4-Substituted phenylacetamides and aryl ureas as agonists for the orphan receptor GPR88

Abstract

The present disclosure provides novel 4-substituted phenylacetamide and aryl urea derivatives that act as agonists for GPR88.The compounds of the present disclosure are believed to be useful for treating diseases and conditions caused by physiological processes that involve the orphan receptor GPR88, including diverse brain and behavioral functions such as cognition, mood, motor control, and reward-based learning.GPR88 has emerged as a novel drug target for central nervous system disorders, including schizophrenia, Parkinson's disease, anxiety, and addiction.One particular indication for which GPR88 agonists are promising is alcohol use disorder (AUD).

Description

[Technical field]

[0001] Federally sponsored research This disclosure was made with Government support under R01AA026820 awarded by the NIH. The Government has certain rights in this disclosure.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 302,835, filed January 25, 2022, and U.S. Provisional Patent Application No. 63 / 419,470, filed October 26, 2022, both of which are incorporated by reference in their entireties herein.

[0003] The present disclosure provides novel 4-substituted phenylacetamide derivatives that act as agonists for GPR88. The compounds of the present disclosure are believed to be useful for treating diseases and conditions caused by physiological processes that involve the orphan receptor GPR88, including diverse brain and behavioral functions such as cognition, mood, motor control, and reward-based learning. GPR88 has emerged as a novel drug target for central nervous system disorders, including schizophrenia, Parkinson's disease, anxiety, addiction, and attention-deficit / hyperactivity disorder (ADD / ADHD). One particular indication for which GPR88 agonists are promising is alcohol use disorder (AUD). [Background technology]

[0004] Alcoholism is a heterogeneous, chronic, relapsing disorder with significant emotional, social, and economic costs. See, e.g., Rehm et al., Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009, 373, 2223-2233, and Thavorncharoensap et al., The economic impact of alcohol consumption: a systematic review. Substance Abuse Treatment, Prevention, and Policy 2009, 4, 20, each of which is incorporated herein by reference for such background teachings. In the United States, alcohol is the third leading cause of preventable death, and the cost of alcoholism reached $249 billion in 2010 (CDC). At the neurobiological level, alcohol activates multiple primary and secondary molecular targets in the brain, causing widespread changes in gene expression and synaptic plasticity. See, e.g., Costardi et al., A review on alcohol: from the central action mechanism to chemical dependency. Revista da Associacao Medica Brasileira 2015, 61, 381-387, which is incorporated by reference herein for such background teachings. Primarily, alcohol acts by inhibiting the GABA Aand NMDA ionotropic receptors, mediating gamma-aminobutyric acid (GABA) and glutamate neurotransmission. Alcohol enhances GABA action and antagonizes glutamatergic action, thus acting as a central nervous system (CNS) depressant. In addition, both dopamine and opioid peptide systems in the basal forebrain are involved in alcohol reward. Thus, the competitive opioid antagonist naltrexone and the functional glutamate antagonist acamprosate provide proof of concept for the pharmacotherapy of alcoholism and dependence. See, for example, Bouza et al., Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004, 99, 811-828, which is incorporated herein by reference for such background teachings. However, both drugs face significant challenges, including lack of fixation, low efficacy, and significant side effects. In addition, alcohol-dependent individuals represent a heterogeneous group, and it is unlikely that a single pharmacological treatment will be effective for all alcoholics. Therefore, novel therapeutic strategies are needed to successfully treat alcoholism.

[0005] GPR88 is a Gα i / oGPR88 is an orphan G-protein-coupled receptor (GPCR) that has robust expression in striatal medium spiny neurons (MSNs) throughout the dorsal and ventral regions. See, e.g., Mizushima et al., A novel G-protein-coupled receptor gene expressed in striatum. Genomics 2000, 69, 314-321; Van Waes et al., GPR88-a putative signaling molecule predominantly expressed in the striatum: Cellular localization and developmental regulation. Basal Ganglia 2011, 1, 83-89; and Massart et al., Striatal GPR88 expression is confined to the whole projection neuron population and is regulated by dopaminergic and glutamatergic afferents. European Journal of Neuroscience 2009, 30, 397-414, each of which is incorporated herein by reference for such background teachings. This distribution is consistent with transcriptional profiling studies linking GPR88 to various striatal disorders, including Parkinson's disease, schizophrenia, and drug addiction. See, e.g., Ye et al., Orphan receptor GPR88 as an emerging neurotherapeutic target. ACS Chemical Neuroscience 2019, 10, 190-200, which is incorporated herein by reference for such background teaching. More direct evidence of GPR88 function comes from GPR88 knockout (KO) studies, suggesting that GPR88 plays an important role in controlling striatal functions involved in the reward system.See, e.g., Logue et al., The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders? Molecular and Cellular Neuroscience 2009, 42, 438-447, and Quintana et al., Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors. Nature Neuroscience 2012, 15, 1547-1555, each of which is incorporated by reference herein for such background teachings. Of direct relevance to alcoholism, GPR88 KO mice exhibited enhanced voluntary alcohol drinking compared to wild-type mice in both moderate and binge drinking paradigms. See, for example, Ben Hamida, et al., Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks. Biological Psychiatry 2018, 84, 202-212, which is incorporated herein by reference for such background teachings. Importantly, no changes in water intake, preference, and alcohol metabolism were observed in these mice. Furthermore, mice lacking the GPR88 gene showed enhanced motivation for alcohol intake and alcohol-seeking behavior using operant self-administration. Consistent with the results of the KO study, the inventors recently developed a potent, highly selective, brain-penetrant GPR88 agonist, designated RTI-13951-33, which, when administered intraperitoneally, significantly reduced alcohol self-administration and alcohol intake in a dose-dependent manner in rats without affecting locomotor activity and sucrose self-administration.See, e.g., Jin et al., Discovery of a potent, selective, and brain-penetrant small molecule that activates the orphan receptor GPR88 and reduces alcohol intake. Journal of Medicinal Chemistry 2018, 61, 6748-6758, which is incorporated herein by reference for such background teachings. Given the lack of modulatory effects on sucrose self-administration at doses that reduce alcohol self-administration, this suggests that the GPR88 agonist had a selective effect for alcohol reinforcement. Taken together, both genetic modification and pharmacological studies support the use of GPR88 agonists as novel therapeutic tools for treating alcoholism and related disorders.

[0006] To understand the pharmacology of the GPR88 receptor for therapeutic applications, the development of structurally distinct chemotypes that exhibit potent and selective GPR88 agonism is of paramount importance. In this regard, the compound known as 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide (1)] and its hydroxyl analogue 2 have advanced our knowledge in the related pharmacophore: [ka]

[0007] Reference is made to WO2011 / 044195A1, WO2011 / 044225A1, US2011 / 0251196A1, US2011 / 0245264A1, and Dzierba et al., Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88. Bioorganic & Medicinal Chemistry Letters 2015, 25, 1448-1452, each of which is incorporated by reference for such teachings. In the Lance time-resolved fluorescence resonance energy transfer (TR-FRET) cAMP assay using stable CHO-GPR88 cells, compounds 1 and 2 had ECs of 414 nM and 195 nM, respectively. 50 These compounds had moderate agonist activity at GPR88 with values ​​of 0.01 to 0.01. See, e.g., Jin et al., Design, synthesis, and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists. Bioorganic & Medicinal Chemistry 2017, 25, 805-812, which is incorporated herein by reference for such teachings. These EC 50 Values ​​are the EC values ​​previously reported above. 50 The potency was slightly less than the values ​​shown, possibly due to the relative sensitivity of the two different assay systems. We have explored structure-activity relationships and discovered a series of novel reverse amide and urea analogs of the 2-AMPP scaffold, which exhibit good to moderate agonist activity at GPR88. See, e.g., Jin et al., supra; Rahman, et al., Design, synthesis, and structure-activity relationship studies of (4-alkoxyphenyl)glycinamides and bioisosteric 1,3,4-oxadiazoles as GPR88 agonists. Journal of Medicinal Chemistry 2020, 63, 14989-15012; and Rahman, et al., Evaluation of amide bioisosteres leading to 1,2,3-triazole containing compounds as GPR88 agonists: Design, synthesis, and structure-activity relationship studies. Journal of Medicinal Chemistry 2021, 64, 12397-12413, each of which is incorporated by reference for such teachings. The present disclosure provides novel 4-substituted phenylacetamide and aryl urea derivatives that act as agonists for GPR88, which have structural differences from known compounds that provide unexpected benefits, including potency against the GPR88 target. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2011 / 044195A1 [Patent Document 2] International Publication No. 2011 / 044225A1 [Patent Document 3] US Patent Application Publication No. 2011 / 0251196A1 [Patent Document 4] U.S. Patent Application Publication No. 2011 / 0245264 A1

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[0010] The compounds of the present disclosure provide potent agonism for the orphan receptor GPR88. Thus, the compounds of the present disclosure offer therapeutic potential for the treatment of striatal-related disorders such as Parkinson's disease, schizophrenia, and alcoholism. All compounds were evaluated for GPR88 agonist activity in the in vitro GPR88 Lance TR-FRET cAMP assay previously established by the inventors. See Jin et al., 2018, Rahman et al., 2020, and Rahman et al., 2021, supra. As will be described, the TR-FRET signal was converted to fmol cAMP by interpolating from a standard cAMP curve. Fmol cAMP was plotted against the logarithm of compound concentration, and the data was fitted to a three-parameter logistic curve to obtain the maximum response (E max ) and EC 50 A value was generated.

[0011] One embodiment of the present disclosure is a compound of formula (I), or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 1 But hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, NH2, NHC 1-10 Alkyl, N(C 1-10 Alkyl)2, S(O)C 1-10 Alkyl, S(O)2C 1-10 Alkyl, NHSO2C 1-10 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycle, C 6-10 Aryl and C 5-10 Heteroaryl; A 1 but, a) a 6-membered aromatic ring which may contain one N heteroatom, or b) a 10-membered fused aromatic ring system which may contain 1 or 2 N heteroatoms; X is CH or N; R 2 But (CH2) n2 R 20 and 、 n2 is 0, 1, 2, or 3; R 20 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, NO2, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N3, S(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, NHSO2C 1-6 Alkyl, C(O)C1-6 Alkyl, C(O)OC 1-6 Alkyl, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl)2, CH(NH2)C 1-6 Alkyl, CH(N[C 1-6 Alkyl]2)C 1-6 Alkyl, CH(NH2)C 1-6 Alkylene-OC 1-6 Alkyl, CH(N[C 1-6 Alkyl]2)C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycle, C 6-10 Aryl and C 5-10 Heteroaryl; R 4 But (CH2) n4 R 40 and n4 is 0, 1, 2, or 3; R 40 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, NO2, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N3, S(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, NHSO2C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, NHC(O)C 1-6 Alkyl, N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C(O)N(C 1-6 alkyl)2, CH(NH2)C 1-6 Alkyl, CH(N[C1-6 Alkyl]2)C 1-6 Alkyl, CH(NH2)C 1-6 Alkylene-OC 1-6 Alkyl, CH(N[C 1-6 Alkyl]2)C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycle, C 6-10 Aryl and C 5-10 Heteroaryl; L 1 but, a) a divalent C3 cycloalkyl, b) [(CR L )2] m or c) is a bond; m is 0, 1, 2, or 3; Each R L are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, NO2, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N3, S(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, NHSO2C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, NHC(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycle, C 6-10 Aryl and C 5-10 Heteroaryl; A 2 but, a) a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from O, N, or S; or b) a six-membered aromatic ring which may contain one heteroatom; R3 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, NO2, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N3, S(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, NHSO2C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, NHC(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocycle, C 6-10 Aryl and C 5-10 Heteroaryl; During the ceremony, Each C 3-6 Cycloalkyl, 5-7 membered heterocycle, C 6-10 Aryl and C 5-10 Heteroaryl is unsubstituted or contains 1, 2, or 3 (CH) 0-3 R S is replaced by Each R S But, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, NO2, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, N3, S(O)C 1-6 Alkyl, S(O)2C 1-6 Alkyl, NHSO2C 1-6 Alkyl, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl, NHC(O)C 1-6 Alkyl, C(O)NHC 1-6 Alkyl, unsubstituted C 3-6Cycloalkyl, O-unsubstituted C 3-6 Cycloalkyl, unsubstituted 5-7 membered heterocycle, unsubstituted C 6-10 Aryl and unsubstituted C 5-10 The present invention includes a compound of formula (I) selected from the group consisting of: heteroaryl, or a pharma- ceutically acceptable salt thereof.

[0012] In one embodiment, R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, (CH2) 0-3 C 3-6 Cycloalkyl or OC 3-6 C optionally substituted with cycloalkyl 1-10 Alkyl, C 2-10 Alkynyl, C 1-10 Alkoxy, or C6 aryl.

[0013] In one embodiment, R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, or (CH2) 0-3 C 3-6 C optionally substituted with cycloalkyl 1-10 It is alkoxy or C6 aryl.

[0014] In one embodiment, A 1 is phenyl.

[0015] In one aspect, X is CH. In one aspect, n2 is 1. In one aspect, R 20 is OH.

[0016] In one embodiment, X is N. In one embodiment, n2 is 1. In one embodiment, R 20 is CH(NH2)C 1-6 Alkyl, CH(N[C 1-6 Alkyl]2)C 1-6 Alkyl, CH(NH2)C 1-6Alkylene-OC 1-6 Alkyl, or CH(N[C 1-6 Alkyl]2)C 1-6 Alkylene-OC 1-6 It is an alkyl.

[0017] In one embodiment, R 4 is H or C 1-6 It is an alkyl.

[0018] In one embodiment, L 1 is a divalent C cycloalkyl.

[0019] In one embodiment, L 1 is [C(R L )2] m It is.

[0020] In one embodiment, one R L is H and one R L is C 1-6 It is an alkyl.

[0021] In one embodiment, A 2 is phenyl.

[0022] In one embodiment, R 3 is hydrogen or C 1-6 It is an alkyl.

[0023] One embodiment of the present disclosure includes a compound, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: [ka] [ka] [ka] [ka]

[0024] One embodiment of the present disclosure includes a compound, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: [ka] [ka] [ka]

[0025] One embodiment of the disclosure includes a method of treating a disorder in a patient in need of such treatment, where modulation of a G protein-coupled receptor is beneficial, comprising administering a compound of the disclosure.

[0026] One embodiment of the present disclosure includes the use of a compound of the present disclosure in the manufacture of a medicament for the treatment of a disorder or disease, where modulation of a G protein-coupled receptor is beneficial to a patient in need thereof.

[0027] One embodiment of the present disclosure includes a compound of the present disclosure for use in the treatment of a disorder in which modulation of a G protein-coupled receptor is beneficial to a patient in need of such treatment.

[0028] In one aspect, the method, use, or compound for use provides treatment for a neurological disorder. In one aspect, the method, use, or compound for use includes that the neurological disorder is selected from one or more of psychosis, cognitive deficits in schizophrenia, affective disorders, attention deficit hyperactivity disorder, bipolar disorder, drug addiction, alcohol addiction, food addiction, activity addiction, Parkinson's disease, and Alzheimer's disease. In one aspect, the method, use, or compound for use provides treatment for a metabolic disorder. In one aspect, the method, use, or compound for use includes that the metabolic disorder is selected from one or more of obesity and diabetes. In one aspect, the method, use, or compound for use provides treatment for an alcohol use disorder.

[0029] In one aspect, the compounds of the present disclosure can be used as GPR88 receptor agonists and can exhibit greater efficacy and experience reduced side effects, resulting in improved efficacy, pharmacokinetics, and safety.The compounds are believed to be useful in the treatment of diseases and conditions caused by agonism of the GPR88 receptor.

[0030] The scope of the present disclosure includes all combinations of the aspects, embodiments, and preferences described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The following definitions are meant to clarify, not limit, the defined terms. If certain terms used herein are not specifically defined, such terms should not be considered indefinite. Rather, the terms are used within their accepted meanings.

[0032] As used throughout this specification, preferred numbers of atoms, such as carbon atoms, are, for example, "C x-y The term "alkyl" refers to an alkyl group, as defined herein, containing a specified number of carbon atoms. Similar terms apply to other preferred terms and ranges. Thus, for example, C 1-4Alkyl refers to a straight or branched chain hydrocarbon containing 1 to 4 carbon atoms.

[0033] As used herein, the term "alkyl", alone or in combination with any other term, refers to a straight or branched chain hydrocarbon. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, iso-pentyl, n-pentyl, n-hexyl, and the like.

[0034] As used herein, the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-carbon double bonds, which may be optionally substituted, with multiple degrees of substitution permitted. Examples of "alkenyl" as used herein include, but are not limited to, vinyl and allyl.

[0035] As used herein, the term "alkoxy" refers to the group O-alkyl.

[0036] As used herein, the term "alkylene" refers to an optionally substituted straight-chain divalent hydrocarbon radical. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

[0037] As used herein, the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-carbon triple bonds, which may be optionally substituted, with multiple degrees of substitution permitted. Examples of "alkynyl" as used herein include, but are not limited to, ethynyl.

[0038] As used herein, the term "aryl" refers to a single benzene ring, a fused, bridged, or spirocyclic benzene ring system, which may be optionally substituted, with multiple degrees of substitution permitted. Examples of "aryl" groups that may be used include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Preferred aryl rings have 5 to 10 members.

[0039] As used herein, fused benzene ring systems encompassed within the term "aryl" include fused polycyclic hydrocarbons, i.e., cyclic hydrocarbons having less than the maximum number of non-cumulative double bonds, e.g., a saturated hydrocarbon ring (cycloalkyl, e.g., a cyclopentyl ring) is fused with an aromatic ring (aryl, e.g., a benzene ring) to form groups such as, for example, indanyl and acenaphthalenyl, and also, as non-limiting examples, groups such as dihydronaphthalene and tetrahydronaphthalene.

[0040] As used herein, the term "cycloalkyl" refers to a fully saturated, optionally substituted monocyclic, bicyclic, bridged, or spirocyclic hydrocarbon ring, with multiple degrees of substitution permitted. Exemplary "cycloalkyl" groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0041] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0042] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with at least one halogen. Examples of branched or straight chain "haloalkyl" groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl, each independently substituted with one or more halogens, such as fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include substituents such as perfluoroalkyl groups, such as CF3.

[0043] As used herein, the term "heteroaryl" refers to a monocyclic 5- to 7-membered aromatic ring, which may be optionally substituted, with multiple degrees of substitution permitted, or a fused, bridged, or spirocyclic aromatic ring system containing two or more of such rings. Preferably, such rings contain 5 to 10 members. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, with N-oxides, sulfur oxides, and dioxides being permissible heteroatom substitutions. Examples of "heteroaryl" groups as used herein include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyridine, and pyrazolopyrimidine.

[0044] As used herein, the terms "heterocycle" and "heterocyclyl" refer to fully saturated, optionally substituted, monocyclic, bicyclic, bridged, or spirocyclic hydrocarbon rings, which allow multiple degrees of substitution, containing one or more heteroatoms selected from nitrogen, sulfur, and / or oxygen atoms, with N-oxides, sulfur oxides, and dioxides being permitted. Exemplary "heterocyclyl" groups as used herein include, but are not limited to, azetidine, pyrrolidinyl, piperidinyl, piperazinyl, hexahydroazepine, and morpholinyl.

[0045] Typically, but not necessarily, the salts of the present disclosure are pharma- ceutically acceptable salts. The salts encompassed within the term "pharma-ceutically acceptable salts" refer to non-toxic salts of the compounds of the present disclosure. The salts of the compounds of the present disclosure may include acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, and laurate. , malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, acetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, triethiodide, trimethylammonium, and valerate. Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the present disclosure and these should be considered to form a further aspect of the present disclosure.

[0046] Compounds of formula (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism can generally occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as X-ray diffraction patterns, solubility, and melting point.

[0047] As used herein, the term "effective amount" refers to an amount of a drug or agent that will elicit a biological or medical response in a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. The term "therapeutically effective amount" refers to any amount that results in the treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a slowing of the rate of progression of a disease or disorder, compared to a corresponding subject not receiving such amount. The term also includes within its scope an amount effective to enhance normal physiological function.

[0048] For use in therapy, a therapeutically effective amount of the compounds of formula (I), and salts or solvates thereof, may be administered as raw chemicals. In addition, the active ingredient may be presented as a pharmaceutical composition.

[0049] Thus, the present disclosure further provides a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I), or salts or solvates thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients. The compounds of formula (I), or salts or solvates thereof, are as described herein. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.

[0050] GPR88 is a striatum-enriched orphan G protein-coupled receptor (GPCR) whose expression varies across development in rodent, monkey, and human brains. Genetic association studies in humans have revealed associations between GPR88 function and several psychiatric, neurodevelopmental, or neurodegenerative disorders, including schizophrenia, bipolar disorder, speech delay, and chorea. In rodents, Gpr88 gene transcript levels were found to be modified after exposure to various psychoactive drugs, such as mood stabilizers, antidepressants, methamphetamine, L-DOPA, and drugs of abuse. GPR88 is a promising target for the development of innovative treatments for CNS pathologies. In mice, deletion of the Gpr88 gene primarily alters striatal physiology, striatal-centered brain networks, and striatal-dependent behaviors, with severe deficits in motor coordination and skill learning, hyperactivity, stereotypy, and altered reward-driven behaviors. However, GPR88 function is not observed in Gpr88 null (Gpr88 - / - ) According to extrastriatal GPR88 expression in mice and extensive modifications in brain connectivity, gene expression, and behavioral responses, extending beyond striatal-mediated responses, GPR88 has profound effects on brain physiology and controls a vast repertoire of behaviors.

[0051] The compounds of the present disclosure are believed to be useful for treating psychiatric, neurodevelopmental or neurodegenerative disorders.GPR88 regulation affects the control of various brain and behavioral functions, including cognition, mood, motor control, cue-based reward learning, and basal ganglia-related disorders.The compounds of the present disclosure are believed to be useful for treating CNS disorders, including schizophrenia, Parkinson's disease, anxiety, and addiction.In particular, the compounds of the present disclosure are believed to be useful for treating alcohol use disorder (AUD).

[0052] The compounds of the present disclosure can be used for any disease of disorders in which the modulation of G protein-coupled receptors is beneficial.In one embodiment, the compounds of the present disclosure can be used to treat neurological disorders.In one aspect, the neurological disorders are selected from one or more of psychosis, cognitive deficits in schizophrenia, affective disorders, attention deficit hyperactivity disorder, bipolar disorder, drug addiction, alcoholism, food addiction, activity addiction, Parkinson's disease, and Alzheimer's disease.In another embodiment, the compounds of the present invention can be used to treat metabolic disorders.In one aspect, the metabolic disorders are selected from one or more of obesity and diabetes.

[0053] The therapeutically effective amount of the compounds of the present disclosure will depend on many factors. For example, the species, age, and weight of the recipient, the exact condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount should ultimately be at the discretion of the attending physician or veterinarian. Nevertheless, an effective amount of the compound of formula (I) for the treatment of humans suffering from frailty should generally be in the range of 0.1-100 mg / kg body weight of the recipient (mammal) per day. More usually, the effective amount should be in the range of 0.1-20 mg / kg body weight per day. Thus, for a 70 kg adult mammal, an example of a practical amount per day would usually be 10-2000 mg. This amount may be given in a single dose per day, or in multiple (such as 2, 3, 4, 5, or more) partial doses per day such that the total daily dose is the same. The effective amount of a salt or solvate thereof may be determined as a percentage of the effective amount of the compound of formula (I) itself. Similar dosages should be appropriate for the treatment of other conditions mentioned herein. Pharmaceutical preparations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such units may contain, as a non-limiting example, 1 mg to 2 g of a compound of formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of active ingredient, as recited herein above. Such pharmaceutical preparations may be prepared by any of the methods well known in the art of pharmacy.

[0054] The pharmaceutical formulations may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example, by bringing the active ingredient into association with the carrier(s) or excipient(s). By way of example, and not meant to limit the disclosure, for certain conditions and disorders for which the compounds of the present disclosure are believed to be useful, certain routes may be preferred over others. In addition, pharmaceutical formulations may be used to allow delayed or extended exposure to the compounds of formula (I) under circumstances where such delayed or extended exposure would improve therapy.

[0055] Pharmaceutical preparations adapted for oral administration can be presented as separate units such as capsules or tablets; powders or granules; or solutions or suspensions, each of which contains an aqueous or non-aqueous liquid; edible foams or whips; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. For example, for administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharma-ceutically acceptable inert carrier such as ethanol, glycerol, water, etc. In general, powders are prepared by grinding the compound to a suitable fine size and mixing with a suitable pharmaceutical carrier, such as an edible carbohydrate, for example, starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents can also be present.

[0056] Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or other suitable shell material. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before encapsulation. Disintegrants or solubilizers such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested. Also, suitable binders, lubricants, disintegrants, and coloring agents can be incorporated into the mixture as desired or required. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

[0057] Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. The powder mixture can be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above. Optional ingredients include binders such as carboxymethylcellulose, alliginate, gelatin, or polyvinylpyrrolidone, solution retarders such as paraffin, absorption enhancers such as quaternary salts, and / or absorbents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet granulated with a binder such as syrup, starch paste, acadia mucilage, or a solution of cellulose or polymeric materials, and forced through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet machine, and the result is imperfectly formed slugs that are divided into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed directly into tablets without granulation or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polishing coating of wax can be provided. Dyes can be added to these coatings to distinguish different unit dosages.

[0058] Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of compound.Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared by using non-toxic alcoholic vehicles.Suspensions can generally be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners, etc. can also be added.

[0059] If desired, dosage unit formulations for oral administration can be microencapsulated. The formulations can also be prepared so as to extend or sustain release, for example, by coating or embedding particulate material in polymers, waxes, or the like.

[0060] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, troches, and mouthwashes.

[0061] The compounds of the present disclosure or their salts or solvates may be used alone or in combination with other therapeutic agents. The compounds of formula (I) and the other pharma- ceutical active agent(s) may be administered together or separately, and when administered separately, administration may be simultaneous or sequential in any order. The amounts of the compounds of formula (I) and the other pharma- ceutical active agent(s) and the relative timing of administration will be selected to achieve the desired combined therapeutic effect. The administration of the compounds of formula (I) or their salts or solvates in combination with the other therapeutic agents may be a combination by simultaneous administration in: (1) a single pharmaceutical composition containing the combination of the compounds, or (2) separate pharmaceutical compositions, each containing one of the compounds. Alternatively, the combination may be administered separately in a sequential manner, where one therapeutic agent is administered first and the other is administered second, or vice versa. Such sequential administration may be close in time or remote in time.

[0062] The compounds of the present disclosure can be made by a variety of methods, including well-known standard synthetic methods. Exemplary general synthetic methods are described below and then specific compounds of the present disclosure are prepared in the working examples.

[0063] In all of the examples described below, protecting groups for sensitive or reactive groups are used where necessary, in accordance with general principles of synthetic chemistry. Protecting groups may be prepared according to standard methods of organic synthesis (see, TW Green and PG M Huts (1999) Protecting Groups in Organic Synthesis, 3, incorporated by reference for protecting groups). rd These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present disclosure.

[0064] The present disclosure also provides methods for the synthesis of novel compounds useful as synthetic intermediates in the preparation of compounds of formula (I) and compounds of the present disclosure.

[0065] The compounds can be prepared according to the methods described below using readily available starting materials and reagents. In these reactions, variants that are themselves known to those skilled in the art, but are not mentioned in more detail, can be used.

[0066] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. 13 C or 14Compounds having this structure, except for the replacement of carbon atoms with C-rich carbons, are within the scope of the present disclosure. For example, deuterium has been widely used to investigate the pharmacokinetics and metabolism of biologically active compounds. Although deuterium behaves similarly to hydrogen from a chemical standpoint, there are significant differences in bond energy and bond length between deuterium-carbon bonds and hydrogen-carbon bonds. As a result, the replacement of hydrogen with deuterium in biologically active compounds may generally result in compounds that retain their biochemical potency and selectivity but exhibit significantly different absorption, distribution, metabolism, and / or excretion (ADME) properties compared to their non-isotope-containing counterparts. Thus, deuterium replacement may result in improved drug efficacy, safety, and / or tolerability for some biologically active compounds.

[0067] According to another aspect of the present disclosure, there is also provided a process for the preparation of a pharmaceutical formulation comprising mixing a compound of formula (I) or salts, solvates, and physiologically functional derivatives thereof with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0068] Those skilled in the art of organic synthesis will appreciate that there are multiple means to produce compounds of the present disclosure that are radiolabeled with isotopes suitable for a variety of uses.

[0069] Experimental Section Abbreviation: As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification: [Table 2]

[0070] All solvents and chemicals were reagent grade. Unless otherwise stated, all reagents and solvents were purchased from commercial vendors and used as received. Flash column chromatography was performed on a Teledyne ISCO CombiFlash® Rf system using pre-packed columns. Solvents used included hexane, ethyl acetate (EtOAc), dichloromethane, methanol, and chloroform / methanol / ammonium hydroxide (80:18:2) (CMA-80). Compound purity and characterization were established by a combination of HPLC, TLC, mass spectrometry, and NMR analysis. 1 H and 13 C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer and read with chloroform-d, DMSO-d6, or methanol-d4 with tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as internal reference. Chemical shifts are reported in ppm relative to the reference signal, and coupling constant (J) values ​​are reported in Hertz (Hz).

[0071] Thin-layer chromatography (TLC) was performed using EMD-precoated silica gel 60 F 254 Plates were run and spots were visualized with UV light or iodine stain. Low-resolution mass spectra were obtained using a Waters Alliance HT / Micromass ZQ system (ESI). All test compounds were greater than 95% pure as determined by HPLC on an Agilent 1100 system using an Agilent Zorbax SB-Phenyl, 2.1 mm×150 mm, 5 μm column with a flow rate of 1.0 mL / min and gradient elution using mobile phases (A) H2O containing 0.1% CF3COOH and (B) MeCN.

[0072] All solvents and chemicals were reagent grade. Unless otherwise stated, all reagents and solvents were purchased from commercial vendors and used as received. Flash column chromatography was performed on a Teledyne ISCO CombiFlash® Rf system using pre-packed columns. Solvents used included hexane, ethyl acetate (EtOAc), dichloromethane (DCM), and methanol. Compound purity and characterization were established by a combination of NMR, mass spectrometry, TLC, and HPLC analysis. 1 H and 13 C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer and determined with CDCl3, DMSO-d6, or CD3OD with tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as an internal reference. Chemical shifts are reported in ppm relative to the reference signal, and coupling constant (J) values ​​are reported in Hertz (Hz). Nominal mass spectra were obtained using an Agilent InfinityLab MSD single quadrupole mass spectrometer system (ESI). Thin layer chromatography (TLC) was performed on EMD precoated silica gel 60 F. 254 Plates were run and spots were visualized with UV light or iodine stain. All final compounds were greater than 95% pure as determined by HPLC on a Waters 2695 Separation Module equipped with a Waters 2996 Photodiode Array Detector and a Phenomenex Synergi 4 mm Hydro-RP 80A C18 250 x 4.6 mm column, using a flow rate of 1 mL / min starting with 5% solvent B in 1 min, followed by a 15 min gradient of 5-95% solvent B, followed by 9 min of 95% solvent B (Solvent A, water with 0.1% TFA; Solvent B, acetonitrile with 0.1% TFA and 5% water; absorbance monitored at 280 nm).

[0073] Chemistry and Biology Explanation chemistry The target compounds 3-6 were synthesized according to the reactions shown in Scheme A. O-alkylation of p-iodophenol A1 with 2-methyl-1-pentanol under Mitsunobu conditions provided the ether A2. Reaction of A2 with tert-butyl methylmalonate in the presence of NaH and CuBr led to the malonate intermediate A3. Removal of the tert-butyl group with HCl gave the corresponding acid A4, which was then subjected to acid chloride-mediated coupling with (R)-(+)-α-methylbenzylamine or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU)-mediated coupling with (S)-(-)-α-methylbenzylamine to give the amides A5 and A6, respectively. Reduction of the ester functionality with freshly prepared LiBH4, followed by chromatographic separation of the diastereomeric mixtures provided the pure alcohols 3-6. The absolute stereochemistry of 4 and 5 was confirmed by the asymmetric synthesis shown in Scheme B. [ka]

[0074] Scheme A. Synthesis of compounds 3-6. Reagents and conditions: (a) PPh3, diethyl azodicarboxylate (DEAD), 2-methyl-1-pentanol, tetrahydrofuran (THF), room temperature (rt), overnight; (b) tert-butyl methylmalonate, CuBr, hexamethylphosphoramide (HMPA), NaH, dioxane, reflux, 6 h; (c) 4M HCl in dioxane, dichloromethane (DCM), room temperature, overnight; (d) (COCl)2, catalytic dimethylformamide (DMF), DCM, room temperature, 2 h, followed by (R)-(+)-α-methylbenzylamine, Et3N, DCM, room temperature, overnight, or (S)-(-)-α-methylbenzylamine, HBTU, Et3N, CH3CN, room temperature, 6 h; (e) NaBH4, LiCl, THF-EtOH (1:1), room temperature, 5 h, followed by chromatographic separation of the diastereomeric mixture.

[0075] The asymmetric synthesis of amides 4, 5, and 7-24 was carried out according to the reactions shown in Scheme B. Mitsunobu reaction of methyl 2-(4-hydroxyphenyl)acetate B1 with 2-methyl-1-pentanol gave ether B2a. Saponification of the ester functionality with NaOH followed by acidic workup gave the corresponding carboxylic acid (structure not shown), which was then reacted with oxalyl chloride in dichloromethane (DCM) to give acid chloride B3a. The acid chloride was coupled with (R)-4-benzyl-2-oxazolidinone in the presence of n-BuLi to give amide B4a. Amide B4a was subjected to TiCl4-mediated asymmetric hydroxymethylation in the presence of s-trioxane to give alcohol B5a as the only diastereomer. The oxazolidinone auxiliary was then removed by hydrolysis in the presence of H2O2 and LiOH to give acid B6. Amides 4 and 5 were prepared by coupling of acid B6 with enantiomerically pure (R)-(+)-α-methylbenzylamine and (S)-(-)-α-methylbenzylamine, respectively, using N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). Similarly, amides 9-24 were synthesized by coupling of B6 with appropriate amines, as shown in Table 1. Meanwhile, protection of the phenol group in B1 with triisopropylsilyl chloride (TIPS) gave B2b, which was then converted to B5b by using a procedure similar to that used to prepare B5a. Protection of the methyl alcohol with a methoxyethoxymethyl (MEM) group gave B7, which was subjected to hydrolysis, followed by coupling of the resulting acid with R)-(+)-α-methylbenzylamine and removal of the TIPS protecting group to give phenol B8. Finally, alkylation of B8 with (2S)-2-methylbutyl 4-methylbenzene-1-sulfonate or (2R)-2-methylbutyl 4-methylbenzene-1-sulfonate followed by MEM deprotection with ZnBr2 afforded 7 and 8, respectively. [ka]

[0076] Scheme B. Synthesis of compounds 4, 5, and 7-24. Reagents and conditions: (a) B2a: PPh3, DEAD, 2-methyl-1-pentanol, THF, room temperature, overnight; B2b: TIPS chloride, imidazole, DMF, room temperature, overnight; (b) (i) NaOH, EtOH-H2O (1:1), room temperature, 4 hours, acidic treatment; (ii) (COCl2), catalytic DMF, DCM, room temperature, 4 hours; (c) (R)-4-benzyl-2-oxazolidinone, n-BuLi, THF, -78 (d) (i) TiCl4, DCM, 0°C, 5 min, (ii) DIPEA, 0°C, 1 h, (iii) s-trioxane, TiCl4, 0°C, 4 h, (e) H2O2, LiOH, THF-H2O (4:1), room temperature, 3 h, (f) amine, TCFH, NMI, CH3CN, room temperature, 3 h or overnight, (g) MEM chloride, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), DCM, room temperature, overnight, (h) tetrabutylammonium fluoride (TBAF), THF, 0°C to room temperature, 2 h, (i) (2S)-2-methylbutyl 4-methylbenzene-1-sulfonate or (2R)-2-methylbutyl 4-methylbenzene-1-sulfonate, K2CO3, MeCN, 90°C, overnight, followed by ZnBr2, DCM, room temperature, overnight.

[0077] The target compounds 25-27 and 30-37 were synthesized according to the reactions shown in Scheme C. The conversion of the acid chloride C1 to the 4-bromophenylacetamide derivative C5 was achieved by using a procedure similar to that used to prepare 4 (Scheme B). The aryl bromide C5 (R 4=OH or Me) was subjected to Suzuki coupling with 4-substituted phenylboronic acids to give the biphenyl analogs 25, 27, and 32-35. Similarly, C5 was subjected to Sonogashira coupling with alkynes to give the desired alkyne analogs 36 and 37. Reaction of the acid chloride C1 with (R)-(+)-α-methylbenzylamine gave the amide C6, which was then coupled with 4-propylphenylboronic acid to afford 26. Finally, treatment of alcohol 25 with PPh3 and CBr4 gave the bromide C7, which was then reacted with 1,2,4-triazole or 1,2,3-triazole to give 30 and 31, respectively. [ka]

[0078] Scheme C. Synthesis of compounds 25-27, and 30-37. Reagents and conditions: (a) (R)-4-benzyl-2-oxazolidinone, n-BuLi, THF, -780°C, 1 hour; (b) R 3 For =OH, (i) TiCl4, DCM, 0°C, 5 min, (ii) DIPEA, 0°C, 1 h, (iii) s-trioxane, TiCl4, 0°C, 4 h; R 3 For =Me, sodium bis(trimethylsilyl)amide (NaHMDS), iodoethane, THF, -78 0 °C, then room temperature, overnight; (c) H2O2, LiOH, THF-H2O (4:1), room temperature, 3 h; (d) (R)-(+)-α-methylbenzylamine, TCFH, NMI, CH3CN, room temperature, 3 h; (e) 4-substituted phenylboronic acid, Pd(dppf)Cl2·DCM, K3PO4, dimethoxyethane (DME), H2O, microwave, 160 0 °C, 6 min; or alkyne, Pd(OAc)2, P(o-tol)3, Et3N, CH3CN, 75 0°C, 4 hours; (f) (R)-(+)-α-Methylbenzylamine, Et3N, DCM, room temperature, overnight; (g) PPh3, CBr4, THF, room temperature, overnight; (h) triazole, K2CO3, DMF, room temperature, overnight.

[0079] The target compounds 28 and 29 were synthesized according to the reaction shown in Scheme D. Reaction of 4-iodobromobenzene D1 with tert-butylmethylmalonate in the presence of NaH and CuBr gave 4-bromophenylmalonate D2. Removal of the tert-butyl group with HCl gave acid D3, which was treated with oxalyl chloride to form the corresponding acid chloride (structure not shown). Coupling of the acid chloride with (R)-(+)-α-methylbenzylamine gave amide D4. Suzuki coupling of D4 with 4-propylphenylboronic acid gave target compound 28. Conversion of the ester group in 28 to the corresponding acid followed by coupling with methylamine gave target compound 29. [ka]

[0080] Scheme D. Synthesis of compounds 28 and 29. Reagents and conditions: (a) tert-Butyl methylmalonate, CuBr, HMPA, NaH, dioxane, reflux, 6 h, (b) 4M HCl in dioxane, DCM, rt, overnight, (c) (COCl)2, catalytic DMF, DCM, rt, 2 h, then (R)-(+)-α-methylbenzylamine, Et3N, DCM, rt, overnight, (d) 4-propylphenylboronic acid, Pd(dppf)Cl2·DCM, K3PO4, DME, H2O, microwave, 160 °C, 6 min, (e) (i) NaOH, MeOH-H2O (1:1), rt, 4 h, acid treatment, (ii) methylamine hydrochloride, TCFH, NMI, CH3CN, rt, 3 h.

[0081] Urea derivatives 38-60 were synthesized according to the reactions shown in Scheme E. Substituted aniline E1 and amine (or isocyanate) E2 were coupled by using standard urea coupling methods. Boc-protected ureas E3a-q were then treated with 4 M HCl in dioxane to remove the Boc protecting group, resulting in target compounds 38-54. Meanwhile, 4-bromophenyl derivative E3r was subjected to Suzuki coupling with 4-substituted phenylboronic acid to give biphenyls E4a-e or Sonogashira coupling with 4-methyl-1-pent-1-yne to give E4f. Finally, Boc group deprotection with HCl afforded target compounds 55-60. [ka]

[0082] Scheme E. Synthesis of compounds 38-60. Reagents and conditions: (a) Method A: triphosgene, Et3N, DCM, rt, then reflux; Method B: amine, isocyanate, DCM, rt, (b) Method A: 4M HCl in dioxane, DCM, 0 °C to rt; Method B: TFA, DCM, rt, 30 min, (c) E4a-e: 4-substituted phenylboronic acids, Pd(dppf)Cl2·DCM, K3PO4, DME, H2O, microwave, 160 °C, 6 min; E4f: 4-methyl-1-pent-1-yne, Pd(OAc)2, P(o-tol)3, Et3N, CH3CN, 75 0 °C, 4 hr.

[0083] experiment All solvents and chemicals were reagent grade. Unless otherwise stated, all reagents and solvents were purchased from commercial vendors and used as received. Flash column chromatography was performed on a Teledyne ISCO CombiFlash® Rf system using pre-packed columns. Solvents used included hexane, ethyl acetate (EtOAc), dichloromethane (DCM), and methanol. Compound purity and characterization were established by a combination of NMR, mass spectrometry, TLC, and HPLC analysis. 1 H and13 C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) or a JEOL 400 MHz NMR spectrometer and determined with CDCl3, DMSO-d6, or CD3OD with tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as an internal reference. Chemical shifts are reported in ppm relative to the reference signal, and coupling constant (J) values ​​are reported in Hertz (Hz). Nominal mass spectra were obtained using an Agilent InfinityLab MSD single quadrupole mass spectrometer system (ESI). Thin layer chromatography (TLC) was performed on EMD precoated silica gel 60 F254 plates, and spots were visualized with UV light or iodine stain. All final compounds were greater than 95% pure as determined by HPLC on a Waters 2695 Separation Module equipped with a Waters 2996 Photodiode Array Detector and a Phenomenex Synergi 4 mm Hydro-RP 80A C18 250 x 4.6 mm column using a flow rate of 1 mL / min starting with 5% solvent B in 1 min, followed by a 15 min gradient of 5-95% solvent B, followed by 9 min of 95% solvent B (Solvent A, water with 0.1% TFA; Solvent B, acetonitrile with 0.1% TFA and 5% water; absorbance monitored at 280 nm).

[0084] Synthesis of compounds 3-6 (Scheme A). [ka] 1-Iodo-4-[(2-methylpentyl)oxy]benzene (A2). To a solution of 4-iodophenol (A1) (3.0 g, 13.63 mmol), PPh3 (6.08 g, 23.18 mmol), and 2-methylpentanol (3.38 mL, 27.27 mmol) in THF (50 mL) at room temperature under nitrogen, DEAD (3.93 mL, 23.18 mmol) was added dropwise slowly while keeping the reaction temperature below 35 °C. After the addition, the reaction mixture was stirred at room temperature overnight and quenched with H2O (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-10% EtOAc in hexanes to give A2 (3.56 g, 86% yield) as a pale yellow oil. 1 H NMR(300MHz,CDCl3)δ 7.56-7.31(m,2H),6.68-6.41(m,2H),3.64(ddd,J=15.6,8.9,6.3Hz,2H),2.03 -1.73(m,1H),1.55-1.13(m,4H),0.97(d,J=6.7Hz,3H),0.90(t,J=7.1Hz,3H); 13 C NMR(75MHz,CDCl3)δ 159.3,138.2,117.1,82.6,73.5,35.9,33.0,20.2,17.2,14.6;MS(ESI)m / z 305.2[M+H] + .

[0085] [ka] 1-tert-Butyl 3-methyl-2-{4-[(2-methylpentyl)oxy]phenyl}propanedioate (A3). To a suspension of sodium hydride (60%, 208 mg, 6.25 mmol) in anhydrous dioxane (30 mL) was added HMPA (1.2 mL) and tert-butyl methylmalonate (907 mg, 5.20 mmol). The mixture was stirred at room temperature for 1 h. To the resulting mixture was added copper(I) bromide (896 mg, 6.25 mmol) and A2 (1.9 g, 6.25 mmol), and the mixture was then refluxed under nitrogen for 3 h. After cooling to room temperature, the reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-20% EtOAc in hexanes to give A3 (1.80 g, 99% yield) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.28(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),4.48(s,1H),3.85-3.66(m,5H),2 .02-1.85(m,1H),1.50-1.12(m,13H),0.99(t,J=5.3Hz,3H),0.96-0.85(m,3H); 13 C NMR(75MHz,CDCl3)δ 169.3,167.5,159.2,130.3,125.0,114.6,82.2,73.2,58.1,52.5,35.8,32.9,27.9,20.0,17.0,14.3;MS(ESI)m / z 373.2[M+Na] + .

[0086] [ka] 3-Methoxy-2-{4-[(2-methylpentyl)oxy]phenyl}-3-oxopropanoic acid (A4). To a solution of A3 (550 mg, 1.57 mmol) in DCM (20 mL) was added 4 M HCl in dioxane (3.92 mL, 15.70 mmol) and the resulting reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure to give A4 (460 mg, quantitative yield) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.28(d,J=6.7Hz,2H),6.88(d,J=8.7Hz,2H),4.60(br s,1H),3.92-3.60(m,5H),1.93(dq,J=12.8,6.5Hz,1H),1.63-1.10(m,4H),1.00(d,J=6.7Hz,3H),0.92(t,J=7.0Hz,3H);MS(ESI)m / z 295.2[M+H] + .

[0087] [ka] Methyl 2-{4-[(2-methylpentyl)oxy]phenyl}-2-{[(1R)-1-phenylethyl]carbamoyl}acetate (A5). To a solution of A4 (251 mg, 0.85 mmol) in DCM (10 mL) was added oxalyl chloride (0.15 mL, 1.71 mmol) and DMF (1 drop) and the resulting reaction was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM (10 mL) followed by the addition of Et3N (596 μL, 4.28 mmol) and (R)-(+)-α-methylbenzylamine (165 μL, 1.28 mmol). The mixture was stirred at room temperature for 48 h. The reaction was quenched with saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with additional DCM (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (NaSO) and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give the diastereomeric mixture of A5 (244 mg, 72% yield) as a colorless oil. 1H NMR(300MHz,CDCl3)δ 7.41-7.07(m,8H),6.93-6.72(m,2H),5.08(p,J=7.0Hz,1H),4.48(d,J=1.6Hz,1H),3.87-3.57 (m,5H),1.98-1.83(m,1H),1.60-1.10(m,7H),1.00(dd,J=6.7,1.8Hz,3H),0.96-0.86(m,3H); 13 C NMR(75MHz,CDCl3)δ 166.7,159.3,143.0,129.5,129.5,128.6,128.6,127.2,126.0,114.9,114.9 ,73.2,57.5,52.5,49.0,48.9,35.7,32.9,21.7,20.0,17.0,14.3;MS(ESI)m / z 398.4[M+H] + .

[0088] [ka] Methyl 2-{4-[(2-methylpentyl)oxy]phenyl}-2-{[(1S)-1-phenylethyl]carbamoyl}acetate (A6). To a solution of A4 (200 mg, 0.68 mmol) in MeCN (5 mL) was added HBTU (387 mg, 1.02 mmol), Et3N (284 μL, 2.04 mmol), and (S)-(-)-α-methylbenzylamine (131 μL, 1.02 mmol) and the resulting reaction was stirred at room temperature for 6 h. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give the diastereomeric mixture A6 (257 mg, 31% yield) as a colorless oil. 11H NMR (300 MHz, CDCl3) δ 7.41 - 7.15 (m, 6H), 7.04 (dd, J = 19.6, 7.9 Hz, 1H), 6.86 (t, J = 9.2 Hz, 2H), 5.11 (p, J = 7.0 Hz, 1H), 4.47 (s, 1H), 3.83 - 3.66 (m, 5H), 2.01 - 1.84 (m, 1H), 1.46 (t, J = 7.4 Hz, 4H), 1.41 - 1.12 (m, 3H), 1.07 (br s, 1H), 1.00 (dd, J = 6.7, 2.1 Hz, 3H), 0.92 (t, J = 6.9 Hz, 3H); 13 13C NMR (75 MHz, CDCl3) δ 171.5, 166.6, 159.4, 159.4, 143.0, 142.9, 129.4, 129.4, 128.6, 128.6, 127.3, 127.3, 126.0, 125.8, 125.7, 115.1, 115.0, 73.3, 57.7, 57.6, 52.6, 49.0, 49.0, 35.8, 32.9, 21.9, 21.8, 20.0, 17.0, 14.3; MS (ESI) m / z 398.4 [M + H] + 。

[0089]

Chem.

[0090]

change

[0091] Synthesis of compounds 4, 5, and 7-24 (Scheme B). [ka] Methyl 2-{4-[(2-methylpentyl)oxy]phenyl}acetate (B2a). Following the procedure for the synthesis of A2 starting from B1, the ether B2a (70% yield) was obtained as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.20-7.10(m,2H),6.92-6.72(m,2H),3.85-3.62(m,5H),3.55(s,2H),2.04- 1.79(m,1H),1.59-1.08(m,4H),1.00(d,J=6.7Hz,3H),0.91(t,J=7.1Hz,3H); 13 C NMR(75MHz,CDCl3)δ 172.4,158.5,130.2,125.8,114.6,73.3,51.9,40.3,35.8,32.9,20.0,17.0,14.3;MS(ESI)m / z 251.2[M+H]+ .

[0092] [ka] Methyl 2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)acetate (B2b). To a solution of B1 (5.0 g, 30.08 mmol) in DMF (50 mL) was added TIPS chloride (7.09 mL, 33.09 mmol) and imidazole (4.50 g, 66.18 mmol) and the resulting reaction was stirred at room temperature overnight. The mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-10% EtOAc in hexanes to give B2b (9.4 g, 97% yield) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.11(d,J=8.5Hz,2H),6.82(d,J=8.5Hz,2H),3.67(s,3H),3.54(s,2H),1.35-1.17(m,3H),1.17-0.97(m,18H);MS(ESI)m / z 323.2[M+H] + .

[0093] [ka] 2-{4-[(2-methylpentyl)oxy]phenyl}acetyl chloride (B3a). To a solution of B2a (5.0 g, 20.0 mmol) in EtOH-H2O (60 mL, 2:1) was added 1N NaOH (40 mL, 40.0 mmol) and the reaction was stirred at room temperature for 3 h. The mixture was acidified to pH=2 with 1N HCl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried (Na2SO4) and concentrated under reduced pressure to give the corresponding acid (5 g, quantitative). To a solution of the acid (5.0 g, 21.1 mmol) in DCM (50 mL) was added oxalyl chloride (3.91 mL, 42.32 mmol) and DMF (0.2 mL) and the resulting reaction was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was dried in vacuum to give crude B3a as a yellow residue which was used immediately in the next transformation without characterization.

[0094] [ka] 2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)acetyl chloride (B3b). Following the procedure for the synthesis of B3a starting from B2b, B3b (99% yield) was obtained as a yellow residue which was used immediately in the next transformation without characterization.

[0095] [ka] (4R)-4-benzyl-3-(2-{4-[(2-methylpentyl)oxy]phenyl}acetyl)-1,3-oxazolidin-2-one (B4a). To a solution of (R)-4-benzyl-2-oxazolidinone (3.56 g, 20.1 mmol) in THF (40 mL) at -78°C was slowly added dropwise over 10 min with n-BuLi (2.5 M in hexanes, 8.46 mL, 21.10 mmol). After stirring for an additional 10 min at -78°C, a solution of B3a (5.0 g in 10 mL THF) was added to the above reaction over 10 min at -78°C. The resulting reaction was stirred for 15 min at -78°C, warmed to room temperature and stirred for an additional 1 h. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give B4a (6.43 g, 77% yield) as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.34-7.16(m,5H),7.15-7.03(m,2H),6.96-6.77(m,2H),4.77-4.49(m,1H),4.30-4.10(m,4H),3.88-3.58(m,2H),3.23(dd,J=13 .4,3.1Hz,1H),2.74(dd,J=13.3,9.4Hz,1H),2.01-1.83(m,1H),1.58-1.12(m,4H),1.00(d,J=6.7Hz,3H),0.91(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 171.6,158.6,153.4,135.2,130.8,129.4,128.9,127.3,125.3,114.7, 73.2,66.1,55.3,40.7,37.7,35.8,32.9,20.1,17.0,14.3;MS(ESI)m / z 396.4[M+H] + .

[0096] [ka] (4R)-4-Benzyl-3-[2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)acetyl]-1,3-oxazolidin-2-one (B4b). Following the procedure for the synthesis of B4a starting from B3b, B4b (70% yield) was obtained as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.38-6.97(m,7H),6.77(d,J=8.5Hz,2H),4.69-4.48(m,1H),4.28-3.95(m,4H),3.15(dd,J=13. MS(ESI)m / z 468.6[M+H] + .

[0097] [ka] (4R)-4-Benzyl-3-[(2S)-3-hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}propanoyl]-1,3-oxazolidin-2-one (B5a). To a solution of B4a (6.38 g, 16.13 mmol) in DCM (120 mL) at 0° C., TiCl4 (1 M in toluene, 16.94 mL, 16.94 mmol) was slowly added dropwise over 5 min. The resulting brown solution was stirred at 0° C. for 5 min, after which DIPEA (3.09 mL, 417.74 mmol) was added dropwise. The resulting deep blue mixture was stirred at 0° C. for 1 h. Then, solutions of s-trioxane (1.67 g, 18.55 mmol) and additional TiCl4 (16.94 mL, 16.94 mmol) in DCM (5 mL) were added successively. The mixture was stirred at 0° C. for an additional 4 h, then quenched with saturated aqueous NH4Cl and extracted with additional DCM (3×20 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give B5a (2.2 g, 32% yield) as a colorless oil. 1H NMR(300MHz,CDCl3)δ 7.33-6.99(m,7H),6.74(d,J=8.5Hz,2H),5.11(dd,J=9.2,5.1Hz,1H),4.63-4.39(m,1H),4.25-4.04(m,1H) ,4.04-3.83(m,2H),3.79-3.51(m,3H),3.22(dd,J=13.4,3.2Hz,1H),2.76(dd,J=13.4,9.3Hz,1H),2.42(br s,1H),1.90-1.69(m,1H),1.42-1.08(m,4H),0.90(d,J=6.7Hz,3H),0.87-0.78(m,3H); 13 C NMR(75MHz,CDCl3)δ 173.4,159.0,152.7,135.3,129.9,129.5,129.0,127.3,126.6,114.7,73 .2,65.9,65.2,55.6,51.1,37.9,35.7,32.9,20.0,17.0,14.3;MS(ESI)m / z 408.4[M-H2O+H] + .

[0098] [ka] (4R)-4-Benzyl-3-[(2S)-3-hydroxy-2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)propanoyl]-1,3-oxazolidin-2-one (B5b). Following the procedure for the synthesis of B5a starting from B4b, B5b (59% yield) was obtained as a white foam. 1 H NMR (300MHz, CDCl3) δ 1H NMR(300MHz,CDCl3)δ 7.38-7.10(m,7H),6.86-6.76(m,2H),5.18(dd,J=9.2,5.1Hz,1H),4.72-4.53(m,1H),4.28-4.11(m,2H),3.91-3.70(m,1H),3.33 (dd,J=13.4,3.4Hz,1H),2.86(dd,J=13.4,9.4Hz,1H),2.11(t,J=6.5Hz,1H),1.34-1.16(m,4H),1.14-1.00(m,18H);MS(ESI)m / z 480.0[M-H2O+H] + .

[0099] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}propanoic acid (B6). To a solution of B5a (2.21 g, 5.2 mmol) in THF-H2O (4:1, 50 mL) at 0 °C, LiOH·H2O (436 mg, 10.40 mmol) and H2O2 (30%, 5.89 mL, 52.0 mmol) were added and the resulting reaction was stirred at 0 °C for 4 h. The mixture was partitioned between DCM and H2O. The aqueous layer was acidified to pH = 2 with 1N HCl and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried (Na2SO4) and concentrated under reduced pressure to give crude B6 (quantitative yield) as a white solid, which was used in the next transformation without further purification. 1 H NMR(300MHz,CDCl3)δ 7.40-6.98(m,3H),6.84(d,J=8.5Hz,2H),4.24-3.97(m,1H),3.89-3.57(m,4H),2.00-1 .81(m,1H),1.58-1.08(m,4H),0.99(d,J=6.7Hz,3H),0.91(t,J=7.0Hz,3H);MS(ESI)m / z 265.2[MH] - .

[0100] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-phenylethyl]propenamide (4). Method A: To a solution of B6 (95 mg, 0.36 mmol) in MeCN (5 mL) at room temperature was added DIPEA (0.19 mL, 1.08 mmol), (R)-(+)-α-methylbenzylamine (65 mg, 0.54 mmol), and HBTU (203 mg, 0.54 mmol). After stirring for 5 h, the reaction was quenched with H2O (10 mL) followed by the addition of EtOAc (50 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (10 mL) and brine (2 x 20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give 4 (90 mg, 68% yield) as a white solid. Method B: To a solution of B6 (30 mg, 0.11 mmol) in MeCN (1 mL) at room temperature, (R)-(+)-α-methylbenzylamine (20.5 mg, 0.17 mmol), TCFH (35 mg, 0.12 mmol), and NMI (20.4 mg, 0.25 mmol) were added and the reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give 4 (30 mg, 72% yield) as a white solid. This material was identical to that of 4 prepared in Scheme 1. 1 H NMR and 13 C NMR.

[0101] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1S)-1-phenylethyl]propenamide (5). Following the procedure for the synthesis of 4, starting with B6 and (S)-(-)-α-methylbenzylamine, 5 (70% yield) was obtained as a white solid. This material was identical to that of 5 prepared in Scheme 1. 1 H NMR and 13C NMR.

[0102] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-(2-methylphenyl)ethyl]propenamide (9). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(2-methylphenyl)ethan-1-amine, 9 (75% yield) was obtained as a white solid. 1 H NMR (300MHz, CDCl3) δ 7.17-7.07(m,5H),7.03-6.95(m,1H),6.94-6.74(m,2H),5.75(d,J=7.4Hz,1H) ,5.39-5.14(m,1H),4.07(t,J=10.0Hz,1H),3.82(dd,J=8.9,5.8Hz,1H),3.77- 3.66(m,2H),3.63(dd,J=8.7,4.4Hz,1H),3.56-3.43(m,1H),2.33(s,3H),2.07 -1.86(m,1H),1.60-1.11(m,7H),1.04(d,J=6.7Hz,3H),0.95(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 172.9,159.0,141.0,135.4,130.7,129.5,128.3,127.2,126.2,124.4,115.1 ,73.3,65.2,53.4,46.7,35.8,32.9,21.2,20.0,18.9,17.0,14.3;MS(ESI)m / z 384.4[M+H] + ;HPLC,>97%,t R 18.0 minutes.

[0103] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-(3-methylphenyl)ethyl]propenamide (10). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(3-methylphenyl)ethan-1-amine, 10 (70% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.24-7.09(m,3H),7.05(d,J=7.6Hz,1H),6.97-6.81(m,4H),5.74(d,J=7.7Hz,1H),5.08(p,J=7.0Hz,1H),4.14-4.02(m, 1H),3.89-3.48(m,5H),2.30(s,3H),2.06-1.83(m,1H),1.63-1.11(m,7H),1.03(d,J=6.7Hz,3H),0.94(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 173.3,159.0,142.9,138.2,129.5,128.9,128.5,128.0,126.4,122.7,115.1 ,73.3,65.0,53.2,48.9,35.7,32.9,22.1,21.4,20.0,17.0,14.3;MS(ESI)m / z 384.6[M+H] + ;HPLC,>98%,t R 18.0 minutes.

[0104] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-(4-methylphenyl)ethyl]propenamide (11). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(4-methylphenyl)ethan-1-amine, 11 (80% yield) was obtained as a white solid. 1H NMR(300MHz,CDCl3)δ 7.22-6.97(m,6H),6.88(d,J=8.7Hz,2H),5.72(d,J=7.7Hz,1H),5.08(p,J=7.0Hz,1H),4.08(t,J=9.7Hz,1H),3 .91-3.35(m,5H),2.33(s,3H),2.02-1.85(m,1H),1.59-1.12(m,7H),1.08-0.98(m,3H),0.95(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 384.4[M+H] + ;HPLC,>97%,t R 18.0 minutes.

[0105] [ka] (2S)-N-[(1R)-1-(4-fluorophenyl)ethyl]-3-hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}propenamide (12). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(4-fluorophenyl)ethan-1-amine, 12 (76% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.14-7.06(m,4H),7.02-6.91(m,2H),6.90-6.79(m,2H),5.77(d,J=7.6Hz,1H),5.08(p,J=7.1Hz,1H),4.07(dd,J=10 .9,8.8Hz,1H),3.86-3.56(m,5H),2.05-1.83(m,1H),1.61-1.16(m,7H),1.03(d,J=6.7Hz,3H),0.94(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 173.1,161.9(d,J C,F =245.0Hz), 159.0, 138.9(d,J C,F=3.0Hz), 129.5, 128.2, 127.4(d,J C,F =8.0Hz), 115.3(d,J C,F =21.0Hz),115.1,73.3,65.0,53.4,48.2,35.7,32.9,22.0,20.0,17.0,14.3;MS(ESI)m / z 388.4[M+H] + ;HPLC,>98%,t R 17.4 minutes.

[0106] [ka] (2S)-3-Hydroxy-N-[(1R)-1-(4-methoxyphenyl)ethyl]-2-{4-[(2-methylpentyl)oxy]phenyl}propenamide (13). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(4-methoxyphenyl)ethan-1-amine, 13 (72% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.16-6.99(m,4H),6.92-6.73(m,4H),5.67(d,J=7.7Hz,1H),5.07(p,J=7.0Hz,1H),4.15-4.00(m,1H),3.85-3.7 6(m,4H),3.75-3.48(m,4H),2.05-1.85(m,1H),1.58-1.12(m,7H),1.03(d,J=6.7Hz,3H),0.94(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 400.4[M+H] + ;HPLC,>95%,t R 17.0 minutes.

[0107] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-phenylpropanamide (14). Following the procedure for the synthesis of 4, starting from B6 and aniline, 14 (75% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.34(d,J=8.1Hz,2H),7.26-7.10(m,4H),7.02(t,J=7.4Hz,1H),6.83(d,J=8.6Hz,2H),4.21-4.04(m,1H),3.81-3 .56(m,4H),3.33-3.09(m,1H),1.97-1.78(m,1H),1.51-1.04(m,5H),0.94(d,J=6.7Hz,3H),0.85(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 172.2,159.2,140.4,129.6,129.0,127.9,124.6,120.0,115.3,73.3,65.0,54.5,35.7,32.9,20.0,17.0,14.3;MS(ESI)m / z 342.4[M+H] + ;HPLC,>97%,t R 17.3 minutes.

[0108] [ka] (2S)-N-benzyl-3-hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}propenamide (15). Following the procedure for the synthesis of 4, starting from B6 and benzylamine, 15 (65% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.27-7.13(m,3H),7.13-7.03(m,4H),6.83-6.71(m,2H),5.79(s,1H),4.45-4.21(m,2H),4.15-4.00(m,1) H),3.79-3.49(m,4H),1.96-1.76(m,1H),1.48-1.02(m,5H),0.93(d,J=6.7Hz,3H),0.84(t,J=7.0Hz,3H); 13C NMR(75MHz,CDCl3)δ 174.0,159.0,137.9,129.5,128.7,128.3,127.5,115.1,73.3,65.1,53.5,43.4,35.7,32.9,20.0,17.0,14.3;MS(ESI)m / z 356.4[M+H] + ;HPLC,>95%,t R 16.9 minutes.

[0109] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-(2-phenylethyl)propenamide (16). Following the procedure for the synthesis of 4, starting from B6 and 2-phenylethan-1-amine, 16 (60% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.23-7.05(m,3H),7.04-6.89(m,4H),6.76(d,J=8.7Hz,2H),5.60-5.44(m,1H),4.11-3.93(m,1H),3.80-3.66(m,2H),3.53-3.3 8(m,2H),3.38-3.20(m,1H),2.70-2.59(m,2H),2.02-1.79(m,2H),1.52-1.18(m,5H),1.01-0.90(m,3H),0.85(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 370.4[M+H] + ;HPLC,>99%,t R 17.4 minutes.

[0110] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-phenylpropyl]propenamide (17). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-phenylpropan-1-amine, 17 (68% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.42-7.16(m,4H),7.10(d,J=8.6Hz,3H),6.91-6.78(m,2H),5.76(d,J=8.1Hz,1H),4.87(q,J=7.5Hz,1H),4.12-3.98(m,1H),3.91-3 .45(m,5H),2.06-1.83(m,1H),1.78-1.65(m,2H),1.56-1.21(m,4H),1.07-0.99(m,3H),0.95(t,J=7.0Hz,3H),0.87(t,J=7.4Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 384.4[M+H] + ;HPLC,>95%,t R 17.6 minutes.

[0111] [ka] (2S)-3-Hydroxy-N-[(1S)-2-methoxy-1-phenylethyl]-2-{4-[(2-methylpentyl)oxy]phenyl}propenamide (18). Following the procedure for the synthesis of 4, starting from B6 and (1S)-2-methoxy-1-phenylethan-1-amine, 18 (50% yield) was obtained as a white solid. 1H NMR(300MHz,CDCl3)δ 7.24-7.10(m,3H),7.10-6.97(m,4H),6.80(d,J=8.7Hz,2H),6.16(d,J=7.7Hz,1H),5.15-4.99(m,1H),4.05-3.85(m,1H),3.79- 3.57(m,4H),3.56-3.39(m,2H),3.21(s,3H),2.00-1.70(m,1H),1.48-1.03(m,4H),0.95(d,J=6.7Hz,3H),0.85(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 400.4[M+H] + ;HPLC,>98%,t R 17.1 minutes.

[0112] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-(2-phenylpropan-2-yl)propenamide (19). Following the procedure for the synthesis of 4, starting from B6 and 2-phenylpropan-2-amine, 19 (65% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.42-7.12(m,7H),7.00-6.83(m,2H),5.73(s,1H),4.05(t,J=9.8Hz,1H),3.90-3.52(m,4H),3.41(br s,1H),2.11-1.82(m,1H),1.65(s,3H),1.61(s,3H),1.55-1.20(m,4H),1.05(d,J=6.7Hz,3H),0.95(t,J=7.0Hz,3H); 13C NMR(75MHz,CDCl3)δ MS(ESI)m / z 384.4[M+H] + ;HPLC,>99%,t R 18.2 minutes.

[0113] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-(1-phenylcyclopropyl)propenamide (20). Following the procedure for the synthesis of 4, starting from B6 and 1-phenylcyclopropan-1-amine, 20 (75% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.22-7.13(m,3H),7.12-6.97(m,4H),6.79(d,J=8.7Hz,2H),6.16(s,1H),4.04-3.92(m,1H),3.78-3.45(m, 5H),1.97-1.76(m,1H),1.49-1.23(m,3H),1.22-1.03(m,5H),0.94(d,J=6.7Hz,3H),0.85(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 382.4[M+H] + ;HPLC,>97%,t R 17.6 minutes.

[0114] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-(pyridin-2-yl)ethyl]propenamide (21). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(pyridin-2-yl)ethan-1-amine, 21 (70% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 8.34(d,J=4.3Hz,1H),7.55(td,J=7.7,1.8Hz,1H),7.16-6.98(m,4H),6.88-6.54(m,3H),5.05(p,J=6.9Hz,1H),4.03(dd, J=11.0,8.4Hz,1H),3.80-3.52(m,4H),1.96-1.68(m,1H),1.51-0.99(m,7H),0.93(d,J=6.7Hz,3H),0.84(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 173.3,160.7,158.9,148.9,136.8,129.5,128.5,122.2,121.2,115.0, 73.3,65.2,53.6,49.9,35.7,32.9,22.3,20.0,17.0,14.3;MS(ESI)m / z 371.4[M+H] + ;HPLC,>95%,t R 12.6 minutes.

[0115] [ka] (2S)-N-[(1R)-1-(furan-2-yl)ethyl]-3-hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}propenamide (22). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(furan-2-yl)ethan-1-amine, 22 (65% yield) was obtained as a white solid. 1H NMR(300MHz,CDCl3)δ 7.33-7.23(m,1H),7.14(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),6.27(dd,J=3.1,1.9Hz,1H),6.03(d,J=3.2Hz,1H),5.76(d,J=8.4Hz,1H),5.32- 5.15(m,1H),4.10(dd,J=10.8,8.8Hz,1H),3.88-3.60(m,4H),2.05-1.79 (m,1H),1.56-1.13(m,7H),1.02(d,J=6.7Hz,3H),0.93(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 360.4[M+H] + ;HPLC,>95%,t R 16.5 minutes.

[0116] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R)-1-(thiophen-2-yl)ethyl]propenamide (23). Following the procedure for the synthesis of 4, starting from B6 and (1R)-1-(thiophen-2-yl)ethan-1-amine, 23 (70% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.16-6.96(m,3H),6.87-6.65(m,4H),5.68(d,J=8.2Hz,1H),5.43-5.23(m,1H),4.16-3.89(m,1H),3.78-3.32(m ,5H),1.95-1.73(m,1H),1.45(d,J=6.8Hz,3H),1.41-1.05(m,4H),0.93(d,J=6.7Hz,3H),0.84(t,J=7.0Hz,3H); 13C NMR(75MHz,CDCl3)δ MS(ESI)m / z 376.4[M+H] + ;HPLC,>99%,t R 17.2 minutes.

[0117] [ka] (2S)-3-Hydroxy-2-{4-[(2-methylpentyl)oxy]phenyl}-N-[(1R,2S)-2-phenylcyclopropyl]propenamide (24). Following the procedure for the synthesis of 4, starting from B6 and (1R,2S)-2-phenylcyclopropan-1-amine, 24 (73% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.37-7.07(m,7H),6.89(d,J=8.6Hz,2H),5.84(br s,1H),4.22-4.06(m,1H),3.86-3.50(m,4H),2.94-2.83(m,1H),2.06-1.80(m,2H), 1.56-1.15(m,6H),1.14-1.05(m,1H),1.03(d,J=6.7Hz,3H),0.94(t,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 382.4[M+H] + ;HPLC,>95%,t R 17.6 minutes.

[0118] [ka] (4R)-4-Benzyl-3-[(2S)-3-[(2-methoxyethoxy)methoxy]-2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)propanoyl]-1,3-oxazolidin-2-one (B7). To a solution of B5b in DCM (10 mL) was added DIPEA (210 μL, 1.21 mmol), DMAP (10 mg, 0.08 mmol), and MEM chloride (69 μL, 0.06 mmol) and the resulting reaction was stirred at room temperature overnight. The reaction was diluted with HO (20 mL). The layers were separated and the aqueous layer was extracted with additional DCM (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (NaSO), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give B7 (242 mg, quantitative yield) as a colorless film. 1 H NMR (300MHz, CDCl3) δ 7.39-7.11(m,7H),6.80(d,J=8.5Hz,2H),5.37(dd,J=10.2,4.7Hz,1H),4.8 3-4.70(m,2H),4.70-4.55(m,1H),4.30(t,J=9.8Hz,1H),4.15-3.96(m,2H), 3.78-3.63(m,3H),3.60-3.50(m,2H),3.38(s,3H),3.26(dd,J=13.5,2.8Hz ,1H),2.99-2.72(m,1H),1.36-1.14(m,3H),1.14-0.94(m,18H);MS(ESI)m / z 608.4[M+Na] + .

[0119] [ka] (2S)-2-(4-hydroxyphenyl)-3-[(2-methoxyethoxy)methoxy]-N-[(1R)-1-phenylethyl]propenamide (B8). The oxazolidinone auxiliary in B7 was removed according to the procedure for the synthesis of B6 to give (2S)-3-[(2-methoxyethoxy)methoxy]-2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)propanoic acid (99% yield) as a colorless oil. MS (ESI) m / z 449.6 [M+Na] + Coupling of the acid with (R)-(+)-α-methylbenzylamine was carried out according to the procedure for the synthesis of 4 to give (2S)-3-[(2-methoxyethoxy)methoxy]-N-[(1R)-1-phenylethyl]-2-(4-{[tris(propan-2-yl)silyl]oxy}phenyl)propanamide (33% yield) as a colorless oil. MS (ESI) m / z 530.8 [M+H] + To a solution of the above amide (570 mg, 1.08 mmol) in THF (20 mL) at 0 °C, TBAF (1.0 M in THF, 1.61 mL, 1.61 mmol) was added and the resulting reaction was stirred at 0 °C for 2 h. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give B8 (380 mg, 94% yield) as a colorless residue. 1 H NMR(300MHz,CD3OD)δ 7.26-7.04(m,7H),6.74(d,J=8.5Hz,2H),5.12-4.92(m,4H),4.82-4.56(m,2H),4.14(t,J=9.6Hz,1H),3.8 4(dd,J=9.6,5.1Hz,1H),3.77-3.60(m,3H),3.52(dd,J=5.8,3.3Hz,2H),1.43(d,J=7.0Hz,3H);MS(ESI)m / z 374.0[M+H] + .

[0120] [ka] (2S)-3-Hydroxy-2-{4-[(2S)-2-methylbutoxy]phenyl}-N-[(1R)-1-phenylethyl]propenamide (7). A mixture of B8 (100 mg, 0.27 mmol), (2S)-2-methylbutyl 4-methylbenzene-1-sulfonate (97 mg, 0.41 mmol), and K2CO3 (111 mg, 0.80 mmol) in MeCN (3 mL) was heated at 90 °C overnight in a sealed vessel. The reaction was cooled to room temperature and diluted with EtOAc (5 mL) and H2O (5 mL). The layers were separated and the aqueous layer was extracted with additional EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried (Na2SO4), and concentrated under reduced procedure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give (2S)-3-[(2-methoxyethoxy)methoxy]-2-{4-[(2S)-2-methylbutoxy]phenyl}-N-[(1R)-1-phenylethyl]-propanamide (82 mg, 69% yield) as a colorless oil. MS (ESI) m / z 444.6 [M+H] + To a solution of the above ether (71 mg, 0.16 mmol) in DCM (10 mL) was added ZnBr2 (61 mg, excess) and the reaction was stirred at room temperature overnight. The reaction was diluted with DCM (5 mL), washed with brine (2 x 10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed using 12% isopropylamine (IPA) in hexanes on a ChiralPak IA (5 μm) column to give 7 (20 mg, 35% yield) as a white solid. 1H NMR(300MHz,CDCl3)δ 7.33-7.17(m,3H),7.16-7.03(m,4H),6.91-6.79(m,2H),5.74(d,J=7.4H z,1H),5.10(p,J=7.0Hz,1H),4.13-4.00(m,1H),3.85-3.76(m,1H),3.76- 3.59(m,3H),3.57-3.47(m,1H),1.93-1.77(m,1H),1.65-1.48(m,1H),1. 45-1.35(m,3H),1.35-1.12(m,1H),1.08-0.98(m,3H),0.98-0.88(m,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 356.6[M+H] + ;HPLC,>99%,t R 6.2 min (12% IPA / hexane; 5 μm ChiralPak IA column).

[0121] [ka] (2S)-3-Hydroxy-2-{4-[(2R)-2-methylbutoxy]phenyl}-N-[(1R)-1-phenylethyl]propenamide (8). Following the procedure for the synthesis of 7, starting from (2R)-2-methylbutyl 4-methylbenzene-1-sulfonate, 8 (33% yield) was obtained as a white solid. 1H NMR (300MHz, CDCl3) δ 7.36-7.20(m,3H),7.18-7.05(m,4H),6.93-6.82(m,2H),5.74(d,J=7.6Hz,1H ),5.12(p,J=7.1Hz,1H),4.16-3.99(m,1H),3.87-3.78(m,1H),3.78-3.59(m,3 H),3.55(dd,J=8.8,4.2Hz,1H),1.95-1.77(m,1H),1.65-1.48(m,1H),1.43(d, J=7.0Hz,3H),1.37-1.17(m,1H),1.03(d,J=6.7Hz,3H),0.97(t,J=7.4Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 356.4[M+H] + ;HPLC,>99%,t R 6.3 min (12% IPA / hexane; 5 μm ChiralPak IA column).

[0122] Synthesis of compounds 25-27 and 30-37 (Scheme C). [ka] (4R)-4-Benzyl-3-[2-(4-bromophenyl)acetyl]-1,3-oxazolidin-2-one (C2). Following the procedure for the synthesis of B4a, starting from 2-(4-bromophenyl)acetyl chloride (C1), C2 (49% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.48(d,J=8.4Hz,2H),7.34-7.25(m,3H),7.22(d,J=8.4Hz,2H),7.13(dd,J=7.5,2.0Hz,2H),4.73-4.58(m, 1H),4.30(d,J=15.8Hz,1H),4.25-4.11(m,3H),3.26(dd,J=13.4,3.4Hz,1H),2.76(dd,J=13.4,9.5Hz,1H);13 C NMR(75MHz,CDCl3)δ 170.7,153.4,135.0,132.5,131.7,131.5,129.4,129.0,127.4,121.4,66.2,55.3,41.0,37.7;MS(ESI)m / z 374.2[M+H] + ( 79 Br), 376.2 [M+H] + ( 81 Br).

[0123] [ka] (4R)-4-Benzyl-3-[(2S)-2-(4-bromophenyl)-3-hydroxypropanoyl]-1,3-oxazolidin-2-one (C3a). Following the procedure for the synthesis of B5a starting from C2, C3a (54% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.45(d,J=8.5Hz,2H),7.38-7.18(m,7H),5.19(dd,J=8.9,5.0Hz,1H),4.66(ddt,J=12.4,6.6,3.1Hz,1H),4.20(ddd,J=9.2,7.9,5.9Hz,1H) ,4.15-4.04(m,2H),3.86(ddd,J=11.2,6.3,5.0Hz,1H),3.33(dd,J=13.4,3.5Hz,1H),2.96-2.77(m,1H),2.16(t,J=6.6Hz,1H);MS(ESI)m / z 426.0[M+Na] + ( 79 Br), 428.0 [M+Na] + ( 81 Br).

[0124] [ka] (4R)-4-Benzyl-3-[(2R)-2-(4-bromophenyl)butanoyl]-1,3-oxazolidin-2-one (C3b). To a solution of C2 (1.0 g, 2.67 mmol) in THF (30 mL) at 0° C., NaHMDS (1.0 M in THF, 2.94 mL, 2.94 mmol) was added slowly and the resulting reaction was stirred at 0° C. for 30 min. Then, iodoethane (1.07 mL, 13.36 mmol) was added slowly at 0° C. and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was cooled to 0° C. and quenched with saturated aqueous NH4Cl (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give C3b (584 mg, 55% yield) as a pale green oil. MS (ESI) m / z 402.2 [M+H] + ( 79 Br), 404.4[M+H] + ( 81 Br).

[0125] [ka] (2S)-2-(4-Bromophenyl)-3-hydroxypropanoic acid (C4a). Following the procedure for the synthesis of B6 starting from C3a, C4a (61% yield) was obtained as a white solid. 1 H NMR(300MHz,CD3OD)δ 7.48(d,J=8.5Hz,2H),7.26(d,J=8.4Hz,2H),4.10-3.98(m,1H),3.78-3.67(m,2H). 13 C NMR(75MHz,CD3OD)δ 175.5,137.4,132.7,131.3,122.3,64.8,55.2.

[0126] [ka] (2R)-2-(4-Bromophenyl)butanoic acid (C4b). Following the procedure for the synthesis of B6, starting from C3b, C4b (60% yield) was obtained as a white solid. MS (ESI) m / z 240.8 [MH] - ( 79 Br), 242.8[MH] - ( 81 Br). This compound was used in the next transformation without further characterization.

[0127] [ka] (2S)-2-(4-bromophenyl)-3-hydroxy-N-[(1R)-1-phenylethyl]propenamide (C5a). To a mixture of C4a (49 mg, 0.20 mmol) and (R)-(+)-α-methylbenzylamine (29 mg, 0.24 mmol) in CH3CN (3 mL) at room temperature, TCFH (62 mg, 0.22 mmol) and NMI (34 mg, 0.42 mmol) were added successively and the resulting reaction was stirred at room temperature for 3 h. The solvent was evaporated and the residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give C5a (48 mg, 68%) as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.45(d,J=8.4Hz,2H),7.33-7.22(m,3H),7.16-7.04(m,4H),5.72(d,J=7.5Hz,1H),5.11(p,J=7.1Hz,1H),4.12- 3.93(m,1H),3.87-3.70(m,1H),3.63(dd,J=8.4,4.2Hz,1H),3.27(dd,J=8.2,4.9Hz,1H),1.44(d,J=6.9Hz,3H). 13 C NMR(75MHz,CDCl3)δ 171.8,142.8,135.6,132.2,130.1,128.6,127.4,125.8,121.9,64.9,53.7,49.1,21.9;MS(ESI)m / z 348.0[M+H] + ( 79 Br), 340.0 [M+H] + (81 Br).

[0128] [ka] (2R)-2-(4-Bromophenyl)-N-[(1R)-1-phenylethyl]butanamide (C5b). Following the procedure for the synthesis of C5a, starting from C4b, afforded the amide C5b (64% yield) as a white solid. MS (ESI) m / z 346.2 [M+H] + ( 79 Br), 348.2 [M+H] + ( 81 Br).

[0129] [ka] 2-(4-Bromophenyl)-N-[(1R)-1-phenylethyl]acetamide (C6). To a solution of 4-bromophenylacetyl chloride (C1) (234 mg, 1 mmol) in DCM (10 mL) at room temperature, (R)-(+)-α-methylbenzylamine (145 mg, 1.2 mmol) and Et3N (279 μL, 2 mmol) were added and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give C6 (240 mg, 75% yield) as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.46(d,J=8.3Hz,2H),7.39-7.17(m,5H),7.12(d,J=8.3Hz,2H),5.70(d,J=6.2 Hz,1H),5.10(p,J=7.0Hz,1H),3.49(s,2H),1.42(d,J=6.9Hz,3H);MS(ESI)m / z 318.2[M+H] + ( 79 Br), 320.2 [M+H] + ( 81 Br).

[0130] [ka] (2S)-3-Hydroxy-N-[(1R)-1-phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}propenamide (25). A mixture of C5a (100 mg, 0.26 mmol), 4-propylphenylboronic acid (65 mg, 0.40 mmol), Pd(dppf)Cl2·CH2Cl2 (22 mg, 0.03 mmol), and K3PO4 (169 mg, 0.80 mmol) in dimethoxyethane (6 mL) and H2O (1.5 mL) was heated at 160 °C for 6 min under microwave irradiation. The resulting mixture was poured into cold 1N NaOH (15 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give 25 (83 mg, 75% yield) as an off-white solid. 1 H NMR(300MHz,CDCl3)δ 7.68-7.40(m,4H),7.36-7.19(m,7H),7.18-7.09(m,2H),5.79(d,J=7.7Hz ,1H),5.16(p,J=7.0Hz,1H),4.29-4.05(m,1H),3.94-3.65(m,2H),3.50(br s,1H),2.76-2.53(m,2H),1.70(td,J=7.5,3.8Hz,2H),1.46(d,J=6.9Hz,3H),1.00(t,J=7.3Hz,3H); 13 C NMR(75MHz,CDCl3)δ 172.7,143.0,142.2,140.8,137.7,135.2,129.0,128.9,128.6,127.6,1 27.3,126.8,125.8,65.1,53.9,48.9,37.7,24.5,22.0,13.8;MS(ESI)m / z 388.4[M+H] + ;HPLC,>99%,t R 17.4 minutes.

[0131] [ka] N-[(1R)-1-Phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}acetamide (26). Following the procedure for the synthesis of 25 starting from C6, 26 (99% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.58-7.46(m,4H),7.34-7.14(m,9H),5.91(d,J=7.5Hz,1H),5.12(p,J=7.0Hz,1H),3.57( s,2H),2.72-2.45(m,2H),1.78-1.58(m,2H),1.40(d,J=6.9Hz,3H),0.97(t,J=7.3Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 358.4[M+H] + ;HPLC,>98%,t R 18.8 minutes.

[0132] [ka] (2R)-N-[(1R)-1-Phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}butanamide (27). Following the procedure for the synthesis of 25, starting from C5b, 27 (80% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.56(t,J=7.7Hz,4H),7.43-7.21(m,7H),7.18-7.07(m,2H),5.84(d,J=7.9Hz,1H),5.15(p,J=7.0Hz,1H),3.34(t,J=7.6Hz ,1H),2.83-2.55(m,2H),2.40-2.17(m,1H),1.94-1.79(m,1H),1.79-1.62(m,2H),1.47(d,J=6.9Hz,3H),1.11-0.87(m,6H); 13C NMR(75MHz,CDCl3)δ 172.6,143.2,141.9,140.0,138.7,138.1,128.9,128.5,128.4,127.2,127. 1,126.8,125.9,54.9,48.7,37.7,26.4,24.5,21.9,13.9,12.4;MS(ESI)m / z 386.6[M+H] + ;HPLC,>99%,t R 19.6 minutes.

[0133] [ka] (2R)-3-Bromo-N-[(1R)-1-phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}propenamide (C7). A solution of 25 (5 mg, 0.01 mmol), CBr4 (6.4 mg, 0.02 mmol), and PPh3 (5.1 mg, 0.02 mmol) in THF (1 mL) was stirred at room temperature for 2 h. The reaction was diluted with DCM (5 mL) and washed with H2O (10 mL). The layers were separated and the organic layer was washed with brine (2 x 5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give C7 (3 mg, 52% yield) as an off-white solid. 1 H NMR (300MHz, CDCl3) δ 7.50(dd,J=12.8,8.2Hz,4H),7.37-7.28(m,2H),7.28-7.14(m,5H),7.09(dd,J=7 .3,1.8Hz,2H),5.97(d,J=7.8Hz,1H),5.12(p,J=7.0Hz,1H),4.09(t,J=9.4Hz,1H) ,3.81(dd,J=8.9,5.8Hz,1H),3.55(dd,J=9.8,5.8Hz,1H),2.77-2.54(m,2H),1.67 (dd,J=15.0,7.4Hz,2H),1.47(d,J=6.9Hz,3H),0.97(t,J=7.3Hz,3H);MS(ESI)m / z 450.2[M+H] + ( 79 Br), 452.2 [M+H] + (81 Br).

[0134] [ka] (2S)-N-[(1R)-1-Phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}-3-(4H-1,2,4-triazol-4-yl)propenamide (30). A solution of C7 (15 mg, 0.03 mmol), 1,2,4-triazole (3.4 mg, 0.05 mmol), and K2CO3 (13.8 mg, 0.1 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction was diluted with EtOAc (5 mL) and H2O (5 mL). The layers were separated and the aqueous layer was extracted with additional EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give 30 (3 mg, 20% yield) as a white solid. 1 H NMR(300MHz,)δ 8.30(s,1H),8.02(s,1H),7.66-7.46(m,5H),7.37(d,J=8.2Hz,1H),7.27(d,J=8.0Hz,3H),7.16(d,J=7.0Hz,2H),7.0 9-7.01(m,2H),4.57-4.25(m,4H),2.64(t,J=7.4Hz,2H),1.78-1.54(m,2H),1.40-1.21(m,4H),0.98(t,J=7.3Hz,3H); 13 C NMR(75MHz,CD3OD)δ 172.1,152.3,145.7,130.0,129.4,129.4,129.3,128.2,128.1,128.2,128.0,1 27.9,127.9,126.8,126.7,52.9,52.7,38.6,25.7,22.2,22.0,14.1;MS(ESI)m / z 439.6[M+H] + ;HPLC,>95%,t R 17.9 minutes.

[0135] [ka] (2S)-N-[(1R)-1-Phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}-3-(1H-1,2,3-triazol-1-yl)propenamide (31). Following the procedure for the synthesis of 30, starting from 1,2,3-triazole, 31 (25% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.59-7.42(m,5H),7.40-7.13(m,10H),5.72(d,J=7.8Hz,1H),5.20(dd,J=13.5,8.0Hz,1H),5.09(p,J=7.1Hz,1H),4.75(dd,J =13.6,7.4Hz,1H),4.26(t,J=7.6Hz,1H),2.72-2.49(m,2H),1.78-1.62(m,2H),1.38(d,J=6.9Hz,3H),0.97(t,J=7.3Hz,3H); 13 C NMR(75MHz,CDCl3)δ 169.6,142.7,142.1,140.9,138.5,137.7,134.8,134.0,128.9,128.6,128.4,1 27.4,127.3,126.8,126.1,56.9,52.5,48.9,37.7,24.5,21.2,13.8;MS(ESI)m / z 439.6[M+H] + ;HPLC,>99%,t R 18.8 minutes.

[0136] [ka] (2S)-2-{4'-cyclobutyl-[1,1'-biphenyl]-4-yl}-3-hydroxy-N-[(1R)-1-phenylethyl]propenamide (32). Following the procedure for the synthesis of 25, starting from C5a and 4-cyclobutylphenylboronic acid, 32 (65% yield) was obtained as an off-white solid. 1H NMR(300MHz,CDCl3)δ 7.64-7.45(m,4H),7.42-7.21(m,7H),7.14(ddd,J=7.8,5.7,1.4Hz,2H),5.77(d,J =7.9Hz,1H),5.13(p,J=7.1Hz,1H),4.19-4.09(m,1H),3.80(dd,J=11.0,4.1Hz,1H ),3.73(dd,J=8.5,4.2Hz,1H),3.59(p,J=8.7Hz,1H),3.47(s,1H),2.48-2.27(m,2 H),2.29-2.11(m,2H),2.10-1.95(m,1H),1.95-1.74(m,1H),1.43(d,J=6.9Hz,3H); 13 C NMR(75MHz,CDCl3)δ 172.7,145.8,143.0,140.8,137.8,135.3,129.1,128.9,128.6,127.6,1 27.3,126.8,125.8,65.1,54.0,49.0,40.1,29.8,22.0,18.3;MS(ESI)m / z 400.2[M+H] + ;HPLC,>99%,t R 18.3 minutes.

[0137] [ka] (2S)-2-[4'-(cyclopropylmethyl)-[1,1'-biphenyl]-4-yl]-3-hydroxy-N-[(1R)-1-phenylethyl]propenamide (33). Following the procedure for the synthesis of 25, starting from C5a and 4-cyclopropylmethylphenylboronic acid, 33 (30% yield) was obtained as an off-white solid. 1H NMR(300MHz,CDCl3)δ 7.55(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),7.38-7.32(m,2H),7.30-7.21(m,5H), 7.16-7.08(m,2H),5.78(d,J=7.9Hz,1H),5.13(p,J=7.1Hz,1H),4.14(ddd,J=13.1, 7.0,3.5Hz,1H),3.88-3.64(m,2H),3.47(dd,J=8.5,4.5Hz,1H),2.60(d,J=6.9Hz,2 H),1.44(d,J=6.9Hz,3H),1.10-0.93(m,1H),0.64-0.48(m,2H),0.29-0.17(m,2H); 13 C NMR(75MHz,CDCl3)δ 172.7,143.0,141.7,140.8,137.9,135.3,128.9,128.9,128.6,127.6,1 27.3,126.9,125.8,65.1,53.9,48.9,40.0,22.0,11.8,4.7;MS(ESI)m / z 400.2[M+H] + ;HPLC,>99%,t R 17.1 minutes.

[0138] [ka] (2S)-2-{4'-cyclopropoxy-[1,1'-biphenyl]-4-yl}-3-hydroxy-N-[(1R)-1-phenylethyl]propenamide (34). Following the procedure for the synthesis of 25, starting from C5a and (4-cyclopropyloxyphenyl)boronic acid, 34 (33% yield) was obtained as an off-white solid. 1 H NMR(300MHz,CDCl3)δ 7.59-7.43(m,4H),7.34-7.21(m,5H),7.18-7.05(m,4H),5.78(d,J=7.9Hz,1H),5.13(p,J=7.1Hz,1H), 4.13(dd,J=11.0,8.5Hz,1H),3.89-3.61(m,3H),2.80(s,1H),1.43(d,J=6.9Hz,3H),0.88-0.70(m,4H); 13C NMR(75MHz,CDCl3)δ MS(ESI)m / z 402.2[M+H] + ;HPLC,>99%,t R 15.8 minutes.

[0139] [ka] (2S)-2-{4'-cyclobutoxy-[1,1'-biphenyl]-4-yl}-3-hydroxy-N-[(1R)-1-phenylethyl]propenamide (35). Following the procedure for the synthesis of 25, starting from C5a and (4-cyclobutyloxyphenyl)boronic acid, 35 (43% yield) was obtained as a white solid. 1 H NMR(300MHz, CDCl3δ 7.55-7.37(m,4H),7.33-7.19(m,5H),7.13(dd,J=8.0,1.7Hz,2H),6.89(d,J=8.7Hz,2H),5.7 5(d,J=8.0Hz,1H),5.13(p,J=7.2Hz,1H),4.68(p,J=7.2Hz,1H),4.13(dd,J=11.0,8.6Hz,1H), 3.79(dd,J=10.9,4.5Hz,1H),3.72(dd,J=8.6,4.2Hz,1H),3.47(s,1H),2.58-2.38(m,2H),2. 20(dtd,J=12.6,9.9,7.8Hz,2H),2.03-1.80(m,1H),1.79-1.65(m,1H),1.43(d,J=7.0Hz,3H); 13 C NMR(75MHz,CDCl3)δ 172.7,157.4,142.9,140.5,134.8,132.7,128.9,128.6,127.6,127.3,127.3,125.8,115.3,71.6,65.1,53.9,48.9,30.7,22.0,13.3. MS(ESI)m / z416.2[M+H] + ;HPLC,>99%,t R 17.2 minutes.

[0140] [ka] (2S)-3-Hydroxy-2-[4-(pent-1-yn-1-yl)phenyl]-N-[(1R)-1-phenylethyl]propenamide (36). A mixture of C5a (40 mg, 0.11 mmol), tri-o-tolylphosphine (7 mg, 0.02 mmol), Pd(OAc)2 (2.6 mg, 0.01 mmol), Et3N (48 μL, 0.34 mmol), 1-pentyne (12.5 μL, 0.12 mmol) in MeCN (2 mL) was heated at 75 °C for 4 h in a sealed vessel. The reaction was cooled to room temperature, quenched with H2O (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give 36 (31 mg, 80% yield) as a brownish solid. 1 H NMR(300MHz,CDCl3)δ 7.36(d,J=8.2Hz,2H),7.32-7.21(m,3H),7.15-7.07(m,4H),5.65(d,J=7.4Hz,1H),5.10(p,J=7.1Hz,1H),4.18-3.98(m,1H),3.83 -3.59(m,2H),3.38(dd,J=8.5,4.5Hz,1H),2.39(t,J=7.0Hz,2H),1.75-1.59(m,2H),1.42(d,J=6.9Hz,3H),1.05(t,J=7.4Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 436.4[M+H] + ;HPLC,>99%,t R 15.7 minutes.

[0141] [ka] (2S)-3-Hydroxy-2-[4-(3-methylbut-1-yn-1-yl)phenyl]-N-[(1R)-1-phenylethyl]propenamide (37). Following the procedure for the synthesis of 36 starting from 3-methylbut-1-yne, 37 (27% yield) was obtained as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.36(d,J=8.0Hz,2H),7.31-7.17(m,3H),7.16-7.01(m,4H),5.72(d,J=7.8Hz,1H),5.09(p,J=7.1Hz,1H),4.06(d,J=9.9 Hz,1H),3.84-3.71(m,1H),3.66(dd,J=8.8,4.1Hz,1H),2.87-2.64(m,2H),1.41(d,J=6.9Hz,3H),1.26(d,J=6.9Hz,6H); 13 C NMR(75MHz,CDCl3)δ 172.4,142.9,135.7,132.2,128.6,128.3,127.3,125.7,123.8,96.7,79.1,64.9,54.0,49.0,22.9,22.0,21.1;MS(ESI)m / z 336.2[M+H] + ;HPLC,>99%,t R 15.8 minutes.

[0142] Synthesis of compounds 28 and 29 (Scheme D). [ka] 1-tert-Butyl 3-methyl 2-(4-bromophenyl)propanedioate (D2). Following the procedure for the synthesis of A3 starting from 1-bromo-4-iodobenzene (D1), D2 (53% yield) was obtained as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 7.47(d,J=8.5Hz,2H),7.27(d,J=8.5Hz,2H),4.52(s,1H),3.72(s,3H),1.44(s,9H); 13C NMR(75MHz, CDCl3)δ 168.4,166.6,132.2,131.6,131.0,127.3,82.6,58.1,52.6,27.9.

[0143] [ka] 2-(4-Bromophenyl)-3-methoxy-3-oxopropanoic acid (D3). Following the procedure for the synthesis of A4 starting from D2 gave crude D3 (quantitative yield), which was used in the next transformation without purification.

[0144] [ka] Methyl 2-(4-bromophenyl)-2-{[(1R)-1-phenylethyl]carbamoyl}acetate (D4). Following the procedure for the synthesis of A5 starting from D3, the diastereomeric mixture D4 (70% yield) was obtained as a yellow solid. 1 H NMR(300MHz,CDCl3)δ 7.46(dd,J=11.5,8.5Hz,2H),7.38-7.07(m,7H),5.09(p,J=6.8Hz,1H),4.46(d,J=4.5Hz,1H),3.73(d,J=3.7Hz,3H),1.47(dd,J=6.9,3.9Hz,3H); 13 C NMR(75MHz,CDCl3)δ MS(ESI)m / z 376.2[M+H] + ( 79 Br), 378.2 [M+H] + ( 81 Br).

[0145] [ka] Methyl 2-{[(1R)-1-phenylethyl]carbamoyl}-2-{4'-propyl-[1,1'-biphenyl]-4-yl}acetate (28). Following the procedure for the synthesis of 25, starting from D4, the diastereomeric mixture 28 (78% yield) was obtained as a brown solid. 1 H NMR(300MHz,CDCl3)δ 7.66-7.35(m,5H),7.35-7.12(m,8H),5.21-4.96(m,1H),4.61-4.41(m,1H),3.81-3.65(m,4H), 2.62(t,J=7.6Hz,2H),1.76-1.59(m,2H),1.53-1.40(m,3H),0.97(t,J=7.3Hz,3H);MS(ESI)m / z 416.6[M+H] + ;HPLC,>99%,t R 18.5 min, 18.6 min (1:1 two peaks).

[0146] [ka] N-Methyl-N'-[(1R)-1-phenylethyl]-2-{4'-propyl-[1,1'-biphenyl]-4-yl}propanediamide (29). To a solution of 28 (100 mg, 0.24 mmol) in MeOH-HO (3 mL, 1:1) was added 1N NaOH (482 μL, 0.48 mmol) and the reaction was stirred at room temperature for 3 h. The mixture was acidified to pH=2 with 1N HCl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried (NaSO), and concentrated under reduced pressure to give the corresponding acid (94 mg, 98% yield) as a brownish solid. 1 H NMR(300MHz,CDCl3)δ 7.66-6.99(m,13H),6.61(br s,1H),5.11(dd,J=13.6,6.9Hz,1H),4.48(d,J=14.3Hz,1H),2.74-2.53(m,2 H),1.82-1.55(m,2H),1.51-1.30(m,3H),0.97(t,J=7.3Hz,3H);MS(ESI)m / z 402.4[M+H] +To a solution of the above acid (60 mg, 0.15 mmol) in MeCN (2 mL) was added TCFH (46 mg, 0.16 mmol), NMI (25 μL, 0.31 mmol), and methylamine hydrochloride (15 mg, 0.22 mmol), and the resulting reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (10 mL) and H2O (15 mL). The layers were separated and the aqueous layer was extracted with additional EtOAc (2×10 mL). The combined organic layers were washed with brine (3×15 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using 0-100% EtOAc in hexanes to give the diastereomeric mixture 29 (44 mg, 71% yield) as a white solid. 1 H NMR(300MHz,CDCl3)δ 7.59-7.36(m,5H),7.35-7.12(m,8H),5.03(dd,J=15.6,8.6Hz,1H),4.62-4.36(m,1H),2.86(s,3H),2.83 -2.75(m,2H),2.71-2.54(m,2H),1.76-1.57(m,2H),1.53-1.39(m,3H),0.97(t,J=7.3Hz,3H);MS(ESI)m / z 415.4[M+H] + ;HPLC,>99%,t R 18.0 minutes (primary), 18.1 minutes (secondary).

[0147] Synthesis of compounds 38-60 (Scheme E) [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-1-phenyl-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (38). To a solution of tert-butyl N-[(2S,3S)-3-methyl-1-({4'-propyl-[1,1'-biphenyl]-4-yl}amino)pentan-2-yl]carbamate (E1a) (30 mg, 0.07 mmol) in DCM (1 mL) was added phenyl isocyanate (E2a) (10.5 μL, 0.09 mmol). The reaction was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by column chromatography on silica gel using EtOAc in hexanes to give the Boc-protected urea E3a (23.6 mg, 75% yield) as an off-white solid. 1 H NMR(300MHz,CDCl3)δ 7.69(d,J=8.3Hz,2H),7.53(d,J=8.1Hz,2H),7.43(d,J=8.1Hz,2H),7.33-7.17(m,7H),7.06-6.93(m ,1H),6.22(s,1H),5.24(d,J=9.1Hz,1H),4.37(dd,J=14.2,11.5Hz,1H),3.77(tt,J=9.1,4.2Hz,1H), 3.22(dd,J=14.3,4.0Hz,1H),2.65(t,J=7.6Hz,2H),1.71(t,J=7.5Hz,2H),1.60-1.46(m,1H),1.40(s ,9H),1.21-1.04(m,1H),0.98(t,J=7.3Hz,3H),0.94-0.87(m,3H),0.84(d,J=7.3Hz,3H);MS(ESI)m / z 530.20[M+H] + The Boc-protected intermediate E3a (23.6 mg, 0.05 mmol) was dissolved in DCM (5 mL) followed by the addition of HCl (4 M in dioxane, 50 μL, 0.5 mmol). The reaction was stirred at room temperature until judged complete by TLC analysis. The solvent was evaporated and the residue was triturated with hexane to give the hydrochloride salt of 38 (20.6 mg, 99% yield) as an off-white solid. 11H NMR (300 MHz, CD3OD) δ 7.80 (d, J = 6.9 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.03 (t, J = 7.2 Hz, 1H), 4.23 (dd, J = 15.1, 8.3 Hz, 1H), 3.78 (d, J = 14.9 Hz, 1H), 2.64 (t, J = 7.5 Hz, 1H), 1.76 (d, J = 10.8 Hz, 1H), 1.68 (q, J = 7.4 Hz, 1H), 1.40 (q, J = 6.7 Hz, 1H), 1.24 (dt, J = 10.3, 5.8 Hz, 1H), 0.97 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.1 Hz, 2H); 13 13C NMR (75 MHz, CD3OD) δ 158.4, 143.7, 142.5, 141.1, 140.0, 138.4, 130.2, 129.8, 129.6, 129.5, 127.9, 124.7, 122.2, 57.1, 51.1, 38.6, 37.1, 26.4, 25.6, 14.2, 14.0, 11.7; MS (ESI) m / z 430.20 [M + H] + ; HPLC, >99%, t R 16.9 minutes.

[0148] [Chemical formula] 3-[(2S,3S)-2-amino-3-methylpentyl]-1-methyl-1-phenyl-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (39). To a solution of N-methylaniline (E2b) (10.7 μL, 0.1 mmol) in DCM (1 mL) at 0° C. under nitrogen, triphosgene (29.6 mg, 0.1 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with 1 M HCl and extracted with DCM (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the corresponding carbamoyl chloride as a colorless residue. The prepared carbamoyl chloride was added dropwise to a solution of E1a (45.1 mg, 0.11 mmol), DMAP (2.0 mg), and pyridine (16.1 μL, 0.2 mmol) in DCE (5 mL) at 0° C. under nitrogen. The reaction was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with DCM (10 mL). The organic layer was washed with water (2×20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel using EtOAc and hexane to give the Boc-protected urea E3b (17.5 mg, 32% yield). 1 H NMR(300MHz,CDCl3)δ 7.36(d,J=8.2Hz,2H),7.21(dd,J=8.3,6.7Hz,4H),7.01(t,J=7.5Hz,2H),6.92(t,J=7.0Hz,1H),6. 83-6.69(m,4H),5.64(d,J=8.0Hz,1H),4.14(dd,J=14.2,11.7Hz,1H),3.65(td,J=8.1,4.5Hz,1H), 3.26 (dd, J = 14.2, 3.8 Hz, 1H), 3.16 (s, 3H), 2.67-2.54 (m, 2H), 1.66 (dt, J = 15.0, 7.5 Hz, 2H), 1.49 (s, 9H), 1.39 (q, J = 7.8 Hz, 2H), 1.09 (dd, J = 8.5, 5.9 Hz, 1H), 0.97 (t, J = 7.3 Hz, 3H), 0.92-0.76 (m, 6H). Deprotection of the Boc group with 4 M HCl in dioxane following the procedure for the synthesis of 38 afforded the hydrochloride salt of 39 (9.6 mg, 68% yield) as an off-white solid. 1H NMR(300MHz,CD3OD)δ 7.39(d,J=7.8Hz,2H),7.31(d,J=7.6Hz,2H),7.22(d,J=7.8Hz,2H),7.12-6. 88(m,5H),6.84(d,J=7.5Hz,2H),4.06(dd,J=15.3,8.5Hz,1H),3.69(d,J=15 .3Hz,1H),3.23(s,3H),3.13(d,J=7.6Hz,1H),2.61(t,J=7.5Hz,2H),1.66(h ,J=7.3Hz,3H),1.33-1.06(m,2H),1.01-0.85(m,6H),0.74(t,J=7.2Hz,3H); 13 C NMR(75MHz,CD3OD)δ 163.7,145.8,143.3,142.1,140.2,138.7,130.0,128.5,128.2,127.6,127.4, 126.9,56.6,52.1,40.1,38.6,37.3,26.4,25.7,14.1,14.0,11.5;MS(ESI)m / z 444.20[M+H] + ;HPLC,>98%,t R 17.6 minutes.

[0149] [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-1-benzyl-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (40). Following the procedure for the synthesis of 38, starting from E1a and benzyl isocyanate (E2c), gave the Boc-protected urea E3c (80% yield), which was then deprotected with HCl to give the hydrochloride salt of 40 (95% yield) as an off-white solid. 1H NMR(300MHz,CD3OD)δ 7.75(d,J=8.4Hz,2H),7.56(d,J=8.0Hz,2H),7.45(d,J=8.3Hz,2H),7.32-6.95(m,7 H),4.83-4.63(m,1H),4.38-4.18(m,2H),4.12(dd,J=15.4,8.8Hz,1H),3.87-3.54(m ,1H),3.27-3.17(m,1H),3.28-3.14(m,1H),2.63(t,J=7.5Hz,2H),1.83-1.50(m,3H) ,1.50-1.29(m,1H),1.29-1.07(m,1H),0.96(t,J=7.9Hz,6H),0.86(t,J=7.4Hz,3H); 13 C NMR(75MHz,CD3OD)δ 160.8,149.7,142.6,141.4,141.1,138.5,130.2,129.8,129.7,129.4,128.2,128 .0,127.9,57.4,51.3,45.4,38.6,37.0,26.2,25.7,14.3,14.0,11.6;MS(ESI)m / z 444.40[M+H] + ;HPLC,>99%,t R 17.0 minutes.

[0150] [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-1-[(1R)-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (41). Following the procedure for the synthesis of 38, starting from E1a and (R)-(+)-α-methylbenzyl isocyanate (E2d), gave the Boc-protected urea E3d (65% yield), which was then deprotected with HCl to give the hydrochloride salt of 41 (76% yield) as a white solid. 1H NMR(400MHz,CD3OD)δ 7.73(d,J=8.4Hz,2H),7.55(d,J=8.1Hz,2H),7.40(d,J=8.4Hz,2H),7.32-7.12(m,7 H),4.95(q,J=7.0Hz,1H),4.05(dd,J=15.3,8.7Hz,1H),3.72(dd,J=15.3,2.6Hz,1H) ,3.23-3.08(m,1H),2.62(t,J=7.6Hz,2H),1.80-1.51(m,3H),1.46-1.26(m,4H),1. 26-1.06(m,1H),0.94(t,J=7.3Hz,3H),0.90(d,J=6.9Hz,3H),0.82(t,J=7.4Hz,3H); 13 C NMR(100MHz,CD3OD)δ 158.6,144.4,142.4,141.1,140.1,137.1,128.8,128.4,128.2,126.7,126.5,12 5.7,55.9,50.6,49.9,37.3,35.7,24.9,24.4,21.4,12.9,12.7,10.3;MS(ESI)m / z 458.30[M+H] + ;HPLC,>99%,t R 17.5 minutes.

[0151] [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-1-[(1S)-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (42). Following the procedure for the synthesis of 38, starting from E1a and (S)-(-)-α-methylbenzyl isocyanate (E2e), gave the Boc-protected urea E3e (76% yield), which was then deprotected with HCl to give the hydrochloride salt of 42 (80% yield) as a white solid. 1H NMR (400MHz, CD3OD) δ 7.75(d,J=8.5Hz,2H),7.56(d,J=8.1Hz,2H),7.43(d,J=8.5Hz,2H),7.30-7. 11(m,7H),4.97-4.89(m,1H),4.05(dd,J=15.3,8.8Hz,1H),3.78-3.53(m,1H) ,3.23-3.14(m,1H),2.62(t,J=7.6Hz,2H),1.78-1.50(m,3H),1.40-1.29(m, 4H),1.21-1.08(m,1H),1.00-0.85(m,6H),0.80(t,J=7.4Hz,3H);MS(ESI)m / z 458.30[M+H] + ;HPLC,>99%,t R 17.7 minutes.

[0152] [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-3-(4-hexylphenyl)-1-[(1S)-1-phenylethyl]urea (43). Following the procedure for the synthesis of 38, starting with tert-butyl N-[(2S,3S)-1-[(4-hexylphenyl)amino]-3-methylpentan-2-yl]carbamate (E1b) and (S)-(−)-α-methylbenzyl isocyanate (E2e), gave the Boc-protected urea E3f (63% yield), which was then deprotected with HCl to give the hydrochloride salt of 43 (quantitative yield) as a white solid. 1 H NMR(300MHz,CD3OD)δ 6.97-7.37(m,9H),3.96(dd,J=15.26,8.85Hz,1H),3.50-3.69(m,2H),3.49-3.56(m,1H),3.41-3.50(m,1H),3.04-3.15(m,1H),2.57 (t,J=7.63Hz,2H),1.45-1.68(m,3H),1.15-1.32(m,10H),1.07(dd,J=15.26,6.97Hz,1H),0.74-0.87(m,4H),0.69(t,J=7.35Hz,3H); 13C NMR(75MHz,CD3OD)δ 159.8,145.9,144.8,140.1,131.6,129.5,129.2,127.9,126.8,57.1,51.8,51. 0,36.9,36.4,32.8,32.4,30.0,26.3,23.7,22.7,14.4,14.3,11.6;MS(ESI)m / z 424.30[M+H] + ;HPLC,>98%,t R 17.7 minutes.

[0153] [ka] 1-[(2S,3S)-2-Amino-3-methylpentyl]-3-[(1R,2S)-2-phenylcyclopropyl]-1-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (44). Following the procedure for the synthesis of 38, starting from E1a and [(1S,2R)-2-isocyanatocyclopropyl]benzene (E2f), gave the Boc-protected urea E3g (50% yield), which was then deprotected with HCl to give the hydrochloride salt of 44 (60% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.72(d,J=8.5Hz,2H),7.54(d,J=8.2Hz,2H),7.39(d,J=8.5Hz,2H),7.26(d,J=8.2Hz,2H),7.20( t,J=7.4Hz,2H),7.14-7.04(m,3H),4.11(dd,J=15.3,9.0Hz,1H),3.68(dd,J=15.3,2.7Hz,1H),3 .26-3.17(m,1H),2.82-2.68(m,1H),2.68-2.54(m,2H),2.02-1.87(m,1H),1.79-1.54(m,3H),1. 44-1.30(m,1H),1.25-1.11(m,1H),1.11-1.03(m,2H),1.03-0.87(m,6H),0.83(t,J=7.4Hz,3H); 13C NMR(100MHz,CD3OD)δ 160.1,142.4,141.3,141.0,139.9,137.2,128.8,128.4,128.1,127.9,126.5,125.8,12 5.5,55.8,49.7,37.3,35.7,33.3,25.0,24.4,24.0,15.3,12.9,12.7,10.3;MS(ESI)m / z 470.40[M+H] + ;HPLC,>97%,t R 17.6 minutes.

[0154] [ka] 1-[(2S,3S)-2-Amino-3-methylpentyl]-3-[(1S,2R)-2-phenylcyclopropyl]-1-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (45). Following the procedure for the synthesis of 38, starting from E1a and [(1R,2S)-2-isocyanatocyclopropyl]benzene (E2g), gave the Boc-protected urea E3h (60% yield), which was then deprotected with HCl to give the hydrochloride salt of 45 (95% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.72(d,J=7.5Hz,2H),7.55(d,J=7.3Hz,2H),7.39(d,J=7.5Hz,2H),7.27(d,J=7.5Hz,2H),7.20 (t,J=7.6Hz,2H),7.14-7.03(m,3H),4.12(dd,J=15.2,9.0Hz,1H),3.69(d,J=1.5Hz,1H),3.26- 3.16(m,1H),2.79-2.67(m,1H),2.62(t,J=7.5Hz,2H),1.98-1.86(m,1H),1.76-1.57(m,3H),1. 45-1.31(m,1H),1.25-1.14(m,1H),1.14-1.04(m,2H),1.02-0.88(m,6H),0.83(t,J=7.2Hz,3H); 13C NMR(75MHz,CD3OD)δ 160.1,142.4,141.3,141.0,140.0,137.2,128.8,128.4,128.2,127.9,126.5,125.8,12 5.5,55.8,49.7,39.6,37.3,33.3,25.0,24.4,24.3,15.0,12.9,12.7,10.3,MS(ESI)m / z 470.40[M+H] + ;HPLC,>95%,t R 17.6 minutes.

[0155] [ka] 1-[(2S,3S)-2-Amino-3-methylpentyl]-3-(1-phenylcyclopropyl)-1-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (46). Triphosgene (27 mg, 0.09 mmol) was dissolved in DCM (1 mL) at room temperature. A mixture of 1-phenylcyclopropan-1-amine (E2h) (33 mg, 0.25 mmol) and DIPEA (52 μL, 0.3 mmol) in DCM (1 mL) was added dropwise to the above solution over 5 min. After stirring for 20 min, a solution of E1a (102 mg, 0.25 mmol) and DIPEA (52 μL, 0.3 mmol) in DCM (1 mL) was added in one portion. The reaction was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel using EtOAc in hexane to give the Boc-protected urea E3i (29% yield) as a clear residue. MS (ESI) m / z 570.4 [M+H] + Deprotection of the Boc group with TFA in DCM afforded 46 trifluoroacetate (32 mg, 76% yield) as a white solid. 1H NMR (300MHz, CD3OD) δ 7.76(d,J=8.4Hz,2H),7.57(d,J=8.2Hz,2H),7.44(d,J=8.5Hz,2H),7.32-7. 17(m,6H),7.17-7.06(m,1H),4.06(dd,J=15.2,8.7Hz,1H),3.74(dd,J=15.2 ,3.1Hz,1H),3.28-3.17(m,1H),2.63(t,J=7.5Hz,2H),1.85-1.57(m,3H),1. 52-1.32(m,1H),1.31-1.05(m,5H),1.03-0.90(m,6H),0.84(t,J=7.3Hz,3H); 13 C NMR(75MHz,CD3OD)δ 160.9,144.9,143.7,142.5,141.5,138.6,130.2,129.9,129.6,129.2,127.9,127.0,12 6.2,57.3,51.3,38.7,37.0,36.4,26.2,25.7,19.1,18.9,14.3,14.1,11.7;MS(ESI)m / z 470.4[M+H] + ;HPLC,>99%,t R 17.3 minutes.

[0156] [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-1-[(1S)-1-phenylpropyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (47). Following the procedure for the synthesis of 46, starting from E1a and (1S)-1-phenylpropan-1-amine (E2i), gave the Boc-protected urea E3j (46% yield), which was then deprotected with HCl to give the hydrochloride salt of 47 (90% yield) as an off-white solid. 1H NMR(300MHz,CD3OD)δ7.78(d,J=8.2Hz,2H),7.59(d,J=7.9Hz,2H),7.46(d,J=8.1H z,2H),7.34-7.24(m,4H),7.24-7.13(m,3H),4.64(t,J=7.4Hz,1H),4.03(dd,J=15. 3,8.6Hz,1H),3.71(dd,J=15.5,2.8Hz,1H),3.27-3.14(m,1H),2.64(t,J=7.5Hz,2 H),1.75-1.59(m,5H),1.46-1.06(m,2H),0.97(t,J=7.3Hz,3H),0.93-0.75(m,9H); 13 C NMR(75MHz,CD3OD)δ160.1,144.9,143.8,142.5,141.5,138.5,130.2,129.9,129.7,129.4,128.0,127. 9,127.5,58.5,57.4,51.3,38.7,37.0,30.5,26.3,25.7,14.4,14.1,11.7,11.6;MS(ESI)m / z472.4[M+H] + ;HPLC,>99%,t R 18.1 minutes.

[0157] [ka] 3-[(2S,3S)-2-Amino-3-methylpentyl]-1-[(1R)-2-methoxy-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (48). Following the procedure for the synthesis of 46, starting from E1a and (1S)-1-phenylpropan-1-amine (E2j), gave the Boc-protected urea E3k (57% yield), which was then deprotected with HCl to give the hydrochloride salt of 48 (quantitative yield) as an off-white solid. 1H NMR(300MHz,CD3OD)δ 7.80(d,J=7.6Hz,2H),7.59(d,J=7.7Hz,2H),7.50(d,J=7.8Hz,2H),7.36-7.19(m,7H ),5.02(t,J=6.1Hz,1H),4.16(dd,J=15.2,8.9Hz,1H),3.64(d,J=15.3Hz,1H),3.58- 3.44(m,2H),3.30(s,3H),3.26-3.15(m,1H),2.64(t,J=7.5Hz,2H),1.69(h,J=7.4Hz ,3H),1.42-1.30(m,1H),1.26-1.10(m,1H),1.03-0.92(m,6H),0.83(t,J=7.2Hz,3H); 13 C NMR(75MHz,CD3OD)δ 160.0,143.8,142.7,141.7,141.2,138.4,130.2,129.9,129.7,129.4,128.4,127.9,12 7.7,76.5,59.3,57.3,56.1,50.9,38.7,37.1,26.4,25.7,14.2,14.1,11.7;MS(ESI)m / z 488.4[M+H] + ;HPLC,>99%,t R 17.4 minutes.

[0158] [ka] 1-[(2S,3S)-2-Amino-3-methylpentyl]-3-[(1S)-1-(furan-2-yl)ethyl]-1-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (49). Following the procedure for the synthesis of 46, starting from E1a and (1S)-1-(furan-2-yl)ethan-1-amine (E2k), gave the Boc-protected urea E3l (20% yield), which was then deprotected with HCl to give the hydrochloride salt of 49 (55% yield) as an off-white solid. MS (ESI) m / z 448.40 [M+H] + ;HPLC,>95%,t R 17.1 minutes.

[0159] [ka] 3-[(2S)-2-Amino-4-methylpentyl]-1-[(1S)-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (50). Following the procedure for the synthesis of 38, starting with tert-butyl N-[(2S)-4-methyl-1-({4'-propyl-[1,1'-biphenyl]-4-yl}amino)pentan-2-yl]carbamate (E1c) and (S)-(-)-α-methylbenzyl isocyanate (E2e), gave the Boc-protected urea E3m (60% yield), which was then deprotected with HCl to give the hydrochloride salt of 50 (90% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ 7.74(d,J=8.3Hz,2H),7.55(d,J=8.1Hz,2H),7.43(d,J=8.3Hz,2H),7.31-7. 10(m,7),4.98-4.88(m,1H),3.95(dd,J=15.2,7.8Hz,1H),3.76(dd,J=15.2, 3.0Hz,1H),3.36-3.31(m,1H),2.61(t,J=7.5Hz,2H),1.74-1.58(m,2H),1.5 8-1.42(m,2H),1.42-1.24(m,4H),0.94(t,J=7.3Hz,3H),0.88-0.70(m,6H); 13 C NMR(75MHz,CD3OD)δ 158.4 150.3,144.6,142.4,141.1,140.4,137.1,128.8,128.4,128.1,126.6,126.5, 125.6,52.1,50.6,50.3,39.3,37.3,24.4,24.1,21.3,20.9,12.7;MS(ESI)m / z 458.4[M+H] + ;HPLC,>99%,t R 17.5 minutes.

[0160] [ka] 3-[(2R)-2-Amino-4-methylpentyl]-1-[(1S)-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (51). Following the procedure for the synthesis of 38, starting with tert-butyl N-[(2R)-4-methyl-1-({4'-propyl-[1,1'-biphenyl]-4-yl}amino)pentan-2-yl]carbamate (E1d) and (S)-(-)-α-methylbenzyl isocyanate (E2e), gave the Boc-protected urea E3n (70% yield), which was then deprotected with HCl to give the hydrochloride salt of 51 (90% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ 7.73(d,J=8.3Hz,2H),7.54(d,J=8.1Hz,2H),7.41(d,J=8.3Hz,2H),7.32-7.1 2(m,7H),4.93(q,J=7.0Hz,1H),3.93(dd,J=15.2,7.4Hz,1H),3.80(dd,J=15.1 ,3.0Hz,1H),3.38-3.30(m,1H),2.61(t,J=7.5Hz,2H),1.77-1.57(m,2H),1.57 -1.44(m,2H),1.44-1.23(m,4H),0.94(t,J=7.3Hz,3H),0.80(d,J=6.0Hz,6H); 13 C NMR(75MHz,CD3OD)δ 158.5,144.4,142.4,141.0,140.5,137.1,128.8,128.4,128.1,128.1,126.6,126.5 ,125.7,52.2,50.6,50.3,39.3,37.3,24.4,24.1,21.4,21.3,20.9,12.7;MS(ESI)m / z 458.35[M+H] + ;HPLC,>99%,t R 17.6 minutes.

[0161] [ka] 3-[(2S)-2-Aminopropyl]-1-[(1S)-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (52). Following the procedure for the synthesis of 38, starting with tert-butyl N-[(2S)-1-({4'-propyl-[1,1'-biphenyl]-4-yl}amino)propan-2-yl]carbamate (E1e) and (S)-(-)-α-methylbenzyl isocyanate (E2e), gave Boc-protected E3o (65% yield), which was then deprotected with HCl to give the hydrochloride salt of 52 (70% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.74(d,J=8.3Hz,2H),7.54(d,J=8.1Hz,2H),7.42(d,J=8.3Hz,2H),7.31 -7.08(m,7H),4.98-4.88(m,1H),3.97(dd,J=14.9,8.1Hz,1H),3.67(dd, J=14.9,4.1Hz,1H),3.47-3.32(m,1H),2.67-2.44(m,2H),1.78-1.54(m, 2H),1.31(t,J=9.3Hz,3H),1.23(t,J=10.4Hz,3H),0.94(t,J=7.3Hz,3H); 13 C NMR(100MHz,CD3OD)δ 158.1,144.6,142.4,141.1,140.3,137.2,128.8,128.5,128.3,128.1,126. 6,126.5,125.5,53.4,50.5,42.6,37.3,24.4,21.4,15.3,12.7;MS(ESI)m / z 416.20[M+H] + ;HPLC,>97%,t R 16.2 minutes.

[0162] [ka] 1-[(1S)-1-Phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}-3-{[(2S)-pyrrolidin-2-yl]methyl}urea (53). Following the procedure for the synthesis of 38, starting with tert-butyl (2S)-2-[({4'-propyl-[1,1'-biphenyl]-4-yl}amino)methyl]pyrrolidine-1-carboxylate (E1f) and (S)-(-)-α-methylbenzyl isocyanate (E2e), gave the Boc-protected urea E3p (99% yield), which was then deprotected with HCl to give the hydrochloride salt of 53 (98% yield) as a white solid. 1 H NMR(300MHz,CD3OD)δ 7.77(d,J=7.0Hz,2H),7.57(d,J=7.6Hz,2H),7.46(d,J=7.2Hz,2H),7.3 5-7.10(m,8H),4.94(d,J=6.8Hz,1H),4.26-3.96(m,1H),3.78(d,J=12. 6Hz,2H),2.74-2.47(m,2H),2.19-1.82(m,3H),1.68(q,J=7.4Hz,3H),1.36(d,J=6.6Hz,3H),0.96(t,J=7.2Hz,3H),0.88(q,J=7.1,6.7Hz,1H); 13 C NMR(75MHz,CD3OD)δ 160.0,145.9,143.7,142.4,141.5,138.5,130.1,129.8,129.6,129.4,127.9,127 .7,126.9,61.7,52.9,52.0,46.6,38.6,28.5,25.6,24.7,22.5,14.0;MS(ESI)m / z 442.40[M+H] + ;HPLC,>99%,t R 16.9 minutes.

[0163] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-1-[(1S)-1-phenylethyl]-3-{4'-propyl-[1,1'-biphenyl]-4-yl}urea (54). Following the procedure for the synthesis of 38, starting with tert-butyl N-[(2R,3R)-3-methoxy-1-({4'-propyl-[1,1'-biphenyl]-4-yl}amino)butan-2-yl]carbamate (E1g) and (S)-(-)-α-methylbenzyl isocyanate (E2e), gave the Boc-protected urea E3q (70% yield), which was then deprotected with HCl to give the hydrochloride salt of 54 (83% yield) as a white solid. 1 H NMR(300MHz,CD3OD)δ 7.77(d,J=7.9Hz,2H),7.58(d,J=7.8Hz,2H),7.45(d,J=8.0Hz,2H),7.35-7.13(m, 7H),4.94(q,J=6.8Hz,1H),4.06(dd,J=15.1,7.3Hz,1H),3.83(dd,J=15.1,3.9Hz,1 H),3.45(t,J=6.1Hz,1H),3.29(s,3H),3.20(s,1H),2.64(t,J=7.5Hz,2H),1.68(h ,J=7.3Hz,2H),1.36(d,J=7.0Hz,3H),1.11(d,J=6.1Hz,3H),0.97(t,J=7.3Hz,3H); 13 C NMR(75MHz,CD3OD)δ 159.7,145.9,143.8,142.5,141.6,138.4,130.2,129.8,129.5,129.4,127.9,127 .9,126.9,75.0,57.9,56.8,52.0,51.4,38.6,25.7,22.6,15.6,14.0;MS(ESI)m / z 460.25[M+H] + ;HPLC,>99%,t R 17.0 minutes.

[0164] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-1-[(1S)-1-phenylethyl]-3-{4'-methyl-[1,1'-biphenyl]-4-yl}urea (55). Following the procedure for the synthesis of 38, starting from tert-butyl N-[(2R,3R)-1-[(4-bromophenyl)amino]-3-methoxybutan-2-yl]carbamate (E1h) and (S)-(-)-α-methylbenzyl isocyanate (E2e), tert-butyl N-[(2R,3R)-1-[(4-bromophenyl)({[(1S)-1-phenylethyl]carbamoyl})amino]-3-methoxybutan-2-yl]carbamate (E3r) (52% yield) was obtained as an off-white solid. 1 H NMR(300MHz,CDCl3)δ 7.53(d,J=8.5Hz,2H),7.39-7.00(m,7H),5.13(d,J=9.0Hz,1H),4.98(p,J=7.1Hz,1H),4.74(d,J=7.9Hz,1H),4.29-3.96(m,1H) ),3.71(d,J=4.8Hz,1H),3.52-3.24(m,2H),3.19(s,3H),1.45(s,9H),1.38(t,J=7.3Hz,3H),1.09(d,J=6.3Hz,3H);MS(ESI)m / z 520.20[M+H] + ( 79 Br), 522.20 [M+H] + ( 81 Suzuki coupling of E3r with 4-methylphenylboronic acid was carried out according to the procedure used for the synthesis of 25 to give the Boc-protected biphenyl urea E4a (60% yield), which was then deprotected with HCl to give the hydrochloride salt of 55 (80% yield) as a white solid (80%). 1H NMR(400MHz,CD3OD)δ 7.74(d,J=8.5Hz,2H),7.53(d,J=8.1Hz,2H),7.42(d,J=8.4Hz,2H),7.34-7.09(m,7H),4.95-4.88(m,1H),3.80(dd,J=15.2,4.1Hz,1H),3 .75-3.52(m,1H),3.42(p,J=6.2Hz,1H),3.27-3.23(m,3H),3.22-3.11(m,1H),2.36(s,3H),1.33(d,J=7.1Hz,3H),1.08(d,J=6.2Hz,3H); 13 C NMR(100MHz,CD3OD)δ 158.3,144.6,141.1,140.2,137.6,136.8,129.4,128.4,128.1,128.1,126. 6,126.5,125.6,73.6,56.4,55.4,50.6,50.0,21.3,19.8,14.2;MS(ESI)m / z 432.20[M+H] + ;HPLC,>99%,t R 15.3 minutes.

[0165] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-1-[(1S)-1-phenylethyl]-3-{4'-ethyl-[1,1'-biphenyl]-4-yl}urea (56). Following the procedure for the synthesis of 55, starting from E3r and 4-ethylphenylboronic acid, gave the Boc-protected biphenylurea E4b (62% yield), which was then deprotected with HCl to give the hydrochloride salt of 56 (80% yield) as a white solid. 1H NMR(300MHz,CD3OD)δ 7.78(d,J=6.7Hz,2H),7.59(d,J=7.7Hz,2H),7.46(d,J=7.2Hz,2H),7.36-7.10(m,9H),4.94(d,J=6.2Hz,1H),4.83-4.69(m,0H),3.47 (d,J=8.3Hz,1H),3.29(s,3H),3.21(s,3H),2.69(q,J=7.5Hz,2H),1.36(d,J=6.7Hz,3H),1.26(t,J=7.5Hz,3H),1.11(d,J=5.3Hz,3H); 13 C NMR(75MHz,CD3OD)δ 159.7,145.9,145.4,142.5,141.63,138.4,129.9,129.6,129.5,128.0,128 .0,127.0,75.0,57.9,56.9,52.0,51.5,29.5,22.7,16.1,15.7;MS(ESI)m / z 446.20[M+H] + ;HPLC,>99%,t R 14.4 minutes.

[0166] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-1-[(1S)-1-phenylethyl]-3-{4'-methoxy-[1,1'-biphenyl]-4-yl}urea (57). Following the procedure for the synthesis of 55, starting from E3r and 4-methoxyphenylboronic acid, gave the Boc-protected biphenylurea E4c (65% yield), which was then deprotected with HCl to give the hydrochloride salt of 57 (85% yield) as a white solid. 1H NMR(400MHz,CD3OD)δ 7.72(d,J=8.5Hz,2H),7.61-7.55(m,2H),7.41(d,J=8.5Hz,2H),7.30-7.14(m,5),7.04-6.96(m,2H),4.91(q,J=7.1Hz,1H),4.03(dd,J= 15.1,7.5Hz,1H),3.84-3.75(m,4H),3.42(p,J=6.2Hz,1),3.26(s,3H),3.19-3.10(m,1H),1.33(d,J=7.1Hz,3H),1.08(d,J=6.2Hz,3H); 13 C NMR(100MHz,CD3OD)δ 159.9,158.3,144.6,140.8,139.8,132.0,128.2,128.1,128.1,127.8,126. 6,125.6,114.1,73.6,56.4,55.4,54.4,50.6,50.0,21.3,14.2;MS(ESI)m / z 448.40[M+H] + ;HPLC,>99%,t R 14.5 minutes.

[0167] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-1-[(1S)-1-phenylethyl]-3-{4'-ethoxy-[1,1'-biphenyl]-4-yl}urea (58). Following the procedure for the synthesis of 55, starting from E3r and 4-ethoxyphenylboronic acid, gave the Boc-protected biphenylurea E4d (69% yield), which was then deprotected with HCl to give the hydrochloride salt of 58 (80% yield) as a white solid. 1H NMR(300MHz,CD3OD)δ 7.81-7.69(m,2H),7.60(d,J=7.8Hz,2H),7.51-7.39(m,3H),7.32-7.11(m,6H),7.01(d,J=7.3Hz,2H),4.97-4.90(m,1H),4.08(q,J=6.7 Hz,3H),3.82(d,J=14.0Hz,1H),3.45(d,J=7.0Hz,1H),3.21(s,1H),1.55-1.20(m,7H),1.18-1.03(m,3H),0.93(dd,J=26.8,7.0Hz,1H); 13 C NMR(75MHz,CD3OD)δ 160.5,159.7,145.9,142.3,141.2,133.3,129.6,129.5,129.2,128.0,127 .0,116.1,75.0,64.7,57.9,56.9,52.0,51.5,22.8,15.8,15.2;MS(ESI)m / z 462.20[M+H] + ;HPLC,>98%,t R 15.2 minutes.

[0168] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-1-[(1S)-1-phenylethyl]-3-[4'-(propan-2-yloxy)-[1,1'-biphenyl]-4-yl]urea (59). Following the procedure for the synthesis of 55, starting from E3r and 4-isoproxyphenylboronic acid, gave the Boc-protected biphenylurea E4e (69% yield), which was then deprotected with HCl to give the hydrochloride salt of 59 (80% yield) as a white solid. 1H NMR(400MHz,CD3OD)δ 7.72(d,J=8.2Hz,2H),7.56(d,J=8.5Hz,2H),7.40(d,J=8.3Hz,2H),7.32-7 .10(m,5H),6.97(d,J=8.6Hz,2H),4.91(q,J=7.0Hz,1H),4.70-4.55(m,1H), 4.03(dd,J=15.2,7.5Hz,1H),3.80(dd,J=15.1,3.9Hz,1H),3.48-3.35(m,1H ),3.26(s,3H),3.21-3.10(m,1H),1.39-1.24(m,9H),1.08(d,J=6.2Hz,3H); 13 C NMR(100MHz,CD3OD)δ 158.3,158.0,144.6,140.9,139.8,131.9,128.1,128.1,127.8,126.6,125 .6,116.0,73.6,69.7,56.4,55.4,50.6,50.0,21.3,21.0,14.2;MS(ESI)m / z 476.40[M+H] + : HPLC, >99%,t R 15.7 minutes.

[0169] [ka] 3-[(2R,3R)-2-Amino-3-methoxybutyl]-3-[4-(4-methylpent-1-yn-1-yl)phenyl]-1-[(1S)-1-phenylethyl]urea (60). Sonogashira coupling of E3r and 4-methyl-1-pent-1-yne was carried out according to the procedure used for the synthesis of 36 to give the Boc-protected (4-methylpent-1-yn-1-yl)phenylurea E4f (75% yield), which was deprotected with HCl to give the hydrochloride salt of 60 (75% yield) as a white solid. 1H NMR(400MHz,CD3OD)δ 7.48(d,J=8.5Hz,2H),7.33-7.11(m,7H),4.92-4.87(m,1H),3.98(dd,J=15.2,7.4Hz,1H),3.76(dd,J=15.2,4.0Hz,1H),3.38(p, J=6.2Hz,1H),3.25(s,3H),3.18-3.05(m,1H),2.30(d,J=6.5Hz,2H),1.95-1.80(m,1H),1.32(d,J=7.1Hz,3H),1.11-0.98(m,9H); 13 C NMR(100MHz,CD3OD)δ MS(ESI)m / z 422.40[M+H] + ;HPLC,>99%,t R 15.9 minutes.

[0170] Pharmacology Materials. Cell culture materials were purchased from Fisher SSI. Forskolin was purchased from Sigma-Aldrich. Lance Ultra kit (TRF0262) was purchased from PerkinElmer.

[0171] Lance™ Ultra cAMP assay using stable PPLS-HA-GPR88 CHO cells. All cAMP assays were performed using our previously published methods. See, for example, Jin et al., Effect of substitution on the aniline moiety of the GPR88 agonist 2-PCCA: synthesis, structure-activity relationships, and molecular modeling studies. ACS Chemical Neuroscience 2016, 7, 1418-1432, which is incorporated herein by reference for such teachings. A stimulation buffer was prepared containing 1× Hank's Balanced Salt Solution (HBSS), 5 mM HEPES, 0.1% BSA stabilizer, and 0.5 mM final IBMX, titrated to pH 7.4 at room temperature. Serial dilutions of test compound (5 μL) and 300 nM forskolin (5 μL), both prepared at 4x the desired final concentration in 2% DMSO / stimulation buffer, were added to a 96-well white ½ area microplate (PerkinElmer). A cAMP standard curve was prepared at 4x the desired final concentration in stimulation buffer and 5 μL was added to the assay plate. Stable PPLS-HA-GPR88 CHO cells were lifted with Versene and spun at 270 g for 10 min. The cell pellet was resuspended in stimulation buffer and 4,000 cells (10 μL) were added to each well except the well containing the cAMP standard curve. After 30 min incubation at room temperature, Eu-cAMP tracer and uLIGHT-anti-cAMP working solutions were added according to the manufacturer's instructions. After 1 h incubation at room temperature, the TR-FRET signal (ex 337 nm) was read on a CLARIOstar multimode plate reader (BMG Biotech, Cary, NC).

[0172] Data analysis. TR-FRET signal (665 nm) was converted to fmol cAMP by interpolation from a standard cAMP curve. Fmol cAMP was plotted against the logarithm of compound concentration and the data was fitted to a three-parameter logistic curve to obtain the EC 50 E values ​​were generated (Prism, version 6.0, GraphPad Software, Inc., San Diego, CA) for each test compound relative to the reference compound RTI-13951-33. max Values ​​are expressed as % control E max The signal was calculated using the formula: maximum test compound signal / maximum control signal)×100. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] a pEC 50 Values ​​are the mean ± SEM of at least three independent experiments performed in duplicate. b E max Values ​​are % of RTI-13951-33 maximum signal (mean ± SEM).

[0173] Below are the details of this page: [ PMC free article ] [ PubMed ] 1.Rehm,J.;Mathers,C.;Popova,S.;Thavorncharoensap,M.;Teerawattananon,Y.;Patra,J. 2.Thavorncharoensap,M.;Teerawattananon,Y.;Yothasamut,J.;Lertpitakpong,C.;Chaikledkaew,U. 3.Costardi,JV;Nampo,RA;Silva,GL;Ribeiro,MA;Stella,HJ;Stella,MB;Malheiros,SV,A review on alcohol: from the central action mechanism to chemical dependency. 4.Bouza,C.;Angeles,M.;Munoz,A.;Amate,JM,Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence:a systematic review.Addiction 2004,99,811-828. 5.Mizushima,K.;Miyamoto,Y.;Tsukahara,F.;Hirai,M.;Sakaki,Y.;Ito,T.,A novel G-protein-coupled receptor gene expressed in striatum.Genomics 2000,69,314-321. 6.Van Waes,V.;Tseng,K.Y.;Steiner,H.,GPR88-a putative signaling molecule predominantly expressed in the striatum:Cellular localization and developmental regulation.Basal Ganglia 2011,1,83-89. 7.Massart,R.;Guilloux,J.P.;Mignon,V.;Sokoloff,P.;Diaz,J.,Striatal GPR88 expression is confined to the whole projection neuron population and is regulated by dopaminergic and glutamatergic afferents.European Journal of Neuroscience 2009,30,397-414. 8.Ye,N.;Li,B.;Mao,Q.;Wold,E.A.;Tian,S.;Allen,J.A.;Zhou,J.,Orphan receptor GPR88 as an emerging neurotherapeutic target.ACS Chemical Neuroscience 2019,10,190-200. 9.Logue,S.F.;Grauer,S.M.;Paulsen,J.;Graf,R.;Taylor,N.;Sung,M.A.;Zhang,L.;Hughes,Z.;Pulito,V.L.;Liu,F.;Rosenzweig-Lipson,S.;Brandon,N.J.;Marquis,K.L.;Bates,B.;Pausch,M.,The orphan GPCR,GPR88,modulates function of the striatal dopamine system:a possible therapeutic target for psychiatric disorders?Molecular and Cellular Neuroscience 2009,42,438-447. 10.Quintana,A.;Sanz,E.;Wang,W.;Storey,G.P.;Guler,A.D.;Wanat,M.J.;Roller,B.A.;La Torre,A.;Amieux,P.S.;McKnight,G.S.;Bamford,N.S.;Palmiter,R.D.,Lack of GPR88 enhances medium spiny neuron activity and alters motor-and cue-dependent behaviors.Nature Neuroscience 2012,15,1547-1555. 11.Ben Hamida,S.;Mendonca-Netto,S.;Arefin,T.M.;Nasseef,M.T.;Boulos,L.J.;McNicholas,M.;Ehrlich,A.T.;Clarke,E.;Moquin,L.;Gratton,A.;Darcq,E.;Harsan,L.A.;Maldonado,R.;Kieffer,B.L.,Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks.Biological Psychiatry 2018,84,202-212. 12.Jin,C.;Decker,A.M.;Makhijani,V.H.;Besheer,J.;Darcq,E.;Kieffer,B.L.;Maitra,R.,Discovery of a potent,selective,and brain-penetrant small molecule that activates the orphan receptor GPR88 and reduces alcohol intake.Journal of Medicinal Chemistry 2018,61,6748-6758. 13.Dzierba,C.D.;Bi,Y.;Dasgupta,B.;Hartz,R.A.;Ahuja,V.;Cianchetta,G.;Kumi,G.;Dong,L.;Aleem,S.;Fink,C.;Garcia,Y.;Green,M.;Han,J.;Kwon,S.;Qiao,Y.;Wang,J.;Zhang,Y.;Liu,Y.;Zipp,G.;Liang,Z.;Burford,N.;Ferrante,M.;Bertekap,R.;Lewis,M.;Cacace,A.;Grace,J.;Wilson,A.;Nouraldeen,A.;Westphal,R.;Kimball,D.;Carson,K.;Bronson,J.J.;Macor,J.E.,Design,synthesis,and evaluation of phenylglycinols and phenyl amines as agonists of GPR88.Bioorgic&Medicinal Chemistry Letters 2015,25,1448-1452. 14.Jin,C.;Decker,A.M.;Langston,T.L.,Design,synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists.Bioorganic&Medicinal Chemistry 2017,25,805-812. 15.Rahman,M.T.;Decker,A.M.;Langston,T.L.;Mathews,K.M.;Laudermilk,L.;Maitra,R.;Ma,W.;Darcq,E.;Kieffer,B.L.;Jin,C.,Design,synthesis,and structure-activity relationship studies of(4-alkoxyphenyl)glycinamides and bioisosteric 1,3,4-oxadiazoles as GPR88 agonists.Journal of Medicinal Chemistry 2020,63,14989-15012. 16.Rahman,M.T.;Decker,A.M.;Laudermilk,L.;Maitra,R.;Ma,W.;Ben Hamida,S.;Darcq,E.;Kieffer,B.L.;Jin,C.,Evaluation of amide bioisosteres leading to 1,2,3-triazole containing compounds as GPR88 agonists:Design,synthesis,and structure-activity relationship studies.Journal of Medicinal Chemistry 2021,64,12397-12413. 17.Jin,C.;Decker,A.M.;Harris,D.L.;Blough,B.E.,Effect of substitution on the aniline moiety of the GPR88 agonist 2-PCCA:Synthesis,structure-activity relationships,and molecular modeling studies.ACS Chemical Neuroscience 2016,7,1418-1432.

[0174] The specific pharmacological response observed may vary with and depending on the particular active compound selected, or whether a pharmaceutical carrier is present, as well as the type of formulation and method of administration used, and such expected variations or differences in results are contemplated in accordance with the practice of the present disclosure.

[0175] Although specific embodiments of the present disclosure are illustrated and described in detail herein, the present disclosure is not limited thereto.The above detailed description is provided as an example of the present disclosure and should not be interpreted as constituting any limitation of the present disclosure.Modifications are obvious to those skilled in the art, and all modifications that do not depart from the spirit of the present disclosure are intended to be included in the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R １ is hydrogen, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C １－１０ Alkoxy, C １－１０ Haloalkyl, NH ２ , N.H.C. １－１０ Alkyl, N(C １－１０ Alkyl) ２ , S(O)C １－１０ Alkyl, S(O) ２ C １－１０ Alkyl, NHSO ２ C １－１０ Alkyl, C ３－６ Cycloalkyl, 5- to 7-membered heterocycle, C ６－１０ Aryl, and C ５－１０ Heteroaryl; A １ but, c) a 6-membered aromatic ring which may contain one N heteroatom, or d) a 10-membered fused aromatic ring system which may contain 1 or 2 N heteroatoms; X is CH or N; R ２ However, (CH ２ ) ｎ２ -R ２０ and 、 n2 is 0, 1, 2, or 3; R ２０ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, OH, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, NO ２ , C.N., N.H. ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , N ３ , S(O)C １－６ Alkyl, S(O) ２ C １－６ Alkyl, NHSO ２ C １－６ Alkyl, C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, NHC(O)C １－６ Alkyl, N(C １－６ Alkyl)C(O)C １－６ Alkyl, C(O)NHC １－６ Alkyl, C(O)N(C １－６ Alkyl) ２ , CH(NH ２ ) C １－６ Alkyl, CH(N[C １－６ Alkyl] ２ ) C １－６ Alkyl, CH(NH ２ ) C １－６ Alkylene -O-C １－６ Alkyl, CH(N[C １－６ Alkyl] ２ ) C １－６ Alkylene -O-C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 7-membered heterocycle, C ６－１０ Aryl, and C ５－１０ Heteroaryl; R ４ However, (CH ２ ) ｎ４ -R ４０ and n4 is 0, 1, 2, or 3; R ４０ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, OH, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, NO ２ , C.N., N.H. ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , N ３ , S(O)C １－６ Alkyl, S(O) ２ C １－６ Alkyl, NHSO ２ C １－６ Alkyl, C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, NHC(O)C １－６ Alkyl, N(C １－６ Alkyl)C(O)C １－６ Alkyl, C(O)NHC １－６ Alkyl, C(O)N(C １－６ Alkyl) ２ , CH(NH ２ ) C １－６ Alkyl, CH(N[C １－６ Alkyl] ２ ) C １－６ Alkyl, CH(NH ２ ) C １－６ Alkylene -O-C １－６ Alkyl, CH(N[C １－６ Alkyl] ２ ) C １－６ Alkylene -O-C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 7-membered heterocycle, C ６－１０ Aryl, and C ５－１０ Heteroaryl; L １ but, d) Divalent C ３ Cycloalkyl, e) [(CR Ｌ ) ２ ] ｍ or f) a bond; m is 0, 1, 2, or 3; Each R Ｌ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, OH, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, NO ２ , C.N., N.H. ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , N ３ , S(O)C １－６ Alkyl, S(O) ２ C １－６ Alkyl, NHSO ２ C １－６ Alkyl, C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, NHC(O)C １－６ Alkyl, C(O)NHC １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 7-membered heterocycle, C ６－１０ Aryl, and C ５－１０ Heteroaryl; A ２ but, c) a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from O, N, or S; or d) a 6-membered aromatic ring which may contain one heteroatom; R ３ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, NO ２ , C.N., N.H. ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , N ３ , S(O)C １－６ Alkyl, S(O) ２ C １－６ Alkyl, NHSO ２ C １－６ Alkyl, C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, NHC(O)C １－６ Alkyl, C(O)NHC １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 7-membered heterocycle, C ６－１０ Aryl, and C ５－１０ Heteroaryl; During the ceremony, Each C ３－６ Cycloalkyl, 5- to 7-membered heterocycle, C ６－１０ Aryl, and C ５－１０ Heteroaryl is unsubstituted or contains 1, 2, or 3 (CH ２ ) ０－３ R Ｓ is replaced by Each R Ｓ But, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, OH, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, NO ２ , C.N., N.H. ２ , N.H.C. １－６ Alkyl, N(C １－６ Alkyl) ２ , N ３ , S(O)C １－６ Alkyl, S(O) ２ C １－６ Alkyl, NHSO ２ C １－６ Alkyl, C(O)C １－６ Alkyl, C(O)OC １－６ Alkyl, NHC(O)C １－６ Alkyl, C(O)NHC １－６ Alkyl, unsubstituted C ３－６ Cycloalkyl, O-unsubstituted C ３－６ Cycloalkyl, unsubstituted 5- to 7-membered heterocycle, unsubstituted C ６－１０ Aryl, and unsubstituted C ５－１０ A compound of formula (I), or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: heteroaryl.

2. R １ But, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, (CH ２ ) ０－３ C ３－６ Cycloalkyl or OC ３－６ C optionally substituted with cycloalkyl; １－１０ Alkyl, C ２－１０ Alkynyl, C １－１０ Alkoxy or C ６ The compound of claim 1 which is aryl.

3. R １ But, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, or (CH ２ ) ０－３ C ３－６ C optionally substituted with cycloalkyl; １－１０ Alkoxy or C ６ 3. The compound of claim 1 or 2, which is aryl.

4. A １ The compound according to any one of claims 1 to 3, wherein is phenyl.

5. The compound according to any one of claims 1 to 4, wherein X is CH.

6. The compound of claim 5, wherein n2 is 1.

7. R ２０ The compound according to claim 6, wherein is OH.

8. The compound according to any one of claims 1 to 4, wherein X is N.

9. The compound of claim 8, wherein n2 is 1.

10. R ２０ But CH(NH ２ ) C １－６ Alkyl, CH(N[C １－６ Alkyl] ２ ) C １－６ Alkyl, CH(NH ２ ) C １－６ Alkyl-O-C １－６ Alkyl, or CH(N[C １－６ Alkyl] ２ ) C １－６ Alkyl-O-C １－６ The compound of claim 9 which is alkyl.

11. R ４ is H or C １－６ The compound according to any one of claims 1 to 10, which is alkyl.

12. L １ But divalent C ３ The compound of any one of claims 1 to 11, which is cycloalkyl.

13. L １ is [C(R Ｌ ) ２ ] ｍ The compound according to any one of claims 1 to 11,

14. m is 1 and one R Ｌ is H and one R Ｌ But, C １－６ The compound of claim 13, which is alkyl.

15. A ２ The compound according to any one of claims 1 to 14, wherein is phenyl.

16. R ３ is hydrogen or C １－６ The compound according to any one of claims 1 to 15, which is alkyl.

17. A compound selected from the group consisting of: 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】

18. A compound selected from the group consisting of: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】

19. 20. A method of treating a disorder in a patient in need thereof, wherein modulation of a G protein coupled receptor is beneficial, comprising administering a compound according to any one of claims 1 to 18.

20. 20. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of a disorder or a disorder disease, wherein modulation of a G protein coupled receptor is beneficial to a patient in need of such treatment.

21. A compound according to any one of claims 1 to 18 for use in the treatment of a disorder in which modulation of a G protein coupled receptor is beneficial to a patient in need of such treatment.

22. 22. A method, use or compound for use according to claim 19, 20 or 21 for treating a neurological disorder.

23. 23. The method, use or compound for use according to claim 22, wherein the neurological disorder is selected from one or more of psychosis, cognitive deficits in schizophrenia, affective disorders, attention deficit hyperactivity disorder, bipolar disorder, drug addiction, alcohol addiction, food addiction, activity addiction, Parkinson's disease and Alzheimer's disease.

24. 22. A method, use or compound for use according to claim 19, 20 or 21 for treating a metabolic disease.

25. 25. The method, use or compound for use according to claim 24, wherein the metabolic disease is selected from one or more of obesity and diabetes.

26. 22. A method, use or compound for use as claimed in claim 19, 20 or 21 for treating alcohol use disorder.

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