7.70 (m, 1 H), 7.77 (d, J = 8.5 Hz, 1 H); ESI-MS m / z [M+H]+212.1.

[0339] STEP B: methyl 2-(4-chlorobenzo[d]isoxazol-3-yl)acetate

[0340] The title compound wasof PREPARATION 41, using 2-(4- chlorobenzo[d]isoxazol-3-yl)acetic acid (1.5 g, 7.09 mmol), and was obtained as a white solid (1.5 g, 94%).1H NMR (400 MHz, DMSO-d6) δ ppm 3.68 (s, 3 H), 4.29 (s, 2 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.68 (t, J = 8.1 Hz, 1 H), 7.76 - 7.81 (m, 1 H); ESI-MS m / z [M+H]+226.1.

[0341] STEP C: methyl 2-(4-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoate

[0342] The title compound was prepared like STEP D of PREPARATION 41, using methyl 2-(4-chlorobenzo[d]isoxazol-3-yl)acetate (1.50 g, 6.65 mmol), and was obtained as a yellow oil (626 mg, 37%). ESI-MS m / z [M+H]+254.2.

[0343] STEP D: 2-(4-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoic acid

[0344] A solution of methyl 2-(4-chlorobenzo[d]isoxazol-3-yl)-2-methylpropanoate (626 mg, 2.47 mmol) in MeOH (6.17 mL) was treated with aqueous LiOH (3 M, 2.5 mL, 7.40 mmol) at room temperature and the resulting cloudy reaction mixture was stirred at room temperature for 16 h and then at 65°C for 16 h. The reaction mixture was acidified to pH 2-3 by the dropwise addition of 6 N HCl. The acidified solution was transferred to a separatory funnel and extracted with EtOAc (3 x 75 mL). The organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography (ISCO) using a gradient of 40-100% EtOAc in heptanes. The title compound was obtained as a white solid (500 mg, 85%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (s, 6 H), 7.47 (dd, J = 7.8, 0.8 Hz, 1 H), 7.62 - 7.70 (m, 1 H), 7.75 - 7.80 (m, 1 H), 12.96 (s, 1 H); ESI-MS m / z [M+H]+240.1.

[0345] PREPARATION 45: 2-methyl-2-(1-methyl-1H-indazol-3-yl)propanoic acid

[0346] STEP A: methyl 2-(1-acetate

[0347] To a 250 mL flaskindazol-3-yl)acetic acid (5.00 g, 26.3 mmol) in methanol (53.2 mL) was added thionyl chloride (1.917 mL, 26.3 mmol) over 1 minute at 0°C. The mixture was stirred for 1 h at 0°C, and then stirred at 66°C for 20 h. The reaction mixture was concentrated via rotary evaporation and dried in vacuo to provide crude product (6.05 g). The crude residue was partitioned with EtOAc (100 mL) and water (50 mL), and the layers were separated. The organic phase was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in toluene (1 mL) and purified by flash silica column chromatography (ISCO, 120 g RediSep Rf Gold® column) using a gradient of0-100% EtOAc in heptanes. The pure fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide the title compound as a yellow solid (4.34 g, 81%).1H NMR (400 MHz, DMSO-d6) δ ppm 3.62 (s, 3 H), 3.99 (s, 3 H), 4.01 (s, 2 H), 7.12 (ddd, J = 8.0, 7.0, 0.8 Hz, 1 H), 7.39 (ddd, J = 8.3, 7.0, 1.0 Hz, 1 H), 7.55 - 7.62 (m, 1 H), 7.70 (dt, J = 8.2, 0.9 Hz, 1 H); ESI-MS m / z [M+H]+205.0.

[0348] STEP B: methyl 2-methyl-2-(1-methyl-1H-indazol-3-yl)propanoate

[0349] To a 500 mL flask 1H-indazol-3-yl)acetate (4.33g, 21.2 mmol) in THF (46 mL) was amide solution (1 M in THF, 70.0 mL, 70.0 mmol) dropwise over 15 minutes at -20°C via an addition funnel. The mixture was stirred for 1 h at -20°C, and then iodomethane (4.36 mL, 70.0 mmol) was added dropwise over 20 minutes via an addition funnel. The reaction mixture was allowed to warm to room temperature over 5 h and was stirred for an additional 4 days. The resulting suspension was cooled on ice, quenched with saturated NH4Cl (50 mL), and partitioned with EtOAc (300 mL) and water (25 mL), and the layers were separated. The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation to provide crude product (5.48 g). The crude material was dissolved in toluene (7 mL) and purified by flash silica column chromatography (ISCO, 220 g RediSep Rf Gold® column) using a gradient of 0-100% EtOAc in heptanes. The appropriate fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide the title compound as a yellow solid (3.57 g, 72%). ESI-MS m / z [M+H]+233.2.

[0350] STEP C: 2-methyl-2-(1-methyl-1H-indazol-3-yl)propanoic acid

[0351] To a 50 mL flask charged with methyl 2-methyl-2-(1-methyl-1H-indazol-3- yl)propanoate (3.57 g, 15.4 mmol) in THF (100 mL) was added aqueous LiOH (1 M, 30.7 mL, 30.7 mmol) at room temperature. The mixture was stirred for 70 h at 60°C, cooled to room temperature, and partitioned with EtOAc (100 mL) and water (20 mL). The layers were separated and the organic phase was washed with water (2 x 20 mL). The aqueous extracts were combined, acidified with HCl (3 N, 10 mL) to pH 2, and the product was extracted with EtOAc (2 x 100 mL). The organic extracts were combined, washed with brine (50 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo to provide the title compound as a white solid (3.31 g, 99%). ESI-MS m / z [M+H]+219.1.

[0352] PREPARATION 46: 2-methyl-2-(7-methylbenzo[d]isoxazol-3-yl)propanoic acid

[0353] STEP A: methyl 2- isoxazol-3-yl)propanoate

[0354] To a 200 mL round- was added methyl 2-(7-methylbenzo[d]isoxazol-3-yl) in THF (50 mL). The mixture was cooled to -20°C under nitrogen, and lithium bis(trimethylsilyl)amide (1 M in THF, 9.75 mL, 9.75 mmol) was added dropwise and allowed to stir for 1 h at -20°C. Iodomethane (1.582 mL, 17.06 mmol) was added and the reaction mixture was allowed to warm to room temperature and stir overnight. Lithium bis(trimethylsilyl)amide (1 M in THF, 4.87 mL, 4.87 mmol) was added. The mixture was allowed to stir for 15 minutes, followed by the addition of more iodomethane (0.452 mL, 4.87 mmol). The mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2 x 100 mL). The organics were combined, dried over MgSO4, and concentrated to give the title compound, which was carried forward without additional purification (1.2 g, assumed quantitative, 94% content). ESI-MS m / z [M+H]+234.10.

[0355] STEP B: 2-methyl-2-(7-methylbenzo[d]isoxazol-3-yl)propanoic acid

[0356] In a 100 mL round-bottomed flask with a stir bar, methyl 2-methyl-2-(7- methylbenzo[d]isoxazol-3-yl)propanoate (1.13 g, 4.84 mmol) was dissolved in THF (30 mL). Aqueous LiOH (1 M, 9.69 mL, 9.69 mmol) was added and the reaction mixture was heated at 60°C overnight. The mixture was allowed to cool to room temperature and was extracted with EtOAc (100 mL) and water (2 x 100 mL). The aqueous layers were combined and acidified with 6 N HCl to pH 3 and extracted with EtOAc (2 x 100 mL). The organics were combined and dried with MgSO4, filtered, and concentrated to give the title compound as a yellow oil (985 mg, 93%).1H NMR (400 MHz, CDCl3) δ ppm 1.82 (s, 6 H), 2.10 (s, 1 H), 2.56 (s, 3 H), 7.18 (t, J = 7.4 Hz, 1 H), 7.30 (d, J = 7.0 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H); ESI-MS m / z [M+H]+220.00.

[0357] PREPARATION 47: 2-methyl-2-(3-methyl-1H-indazol-1-yl)propanoic acid

[0358] STEP A: methyl 2-methyl ndazol-1-yl)propanoate

[0359] To a mixture of 2-(3- acid (510 mg, 2.68 mmol) inDMF (15 mL) was added sodium mg, 13.4 mmol), followed by iodomethane (835 µL, 13.4 mmol) at room temperature. After 4 hours, additional iodomethane (334 µL, 5.36 mmol) and sodium hydride (60 wt %, 214 mg, 5.36 mmol) were added, and the mixture was heated to 55°C for 30 minutes. After cooling to 0°C, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product mixture. Purification by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 5-25% EtOAc in heptanes gave the title compound (430 mg, 69%). ESI-MS m / z [M+H]+233.2.

[0360] STEP B: 2-methyl-2-(3-methyl-1H-indazol-1-yl)propanoic acid To a mixture of methyl 2-methyl-2-(3-methyl-1H-indazol-1-yl)propanoate (0.430 g, 1.85 mmol) in methanol (3 mL) was added aqueous LiOH (1 N, 6 mL). The mixture was heated to 55°C for 1 h and then stirred at room temperature for 48 h to allow the reaction to go to completion. The mixture was then neutralized, and the resulting precipitate was collected on a fritted glass filter, washed with deionized water, and dried under nitrogen to give the title compound (240 mg, 55%). ESI-MS m / z [M+H]+219.0.

[0361] PREPARATION 48: 2-(3-methoxyphenyl)-2-methylpropanoic acid

[0362] STEP A: methyl 2-(3-

[0363] To a mixture of methyl 2-(3-methoxyphenyl)acetate (1.20 g, 6.66 mmol) in DMF (25 mL) was added sodium hydride (60 wt %, 0.932 g, 23.3 mmol), followed by iodomethane (1.45 mL, 23.3 mmol) at room temperature. After 4 h at room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated to give the crude product mixture. Purification by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 5-25% EtOAc in heptanes gave the title compound (1.27 g, 92%). ESI-MS m / z [M-CO2CH3]+149.1.

[0364] STEP B: 2-(3-methoxyphenyl)-2-methylpropanoic acid

[0365] A mixture of methyl 2-(3-methoxyphenyl)-2-methylpropanoate (1.27 g, 6.10 mmol) in methanol (5 mL) and aqueous LiOH (1 N, 20 mL) was stirred at room temperature for 18 h. The reaction mixture was neutralized and then partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. ESI-MS m / z [M+H]+195.1.

[0366] PREPARATION 49: 2-methyl-2-(3-(trifluoromethyl)phenyl)propanoic acid

[0367] STEP A: methyl 2-phenyl)propanoate

[0368] To a mixture of 2-(3-acid (1.00 g, 4.90 mmol) in DMF (25 mL) was added sodium hydride (60 wt %, 0.980 g, 24.49 mmol), followed by iodomethane (1.525 mL, 24.49 mmol) at room temperature. After stirring for 2 h at room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product mixture. Purification by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 5-30% EtOAc in heptanes gave the title compound (0.777 g, 64%). ESI-MS m / z [M+H]+247.3.

[0369] STEP B: 2-methyl-2-(3-(trifluoromethyl)phenyl)propanoic acid

[0370] A mixture of methyl 2-methyl-2-(3-(trifluoromethyl)phenyl)propanoate (0.777 g, 3.16 mmol) in methanol (5 mL) and aqueous LiOH (1 N, 20 mL) was stirred at 55°C for 2 h. The reaction mixture was cooled to room temperature, neutralized, and then partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. ESI-MS m / z [M+H]+233.1.

[0371] PREPARATION 50: 2-(2,3-difluorophenyl)-2-methylpropanoic acid

[0372] STEP A: methyl 2-(2,3-

[0373] To a mixture of 2-(2,3- acid (500 mg, 2.90 mmol) in DMF (10mL) was added sodium hydride (60 wt %, 581 mg, 14.5 mmol), followed by iodomethane (904 µL, 14.5 mmol) at room temperature. After 3 h, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product mixture. Purification by flash silica column chromatography (ISCO, 24 g RediSep Rf Gold® column) using a gradient of 5-25% EtOAc in heptanes gave the title compound (427 mg, 69%). ESI-MS m / z [M+H]+215.1.

[0374] STEP B: 2-(2,3-difluorophenyl)-2-methylpropanoic acid

[0375] To a mixture of methyl 2-(2,3-difluorophenyl)-2-methylpropanoate (427 mg, 1.99 mmol) in methanol (5 mL) was added aqueous LiOH (1 N, 20 mL). The mixture was stirred at room temperature for 18 h to allow the reaction to go to completion. The mixture was then neutralized, and the resulting precipitate was collected on a fritted glass filter, washed with deionized water, and dried under nitrogen to give the title compound (350 mg, 188%). ESI- MS m / z [M+H]+201.1.

[0376] PREPARATION 51: 2-(3-(difluoromethyl)phenyl)-2-methylpropanoic acid

[0377] STEP A: methyl 2-(3-(difluoromethyl)phenyl)-2-methylpropanoate

[0378] To a mixture of 2-(3- acid (100 mg, 0.537 mmol) in DMF (5 mL) was added sodium2.69 mmol), followed by iodomethane (167 µL, 2.69 mmol) at room temperature. After stirring for 14 h at room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product mixture. Purification by flash silica column chromatography (ISCO, 24 g RediSep Rf Gold® column) using a gradient of 5-40% EtOAc in heptanes gave the title compound (65 mg, 53%).

[0379] STEP B: 2-(3-(difluoromethyl)phenyl)-2-methylpropanoic acid

[0380] A mixture of 2-(3-(difluoromethyl)phenyl)-2-methylpropanoate (65 mg, 0.285 mmol) in methanol (5 mL) and aqueous LiOH (1 N, 20 mL) was stirred at room temperature for 15 h. The reaction mixture was acidified to pH < 2, and then partitioned between brine and EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. ESI-MS m / z [M+H]+215.1.

[0381] PREPARATION 52: 3-methoxy-2-methyl-2-phenylpropanoic acid

[0382] STEP A: methyl 3-

[0383] To a flask charged with%, 0.618 g, 15.4 mmol) in THF (22 mL) and DMF (11 mL) was added iodomethane (2.0 M in MTBE, 7.72 mL, 15.4 mmol) at room temperature. The mixture was cooled to 0°C, and methyl 3-hydroxy-2-methyl-2- phenylpropanoate (1.00 g, 5.15 mmol) was added as a solution in THF (11 mL) over 2minutes. The mixture was stirred at 0°C for 1 h, warmed slowly to room temperature over 1 h, and stirred for an additional 16 h. The reaction mixture was poured into ice (100 g) and the crude product was extracted with Et2O (3 x 50 mL). The organic extracts were combined, washed with water (2 x 50 mL) and then brine (50 mL), dried over Na2SO4, filtered, rinsed with Et2O, and dried in vacuo to provide the crude product as a yellow oil. The crude material was dissolved in toluene (5 mL) and purified by flash silica column chromatography (ISCO, 120 g RediSep Rf Gold® column) using a gradient of 0-100% EtOAc in heptanes. The pure fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide the title compound as a colorless oil (0.596 g, 56%). ESI-MS m / z [M+H]+209.1.

[0384] STEP B: 3-methoxy-2-methyl-2-phenylpropanoic acid

[0385] To a flask charged with methyl 3-methoxy-2-methyl-2-phenylpropanoate (0.583 g, 2.80 mmol) in MeOH (42.5 mL) was added aqueous NaOH (2.0 M, 42.0 mL, 84 mmol) at room temperature. The mixture was stirred at 23°C for 15 h and concentrated via rotary evaporation. The mixture was acidified with 3 N HCl (30 mL), and the crude product was extracted with Et2O (3 x 50 mL). The organic extracts were combined, washed with water and then brine, dried over Na2SO4, filtered, rinsed with Et2O, and dried in vacuo to provide the title compound as an oil (0.534 g, 98%). ESI-MS m / z [M+Na]+217.1.

[0386] PREPARATION 53: 2-(5-(difluoromethyl)pyridin-2-yl)-2,2-difluoroacetic acid

[0387] STEP A: ethyl 2-(5-yl)-2,2-difluoroacetate

[0388] To a vial charged(1.00 g, 3.94 mmol) and ethyl bromodifluoroacetate (0.505 mL, 3.94 mmol) in DMSO (20 mL) was added copper (0.500 g, 7.87 mmol) at room temperature. The reaction mixture was stirred at 80°C for 17 h. The reaction mixture was cooled to room temperature and poured into a solution of K2HPO4(9 g) in water (112 mL) with vigorous stirring. The resulting suspension was filtered, rinsed with Et2O (100 mL), and the filtrate was partitioned with brine (100 mL). The layers were separated, and the aqueous phase was washed with Et2O (2 x 25 mL). The organic extractswere combined, washed with brine (100 mL), dried over Na2SO4, filtered, rinsed with Et2O, and concentrated via rotary evaporation to provide a light yellow oil. The crude material was dissolved in toluene (1 mL) and purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 0-100% EtOAc in heptanes. The pure fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide the title compound as a colorless oil (0.6197 g, 63%).1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J = 7.2 Hz, 3 H), 4.31 (q, J = 7.1 Hz, 2 H), 6.50 - 6.86 (m, 1 H), 7.61 (d, J = 8.3 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2 H);19F NMR (376 MHz, CDCl3) δ ppm -112.05 (d, J = 55.9 Hz, 2 F), -104.17 (s, 2 F).

[0389] STEP B: 2-(5-(difluoromethyl)pyridin-2-yl)-2,2-difluoroacetic acid

[0390] To a flask charged with ethyl 2-(4-(difluoromethyl)phenyl)-2,2-difluoroacetate (0.6067 g, 2.425 mmol) in dioxane (7.27 mL) was added aqueous LiOH (1 M, 7.27 mL, 7.27 mmol) at room temperature. The reaction mixture was stirred at 23°C for 15 minutes, concentrated via rotary evaporation, and acidified with 3 N HCl (2 mL) to pH 5. The product was extracted with EtOAc (2 x 10 mL), and the organic extracts were combined, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo to provide the title compound as a white solid (461 mg, 86%).1H NMR (400 MHz, DMSO-d6) δ ppm 6.94 - 7.27 (m, 1 H), 7.65 - 7.80 (m, 4 H); ESI-MS m / z [M+H]+222.3.

[0391] PREPARATION 54: 2-(5-chloropyridin-2-yl)-2,2-difluoroacetic acid

[0392] STEP A: ethyl 2-(5-

[0393] To a flask charged(2.00 g, 10.4 mmol) and copper (1.486 g, 23.38 mmol) in DMSO (10 mL) was added ethyl bromodifluoroacetate (1.466 mL, 11.43 mmol) at room temperature. The reaction mixture was stirred at 50°C for 10 minutes, then stirred at 70°C for 17 h, cooled to room temperature, and diluted with EtOAc (50 mL). Next, a solution of KH2PO4(1.27 M, 50 mL) was added slowly to the flask. The resulting suspension was stirred for 30 minutes, filtered through Celite®, and rinsed with EtOAc (25 mL). The layers were separated, and the organic phase was washed with water (25 mL) and then brine (25 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated viarotary evaporation to provide an orange oil. The crude material was dissolved in toluene (2 mL) and purified by flash silica column chromatography (ISCO, 80 g RediSep Rf Gold® column) using a gradient of 0-100% EtOAc in heptanes. The appropriate fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide the title compound as a colorless oil (1.83 g, 75%).1H NMR (400 MHz, CDCl3) δ ppm 1.33 (t, J = 7.0 Hz, 3 H), 4.37 (q, J = 7.0 Hz, 2 H), 7.70 (dd, J = 8.5, 0.8 Hz, 1 H), 7.84 (dd, J = 8.4, 2.4 Hz, 1 H), 8.60 (d, J = 2.5 Hz, 1 H); ESI-MS m / z [M+H]+236.1.

[0394] STEP B: 2-(5-chloropyridin-2-yl)-2,2-difluoroacetic acid

[0395] To a flask charged with ethyl 2-(5-chloropyridin-2-yl)-2,2-difluoroacetate (1.78 g, 7.55 mmol) in dioxane (23 mL) was added aqueous LiOH (1 M, 22.66 mL, 22.66 mmol) at room temperature. The reaction mixture was stirred at 23°C for 15 minutes, concentrated via rotary evaporation, and acidified with HCl (3 N, 7 mL) to pH 2. The product was extracted with EtOAc (2 x 10 mL), and the organic extracts were combined, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo to provide the title compound as an off-white solid (1.492 g, 95%). ESI-MS m / z [M+H]+208.1.

[0396] PREPARATION 55: 2-(4-fluoro-3-methylphenyl)-2-methylpropanoic acid

[0397] STEP A: methyl 2-(4-acetate

[0398] A solution of 2-(4-acid (380 mg, 2.26 mmol) in MeOH (9.04 mL) was treated with thionyl chloride (330 µL, 4.52 mmol) dropwise via syringe at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (15 mL) and extracted with DCM (3 x 30 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a colorless oil (389 mg, 94%), which was utilized directly for the next step without further purification. ESI- MS m / z [M+H]+183.2.

[0399] STEP B: methyl 2-(4-fluoro-3-methylphenyl)-2-methylpropanoate

[0400] A solution of methyl 2-( yl)acetate (389 mg, 2.14 mmol) in THF (14.2 mL) at 0°C was treated with sodium hydride (60 wt %, 342 mg, 8.54 mmol) and the solution was stirred at room temperature for 30 minutes. MeI (534 µL, 8.54 mmol) was then added dropwise via syringe at 0°C, and the resulting reaction mixture was allowed to warm up slowly to room temperature and stirred for 16 h. The reaction mixture was quenched at 0°C by the dropwise addition of saturated aqueous NH4Cl (20 mL). The solution was transferred into a separatory funnel and extracted with EtOAc (1 x 50 mL) and DCM (2 x 50 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent was removed under reduced pressure (water bath maintained at room temperature). The title compound was obtained as an orange oil (449 mg, assumed quantitative) and was utilized directly for the next step without further purification. ESI-MS m / z [M+ H]+211.3.

[0401] STEP C: 2-(4-fluoro-3-methylphenyl)-2-methylpropanoic acid

[0402] A solution of methyl 2-(4-fluoro-3-methylphenyl)-2-methylpropanoate (449 mg, 2.14 mmol) in MeOH (7.12 mL) was treated with aqueous LiOH (3 M, 4.27 mL, 12.8 mmol) at room temperature and the resulting reaction mixture was stirred for 48 h. The reaction mixture was acidified to pH 3-4 by the dropwise addition of 1 N HCl. The acidified solution was extracted with EtOAc (1 x 30 mL) and DCM (2 x 30 mL). The organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography (ISCO) using a gradient of 0-100% EtOAc in heptanes to give the title compound as a white solid (99 mg, 24% over two steps). ESI-MS m / z [M+H]+197.3.

[0403] PREPARATION 56: methyl 2-(3-fluoro-5-methylphenyl)-2-methylpropanoate

[0404] The title compound wasstep procedure in PREPARATION 55, using 2-(3-fluoro-5-methylphenyl)acetic acid (360 mg, 2.14 mmol), and was obtained as a yellow solid (300 mg, 71% over three steps).1H NMR (400 MHz, CDCl3) δ ppm 1.59 (s, 6H), 2.36 (s, 3 H), 6.79 (ddt, J = 9.3, 1.8, 1.0 Hz, 1 H), 6.92 (dt, J = 10.1, 2.2 Hz, 1 H), 6.97 - 6.99 (m, 1 H); ESI-MS m / z [M+H]+197.3.

[0405] PREPARATION 57: 2,3,3,3-tetrafluoro-2-(m-tolyl)propanoic acid

[0406] STEP A: ethyl 2,3,3,3-

[0407] To a 0°C solution of 2-(m-tolyl)propanoate (0.262 g,1.00 mmol) in DCM (2.00 mL) was 1.28 mmol). The mixture was stirred at 0°C for 30 minutes and water (10 mL) was carefully added. The mixture was extracted with heptanes (2 x 10 mL) and the combined organic extracts were washed with brine (2 x 5 mL), dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil (0.225 g, 85%).1H NMR (400 MHz, CDCl3) δ ppm 1.35 (t, J = 7.2 Hz, 3 H), 2.41 (s, 3 H), 4.30 - 4.45 (m, 2 H), 7.27 - 7.30 (m, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.41 - 7.49 (m, 2 H);19F NMR (376 MHz, CDCl3) δ ppm -172.50 (q, J = 6.8 Hz, 1 F), -77.04 (d, J = 6.8 Hz, 3 F).

[0408] STEP B: 2,3,3,3-tetrafluoro-2-(m-tolyl)propanoic acid

[0409] A solution of ethyl 2,3,3,3-tetrafluoro-2-(m-tolyl)propanoate (0.220 g, 0.833 mmol) in dioxane (2.5 mL) was treated with aqueous lithium hydroxide (1 M, 2.5 mL, 2.5 mmol). The mixture was stirred for 5 minutes and concentrated in vacuo to remove dioxane. The residual aqueous layer was acidified to pH 1-2 with aqueous HCl (6 M) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as an oil (96.4 mg, 49%).1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 7.22 - 7.29 (m, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.41 - 7.50 (m, 2 H).

[0410] PREPARATION 58: 2,3,3,3-tetrafluoro-2-(4-fluorophenyl)propanoic acid

[0411] The title compound was prepared like the two-step procedure in PREPARATION 57, using ethyl 3,3,3-trifluoro-2-(4-fluorophenyl)-2-hydroxypropanoate (0.631 g, 2.37 mmol), and was obtained as a clear oil (0.317 g, 56% over two steps).1H NMR (400 MHz, DMSO-d6) δ ppm 7.16 - 7.32 (m, 2 H), 7.73 (dd, J = 8.8, 5.5 Hz, 2 H).

[0412] PREPARATION 59: 5-chloro-1-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid

[0413] STEP A: methyl 5- 1-carboxylate

[0414] A solution of 5-chloro- 1-carboxylic acid (0.935 g, 4.76mmol) in DCM (10 mL) was (0.694 mL, 9.51 mmol) was slowly added and the mixture was stirred for 10 minutes, then warmed to 0°C and allowed to stir for 1 h. Methanol (10 mL) was added and the reaction was stirred at room temperature for 4 h. The mixture was concentrated with silica gel and purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using 20% EtOAc in heptanes to give the title compound as a yellow oil (904 mg, 90%).1H NMR (400 MHz, CD3OD) δ ppm 2.23 - 2.46 (m, 2 H), 2.89 (dt, J = 15.8, 7.6 Hz, 1 H), 2.98 - 3.11 (m, 1 H), 3.71 (s, 3 H), 4.03 (t, J = 7.4 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 7.23 (s, 1 H), 7.28 (d, J = 8.3 Hz, 1 H); ESI-MS m / z [M+H]+211.1.

[0415] STEP B: methyl 5-chloro-1-fluoro-2,3-dihydro-1H-indene-1-carboxylate

[0416] In a 20 mL vial, BuLi2.85 mmol) was added in small portions to a cold (-78°C) solution of diisopropylamine (0.419 mL, 2.99 mmol) in THF (5 mL). The mixture was warmed to 0°C for 10 minutes and then cooled to -78°C. To the resulting solution, methyl 5-chloro-2,3-dihydro-1H-indene-1-carboxylate (0.300 g, 1.42 mmol) was added. The mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.898 g, 2.85 mmol) in THF (5 mL). Upon completion of addition, the mixture was warmed to 0°C and stirred for 1.5 h. The mixture was diluted with heptane (10 mL) and isopropyl alcohol (0.5 mL) andquenched with water (10 mL). The organic layer was separated, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude residue was purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 10-30% EtOAc in heptanes gradient to give the title compound (301 mg, 69% yield, 75% purity).1H NMR (400 MHz, CD3OD) δ ppm 2.37 - 2.56 (m, 1 H), 2.82 (dddd, J = 19.4, 14.1, 8.6, 5.5 Hz, 1 H), 2.99 - 3.24 (m, 2 H), 3.79 (s, 3 H), 7.22 -7.39 (m, 3 H).

[0417] STEP C: 5-chloro-1-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid

[0418] To a 5 mL vial with a stir bar was added methyl 5-chloro-1-fluoro-2,3-dihydro-1H- indene-1-carboxylate (237 mg, 1.04 mmol) in THF (8 mL). Aqueous sodium hydroxide (1 M, 4.15 mL, 4.15 mmol) was added and the mixture was stirred for 30 minutes. The mixture was concentrated under reduced pressure and extracted with EtOAc (50 mL) and water (50 mL). The aqueous phase was separated and treated with 10 drops of concentrated HCl to reach pH 1-2, then extracted with EtOAc (2 x 50 mL). The combined organics were dried with MgSO4, filtered, and concentrated to give the title compound (162 mg, 73%).1H NMR (400 MHz, CD3OD) δ ppm 2.36 - 2.53 (m, 1 H), 2.74 - 2.90 (m, 1 H), 2.98 - 3.22 (m, 2 H), 7.25 - 7.32 (m, 1 H), 7.33 - 7.41 (m, 2 H).

[0419] PREPARATION 60: 2-(3-(difluoromethyl)phenyl)-2,2-difluoroacetic acid

[0420] STEP A: ethyl 2-(3-difluoroacetate

[0421] To a vial charged(1.00 g, 3.94 mmol) and ethyl bromodifluoroacetate (0.505 mL, 3.94 mmol) in DMSO (15 mL) was added copper (0.500 g, 7.87 mmol) at room temperature. The reaction mixture was stirred at 80°C for 6 h. The reaction mixture was cooled to room temperature and poured into a solution of K2HPO4 (10 g) in water (100 mL) with vigorous stirring. The mixture was filtered through a pad of Celite® and rinsed with diethyl ether (100 mL). The filtrate was extracted with diethyl ether (2 x 100 mL) and the organics were separated and dried over MgSO4. The organics were concentrated along with silica gel and purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 20-90% EtOAc in heptanes to give the title compound as a clear oil (0.710 g, 72%).1H NMR (400 MHz, CD3OD) δ ppm 1.27 (t, J =7.2 Hz, 3 H), 4.25 - 4.36 (m, 2 H), 6.71-6.99 (t, 1 H), 7.55 - 7.69 (m, 1 H), 7.69 - 7.81 (m, 3 H); ESI-MS m / z [M+H]+251.2.

[0422] STEP B: 2-(3-(difluoromethyl)phenyl)-2,2-difluoroacetic acid

[0423] To a 20 mL vial equipped with stir bar was added ethyl 2-(3- (difluoromethyl)phenyl)-2,2-difluoroacetate (100 mg, 0.400 mmol) in THF (5 mL), followed by aqueous NaOH (4 M, 0.400 mL, 1.60 mmol). The mixture was allowed to stir at room temperature for 2 h. The mixture was treated with water (5 mL) and acidified to pH 2 with concentrated HCl. The mixture was extracted with brine (10 mL) and EtOAc (2 x 10 mL). The organics were separated, dried with MgSO4, filtered, and concentrated to give the title compound (110 mg, 87%).1H NMR (400 MHz, CD3OD) δ ppm 6.70 - 6.98 (t, 1 H), 7.57 - 7.69 (m, 1 H), 7.69 - 7.81 (m, 3 H); ESI-MS m / z [M+H]+203.2.

[0424] PREPARATION 61: 2-(3,4-difluorophenyl)-2,2-difluoroacetic acid

[0425] STEP A: ethyl 2-(3,4-

[0426] To neat ethyl 2-(3,4-(0.787 mL, 4.67 mmol) in an ice bath was slowly added DAST (0.864 mL, 6.54 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was slowly added to ice water, extracted three times with heptanes, filtered through Na2SO4, and concentrated in vacuo. The crude residue was purified by flash silica column chromatography (ISCO) using a gradient of 0-50% EtOAc in heptanes to give the title compound (0.925 g, 84%).1H NMR (400 MHz, CD3OD) δ ppm 1.30 (t, J = 7.2 Hz, 3 H) 4.34 (q, J = 7.2 Hz, 2 H), 7.41 - 7.49 (m, 2 H), 7.55 (t, J = 9.1 Hz, 1 H).

[0427] STEP B: 2-(3,4-difluorophenyl)-2,2-difluoroacetic acid

[0428] In a round-bottomed flask, aqueous lithium hydroxide (1 M, 15.67 mL, 15.67 mmol) was added to a solution of ethyl 2-(3,4-difluorophenyl)-2,2-difluoroacetate (0.925 g, 3.92 mmol) in MeOH (9.79 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then extracted with EtOAc. The aqueous layer was acidified with HCl (1 M) to pH 3 and then extracted three times with EtOAc. The organiclayers were combined, filtered over Na2SO4, and concentrated in vacuo to give the title compound (0.681 g, 84%).1H NMR (400 MHz, CD3OD) δ ppm 7.38 - 7.58 (m, 3 H).

[0429] PREPARATION 62: 2,2-difluoro-2-(5-fluoro-2-methylphenyl)acetic acid F O

[0430] STEP A: methyl 2,2- methylphenyl)acetate

[0431] The title compound (0.421 like STEP A of PREPARATION61, using methyl 2-(5-fluoro-2- - (0.500 g, 2.55 mmol).1H NMR (400 MHz, CD3OD) δ ppm 2.35 (s, 2 H), 3.88 (s, 3 H), 7.15 - 7.21 (m, 1 H), 7.28 - 7.35 (m, 2 H).

[0432] STEP B: 2,2-difluoro-2-(5-fluoro-2-methylphenyl)acetic acid

[0433] The title compound (0.259 g, 66%) was prepared like STEP B of PREPARATION 61, using methyl 2,2-difluoro-2-(5-fluoro-2-methylphenyl)acetate (0.421 g, 1.93 mmol).

[0434] PREPARATION 63: 2,2-difluoro-2-(4-fluoro-3-methylphenyl)acetic acid

[0435] STEP A: ethyl 2,2-acetate

[0436] The title compoundSTEP A of PREPARATION 61, using ethyl 2-(4-fluoro-3-methylphenyl)-2-oxoacetate (1.00 g, 4.76 mmol).1H NMR (400 MHz, CD3OD) δ ppm 1.29 (t, J = 7.2 Hz, 3 H), 2.33 (d, J = 1.9 Hz, 3 H), 4.32 (q, J = 7.2 Hz, 2 H), 7.17 (t, J = 9.0 Hz, 1 H), 7.42 - 7.53 (m, 2 H).

[0437] STEP B: 2,2-difluoro-2-(4-fluoro-3-methylphenyl)acetic acid

[0438] The title compound (0.372 g, 42%) was prepared like STEP B of PREPARATION 61, using ethyl 2,2-difluoro-2-(4-fluoro-3-methylphenyl)acetate (1.0 g, 4.3 mmol).

[0439] PREPARATION 64: 2,2-difluoro-2-(3-fluoro-5-methylphenyl)acetic acid

[0440] STEP A: ethyl 2,2- acetate

[0441] To a stirred solution of (0.141 mL, 1.06 mmol) inDMSO (1.32 mL), copper 2-bromo-2,2-difluoroacetate (0.163 mL, 1.27 mmol) were added at room temperature. The mixture was then stirred at 55°C overnight. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO) using a gradient of 0-50% EtOAc in heptanes to afford the title compound (48 mg, 20%).1H NMR (400 MHz, CD3OD) δ ppm 1.18 (t, J = 7.2 Hz, 3 H), 2.31 (s, 3 H), 4.21 (q, J = 7.2 Hz, 2 H), 7.02 (t, J = 8.8 Hz, 2 H), 7.13 (s, 1 H).

[0442] STEP B: 2,2-difluoro-2-(3-fluoro-5-methylphenyl)acetic acid

[0443] To a solution of ethyl 2,2-difluoro-2-(3-fluoro-5-methylphenyl)acetate (48 mg, 0.207 mmol) in MeOH (1.03 mL) was added aqueous lithium hydroxide (1 M, 827 µL, 0.827 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, diluted in water, and extracted with EtOAc. The aqueous layer was then acidified to pH 3 and extracted three times with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound (24 mg, 57%).1H NMR (400 MHz, CD3OD) δ ppm 2.42 (s, 3 H), 7.10 - 7.15 (m, 2 H), 7.26 (s, 1 H).

[0444] PREPARATION 65: 2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetic acid

[0445] STEP A: ethyl 2,2-acetate

[0446] The title compound (0. ive) was prepared like STEP A of PREPARATION 64, using 4-fluoro-1-iodo-2-methylbenzene (1.00 g, 4.24 mmol), ethyl 2- bromo-2,2-difluoroacetate (0.652 mL, 5.08 mmol), and copper (0.700 g, 11.0 mmol) in DMSO (4.92 mL).1H NMR (400 MHz, CD3OD) δ ppm 1.17 (t, J = 7.1 Hz, 3 H), 2.29 (t, J = 2.0 Hz, 3 H), 4.22 (q, J = 7.1 Hz, 2 H), 6.91 - 6.99 (m, 2 H), 7.47 (dd, J = 8.3, 5.7 Hz, 1 H).

[0447] STEP B: 2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetic acid

[0448] The title compound (0.247 g, 28% yield over two steps) was prepared like STEP B of PREPARATION 64, using ethyl 2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetate (0.984 g, 4.24 mmol).

[0449] PREPARATION 66: 2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetic acid

[0450] STEP A: ethyl 2,2- acetate

[0451] The title compoundlike STEP A of PREPARATION 64, using 1-fluoro-3-iodo-2-methylbenzene (1.00 g, 4.24 mmol), ethyl 2-bromo-2,2- difluoroacetate (0.652 mL, 5.08 mmol), and copper (0.700 g, 11.0 mmol) in DMSO (4.92 mL).1H NMR (400 MHz, CD3OD) δ ppm 1.29 (t, J = 7.2 Hz, 3 H), 2.30 (q, J = 1.9 Hz, 3 H), 4.34 (q, J = 7.2 Hz, 2 H,) 7.22 - 7.29 (m, 1 H,) 7.32 - 7.44 (m, 2 H).

[0452] STEP B: 2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetic acid

[0453] The title compound (120 mg, 14%) was prepared like STEP B of PREPARATION 64, using ethyl 2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetate (0.96 g, 4.13 mmol).

[0454] PREPARATION 67: 2,2-difluoro-2-(4-fluoro-3-methoxyphenyl)acetic acid

[0455] STEP A: ethyl 2,2-acetate

[0456] The title compound ( e STEP A of PREPARATION 64, using 1-fluoro-4-iodo-2-methoxy enzene ( . g, . mmol), ethyl 2-bromo-2,2- difluoroacetate (0.881 mL, 6.87 mmol), and copper (0.946 g, 14.9 mmol) in DMSO (6.65 mL).1H NMR (400 MHz, CD3OD) δ ppm 0.89 - 0.95 (m, 1 H), 1.30 (t, J = 7.1 Hz, 3 H), 3.93 (s, 3 H), 4.30 - 4.41 (m, 2 H), 7.16 - 7.32 (m, 3 H).

[0457] STEP B: 2,2-difluoro-2-(4-fluoro-3-methoxyphenyl)acetic acid

[0458] The title compound was prepared like STEP B of PREPARATION 64, using ethyl 2,2-difluoro-2-(4-fluoro-3-methoxyphenyl)acetate (1.2 g, 4.83 mmol).

[0459] PREPARATION 68: 2,2-difluoro-2-(3-fluoro-4-methoxyphenyl)acetic acid

[0460] STEP A: ethyl 2,2- acetate

[0461] The title compoundSTEP A of PREPARATION 64, using 2-fluoro-4-iodo-1-methoxybenzene (1.25 g, 4.96 mmol), ethyl 2-bromo-2,2- difluoroacetate (0.763 mL, 5.95 mmol), and copper (0.819 g, 12.9 mmol) in DMSO (5.76 mL).1H NMR (400 MHz, CD3OD) δ ppm 1.27 - 1.39 (m, 3 H), 3.94 (s, 3 H), 4.32 (q, J = 7.2 Hz, 2 H), 7.23 (t, J = 8.5 Hz, 1 H), 7.29 - 7.41 (m, 2 H).

[0462] STEP B: 2,2-difluoro-2-(3-fluoro-4-methoxyphenyl)acetic acid

[0463] The title compound (0.288 g, 37%) was prepared like STEP B of PREPARATION 64, using ethyl 2,2-difluoro-2-(3-fluoro-4-methoxyphenyl)acetate (0.875 g, 3.53 mmol).

[0464] PREPARATION 69: 2-(3,5-difluorophenyl)-2,2-difluoroacetic acid

[0465] STEP A: ethyl 2-(3,5-

[0466] To neat ethyl 2-(3,5-difl te (1.575 mL, 9.34 mmol) in an ice bath was slowly added DAST (1.7 m , 3.0 mmo ). The reaction mixture was stirred overnight at room temperature. The reaction mixture was slowly added to ice water and then extracted with heptane. The organic layers were combined, filtered over Na2SO4, and then concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO) using a gradient of 0-50% EtOAc in heptanes to afford the title compound (1.6 g, 72%).1H NMR (400 MHz, CD3OD) δ ppm 1.31 (t, J = 7.2 Hz, 3 H), 4.35 (q, J =7.2 Hz, 2 H), 7.15 - 7.30 (m, 3 H).

[0467] STEP B: 2-(3,5-difluorophenyl)-2,2-difluoroacetic acid

[0468] In a 100ml round bottom flask, aqueous lithium hydroxide (1 M, 27.1 mL, 27.1 mmol) was added to a solution of ethyl 2-(3,5-difluorophenyl)-2,2-difluoroacetate (1.6 g, 6.77 mmol) in MeOH (16.94 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo and extracted with EtOAc. The aqueous layer was acidified with HCl (1 M) to pH 3 and extracted again with EtOAc. The organic layers were combined, filtered over Na2SO4, and concentrated in vacuo to give the title compound (0.856 g, 61%).

[0469] PREPARATION 70: 2-(3,4-difluorophenyl)-2-fluoropropanoic acid

[0470] STEP A: methyl 2-(3,4-

[0471] To a solution of 2-(3,4-acid (5.00 g, 26.9 mmol) in MeOH (53.7 mL) at 0°C was added dropwise thionyl chloride (3.92 mL, 53.7 mmol), and the mixture was stirred at 0°C for 2 h. The mixture was then concentrated in vacuo and the residue was diluted with heptanes (10 mL). The solution was washed with water (7 mL) and then brine (5 mL), dried over Na2SO4, and concentrated in vacuo to afford the title compoundas a light yellow oil (5.03 g, 94%).1H NMR (400 MHz, CD3OD) δ ppm 1.47 (d, J = 7.2 Hz, 3 H), 3.68 (s, 3 H), 3.80 (q, J = 7.2 Hz, 1 H), 7.08 - 7.14 (m, 1 H), 7.17 - 7.28 (m, 2 H).

[0472] STEP B: methyl 2-(3,4-difluorophenyl)-2-fluoropropanoate

[0473] A solution of mmol) and THF (36.3 mL) was degassed under vacuum andtimes. The solution was cooled to - 78°C before addition of n-BuLi (2.5 M, 11.25 mL, 28.1 mmol). The reaction vessel was transferred to an ice / water bath, allowed to stir for 10 minutes, and then transferred back into the -78°C bath and stirred for 15 minutes. Methyl 2-(3,4-difluorophenyl)propanoate (5.027 g, 25.1 mmol) in THF (2 mL) was added dropwise over 5 minutes and then stirred for 30 minutes. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (9.11 g, 28.9 mmol) in THF (36.3 mL) was then added slowly over 10 minutes. The reaction was allowed to warm to 0°C and stir for 10 minutes. The reaction was diluted with heptanes (3 mL) and then quenched slowly with water (3 mL). THF was removed in vacuo. The residue was taken up into saturated aqueous NH4Cl and EtOAc, extracted with EtOAc, filtered through Na2SO4, and concentrated in vacuo to afford a white solid. The crude residue was taken up into heptanes (190 mL) and EtOAc (10 mL), sonicated for 1 h, and then filtered through Celite® and concentrated in vacuo. The crude material was taken up into DCM, concentrated onto Celite® and purified by flash silica column chromatography (ISCO, ELS detection) using 10% EtOAc in heptanes to give the title compound (3.278 g, 60%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.83 - 1.98 (m, 3 H), 3.68 - 3.75 (m, 3 H), 7.24 - 7.39 (m, 1 H), 7.45 - 7.62 (m, 2 H).

[0474] STEP C: 2-(3,4-difluorophenyl)-2-fluoropropanoic acid

[0475] To a solution of methyl 2-(3,4-difluorophenyl)-2-fluoropropanoate (3.278 g, 15.02 mmol) in dioxane (50.1 mL) was added aqueous LiOH (1 M, 45.1 mL, 45.1 mmol). The reaction mixture was stirred overnight. The solution was concentrated in vacuo, diluted with water, and acidified with 1 M HCl to pH 1-2. The resulting solution was extracted with EtOAc, filtered over Na2SO4, and concentrated in vacuo. The oil was diluted with heptanes and then concentrated in vacuo to afford the title compound as a light yellow, clear oil (2.839 g, 93%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 - 1.91 (m, 3 H), 7.23 - 7.42 (m, 1 H), 7.42 - 7.62 (m, 2 H), 13.36 - 14.15 (m, 1 H).

[0476] PREPARATION 71: 2-(3,5-difluorophenyl)-2-fluoropropanoic acid

[0477] The title compound was step procedure in 70, using 2-(3,5- difluorophenyl)propanoic acid, was obtained as a clear oil (2.953 g, 54% over three steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.76 - 1.94 (m, 3 H), 7.06 - 7.22 (m, 2 H), 7.22 - 7.36 (m, 1 H), 13.38 - 14.08 (m, 1 H).

[0478] EXAMPLE 1: N-(1-(azetidin-1-ylmethyl)-2,2-difluorocyclopropyl)-1-(3- chlorophenyl)cyclopropane-1-carboxamide

[0479] STEP A: tert-butyl cyclopropyl)carbamate

[0480] To a solution of 1-((tert--2,2-difluorocyclopropane-1- carboxylic acid (2.37 g, 10.0 mmol) in DME (10 mL) at -15°C was added 4- methylmorpholine (1.11 mL, 10.1 mmol), followed by isobutyl carbonochloridate (1.32 mL, 10.1 mmol). The solution was stirred for 5 minutes. The precipitated NMM hydrochloride was then removed via vacuum filtration and washed with DME (2 x 1 mL). The washings were combined with the filtrate in a flask and cooled to -20°C. An aqueous solution of sodium borohydride (0.567 g, 15.0 mmol) in water (2 mL) was added rapidly to the flask. Gas evolution was observed. The reaction was stirred for another 10 minutes and then quenched by the addition of water (10 mL). The mixture was diluted with EtOAc (30 mL) and the aqueous phase was separated and extracted with EtOAc (2 x 25 mL). The organic layers were combined, dried over Na2SO4, decanted, and concentrated to afford a mixture of the title compound and isobutyl alcohol which was used in the next step without further purification (1.79 g).1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (d, J= 6.6 Hz, 1 H), 1.39 (s, 9 H), 1.44 - 1.51 (m, 1 H), 1.57 - 1.63 (m, 1 H), 1.64 - 1.73 (m, 1 H), 3.16 (dd, J = 6.3, 5.3Hz, 1 H), 3.25 (s, 1 H), 3.29 (s, 3 H), 3.44 (s, 2 H), 3.67 (br dd, J = 11.6, 6.0 Hz, 1 H), 4.36 (t, J = 5.3 Hz, 1 H), 4.88 (br d, J = 4.9 Hz, 1 H), 7.37 (br s, 1 H).

[0481] STEP B: tert-butyl (2,2-difluoro-1-formylcyclopropyl)carbamate

[0482] To a -55°C solution of mL, 7.50 mmol) in DCM (10 mL) wasadded dropwise a solution of (0.642 mL, 7.50 mmol) in DCM (2 mL). Upon complete addition, the reaction was stirred for 5 minutes, and then tert-butyl (2,2- difluoro-1-(hydroxymethyl)cyclopropyl)carbamate (1.116 g, 5.00 mmol) was added as a solution in CH2Cl2(2 mL). The mixture was stirred for an additional 15 minutes. Triethylamine (4.18 mL, 30.0 mmol) was added and the reaction was stirred for 5 minutes and then allowed to slowly warm to ambient temperature. After 2 h, water (10 mL) was added and the reaction was extracted with DCM (3 x 8 mL). The organic layers were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO, 40 g RediSep Rf Gold® column) using a gradient of 10-40% EtOAc in heptanes to afford the title compound as a white solid (0.560 g, 51%).1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9 H), 1.87 - 2.10 (m, 1 H), 2.54 - 2.75 (m, 1 H), 5.29 (br s, 1 H), 9.43 (br s, 1 H).

[0483] STEP C: tert-butyl (1-(azetidin-1-ylmethyl)-2,2-difluorocyclopropyl)carbamate

[0484] To a solution of tert-carbamate (0.560 g, 2.53 mmol) and azetidine (0.256 mL, 3.80 mmol) in DCM (10.13 mL) was added triethylamine (1.76 mL, 12.6 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was then treated with sodium triacetoxyborohydride (1.07 g, 5.06 mmol) and stirred at ambient temperature for 2 h. The mixture was quenched with water (30 mL) and extracted with iPrOAc (40 mL, 15 mL). The combined organic layers were washed with water (2 x 20 mL) and then brine (30 mL), dried over Na2SO4, and concentrated invacuo at 60°C for 1 h to afford the title compound as a clear oil (0.632 g, 95%).1H NMR (400 MHz, CDCl3) δ ppm 1.41 - 1.54 (m, 11 H), 2.10 (quin, J = 7.0 Hz, 2 H), 2.35 - 2.63 (m, 1 H), 2.78 - 3.07 (m, 1 H), 3.29 (t, J = 7.0 Hz, 4 H), 5.05 (br s, 1 H).

[0485] STEP D: 1-(azetidin-1-ylmethyl)-2,2-difluorocyclopropan-1-amine

[0486] Tert-butyl (1-(azetidin-1- carbamate (0.625 g,2.38 mmol) was treated with HCl (4 mL, 47.7 mmol). The resulting mixture was stirred at ambient temperature for 1 h, and then diluted with diethyl ether (20 mL) and triturated until a fine suspension resulted. The liquid was decanted and the residue was washed with diethyl ether (10 mL). The ether was decanted and the residue was concentrated in vacuo to afford a dihydrochloride salt of the title compound as a white solid (0.280 g, 50%). ESI-MS m / z [M+H]+163.0.

[0487] STEP E: N-(1-(azetidin-1-ylmethyl)-2,2-difluorocyclopropyl)-1-(3- chlorophenyl)cyclopropane-1-carboxamide

[0488] A suspension of 1-(3-chlorophenyl)cyclopropane-1-carboxylic acid (77 mg, 0.392 mmol), 1-(azetidin-1-ylmethyl)-2,2-difluorocyclopropan-1-amine dihydrochloride (101 mg, 0.431 mmol) and HATU (179 mg, 0.470 mmol) in DMA (0.9 mL) was treated with DIPEA (0.341 mL, 1.958 mmol). The mixture was stirred at ambient temperature for 15 minutes. The mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 3 mL). The combined organics were concentrated in vacuo and the residue was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 150 mm) using a gradient of 20-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). The product-containing fraction was concentrated in vacuo. The residue was dissolved in CDCl3 (3 mL), treated with DARCO 60G charcoal for 5 minutes, and filtered. The solvent was concentrated in vacuo to afford the title compound as a red film (2.7 mg, 2%) as a red film.1H NMR (400 MHz, CDCl3) δ ppm 1.00 - 1.16 (m, 2 H), 1.48 - 1.67 (m, 4 H), 2.08 (quin, J = 7.0 Hz, 2 H), 2.50 (br d, J = 13.4 Hz, 1 H), 2.83 - 2.96 (m, 1 H), 3.18 - 3.33 (m, 4 H), 5.78 (br s, 1 H), 7.28 - 7.45 (m, 4 H); ESI-MS m / z [M+H]+341.2.

[0489] EXAMPLE 2: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-ethoxy-2-phenylacetamide

[0490] A solution of HATU (5 ethoxy-2-phenylacetic acid (25.0 mg, 0.138 mmol), DIEA (0.088 mL, 0.502 mmol), and NMP (0.5 mL) was stirred for 10 minutes. Next, 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (25.0 mg, 0.126 mmol) was added. The solution was stirred at ambient temperature for 18 h and then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). The crude material (34.4 mg) was dissolved in MeOH (5 mL), adsorbed on NH silica gel (177 mg), and purified by flash silica column chromatography (ISCO, Shoko Scientific Purif-Pack®NH 60 µM size 20 half column) using a gradient of 0-10% MeOH in DCM. The appropriate fractions were combined, concentrated via rotary evaporation, and dried in vacuo. The impure product was diluted with MeOH (0.25 mL), filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®), rinsed with MeOH (0.25 mL), and repurified via preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). The pure fractions were combined and solvent was removed via rotary evaporation at 45°C. The material was dried in vacuo to give the title compound as a light yellow film (4.9 mg, 14%).1H NMR (400 MHz, CD3CN) δ ppm 0.46 - 0.82 (m, 4 H), 1.92 - 1.96 (m, 1 H), 2.25 - 2.68 (m, 4 H), 3.13 (t, J = 7.0 Hz, 3 H), 3.30 (s, 3 H), 3.49 - 3.56 (m, 1 H), 3.56 - 3.63 (m, 1 H), 3.89 (dd, J = 8.9, 8.2 Hz, 1 H), 6.80 (br s, 1 H), 7.24 - 7.30 (m, 1 H), 7.30 - 7.40 (m, 4 H); ESI-MS m / z [M+H]+289.2.

[0491] EXAMPLE 3: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3-methoxy-2-methyl-2- phenylpropanamide

[0492] To a vial charged withacid (25.0 mg, 0.129 mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (30.8 mg, 0.154 mmol), and HATU (58.7 mg, 0.154 mmol) in DMF (1 mL) was added DIPEA (112 µL, 0.644mmol) at room temperature. The reaction mixture was stirred at 23°C for 16 h. The crude mixture was filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®) and purified via preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). The appropriate fractions were combined and solvent was removed via rotary evaporation at 45°C. The resulting mixture was dried in vacuo. The impure product was taken up in MeOH (0.5 mL) and repurified via preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA). The pure fractions were combined, concentrated via rotary evaporation, and dried in vacuo to provide a TFA salt of the title compound. The TFA salt was dissolved in MeOH (1.0 mL), passed through a 100 mg basic cartridge (Agilent Stratospheres PL-HCO3MP SPE) to remove TFA, and the cartridge was rinsed with MeOH (3 x 1 mL). The filtrate was concentrated via rotary evaporation and dried in vacuo to give the title compound as a colorless film (9.2 mg, 24%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.34 - 0.66 (m, 4 H), 1.40 (br s, 3 H), 1.76 - 1.99 (m, 2 H), 2.39 - 2.46 (m, 3 H), 2.96 - 3.12 (m, 4 H), 3.28 (br s, 3 H), 3.46 - 3.61 (m, 1 H), 3.67 - 3.89 (m, 1 H), 7.10 - 7.52 (m, 6 H); ESI-MS m / z [M+H]+303.2.

[0493] EXAMPLE 4: 2-(3-chlorophenyl)-N-(1-((2,4-dimethylazetidin-1- yl)methyl)cyclopropyl)-2-methylpropanamide

[0494] To a 4 mL vial-N-(1- formylcyclopropyl)-2-methylpropanamide (30 mg, 0.113 mmol), 2,4-dimethylazetidine hydrochloride (41.2 mg, 0.339 mmol), and triethylamine (0.157 mL, 1.129 mmol) in DCM (2 mL). The mixture was allowed to stir for 1 h at room temperature. Sodium triacetoxyborohydride (47.9 mg, 0.226 mmol) was added and the solution was stirred at room temperature for 2 h. The mixture was quenched with water (0.2 mL), concentrated, and taken up in DMF (1 mL) and MeOH (1 mL). The product was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 150 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10) to give the title compound (13 mg, 34%).1H NMR (400 MHz, CDCl3) δ ppm 0.39 - 0.55 (m, 1 H), 0.56 - 0.71 (m, 2 H), 0.74 - 0.86 (m, 1 H), 1.05 (d, J = 6.3 Hz, 6 H), 1.50(s, 6 H), 1.77 (t, J = 6.4 Hz, 2 H), 2.00 (d, J = 13.3 Hz, 1 H), 2.98 (dd, J = 13.4, 0.9 Hz, 1 H), 3.29 - 3.50 (m, 2 H), 5.73 (br s, 1 H), 7.15 - 7.30 (m, 3 H), 7.35 (s, 1 H); ESI-MS m / z [M+H]+336.2.

[0495] EXAMPLE 5: (R)-2-(3-chlorophenyl)-2-methyl-N-(1-((2-methylazetidin-1- yl)methyl)cyclopropyl)propanamide

[0496] To a 4 mL vial -N-(1-formylcyclopropyl)-2- , (R)-2-methylazetidine benzenesulfonate (32.4 mg, 0.141 mmol), and triethylamine (0.131 mL, 0.941 mmol) in DCM (1 mL). The reaction mixture was allowed to stir for 1 h at room temperature. Sodium triacetoxyborohydride (39.9 mg, 0.188 mmol) was added and the solution was stirred at room temperature for 2 h. The mixture was quenched with water (0.2 mL), concentrated, and taken up in DMF (1 mL) and MeOH (1 mL). The product was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 150 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10) to give the title compound as a white semisolid (17 mg, 56%).1H NMR (400 MHz, CD3OD) δ ppm 0.49 - 0.73 (m, 4 H), 1.09 (d, J = 6.3 Hz, 3 H), 1.49 (d, J = 2.8 Hz, 6 H), 1.69 - 1.86 (m, 1 H), 2.04 (dtd, J = 10.0, 7.7, 2.1 Hz, 1 H), 2.44 - 2.61 (m, 2 H), 2.74 (dt, J = 9.7, 7.4 Hz, 1 H), 3.14 (dd, J = 15.2, 6.6 Hz, 1 H,) 7.14 - 7.41 (m, 4 H); ESI-MS m / z [M+H]+321.1.

[0497] EXAMPLE 6: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3- (difluoromethoxy)phenyl)-2-methylpropanamide

[0498] To a 4 mL vialphenyl)-2- methylpropanoic acid (30 mg, 0.130 mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (31.1 mg, 0.156 mmol), and DIPEA (0.114 mL, 0.652 mmol) in THF (1 mL). HATU (59.5 mg, 0.156 mmol) was added and the reaction was stirred at room temperature for 2 h. DMF (1 mL) was added and the reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 150 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) inwater (10 mM NH4HCO3, pH 9.5-10). The product was further purified by flash silica column chromatography (ISCO, NH column) using a gradient of 10-20% MeOH in DCM to give the title compound (3.5 mg, 7.9%).1H NMR (400 MHz, CD3OD) δ ppm 0.51 - 0.78 (m, 4 H), 1.50 (s, 6 H), 2.06 (quin, J = 7.2 Hz, 2 H), 2.56 (s, 2 H), 3.22 (t, J = 7.2 Hz, 4 H), 6.61 (s, 1 H), 6.79 (s, 1 H), 6.96 - 7.05 (m, 1 H), 7.09 (t, J = 2.0 Hz, 1 H), 7.20 (ddd, J = 7.8, 1.8, 0.9 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H); ESI-MS m / z [M+H]+339.3.

[0499] EXAMPLE 7: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(p-tolyl)propanamide

[0500] To a 2 mL N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4- salt (EXAMPLE 66, 25 mg, 0.064 mmol), trimethylboroxine (12.0 mg, 0.096 mmol), and XPhos Pd G2 (5.0 mg, 6.4 µmol) in dioxane (1.0 mL) and saturated aqueous NaHCO3(0.5 mL). The reaction mixture was heated in a Biotage® microwave reactor at 120°C for 30 minutes. The mixture was diluted with DMF (200 µL) and MeOH (1 mL). The fixture was filtered and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA) to give a TFA salt of the title compound (9 mg, 38%).1H NMR (400 MHz, CD3OD) δ ppm 0.67 - 0.85 (m, 2 H), 0.85 - 0.96 (m, 2 H), 1.39 (d, J = 7.0 Hz, 3 H), 2.11 - 2.36 (m, 4 H), 2.53 (dt, J = 11.8, 9.4 Hz, 1 H), 3.12 - 3.27 (m, 1 H), 3.35 (m, 1 H), 3.51 (q, J = 7.2 Hz, 1 H), 3.85 (q, J = 9.7 Hz, 1 H), 3.99 (q, J = 9.7 Hz, 1 H), 4.05 - 4.25 (m, 2 H), 7.03 - 7.25 (m, 4 H), 8.27 (br s, 1 H); ESI-MS m / z [M+H]+273.3.

[0501] EXAMPLE 8: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-N,2- dimethylpropanamide

[0502] To a solution of N--2-(3-chlorophenyl)-2- methylpropanamide (EXAMPLE 176, 136 mg, 0.443 mmol) in DMF (2 mL) in an ice bath was added sodium hydride (60 wt %, 53.2 mg, 1.33 mmol). The mixture was stirred at 0°C for 30 minutes before iodomethane (41.4 µL, 0.665 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between brineand EtOAc. The aqueous layer was extracted two more times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give a crude product mixture. The product was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 150 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Product-containing fractions were lyophilized to give the title compound (7 mg, 5%).1H NMR (400 MHz, CD3OD) δ ppm 0.92 - 0.98 (m, 2 H), 1.04 - 1.10 (m, 2 H), 1.49 - 1.55 (m, 7 H), 2.35 - 2.46 (m, 1 H), 2.47 - 2.50 (m, 3 H), 2.55 - 2.70 (m, 1 H), 3.36 (s, 2 H), 4.03 - 4.16 (m, 2 H), 4.30 - 4.40 (m, 2 H), 7.08 - 7.13 (m, 1 H), 7.18 - 7.22 (m, 1 H), 7.24 - 7.30 (m, 1 H), 7.32 - 7.38 (m, 1 H).

[0503] The compounds of EXAMPLES 9 to 17 were prepared as shown in Scheme A.

[0504] Reaction conditions: A solution of T3P (0.143 mL, 0.251 mmol), DIPEA (0.088 mL, 0.502 mmol), and NMP (0.5 mL) was added to 1-(azetidin-1-ylmethyl)cyclopropan-1- amine dihydrochloride (25 mg, 0.126 mmol) and acid (0.151 mmol). The resulting solution was stirred at ambient temperature for 18 h.

[0505] Purification conditions A1: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-70% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Fractions containing product were repurified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 5-50% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0506] Purification conditions A2: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-70% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Fractions containing product were repurified using the same conditions.

[0507] EXAMPLE 9: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-6-chloro-2,3-dihydro-1H- indene-1-carboxamide

[0508] A TFA salt of the title s in Scheme A using purification conditions A1 (27.5 mg). ESI-MS m / z [M+H] 305.10.

[0509] EXAMPLE 10: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(6- (trifluoromethyl)pyridin-2-yl)propanamide

[0510] The title compound purification conditions A2(7.5 mg). ESI-MS m / z

[0511] EXAMPLE 11: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(6-chloropyridin-2- yl)cyclopropane-1-carboxamide

[0512] A TFA salt of the in Scheme A using purificationconditions A1 (14.6 mg). ESI-MS m / z [M+H]+306.10.

[0513] EXAMPLE 12: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(pyridin-2- yl)cyclopropane-1-carboxamide

[0514] The title compoundusing purification conditions A2 (10.5 mg). ESI-MS m / z [M+H]+272.15.

[0515] EXAMPLE 13: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-fluoro-2,3-dihydro-1H- indene-1-carboxamide

[0516] A TFA salt of thein Scheme A using purification conditions A1 (17.5 mg). ESI-MS m / z [M+H]+289.10.

[0517] EXAMPLE 14: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- (trifluoromethyl)phenyl)cyclopropane-1-carboxamide

[0518] A TFA salt of the Scheme A using purification conditions A1 (11.5 mg).1H0.74 - 0.85 (m, 4 H), 1.06 - 1.18 (m, 2 H), 1.06 - 1.16 (m, 2 H), 1.53 - 1.67 (m, 2 H), 2.24 - 2.45 (m, 1 H), 2.60 - 2.81 (m, 1 H), 3.18 - 3.32 (m, 2 H), 3.74 - 3.92 (m, 2 H), 4.28 - 4.55 (m, 2 H), 6.56 - 6.66 (m, 1 H), 7.44 - 7.61 (m, 4 H), 8.39 - 8.81 (m, 2 H), 11.29 - 11.70 (m, 1 H); ESI-MS m / z [M+H]+339.15.

[0519] EXAMPLE 15: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4- (trifluoromethyl)phenyl)cyclopropane-1-carboxamide

[0520] A TFA salt of the Scheme A using purificationconditions A1 (11.7 mg).1H NMR (400 MHz, CDCl3) δ ppm 0.78 - 0.87 (m, 4 H), 1.07 - 1.18 (m, 2 H), 1.55 - 1.67 (m, 2 H), 2.30 - 2.43 (m, 1 H), 2.64 - 2.79 (m, 1 H), 3.25 - 3.34 (m, 2 H), 3.26 - 3.34 (m, 2 H), 3.81 - 3.94 (m, 2 H), 4.38 - 4.49 (m, 2 H), 6.50 - 6.62 (m, 1 H), 6.55 - 6.60 (m, 1 H), 7.39 - 7.47 (m, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 10.41 - 10.57 (m, 2 H), 10.67 - 10.92 (m, 1 H); ESI-MS m / z [M+H]+339.10.

[0521] EXAMPLE 16: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-bromo-2,3-dihydro-1H- indene-1-carboxamide

[0522] A TFA salt of theScheme A using purification conditions A1 (20.9 mg).1H NMR (400 MHz, CDCl3) δ ppm 0.82 - 0.89 (m, 2 H), 0.89 - 1.00 (m, 2 H), 2.24 - 2.42 (m, 3 H), 2.65 - 2.81 (m, 1 H), 2.83 - 2.96 (m, 1 H), 3.04 - 3.17 (m, 1 H), 3.20 - 3.30 (m, 1 H), 3.32 - 3.44 (m, 1 H), 3.75 - 3.93 (m, 3 H), 4.38 - 4.53 (m, 2 H), 7.01 - 7.12 (m, 1 H), 7.22 - 7.30 (m, 1 H), 7.33 - 7.41 (m, 1 H), 7.81 - 7.93 (m, 1 H), 9.30 - 9.67 (m, 2 H), 11.47 - 11.76 (m, 1 H); ESI-MS m / z [M+H]+349.05, 351.05.

[0523] EXAMPLE 17: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-cyanophenyl)-2- methylpropanamide

[0524] A TFA salt of the Scheme A using purification conditions A1 (14.6 mg).

[0525] EXAMPLE 18: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1- phenylcyclopropane-1-carboxamide

[0526] To a 500 mL round- were added 2,2-difluoro-1-phenylcyclopropane-1- g, , 1-(azetidin-1- ylmethyl)cyclopropan-1-amine dihydrochloride (3.01 g, 15.1 mmol), and DIPEA (11.0 mL, 63.1 mmol) in THF (100 mL). HATU (5.76 g, 15.1 mmol) was added and the reaction was allowed to stir at room temperature overnight. The mixture was concentrated and extracted with EtOAc (2 x 100 mL) and brine (100 mL). The organics were combined and dried with MgSO4, then concentrated with silica gel and purified via flash silica column chromatography on an amine column (ISCO, NH column) using a gradient of 30-90% EtOAc in heptanes, followed by 20% MeOH in DCM. Fractions containing product were concentrated and repurified by flash silica column chromatography (ISCO, NH column) using a gradient of 50-90% EtOAc in heptanes to give the title compound as a light yellow solid (893 mg, 23%).1H NMR (400 MHz, CD3OD) δ ppm 0.50 - 0.74 (m, 4 H), 1.85 (ddd, J = 12.3, 8.2, 5.1 Hz, 1 H), 2.01 (quin, J = 7.2 Hz, 2 H), 2.30 - 2.46 (m, 1 H), 2.46 - 2.55 (m, 2 H), 3.02 - 3.20 (m, 4 H), 7.27 - 7.43 (m, 3 H), 7.43 - 7.52 (m, 2 H); ESI-MS m / z [M+H]+307.20.

[0527] EXAMPLE 19: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1- phenylcyclopropane-1-carboxamide

[0528] Racemic N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1- phenylcyclopropane-1-carboxamide (893 mg, 2.91 mmol) was purified by SFC. The first peak was collected and arbitrarily assigned as having (R) stereochemistry to give the title compound as a white solid (251.6 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.50 - 0.71 (m, 4 H), 1.86 (ddd, J = 12.3, 8.2, 5.1 Hz, 1 H), 2.01 (quin, J = 7.2 Hz, 2 H), 2.39 (ddd, J = 13.5, 8.1, 5.3 Hz, 1 H), 2.45 - 2.56 (m, 2 H), 3.14 (sxt, J = 7.0 Hz, 4 H), 7.29 - 7.43 (m, 3 H), 7.47 (d, J = 7.3 Hz, 2 H); ESI-MS m / z [M+H]+307.20.

[0529] EXAMPLE 20: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1- phenylcyclopropane-1-carboxamide

[0530] Racemic N-(1- -2,2-difluoro-1-phenylcyclopropane-1- mg, was purified by SFC. The second peak was collected and arbitrarily assigned as having (S) stereochemistry to give the title compound as a white solid (158.3 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.49 - 0.74 (m, 4 H), 1.85 (ddd, J = 12.3, 8.2, 5.1 Hz, 1 H), 2.01 (quin, J = 7.2 Hz, 2 H), 2.39 (ddd, J = 13.5, 8.1, 5.3 Hz, 1 H), 2.44 - 2.55 (m, 2 H,) 3.13 (sxt, J = 7.1 Hz, 4 H), 7.29 - 7.44 (m, 3 H), 7.44 - 7.52 (m, 2 H); ESI-MS m / z [M+H]+307.20.

[0531] EXAMPLE 21: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-chloro-1-hydroxy-2,3- dihydro-1H-indene-1-carboxamide

[0532] To a 4 mL vial withfluoro-2,3-dihydro-1H-indene- 1-carboxylic acid (54 mg, 0.252 mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (60.1 mg, 0.302 mmol), and DIPEA (0.220 mL, 1.26 mmol) in THF (3 mL). HATU (115 mg, 0.302 mmol) was added and the reaction was allowed to stir at room temperature for 2 h. DMF (1 mL) was added, and the reaction mixture was filtered and purified via preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA) to give a TFA salt of the title compound (21 mg, 26%).1H NMR (400 MHz, CD3OD) δ ppm 0.77 - 0.92 (m, 1 H), 0.92 - 1.07 (m, 3 H), 2.08 - 2.22 (m, 1 H), 2.28 - 2.44 (m, 1 H,) 2.60 (dt, J = 11.7, 9.5Hz, 1 H), 2.75 (dt, J = 13.4, 6.6 Hz, 1 H), 3.05 (t, J = 7.2 Hz, 2 H), 3.29 - 3.37 (m, 2 H), 3.37 - 3.47 (m, 1 H), 4.11 (q, J = 9.4 Hz, 2 H), 4.20 - 4.40 (m, 2 H), 7.06 - 7.24 (m, 2 H), 7.27 (s, 1 H), 8.58 (s, 1 H); ESI-MS m / z [M+H]+321.3.

[0533] EXAMPLE 22: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3-difluoro-2- phenylpropanamide

[0534] To a vial charged with acid (25 mg, 0.134 mmol),1-(azetidin-1-ylmethyl) (26.7 mg, 0.134 mmol), and DIPEA (0.094 mL, 0.537 mmol) in DMF (0.45 mL) was added T3P (50 wt % in EtOAc, 0.104 mL, 0.175 mmol) at room temperature. The reaction mixture was stirred for several hours at room temperature. The mixture was diluted with MeOH (1 mL), filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®), and purified twice by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). The pure fractions were combined and solvent was removed via rotary evaporation at 45°C. The residue was dried in vacuo to give the title compound as a white solid (1.4 mg, 3.5%).1H NMR (400 MHz, CDCl3) δ ppm 0.61 - 0.70 (m, 2 H), 0.70 - 0.80 (m, 2 H), 2.06 (quin, J = 7.1 Hz, 2 H), 2.41 - 2.70 (m, 2 H), 3.20 (t, J = 7.0 Hz, 4 H), 3.75 (ddd, J = 15.1, 9.9, 5.6 Hz, 1 H), 6.14 (br s, 1 H), 6.18 - 6.50 (m, 1 H), 7.33 - 7.44 (m, 5 H).

[0535] The compounds of EXAMPLES 23 to 47 were prepared as shown in Scheme B.

[0536] Reaction conditions BB1: A solution of HATU (63.0 mg, 0.166 mmol), carboxylic acid (0.166 mmol), and DIPEA (105 µL, 0.603 mmol) in NMP (0.5 mL) was stirred for 10 minutes. To this mixture was added 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (30.0 mg, 0.151 mmol) and the resulting mixture was stirred for an additional 2 h.

[0537] Reaction conditions BB2: A solution of HATU (52.5 mg, 0.138 mmol), carboxylic acid (0.138 mmol), and DIPEA (0.088 mL, 0.502 mmol) in NMP (0.5 mL) was stirred for 10minutes. To this mixture was added 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (25.0 mg, 0.126 mmol) and the resulting mixture was stirred at room temperature for 18 h.

[0538] Purification conditions B1: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 5-50% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0539] Purification conditions B2: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0540] Purification conditions B3: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Fractions containing product were collected and repurified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 5-50% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0541] EXAMPLE 23: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6- dichlorophenyl)acetamide

[0542] The title compoundusing reaction conditions BB1 and purification conditions B2 (11.2 mg, 24%).1H NMR (400 MHz, CD3OD) δ ppm 0.70 - 0.76 (m, 4 H), 0.71 - 0.76 (m, 4 H), 2.13 - 2.22 (m, 2 H), 2.66 - 2.72 (m, 2 H), 3.42 - 3.47 (m, 4 H), 3.88 - 3.92 (m, 2 H), 3.88 - 3.91 (m, 2 H), 7.21 - 7.27 (m, 1 H), 7.35 - 7.40 (m, 2 H); ESI-MS m / z [M+H]+313.1.

[0543] EXAMPLE 24: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-methyl-2,3-dihydro-1H- indene-1-carboxamide

[0544] The title compoundB using reaction conditions BB1 and purification conditions B2 (10.5 mg, 24%).1H NMR (400 MHz, CD3OD) δ ppm 0.52 -0.77 (m, 4 H), 1.43 - 1.48 (m, 3 H), 1.90 - 1.99 (m, 1 H), 2.07 - 2.15 (m, 1 H), 2.32 - 2.40 (m, 1 H), 2.50 - 2.64 (m, 3 H), 2.86 - 3.02 (m, 2 H), 3.32 - 3.37 (m, 2 H), 7.14 - 7.28 (m, 4 H); ESI-MS m / z [M+H]+285.2.

[0545] EXAMPLE 25: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6- dichlorophenyl)propanamide

[0546] A TFA salt of the title in Scheme B using reactionconditions BB1 and purification NMR (400 MHz, CD3OD) δ ppm 0.73 - 0.80 (m, 1 H), 0.84 - 0.92 (m, 1 H), 0.96 - 1.10 (m, 2 H), 1.43 - 1.49 (m, 3 H), 2.31 - 2.43 (m, 1 H), 2.53 - 2.68 (m, 1 H), 3.27 - 3.31 (m, 1 H), 3.32 - 3.38 (m, 1 H), 4.05 - 4.21 (m, 2 H), 4.22 - 4.30 (m, 1 H), 4.32 - 4.40 (m, 1 H), 4.46 - 4.53 (m, 1 H), 7.21 - 7.27 (m, 1 H), 7.36 - 7.42 (m, 2 H), 7.83 - 7.95 (m, 1 H); ESI-MS m / z [M+H]+327.1.

[0547] EXAMPLE 26: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(p-tolyl)cyclobutane-1- carboxamide

[0548] A TFA salt of theScheme B using reaction conditions BB1 and purification conditions B1 (15.5 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.70 - 0.76 (m, 2 H), 0.85 - 0.91 (m, 2 H), 1.79 - 1.95 (m, 2 H), 2.13 - 2.26 (m, 1 H), 2.28 - 2.32 (m, 3 H), 2.40 - 2.53 (m, 3 H), 2.68 - 2.78 (m, 2 H), 3.20 - 3.25 (m, 2 H), 3.72 - 3.84 (m, 2 H), 4.00 - 4.10 (m, 2 H), 7.13 - 7.19 (m, 2 H), 7.22 - 7.28 (m, 2 H), 7.70 - 7.83 (m, 1 H); ESI-MS m / z [M+H]+299.2.

[0549] EXAMPLE 27: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2- chlorophenyl)acetamide

[0550] A TFA salt of the title compound was prepared as in Scheme B using reaction conditions BB1 and purification conditions B1 (10.6 mg). ESI-MS m / z [M+H]+279.1.

[0551] EXAMPLE 28: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)-2,2- difluoroacetamide

[0552] The title compound using reaction conditions BB1 and purification conditions B2. [M+H]+315.1.

[0553] EXAMPLE 29: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- chlorophenyl)cyclobutane-1-carboxamide

[0554] A TFA salt of the in Scheme B using reactionconditions BB1 and . MS m / z [M+H]+319.1.

[0555] EXAMPLE 30: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(m- tolyl)propanamide

[0556] A TFA salt of theScheme B using reaction conditions BB1 and purification conditions B1 (33.2 mg). ESI-MS m / z [M+H]+273.2.

[0557] EXAMPLE 31: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(m-tolyl)propanamide

[0558] A TFA salt of theScheme B using reaction conditions BB1 and purification conditions B1 (25.1 mg). ESI-MS m / z [M+H]+273.2.

[0559] EXAMPLE 32: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylacetamide

[0560] The title compoundusing reaction conditions BB2 and purification conditions B2 (12.2 mg, 40%). ESI-MS m / z [M+H]+245.1.

[0561] EXAMPLE 33: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methoxy-2- phenylacetamide

[0562] A TFA salt of the title as in Scheme B using reaction conditions BB2 and purification conditions B3 (10.4 mg). ESI-MS m / z [M+H]+275.15.

[0563] EXAMPLE 34: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methoxy-2- phenylacetamide

[0564] A TFA salt of the title in Scheme B using reactionconditions BB2 and purification NMR (400 MHz, CD3CN) δ ppm 0.70 - 0.77 (m, 1 H), 0.81 - 0.92 (m, 3 H), 2.10 - 2.27 (m, 1 H), 2.41 - 2.56 (m, 1 H), 3.13 - 3.26 (m, 2 H), 3.27 (s, 3 H), 3.73 - 3.91 (m, 2 H), 4.13 - 4.27 (m, 2 H), 4.55 - 4.58 (m, 1 H), 7.32 - 7.39 (m, 5 H), 7.97 - 8.05 (m, 1 H); ESI-MS m / z [M+H]+275.15.

[0565] EXAMPLE 35: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-6-bromo-2,3-dihydro-1H- indene-1-carboxamide

[0566] A TFA salt of the titlein Scheme B using reaction conditions BB2 and purification conditions B3 (33.5 mg).1H NMR (400 MHz, CD3CN) δ ppm 0.76 - 0.84 (m, 1 H), 0.84 - 0.94 (m, 3 H), 2.17 - 2.35 (m, 3 H), 2.49 - 2.63 (m, 1 H), 2.77 - 2.87 (m, 1 H), 2.93 - 3.02 (m, 1 H), 3.20 - 3.32 (m, 3 H), 3.79 - 3.86 (m, 1 H), 3.91 - 4.00 (m, 2 H), 4.22 - 4.33 (m, 2 H), 7.13 - 7.19 (m, 1 H), 7.31 - 7.36 (m, 1 H), 7.37 - 7.41 (m, 1 H), 7.76 - 7.91 (m, 1 H), 10.34 - 10.66 (m, 1 H); ESI-MS m / z [M+H]+349.1, 351.1.

[0567] EXAMPLE 36: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylbutanamide

[0568] A TFA salt of the titlein Scheme B using reaction conditions BB2 and purification conditions B3 (19.5 mg). ESI-MS m / z [M+H]+273.2.

[0569] EXAMPLE 37: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-chloro-2,3-dihydro-1H- indene-1-carboxamide

[0570] A TFA salt of the Scheme B using reaction conditions BB2 andNMR (400 MHz, CD3CN) δ ppm 0.73 - 0.79 (m, 1 H), 0.83 - 0.90 (m, 3 H), 2.22 - 2.32 (m, 3 H), 2.48 - 2.63 (m, 1 H), 2.81 - 2.92 (m, 1 H), 2.97 - 3.06 (m, 1 H), 3.13 - 3.20 (m, 1 H), 3.29 - 3.34 (m, 1 H), 3.75 - 3.80 (m, 1 H), 3.88 - 3.99 (m, 2 H), 4.21 - 4.32 (m, 2 H), 7.11 - 7.17 (m, 1 H), 7.18 (s, 1 H), 7.23 - 7.27 (m, 1 H), 7.91 - 8.08 (m, 1 H), 10.87 - 11.26 (m, 1 H); ESI-MS m / z [M+H]+305.1.

[0571] EXAMPLE 38: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylbutanamide

[0572] The title compound using reaction conditions BB2and purification conditions B2 (4.8 mg, 14%). ESI-MS m / z [M+H]+273.2.

[0573] EXAMPLE 39: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methoxy-2- phenylpropanamide

[0574] A TFA salt of the titlein Scheme B using reaction conditions BB2 and purification conditions B3 (23.2 mg). ESI-MS m / z [M+H]+289.2.

[0575] EXAMPLE 40: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chloro-6- methylphenyl)acetamide

[0576] The title compoundB using reaction conditions BB2 and purification conditions B2 (16.6 mg, 45%).1H NMR (400 MHz, CD3CN) δ ppm 0.80 - 0.86 (m, 2 H), 0.86 - 0.92 (m, 2 H), 2.24 - 2.35 (m, 4 H), 2.49 - 2.62 (m, 1 H), 3.22 - 3.27 (m, 2 H), 3.67 - 3.70 (m, 2 H), 3.91 - 4.02 (m, 2 H), 4.22 - 4.33 (m, 2 H), 7.11 - 7.18 (m, 2 H),7.21 - 7.26 (m, 1 H), 7.48 - 7.62 (m, 1 H), 7.50 - 7.59 (m, 1 H), 9.91 - 10.26 (m, 1 H); ESI- MS m / z [M+H]+293.1.

[0577] EXAMPLE 41: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- methoxyphenyl)cyclopropane-1-carboxamide

[0578] A TFA salt of the Scheme B using reaction conditions BB2 and. MS m / z [M+H]+301.2.

[0579] EXAMPLE 42: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6- dimethylphenyl)acetamide

[0580] The title compound using reaction conditions BB2and purification conditions B2 (13.6 mg, 40%). ESI-MS m / z [M+H]+273.2.

[0581] EXAMPLE 43: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3,3-trifluoro-2- phenylpropanamide

[0582] A TFA salt of the titlein Scheme B using reaction conditions BB2 and purification conditions B3 (43.0 mg). ESI-MS m / z [M+H]+313.1.

[0583] EXAMPLE 44: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3-phenyloxetane-3- carboxamide

[0584] A TFA salt of the titlein Scheme B using reaction conditions BB2 and purification conditions B3 (28.8 mg). ESI-MS m / z [M+H]+287.1.

[0585] EXAMPLE 45: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4- fluorophenyl)cyclopropane-1-carboxamide

[0586] The title compound w using reaction conditions BB2 and purification conditions B2 ( 8. mg, 9%). S - S m / z [M+H]+289.1.

[0587] EXAMPLE 46: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- chlorophenyl)cyclobutane-1-carboxamide

[0588] The title compound using reaction conditions BB2and purification conditions B2 mg, . [M+H]+319.1.

[0589] EXAMPLE 47: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-4-chloro-2,3-dihydro-1H- indene-1-carboxamide

[0590] A TFA salt of the in Scheme B using reactionconditions BB2 and purification conditions B3 (14.6 mg). ESI-MS m / z [M+H]+305.1.

[0591] The compounds of EXAMPLES 48 to 77 were prepared as shown in Scheme C.

[0592] Reaction conditions: To a vial with a stir bar was added carboxylic acid (0.1 – 0.25 mmol, 1.0 eq), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (1.2 eq), and DIPEA (4.0 – 5.0 eq) in THF (2 mL). HATU (1.2 – 1.3 eq) was added and the reaction mixture was allowed to stir at room temperature for 2 h.

[0593] Purification conditions C1: DMF (0.2 – 1 mL) was added to the reaction mixture, which was then filtered and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0594] Purification conditions C2: DMF (0.2 – 1 mL) was added to the reaction mixture, which was then filtered and purified by preparative HPLC (Phenomenex Gemini® NX-C18,5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0595] Purification conditions C3: DMF (1 mL) was added to the reaction mixture, which was then filtered and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Fractions containing product were collected and repurified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0596] Purification conditions C4: DMF (1 mL) was added to the reaction mixture, which was then filtered and purified by preparative HPLC Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA). Fractions containing product were collected and repurified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0597] EXAMPLE 48: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-2- fluorophenyl)-2-methylpropanamide

[0598] The title compoundpurification conditions C2 to give a brown / orange film (18 mg, 48%).1H NMR (400 MHz, CDCl3) δ ppm 0.50 - 0.72 (m, 3 H), 0.78 (s, 1 H), 1.43 - 1.50 (m, 3 H), 1.50 - 1.60 (m, 3 H), 1.98 - 2.15 (m, 1 H), 2.34 (br s, 2 H), 2.53 (s, 2 H), 3.21 (t, J = 7.0 Hz, 2 H), 5.71 - 5.82 (m, 1 H), 7.04 (t, J = 10.4 Hz, 1 H), 7.08 - 7.18 (m, 1 H), 7.23 - 7.35 (m, 1 H); ESI-MS m / z [M+H]+325.1.

[0599] EXAMPLE 49: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2- phenylpropanamide

[0600] The title compoundusing purification conditions C2 to give a brown / orange semisolid (15 mg, 36%).1H NMR (400 MHz, CDCl3) δ ppm 0.52 -0.65 (m, 4 H), 1.45 - 1.56 (m, 6 H), 2.01 (quin, J = 7.0 Hz, 2 H), 2.49 (s, 2 H), 3.13 (t, J = 7.0 Hz, 4 H), 5.57 (br s, 1 H), 7.18 - 7.28 (m, 1 H), 7.32 (s, 2 H), 7.34 (s, 2 H); ESI-MS m / z [M+H]+273.1.

[0601] EXAMPLE 50: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluorophenyl)-2- methylpropanamide

[0602] A TFA salt of the title in Scheme C using purificationconditions C3 to give a clear MHz, CDCl3) δ ppm 0.81 (br d, J = 3.8 Hz, 4 H), 1.56 (s, 6 H), 2.10 - 2.29 (m, 1 H), 2.64 (dt, J = 11.9, 9.5 Hz, 1 H), 3.15 (br d, J = 3.0 Hz, 2 H), 3.48 - 3.67 (m, 2 H), 4.11 - 4.29 (m, 2 H), 6.92 (t, J = 8.1 Hz, 1 H), 7.10 (dt, J = 10.8, 2.1 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (s, 1 H), 7.28 - 7.33 (m, 1 H), 7.46 - 7.58 (m, 1 H); ESI-MS m / z [M+H]+291.1.

[0603] EXAMPLE 51: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-ethylphenyl)-2- methylpropanamide

[0604] The title compoundpurification conditions C2 to give a clear oil (22 mg, 56%).1H NMR (400 MHz, CDCl3) δ ppm 0.59 (dt, J = 4.8, 1.7 Hz, 4 H), 1.23 (t, J = 7.5 Hz, 3 H), 2.00 (quin, J = 7.0 Hz, 3 H), 2.48 (s, 2 H), 2.63 (q, J = 7.6 Hz, 2 H), 3.12 (t, J = 7.0 Hz, 4 H), 5.56 (br s, 1 H), 7.10 - 7.19 (m, 2 H), 7.20 - 7.28 (m, 2 H); ESI-MS m / z [M+H]+301.2.

[0605] EXAMPLE 52: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-cyanophenyl)-2- methylpropanamide

[0606] A TFA salt of theScheme C using purification conditions C3 to give a clear oil (10 mg, 19%).1H NMR (400 MHz, CDCl3) δ ppm 0.80 (s, 4 H), 2.12 - 2.34 (m, 1 H), 2.48 (br s, 2 H), 2.58 - 2.76 (m, 1 H), 3.16 (br s, 2 H), 3.62 (br d, J =7.0 Hz, 2 H), 4.24 (br s, 2 H), 7.41 - 7.54 (m, 2 H), 7.54 - 7.67 (m, 2 H), 7.75 (s, 1 H), 12.90 - 13.19 (m, 1 H); ESI-MS m / z [M+H]+298.1.

[0607] EXAMPLE 53: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-4- fluorophenyl)-2-methylpropanamide

[0608] The title compound purification conditions C2to give a light yellow MHz, CDCl3) δ ppm 0.62 (dt, J = 4.8, 1.7 Hz, 4 H), 1.50 (s, 6 H), 2.02 (quin, J = 7.0 Hz, 3 H), 2.47 (s, 2 H), 3.14 (t, J = 6.9 Hz, 4 H), 5.66 (br s, 1 H), 7.09 (t, J = 8.7 Hz, 1 H), 7.22 (ddd, J = 8.8, 4.5, 2.5 Hz, 1 H), 7.40 (dd, J = 6.9, 2.4 Hz, 1 H).

[0609] EXAMPLE 54: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5-chloro-2- fluorophenyl)-2-methylpropanamide

[0610] The title compoundpurification conditions C2 to give a white semisolid (17 mg, 45%).1H NMR (400 MHz, CDCl3) δ ppm 0.56 - 0.73 (m, 4 H), 1.42 - 1.57 (m, 6 H), 2.02 (quin, J = 7.0 Hz, 2 H), 2.51 (s, 2 H), 3.18 (t, J = 7.0 Hz, 4 H), 5.68 (br s, 1 H), 6.96 (dd, J = 10.7, 8.7 Hz, 1 H), 7.18 - 7.28 (m, 1 H), 7.32 (dd, J = 6.6, 2.6 Hz, 1 H); ESI-MS m / z [M+H]+325.1.

[0611] EXAMPLE 55: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-5- fluorophenyl)-2-methylpropanamide

[0612] The title compoundpurification conditions C2 to give a white solid (20 mg, 53%).1H NMR (400 MHz, CDCl3) δ ppm 0.55 - 0.71 (m, 4 H), 1.49 (s, 6 H), 2.03 (quin, J = 7.0 Hz, 2 H), 2.47 (s, 2 H), 3.14 (t, J = 7.0 Hz, 4 H), 5.64 (br s, 1 H), 6.91 - 7.04 (m, 2 H), 7.15 (t, J = 1.4 Hz, 1 H); ESI-MS m / z [M+H]+325.05.

[0613] EXAMPLE 56: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-3- fluorophenyl)-2-methylpropanamide

[0614] The title compound using purification conditions C2 to give a white solid (20 mg,δ ppm 0.62 (dt, J = 6.1, 1.8 Hz, 4 H), 1.50 (s, 6 H), 2.02 (quin, J = 7.0 Hz, 2 H), 2.47 (s, 2 H), 3.14 (t, J = 7.0 Hz, 4 H), 5.67 (br s, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.19 (dd, J = 10.8, 2.3 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H); ESI-MS m / z [M+H]+325.1.

[0615] EXAMPLE 57: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-3- methoxyphenyl)-2-methylpropanamide

[0616] The title purification conditions C2to give a clear oil (14 mg, 37%).1H NMR (400 MHz, CD3OD) δ ppm 0.54 - 0.74 (m, 4 H), 1.44 - 1.55 (m, 6 H), 2.07 (quin, J = 7.2 Hz, 2 H), 2.38 (br s, 2 H), 2.52 - 2.60 (m, 2 H), 3.23 (t, J = 7.2 Hz, 2 H), 3.81 - 3.93 (m, 3 H), 6.82 - 6.93 (m, 1 H), 6.95 - 7.08 (m, 2 H); ESI-MS m / z [M+H]+321.1.

[0617] EXAMPLE 58: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-fluoro-5- methoxyphenyl)-2-methylpropanamide

[0618] The titlepurification conditions C2 to give a clear oil (15 mg, 40%).1H NMR (400 MHz, CDCl3) δ ppm 0.50 - 0.71 (m, 3 H), 0.77 (s, 1 H), 1.24 - 1.41 (m, 1 H), 1.41 - 1.53 (m, 6 H), 2.02 (quin, J = 7.0 Hz, 1 H), 2.32 (br s, 2 H), 2.51 (s, 2 H), 3.18 (t, J = 7.0 Hz, 1 H), 3.71 - 3.86 (m, 3 H), 5.63 - 5.77 (m, 1 H), 6.65 - 6.79 (m, 1 H), 6.82 - 6.99 (m, 2 H); ESI-MS m / z [M+H]+321.1.

[0619] EXAMPLE 59: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(p- tolyl)propanamide

[0620] The title compound sing purification conditions C2 to give a clear oil (19 mg, 47%). H NMR (400 MHz, CD3OD) δ ppm 0.50 - 0.72 (m, 4 H), 1.40 - 1.50 (m, 7 H), 2.06 (quin, J = 7.2 Hz, 1 H), 2.23 - 2.35 (m, 3 H), 2.35 - 2.48 (m, 2 H), 2.55 (s, 2 H), 3.22 (br t, J = 7.2 Hz, 2 H), 7.04 - 7.17 (m, 2 H), 7.17 - 7.25 (m, 2 H); ESI-MS m / z [M+H]+287.2.

[0621] EXAMPLE 60: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3- fluorophenyl)propanamide

[0622] A TFA salt of the in Scheme C using purificationconditions C3 to give a clear oil (3.0 mg, 5.4%) NMR (400 MHz, CD3OD) δ ppm 0.69 - 0.86 (m, 2 H), 0.89 - 1.00 (m, 2 H), 1.42 (d, J = 7.0 Hz, 3 H), 2.19 - 2.40 (m, 1 H), 2.45 - 2.65 (m, 1 H), 3.20 - 3.37 (m, 2 H), 3.57 (q, J = 7.0 Hz, 1 H), 3.88 - 4.11 (m, 2 H), 4.11 - 4.29 (m, 2 H), 6.97 (t, J = 8.3 Hz, 1 H), 7.08 (d, J = 10.2 Hz, 1 H), 7.11 (d, J = 7.6 Hz, 1 H), 7.32 (td, J = 7.9, 6.0 Hz, 1 H); ESI-MS m / z [M+H]+277.2.

[0623] EXAMPLE 61: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4- fluorophenyl)propanamide

[0624] A TFA salt of the titlein Scheme C using purification conditions C3 to give a clear oil (2.0 mg, 3.6%).1H NMR (400 MHz, CD3OD) δ ppm 0.69 - 0.86 (m, 2 H), 0.88 - 0.98 (m, 2 H), 1.41 (d, J = 7.0 Hz, 3 H), 2.21 - 2.38 (m, 1 H), 2.56 (dt, J = 11.7, 9.5 Hz, 1 H), 3.19 - 3.37 (m, 2 H), 3.55 (q, J = 7.0 Hz, 1 H), 3.93 (d, J = 10.0 Hz, 1 H), 3.97 - 4.07 (m, 1 H), 4.17 (td, J = 10.0, 4.1 Hz, 2 H), 6.98 - 7.10 (m, 2 H), 7.31 (s, 1 H), 7.32 - 7.34 (m, 1 H); ESI-MS m / z [M+H]+277.2.

[0625] EXAMPLE 62: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(o-tolyl)acetamide

[0626] A TFA salt of the title compound was prepared as in Scheme C using purification conditions C3 to give a clear oil (6 mg, 8.4%).1H NMR (400 MHz, CD3OD) δ ppm 0.79 - 1.02 (m, 4 H), 2.28 (s, 3 H), 2.31 - 2.44 (m, 1 H), 2.58 (dt, J = 11.7, 9.5 Hz, 1 H), 3.32 - 3.35 (m, 2 H), 3.53 (s, 2 H), 3.98 - 4.15 (m, 2 H), 4.18 - 4.32 (m, 2 H), 7.00 - 7.22 (m, 4 H), 8.37 (br s, 1 H); ESI-MS m / z [M+H]+259.2.

[0627] EXAMPLE 63: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3- chlorophenyl)propanamide

[0628] A TFA salt of the in Scheme C using purificationconditions C1 to give a white mg, (400 MHz, CD3OD) δ ppm 0.67 - 0.87 (m, 2 H), 0.87 - 1.00 (m, 2 H), 1.42 (d, J = 7.0 Hz, 3 H), 2.20 - 2.39 (m, 1 H), 2.45 - 2.67 (m, 1 H), 3.29 - 3.41 (m, 2 H), 3.56 (q, J = 7.0 Hz, 1 H), 3.85 - 4.09 (m, 2 H), 4.09 - 4.30 (m, 2 H), 7.17 - 7.39 (m, 4 H) 8.42 (br s, 1 H); ESI-MS m / z [M+H]+293.2.

[0629] EXAMPLE 64: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-fluoro-6- methoxyphenyl)acetamide

[0630] A TFA salt of thein Scheme C using purification conditions C1 to give a clear oil (34 mg, 54%).1H NMR (400 MHz, CD3OD) δ ppm 0.81 - 1.04 (m, 4 H), 2.37 (ddt, J = 11.7, 9.2, 4.7 Hz, 1 H), 2.52 - 2.70 (m, 1 H), 3.32 - 3.35 (m, 2 H), 3.54 (d, J = 1.0 Hz, 2 H), 3.82 (s, 3 H), 4.02 - 4.20 (m, 2 H), 4.20 - 4.35 (m, 2 H), 6.72 (t, J = 8.6 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 7.26 (td, J = 8.3, 6.9 Hz, 1 H), 8.39 (br s, 1 H); ESI-MS m / z [M+H]+293.2.

[0631] EXAMPLE 65: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluoro-5- methoxyphenyl)-2-methylpropanamide

[0632] A TFA salt of the title compound was prepared as in Scheme C using purification conditions C1 to give a clear oil (7 mg, 12%).1H NMR (400 MHz, CD3OD) δ ppm 0.67 - 0.80 (m, 2 H), 0.89 - 0.99 (m, 2 H), 1.50 (s, 6 H), 2.25 - 2.44 (m, 1 H), 2.59 (dt, J = 11.7, 9.3 Hz, 1 H), 3.18 - 3.38 (m, 2 H), 3.78 (s, 3 H), 3.97 - 4.12 (m, 2 H), 4.17 - 4.30 (m, 2 H), 6.51 - 6.70 (m, 3 H), 7.66 (s, 1 H); ESI-MS m / z [M+H]+321.3.

[0633] EXAMPLE 66: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4- chlorophenyl)propanamide

[0634] A TFA salt of the in Scheme C using purificationconditions C1 to give a white mg, (400 MHz, CD3OD) δ ppm 0.67 - 0.86 (m, 2 H), 0.87 - 0.97 (m, 2 H), 1.41 (d, J = 7.0 Hz, 3 H), 2.19 - 2.37 (m, 1 H), 2.56 (dt, J = 11.7, 9.4 Hz, 1 H), 3.21 - 3.29 (m, 1 H), 3.29 - 3.38 (m, 1 H), 3.56 (q, J = 7.0 Hz, 1 H), 3.84 - 4.09 (m, 2 H), 4.09 - 4.28 (m, 2 H), 7.22 - 7.37 (m, 4 H), 8.40 (s, 1 H); ESI-MS m / z [M+H]+293.2.

[0635] EXAMPLE 67: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(p-tolyl)propanamide

[0636] A TFA salt of theScheme C using purification conditions C1 to give a white solid (9 mg, 20%).1H NMR (400 MHz, CD3OD) δ ppm 0.70 - 1.00 (m, 4 H), 1.39 (d, J = 7.0 Hz, 3 H), 2.13 - 2.37 (m, 4 H), 2.45 - 2.63 (m, 1 H), 3.14 - 3.26 (m, 1 H), 3.26 - 3.38 (m, 1 H), 3.51 (q, J = 7.1 Hz, 1 H), 3.85 (q, J = 9.7 Hz, 1 H), 3.99 (q, J = 9.7 Hz, 1 H), 4.04 - 4.24 (m, 2 H), 7.02 - 7.25 (m, 4 H), 8.28 (br s, 1 H); ESI-MS m / z [M+H]+273.3.

[0637] EXAMPLE 68: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(o-tolyl)cyclopropane-1- carboxamide

[0638] The title compoundusing purification conditions C4 to give a clear oil (6.5 mg, 16%, 95% purity).1H NMR (400 MHz, CD3OD) δ ppm 0.47 -0.60 (m, 2 H), 0.61 - 0.69 (m, 2 H), 1.02 (q, J = 3.5 Hz, 2 H), 1.56 (q, J = 3.8 Hz, 2 H), 2.11 (quin, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 2.58 (s, 2 H), 3.23 - 3.37 (m, 4 H), 7.12 - 7.28 (m, 3 H), 7.32 (d, J = 6.5 Hz, 1 H); ESI-MS m / z [M+H]+285.2.

[0639] EXAMPLE 69: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(m-tolyl)cyclopropane-1- carboxamide

[0640] A TFA salt of the Scheme C using purificationconditions C1 to give a clear MHz, CD3OD) δ ppm 0.69 - 0.83 (m, 2 H), 0.87 - 0.97 (m, 2 H), 1.02 - 1.12 (m, 2 H), 1.46 - 1.54 (m, 2 H), 2.33 - 2.44 (m, 4 H), 2.59 (dt, J = 11.7, 9.3 Hz, 1 H), 3.26 (s, 2 H), 4.02 - 4.16 (m, 2 H), 4.18 - 4.32 (m, 2 H), 6.89 (br s, 1 H), 7.06 - 7.30 (m, 4 H); ESI-MS m / z [M+H]+285.3.

[0641] EXAMPLE 70: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(o-tolyl)cyclobutane-1- carboxamide

[0642] A TFA salt of the titlein Scheme C using purification conditions C1 to give a white solid (23 mg, 44%).1H NMR (400 MHz, CD3OD) δ ppm 0.61 - 0.77 (m, 2 H), 0.85 - 0.94 (m, 2 H), 1.73 - 1.91 (m, 1 H), 1.99 - 2.14 (m, 1 H), 2.16 (s, 3 H), 2.24 (ddd, J = 9.4, 7.0, 4.6 Hz, 1 H), 2.41 - 2.57 (m, 3 H), 2.70 - 2.86 (m, 2 H), 3.25 (s, 2 H), 3.75 - 3.94 (m, 2 H), 4.01 - 4.14 (m, 2 H), 7.03 - 7.18 (m, 3 H), 7.22 (t, J = 7.3 Hz, 1 H), 7.34 (dd, J = 7.6, 1.1 Hz, 1 H); ESI-MS m / z [M+H]+299.3.

[0643] EXAMPLE 71: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- fluorophenyl)cyclopropane-1-carboxamide

[0644] A TFA salt of thein Scheme C using purification conditions C1 to give a clear oil (26 mg, 40%).1H NMR (400 MHz, CD3OD) δ ppm 0.74 - 0.85 (m, 2 H), 0.89 - 0.95 (m, 2 H), 1.05 - 1.15 (m, 2 H), 1.46 - 1.58 (m, 2 H), 2.36 (ddd, J = 9.5, 7.0, 4.8 Hz, 1 H), 2.59 (dt, J = 11.7, 9.3 Hz, 1 H), 3.23 - 3.29 (m, 2 H), 4.02 - 4.15 (m, 2 H), 4.20 - 4.32 (m, 2 H), 7.00 - 7.23 (m, 4 H), 7.37 (td, J = 8.0, 6.0 Hz, 1 H); ESI-MS m / z [M+H]+289.2.

[0645] EXAMPLE 72: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4- (difluoromethyl)phenyl)propanamide

[0646] A TFA salt of the Scheme C using purificationconditions C1 to give a white . [M+H]+309.25.

[0647] EXAMPLE 73: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3- (difluoromethyl)phenyl)-2,2-difluoroacetamide

[0648] A TFA salt of the Scheme C using purificationconditions C1 to give a clear mg, MHz, CD3OD) δ ppm 0.81 - 0.93 (m, 2 H), 0.98 - 1.06 (m, 2 H), 2.26 - 2.42 (m, 1 H), 2.49 - 2.67 (m, 1 H), 3.33 - 3.41 (m, 2 H), 3.98 - 4.14 (m, 2 H), 4.14 - 4.29 (m, 2 H), 6.84 (t, J = 56 Hz, 1 H), 7.52 - 7.68 (m, 1 H) 7.68 - 7.82 (m, 3 H); ESI-MS m / z [M+H]+331.25.

[0649] EXAMPLE 74: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5-fluoro-7- methylbenzo[d]isoxazol-3-yl)-2-methylpropanamide

[0650] A TFA salt of theScheme C using purification conditions C1 to give a light orange semi-solid (44 mg, 54%).1H NMR (400 MHz, CDCl3) δ ppm 0.86 (br d, J = 1.5 Hz, 4 H), 1.74 (s, 6 H), 2.25 - 2.37 (m, 1 H), 2.55 (s, 3 H), 2.66 - 2.80 (m, 1 H), 3.26 (d, J = 5.0 Hz, 2 H), 3.72 - 3.86 (m, 2 H), 4.36 - 4.47 (m, 2 H), 7.09 (ddd, J = 9.4, 2.3, 0.9 Hz, 1 H), 7.15 - 7.20 (m, 1 H), 7.80 (s, 1 H); ESI-MS m / z [M+H]+346.4.

[0651] EXAMPLE 76: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- methylbenzyl)cyclopropane-1-carboxamide O

[0652] A TFA salt of the title compound was prepared as in Scheme C using purification conditions C1 to give a light orange solid (79 mg, 79%).1H NMR (400 MHz, CDCl3) δ ppm 0.57 - 0.62 (m, 2 H), 0.70 - 0.76 (m, 2 H), 0.80 - 0.84 (m, 2 H), 1.22 - 1.27 (m, 2 H), 2.20 (dtd, J = 16.6, 9.2, 4.5 Hz, 1 H), 2.31 (s, 3 H), 2.53 - 2.68 (m, 1 H), 2.93 (s, 2 H), 3.14 (d, J = 4.8 Hz, 2 H), 3.54 - 3.64 (m, 2 H), 4.17 - 4.27 (m, 2 H), 6.96 - 7.02 (m, 1 H), 7.10 - 7.17 (m, 3 H), 7.29 (s, 1 H), 12.59 - 12.75 (m, 1 H); ESI-MS m / z [M+H]+299.4.

[0653] EXAMPLE 77: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4- chlorobenzyl)cyclopropane-1-carboxamide

[0654] A TFA salt of the Scheme C using purificationconditions C1 to give an orange mg, MHz, CDCl3) δ ppm 0.64 - 0.69 (m, 2 H), 0.73 - 0.78 (m, 2 H), 0.82 - 0.86 (m, 2 H), 1.20 - 1.32 (m, 2 H), 2.21 - 2.35 (m, 1 H), 2.67 (dquin, J = 12.0, 9.4 Hz, 1 H), 2.97 (s, 2 H), 3.16 (d, J = 5.0 Hz, 2 H), 3.53 - 3.66 (m, 2 H), 4.22 - 4.33 (m, 2 H), 7.24 - 7.32 (m, 4 H), 7.57 (s, 1 H), 12.69 - 12.86 (m, 1 H); ESI-MS m / z [M+H]+319.3.

[0655] EXAMPLE 78: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(m- tolyl)propanamide

[0656] To a 500 mL round-added 2-methyl-2-(m- tolyl)propanoic acid (0.700 g, 3.93 mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (0.938 g, 4.71 mmol), and DIPEA (3.43 mL, 19.6 mmol) in THF (50 mL). HATU (1.792 g, 4.71 mmol) was added and the reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated and partitioned between EtOAc (2 x 100 mL) and saturated aqueous sodium bicarbonate. The combined organics were dried over magnesium sulfate, concentrated with silica gel, and purified by flash silica column chromatography (ISCO, NH silica column) using a gradient of 30-90% EtOAc in heptanes, followed by 10% methanol in DCM. Fractions containing product were evaporated to give the title compound as a clear oil that solidified to a white solid (599 mg, 53%).1H NMR (400 MHz, CDCl3) δ ppm 0.53 - 0.71 (m, 4 H), 1.48 (s, 6 H), 2.04 (quin, J = 7.2 Hz, 2 H), 2.32 (s,3 H), 2.54 (s, 2 H), 3.14 - 3.23 (m, 4 H), 7.03 (d, J = 7.2 Hz, 1 H), 7.07 - 7.24 (m, 3 H); ESI- MS m / z [M+H]+287.30.

[0657] EXAMPLE 79: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2- chlorophenyl)propanamide

[0658] To a mixture of 2-(2- (4.7 g, 25.5 mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine mmol), and DIPEA (22.23 mL, 127 mmol) in THF (150 mL) was added HATU (11.62 g, 30.5 mmol). The reaction was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated and DMF (1 mL) was added. The mixture was filtered and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 20 µm, ID 25 mm x 150 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10) to give the title compound (5.38 g, 72%).1H NMR (400 MHz, CD3OD) δ ppm 0.64 - 0.82 (m, 4 H), 1.24 (t, J = 7.2 Hz, 1 H), 1.32 - 1.37 (m, 1 H), 1.42 (d, J = 7.0 Hz, 3 H), 2.01 (s, 1 H), 2.12 - 2.25 (m, 2 H), 2.71 (br d, J = 13.3 Hz, 1 H), 2.88 (d, J = 13.0 Hz, 1 H), 3.52 (br t, J = 7.4 Hz, 3 H), 4.04 (q, J = 7.4 Hz, 1 H), 4.08 - 4.14 (m, 1 H), 7.14 - 7.33 (m, 2 H), 7.37 (dd, J = 7.8, 1.2 Hz, 1 H), 7.43 (dd, J = 7.8, 1.8 Hz, 1 H); ESI-MS m / z [M+H]+293.10.

[0659] EXAMPLE 80: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2- chlorophenyl)propanamide

[0660] Racemic N-(1--2-(2-chlorophenyl)propanamide (EXAMPLE 79) (5.3 g, 18 mmol) was purified by SFC (ChiralPak IC, 5 µm, ID 30 mm x 250 mm) using 40% isopropanol (w / 0.1% NH4OH) in CO2. The first peak was collected and arbitrarily assigned as having (S) stereochemistry to give the title compound as a white solid (1.59 g, 30%).1H NMR (400 MHz, CD3OD) δ ppm 0.52 - 0.74 (m, 4 H), 1.41 (d, J = 7.0 Hz, 3 H), 2.07 (quin, J = 7.2 Hz, 2 H), 2.45 (d, J = 12.8 Hz, 1 H), 2.70 (d, J = 13.0 Hz, 1 H), 3.26 (t, J = 7.2 Hz, 4 H), 4.04 (q, J = 7.0 Hz, 1 H), 7.18 - 7.24 (m, 1 H), 7.28 (t, J = 7.3 Hz, 1 H), 7.37 (dd, J = 7.9, 1.4 Hz, 1 H), 7.44 (dd, J = 7.8, 1.8 Hz, 1 H); ESI-MS m / z [M+H]+293.20.

[0661] EXAMPLE 81: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2- chlorophenyl)propanamide

[0662] Racemic N-(1- -2-(2-chlorophenyl)propanamide (EXAMPLE 79) (5.3 g, 18IC, 5 µm, ID 30 mm x 250 mm) using 40% isopropanol (w / 0.1% NH4OH) in CO2. The second peak was collected and arbitrarily assigned as having (R) stereochemistry to give the title compound as a white solid (1.52 g, 29%).1H NMR (400 MHz, CD3OD) δ ppm 0.54 - 0.73 (m, 4 H), 1.41 (d, J = 7.3 Hz, 3 H), 2.07 (quin, J = 7.2 Hz, 2 H), 2.45 (d, J = 12.8 Hz, 1 H), 2.71 (d, J = 13.0 Hz, 1 H), 3.21 - 3.29 (m, 4 H), 4.04 (q, J = 7.0 Hz, 1 H), 7.18 - 7.24 (m, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.37 (dd, J = 7.9, 1.4 Hz, 1 H), 7.44 (dd, J = 7.6, 1.6 Hz, 1 H); ESI-MS m / z [M+H]+293.20.

[0663] The compounds of EXAMPLES 82 to 91 were prepared as shown in Scheme D.

[0664] Reaction conditions: To a vial with a stir bar were added carboxylic acid (0.1 – 0.25 mmol, 1.0 eq), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (1.2 – 1.5 eq), and triethylamine (5.0 – 6.0 eq) in THF (0.2 M). HATU (1.2 – 1.3 eq) was added and the reaction mixture was allowed to stir at room temperature for 8 – 16 h. The reaction mixture was diluted with methanol and filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®), then purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0665] EXAMPLE 82: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4- fluorobenzyl)cyclopropane-1-carboxamide

[0666] A TFA salt of the title compound was prepared as in Scheme D to give a pale yellow solid (52 mg, 81%).1H NMR (400 MHz, CDCl3) δ ppm 0.58 - 0.64 (m, 2 H), 0.69 - 0.75 (m, 2 H), 0.77 - 0.82 (m, 2 H), 1.19 - 1.32 (m, 2 H), 2.10 - 2.34 (m, 1 H), 2.52 - 2.76 (m, 1 H), 2.94 (s, 2 H), 3.13 (d, J = 5.0 Hz, 2 H), 3.53 - 3.67 (m, 2 H), 4.19 - 4.34 (m, 2 H), 6.91 - 6.98 (m, 2 H), 7.27 - 7.33 (m, 2 H), 7.54 (s, 1 H), 12.82 - 13.15 (m, 1 H); ESI-MS m / z [M+H]+303.2.

[0667] EXAMPLE 83: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- methylbenzyl)cyclopropane-1-carboxamide

[0668] A TFA salt of the in Scheme D to give a pale 1orange solid (42 mg, 65%). H ppm 0.64 - 0.81 (m, 6 H), 1.20 - 1.32 (m, 2 H), 2.12 - 2.28 (m, 1 H), 2.32 (s, 3 H), 2.54 - 2.68 (m, 1 H), 2.97 (s, 2 H), 3.13 (d, J = 4.8 Hz, 2 H), 3.52 - 3.66 (m, 2 H), 4.17 - 4.26 (m, 2 H), 7.05 - 7.10 (m, 2 H), 7.11 - 7.16 (m, 1 H), 7.27 - 7.31 (m, 1 H), 7.60 (s, 1 H), 12.94 - 13.24 (m, 1 H); ESI-MS m / z [M+H]+299.2.

[0669] EXAMPLE 84: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3-(4-chlorophenyl)-2,2- dimethylpropanamide

[0670] A TFA salt of theScheme D to give an orange solid (37 mg, 60%).1H NMR (400 MHz, CDCl3) δ ppm 0.80 (s, 4 H), 1.19 (s, 6 H), 2.25 (dtd, J = 16.5, 9.2, 4.3 Hz, 1 H), 2.61 - 2.71 (m, 1 H), 2.80 (s, 2 H), 3.13 (d, J = 5.0 Hz, 2 H), 3.47 - 3.57 (m, 2 H), 4.26 - 4.35 (m, 2 H), 7.10 - 7.16 (m, 2 H), 7.20 - 7.25 (m, 2 H), 7.50 (s, 1 H), 13.08 - 13.28 (m, 1 H); ESI-MS m / z [M+H]+321.15.

[0671] EXAMPLE 85: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- chlorobenzyl)cyclopropane-1-carboxamide

[0672] A TFA salt of theScheme D to give a pale orange solid (44 mg, 71%).1H NMR (400 MHz, CDCl3) δ ppm 0.63 - 0.69 (m, 2 H), 0.70 -0.76 (m, 2 H), 0.80 - 0.84 (m, 2 H), 1.23 - 1.29 (m, 2 H), 2.17 - 2.30 (m, 1 H), 2.64 (dquin, J = 12.0, 9.5 Hz, 1 H), 2.95 (s, 2 H), 3.14 (d, J = 5.3 Hz, 2 H), 3.56 - 3.67 (m, 2 H), 4.21 - 4.32 (m, 2 H), 7.13 - 7.22 (m, 3 H), 7.33 (s, 1 H), 7.59 (s, 1 H), 12.80 - 13.07 (m, 1 H); ESI-MS m / z [M+H]+319.1.

[0673] EXAMPLE 86: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- chlorobenzyl)cyclopropane-1-carboxamide

[0674] A TFA salt of the in Scheme D to give an orange oil(68 mg, 65%).1H NMR (400 - (m, 6 H), 1.21 - 1.26 (m, 2 H), 2.22 - 2.33 (m, 1 H), 2.64 - 2.76 (m, 1 H), 3.15 (s, 2 H), 3.20 (d, J = 4.8 Hz, 2 H), 3.65 - 3.76 (m, 2 H), 4.32 - 4.41 (m, 2 H), 7.11 - 7.19 (m, 2 H), 7.31 - 7.37 (m, 2 H), 7.55 (s, 1 H), 12.98 - 13.16 (m, 1 H); ESI-MS m / z [M+H]+319.1.

[0675] EXAMPLE 87: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-3- methylphenyl)-2-methylpropanamide

[0676] A TFA salt of thein Scheme D to give an orange solid (72 mg, 82%).1H NMR (400 MHz, CDCl3) δ ppm 0.80 (td, J = 3.3, 1.2 Hz, 4 H), 1.54 (s, 6 H), 2.26 (d, J = 2.0 Hz, 3 H), 2.55 - 2.73 (m, 1 H), 3.17 (d, J = 4.8 Hz, 2 H), 3.55 - 3.67 (m, 2 H), 4.15 - 4.25 (m, 2 H), 6.93 (t, J = 8.9 Hz, 1 H), 7.12 - 7.17 (m, 1 H), 7.21 (dd, J = 7.2, 2.1 Hz, 1 H), 7.25 (s, 1 H), 12.73 - 12.87 (m, 1 H); ESI-MS m / z [M+H]+305.4.

[0677] EXAMPLE 88: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluoro-5- methylphenyl)-2-methylpropanamide

[0678] A TFA salt of theScheme D to give a yellow solid (56 mg, 47%).1H NMR (400 MHz, CDCl3) δ ppm 0.79 - 0.86 (m, 4 H), 1.51 - 1.59 (m, 6 H), 2.17 - 2.29 (m, 1 H), 2.34 (s, 3 H), 2.55 - 2.74 (m, 1 H), 3.18 (d, J = 4.8 Hz, 2 H), 3.58 -3.70 (m, 2 H), 4.16 - 4.26 (m, 2 H), 6.75 (ddt, J = 9.2, 1.8, 1.0 Hz, 1 H), 6.86 (dt, J = 10.5, 1.8 Hz, 1 H), 6.98 (s, 1 H), 7.30 (s, 1 H); ESI-MS m / z [M+H]+305.3.

[0679] EXAMPLE 89: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4- methylbenzyl)cyclopropane-1-carboxamide

[0680] A TFA salt of the Scheme D to give an orange oil(73 mg, 60%).1H NMR - (m, 2 H), 0.71 - 0.76 (m, 2 H), 0.79 - 0.84 (m, 2 H), 1.21 - 1.25 (m, 2 H), 2.12 - 2.24 (m, 1 H), 2.29 (s, 3 H), 2.59 (dquin, J = 12.0, 9.4 Hz, 1 H), 2.92 (s, 2 H), 3.15 (d, J = 5.3 Hz, 2 H), 3.52 - 3.63 (m, 2 H), 4.16 - 4.26 (m, 2 H), 7.07 (d, J = 7.8 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.25 (s, 1 H), 12.27 - 12.49 (m, 1 H); ESI-MS m / z [M+H]+299.4.

[0681] EXAMPLE 90: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- fluorobenzyl)cyclopropane-1-carboxamide

[0682] A TFA salt of thein Scheme D to give a colorless oil (83 mg, 68%).1H NMR (400 MHz, CDCl3) δ ppm 0.73 - 0.75 (m, 2 H), 0.76 - 0.81 (m, 4 H), 1.14 - 1.22 (m, 2 H), 2.20 - 2.32 (m, 1 H), 2.67 (dquin, J = 12.0, 9.4 Hz, 1 H), 3.01 (s, 2 H), 3.20 (d, J = 5.0 Hz, 2 H), 3.62 - 3.75 (m, 2 H), 4.29 - 4.39 (m, 2 H), 6.97 - 7.08 (m, 2 H), 7.18 (tdd, J = 7.7, 5.4, 1.8 Hz, 1 H), 7.31 (td, J = 7.5, 1.8 Hz, 1 H), 7.46 (s, 1 H), 12.45 - 12.69 (m, 1 H); ESI-MS m / z [M+H]+303.3.

[0683] EXAMPLE 91: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- fluorobenzyl)cyclopropane-1-carboxamide O

[0684] A TFA salt of theScheme D to give an orange semi-solid (78 mg, 67%).1H NMR (400 MHz, CDCl3) δ ppm 0.60 - 0.66 (m, 2 H), 0.70 - 0.76 (m, 2 H), 0.79 - 0.84 (m, 2 H), 1.24 - 1.29 (m, 2 H), 2.18 - 2.31 (m, 1 H), 2.65 (dquin, J = 12.0, 9.4 Hz, 1 H), 2.97 (s, 2 H), 3.15 (d, J = 5.0 Hz, 2 H), 3.58 - 3.70 (m, 2 H), 4.22 - 4.34(m, 2 H), 6.84 - 6.91 (m, 1 H), 7.02 - 7.12 (m, 2 H), 7.22 (td, J = 7.9, 6.0 Hz, 1 H), 7.52 (s, 1 H), 12.71 - 12.86 (m, 1 H); ESI-MS m / z [M+H]+303.3.

[0685] The compounds of EXAMPLES 92 to 97 were prepared as shown in Scheme E. Scheme E

[0686] Reaction conditions: To a vial with a stir bar were added carboxylic acid (0.1 – 0.25 mmol, 1.0 eq), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine (1.0 eq), HATU (1.2 eq) and triethylamine (4.0 eq) in DMF (2 mL). The reaction mixture was allowed to stir at room temperature for 2 – 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0687] EXAMPLE 92: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,4-difluorophenyl)-2,2- difluoroacetamide

[0688] A TFA salt of thein Scheme E to give a clear oil (4 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.89 - 1.07 (m, 4 H), 2.31 - 2.46 (m, 1 H), 2.54 - 2.69 (m, 1 H), 3.39 (s, 2 H), 4.12 (q, J = 9.5 Hz, 2 H), 4.19 - 4.32 (m, 2 H), 7.40 - 7.48 (m, 2 H), 7.56 (t, J = 9.2 Hz, 1 H).

[0689] EXAMPLE 93: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(5-fluoro-2- methylphenyl)acetamide

[0690] A TFA salt of the titleas in Scheme E to give a clear oil (15 mg).1H NMR (400 MHz CD3OD) δ ppm 0.92 - 1.10 (m, 4 H), 2.37 (s, 4 H), 2.49 - 2.70 (m, 1 H), 3.41 (s, 2 H), 4.13 (q, J = 9.0 Hz, 2 H), 4.28 (br s, 2 H), 7.17 (td, J = 8.3, 2.9 Hz, 1 H), 7.26 - 7.35 (m, 2 H); ESI-MS m / z [M+H]+313.3.

[0691] EXAMPLE 94: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-fluoro-3- methylphenyl)acetamide

[0692] A TFA salt of the in Scheme E to give a yellow- orange oil (1 mg).1H NMR- 1.07 (m, 4 H), 2.33 (d, J = 1.9 Hz, 3 H), 2.53 - 2.68 (m, 1 H), 3.35 - 3.42 (m, 2 H), 4.10 (q, J = 9.4 Hz, 2 H), 4.18 - 4.30 (m, 2 H), 7.17 (t, J = 9.0 Hz, 1 H), 7.42 - 7.46 (m, 1 H), 7.50 (d, J = 6.9 Hz, 1 H); ESI-MS m / z [M+H]+313.3.

[0693] EXAMPLE 95: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-fluoro-2- methylphenyl)acetamide

[0694] A TFA salt of the in Scheme E to give a yellow-orange semisolid (11 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.92 - 1.10 (m, 4 H), 2.42 (t, J = 2.0 Hz, 3 H), 2.52 - 2.70 (m, 1 H), 3.41 (s, 2 H), 4.13 (q, J = 9.5 Hz, 2 H), 4.22 - 4.33 (m, 2 H), 7.01 - 7.10 (m, 2 H), 7.56 (dd, J = 8.6, 5.7 Hz, 1 H); ESI-MS m / z [M+H]+313.3.

[0695] EXAMPLE 96: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-fluoro-2- methylphenyl)acetamide

[0696] A TFA salt of thein Scheme E to give a clear oil (9 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.93 - 1.09 (m, 4 H), 2.31 (q, J = 1.9 Hz, 3 H), 2.35 - 2.48 (m, 1 H), 2.54 - 2.70 (m, 1 H), 3.41 (s, 2 H), 4.13 (q, J = 9.6 Hz, 2 H), 4.22 - 4.33 (m, 2 H), 7.22 - 7.41 (m, 3 H); ESI-MS m / z [M+H]+313.3.

[0697] EXAMPLE 97: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-fluoro-5- methylphenyl)acetamide

[0698] A TFA salt of the title in Scheme E to give a light yellow solid (10 mg).1H NMR (400 MHz, CD3OD) δ ppm 0.88 - 1.07 (m, 4 H), 2.35 - 2.44 (m, 3 H), 2.50 - 2.68 (m, 1 H), 3.38 (s, 2 H), 4.09 (q, J = 9.2 Hz, 2 H), 4.25 (br s, 2 H), 7.14 (d, J = 9.5 Hz, 2 H), 7.25 (s, 1 H); ESI-MS m / z [M+H]+313.3.

[0699] EXAMPLE 98: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,5-difluorophenyl)-2,2- difluoroacetamide

[0700] In a 100 mL flask, 2- acid (0.856 g, 4.11mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (0.819 g, 4.11 mmol), HATU (1.564 g, 4.11 mmol), and DIPEA (3.59 mL, 20.6 mmol) were added to DMF (20 mL). The reaction mixture was set to stir at room temperature for several hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were filtered through NaSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10- 100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA). Fractions were collected and concentrated. The product was taken into solution and filtered through a basic cartridge (Agilent Stratospheres PL-HCO3 MP SPE). The filtrate was evaporated to give the title compound as a tan solid (0.374 g, 29%).1H NMR (400 MHz, CD3OD) δ ppm 0.68 - 0.83 (m, 4 H), 2.09 (quin, J = 7.1 Hz, 2 H), 2.58 (s, 2 H), 3.26 (t, J = 7.1 Hz, 3 H), 3.37 (s, 2 H), 7.14 - 7.21 (m, 1 H), 7.27 - 7.35 (m, 2 H); ESI-MS m / z [M+H]+317.3.

[0701] EXAMPLE 99: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2- phenylacetamide

[0702] To a suspension of 1-1-amine dihydrochloride (13.13 g, 62.6 mmol) in EtOAc (114 mL) was added triethylamine (33.3 mL, 239 mmol). Themixture was stirred vigorously for 4 h at ambient temperature. The resulting precipitate was filtered off and washed with EtOAc (40 mL). The mother liquor and washes were treated with 2,2-difluoro-2-phenylacetic acid (10.0 g, 56.9 mmol) and HATU (25.7 g, 65.5 mmol) and stirred at room temperature for 2 h. The resulting light brown suspension was filtered and solvents were removed in vacuo. The crude residue was dissolved in EtOAc (25 mL) and purified by flash silica column chromatography (ISCO, 330 g RediSep® gold column). The resulting yellow product (11 g) was dried under vacuum for 16 h. The solid was suspended in water (60 mL) and granulated for 2 d with periodic shaking and sonication to keep the suspension uniform. The mixture was cooled to 0°C, and the solid was filtered, washed with cold (0°C) water (20 mL) and dried under the flow of nitrogen to afford the title compound (4.80 g, 30%) as a white solid. The product contained 0.08 mol % of TMU and was combined with an additional batch of material prepared in the same manner for further purification. A suspension of crude N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-phenylacetamide (22 g, 78 mmol) in water (120 mL) was stirred vigorously for 3 days. The resulting fine suspension was filtered, washed with water (40 mL) and dried in the flow of nitrogen to afford the title compound (11.12 g, 50%) as an off-white solid (contains 0.06 mol% of TMU).1H NMR (400 MHz, DMSO-d6) δ ppm 0.68 (s, 4 H), 1.98 (quin, J = 6.9 Hz, 2 H), 2.51 (s, 2 H), 3.15 (t, J = 6.9 Hz, 4 H), 7.56 - 7.66 (m, 3 H), 7.66 - 7.71 (m, 2 H), 9.07 (s, 1 H); ESI-MS m / z [M+H]+281.3.

[0703] EXAMPLE 100: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-cyanophenyl)-2,2- difluoroacetamide

[0704] To a solution of 2-acid (60.3 mg, 0.306 mmol), 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (60.9 mg, 0.306 mmol) and HATU (140 mg, 0.367 mmol) in DMA (612 µL) was added DIPEA (213 µL, 1.224 mmol), and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was diluted with MeOH (1 mL) and purified by preparative HPLC (Phenomenex Gemini® NX- C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 20-60% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Fractions containing pure product were lyophilized to afford the title compound as a white solid (51 mg, 55%).

[0705] EXAMPLE 101: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3- methoxyphenyl)acetamide

[0706] A mixture of 2,2- acid (77 mg, 0.38 mmol) and 1-(azetidin-1-ylmethyl)(76 mg, 0.38 mmol) in DMA (1.27 mL) was treated with DIPEA (265 µL, 1.52 mmol) and HATU (173 mg, 0.456 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®) filter, rinsing with MeOH. The filtrate was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) over two injections using a gradient of 10-50% ACN (w / 0.035% TFA) in water (w / 0.05% TFA). Fractions containing clean desired product were evaporated. The residue was taken up in MeOH and passed through a basic cartridge (Agilent Stratospheres PL-HCO3MP SPE). The filtrate was evaporated and the residue was lyophilized to afford the title compound as a white semisolid (48.5 mg, 41%).1H NMR (400 MHz, CD3OD) δ ppm 0.68 - 0.82 (m, 4 H), 2.00 - 2.14 (m, 2 H), 2.58 (s, 2 H), 3.23 (t, J = 7.1 Hz, 4 H), 3.85 (s, 3 H), 7.05 - 7.11 (m, 1 H), 7.15 - 7.21 (m, 2 H), 7.36 - 7.43 (m, 1 H); ESI-MS m / z [M+H]+311.20.

[0707] EXAMPLE 102: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4- methoxyphenyl)acetamide

[0708] A mixture of 2,2-acid (77 mg, 0.38 mmol) and 1-(azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (76 mg, 0.38 mmol) in DMA (1.27 mL) was treated with DIPEA (265 µL, 1.52 mmol) and HATU (173 mg, 0.456 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®) filter, rinsing with MeOH. The filtrate was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) over two injections using a gradient of 10-50% ACN (w / 0.035% TFA) in water (w / 0.05% TFA). Fractions containing clean desired product were evaporated. The residue was taken up in MeOH and passed through a basic cartridge (Agilent Stratospheres PL-HCO3MP SPE). The filtrate was evaporated and the residue was lyophilized to afford thetitle compound as a white semisolid (40.9 mg, 35%).1H NMR (400 MHz, CD3OD) δ ppm 0.68 - 0.80 (m, 2 H), 2.02 - 2.14 (m, 1 H), 2.59 (s, 1 H), 3.25 (t, J = 7.1 Hz, 2 H), 3.85 (s, 2 H), 7.01 (d, J = 9.0 Hz, 1 H), 7.54 (d, J = 9.0 Hz, 1 H); ESI-MS m / z [M+H]+311.20.

[0709] EXAMPLE 103: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3- fluorophenyl)propanamide

[0710] To a solution of 2- acid (1.024 g, 5.50 mmol), 1-(azetidin-1-ylmethyl) (1.095 g, 5.50 mmol), and HATU (2.510 g, 6.60 mmol) in DMA (11.00 mL) was added DIPEA (3.83 mL, 22.00 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 20-60% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10). Pure product-containing fractions were lyophilized to afford the title compound as a white solid (1.20 g, 74%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.50 - 0.64 (m, 4 H), 1.77 (d, J = 22.8 Hz, 3 H), 1.90 (quin, J = 6.9 Hz, 2 H), 2.35 - 2.46 (m, 2 H), 2.53 - 2.65 (m, 1 H), 3.06 (t, J = 6.9 Hz, 4 H), 7.17 - 7.24 (m, 1 H), 7.30 - 7.37 (m, 2 H), 7.40 - 7.50 (m, 1 H), 8.29 - 8.37 (m, 1 H); ESI-MS m / z [M+H]+295.0.

[0711] EXAMPLE 104: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3- fluorophenyl)propanamide

[0712] Racemic N-(1-2-fluoro-2-(3- fluorophenyl)propanamide (EXAMPLE 103) (999 mg, 3.39 mmol) was purified by SFC (ChiralPak AD, 5 µm, ID 30 mm x 250 mm) using 15% isopropanol in CO2. The first peak was collected and arbitrarily assigned as having (S) stereochemistry to give a white solid (390.3 mg, 39%, > 99% ee). ESI-MS m / z [M+H]+295.0.

[0713] EXAMPLE 105: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3- fluorophenyl)propanamide

[0714] Racemic N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3- fluorophenyl)propanamide (EXAMPLE 103) (999 mg, 3.39 mmol) was purified by SFC (ChiralPak AD, 5 µm, ID 30 mm x 250 mm) using 15% isopropanol in CO2. The second peak was collected and arbitrarily assigned as having (R) stereochemistry to give a white solid (390.1 mg, 39%, > 99% ee). ESI-MS m / z [M+H]+295.0.

[0715] The compounds of EXAMPLES 106 to 130 were prepared as shown in Scheme F.

[0716] a were – , 1- ylmethyl)cyclopropan-1-amine dihydrochloride (1.0 eq) and HATU (1.2 – 1.3 eq) in DMA (0.1 – 0.5 M). The mixture was treated with DIPEA (4.0 – 5.0 eq) and stirred at room temperature for 30 minutes – 18 h.

[0717] Purification conditions F1: The mixture was diluted with water (2.5 mL) and extracted with EtOAc (2 x 1 mL). The combined organic extracts were concentrated in vacuo. The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-70% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0718] Purification conditions F2: The mixture was diluted with water (3 mL), and the aqueous layer was decanted. The residue was washed with water (2 x 2 mL) and dried under a stream of nitrogen. The residue was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-90% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0719] Purification conditions F3: The mixture was diluted with water (3 mL) and extracted with EtOAc (2 x 1 mL). The combined organic extracts were concentrated in vacuo. The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-40% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0720] Purification conditions F4: The mixture was diluted with MeOH (1 mL), filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®) filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 20- 60% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mMNH4HCO3, pH 9.5-10). The pure fractions were combined and partitioned with EtOAc (50 mL). The layers were separated, and the aqueous phase was washed with EtOAc (2 x 25 mL). The organic extracts were combined, washed with brine (25 mL), dried over Na2SO4, filtered, rinsed with EtOAc, concentrated via rotary evaporation at 40°C, and dried in vacuo.

[0721] Purification conditions F5: The mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 20-60% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0722] Purification conditions F6: The mixture was diluted with brine (20 mL) and extracted with EtOAc (3 x 7 mL). The organic extracts were combined and washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-40% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0723] Purification conditions F7: The mixture was diluted with MeOH (1 mL), filtered through a hydrophilic PTFE 0.45 µm filter (Millipore®) filter, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10- 65% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0724] EXAMPLE 106: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4- chlorobenzo[d]isoxazol-3-yl)-2-methylpropanamide

[0725] A TFA salt of thein Scheme F using purification conditions F1 (2.5 mg). ESI-MS m / z [M+H]+348.1.

[0726] EXAMPLE 107: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(7- chlorobenzo[d]isoxazol-3-yl)-2-methylpropanamide

[0727] A TFA salt of theScheme F using purification conditions F1 (1.9 mg). ESI-MS m / z [M+H]+348.1.

[0728] EXAMPLE 108: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5,6- dimethylbenzo[d]isoxazol-3-yl)-2-methylpropanamide

[0729] A TFA salt of the Scheme F using purification conditions F1 (5.1 mg).1H0.56 - 0.65 (m, 2 H), 0.80 - 0.88 (m, 2 H), 1.63 (s, 6 H), 2.10 - 2.22 (m, 1 H), 2.32 (s, 3 H), 2.36 - 2.45 (m, 4 H), 3.26 (s, 2 H), 3.88 - 4.13 (m, 4 H), 7.42 (s, 1 H), 7.52 (s, 1 H), 8.09 (s, 1 H), 9.24 - 9.43 (m, 1 H); ESI-MS m / z [M+H]+342.2.

[0730] EXAMPLE 109: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-2- fluoropropanamide

[0731] The title compound purification conditions F2 togive a clear oil (10 mg, 26%).1H NMR (400 MHz, CD3OD) δ ppm 0.75 - 0.81 (m, 1 H), 0.90 (dd, J = 10.4, 4.7 Hz, 1 H), 0.93 - 1.01 (m, 3 H), 1.86 (d, J = 23.1 Hz, 3 H), 2.25 - 2.36 (m, 1 H), 2.49 - 2.63 (m, 1 H), 3.32 (d, J = 1.4 Hz, 2 H), 3.94 - 4.09 (m, 2 H), 4.13 - 4.24 (m, 2 H), 7.35 - 7.45 (m, 3 H), 7.51 - 7.55 (m, 1 H), 8.79 (br s, 1 H); ESI-MS m / z [M+H]+311.2.

[0732] EXAMPLE 110: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-2,2- difluoroacetamide

[0733] A TFA salt of thein Scheme F using purification conditions F3 to give a tan oil (3 mg, 6%). ESI-MS m / z [M+H]+315.1.

[0734] EXAMPLE 111: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(o- tolyl)acetamide

[0735] A TFA salt of the title compound was prepared as in Scheme F using purification conditions F3 to give a tan oil (3 mg, 6%).1H NMR (400 MHz, CDCl3) δ ppm 0.88 - 1.03 (m, 4 H), 2.29 - 2.39 (m, 1 H), 2.45 (t, J = 2.1 Hz, 3 H), 2.67 - 2.84 (m, 1 H), 3.24 (d, J = 3.1 Hz, 2 H), 3.70 - 3.84 (m, 2 H), 4.35 - 4.47 (m, 2 H), 7.21 - 7.28 (m, 2 H), 7.54 - 7.58 (m, 1 H), 8.87 (br s, 1 H), 13.90 (br s, 1 H); ESI-MS m / z [M+H]+295.2.

[0736] EXAMPLE 112: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2,2- difluoroacetamide

[0737] A TFA salt of the in Scheme F using purificationconditions F3 to give a tan oil mg, CDCl3) δ ppm 0.85 - 1.01 (m, 4 H), 2.25 - 2.41 (m, 1 H), 2.70 - 2.82 (m, 1 H), 3.21 (br d, J = 3.0 Hz, 2 H), 3.76 (br dd, J = 9.7, 4.4 Hz, 2 H), 4.41 (br s, 2 H), 7.44 (m, J = 8.8 Hz, 2 H), 7.59 (m, J = 8.8 Hz, 2 H), 9.11 (br s, 1 H), 13.87 (br s, 1 H); ESI-MS m / z [M+H]+315.1.

[0738] EXAMPLE 113: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4- (difluoromethyl)phenyl)-2,2-difluoroacetamide

[0739] The title compoundpurification conditions F4 to give a light yellow oil (44 mg, 59%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.60 (s, 4 H), 1.84 - 1.97 (m, 2 H), 2.43 (s, 2 H), 3.07 (t, J = 6.9 Hz, 4 H), 7.70 - 7.74 (m, 2 H), 7.74 - 7.80 (m, 2 H);19F NMR (376 MHz, DMSO-d6) δ ppm -110.84 (br d, J = 55.9 Hz, 2 F), -101.10 (s, 2 F); ESI-MS m / z [M+H]+331.1.

[0740] EXAMPLE 114: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5-chloropyridin-2-yl)- 2,2-difluoroacetamide

[0741] The title compoundpurification conditions F5 to give a white solid (52.9 mg, 70%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.62 (s, 4 H), 1.92(quin, J = 6.9 Hz, 2 H), 2.45 (s, 2 H), 3.11 (t, J = 6.9 Hz, 4 H), 7.77 - 7.85 (m, 1 H), 8.15 (dd, J = 8.4, 2.4 Hz, 1 H), 8.73 (d, J = 2.3 Hz, 1 H), 9.02 (s, 1 H); ESI-MS m / z [M+H]+316.1.

[0742] EXAMPLE 115: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(4- fluorophenyl)propanamide

[0743] A TFA salt of the in Scheme F using purificationconditions F6 to give a white (400 MHz, DMSO-d6) δ ppm 0.51 - 0.62 (m, 1 H), 0.69 - 0.89 (m, 4 H), 1.75 (d, J = 24.0 Hz, 4 H), 2.08 (ddd, J = 9.1, 6.8, 4.4 Hz, 1 H), 2.25 - 2.41 (m, 1 H), 3.07 - 3.20 (m, 2 H), 3.78 - 4.04 (m, 5 H), 7.09 - 7.24 (m, 3 H), 7.38 - 7.46 (m, 2 H), 8.67 (d, J = 2.13 Hz, 1 H), 9.40 (br s, 1 H); ESI-MS m / z [M+H]+295.3.

[0744] EXAMPLE 116: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(2- fluorophenyl)acetamide

[0745] The title compoundF using purification conditions F5 to give a white solid (155 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (s, 4 H), 1.82 - 1.90 (m, 2 H), 2.40 - 2.41 (m, 2 H), 3.06 (t, J = 6.9 Hz, 4 H), 7.28 (t, J = 8.5 Hz, 2 H), 7.54 (s, 1 H), 7.62 (t, J = 7.7 Hz, 1 H), 8.97 (s, 1 H); ESI-MS m / z [M+H]+299.2.

[0746] EXAMPLE 117: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4- fluorophenyl)acetamide

[0747] The title compoundusing purification conditions F5 to give a white solid (180 mg, 50%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.53 (s, 4 H), 1.84 (quin, J = 6.9 Hz, 2 H), 2.36 (s, 2 H), 3.01 (t, J = 6.9 Hz, 4 H), 7.29 (t, J = 8.3 Hz, 2 H), 7.55 - 7.67 (m, 2 H), 8.94 (s, 1 H); ESI-MS m / z [M+H]+299.2.

[0748] EXAMPLE 118: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(p- tolyl)acetamide

[0749] The title compound sing purification conditions F5 to give a white solid (75 mg, 63%). ( 00 z, SO-d6) δ ppm 0.49 - 0.57 (m, 4 H), 1.84 (quin, J = 6.9 Hz, 2 H), 2.28 (s, 3 H), 2.36 (s, 2 H), 3.02 (t, J = 6.9 Hz, 4 H), 7.24 (m, J = 8.0 Hz, 2 H), 7.42 (m, J = 8.2 Hz, 2 H), 8.87 (s, 1 H); ESI-MS m / z [M+H]+295.3.

[0750] EXAMPLE 119: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3- fluorophenyl)acetamide

[0751] The title compound using purification conditions F5 togive a white solid (65.2 mg, d6) δ ppm 0.49 - 0.60 (m, 4 H), 1.84 (quin, J = 6.9 Hz, 2 H), 2.35 (s, 2 H), 3.01 (t, J = 6.9 Hz, 4 H), 7.34 (td, J = 8.6, 2.3 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 1 H), 7.43 - 7.54 (m, 2 H), 8.97 (s, 1 H); ESI-MS m / z [M+H]+299.2.

[0752] EXAMPLE 120: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-4- fluorophenyl)-2,2-difluoroacetamide

[0753] The title compoundpurification conditions F5 to give a white solid (36 mg, 39%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.49 - 0.61 (m, 4 H), 1.85 (quin, J = 6.9 Hz, 2 H), 2.35 (s, 2 H), 3.02 (t, J = 6.9 Hz, 4 H), 7.52 (t, J = 8.9 Hz, 1 H), 7.60 (ddd, J = 8.8, 4.6, 2.3 Hz, 1 H), 7.85 (dd, J = 7.0, 2.2 Hz, 1 H), 8.99 (s, 1 H); ESI-MS m / z [M+H]+333.2.

[0754] EXAMPLE 121: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(m- tolyl)propanamide

[0755] The title compoundpurification conditions F5 to give a white solid (58 mg, 36%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.41 - 0.56 (m, 4 H),1.67 (d, J = 24.3 Hz, 3 H), 1.82 (quin, J = 6.9 Hz, 2 H), 2.25 (s, 3 H), 2.34 (s, 2 H), 2.99 (t, J = 6.9 Hz, 4 H), 7.06 - 7.11 (m, 1 H), 7.16 - 7.21 (m, 2 H), 7.21 - 7.25 (m, 1 H), 8.09 - 8.19 (m, 1 H); ESI-MS m / z [M+H]+291.3.

[0756] EXAMPLE 122: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(2- fluorophenyl)propanamide

[0757] The title compound F using purification conditions F5 togive a white solid (99 mg, 61%) d6) δ ppm 0.41 - 0.63 (m, 4 H), 1.76 (d, J = 22.7 Hz, 3 H), 1.86 (quin, J = 6.9 Hz, 2 H), 2.34 (d, J = 12.4 Hz, 1 H), 2.47 (d, J = 11.9 Hz, 1 H), 3.06 (t, J = 6.9 Hz, 4 H), 7.09 - 7.20 (m, 2 H), 7.34 - 7.43 (m, 1 H), 7.47 (tt, J = 8.0, 1.6 Hz, 1 H), 8.18 (d, J = 1.8 Hz, 1 H); ESI-MS m / z [M+H]+295.3.

[0758] EXAMPLE 123: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)-2- fluoropropanamide

[0759] The title compoundF using purification conditions F5 to give a white solid (85 mg, 50%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 - 0.62 (m, 4 H), 1.78 (d, J = 23.0 Hz, 3 H), 1.86 (quin, J = 6.9 Hz, 2 H), 2.37 (d, J = 12.7 Hz, 1 H), 2.44 (d, J = 12.7 Hz, 1 H), 2.99 - 3.10 (m, 4 H), 7.27 - 7.41 (m, 3 H), 7.50 - 7.57 (m, 1 H), 8.11 (br s, 1 H); ESI-MS m / z [M+H]+311.2.

[0760] EXAMPLE 124: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,4-difluorophenyl)-2- fluoropropanamide

[0761] The title compoundusing purification conditions F5 to give a white solid (32 mg, 41%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.47 - 0.58 (m, 4 H), 1.76 (d, J = 22.7 Hz, 3 H), 1.85 (quin, J = 6.9 Hz, 2 H), 2.33 (d, J = 12.8 Hz, 1 H), 2.46 (d, J = 12.8 Hz, 1 H), 3.04 (t, J = 6.9 Hz, 4 H), 6.99 - 7.10 (m, 1 H), 7.19 (ddd, J = 11.5, 9.2, 2.4 Hz, 1 H), 7.50 - 7.57 (m, 1 H), 8.21 (br d, J = 1.5 Hz, 1 H); ESI-MS m / z [M+H]+313.3.

[0762] EXAMPLE 125: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-cyanophenyl)-2,2- difluoroacetamide

[0763] The title compound purification conditions F5 to give a white solid (35 mg,d6) δ ppm 0.60 (s, 4 H), 1.91 (quin, J = 6.9 Hz, 2 H), 2.41 (s, 2 H), 3.07 (t, J = 6.9 Hz, 4 H), 7.81 (m, J = 8.4 Hz, 2 H), 8.02 (m, J = 8.3 Hz, 2 H), 9.12 (br s, 1 H); ESI-MS m / z [M+H]+306.3.

[0764] EXAMPLE 126: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,3,3,3-tetrafluoro-2-(m- tolyl)propanamide

[0765] The title compound purification conditions F5 togive a colorless oil (26 mg, 19%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.43 - 0.63 (m, 4 H), 1.81 (quin, J = 6.9 Hz, 2 H), 2.29 (s, 3 H), 2.37 (s, 2 H), 2.98 (t, J = 6.9 Hz, 4 H), 7.26 - 7.30 (m, 1 H), 7.30 - 7.36 (m, 1 H), 7.36 - 7.41 (m, 2 H), 8.83 (s, 1 H); ESI-MS m / z [M+H]+345.3.

[0766] EXAMPLE 127: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,3,3,3-tetrafluoro-2-(4- fluorophenyl)propanamide

[0767] The title compoundusing purification conditions F5 to give a white solid (40 mg, 26%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.44 - 0.61 (m, 4 H), 1.81 (quin, J = 6.9 Hz, 2 H), 2.37 (s, 2 H), 2.98 (t, J = 6.9 Hz, 4 H), 7.26 - 7.35 (m, 2 H), 7.61 - 7.69 (m, 2 H), 8.91 (s, 1 H); ESI-MS m / z [M+H]+349.3.

[0768] EXAMPLE 128: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(6- methylpyridin-2-yl)acetamide

[0769] The title compound was prepared as in Scheme F using purification conditions F7 to give a white solid (11.1 mg, 7.5%).1H NMR (400 MHz, CD3OD) δ ppm 0.70 - 0.86 (m, 4 H), 2.10 (quin, J = 7.2 Hz, 2 H), 2.52 (s, 3 H), 2.62 (s, 2 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.82 (t, J = 7.8 Hz, 1 H); ESI-MS m / z [M+H]+296.25.

[0770] EXAMPLE 129: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,4-difluorophenyl)-2- fluoropropanamide

[0771] The title compound using purification conditions F5 togive a white solid (0.159 g, δ ppm 0.59 - 0.73 (m, 3 H), 0.75 - 0.89 (m, 1 H), 1.72 - 1.88 (m, 3 H), 1.98 - 2.13 (m, 2 H), 2.40 - 2.52 (m, 2 H), 3.10 - 3.21 (m, 4 H), 6.67 - 6.94 (m, 1 H), 6.99 - 7.18 (m, 1 H), 7.18 - 7.33 (m, 1 H), 7.33 - 7.47 (m, 1 H); ESI-MS m / z [M+H]+313.20.

[0772] EXAMPLE 130: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,5-difluorophenyl)-2- fluoropropanamide

[0773] The title compoundusing purification conditions F5 to give a white solid (0.204 g, 63%).1H NMR (400 MHz, CDCl3) δ ppm 0.57 - 0.87 (m, 4 H), 1.69 - 1.93 (m, 3 H), 1.97 - 2.11 (m, 2 H), 2.40 - 2.58 (m, 2 H), 3.08 - 3.25 (m, 4 H), 6.66 - 6.92 (m, 2 H), 7.02 - 7.17 (m, 2 H); ESI-MS m / z [M+H]+313.25.

[0774] EXAMPLE 131: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2- fluoropropanamide

[0775] To a solution of 2-acid (0.905 g, 4.47 mmol), 1- (azetidin-1-ylmethyl)cyclopropan-1-amine dihydrochloride (0.907 g, 4.56 mmol), and HATU (2.038 g, 5.36 mmol) in DMA (8.93 mL) was added DIPEA (3.12 mL, 17.9 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was dilutedwith methanol, filtered, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10) over multiple injections. The combined fractions were frozen and lyophilized to give the title compound as a white solid (0.82 g, 59%).1H NMR (400 MHz, CDCl3) δ ppm 0.63 - 0.81 (m, 4 H), 1.68 - 1.91 (m, 3 H), 1.95 - 2.17 (m, 2 H), 2.40 - 2.60 (m, 2 H), 3.16 (t, J = 7.0 Hz, 4 H), 6.72 - 6.93 (m, 1 H), 7.29 - 7.42 (m, 2 H), 7.42 - 7.50 (m, 2 H).

[0776] EXAMPLE 132: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2- fluoropropanamide

[0777] Racemic N-(1- (4-chlorophenyl)-2-fluoropropanamide g, was purified by SFC. The first peak was collected and arbitrarily assigned as having (S) stereochemistry to give a white solid (367 mg, 45%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.44 - 0.69 (m, 4 H), 1.62 - 1.82 (m, 3 H), 1.82 - 1.97 (m, 2 H), 2.40 (d, J = 1.3 Hz, 2 H), 3.05 (t, J = 6.9 Hz, 4 H), 7.43 - 7.48 (m, 2 H), 7.48 - 7.54 (m, 2 H), 8.25 - 8.37 (m, 1 H); ESI-MS m / z [M+H]+310.9.

[0778] EXAMPLE 133: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2- fluoropropanamide

[0779] Racemic N-(1-(4-chlorophenyl)-2- fluoropropanamide (EXAMPLE 131) (0.82 g, 2.64 mmol) was purified by SFC. The second peak was collected and arbitrarily assigned as having (R) stereochemistry to give a white solid (346 mg, 42%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 - 0.67 (m, 4 H), 1.67 - 1.82 (m, 3 H), 1.89 (quin, J = 6.9 Hz, 2 H), 2.35 - 2.45 (m, 2 H), 2.97 - 3.10 (m, 4 H), 7.42 - 7.48 (m, 2 H), 7.48 - 7.55 (m, 2 H), 8.23 - 8.37 (m, 1 H); ESI-MS m / z [M+H]+310.9.

[0780] EXAMPLE 134: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2- phenylpropanamide

[0781] To a solution of 2-fluor d (0.975 g, 5.80 mmol), 1-(azetidin- 1-ylmethyl)cyclopropan-1-amine dihydrochloride (1.178 g, 5.91 mmol), and HATU (2.65 g, 6.96 mmol) in DMA (11.60 mL) was added DIPEA (4.05 mL, 23.2 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with methanol, filtered, and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10) over multiple injections. The combined fractions were frozen and lyophilized to give the title compound as a white solid (999 mg, 62%).1H NMR (400 MHz, CDCl3) δ ppm 0.56 - 0.87 (m, 4 H), 1.67 - 1.92 (m, 3 H), 1.93 - 2.11 (m, 2 H), 2.39 - 2.49 (m, 1 H), 2.51 - 2.62 (m, 1 H), 3.05 - 3.23 (m, 4 H), 6.75 - 6.89 (m, 1 H), 7.22 - 7.60 (m, 5 H).

[0782] EXAMPLE 135: (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2- phenylpropanamide

[0783] Racemic N-(1--2-fluoro-2-phenylpropanamide (999 mg, 3.61 mmol) was purified by SFC. The first peak was collected and arbitrarily assigned as having (S) stereochemistry to give a white solid (429 mg, 43%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.44 - 0.65 (m, 4 H), 1.69 - 1.81 (m, 3 H), 1.83 - 1.96 (m, 2 H), 2.34 - 2.47 (m, 2 H), 3.05 (t, J = 6.9 Hz, 4 H), 7.28 - 7.43 (m, 3 H), 7.44 - 7.54 (m, 2 H), 8.19 - 8.35 (m, 1 H); ESI-MS m / z [M+H]+277.0.

[0784] EXAMPLE 136: (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2- phenylpropanamide

[0785] Racemic N-(1--2-fluoro-2-phenylpropanamide (999 mg, 3.61 mmol) was purified by SFC. The second peak was collected and arbitrarily assigned as having (R) stereochemistry to give a white solid (438 mg, 44%).1H NMR (400 MHz, DMSO-d6) δ ppm 0.45 - 0.64 (m, 4 H), 1.64 - 1.80 (m, 3 H), 1.89 (quin, J = 6.9 Hz, 2H), 2.34 - 2.48 (m, 2 H), 3.06 (t, J = 6.9 Hz, 4 H), 7.27 - 7.44 (m, 3 H), 7.44 - 7.54 (m, 2 H), 8.20 - 8.33 (m, 1 H); ESI-MS m / z [M+H]+277.0.

[0786] The compounds of EXAMPLES 137 to 142 were prepared as shown in Scheme G. O HATU, DIPEA O N N R OH H2N DMF R N

[0787] – ylmethyl)cyclopropan-1-amine dihydrochloride (1.2 eq) were dissolved / suspended in ACN:DMF (1:1 to 4:1, 0.2 M – 0.4 M) at room temperature, followed by addition of HATU (1.2 eq). After 10 minutes, DIPEA (4.0 eq) was added at room temperature, and the mixture was stirred overnight.

[0788] Purification conditions G1: The mixture was diluted with ACN and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0789] Purification conditions G2: The mixture was diluted with ACN and purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0790] EXAMPLE 137: trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2- phenylcyclopropane-1-carboxamide

[0791] The title compoundusing purification conditions G1 to give a white solid (28 mg, 65%).1H NMR (400 MHz, CD3OD) δ ppm 0.66 - 0.74 (m, 4 H), 1.14 - 1.25 (m, 1 H), 1.42 - 1.51 (m, 1 H), 1.76 - 1.85 (m, 1 H), 2.08 - 2.18 (m, 2 H), 2.30 - 2.41 (m, 1 H), 2.54 - 2.62 (m, 1 H), 2.62 - 2.76 (m, 1 H), 3.35 (t, J = 7.2 Hz, 4 H), 7.05 - 7.11 (m, 2 H), 7.11 - 7.18 (m, 1 H), 7.20 - 7.31 (m, 2 H); ESI-MS m / z [M+H]+271.2.

[0792] EXAMPLE 138: cis-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2- phenylcyclopropane-1-carboxamide

[0793] The title compound w using purification conditions G1 to give a white solid (11.0 mg, 6.6%). H NMR (400 MHz, CD3OD) δ ppm 0.16 - 0.29 (m, 1 H), 0.41 - 0.52 (m, 2 H), 0.52 - 0.62 (m, 1 H), 1.15 - 1.25 (m, 1 H), 1.65 (d, J = 7.2 Hz, 1 H), 1.96 - 2.12 (m, 3 H), 2.27 - 2.36 (m, 1 H), 2.40 - 2.50 (m, 1 H), 2.50 - 2.60 (m, 1 H), 3.16 - 3.29 (m, 4 H), 7.07 - 7.36 (m, 4 H); ESI-MS m / z [M+H]+271.1.

[0794] EXAMPLE 139: trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-3- phenylcyclopropane-1-carboxamide

[0795] The title compound using purification conditions G1to give a white solid (26 mg, 17%).1H NMR (400 MHz, CD3OD) δ ppm 0.72 - 0.78 (m, 4 H), 2.08 - 2.20 (m, 2 H), 2.51 - 2.60 (m, 1 H), 2.68 - 2.86 (m, 2 H), 3.33 - 3.40 (m, 4 H), 3.41 - 3.51 (m, 1 H), 7.22 - 7.40 (m, 5 H); ESI-MS m / z [M+H]+307.3.

[0796] EXAMPLE 140: trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-dimethyl-3- phenylcyclopropane-1-carboxamide

[0797] The title compoundusing purification conditions G1 to give a colorless film (45 mg, 29%).1H NMR (400 MHz, CD3OD) δ ppm 0.72 - 0.83 (m, 4 H), 0.86 (s, 3 H), 1.31 (s, 3 H), 1.86 - 1.95 (m, 1 H), 2.23 (t, J = 7.4 Hz, 1 H), 2.58 - 2.64 (m, 1 H), 2.70 - 2.76 (m, 1 H), 2.84 - 2.95 (m, 1 H), 3.50 - 3.63 (m, 3 H), 7.10 - 7.22 (m, 1 H), 7.22 - 7.31 (m, 1 H).

[0798] EXAMPLE 141: trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2- chlorophenyl)cyclopropane-1-carboxamide

[0799] A TFA salt of the title compound was prepared as in Scheme G using purification conditions G2 to give a colorless film (9 mg, 5%).1H NMR (400 MHz, CD3OD) δ ppm 0.86 - 1.07 (m, 4 H), 1.27 - 1.42 (m, 1 H), 1.51 - 1.61 (m, 1 H), 1.65 - 1.75 (m, 1 H), 2.30 - 2.47 (m, 1 H), 2.54 - 2.73 (m, 2 H), 3.34 - 3.41 (m, 2 H), 4.07 - 4.22 (m, 2 H), 4.23 - 4.41 (m, 2 H), 7.03 - 7.13 (m, 1 H), 7.16 - 7.26 (m, 2 H), 7.33 - 7.41 (m, 1 H), 8.60 - 8.73 (m, 1 H); ESI- MS m / z [M+H]+305.3.

[0800] EXAMPLE 142: (1R,2R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2- phenylcyclopropane-1-carboxamide

[0801] The title compound using purification conditions G1to give a white solid (72 mg, δ ppm 0.71 - 0.81 (m, 3 H), 1.17 - 1.24 (m, 1 H), 1.44 - 1.51 (m, 1 H), 1.76 - 1.84 (m, 1 H), 2.20 (quin, J = 7.4 Hz, 1 H), 2.32 - 2.40 (m, 1 H), 2.70 - 2.87 (m, 2 H), 3.48 - 3.59 (m, 3 H), 7.06 - 7.11 (m, 2 H), 7.12 - 7.18 (m, 1 H), 7.21 - 7.28 (m, 2 H).

[0802] The compounds of EXAMPLES 143 to 188 were prepared as shown in Scheme H.

[0803] Reaction conditions: A mixture of acid (0.090 – 0.357 mmol, 1.0 eq), 1-(azetidin-1- ylmethyl)cyclopropan-1-amine dihydrochloride (1.0 eq), HATU (1.0 – 2.0 eq), and DIPEA (2.0 – 5.0 eq) in DMF (0.09 – 0.18 M) was stirred at room temperature for 0.5 – 16 h.

[0804] Purification conditions H1: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0805] Purification conditions H2: The reaction mixture was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% ACN (w / 0.035% TFA) in water (w / 0.05% TFA).

[0806] Purification conditions H3: The reaction mixture was partitioned between brine and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic layers were dried over magnesium sulfate or sodium sulfate, filtered, andconcentrated. The crude product was purified by preparative HPLC (Phenomenex Gemini® NX-C18, 5 µm, ID 30 mm x 100 mm) using a gradient of 10-100% water / ACN (10 mM NH4HCO3 in 20 / 80 water / ACN, pH 9.5-10) in water (10 mM NH4HCO3, pH 9.5-10).

[0807] EXAMPLE 143: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(o- tolyloxy)cyclopropane-1-carboxamide

[0808] The title compound using purification conditions H1to give a colorless film (30.0 CD3OD) δ ppm 0.72 (t, J = 7.4 Hz, 3 H), 0.84 - 0.98 (m, 1 H), 1.26 - 1.45 (m, 3 H), 1.64 - 1.78 (m, 2 H), 1.86 (d, J = 6.6 Hz, 6 H), 1.95 - 2.06 (m, 1 H), 2.22 (s, 3 H), 2.74 - 2.94 (m, 2 H), 3.39 - 3.54 (m, 1 H), 6.54 - 6.65 (m, 1 H), 7.07 - 7.15 (m, 1 H), 7.59 - 7.71 (m, 1 H), 8.06 - 8.17 (m, 1 H); ESI-MS m / z [M+H]+301.2.

[0809] EXAMPLE 144: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-1H-indol-1- yl)-2-methylpropanamide

[0810] A TFA salt of thein Scheme H using purification conditions H2 to give a tan film (8.6 mg, 8.2%).1H NMR (400 MHz, CD3OD) δ ppm 0.62 - 0.68 (m, 2 H), 0.84 - 0.91 (m, 2 H), 1.81 (s, 6 H), 2.20 - 2.30 (m, 1 H), 2.49 - 2.60 (m, 1 H), 3.27 (s, 2 H), 3.88 - 4.02 (m, 2 H), 4.11 - 4.23 (m, 2 H), 6.53 - 6.62 (m, 1 H), 6.71 - 6.81 (m, 1 H), 6.93 - 7.03 (m, 1 H), 7.06 - 7.14 (m, 1 H), 7.44 (s, 1 H), 7.81 - 7.86 (m, 1 H); ESI-MS m / z [M+H]+330.3.

[0811] EXAMPLE 145: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(6-methyl-1H- pyrrolo[2,3-b]pyridin-1-yl)propanamide

[0812] A TFA salt of theScheme H using purification conditions H2 to give a reddish brown film (18.7 mg, 15%).1H NMR (400 MHz, CD3OD) δ ppm 0.75 - 0.82 (m, 2 H), 0.85 - 0.93 (m, 2 H), 1.81 (s, 6 H), 2.25 - 2.41 (m, 1 H), 2.55 (s, 4H), 3.28 (s, 2 H), 4.01 - 4.14 (m, 2 H), 4.20 - 4.33 (m, 2 H), 6.41 - 6.50 (m, 1 H), 6.91 - 7.01 (m, 1 H), 7.38 - 7.49 (m, 1 H), 7.78 - 7.84 (m, 1 H); ESI-MS m / z [M+H]+327.4.

[0813] EXAMPLE 146: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-1H- pyrrolo[2,3-b]pyridin-1-yl)-2-methylpropanamide Cl O N N N

[0814] A TFA salt of the Scheme H using purificationconditions H2 to give a green (400 MHz, CD3OD) δ ppm 0.73 - 1.00 (m, 4 H), 1.81 (s, 6 H), 2.31 - 2.47 (m, 1 H), 2.54 - 2.66 (m, 1 H), 4.07 - 4.21 (m, 2 H), 4.26 - 4.38 (m, 2 H), 6.57 - 6.68 (m, 1 H), 7.09 - 7.24 (m, 1 H), 7.58 - 7.69 (m, 1 H), 7.90 - 8.00 (m, 1 H), 8.09 - 8.18 (m, 1 H); ESI-MS m / z [M+H]+347.3.

[0815] EXAMPLE 147: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4- chlorophenoxy)cyclopropane-1-carboxamide

[0816] A TFA salt of the Scheme H using purificationconditions H2 to give a colorless film (5.8 mg, 5.3%).1H NMR (400 MHz, CD3OD) δ ppm 0.70 - 0.79 (m, 2 H), 0.90 - 0.99 (m, 2 H), 1.12 - 1.22 (m, 2 H), 1.51 - 1.62 (m, 2 H), 2.27 - 2.40 (m, 1 H), 2.52 - 2.66 (m, 1 H), 2.87 - 3.20 (m, 1 H), 3.32 (s, 1 H), 4.00 - 4.15 (m, 2 H), 4.24 (br d, J = 4.6 Hz, 2 H), 6.82 - 6.95 (m, 2 H), 7.24 - 7.32 (m, 2 H), 8.44 - 8.53 (m, 1 H).

[0817] EXAMPLE 148: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- chlorophenoxy)cyclopropane-1-carboxamide

[0818] A TFA salt of thein Scheme H using purification conditions H2 to give a colorless film (7.3 mg, 6.7%).1H NMR (400 MHz, CD3OD) δ ppm 0.72 - 0.88 (m, 2 H), 0.91 - 1.00 (m, 2 H), 1.13 - 1.27 (m, 2 H), 1.54 - 1.66 (m, 2 H), 2.28 - 2.45 (m, 1 H), 2.53 - 2.66 (m, 1 H), 3.03 - 3.16 (m, 1 H), 3.33 - 3.39 (m, 1 H), 4.01 - 4.17 (m, 2 H), 4.20 - 4.33 (m, 2 H), 6.91 - 7.03 (m, 2 H), 7.18 - 7.30 (m, 1 H), 7.34 - 7.43 (m, 1 H), 8.38 - 8.46 (m, 1 H).

[0819] EXAMPLE 149: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- fluorophenoxy)cyclopropane-1-carboxamide

[0820] A TFA salt of the in Scheme H using purification conditions H2 to give a(400 MHz, CD3OD) δ ppm 0.76 - 0.87 (m, 2 H), 0.92 - 1.01 (m, 2 H), 1.20 (s, 2 H), 1.56 (s, 2 H), 2.31 - 2.44 (m, 1 H), 2.52 - 2.64 (m, 1 H), 3.33 (s, 2 H), 4.04 - 4.15 (m, 2 H), 4.21 - 4.32 (m, 2 H), 6.92 - 7.03 (m, 2 H), 7.05 - 7.16 (m, 2 H); ESI-MS m / z [M+H]+305.4.

[0821] EXAMPLE 150: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- (trifluoromethyl)phenoxy)cyclopropane-1-carboxamide

[0822] The title compound using purification conditions H1to give a brown film (9.7 mg, 11%).1H NMR (400 MHz, CD3OD) δ ppm 0.61 - 0.72 (m, 3 H), 0.79 (s, 1 H), 1.15 (dd, J = 3.1, 1.4 Hz, 3 H), 1.45 - 1.63 (m, 3 H), 2.00 - 2.12 (m, 1 H), 2.56 (s, 1 H), 2.87 (s, 1 H), 3.24 (t, J = 7.1 Hz, 2 H), 3.56 (s, 1 H), 7.10 - 7.18 (m, 2 H), 7.50 - 7.65 (m, 2 H).

[0823] EXAMPLE 151: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- (trifluoromethoxy)phenoxy)cyclopropane-1-carboxamide

[0824] A TFA salt of theScheme H using purification conditions H2 to give a colorless film (5.7 mg, 4.7%).1H NMR (400 MHz, CD3OD) δ ppm 0.73 - 0.85 (m, 2 H), 0.96 (s, 2 H), 1.17 (d, J = 3.3 Hz, 2 H), 1.61 (d, J = 3.3 Hz, 2 H), 2.28 - 2.44 (m, 1 H), 2.51 - 2.67 (m, 1 H), 3.02 - 3.12 (m, 1 H), 3.33 - 3.39 (m, 1 H), 4.03 - 4.17 (m, 2 H), 4.22 - 4.32 (m, 2 H), 7.00 - 7.14 (m, 2 H), 7.26 - 7.34 (m, 2 H), 8.36 - 8.46 (m, 1 H).

[0825] EXAMPLE 152: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- methoxyphenoxy)cyclopropane-1-carboxamideH3C O O O N

[0826] A TFA salt of the in Scheme H using purification conditions H2 to give a(400 MHz, CD3OD) δ ppm 0.72 - 0.84 (m, 2 H), 0.91 - 1.01 (m, 2 H), 1.09 - 1.24 (m, 2 H), 1.50 (d, J = 3.3 Hz, 2 H), 2.27 - 2.38 (m, 1 H), 2.50 - 2.67 (m, 1 H), 3.33 (s, 2 H), 3.82 (s, 3 H), 4.00 - 4.12 (m, 2 H), 4.17 - 4.29 (m, 2 H), 6.83 - 6.91 (m, 2 H), 6.95 - 7.07 (m, 2 H), 8.35 - 8.43 (m, 1 H); ESI-MS m / z [M+H]+317.4.

[0827] EXAMPLE 153: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-chloro-1H-indol-1- yl)-2-methylpropanamide

[0828] A TFA salt of the in Scheme H using purificationconditions H2 to give a reddish brown film (42.2 mg, 30%).1H NMR (400 MHz, CD3OD) δ ppm 0.60 - 0.70 (m, 2 H), 0.87 - 0.96 (m, 2 H), 1.79 (s, 6 H), 2.18 - 2.34 (m, 1 H), 2.48 - 2.64 (m, 1 H), 3.29 (s, 2 H), 3.90 - 4.03 (m, 2 H), 4.13 - 4.26 (m, 2 H), 6.46 - 6.56 (m, 1 H), 7.00 - 7.08 (m, 1 H), 7.11 - 7.17 (m, 1 H), 7.44 - 7.49 (m, 1 H), 7.50 - 7.57 (m, 1 H), 7.90 - 7.98 (m, 1 H); ESI-MS m / z [M+H]+346.3.

[0829] EXAMPLE 154: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(7-chloro-1H-indol-1- yl)-2-methylpropanamide

[0830] A TFA salt of thein Scheme H using purification conditions H2 to give a tan film (6.1 mg, 5.3%).1H NMR (400 MHz, CD3OD) δ ppm 0.79 - 0.83 (m, 2 H), 1.17 (d, J = 6.9 Hz, 3 H), 2.07 - 2.17 (m, 2 H), 2.21 - 2.29 (m, 1 H), 2.46 - 2.56 (m, 1 H), 2.94 - 3.00 (m, 1 H), 3.08 - 3.12 (m, 2 H), 3.23 - 3.27 (m, 1 H), 3.64 - 3.71 (m, 2 H), 3.93 - 4.01 (m, 2 H), 4.41 - 4.53 (m, 1 H), 6.42 - 6.51 (m, 1 H), 6.93 - 7.02 (m, 1 H), 7.12 - 7.16 (m, 2 H), 7.43 - 7.51 (m, 1 H); ESI-MS m / z [M+H]+346.3.

[0831] EXAMPLE 155: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-1H-indol-1- yl)-2-methylpropanamide

[0832] A TFA salt of the title s in Scheme H using purification conditions H2 to give a tan film (16.9 mg, 15%). H NMR (400 MHz, CD3OD) δ ppm 0.46 - 0.48 (m, 1 H), 0.70 - 0.79 (m, 2 H), 1.15 - 1.21 (m, 4 H), 2.11 - 2.21 (m, 1 H), 2.39 - 2.50 (m, 1 H), 2.83 - 2.92 (m, 1 H), 2.96 - 3.02 (m, 1 H), 3.08 - 3.16 (m, 1 H), 3.39 - 3.48 (m, 1 H), 3.72 - 3.82 (m, 1 H), 3.87 - 3.94 (m, 1 H), 3.99 - 4.05 (m, 1 H), 4.11 - 4.18 (m, 1 H), 4.33 - 4.42 (m, 1 H), 7.11 - 7.18 (m, 1 H), 7.23 - 7.32 (m, 2 H), 7.47 - 7.52 (m, 2 H), 8.16 - 8.25 (m, 1 H); ESI-MS m / z [M+H]+346.3.

[0833] EXAMPLE 156: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-1H- pyrrolo[2,3-b]pyridin-1-yl)butanamide

[0834] A TFA salt of the Scheme H using purificationconditions H2 to give a colorless film (39.7 mg, 34%).1H NMR (400 MHz, CD3OD) δ ppm 0.82 (m, 7 H), 2.11 - 2.31 (m, 3 H), 2.47 - 2.59 (m, 1 H), 3.19 - 3.27 (m, 1 H), 3.34 - 3.40 (m, 1 H), 3.91 - 4.07 (m, 2 H), 4.09 - 4.27 (m, 2 H), 5.23 - 5.37 (m, 1 H), 6.57 - 6.70 (m, 1 H), 7.18 (d, J = 5.1 Hz, 1 H)7.60 - 7.71 (m, 1 H), 8.12 - 8.21 (m, 1 H), 8.65 - 8.74 (m, 1 H); ESI- MS m / z [M+H]+347.3.

[0835] EXAMPLE 157: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2- cyclopropylphenoxy)cyclopropane-1-carboxamide

[0836] A TFA salt of thein Scheme H using purification conditions H2 to give a white solid (36.1 mg, 33%).1H NMR (400 MHz, CD3OD) δ ppm 0.55 - 0.64 (m, 2 H), 0.75 - 0.84 (m, 2 H), 0.86 - 0.93 (m, 2 H), 0.93 - 1.00 (m, 2 H), 1.13 - 1.23 (m, 2 H), 1.49 - 1.62 (m, 2 H), 2.16 (s, 1 H), 2.23 - 2.40 (m, 1 H), 2.50 - 2.66 (m, 1 H), 3.33 (s, 2 H), 4.01 - 4.14 (m, 2 H), 4.17 - 4.32 (m, 2 H), 6.76 - 6.86 (m, 2 H), 6.90 (d, J = 0.8Hz, 1 H), 7.07 (ddd, J = 8.2, 7.3, 1.8 Hz, 1 H), 8.24 - 8.35 (m, 1 H); ESI-MS m / z [M+H]+327.3.

[0837] EXAMPLE 158: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3- chlorophenoxy)cyclopropane-1-carboxamide

[0838] A TFA salt of the Scheme H using purificationconditions H2 to give a (400 MHz, CD3OD) δ ppm 0.73 (d, J = 1.4 Hz, 2 H), 0.95 (d, J = 1.5 Hz, 2 H), 1.20 (d, J = 3.3 Hz, 2 H), 1.58 (d, J = 3.1 Hz, 2 H), 2.26 - 2.41 (m, 1 H), 2.51 - 2.68 (m, 1 H), 3.32 (s, 2 H), 4.00 - 4.14 (m, 2 H), 4.17 - 4.34 (m, 2 H), 6.80 - 6.89 (m, 1 H), 6.90 - 6.95 (m, 1 H), 6.95 - 7.06 (m, 1 H), 7.21 - 7.32 (m, 1 H), 8.42 - 8.56 (m, 1 H); ESI-MS m / z [M+H]+321.2.

[0839] EXAMPLE 159: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2- chlorophenoxy)butanamide

[0840] A TFA salt of the titlein Scheme H using purification conditions H2 to give a white solid (29.5 mg, 27%).1H NMR (400 MHz, CD3OD) δ ppm 0.99 (s, 4 H), 1.05 (t, J = 7.4 Hz, 3 H), 1.91 - 2.01 (m, 2 H), 2.25 - 2.37 (m, 1 H), 2.51 - 2.63 (m, 1 H), 3.35 (s, 2 H), 4.01 - 4.13 (m, 2 H), 4.17 - 4.33 (m, 2 H), 4.54 - 4.64 (m, 1 H), 6.93 - 7.05 (m, 2 H), 7.19 - 7.28 (m, 1 H), 7.36 - 7.44 (m, 1 H), 8.36 - 8.46 (m, 1 H); ESI-MS m / z [M+H]+323.3.

[0841] EXAMPLE 160: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-chloro-1H- pyrrolo[2,3-b]pyridin-1-yl)cyclopropane-1-carboxamide

[0842] The title compoundpurification conditions H1 to give a white solid (21.4 mg, 29%).1H NMR (400 MHz, CD3OD) δ ppm 0.51 - 0.62 (m, 4 H), 1.44 (d, J = 3.3 Hz, 2 H), 1.83 (d, J = 3.3 Hz, 2 H), 2.04 (s, 2 H), 2.50 (s, 2 H), 3.21 (t, J = 7.2 Hz, 4 H), 6.65 (d, J = 3.8 Hz, 1 H), 7.22 (d, J = 5.3 Hz, 1 H), 7.52 (d, J = 3.8 Hz, 1 H), 8.18 (d, J = 5.3 Hz, 1 H); ESI-MS m / z [M+H]+345.3.

[0843] EXAMPLE 161: N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-chloro-1H- pyrrolo[2,3-b]pyridin-1-yl)-3-methylbutanamide

[0844] The title compound using purification conditions H1 to give a white solid (4...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula 1, or a pharmaceuticallyG is a cyclic group G-4: R2X1,X1is from CR1and N; X3is selected from CR3and N; n is selected from 0, 1, 2, 3 and 4; R1, R2, R3and R4are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4alkyl, C3-6cycloalkyl, and C1-4alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and (a) when G is represented by G-1: m is 1; L1is selected from CR6R7, O and a bond; R5is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R6and R7are each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo, orR6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo; (b) when G is represented by G-2: m is 1; and X5ais selected from NR5aand O, wherein R5ais selected from hydrogen, C1-4alkyl, and C3-6 cycloalkyl; (c) when G is represented by G-3: m is 1; X6ais selected from CR6aand N, wherein R6ais selected from hydrogen and C1-4alkyl; and R5bis selected from: (i) hydrogen, halo, and (ii) C1-4 alkyl and C3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo; and (d) when G is represented by G-4: m is 0; p is selected from 0 and 1; X5cis selected from CH2, NR5cand O, wherein R5cis selected from hydrogen, C1-4alkyl, and C3-6 cycloalkyl; and R9ais selected from hydrogen, halo, hydroxy, cyano, C1-4alkyl, and C1-4alkoxy; R8and R9are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4 alkyl and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-4alkoxy, or R8and R9, together with the carbon atom to which they are attached, form a C3-5 oxacycloalkylidene, which is unsubstituted, or a C3-6cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo; R10at each occurrence is independently selected from halo; and R11and R12are each independently selected from C1-4 alkyl, orR11and R12, together with the nitrogen atom to which they are attached, form a C3-5 heterocyclyl group selected from azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-4alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X1is CR1.

3. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R1is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3alkyl, C3-6cycloalkyl, and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X1is N.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X3is CR3.

6. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R3is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3alkyl, C3-6cycloalkyl, and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X3is N.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R2is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3alkyl, C3-6cycloalkyl, and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R4is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3alkyl, C3-6cycloalkyl, and C1-3alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein G is a cyclic group represented by Formula G-1, , L1is selected from CR6R7, O andR5is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and R6and R7are each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo, or R6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

11. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein L1is CR6R7.

12. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R6and R7are each independently selected from hydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

13. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R6is hydrogen, and R7and R8together form a CR7aR8agroup bridging the carbon atoms to which they are attached, wherein R7aand R8aare each independently selected fromhydrogen, halo, and C1-4 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

14. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R7aand R8aare each independently selected from hydrogen, halo, and C1-3 alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

15. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein L1is O.

16. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein L1is a bond.

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 10 to 16, wherein R5is selected from: (i) hydrogen, halo, hydroxy, cyano, and (ii) C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein G is a cyclic group represented by Formula G-2, R2X1N , X5ais selected from NR5aand O;R5ais selected from hydrogen, C1-4 alkyl, and C3-6 cycloalkyl.

19. The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein X5ais NR5a.

20. The compound or pharmaceutically acceptable salt thereof according to claim 19, wherein R5ais selected from hydrogen, C1-3 alkyl, and C3-6 cycloalkyl.

21. The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein X5ais O.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein G is a cyclic group represented by Formula G-3, , X6ais selected from CR6aand N;R6ais selected from hydrogen and C1-4alkyl; and R5bis selected from: (i) hydrogen, halo, and (ii) C1-4 alkyl and C3-6 cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo.

23. The compound or pharmaceutically acceptable salt thereof according to claim 22, wherein X6ais CR6a.

24. The compound or pharmaceutically acceptable salt thereof according to claim 23, wherein R6ais selected from hydrogen and C1-3 alkyl.

25. The compound or pharmaceutically acceptable salt thereof according to claim 22, wherein X6ais N.

26. The compound or pharmaceutically acceptable salt thereof according to any one of claims 22 to 25, wherein R5bis selected from: (i) hydrogen, halo, and (ii) C1-3alkyl and C3-6cycloalkyl, each substituted with 0 to 3 optional substituents independently selected from halo.

27. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein G is a cyclic group represented by Formula G-4,, p is selected from 0 and 1; X5cis selected from CH2, NR5cand O; R5cis selected from hydrogen, C1-4alkyl, and C3-6cycloalkyl; and R9ais selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, and C1-4 alkoxy.

28. The compound or pharmaceutically acceptable salt thereof according to claim 27, wherein X5cis NR5c.

29. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R5cis selected from hydrogen, C1-3 alkyl, and C3-6 cycloalkyl.

30. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein X5cis CH2.

31. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein X5cis O.

32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 27 to 31, wherein p is 0.

33. The compound or pharmaceutically acceptable salt thereof according to any one of claims 27 to 31, wherein p is 1.

34. The compound or pharmaceutically acceptable salt thereof according to any one of claims 27 to 33, wherein R9ais selected from hydrogen, halo, hydroxy, cyano, C1-3alkyl, and C1-3 alkoxy.

35. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein R8and R9are each independently selected from: (i) hydrogen, halo, hydroxy, cyano, and(ii) C1-4 alkyl and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo and C1-4alkoxy.

36. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein R8and R9, together with the carbon atom to which they are attached, form a C3-5oxacycloalkylidene, which is unsubstituted, or a C3-6cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo.

37. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein R8and R9, together with the carbon atom to which they are attached, form a C3oxacycloalkylidene, which is unsubstituted, or a C3-4cycloalkylidene, which is substituted with 0 to 4 optional substituents independently selected from halo.

38. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein R8and R9, together with the carbon atom to which they are attached, form 3-oxacyclobutylidene, cyclopropylidene, 2,2-difluorocyclopropylidene, cyclobutylidene, and 3,3-difluorocyclobutylidene.

39. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, wherein R10at each occurrence is fluoro.

40. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, wherein n is 0.

41. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein R11and R12are each independently selected from C1-3 alkyl.

42. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein R11and R12, together with the nitrogen atom to which they are attached, form a C3-5heterocyclyl group selected from azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, each substituted with 0 to 4 optional substituents independently selected from halo and C1-4alkyl which is substituted with 0 to 3 optional substituents independently selected from halo.

43. The compound according to claim 1, which is selected from the following compounds:N-(1-(azetidin-1-ylmethyl)-2,2-difluorocyclopropyl)-1-(3-chlorophenyl)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-ethoxy-2-phenylacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3-methoxy-2-methyl-2-phenylpropanamide; 2-(3-chlorophenyl)-N-(1-((2,4-dimethylazetidin-1-yl)methyl)cyclopropyl)-2- methylpropanamide; (R)-2-(3-chlorophenyl)-2-methyl-N-(1-((2-methylazetidin-1- yl)methyl)cyclopropyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-(difluoromethoxy)phenyl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(p-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-N,2-dimethylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-6-chloro-2,3-dihydro-1H-indene-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(6-(trifluoromethyl)pyridin-2- yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(6-chloropyridin-2-yl)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(pyridin-2-yl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-fluoro-2,3-dihydro-1H-indene-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-(trifluoromethyl)phenyl)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-(trifluoromethyl)phenyl)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-bromo-2,3-dihydro-1H-indene-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-cyanophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1-phenylcyclopropane-1-carboxamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1-phenylcyclopropane-1- carboxamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-1-phenylcyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-chloro-1-hydroxy-2,3-dihydro-1H-indene-1- carboxamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3-difluoro-2-phenylpropanamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6-dichlorophenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-methyl-2,3-dihydro-1H-indene-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6-dichlorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(p-tolyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-chlorophenyl)cyclobutane-1-carboxamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(m-tolyl)propanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(m-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylacetamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methoxy-2-phenylacetamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methoxy-2-phenylacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-6-bromo-2,3-dihydro-1H-indene-1-carboxamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylbutanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-5-chloro-2,3-dihydro-1H-indene-1-carboxamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylbutanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methoxy-2-phenylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chloro-6-methylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-methoxyphenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6-dimethylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3,3-trifluoro-2-phenylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3-phenyloxetane-3-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-fluorophenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-chlorophenyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-4-chloro-2,3-dihydro-1H-indene-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-2-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-phenylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-ethylphenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-cyanophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-4-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5-chloro-2-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-5-fluorophenyl)-2-methylpropanamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-3-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-3-methoxyphenyl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-fluoro-5-methoxyphenyl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(p-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(o-tolyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-fluoro-6-methoxyphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluoro-5-methoxyphenyl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)propanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(p-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(o-tolyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(m-tolyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(o-tolyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-fluorophenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-(difluoromethyl)phenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-(difluoromethyl)phenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5-fluoro-7-methylbenzo[d]isoxazol-3-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-methylbenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-chlorobenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(m-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)propanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)propanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-methylbenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3-(4-chlorophenyl)-2,2-dimethylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-chlorobenzyl)cyclopropane-1-carboxamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-chlorobenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-3-methylphenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-fluoro-5-methylphenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-methylbenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-fluorobenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-fluorobenzyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,4-difluorophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(5-fluoro-2-methylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-fluoro-3-methylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-fluoro-2-methylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-fluoro-2-methylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-fluoro-5-methylphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,5-difluorophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-phenylacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-cyanophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-methoxyphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-methoxyphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3-fluorophenyl)propanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3-fluorophenyl)propanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(3-fluorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorobenzo[d]isoxazol-3-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(7-chlorobenzo[d]isoxazol-3-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5,6-dimethylbenzo[d]isoxazol-3-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-2-fluoropropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(o-tolyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-(difluoromethyl)phenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(5-chloropyridin-2-yl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(4-fluorophenyl)propanamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(2-fluorophenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(p-tolyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-4-fluorophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(m-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-(2-fluorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)-2-fluoropropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,4-difluorophenyl)-2-fluoropropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-cyanophenyl)-2,2-difluoroacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,3,3,3-tetrafluoro-2-(m-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,3,3,3-tetrafluoro-2-(4-fluorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(6-methylpyridin-2-yl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,4-difluorophenyl)-2-fluoropropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3,5-difluorophenyl)-2-fluoropropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2-fluoropropanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2-fluoropropanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2-fluoropropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-phenylpropanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-phenylpropanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-fluoro-2-phenylpropanamide; trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylcyclopropane-1-carboxamide; cis-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylcyclopropane-1-carboxamide; trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-3-phenylcyclopropane-1- carboxamide; trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-dimethyl-3-phenylcyclopropane-1- carboxamide; trans-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)cyclopropane-1- carboxamide; (1R,2R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylcyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(o-tolyloxy)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-1H-indol-1-yl)-2-methylpropanamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-1- yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-chlorophenoxy)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-chlorophenoxy)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-fluorophenoxy)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-(trifluoromethyl)phenoxy)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-(trifluoromethoxy)phenoxy)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-methoxyphenoxy)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-chloro-1H-indol-1-yl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(7-chloro-1H-indol-1-yl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-1H-indol-1-yl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1- yl)butanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-cyclopropylphenoxy)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-chlorophenoxy)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenoxy)butanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1- yl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3- methylbutanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-cyclopropylphenoxy)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-methyl-1H-indol-1-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-7-fluoro-1H-indol-1-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-(trifluoromethyl)phenoxy)cyclopropane-1- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-(trifluoromethoxy)phenoxy)cyclopropane-1- carboxamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-1H-indol-1-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-1H-indol-1-yl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,3-dichlorophenoxy)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-7-fluoro-1H-indol-1-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1- yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluoro-7-methyl-1H-indol-1-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(7-fluoro-4-methyl-1H-indol-1-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(7-methylbenzo[d]isoxazol-3- yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(3-(trifluoromethyl)phenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chlorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(1-methyl-1H-indazol-3-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(3-methyl-1H-indazol-1-yl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-methoxyphenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3-difluoro-1-phenylcyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-fluorophenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-(difluoromethyl)phenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,3-dihydrobenzofuran-3-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-methyl-1,2,3,4-tetrahydroquinoline-4- carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(3-fluoro-4- methoxyphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chloro-4-fluorophenoxy)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chloro-4-fluorophenoxy)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,4-dichlorophenoxy)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2- methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-chloro-3-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-1-yl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-chlorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-(trifluoromethyl)phenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,6-difluorophenyl)acetamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chloro-6-fluorophenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenyl)-2-methylpropanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,2-difluoro-2-(4-fluoro-3- methoxyphenyl)acetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-chloro-2-fluoro-2-phenylacetamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenoxy)propanamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenoxy)propanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-chlorophenoxy)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(6-methoxypyridin-2-yl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-(difluoromethyl)phenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2,3-difluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(m-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-chlorophenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(2-methoxyphenyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(o-tolyl)propanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(4-methoxyphenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-(3-chloro-2-fluorophenyl)-2-methylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2,3-dihydro-1H-indene-1-carboxamide; (R)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylbutanamide; (S)-N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-phenylpropanamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-phenylcyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-phenylcyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(p-tolyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-methoxyphenyl)cyclopropane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-chlorophenyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(4-fluorophenyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(2-fluorophenyl)cyclobutane-1-carboxamide;N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(m-tolyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-1-(3-fluorophenyl)cyclobutane-1-carboxamide; N-(1-(azetidin-1-ylmethyl)cyclopropyl)-2-methyl-2-(4-(trifluoromethyl)phenyl)propanamide; 2-methyl-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methyl-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-(4-chloro-1H-indol-1-yl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(6-chloro-1H-indol-1-yl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(3-chloro-1H-indol-1-yl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)butanamide; 1-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)cyclopropane-1-carboxamide; 2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)butanamide; 2-(4-methyl-1H-indol-1-yl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(4-chloro-7-fluoro-1H-indol-1-yl)-2-methyl-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-(4-fluoro-1H-indol-1-yl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(4-fluoro-1H-indol-1-yl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)acetamide; 2-(4-chloro-7-fluoro-1H-indol-1-yl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 1-(2-fluorobenzyl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)cyclopropane-1-carboxamide; 1-(3-fluorobenzyl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)cyclopropane-1-carboxamide; 1-(4-fluorobenzyl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)cyclopropane-1-carboxamide; 2-methyl-2-(3-methyl-1H-indazol-1-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-(2,3-difluorophenyl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(3-(difluoromethyl)phenyl)-2-methyl-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-(3-chlorophenyl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide;2-(2-chlorophenoxy)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methyl-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)-2-(6-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-1-yl)propanamide; 2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methyl-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-methyl-2-(1-methyl-1H-indazol-3-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-(3-methoxyphenyl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-(4-methoxyphenyl)-2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-methyl-2-(3-methyl-1H-indol-1-yl)-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)propanamide; 2-methyl-N-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)-2-(3- (trifluoromethyl)phenyl)propanamide; 2-methyl-2-(7-methylbenzo[d]isoxazol-3-yl)-N-(1-(pyrrolidin-1- ylmethyl)cyclopropyl)propanamide; 2-methyl-2-(1-methyl-1H-indazol-3-yl)-N-(1-(piperidin-1- ylmethyl)cyclopropyl)propanamide; N-(1-((diethylamino)methyl)cyclopropyl)-2-methyl-2-(1-methyl-1H-indazol-3- yl)propanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2-methyl-2-(1-methyl-1H-indazol-3- yl)propanamide; N-(1-((dimethylamino)methyl)cyclobutyl)-2-methyl-2-(1-methyl-1H-indazol-3- yl)propanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-1-(2-fluorobenzyl)cyclopropane-1-carboxamide; N-(1-((dimethylamino)methyl)cyclopropyl)-1-(3-fluorobenzyl)cyclopropane-1-carboxamide; N-(1-((dimethylamino)methyl)cyclopropyl)-1-(4-fluorobenzyl)cyclopropane-1-carboxamide; 2-(2-chlorophenyl)-N-(1-((dimethylamino)methyl)cyclopropyl)propanamide; 2-(3-chlorophenyl)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-methylpropanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2-fluoro-2-phenylpropanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2-fluoro-2-(m-tolyl)propanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoro-2-(3-fluorophenyl)acetamide; 2-(3-chlorophenyl)-N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoroacetamide;2-(4-chlorophenyl)-N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoroacetamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide; 2-(4-chlorophenyl)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-fluoropropanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoro-2-(3-methoxyphenyl)acetamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoro-1-phenylcyclopropane-1- carboxamide; (S)-N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoro-1-phenylcyclopropane-1- carboxamide; (R)-N-(1-((dimethylamino)methyl)cyclopropyl)-2,2-difluoro-1-phenylcyclopropane-1- carboxamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2-fluoro-2-(3-fluorophenyl)propanamide; (R)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-fluoro-2-(3-fluorophenyl)propanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-1-phenylcyclobutane-1-carboxamide; (R)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-phenylpropanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-1-(4-fluorophenyl)cyclobutane-1-carboxamide; N-(1-((dimethylamino)methyl)cyclopropyl)-1-(3-fluorophenyl)cyclobutane-1-carboxamide; 2-(4-chlorophenyl)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-methylpropanamide; 4-chloro-N-(1-((dimethylamino)methyl)cyclopropyl)-2,3-dihydro-1H-indene-1-carboxamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2-methyl-2-(m-tolyl)propanamide; (S)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-phenylbutanamide; (R)-N-(1-((dimethylamino)methyl)cyclopropyl)-2-phenylbutanamide; N-(1-((dimethylamino)methyl)cyclopropyl)-2-(3-fluoro-5-methoxyphenyl)-2- methylpropanamide; 2-(3-chlorophenyl)-2-methyl-N-(1-((3-methylazetidin-1-yl)methyl)cyclopropyl)propanamide; 2-(3-chlorophenyl)-2-methyl-N-(1-((2-methylazetidin-1-yl)methyl)cyclopropyl)propanamide; 2-(3-chlorophenyl)-N-(1-((2,2-dimethylazetidin-1-yl)methyl)cyclopropyl)-2- methylpropanamide; or a pharmaceutically acceptable salt of any one of the aforementioned compounds.

44. A pharmaceutical composition comprising: a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 43; and a pharmaceutically acceptable excipient.

45. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 43 for use as a medicament.

46. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 43 for use in treating a disease, disorder or condition selected from Alzheimer’s disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

47. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 43, wherein the disease, disorder or condition is selected from Alzheimer’s disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain, and hyperactivity disorder.

48. A combination comprising a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 43, and at least one additional pharmacologically active agent.

49. The combination according to claim 48, wherein the additional pharmacologically active agent is selected from beta-secretase inhibitors, gamma-secretase inhibitors, HMG- CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.

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