Patent Application
20240360100
The field of the invention relates generally to novel small molecules that bind and/or modulate different forms of serotonin (5-HT) 5-HT2A and 5-HT2C receptors as well as the preparation and the use thereof.
Serotonin (5-HT) is an endogenous small molecule which enacts remarkably pleiotropic actions in the central and peripheral nervous systems as well as immune, intestinal, and cardiovascular systems. Serotonin binds to 14 receptors arrayed within the plasma membrane of cells resident in these systems; these receptors are grouped into six families of G protein coupled receptors (GPCRs) and one ligand-gated ion channel. The 5-HT2R family is composed of triplets (5-HT2AR, 5-HT2BR, 5-HT2CR) and subtype selectivity is a major determining factor regarding the scale of its potential therapeutic utility (Barnes et al., Pharmacological Reviews, 73:310-520, 2021). The discovery of increasingly selective receptor ligands has shown that each 5-HT2R mediates a myriad of functions even though these receptors are related in their molecular structure, amino acid sequences and signaling properties. Of note, 5-HT2CR signaling is a key component of the mechanisms of action underlying the cognitive and behavioral dimensions of substance use disorders (SUDs), particularly well-described for cocaine use disorder (CUD) (Cunningham et al., Handbook of the Behavioral Neurobiology of Serotonin, 2020; Howell and Cunningham, Pharmacological Reviews, 67:176-197, 2015). On the other hand, the 5-HT2AR mediates antipsychotic drug effects, inflammation and pain, and even viral entry into cells and post-viral brain sequela (Elphick et al., Science, 306:1380-1383, 2004; Abbott et al., Neuroscience, 77:575-584, 1997; Flanagan et al., Life Sciences, 236:116790; Couch et al., Neuroimage, 75:177-186, 2013; Couch et al., PloS One, 10:e0130643). The 5-HT2AR is very well characterized as a key mediator of the perceptual and psychedelic states, and mood and cognitive alterations evoked by psychedelics such as d-lysergic acid diethylamide (LSD) and psilocybin (Nichols, Pharmacology and Therapeutics, 101:131-181, 2004; Orejarena et al., International Journal of Neuropsychopharmacology, 14:927-940, 2011). In short, the quest for novel chemical entities through targeting 5-HT2CR and 5-HT2AR actions promises new therapeutic gains in managing a myriad of disorders.
Ligands that selectively enrich 5-HT2R function may be useful in combating impaired serotonergic control that contributes to mental health disorders, SUDs, pain, and inflammatory disorders. The classic approach is to be the development of agonists targeted to bind directly to the orthosteric binding pocket. However, as is the case for the 5-HT2R family, the orthosteric site has co-evolved with 5-HT and is highly conserved among 5-HT2R members. Thus, selectively targeting the orthosteric site of the 5-HT2AR among its closely related subtypes, 5-HT2BR and 5-HT2CR, has proven to be challenging (Barnes et al., Pharmacological Reviews, 73:310-520, 2021). Targeted 5-HT2AR, as well as 5-HT2CR, allosteric modulation provides a pointed approach that broadens the available small molecule toolbox for maximizing neuropsychiatric health.
For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, and alterations and modifications in the illustrated invention, and further applications of the principles of the invention as illustrated therein are herein contemplated as would normally occur to one skilled in the art to which the invention relates.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with the usage of that word in any other document, including any document incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and its associated claims unless a contrary meaning is clearly intended (for example in the document where the term is originally used).
The use of “or” means “and/or” unless stated otherwise.
The use of “a” herein means “one or more” unless stated otherwise or where the use of “one or more” is clearly inappropriate.
The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” and “including” are interchangeable and not intended to be limiting. Furthermore, where the description of one or more embodiments uses the term “comprising,” those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language “consisting essentially of” and/or “consisting of.”
As used herein, the term “about” refers to a ±10% variation from the nominal value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.
The term “alkenyl” as used herein by itself or as part of another group refers to both straight and branched chain radicals. In one embodiment, the alkenyl group has 3-12 carbons. In another embodiment, the alkenyl group has 3-7 carbons. In another embodiment, the alkenyl group has 3-6 carbons. In another embodiment, the alkenyl group has 3-4 carbons (also referred to as “C3-4 alkenyl” or “C3-4 alkenyl”). Alkenyl groups can include, for example, allyl, 2-methallyl, butenyl, -cis-2-butenyl, trans-2-butenyl, 3-pentenyl, and isoprenyl.
The term “alkyl” as used herein by itself or as part of another group refers to both straight and branched chain radicals. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons (also referred to as “Cl-4 alkyl” or “C1-4 alkyl”). The term “alkyl” may include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.
Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.
This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.
The term “alkylene” as used herein refers to straight and branched chain alkyl linking groups, i.e., an alkyl group that links one group to another group in a molecule. In some embodiments, the term “alkylene” may include —(CH2)n- where n is 2-8.
The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
In certain embodiments, the term “cycloalkyl” includes bicyclic ring systems. The bicyclic ring system may be in the form of a bridged, fused, or spiro form.
The term “aryl” refers to a phenyl group, which may be unsubstituted or substituted by one or more groups selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, carbonyl, alkylamido, nitro, amino, dialkylamino, carboxy, thio or thioalkyl.
An “amino” group refers to an —NH2 group.
An “amido” group refers to an —CONH2 group. An alkylamido group refers to an —CONHR group wherein R is as defined above. A dialkylamido group refers to an —CONRR′ group wherein R and R′ are as defined above.
The term “halogen” or “halo” as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine.
The term “hydroxy” or “hydroxyl” as used herein by itself or as part of another group refers to an —OH group.
An “alkoxy” group refers to an —O-alkyl group wherein “alkyl” is as defined above.
A “thio” group refers to an —SH group.
An “alkylthio” group refers to an —SR group wherein R is alkyl as defined above.
The term “heteroaryl” as used herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 7π-electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. The heteroaryl moiety may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy, carbonyl, alkylamido, nitro, amino, dialkylamino, carboxy, thio or thioalkyl. Examples of heteroaryl groups include thienyl, imadizolyl, oxadiazolyl, isoxazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, pyranyl, thianthrenyl, pyrazolyl, pyrazinyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl groups. Especially preferred heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino 1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.
The term “heterocycle” or “heterocyclic ring”, as used herein except where noted, represents a stable 3- to 8-membered monocyclic-, or stable 7- to 11-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Rings may contain one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom that results in the creation of a stable structure. Further, “heterocycle” or “heterocyclic ring” moiety may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy, carbonyl, alkylamido, nitro, amino, dialkylamino, carboxy, thio or thioalkyl. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
In certain embodiments, the term “heterocycle” includes bicyclic ring systems. The bicyclic ring system may be in the form of a bridged, fused, or spiro form.
The term “alkylamino” as used herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms. The term “dialkylamino” as used herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
As used herein, the term “arylalkyl” denotes an alkylene, group substituted with an aryl group, for example, Ph-(CH2)n—, where n is 1-6, Ph-(CH2)3—, Ph-(CH2)2— etc.
A “therapeutically effective amount” is an amount sufficient to decrease, prevent or ameliorate the symptoms associated with a medical condition.
The term “non-hydrogen substituent” refers to a substituent that is not made up solely of hydrogen. Examples of non-hydrogen substituents includes halogen, C1-4 alkyl, C3-8 alkenyl, halogen-substituted C1-4 alkyl, NR9R10, and CN. In some embodiments, non-hydrogen substituent includes methyl. In further embodiments, non-hydrogen substituent includes fluoride (F). In further embodiments, non-hydrogen substituent includes NH2.
Various groups are described above, and below, as substituted or unsubstituted (i.e., optionally substituted). Optionally substituted groups may include one or more substituents independently selected from: halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, oxo, carbamoyl, alkyl, heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In certain aspects the optional substituents may be further substituted with one or more substituents independently selected from: halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl (—C(O)NR2), unsubstituted alkyl, unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, sulfinyl, sulfonyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. Exemplary optional substituents include, but are not limited to: —OH, oxo (═O), —Cl, —F, Br, C1-4alkyl, phenyl, benzyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —NO2, —S(C1-4alkyl), —SO2(C1-4alkyl), —CO2(C1-4alkyl), —SO2—, and —O(C1-4alkyl).
The term “administering” or “administration” refers to contacting one or more cells of a subject (including human, horse, cat, dog, monkey, rat, and mice) with one or more compounds according to the present invention. In some embodiments, administration may occur in vitro. In further embodiments, administration may occur in vivo.
In recent years, allosteric modulators of several GPCRs have been developed and are predicted to have robust promise in the treatment of a variety of biological disorders (May et al., Annu. Rev. Pharmacol. Toxicol., 47:1-51, 2007). The recent preclinical indications of efficacy, coupled with the launch of cinacalcet and maraviroc as the first marketed GPCR allosteric modulators, validate the clinical utility of both positive and negative allosteric modulators (Conn et al., Nature Reviews Drug Discovery, 8:41-54, 2009). The studies reported to date provide proof of concept that fuels the discovery of highly selective allosteric ligands for other GPCRs.
In biochemistry, allostery is the regulation of an enzyme or other protein by binding an effector molecule at an allosteric site(s) on the protein (that is, a site other than the active site of that protein). Thus, a regulatory site of an allosteric protein is physically distinct from the binding site. Effectors that enhance protein function are referred to as positive allosteric modulators (PAMs), whereas those that decrease protein function are called negative allosteric modulators (NAMs) (Christopoulos, Molecular Pharmacology, 86:463-478, 2014). Neutral allosteric ligand (NAL) refers to an allosteric modulator that binds to the allosteric site but has no effects on the response to the orthosteric ligand. (Christopoulos, Molecular Pharmacology, 86:463-478, 2014). For example, the compounds described herein are 5-HT2AR and/or 5-HT2CR PAMs that enhance 5-HT2AR and/or 5-HT2CR function. The compounds can be probes for understanding the biology of these receptors to ultimately develop therapeutics for the treatment of diseases, including, but not limited to mental health disorders (e.g., anxiety, depression, schizophrenia), SUDs, eating disorders and obesity, pain, and inflammatory disorders. Targeting allosteric modulation of the 5-hydroxytryptamine receptor (5-HTR) to identify novel CNS probes with the potential for therapeutic application offers pharmacological advantages to a direct agonist or antagonist approach.
The 5-HTRs are a group of GPCRs and ligand-gated ion channels found in the brain and periphery that mediate important key functions in biology. The 5-HTR family includes 5-HT1 to 5-HT7 with each type having numerous receptor subtypes. The 5-HTRs modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P. The 5-HTRs influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, immunological function, learning, memory, mood, nausea, pain, sleep, and thermoregulation; and are the target of a variety of pharmaceutical and illicit drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.
Without wishing to be bound by a particular theory, one premise is that selective enrichment of 5-HT2CR function will combat vulnerability to cocaine use disorder (CUD) and relapse during recovery. Targeting of the 5-HT2CR remains challenging since each of the 14 5-HT GPCR subtypes share a conserved orthosteric binding site for the endogenous agonist 5-HT.
By targeting a binding site that is spatially distinct from the conserved 5-HT orthosteric site, divergent residues or topological surfaces may be exploited to achieve 5-HT2CR selectivity while enhancing the functional response to 5-HT. Allosteric modulators are being discovered to bind to an identified, spatially distinct allosteric site to selectively potentiate 5-HT2CR, but not 5-HT2AR or 5-HT2BR, signaling in vitro without intrinsic activity at any of these receptors.
One aspect of the invention pertains to compounds identified as allosteric modulators of 5-HT2AR and/or 5-HT2CR, as well as pharmaceutical compositions and methods using the same. Certain embodiments also include methods of identifying and methods of synthesizing the compounds as well as the isomer separations of compounds with chiral centers. Optimization and development of allosteric 5-HT2AR and/or 5-HT2CR modulators that bind sites other than the primary orthosteric ligand binding site generate novel, highly selective, and potent ligands of 5-HT2AR and/or 5-HT2CR. Such molecules may be used as small molecule probes for the study of receptor biology and as effective therapeutics for a variety of diseases.
Another aspect of the present invention provides several highly potent ligands as selective allosteric modulators of 5-HT2AR and/or 5-HT2CR with positive, negative, or neutral allosteric modulator activity. For example, two 5-HT2CR PAMs (CYD-1-79, CTW0415) potentiate in vivo effects of a full 5-HT2CR agonist in male rats, an effect which was blocked by a selective 5-HT2CR antagonist, verifying reliance on 5-HT2CR function (Wild et al., Journal of Medicinal Chemistry, 62:288-305, 2019; Wold et al., Journal of Medicinal Chemistry, 63:7529-7544, 2020). Surprisingly, first-in-class 5-HT2A RPAMs (CTW0404, CTW0419) have been discovered, providing tools to optimize 5-HT2CR PAMs and 5-HT2AR PAMs with favorable drug-like properties and analyze select molecules in proof-of-concept in vivo assays.
The inventors surprisingly identified unique 5-HT2CR PAM molecules that, for the first time, render this receptor a highly actionable target toward mitigating CUD-associated vulnerabilities. The synthetic route to access the first reported selective 5-HT2CR PAM PNU-69176E and its diastereomer. PNU-69176E potentiated 5-HT-evoked Cai2+ release, exhibiting the profile of a 5-HT2CR PAM with agonist-like properties observed at the highest concentration tested in vitro (10 μM). PNU-69176E is a complex molecule with multiple chiral centers, and—a diversification strategy was designed to build on the breakdown of PNU-69176E into three distinct moieties: the central ring, lipophilic tail (LT), and polar head (PH). A first generation of 5-HT2CR PAMs was discovered which bind to an identified, spatially distinct allosteric site to selectively potentiate 5-HT2CR, but not 5-HT2AR or 5-HT2BR, signaling in vitro without intrinsic activity at any of these receptors. As a proof-of-concept, two 5-HT2CR PAMs (CYD-1-79, CTW0415) selectively potentiated in vivo effects of a full 5-HT2CR agonist (Wild et al., Journal of Medicinal Chemistry, 62:288-305, 2019; Wold et al., Journal of Medicinal Chemistry, 63:7529-7544, 2020). CYD-1-79 also suppressed cocaine-seeking in a cocaine use disorder relapse-like behavioral model in male rats (Wild et al., Journal of Medicinal Chemistry, 62:288-305, 2019).
Intriguingly, first-in-class 5-HT2A RPAMs (CTW0414, CTW0419) was also discovered, unlocking an entirely new and innovative line of investigation. CTW0404 and CTW0419 significantly shifted the concentration-response curve for 5-HT-evoked accumulation of the downstream inositol-1,4,5-trisphosphate metabolite inositol monophosphate (IP1) upward with similar efficacy as Cai2+ release in vitro.
The following is a non-limiting list of embodiments of the invention and is meant to be exemplary:
In some embodiments, the invention pertains to racemates or single isomers of compounds with chiral centers disclosed herein including the compounds of Formula I-Formula VI. The stereoisomers may be obtained by known methods such as chiral HPLC separation, stereoselective synthesis, and using optically pure starting reagents.
In certain embodiments, the invention pertains to a compound of any of the following structures:
The method according to embodiment 901, wherein the compound modulates the 5-hydroxytryptamine 2A receptor.
The method according to embodiment 901, wherein the compound modulates the 5-hydroxytryptamine 2C receptor.
The method according to embodiment 901, wherein the compound modulates the 5-hydroxytryptamine 2A receptor and the 5-hydroxytryptamine 2C receptor.
The method according to embodiment 901, wherein the compound modulates the 5-hydroxytryptamine 2A receptor to greater extent than the compound modulates the 5-hydroxytryptamine 2C receptor (such that the compound selectly modulates the 5-hydroxytryptamine 2A receptor over 5-hydroxytryptamine 2C receptor).
The method according to embodiment 901, wherein the compound modulates the 5-hydroxytryptamine 2C receptor to greater extent than the compound modulates the 5-hydroxytryptamine 2A receptor.
A non-limiting list of exemplary embodiments of representative compounds according to the present invention is shown in Table 1:
Exemplary reaction schemes are provided herein for the preparation of representative compounds according to the present invention.
Exemplary embodiments of piperidines according to Formula I (wherein X is “NH”) and Formula II may be prepared according to reaction Scheme I:
Exemplary embodiments of tetrahydropyran amides according to Formula I (wherein X is “O”) and Formula III may be prepared according to reaction Scheme II:
Exemplary embodiments of pyrrolidine amides according to Formula IV wherein X is “NH” may be prepared according to reaction Scheme III:
Exemplary embodiments of substituted tetrahydrofuran amides according to Formula IV wherein X is “O” may be prepared according to reaction Scheme IV:
Exemplary embodiments of substituted azetidine amides according to Formula V wherein X is “NH” may be prepared according to reaction Scheme V:
Exemplary embodiments of substituted oxetane amides according to Formula V wherein X is “O” may be prepared according to reaction Scheme VI:
Exemplary embodiments of substituted aziridine carboxamides according to Formula VI wherein X is “NH” may be prepared according to reaction Scheme VII:
Exemplary embodiments of substituted epoxy amides according to Formula VI wherein X is “O” may be prepared according to reaction Scheme VIII:
Compounds of CTW0508 may be prepared according to reaction Scheme IX:
It is to be understood that the foregoing descriptions are exemplary, and thus do not restrict the scope of the invention.
The following examples as well as the figures are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples or figures represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Syntheses of exemplary embodiments of carboxamide compounds according to the present invention and their synthetic intermediates are described herein.
tert-Butyl 2-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0111). The synthesis of compound AB0111 was conducted by dissolving 1-(tert-butoxycarbonyl)-4-phenethylpiperidine-2-carboxylic acid, EDCI and HOBt in CH2Cl2 at 0° C. under N2 gas. DIPEA was added and after 1 min 2-(4-methylpiperazin-1-yl)ethan-1-amine was added and reaction was left to reach room temperature overnight. After 18 h reaction was quenched with distilled water, extracted with CH2Cl2 and concentration to a colorless oil. Oil was purified by PTLC developed to afford a colorless gel. Yield 44 mg, 72%. 1H NMR (300 MHz, CDCl3) δ 7.36-7.11 (m, 6H), 6.59 (t, J=4.7 Hz, 1H), 4.37 (t, J=6.8 Hz, 1H), 3.78 (dt, J=13.6, 5.3 Hz, 1H), 3.35 (p, J=6.1 Hz, 2H), 3.19 (ddd, J=14.0, 10.1, 4.6 Hz, 1H), 2.79-2.32 (m, 13H), 2.27 (d, J=12.1 Hz, 6H), 1.99 (dd, J=7.2, 4.6 Hz, 2H), 1.92-1.74 (m, 1H), 1.63 (td, J=10.3, 5.8 Hz, 4H), 1.47 (s, 10H), 1.42-1.22 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 172.2, 155.7, 142.3, 128.3, 125.7, 80.5, 77.2, 56.3, 55.7, 55.0, 52.7, 45.9, 38.9, 36.4, 35.9, 33.4, 30.3, 29.9, 29.2, 28.4.
tert-Butyl 2-((2-methoxyethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0118). The synthesis of compound AB0118 was conducted by following a procedure similar to that of compound AB0111. Yield 40 mg as a colorless gel, 77%. 1H NMR (300 MHz, CDCl3) δ 7.22 (dd, J=26.0, 7.6 Hz, 6H), 6.44 (s, 1H), 4.33 (t, J=6.9 Hz, 1H), 3.72 (d, J=30.5 Hz, 1H), 3.48 (s, 4H), 3.31 (s, 3H), 3.18 (s, 1H), 2.73 (s, 2H), 2.03 (s, 4H), 1.71 (s, 3H), 1.47 (s, 10H). 13C NMR (75 MHz, CDCl3) δ 172.3, 155.7, 142.2, 128.3, 128.3, 128.2, 125.7, 125.6, 80.6, 77.4, 77.2, 77.0, 76.6, 71.1, 58.6, 56.1, 39.1, 36.5, 33.3, 30.4, 30.0, 29.6, 29.2, 28.3.
tert-Butyl 2-((2-hydroxyethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0112). The synthesis of compound AB0112 was conducted by following a procedure similar to that of compound AB0111. Yield 34 mg as a colorless gel, 68%. 1H NMR (300 MHz, CDCl3) δ 7.23 (dt, J=29.0, 7.6 Hz, 6H), 6.48 (t, J=6.0 Hz, 1H), 4.18 (dd, J=8.5, 6.1 Hz, 1H), 3.70 (t, J=5.1 Hz, 2H), 3.64-3.51 (m, 1H), 3.39 (dtt, J=13.4, 8.7, 3.4 Hz, 3H), 2.66 (p, J=8.4, 7.1 Hz, 3H), 2.04 (ddd, J=9.4, 5.9, 2.7 Hz, 1H), 1.84 (ddd, J=13.7, 8.1, 4.6 Hz, 2H), 1.62 (ddt, J=15.3, 11.6, 6.5 Hz, 4H), 1.46 (s, 10H), 1.29 (dq, J=14.3, 8.7, 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 173.4, 156.2, 142.1, 128.3, 128.3, 125.7, 81.0, 77.4, 77.2, 77.0, 76.6, 61.7, 57.0, 42.3, 40.4, 36.9, 33.2, 30.9, 30.8, 29.6, 29.5, 28.3.
tert-Butyl 2-((2-(dimethylamino)ethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0113). The synthesis of compound AB0113 was conducted by following a procedure similar to that of compound AB0111. Yield 28 mg as a colorless gel, 51%. 1H NMR (300 MHz, CDCl3) δ 7.34-7.10 (m, 6H), 6.57 (s, 1H), 4.32 (t, J=6.9 Hz, 1H), 3.71 (s, 1H), 3.32 (s, 2H), 3.18 (s, 1H), 2.60 (s, 2H), 2.42 (s, 2H), 2.28 (s, 1H), 2.21 (s, 7H), 2.03 (s, 2H), 1.88 (s, 1H), 1.69 (s, 4H), 1.47 (s, 10H). 13C NMR (75 MHz, CDCl3) δ 172.3, 155.7, 142.3, 128.3, 128.3, 125.7, 125.6, 80.4, 77.4, 77.2, 77.0, 76.6, 57.8, 56.0, 45.1, 39.1, 36.8, 36.5, 33.4, 30.4, 30.1, 29.6, 29.1, 28.3.
tert-Butyl 2-((2-hydroxyethyl)(methyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0114). The synthesis of compound AB0111 was conducted by following a procedure similar to that of compound AB0114. Yield 36 mg as a colorless gel, 73%. 1H NMR (300 MHz, CDCl3) δ 7.42-7.05 (m, 5H), 4.07-3.61 (m, 4H), 3.29 (d, J=14.5 Hz, 2H), 3.05 (d, J=39.5 Hz, 4H), 2.64 (q, J=7.2 Hz, 3H), 1.91 (dtd, J=21.2, 11.1, 10.4, 4.8 Hz, 2H), 1.76-1.49 (m, 4H), 1.44 (d, J=2.5 Hz, 9H), 1.30 (q, J=9.1, 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 173.3, 155.5, 142.1, 128.3, 128.3, 128.2, 125.8, 80.5, 80.4, 77.4, 77.2, 77.0, 76.6, 60.2, 55.3, 52.4, 52.0, 41.0, 37.9, 37.7, 36.8, 33.8, 33.1, 32.9, 31.9, 30.1, 29.6, 29.5, 28.3, 28.3.
tert-Butyl 2-(bis(2-hydroxyethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0115). The synthesis of compound AB0115 was conducted by following a procedure similar to that of compound AB0111. Yield 20 mg as a colorless gel, 35%. 1H NMR (300 MHz, CDCl3) δ 7.44-6.92 (m, 5H), 4.51-2.77 (m, 11H), 2.77-2.50 (m, 2H), 2.20-1.53 (m, 6H), 1.45 (d, J=2.9 Hz, 7H), 1.38-0.67 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 174.1, 173.9, 172.5, 156.6, 142.5, 142.0, 141.9, 128.4, 128.3, 128.3, 128.2, 125.9, 125.8, 125.6, 80.9, 79.5, 77.4, 77.2, 77.0, 76.6, 61.0, 60.4, 54.7, 52.5, 50.9, 50.3, 42.4, 38.0, 33.6, 33.1, 33.1, 32.9, 32.2, 31.9, 31.4, 31.2, 30.2, 29.9, 29.6, 28.4, 28.3, 28.2.
tert-Butyl 2-(((2S,3S)-1,3-dihydroxybutan-2-yl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0116). The synthesis of compound AB0116 was conducted by following a procedure similar to that of compound AB0111. Yield 31 mg as a colorless gel, 54%. 1H NMR (300 MHz, CDCl3) δ 7.44-7.11 (m, 6H), 6.60 (d, J=8.1 Hz, 1H), 4.17 (ddd, J=14.8, 7.6, 4.1 Hz, 2H), 3.97 (dd, J=11.4, 3.6 Hz, 1H), 3.74 (ddd, J=17.9, 8.4, 3.3 Hz, 2H), 3.49 (q, J=5.5 Hz, 2H), 2.86-2.52 (m, 4H), 2.22-2.00 (m, 2H), 1.81 (ddt, J=22.6, 13.8, 7.7 Hz, 3H), 1.76-1.55 (m, 4H), 1.47 (s, 10H), 1.43-1.06 (m, 9H). 13C NMR (75 MHz, CDCl3) δ 173.2, 172.8, 156.8, 156.4, 142.1, 142.1, 128.3, 128.3, 125.8, 125.7, 81.2, 81.1, 77.4, 77.2, 77.0, 76.6, 69.1, 69.0, 64.4, 64.3, 57.7, 55.2, 55.2, 41.2, 37.1, 37.0, 33.1, 33.1, 31.7, 31.3, 31.2, 29.8, 29.6, 28.3, 20.3, 20.3.
tert-Butyl 2-(((2R,3R)-1,3-dihydroxybutan-2-yl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0117). The synthesis of compound AB0117 was conducted by following a procedure similar to that of compound AB0111. Yield 22 mg as a colorless gel, 38%. 1H NMR (300 MHz, CDCl3) δ 7.44-7.05 (m, 6H), 6.60 (d, J=8.1 Hz, 1H), 4.17 (ddd, J=14.4, 7.6, 4.1 Hz, 2H), 3.95 (dd, J=11.3, 3.6 Hz, 1H), 3.74 (ddt, J=15.5, 7.8, 3.5 Hz, 2H), 3.49 (q, J=7.4 Hz, 2H), 2.65 (q, J=6.8 Hz, 5H), 2.24-1.96 (m, 2H), 1.82 (td, J=14.5, 13.6, 5.2 Hz, 2H), 1.74-1.53 (m, 4H), 1.46 (s, 10H), 1.38-1.04 (m, 8H). 13C NMR (75 MHz, CDCl3) δ 173.2, 172.9, 156.8, 156.4, 142.2, 142.1, 128.3, 125.8, 81.2, 81.1, 77.4, 77.2, 77.0, 76.6, 69.0, 68.9, 64.3, 64.2, 57.9, 57.7, 55.2, 55.2, 41.1, 37.1, 37.0, 33.1, 33.1, 31.7, 31.3, 31.2, 29.8, 29.7, 29.6, 28.3, 20.3, 20.3.
tert-Butyl 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0119). The synthesis of compound AB0119 was conducted by following a procedure similar to that of compound AB0111. Yield 62 mg as a colorless gel, 95%. 1H NMR (300 MHz, CDCl3) δ 7.42-7.03 (m, 5H), 6.65 (d, J=7.6 Hz, 1H), 4.62 (dtd, J=12.8, 7.6, 5.2 Hz, 1H), 4.23 (td, J=7.9, 4.3 Hz, 3H), 3.78-3.58 (m, 3H), 3.25 (ddd, J=13.9, 9.4, 4.8 Hz, 1H), 2.63 (q, J=8.5 Hz, 2H), 2.20-1.72 (m, 4H), 1.74-1.51 (m, 3H), 1.45 (d, J=6.9 Hz, 18H). 13C NMR (75 MHz, CDCl3) δ 172.3, 156.1, 156.0, 142.1, 128.3, 128.3, 125.7, 80.9, 79.7, 77.5, 77.2, 77.0, 76.6, 56.6, 56.3, 39.9, 39.3, 36.9, 33.2, 30.4, 30.0, 29.6, 29.2, 28.3.
tert-Butyl 4-(2-(1-(tert-butoxycarbonyl)-4-phenethylpiperidine-2-carboxamido)ethyl)piperazine-1-carboxylate (AB0129). The synthesis of compound AB0129 was conducted by following a procedure similar to that of compound AB0111. Yield 33 mg as a colorless gel, 45%. 1H NMR (300 MHz, CDCl3) δ 7.31-7.12 (m, 7H), 6.54 (t, J=5.1 Hz, 1H), 4.37 (t, J=6.8 Hz, 1H), 3.77 (dt, J=10.4, 4.9 Hz, 1H), 3.44-3.28 (m, 8H), 3.17 (ddd, J=14.3, 10.3, 4.6 Hz, 2H), 2.62 (s, 1H), 2.47 (t, J=6.0 Hz, 3H), 2.35 (t, J=5.1 Hz, 5H), 2.01 (dd, J=14.1, 7.1 Hz, 3H), 1.86 (s, 1H), 1.61 (qt, J=9.4, 6.4, 5.3 Hz, 5H), 1.36 (dd, J=14.0, 5.1 Hz, 4H), 1.30-1.16 (m, 5H), 0.86 (t, J=8.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 172.1, 155.7, 154.6, 142.3, 128.3, 128.3, 125.7, 125.6, 80.5, 79.7, 77.2, 56.4, 55.6, 52.6, 38.8, 36.3, 35.8, 33.4, 30.3, 29.7, 29.6, 29.2, 28.4, 28.3.
tert-Butyl 2-((2-(1,1-dioxidothiomorpholino)ethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0130). The synthesis of compound AB0130 was conducted by following a procedure similar to that of compound AB0111. Yield 36 mg as a colorless gel, 54%. 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=14.8 Hz, 3H), 7.18 (t, J=5.6 Hz, 3H), 6.42 (d, J=5.8 Hz, 1H), 4.35 (t, J=6.9 Hz, 1H), 3.73 (dt, J=11.2, 5.0 Hz, 1H), 3.36 (p, J=7.1 Hz, 2H), 3.16 (ddd, J=14.0, 10.3, 4.6 Hz, 1H), 3.00 (d, J=10.0 Hz, 8H), 2.64 (dt, J=13.0, 7.4 Hz, 5H), 2.08-1.87 (m, 4H), 1.72-1.54 (m, 4H), 1.46 (s, 9H), 1.28 (q, J=10.6, 7.1 Hz, 5H), 0.87 (d, J=10.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 172.3, 155.9, 142.2, 128.3, 125.8, 80.6, 77.4, 77.2, 77.0, 76.6, 60.3, 55.8, 55.2, 51.2, 50.6, 39.2, 36.6, 36.5, 33.4, 30.3, 29.6, 29.6, 29.3, 28.3.
tert-Butyl 2-(((1S,2S)-1,3-dihydroxy-1-(4-(methylthio)phenyl)propan-2-yl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0133). The synthesis of compound AB0133 was conducted by following a procedure similar to that of compound AB011. Yield 60 mg as a colorless gel, 84%. 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 7.16 (ddd, J=18.7, 8.2, 3.6 Hz, 6H), 6.56 (t, J=7.0 Hz, 1H), 5.04 (dd, J=21.3, 3.7 Hz, 1H), 4.25 (s, 1H), 4.20-4.00 (m, 2H), 4.00-3.68 (m, 4H), 3.51-3.37 (m, 1H), 2.66-2.50 (m, 2H), 2.42 (d, J=11.2 Hz, 4H), 2.05 (s, 1H), 1.95-1.61 (m, 3H), 1.45 (d, J=6.0 Hz, 11H), 1.30 (dt, J=18.9, 7.6 Hz, 6H), 1.16 (s, 1H), 0.88 (dd, J=13.4, 6.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 173.1, 173.0, 142.1, 142.1, 138.1, 138.0, 137.7, 137.5, 128.4, 128.3, 128.3, 126.5, 126.4, 126.2, 125.8, 125.7, 81.2, 81.2, 77.4, 77.0, 76.6, 73.4, 73.0, 63.3, 63.0, 60.4, 57.1, 56.7, 56.6, 36.3, 33.1, 33.0, 30.5, 30.4, 29.7, 29.4, 28.3, 15.8, 14.1.
tert-Butyl 2-((2-(2-hydroxyethoxy)ethyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0134). The synthesis of compound AB0134 was conducted by following a procedure similar to that of compound AB0111. Yield 50 mg as a colorless gel, 89%. 1H NMR (300 MHz, CDCl3) δ 7.33-7.12 (m, 6H), 6.66 (t, J=5.7 Hz, 1H), 4.34 (t, J=7.0 Hz, 1H), 3.73 (dt, J=13.9, 4.9 Hz, 3H), 3.51 (ddd, J=22.6, 7.6, 3.4 Hz, 7H), 3.20 (ddd, J=14.1, 10.2, 4.7 Hz, 1H), 2.74-2.54 (m, 3H), 2.10-2.02 (m, 1H), 1.98 (s, 2H), 1.86 (dq, J=13.4, 5.2 Hz, 1H), 1.62 (h, J=10.1, 9.5 Hz, 4H), 1.46 (s, 10H), 1.43-1.30 (m, 2H), 1.26 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 172.4, 156.0, 142.2, 128.3, 128.3, 125.7, 80.7, 77.4, 77.0, 76.6, 72.1, 69.5, 61.6, 55.9, 39.2, 39.0, 36.5, 33.3, 30.2, 29.8, 29.6, 29.1, 28.3.
tert-Butyl 2-((3-morpholinopropyl)carbamoyl)-4-phenethylpiperidine-1-carboxylate (AB0143). The synthesis of compound AB0143 was conducted by following a procedure similar to that of compound AB0111. Yield 28 mg as a colorless gel, 45%. 1H NMR (300 MHz, CDCl3) δ 7.34-7.12 (m, 6H), 6.83 (t, J=5.5 Hz, 1H), 4.25 (t, J=7.1 Hz, 1H), 3.76-3.60 (m, 5H), 3.45-3.19 (m, 3H), 2.65 (ddd, J=14.5, 8.7, 4.6 Hz, 2H), 2.47-2.35 (m, 6H), 2.09-1.95 (m, 2H), 1.88 (dt, J=11.2, 6.1 Hz, 2H), 1.76-1.62 (m, 4H), 1.46 (s, 9H), 1.34 (dd, J=12.7, 5.8 Hz, 2H), 1.27 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 172.3, 156.0, 142.2, 128.3, 125.7, 80.6, 77.4, 77.2, 77.0, 76.6, 66.9, 66.8, 57.4, 56.6, 53.8, 39.9, 38.8, 36.7, 33.3, 30.7, 30.4, 29.6, 29.4, 28.3, 25.3.
N-(2-(4-methylpiperazin-1-yl)ethyl)-4-phenethylpiperidine-2-carboxamide (AB0146). The synthesis of compound AB0146 was conducted by following dissolving AB011 in CH2Cl2 at 0° C. under N2 gas. TFA was added dropwise to solution and reaction was allowed to warm to room temperature over 3 hours. Solvent was removed and oil was redesolved in CH2Cl2 3×. a solution of product CH2Cl2 was treat with NaHCO3, extract with CH2Cl2 and dried over Na2SO4. Removal of solvent gave product with no further purification need. Yield 3.1 mg as a colorless gel, 45%. 1H NMR (300 MHz, MeOD) δ 7.33-7.09 (m, 5H), 3.47-3.33 (m, 1H), 3.24-3.17 (m, 1H), 3.15 (s, 1H), 2.95-2.57 (m, 1H), 2.52 (t, J=6.7 Hz, 5H), 2.29 (s, 3H), 2.01 (d, J=13.2 Hz, 1H), 1.76 (d, J=13.1 Hz, 1H), 1.59 (dt, J=9.1, 6.3 Hz, 3H), 1.31 (s, 3H), 1.22-0.98 (m, 3H). 13C NMR (75 MHz, MeOD) δ 174.5, 142.3, 127.9, 125.3, 59.9, 56.5, 54.3, 52.2, 45.0, 44.5, 38.8, 36.5, 35.7, 35.2, 32.2, 32.0, 29.3.
N-(2-methoxyethyl)-4-phenethylpiperidine-2-carboxamide (AB0122). The synthesis of compound AB0122 was conducted by following a procedure similar to that of compound AB0146. Yield 32 mg as a colorless gel, 84%. 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 3H), 9.58 (s, 1H), 7.74 (s, 1H), 7.56-6.97 (m, 7H), 4.13 (s, 1H), 3.76-3.23 (m, 8H), 3.11 (s, 1H), 2.67 (t, J=7.5 Hz, 2H), 2.18 (d, J=13.6 Hz, 1H), 2.00 (d, J=14.1 Hz, 1H), 1.88-1.38 (m, 5H). 13C NMR (75 MHz, CDCl3) δ 168.9, 141.3, 128.5, 128.2, 126.0, 77.2, 70.2, 58.6, 58.2, 43.7, 39.5, 37.5, 33.4, 33.3, 32.5, 28.0.
N-(2-hydroxyethyl)-4-phenethylpiperidine-2-carboxamide (AB0123). The synthesis of compound AB0123 was conducted by following a procedure similar to that of compound AB0146. Yield 9.5 mg as a colorless gel, 86%. 1H NMR (300 MHz, MeOD) δ 7.32-7.09 (m, 4H), 3.46-3.24 (m, 5H), 3.21-3.06 (m, 2H), 2.72-2.53 (m, 3H), 2.47 (t, J=6.7 Hz, 2H), 2.29 (s, 5H), 2.07-1.96 (m, 1H), 1.76 (d, J=13.2 Hz, 1H), 1.66-1.45 (m, 3H), 1.33 (d, J=12.3 Hz, 1H), 1.22-0.98 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 141.1, 141.1, 128.5, 128.1, 126.1, 77.2, 65.6, 58.3, 43.9, 38.1, 37.3, 33.4, 33.3, 33.2, 32.4, 32.3, 28.0.
N-(2-(dimethylamino)ethyl)-4-phenethylpiperidine-2-carboxamide (AB0124). The synthesis of compound AB0124 was conducted by following a procedure similar to that of compound AB0146. Yield 8 mg as a colorless gel, 64%. 1H NMR (300 MHz, MeOD) δ 7.32-7.22 (m, 2H), 7.22-7.09 (m, 3H), 3.62 (t, J=5.7 Hz, 2H), 3.33 (d, J=11.4 Hz, 4H), 3.25-3.07 (m, 2H), 2.72-2.53 (m, 3H), 2.02 (dq, J=12.6, 2.9 Hz, 1H), 1.76 (dd, J=12.9, 2.9 Hz, 1H), 1.68-1.42 (m, 3H), 1.31 (s, 1H), 1.25-1.00 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 141.1, 128.5, 128.2, 126.1, 77.2, 59.5, 58.0, 44.8, 43.9, 43.8, 37.3, 34.4, 33.4, 32.5, 32.3, 29.7, 28.2.
N-(2-hydroxyethyl)-N-methyl-4-phenethylpiperidine-2-carboxamide (AB0127). The synthesis of compound AB0127 was conducted by following a procedure similar to that of compound AB0146. Yield 17 mg as a colorless gel, 100%. 1H NMR (300 MHz, MeOD) δ 7.33-7.09 (m, 5H), 3.78-3.62 (m, 3H), 3.59-3.40 (m, 2H), 3.22-3.04 (m, 2H), 2.97 (s, 1H), 2.73-2.54 (m, 3H), 1.93 (d, J=13.1 Hz, 1H), 1.77 (d, J=12.8 Hz, 1H), 1.58 (ddt, J=8.4, 5.3, 2.9 Hz, 3H), 1.31 (s, 1H), 1.21-0.97 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 173.3, 155.5, 142.1, 128.3, 128.3, 125.8, 80.5, 80.4, 77.2, 60.2, 55.3, 52.4, 52.0, 41.0, 37.9, 37.7, 36.7, 33.8, 33.1, 32.9, 31.9, 31.9, 30.1, 29.6, 29.5, 28.3.
N,N-bis(2-hydroxyethyl)-4-phenethylpiperidine-2-carboxamide (AB0128). The synthesis of compound AB0128 was conducted by following a procedure similar to that of compound AB0146. Yield 7.2 mg as a colorless gel, 95%. 1H NMR (300 MHz, MeOD) δ 7.33-7.10 (m, 5H), 3.71 (tdd, J=7.8, 6.8, 4.6 Hz, 4H), 3.58 (q, J=6.0 Hz, 2H), 3.45 (dt, J=13.8, 5.9 Hz, 1H), 2.80-2.55 (m, 4H), 1.95 (d, J=13.2 Hz, 1H), 1.77 (d, J=12.8 Hz, 1H), 1.58 (t, J=5.8 Hz, 3H), 1.32 (d, J=3.7 Hz, 3H), 1.14 (s, 1H), 1.10 (s, 1H), 0.91 (d, J=5.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 174.2, 142.0, 128.4, 128.3, 128.3, 125.8, 125.8, 81.0, 61.0, 60.4, 54.7, 52.5, 50.9, 38.0, 32.9, 32.1, 31.9, 29.9, 29.6, 28.3, 28.2.
N-((2S,3S)-1,3-dihydroxybutan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0125). The synthesis of compound AB0125 was conducted by following a procedure similar to that of compound AB0146. Yield 10 mg as a colorless gel, 910%. 1H NMR (300 MHz, MeOD) δ 7.32-7.09 (m, 5H), 4.03 (qt, J=6.4, 3.2 Hz, 1H), 3.82 (tt, J=6.2, 3.2 Hz, 1H), 3.63 (dtd, J=12.8, 11.1, 6.2 Hz, 2H), 3.18 (dddd, J=28.0, 12.6, 4.7, 2.6 Hz, 2H), 2.73-2.54 (m, 3H), 2.06 (d, J=12.4 Hz, 1H), 1.76 (d, J=12.8 Hz, 1H), 1.66-1.50 (m, 3H), 1.48-1.29 (m, 2H), 1.25-1.00 (m, 6H), 0.95-0.87 (m, 1H). 13C NMR (75 MHz, MeOD) δ 168.9, 141.7, 128.0, 127.9, 125.5, 65.6, 61.3, 58.0, 56.4, 48.4, 48.1, 47.8, 47.8, 47.7, 47.7, 47.5, 47.5, 47.4, 47.3, 47.2, 47.2, 47.0, 46.7, 46.7, 46.7, 43.2, 37.5, 33.6, 33.4, 32.1, 27.7, 19.0.
N-((2R,3R)-1,3-dihydroxybutan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0126). The synthesis of compound AB0126 was conducted by following a procedure similar to that of compound AB0146. Yield 11.6 mg as a colorless gel, 98%. 1H NMR (300 MHz, MeOD) δ 7.40-6.99 (m, 5H), 4.03 (dp, J=6.4, 3.2 Hz, 1H), 3.82 (tt, J=6.1, 3.2 Hz, 1H), 3.74-3.52 (m, 2H), 3.33 (p, J=1.6 Hz, 3H), 3.23 (ddd, J=11.6, 5.1, 2.8 Hz, 1H), 3.14 (ddd, J=12.6, 4.2, 2.3 Hz, 1H), 2.73-2.55 (m, 3H), 2.12-1.99 (m, 1H), 1.76 (dt, J=12.8, 2.7 Hz, 1H), 1.66-1.49 (m, 3H), 1.43-1.24 (m, 2H), 1.17 (d, J=6.5 Hz, 4H), 1.14-1.00 (m, 2H). 13C NMR (75 MHz, MeOD) δ 168.9, 141.7, 141.7, 128.0, 127.9, 125.5, 65.6, 65.5, 61.4, 61.3, 58.1, 58.0, 56.4, 56.2, 48.4, 48.1, 48.1, 47.8, 47.8, 47.7, 47.6, 47.5, 47.4, 47.3, 47.2, 47.0, 46.7, 43.2, 37.5, 37.4, 33.7, 33.6, 33.5, 33.4, 32.1, 27.7, 19.2, 19.0.
N-(azetidin-3-yl)-4-phenethylpiperidine-2-carboxamide (AB0121). The synthesis of compound AB0121 was conducted by following a procedure similar to that of compound AB0146. Yield 35 mg as a colorless gel, 100%. 1H NMR (300 MHz, MeOD) δ 7.38-7.09 (m, 5H), 4.84-4.65 (m, 1H), 4.40-4.11 (m, 4H), 3.87 (dd, J=12.7, 3.2 Hz, 1H), 3.45 (ddd, J=12.8, 4.4, 2.1 Hz, 1H), 3.04 (td, J=13.0, 3.1 Hz, 1H), 2.70 (dd, J=8.9, 6.6 Hz, 2H), 2.41-2.28 (m, 1H), 2.02 (d, J=14.2 Hz, 1H), 1.85-1.60 (m, 3H), 1.54-1.25 (m, 3H). 13C NMR (75 MHz, MeOD) δ 168.8, 141.6, 128.0, 127.9, 125.5, 57.6, 52.0, 51.9, 43.3, 42.0, 37.5, 33.4, 33.0, 32.1, 27.7.
4-phenethyl-N-(2-(piperazin-1-yl)ethyl)piperidine-2-carboxamide (AB0131). The synthesis of compound AB0131 was conducted by following a procedure similar to that of compound AB0146. Yield 11 mg as a colorless gel, 100%. 1H NMR (300 MHz, MeOD) δ 7.33-7.09 (m, 5H), 3.37 (dt, J=6.8, 3.5 Hz, 5H), 3.22-3.06 (m, 2H), 2.86 (t, J=5.0 Hz, 4H), 2.72-2.58 (m, 3H), 2.58-2.44 (m, 6H), 2.01 (dq, J=12.5, 2.7 Hz, 1H), 1.76 (d, J=12.9 Hz, 1H), 1.66-1.51 (m, 3H), 1.31 (s, 1H), 1.22-0.98 (m, 2H). 13C NMR (75 MHz, MeOD) δ 174.5, 142.3, 127.9, 125.3, 59.9, 57.2, 53.3, 45.0, 44.7, 38.8, 36.6, 35.5, 35.2, 32.2, 32.0.
N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-phenethylpiperidine-2-carboxamide (AB0132). The synthesis of compound AB0132 was conducted by following a procedure similar to that of compound AB0146. Yield 14 mg as a colorless gel, 100%. 1H NMR (300 MHz, MeOD) δ 7.33-7.09 (m, 4H), 3.23-2.99 (m, 8H), 2.73-2.52 (m, 4H), 2.00 (dq, J=12.6, 2.9 Hz, 1H), 1.82-1.70 (m, 1H), 1.66-1.43 (m, 3H), 1.36-1.28 (m, 1H), 1.22-0.98 (m, 2H). 13C NMR (75 MHz, MeOD) δ 174.6, 142.3, 127.9, 125.3, 59.9, 54.7, 50.7, 50.4, 45.0, 38.8, 36.7, 36.2, 35.2, 32.2, 32.0.
N-((1S,2S)-1,3-dihydroxy-1-(4-(methylthio)phenyl)propan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0135). The synthesis of compound AB0135 was conducted by following a procedure similar to that of compound AB0146. Yield 15 mg as a colorless gel, 62%. 1H NMR (300 MHz, MeOD) δ 7.50-6.80 (m, 12H), 4.98 (t, J=4.2 Hz, 1H), 4.24-4.03 (m, 1H), 3.84 (dd, J=11.2, 5.1 Hz, OH), 3.78-3.65 (m, 1H), 3.55 (ddd, J=10.9, 5.8, 3.1 Hz, 1H), 3.07 (dddd, J=20.9, 14.4, 11.7, 2.8 Hz, 3H), 2.72-2.45 (m, 4H), 2.45-2.35 (m, 4H), 1.89-1.60 (m, 3H), 1.62-0.53 (m, 13H). 13C NMR (75 MHz, MeOD) δ 175.2, 174.5, 142.3, 139.4, 139.2, 137.4, 137.3, 127.9, 127.9, 127.4, 127.2, 126.4, 125.9, 125.7, 125.7, 125.3, 72.8, 70.7, 70.6, 61.2, 60.9, 60.2, 59.6, 56.4, 56.2, 55.4, 44.9, 44.8, 44.7, 38.9, 38.8, 38.7, 36.6, 36.5, 36.3, 35.2, 35.1, 35.0, 32.2, 32.1, 32.0, 14.4, 14.2.
N-(2-(2-hydroxyethoxy)ethyl)-4-phenethylpiperidine-2-carboxamide (AB0136). The synthesis of compound AB0136 was conducted by following a procedure similar to that of compound AB0146. Yield 10 mg as a colorless gel, 52%. 1H NMR (300 MHz, MeOD) δ 7.33-7.09 (m, 5H), 3.69 (dd, J=5.5, 3.9 Hz, 2H), 3.64-3.51 (m, 4H), 3.41 (t, J=5.3 Hz, 2H), 3.31-3.10 (m, 2H), 2.73-2.57 (m, 3H), 2.04 (dq, J=12.7, 2.7 Hz, 1H), 1.67-1.49 (m, 3H), 1.36-1.28 (m, 1H), 1.26-1.03 (m, 2H). 13C NMR (75 MHz, MeOD) δ 173.8, 142.2, 127.9, 125.3, 72.0, 69.0, 60.7, 59.6, 44.7, 38.8, 38.6, 36.1, 35.0, 32.2, 31.5.
N-(3-morpholinopropyl)-4-phenethylpiperidine-2-carboxamide (AB0145). The synthesis of compound AB0145 was conducted by following a procedure similar to that of compound AB0146. Yield 3.2 mg as a colorless gel, 45%. 1H NMR (300 MHz, MeOD) δ 7.33-7.09 (m, 5H), 3.77-3.67 (m, 4H), 3.26 (t, J=6.8 Hz, 5H), 3.20-3.02 (m, 2H), 2.72-2.53 (m, 3H), 2.53-2.35 (m, 5H), 2.04-1.92 (m, 1H), 1.81-1.66 (m, 3H), 1.66-1.47 (m, 3H), 1.32 (d, J=4.2 Hz, 2H), 1.22-0.97 (m, 2H). 13C NMR (75 MHz, MeOD) δ 174.4, 142.3, 127.9, 125.3 66.2 59.9, 56.2 53.3, 44.9, 38.8, 37.3, 36.6, 35.2, 32.2, 32.0, 25.4.
N-((3S,4S)-4-(dimethylamino)tetrahydrofuran-3 yl)-4-phenethylpiperidine-2-carboxamide (AB0281). The synthesis of compound AB0281 was conducted by following a procedure similar to that of compound AB0146. Yield 24.1 mg, 51%. 1H NMR (300 MHz, MeOD) δ 7.23 (tt, J=13.8, 7.3 Hz, 5H), 4.42 (q, J=4.9 Hz, 1H), 4.05 (t, J=8.1 Hz, 2H), 3.69 (dd, J=9.5, 6.0 Hz, 1H), 3.58 (dd, J=9.4, 4.8 Hz, 1H), 3.35 (s, 1H), 3.20 (q, J=11.4, 10.2 Hz, 2H), 2.88 (p, J=6.2, 5.2 Hz, 1H), 2.75-2.55 (m, 3H), 2.31 (s, 5H), 1.97 (d, J=12.8 Hz, 1H), 1.79 (d, J=13.0 Hz, 1H), 1.58 (h, J=9.1, 7.9 Hz, 3H), 1.12 (h, J=12.0 Hz, 2H). 13C NMR (75 MHz, MeOD) δ 173.6, 142.3, 128.0, 125.4, 72.9, 72.3, 70.5, 59.6, 52.2, 44.9, 42.2, 38.7, 36.5, 35.2, 32.2, 32.0. HRMS (ESI) calcd for C20H31N3O2, 345.4870 [M+H]+; found,
N-(1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0282). The synthesis of compound AB0282 was conducted by following a procedure similar to that of compound AB0146. Yield 33.9 mg, 69%. 1H NMR (300 MHz, MeOD) δ 7.36-7.11 (m, 5H), 4.14 (tq, J=7.2, 3.7, 2.2 Hz, 1H), 3.60 (d, J=5.3 Hz, 2H), 3.41-3.12 (m, 3H), 2.87-2.57 (m, 9H), 2.10 (dtd, J=12.6, 5.2, 2.6 Hz, 1H), 1.95-1.71 (m, 5H), 1.73-1.49 (m, 4H), 1.21 (s, 2H). 13C NMR (75 MHz, MeOD) δ 173.7, 142.2, 128.0, 128.0, 127.9, 125.4, 62.6, 62.5, 59.8, 59.7, 56.6, 54.1, 54.0, 49.7, 49.6, 44.8, 44.7, 38.6, 38.6, 35.9, 35.6, 35.0, 34.9, 32.2 31.4, 31.2, 22.9, 22.8.
N-(1-hydroxy-3-(piperidin-1-yl)propan-2-yl)-4 phenethylpiperidine-2-carboxamide (AB0283). The synthesis of compound AB0283 was conducted by following a procedure similar to that of compound AB0146. Yield 19.4 mg, 38%. 1H NMR (300 MHz, MeOD) δ 7.37-7.05 (m, 5H), 4.36-3.91 (m, 2H), 3.79-3.37 (m, 5H), 3.08-2.54 (m, 6H), 2.09-1.14 (m, 17H). 13C NMR (75 MHz, MeOD) δ 174.3, 142.1, 128.0, 127.9, 125.4, 80.4, 63.5, 63.0, 62.1, 59.7, 57.0, 54.3, 36.9, 32.8, 27.3, 24.4.
N-(1,3-dimethoxypropan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0284). The synthesis of compound AB0284 was conducted by following a procedure similar to that of compound AB0146. Yield 12 mg, 26%. 1H NMR (300 MHz, MeOD) δ 7.40-7.03 (m, 5H), 4.19 (p, J=5.6 Hz, 1H), 3.64-3.55 (m, 1H), 3.47 (dd, J=5.5, 2.1 Hz, 4H), 3.35 (d, J=3.4 Hz, 7H), 2.87 (td, J=13.0, 3.1 Hz, 1H), 2.74-2.61 (m, 2H), 2.23-2.12 (m, 1H), 2.00-1.86 (m, 1H), 1.77-1.52 (m, 3H), 1.40-1.20 (m, 2H). 13C NMR (75 MHz, MeOD) δ 170.5, 141.9, 128.0, 127.9, 125.5 71.0, 58.6, 57.9, 57.9, 48.8, 47.6, 47.3, 47.0, 46.8, 43.8, 38.0, 34.7, 34.1, 32.2, 29.2.
N-(1-(dimethylamino)-3-hydroxypropan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0285). The synthesis of compound AB0285 was conducted by following a procedure similar to that of compound AB0146. Yield 12.5 mg, 27%. 1H NMR (300 MHz, MeOD) δ 7.34-7.06 (m, 5H), 4.57-4.40 (m, 1H), 4.07 (s, 1H), 3.82-3.40 (m, 7H), 3.39-3.17 (m, 9H), 2.66 (t, J=7.6 Hz, 3H), 2.11-1.93 (m, 2H), 1.87 (dq, J=9.3, 5.1, 4.2 Hz, 2H), 1.73-1.55 (m, 5H), 1.53-1.25 (m, 16H). 13C NMR (75 MHz, MeOD) δ 174.1, 142.1, 128.0, 127.9, 125.4, 80.2, 71.3, 62.6, 58.4, 57.0, 56.2, 48.4, 48.2, 47.9, 47.6, 47.5, 47.3, 47.3, 47.1, 47.0, 46.7, 36.9, 32.8, 31.2, 29.3, 27.2.
N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-4 phenethylpiperidine-2-carboxamide (AB0288). The synthesis of compound AB0288 was conducted by following a procedure similar to that of compound AB0146. Yield 40 mg, 88%. 1H NMR (300 MHz, MeOD) δ 7.37-7.03 (m, 5H), 3.76 (s, 1H), 3.63 (s, 1H), 3.48-3.35 (m, 1H), 2.92 (td, J=13.1, 3.2 Hz, 1H), 2.68 (q, J=7.2 Hz, 2H), 2.44 (d, J=13.8 Hz, 1H), 1.94 (d, J=13.9 Hz, 1H), 1.63 (q, J=6.9, 6.4 Hz, 4H), 1.51-1.18 (m, 4H), 0.91 (d, J=7.1 Hz, 1H). 13C NMR (75 MHz, MeOD) δ 172.7, 141.9, 128.0, 128.0, 125.5, 125.4, 125.4, 61.3, 59.5, 59.3, 58.1, 43.2, 37.8, 34.0, 33.1, 32.3, 32.2, 28.2.
N-(1,3-dimethoxy-2-(methoxymethyl)propan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0289). The synthesis of compound AB0289 was conducted by following a procedure similar to that of compound AB0146. Yield 20.6 mg, 40%. 1H NMR (300 MHz, MeOD) δ 7.45-6.95 (m, 5H), 3.69 (d, J=12.4 Hz, 5H), 3.36 (d, J=1.9 Hz, 11H), 2.70 (q, J=8.1 Hz, 3H), 2.08 (dt, J=13.0, 2.7 Hz, 1H), 1.82 (dd, J=13.2, 3.4 Hz, 1H), 1.72-1.37 (m, 3H), 1.43-0.94 (m, 2H). 13C NMR (75 MHz, MeOD) δ 173.5, 142.2, 128.1, 128.0, 128.0, 125.4, 70.7, 70.6, 59.9, 59.6, 58.2, 58.2, 44.6, 38.5, 36.2, 34.9, 32.3, 31.1.
4-phenethyl-N-((1R,2S,3R,4S)-2,3,4-trihydroxycyclopentyl)piperidine-2-carboxamide (AB0292). The synthesis of compound AB0292 was conducted by following a procedure similar to that of compound AB0146. Yield 20 mg, 42%. 1H NMR (300 MHz, Chloroform-d) δ 7.21 (dt, J=18.0, 8.7 Hz, 5H), 4.17-3.49 (m, 2H), 3.53-3.22 (m, 3H), 2.92 (t, J=12.7 Hz, 1H), 2.68 (t, J=7.5 Hz, 3H), 2.44 (d, J=14.1 Hz, 1H), 1.93 (d, J=14.2 Hz, 2H), 1.64 (s, 4H), 1.33 (dq, J=24.4, 12.4, 11.7 Hz 3H). 13C NMR (75 MHz, MeOD) δ 172.7, 141.9, 128.1, 128.0, 125.5, 77.1, 76.1, 74.3, 59.5, 43.2, 37.8, 34.0, 33.1, 32.2, 32.1, 28.2.
N-((1s,3R,4S)-3,4-dihydroxycyclopentyl)-4-phenethylpiperidine-2-carboxamide (AB0293). The synthesis of compound AB0293 was conducted by following a procedure similar to that of compound AB0146. Yield 19.1 mg, 42%. 1H NMR (300 MHz, Chloroform-d) δ 7.37-7.03 (m, 5H), 6.13 (d, J=7.4 Hz, 1H), 4.49 (q, J=6.5 Hz, 1H), 4.34-4.13 (m, 3H), 3.81-3.57 (m, 1H), 3.19 (ddd, J=14.0, 9.8, 4.8 Hz, 1H), 2.66 (ddd, J=14.7, 10.9, 6.7 Hz, 3H), 2.34-2.09 (m, 3H), 2.13-1.53 (m, 4H), 1.43-1.16 (m, 3H), 1.04-0.78 (m, 3H). 13C NMR (75 MHz MeOD) δ 172.1, 141.9, 128.0, 127.9, 125.5, 72.5, 58.5, 48.5, 48.2, 47.9 47.6, 47.3 47.0, 46.8, 43.8, 37.9, 37.7, 34.5, 34.0, 32.2, 27.2.
(3-aminoazetidin-1-yl)(4-phenethylpiperidin-2-yl)methanone (AB0294). The synthesis of compound AB0294 was conducted by following a procedure similar to that of compound AB0146. Yield 6.3 mg, 16%. 1H NMR (300 MHz, MeOD) δ 7.48-6.97 (m, 5H), 3.73 (hept, J=6.6 Hz, 1H), 3.42 (ddd, J=16.6, 9.7, 3.5 Hz, 1H), 3.23 (q, J=7.4 Hz, 2H), 3.02-2.85 (m, 1H), 2.69 (t, J=7.4 Hz, 2H), 2.44 (d, J=13.9 Hz, 1H), 1.94 (d, J=13.4 Hz, 1H), 1.64 (dd, J=7.9, 4.8 Hz, 2H), 1.53-1.18 (m, 8H). 13C NMR (75 MHz, MeOD) 13C NMR (75 MHz, MeOD) δ 161.9, 141.9, 128.0, 127.9, 125.5, 59.5, 54.4, 43.3, 42.4, 37.7, 34.0, 33.1, 32.2, 28.1.
N-((3R,4S)-3,4-dihydroxycyclohexyl)-4-phenethylpiperidine-2-carboxamide (AB0295). The synthesis of compound AB0295 was conducted by following a procedure similar to that of compound AB0146. Yield 8.2 mg, 17%. 1H NMR (300 MHz, MeOD) δ 7.23 (dq, J=16.5, 8.4, 8.0 Hz, 5H), 4.15-3.89 (m, 1H), 3.93-3.53 (m, 2H), 3.52-3.36 (m, 1H), 3.13-2.86 (m, 1H), 2.68 (t, J=8.0 Hz, 2H), 2.43 (d, J=13.9 Hz, 1H), 2.22 (d, J=13.9 Hz, 1H), 2.11-1.28 (m, 12H). 13C NMR (75 MHz, MeOD) 13C NMR (75 MHz, MeOD) δ 168.3, 168.0, 141.8, 128.1, 128.0, 125.5, 70.4, 69.9, 68.8, 68.1, 59.5, 58.0, 54.4, 46.6, 43.6, 43.5, 43.3, 42.4, 37.8, 37.6, 36.0, 34.0, 33.8, 33.7, 33.5, 33.1, 32.2, 28.9, 28.1, 27.9, 27.7, 26.5, 25.2.
N-(5,6-dihydroxybicyclo[2.2.1]heptan-2-yl)-4-phenethylpiperidine-2-carboxamide (AB0296). The synthesis of compound AB0296 was conducted by following a procedure similar to that of compound AB0146. Yield 6.3 mg, 13%. 1H NMR (300 MHz, MeOD) δ 7.23 (dq, J=16.4, 8.1, 7.4 Hz, 5H), 3.99 (ddd, J=16.5, 11.2, 5.4 Hz, 1H), 3.87-3.52 (m, 3H), 3.50-3.36 (m, 1H), 3.23 (q, J=7.4 Hz, 1H), 3.02 (td, J=13.2, 3.4 Hz, 1H), 2.69 (td, J=8.4, 7.9, 4.0 Hz, 2H), 2.40-1.58 (m, 9H), 1.52-1.23 (m, 6H), 1.02-0.77 (m, 1H). 13C NMR (75 MHz, MeOD) 13C NMR (75 MHz, MeOD) δ 168.9, 141.8, 128.1, 128.0, 125.6, 73.8, 73.0, 71.4, 68.6, 68.6, 58.0, 57.9, 54.4, 49.1, 49.0, 48.9, 47.0, 43.3, 42.4, 37.7, 37.6, 33.9, 33.7, 33.5, 32.1, 31.1, 30.7, 30.6, 27.8.
4-phenethyl-N-((1R,2S,3R,4S)-2,3,4-trihydroxycyclohexyl)piperidine-2-carboxamide (AB0297). The synthesis of compound AB0297 was conducted by following a procedure similar to that of compound AB0146. Yield 5.9 mg, 16%. 1H NMR (300 MHz, MeOD) 1H NMR δ 7.23 (dq, J=17.2, 8.9, 8.2 Hz, 5H), 4.13-3.61 (m, 3H), 3.53-3.37 (m, 1H), 3.12-2.82 (m, 1H), 2.69 (t, J=7.6 Hz, 2H), 2.56-2.20 (m, 1H), 2.13-1.78 (m, 2H), 1.83-1.53 (m, 4H), 1.51-1.12 (m, 5H). 13C NMR (75 MHz, MeOD) δ 168.7, 141.8, 128.1, 128.0, 125.5, 73.1, 70.7, 69.6, 69.5, 59.5, 58.1, 54.4, 49.6, 48.5, 48.2, 47.9, 47.6, 47.3, 47.0, 46.8, 43.3, 43.2, 42.4, 37.7, 37.6, 33.9, 33.6, 33.1, 32.2, 28.1, 27.8, 25.8, 24.6, 11.7.
100 mg of racemic CTW0404 and CTW0419 were separated by chiral prep-SFC. As for CTW0419, a further separation was performed to increase the e.e.% of the enantiomers. After separation, 41.1 mg of faster eluting enantiomer and 40.9 mg of slower eluting enantiomer of CTW0404 were obtained respectively. As for CTW0419, there're 20.0 mg and 17.7 mg of two enantiomers were obtained respectively.
100%
100%
100%
100%
After concentration, e.e. value for the isomers was tested by the method described above.
After concentration, RPLC-MS was used to test the purity of the enantiomers.
Structure Confirmation via NMR
After concentration, NMR was used to characterize the structures.
1H NMR (300 MHz, CDCl3) δ 7.33-7.25 (m, 2H), 7.19 (td, J=6.1, 1.6 Hz, 3H), 6.94 (d, J=4.5 Hz, 1H), 3.78-3.68 (m, 4H), 3.38 (q, J=6.0 Hz, 2H), 3.23-3.11 (m, 2H), 2.73-2.61 (m, 3H), 2.55-2.43 (m, 6H), 2.19 (dq, J=12.7, 2.9 Hz, 1H), 1.75 (dq, J=10.9, 2.9 Hz, 3H), 1.65-1.53 (m, 2H), 1.19-0.92 (m, 2H).
1H NMR (300 MHz, CDCl3) δ 7.35-7.25 (m, 2H), 7.19 (td, J=6.2, 1.6 Hz, 3H), 6.96 (s, 1H), 3.81-3.67 (m, 4H), 3.39 (q, J=6.0 Hz, 2H), 3.18 (tt, J=8.7, 2.3 Hz, 2H), 2.76-2.60 (m, 3H), 2.56-2.42 (m, 6H), 2.19 (dq, J=12.8, 2.9 Hz, 1H), 1.93-1.69 (m, 3H), 1.65-1.42 (m, 2H), 1.24-0.95 (m, 2H).
1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 2H), 7.15 (d, J=7.6 Hz, 3H), 3.86 (q, J=4.8 Hz, 1H), 3.77-3.60 (m, 4H), 3.13 (ddd, J=10.5, 7.6, 3.2 Hz, 2H), 2.60 (q, J=8.6 Hz, 3H), 2.05 (d, J=12.8 Hz, 1H), 1.73 (d, J=13.2 Hz, 1H), 1.63-1.39 (m, 3H), 1.27-0.97 (m, 3H).
1H NMR (300 MHz, CDCl3) δ 7.33-7.21 (m, 2H), 7.20-7.10 (m, 3H), 3.92-3.79 (m, 1H), 3.74-3.56 (m, 4H), 3.18-3.08 (m, 2H), 2.70-2.49 (m, 3H), 2.04 (d, J=12.9 Hz, 1H), 1.72 (d, J=13.3 Hz, 1H), 1.60-1.38 (m, 3H), 1.05 (q, J=12.2 Hz, 3H).
Absolute Chiral Configuration Test via X-ray Analysis confirm the absolute configuration of each chiral center.
General Method for In Vitro Pharmacological Assessment of Compounds of the Invention. The Chinese hamster ovary (CHO) cell lines stably transfected with human unedited (INI) h5-HT2CR (h5-HT2CR—CHO cells) or the human h5-HT2AR (h5-HT2AR—CHO cells) were a generous gift of K. Berg and W. Clarke (University of Texas Health Science Center, San Antonio, TX) (Berg et al., Molecular Pharmacology, 46:477-484, 1994; Ding et al., ACS Chemical Neuroscience, 3:538-545, 2012). Cells were grown at 37° C., 5% CO2 and 85% relative humidity in GlutaMax α-MEM (Invitrogen, Carlsbad, CA), 5% fetal bovine serum (Atlanta Biologicals, Atlanta, GA), 100 μg/mL hygromycin (Mediatech, Manassas Va.) and were passaged when they reached 80% confluence. Changes in Cai2+ levels were determined using the calcium sensitive dye Calcium 4 or Calcium 6 (FLIPR No-wash kit, Molecular Devices, Sunnyvale, CA). Specifically, cells (150 μL; passages 6-16) were plated in serum-replete medium at a density of 14,000-16,000 (FlexStation 3; Molecular Devices) or 30,000 cells/well (FLIPRTETRA; Molecular Devices) in black-wall 96-well culture plates with optically clear flat bottoms. After −24 hours, the medium was replaced with serum-free (SF) GlutaMax-MEM medium supplemented with 20 nM to 100 μM putrescine (Sigma-Aldrich, St. Louis, MO), 20 nM to 100 μM progesterone (Sigma-Aldrich), and 1:100 ITS (1000 mg/L human recombinant insulin, 550 mg/L human recombinant transferrin, 0.67 mg/L selenious acid; Corning Inc., Corning, NY) (SF+ medium). After an incubation for another 3 h, SF+ medium was replaced with 40 μL of Hank's balanced saline solution (HBSS; without CaCl2 or MgCl2, pH 7.4) plus 40 μL of Calcium dye solution supplemented with 2.5 mM of water-soluble probenecid (Sigma-Aldrich), and then the plate was incubated with dye solution in the dark for 1 h at 37° C., 15 min at room temperature. The compound was diluted at 5× concentration in 1×HBSS. The delivery of compound (20 μL/well) was 15 min prior to the addition of 5-HT (25 μL/well), and a baseline was established for each well before the addition of the compound and 5-HT. The fluorescence readings were then adopted to evaluate the allosteric modulation of 5-HT-induced Cai2+ release. FlexStation 3 or FLIPRTETRA was used to measure fluorescence. For FlexStation 3, a 17 s baseline was established before the compound was added, and fluorescence was recorded every 1.7 s thereafter for 240 s. The maximum peak height of each well was determined by SoftMax software (Pro 5.4.5). For FLIPRTETRA, a 10 s baseline was established before adding the compound, and then record the fluorescence every 1 s for 120 s after the compound or 360 s after 5-HT. The maximum peak height of each well was determined by ScreenWorks 4.0 software. After the final reading, the cells were fixed in 2% paraformaldehyde (Sigma) overnight. A 4-parameter nonlinear regression analysis was used to determine the 5-HT-induced Cai2+ maximum release (Emax) in the presence of the test compound, and calculated from 4-6 biological replicates, each biological replicate performed in technical triplicates. The Emax of the test compound plus 5-HT was normalized to the Emax of 5-HT alone. Subsequently, Welch's unpaired t-test was used for comparison of the Emax means. All statistical analyses were performed with an experimental error rate of α=0.05.
A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
This application claims the benefit of U.S. Provisional Appl. No. 63/234,581, filed Aug. 18, 2021, and U.S. Provisional Appl. No. 63/304,323, filed Jan. 28, 2022. The contents of the aforesaid applications are relied upon and are incorporated by reference herein in their entirety.
This invention was made with government support under Grant Nos. R21 MH093844, R01 DA038446, and T32 DA07287, awarded by the NIH. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US22/40817 | 8/18/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63304323 | Jan 2022 | US | |
| 63234581 | Aug 2021 | US |
