ZA200505323B - Methods forpreparing phenylalkyne derivatives - Google Patents

Methods forpreparing phenylalkyne derivatives Download PDF

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ZA200505323B
ZA200505323B ZA200505323A ZA200505323A ZA200505323B ZA 200505323 B ZA200505323 B ZA 200505323B ZA 200505323 A ZA200505323 A ZA 200505323A ZA 200505323 A ZA200505323 A ZA 200505323A ZA 200505323 B ZA200505323 B ZA 200505323B
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South Africa
Prior art keywords
phenyl
membered heterocyclyl
alkylene
alkyl
heterocyclyl
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ZA200505323A
Inventor
Richard Apodaca
Jill A Jablonowski
Chennagiri R Pandit
Xiaohu Deng
Neelakandha Mani
Wei Xiao
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Ortho Mcneil Pharm Inc
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Priority claimed from PCT/US2002/038480 external-priority patent/WO2003050099A1/en
Application filed by Ortho Mcneil Pharm Inc filed Critical Ortho Mcneil Pharm Inc
Publication of ZA200505323B publication Critical patent/ZA200505323B/en

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    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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Description

. METHODS FOR PREPARING PHENYLALKYNE DERIVATIVES
Field of the Invention
The present invention relates to phenylaltkynes, their synthesis and their use, for example, for the treatment of disorders and conditions mediated by the histamine receptor.
Background of the Invention
Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance.
Histamine exerts a physiological effect via multiple distinct G-protein coupled receptors. It plays a role in immediate hypersensitivity reactions and is released from mast cells following antigen IgE antibody interaction. The actions of released histamine on the vasculature and smooth muscle system account for the symptoms of the allergic response. These actions occur at the
H, receptor (Ash, A.S.F. and Schild, H.O., Br. J. Pharmac. Chemother. 1966, 27:427—-439) and are blocked by the classical antihistamines (e.g. diphenhydramine). Histamine is also an important regulator of gastric acid secretion through its action on parietal cells. These effects of histamine are mediated via the H, receptor (Black, J.W. et al., Nature 1972, 236:385-390) and are blocked by H; receptor antagonists (e.g. cimetidine). The third histamine receptor —H;— was first described as a presynaptic autoreceptor in the central nervous system (CNS) (Arrang, J.-M. et al., Nature 1983, 302:832- 837) controling the synthesis and release of histamine. Recent evidence has emerged showing that the Hj receptors are also located presynaptically as heteroreceptors on serotonergic, noradrenergic, dopaminergic, cholinergic, and
GABAergic (gamma-aminobutyric acid containing) neurons. These Hs receptors have also recently been identified in peripheral tissues such as vascular smooth muscle. Consequently there are many potential therapeutic applications for histamine Hj agonists, antagonists, and inverse agonists. (See: “The Histamine Hz Receptor-A Target for New Drugs”, Leurs, R., and
Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000,
408:860—864.) A fourth histamine receptor —H,— was recently described by
Oda, T. et al. (J. Biol. Chem. 2000, 275(47).36781-36786).
The potential use of histamine Hj agonists in sleep/wake and arousallvigilance disorders is suggested based on animal studies (Lin, J.-S. et al., Brain Res. 1990, 523:325-330; Monti, J.M. et al., Eur. J. Pharmacol. 1991, 205:283-287). Their use in the treatment of migraine has also been suggested (McLeod, R.L. et al., Soc. Neurosci. Abstr. 1996, 22:2010) based on their ability to inhibit neurogenic inflammation. Other applications could be a protective role in myocardial ischemia and hypertension where blockade of norepinephrine release is beneficial (Imamura, M. et al., J. Pharmacol. Exp.
Ther. 1994, 271(3):1259-1266). It has been suggested that histamine Hj agonists may be beneficial in asthma due to their ability to reduce non- adrenergic non-cholinergic (NANC) neurotransmission in airways and to reduce microvascular leakage (Ichinose, M. and Barnes, P.J., Eur. J. Pharmacol. 1989, 174:49-55).
Several indications for histamine Hj; antagonists and inverse agonists have similarly been proposed based on animal pharmacology experiments with known histamine Hz antagonists (e.g. thioperamide). These include dementia,
Alzheimer’s disease (Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21:1977), epilepsy (Yokoyama, H. et al., Eur. J. Pharmacol. 1993, 234:129-133), narcolepsy, eating disorders (Machidori, H. et al., Brain Res. 1992, 590:180- 186), motion sickness, vertigo, attention deficit hyperactivity disorders (ADHD), learning and memory (Barnes, J.C. et al., Soc. Neurosci. Abstr. 1993, 19:1813), and schizophrenia (Schlicker, E. and Marr, I., Naunyn-
Schmiedeberg’s Arch. Pharmacol. 1996, 353:290-294). (Also see: Stark, H. et al., Drugs Future 1996, 21(5):507-520; and Leurs, R. et al., Prog. Drug Res. 1995, 45:107—165 and references cited therein.) Histamine Hj antagonists, alone or in combination with a histamine Hy antagonist, are reported to be useful for the treatment of upper airway allergic response (U.S. Patent Nos. 5.217,986; 5,352,707 and 5,869,479). Recently, a histamine Hj antagonist (GT-2331) was identified and is being developed by Gliatech Inc. (Gliatech Inc.
Press Release Nov. 5, 1998; Bioworld Today, March 2, 1999) for the treatment of CNS disorders.
As noted, the prior art related to histamine Hj; ligands has been comprehensively reviewed (“The Histamine Hj; Receptor-A Target for New
Drugs”, Leurs, R., and Timmerman, H., (Eds.), Elsevier, 1998). Within this reference the medicinal chemistry of histamine His agonists and antagonists was reviewed (see: Krause, M. et al., and Phillips, J.G. and Ali, S.M., respectively). The importance of an imidazole moiety containing only a single substitution in the 4 position was noted together with the deleterious effects of additional substitution on activity. Particularly, methylation of the imidazole ring at any of the remaining unsubstituted positions was reported to strongly decrease activity. Additional publications support the hypothesis that an imidazole function is essential for high affinity histamine Hj; receptor ligands (see: Ali, S.M. et al., J. Med. Chem. 1999, 42:903-909, and Stark, H. et al, and references cited therein). However many imidazole-containing compounds are substrates for histamine methyl transferase, the major histamine metabolizing enzyme in humans, which leads to shortened half-lives and lower bioavailability (see: Rouleau, A. et al., J. Pharmacol. Exp. Ther. 1997, 281(3):1085-1094). In addition, imidazole-containing drugs, via their interaction with the cytochrome P450 monooxygenase system, can result in unfavorable biotransformations due to enzyme induction or enzyme inhibition (see: Kapetanovic, I.M. and Kupferberg, H.J., Drug Metab. Dispos. 1984, 12(5):560-564; Sheets, J.J. and Mason, J.I., Drug Metab. Dispos. 1984, 12(5):603-606; Back, D.J. and Tjia, J.F., Br. J. Pharmacol. 1985, 85:121-126,;
Lavrijsen, K. et al., Biochem. Pharmacol. 1986, 35(11).1867-1878; Albengres,
E. et al., Drug Safety 1998, 18(2):83-97). The poor blood-brain barrier penetration of earlier histamine Hj; receptor ligands may also be associated with the imidazole fragment (Ganellin, C.R. et al., Arch. Pharm. Pharm. Med.
Chem. (Weinheim, Ger.) 1998, 331:395-404).
More recently, several publications have described histamine H3 ligands that do not contain an imidazole moiety, for example: Ganellin, C.R. et al.;
Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.) 1999, 332:389-398; Walczynski, K. et al., Farmaco 1999, 54:684-694, Linney,
I.D. et al, J. Med. Chem. 2000, 43:2362-2370; Tozer, M.J. and Kalindjian,
S.B., Exp. Opin. Ther. Patents 2000, 10:1045-1055; US Patent 5,352,707;
PCT Application WO 99/42458; PCT Application WO 02/076925; and EP
Application 0978512, Feb. 9, 2000.
The compounds of the present invention do not contain the imidazole moiety, and its inherent liabilities, and yet maintain potency at the human Hs receptor as determined by receptor binding to the human histamine Hj receptor (see: Lovenberg, T.W. et al., Mol. Pharmacol. 1999, 55:1101-1107).
Screening using the human receptor is particularly important for the identification of new therapies for the treatment of human disease.
Conventional binding assays, for example, are determined using rat synaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992, 263(1):304- 310), rat cortical membranes (West, R.E. et al., Mol. Pharmacol. 1990, 38:610- 613), and guinea pig brain (Korte, A. et al., Biochem. Biophys. Res. Commun. 1990, 168(3):979-986). Only limited studies have been performed previously using human tissue but these allude to significant differences in the pharmacology of rodent and primate receptors (West, R.E. etal, Eur. J.
Pharmacol. 1999, 377:233-239).
We now describe a series of phenylalkynes with the ability to modulate the activity of the histamine receptor, specifically the Hs receptor, without the inherent problems associated with the presence of an imidazolyl moiety.
Summary of the invention
The present invention is directed to pharmaceutically active phenylalkynes, methods of making them, and methods of using them. The invention features a compound of formula (I)
R! /
RZ—N
R® —
RB a ),
R* R® 0) wherein n is an integer from 0 to 1,
R' and R? are independently selected from C 1.3 alkyl, allyl, and C 3.5 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N; one of R®, R*, and RY is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;
Gis L’Q;
L2 is methylene;
Q is NR®R® wherein R® is independently selected from hydrogen, C 1.6 alkyl,
Ca. alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-membered heterocyclyl)C.¢ alkylene, and (phenyl) C1. alkylene; and R® is independently selected from C 1.5 alkyl, C 16 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-membered heterocyclyl)Cy.s alkylene, and (phenyl) C1.s alkylene; or
Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of Formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1.3 alkyl; and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C1. alkyl, 5-9-membered heterocyclyl, N(C1.¢ alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C1.3 alkylene, phenyl, C,.2-hydroxyalkylene, Cz. alkoxy, (Cs. cycloalkyl)-O-, phenyl, (phenyl)C4.3 alkylene, and (phenyl)C1.3 alkylene-O- and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; or a pharmaceutically acceptable salt, ester, or amide thereof.
The present invention also features methods of making a compound of formula (1), a pharmaceutically acceptable salt, ester, or amide thereof, comprising at least one of the following steps: Reacting a compound of formula (V1) with a compound of formula (V),
R2 /
R'—N —~ )
R4 R3 ) n (V1) (V)
and x1
RS —— n
R4 R3 (vir) performing a nucleophilic substitution of X; in compound of formula (Vill) with an organic base R'R?NH, wherein X is a suitable leaving group in a coupling reaction with an alkyne, and X' is a suitable leaving group in a nucleophilic substitution with an amine.
The present invention also features methods of making a compound of formula (1), a pharmaceutically acceptable salt, ester, or amide thereof, wherein more specifically one of R?® and R%is G, one of the remaining and R* is H, and the other is selected from hydrogen, fluoro, and chloro, comprising: reacting at least one of the compounds of formulae (XXlllw) and (XXlllow) with a compound of formula (V);
RS x?
Ww x2 4
R4 R3 R Ww (XXIlw) (XXHlow) . . .H Pl 2. . . wherein W is C(O)H (denoting # )orG, and X* is a suitable leaving group in a coupling reaction with an alkyne.
The present invention also features methods of making a compound of formula (1), a pharmaceutically acceptable salt, ester, or amide thereof, wherein more specifically R* is G, one of the remaining R® and R®is hydrogen, and the other is selected from hydrogen, fluoro, and chloro G is a m-substituent with respect to the alkyne chain substituent, comprising: reacting a compound of formula (XXIlimw) with a compound of formula (V). } a w R® (XXHImw) wherein W is C(O)H or G, and X? is a suitable leaving group in a coupling reaction with an alkyne. - The present invention also features methods of making a compound of formula (1), a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting a compound of formula (VI1) with an organic base R'R°NH in the presence of a trialkylphosphonium halide and a base.
HO
RS = n
R* R3 (VID)
The invention also features a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier; and methods of preparing or formulating such compositions. A composition of the invention may further include more than one compound of the invention, or a combination therapy (combination formulation or combination of differently formulated active agents).
The invention also provides methods of treating certain conditions and diseases, each of which methods includes administering a therapeutically effective (or jointly effective) amount of a compound or composition of the invention to a subject in need of such treatment. The disclosed compounds are useful in methods for treating or preventing neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag),
attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer’s disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H; receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in a subject in need thereof. For example, the invention features methods for preventing, inhibiting the progression of, or treating upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis.
In yet another embodiment, the disclosed compounds may be used in a combination therapy method including administering a jointly effective dose of an Hj antagonist and administering a jointly effective dose of a histamine Hj, antagonist, such as loratidine (CLARITIN™), desloratidine (CLARINEX™), fexofenadine (ALLEGRA ™) and cetirizine (ZYRTEC™), for the treatment of allergic rhinitis, nasal congestion, and allergic congestion.
In yet another embodiment, the disclosed compounds may be used in a combination therapy method, including administering a jointly effective dose of an Hs antagonist and administering a jointly effective dose of a neurotransmitter re-uptake blocker, such as a selective serotonin re-uptake inhibitor (SSRI) or a non-selective serotonin, dopamine or norepinephrine re- uptake inhibitor, including fluoxetine (PROZAC™), sertraline (ZOLOFT ™), paroxetine (PAXIL™) and amitryptyline, for the treatment of depression, mood disorders or schizophrenia.
Additional features and advantages of the invention will become apparent from the detailed description and examples below, and the appended claims.
Detailed Description of the Invention
The present invention provides phenylalkyne compounds useful for the treatment of disorders and conditions modulated by a histamine receptor.
A. Terms
Certain terms are defined below and by their usage throughout this disclosure.
As used herein, “halo” or “halogen” shall mean monovalent radicals of chlorine, bromine, fluorine and iodine.
As used herein, the term “alkyl”, whether used alone or as part of a substituent group, shall include straight and branched carbon chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, “lower” when used with alkyl means a carbon chain composition of 1-4 carbon atoms. “Alkylene” refers to a bivalent hydrocarbyl group, such as methylene (CH), ethylene (-CH,-CHg-) or propylene (-CH2CH;CH-), and so on.
As used herein, unless otherwise noted, “alkenyl” shall mean a straight or branched hydrocarbon group with at least two hydrogen atoms replaced with a pi bond to form a carbon-carbon double bond, such as propenyl, butenyl, pentenyl, and so on. Where the alkenyl group is R® or R%, the open radical (point of attachment to the rest of the molecule) is on sp° carbon, as illustrated by allyl, and the double bond or bonds is therefore at least alpha (if not beta, gamma, etc.) to the open radical.
As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, “cycloalkyl” shall denote a three- to eight-membered, saturated monocyclic carbocyclic ring structure. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, unless otherwise noted, “cycloalkenyl” shall denote a three- to eight-membered, partially unsaturated, monocyclic, carbocyclic ring structure, wherein the ring structure contains at least one double bond. Suitable examples include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexa-1,3-dienyl and the like.
As used herein, unless otherwise noted, “aryl” shall refer to carbocyclic aromatic groups such as phenyl, naphthyl, and the like. Divalent radicals include phenylene (-CgHa-) which is preferably phen-1,4-diyl, but may also be phen-1 ,3- diyl.
As used herein, unless otherwise noted, “aralkyl” shall mean any alkyl group substituted with an aryl group such as phenyl, naphthyl and the like.
Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.
As used herein, unless otherwise noted, “carbocyclyl” shall mean any cyclic group consisting of 3-13 carbon atoms, and preferably 6-9 carbon atoms, in the skeleton ring or rings, if the carbocycle is a fused or spiro bicyclic or tricyclic group. A carbocycle may be saturated, unsaturated, partially unsaturated, or aromatic. Examples include cycloalkyl, cycloalkenyl, cycloalkynyl; specific examples include phenyl, benzyl, indanyl, and biphenyl. A carbocycle may have substituents that are not carbon or hydrogen, such as hydroxy, halo, halomethyl, and so on as provided elsewhere herein.
As used herein, unless otherwise noted, the terms “heterocycle”, “heterocyclyl” and “heterocyclo” shall denote any three-, four-, five-, six-, seven- or eight-membered monocyclic, eight or nine or ten or eleven membered bicyclic or twelve or thirteen or fourteen membered tricyclic ring structure containing at least one heteroatom moiety selected from the group consisting of N, O, SO,
SO, (C=0), and S, and preferably N, O, or S, optionally containing one to four additional heteroatoms in each ring. In some embodiments, the heterocyclyl contains between 1 and 3 or between 1 and 2 additional heteroatoms. Unless otherwise specified, a heterocyclyl may be saturated, partially unsaturated, aromatic or partially aromatic. The heterocyclyl group may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure.
Exemplary monocyclic heterocyclic groups can include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl, 4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholiny! sulfone, 1,3-dixolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl, tetrazolyl, azetidinyl and the like.
For example, where Q is a saturated 3-13 membered N-linked heterocyclyl, Q necessarily contains at least one nitrogen, and the carbon atoms are sp hybridized.
In general, exemplary bicyclic heterocyclyls include benzthiazolyl, benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N- oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxaliny}, indazolyl, pyrrolopridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1- b]pyridinyl), or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as 1,2,3,4- tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as 1,2,3,4- tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl,
benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyrany! sulfone, dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (such as 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyi, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
N
\_/
S , , and the like.
Exemplary tricyclic heterocyclic groups include acridinyl, phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.
Preferred heterocyclyl groups include morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl, hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl, 45.6,7-tetrahydroindadolyl, benzoxazinyl, benzoxazolyl, benzthiazolyl,
N ND
\ benzimidazolyl, tetrazolyl, oxadiazolyl, S and .
As used herein, unless otherwise noted, the term “heterocyclyl-alkyl” or “heterocyclyl-alkylene” shall denote any alkyl group substituted with a heterocyclyl group, wherein the heterocycly-alkyl group is bound through the alkyl portion to the central part of the molecule. Suitable examples of heterocyclyl-alkyl groups include, but are not limited to piperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl, piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl, pyridylmethyl, pyrimidylethyl, and the like.
When a particular group is "substituted" (e.g., alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. lt is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl(alkyl)amido(alkyl)’ substituent refers to a group of the formula oO
Ikyl a - Ca A : :
The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes prevention, inhibition of onset, or alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
Abbreviations used in the specification, particularly in the Schemes and
Examples, are as follows:
DBAD Di-tert-butyl ==
Ec
Co LC
OFA [=| peamadatonie
OPER || baopopeianie
DMAC (or N,N-dimethylacetamide ow [TT
DMAP 4-N,N-dimethylamino- ee
Ca EL LL
OF | |omaormaide
Co LC
RLS
I
ALL ACE
The next section describes the compounds provided by the invention in more detail.
B. Compounds
The invention features compounds of formula (I) as described, for example, in the above summary section and in the claims. Preferred compounds include those wherein: (a) NR'R? taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino; (b) NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino; (©) NR'R? taken together form piperidinyl or pyrrolidinyl, (d) one of R* and R® is G; (e)R*is G; (f)R%is G; (@nist; (h) Q is a saturated N-linked nitrogen-containing heterocyclyl; (i) Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; (j) substituted Q is selected from N-(C 1.6 alkyl) piperazinyl, N-phenyl- piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl; (k) Q is a monovalent radical of an amine selected from aziridine, 1,4,7- trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza- spiro[4.5]decan-4-one, piperidine-3-carboxylic acid diethylamide, 1,2,3,4,5,6- hexahydro-[2,3"]bipyridinyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin- 1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)- amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl- cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yi-1,3- dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl- pyridin-2-yl-amine, phenylamine, and pyridin-2-ylamine; (1) Q is selected from N-morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 substituents independently selected from hydroxyl, carboxamide, Cq.¢ alkyl, 5-9 membered or 6-9 membered heterocyclyl, N(C1. alkyl)( 5-9 membered or 6-9 membered heterocyclyl),
NH(5-9 membered or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)Ci.3 alkylene, 5-9 membered or 6-9 membered heterocyclyl-O-, C1. alkoxy, (Cas cycloalkyl)-O-, phenyl, (phenyl)C1.3 alkylene, and (pheny!)C.; alkylene-O- where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and Ci.3 alkyl, (m) Q is substituted with a substituent comprising a 5-9 membered or 6- 9 membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C1. alkylene, oxazolyl, thiazolyl, 2,3-dihydro- indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C1.6 alkylene, tetrazolyl, (triazolyl)C1. alkylene, triazolyl, (pyrrolyl)Ci.¢ alkylene, and pyrrolyl; (n) Q is a substituted or unsubstituted N-morpholinyl; (0) R® is hydrogen; (p) R? is selected from phenyl or 5-9 membered aromatic heterocyclyl, wherein said phenyl or aromatic heterocyclyl is optionally substituted with 1-3 substituents selected from halo, nitro, cyano, and Ci. alkyl; (q) RY is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C1. alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C1.6 alkylene, tetrazolyl, (triazolyl)C1. alkylene, triazolyl, (pyrrolyl)Ci.6 alkylene, and pyrrolyl; (r) R® is substituted or unsubstituted phenyl; (s) RY is substituted or unsubstituted pyridyl; (t) wherein nis 1, R' and R? are independently selected from C; alkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N; one of R®, R*, and R® is
G and the two remaining are H; G is LQ; L2 is methylene; Q is NR®R® wherein
R? is independently selected from hydrogen, C1. alkyl, Cs alkenyl, 6-9 membered carbocycle, 3-12 membered heterocyclyl (preferably 5-9 or 6-9), phenyl, (5-9-membered heterocyclyl)C.6 alkylene, and (phenyl) C16 alkylene; and R? is independently selected from Cy.2 alkyl, C3 alkenyl, 5-9 membered carbocyclyl, 3-12 membered heterocyclyl ( for example, 5-9 membered or 6-9 membered heterocyclyl, and in some cases preferably 6-membered), phenyl,
(5-9-membered heterocyclyl)C1. alkylene, and (phenyl) C6 alkylene; or Q is a saturated 3-13 membered N-linked heterocyclyl (preferably 5-9 or 6-9), wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1.3 alkyl; and wherein substituents of Q can be further independently selected from tert-butyloxycarbonyl, carboxamide, 6-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C- hydroxyalkylene, hydroxy, and benzyl, and,where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl; or a pharmaceutically acceptable salt, ester, or amide thereof; (uw) (1) NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, and (2) Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; (v) (1) NR'R? taken together form piperidinyl or pyrrolidinyl, (2) nis 1, and (3) Q is selected from morpholinyl and piperidinyl; (w) Q is morpholinyl or substituted morpholinyl; (x) NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, nis 1, and wherein Q is NR®R® and R® is H and R? is selected from phenyl or aromatic 5-9 membered heterocyclyl, wherein said phenyl or heterocyclyl is optionally substituted with 1-3 substituents selected from halo, nitro, cyano, and C.3 alkyl; or (y) or combinations of the above. )
Examples of compounds of the invention include: 1-[4-(4-piperidin-1- ylmethyl-phenyl)-but-3-ynyl]-piperidine; 1 -[3-(4-piperidin-1-yl-but-1-ynyl)- benzyl]-piperidine; 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine; 4-[3-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine dihydrochloride; 1-[4-(4-pyrrolidin- 1-yl-but-1-ynyl)-benzyl]-piperidine; diethyi-[4-(4-piperidin-1-ylmethyl-phenyl)-
but-3-ynyl]-amine; 4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]- thiomorpholine; 4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-morpholine; 1- methyl-4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperazine; 1-[4-(4- pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine; 4-[4-(4-piperidin-1 -yl-but-1- ynyl)}-benzyl)-morpholine; diethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine; 1-{4-[4-(4-benzy|-piperidin-1-ylmethyl)-phenyl}-but-3-ynyl}-piperidine; 1-[4-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol; 2-{1-[4-(4-piperidin-1 -yl-but-1- ynyl)}-benzyl]-piperidin-2-yl}-ethanol; 1-[4-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]- decahydro-quinoline; 1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4- carboxylic acid amide; 8-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,4-dioxa-8- aza-spiro[4.5]decane; 1-methyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl}- piperazine; cyclohexyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine; indan-1 -yl- [4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine; 1-phenyl-4-[4-(4-piperidin-1-yl- but-1-ynyl)}-benzyl}-piperazine; 1-benzyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)- benzyl]-piperazine; 4-[4-(4-piperidin-1 -yl-but-1-ynyl)-benzyl]-piperazine-1- carboxylic acid tert-butyl ester; 1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]- piperazine; 1-isopropyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine; 1- phenyl-8-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,3,8-triaza-spiro[4.5]decan-4- one; 1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-3-carboxylic acid diethylamide; 1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1 ,2,3,4,5,6-hexahydro- [2,3'bipyridinyl; 1-[3-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]-4-(3-trifluoromethyl- phenyl)-piperazine; 2-{4-[3-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]-piperazin-1-yl}- pyrimidine; 1-[3-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]-piperidine-4-carboxylic acid amide; methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-(2-pyridin-2-yl-ethyl)- amine; [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidin-1-yi-but-1-ynyl)- benzyl]-amine; 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholine; allyl- cyclopentyl-[3-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]-amine; 10-[3-(4-piperidin-1- yl-but-1-ynyl)-benzyl]-1,4,7-trioxa-10-aza-cyclododecane; 1 -[4-(3-thiazolidin-3- ylmethyl-phenyl)-but-3-ynyl]-piperidine; [2-(1 H-indol-3-yl)-ethyl]-methyl-[3-(4- piperidin-1-yl-but-1-ynyl)-benzyl}-amine; 1-{1 -[3-(4-piperidin-1-yl-but-1-ynyl)- benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; phenyl-[3-(4-piperidin- 1-yl-but-1-ynyl)-benzyl]-amine; 1-[4-(3-pyrrolidin-1 -ylmethyl-phenyl)-but-3-ynyl}- piperidine; 1-[3-(4-piperidin-1-yl-but-1 -ynyl)-benzyl}-azacyclotridecane;
dimethyl-[4-(4-piperidin-1-yimethyl-phenyl)-but-3-ynyl]-amine; dimethyl-[4-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-amine; phenyl-[4-(4-piperidin-1-yl-but-1-ynyl)- benzyl]-amine; 1-[4-(3-aziridin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine; 2-{1- [3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yloxy}-pyrimidine; {1-[3-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-pyridin-2-yl-amine; 4-[4-(3- morpholin-4-ylmethyl-phenyl)-but-3-ynyl}-morpholine; 4-[3-(4-thiomorpholin-4- yl-but-1-ynyl)-benzyl]-morpholine; 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]- thiomorpholine; 4-[4-(3-thiomorpholin-4-yimethyl-phenyl)-but-3-ynyl}- morpholine; 4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-thiomorpholine; 4-{4- [3-(4-methyl-piperazin-1-yimethyl)-phenyl}-but-3-ynyl}-morpholine; 4-{4-[3-(4- methyl-piperazin-1-ylmethyl)-phenyl}-but-3-ynyi}-thiomorpholine; 1 -methyl-4-[3- (4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine; 1-[3-(4-piperidin-1-yl-but-1- ynyl)-benzyl]-piperidin-4-ol; 1-[3-(4-morpholin-4-yl-but-1-ynyl)-benzyl]-piperidin- 4-ol; 1-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl}-piperidin-4-ol; 1-{4-[3-(4- methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-piperidine; 4-{4-[3-(4- methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-morpholine; and 4-{4-[3-(4- methoxy-piperidin-1-yimethyl)-phenyi]-but-3-ynyl}-thiomorpholine.
Additional compounds include: 1-[4-(4-piperidin-1-ylmethyl-phenyl)-but- 3-ynyl]-piperidine; 1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine; 4-[3-(4- piperidin-1-yl-but-1-ynyl)-benzyl}-morpholine; 4-[3-(4-piperidin-1 -yl-but-1-ynyl)- benzyl]-morpholine dihydrochloride; 1-[4-(4-pyrrolidin-1-yl-but-1-ynyl)-benzyl]- piperidine; 1-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine; diethyl- [4-(4-piperidin-1-yl-but-1-ynyl)-benzyl}-amine; 1-[4-(4-piperidin-1-yl-but-1-ynyl)- benzyl)-piperidin-4-ol; 2-{1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-2- yl}-ethanol; 1-[4-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]-decahydro-quinoline; 1-{4- (4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-carboxylic acid amide; 8-{4-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]decane; 1 -methyl-4- [4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine; cyclohexyl-[4-(4-piperidin-1- yl-but-1 _ynyl)-benzyll-a mine; indan-1-yl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl}- amine; 1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine; 1-isopropyl-4-[4-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine; 1-phenyl-8-[3-(4-piperidin-1-yl-but- 1-ynyl)-benzyl}-1,3,8-triaza-spiro[4.5]decan-4-one; 1-[3-(4-piperidin-1-yl-but-1-
ynyl)-benzyl]-piperidine-4-carboxylic acid amide; 4-[3-(4-piperidin-1-yl-but-1- ynyl)-benzyl]-thiomorpholine; allyl-cyclopentyl-[{3-(4-piperidin-1 -yl-but-1-ynyl)- benzyl]-amine; 10-[3-(4-piperidin-1-yi-but-1-ynyl)-benzyl]-1,4,7-trioxa-10-aza- cyclododecane; 1-[4-(3-thiazolidin-3-yimethyl-phenyl)-but-3-ynyl]-piperidine; [2- (1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine; 1-{1- [3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yi}-1,3-dihydro- benzoimidazol-2-one; and 1-[4-(3-pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]- piperidine.
More preferred compounds include: 4-[3-(4-piperidin-1-yl-but-1-ynyl)- benzyl]-morpholine and 4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine; and particularly the former.
Additional examples of compounds include: 1-[3-(4-piperidin-1-yl-but-1- ynyl)-benzyl]-piperidine; 4-[3-(4-piperidin-1-yl-but-1-ynyl}-benzyl}-morpholine; 4- [3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine dihydrochloride; 1-phenyl-8- [3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,3,8-triaza-spiro[4.5]decan-4-one; 1-[3- (4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-3-carboxylic acid diethylamide; 1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl}-1 ,2.3,4,5,6-hexahydro-[2,3']bipyridinyl; 1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-4-(3-trifluoromethyl-phenyl)-piperazine; 2-{4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazin-1 -yl}-pyrimidine; 1-[3-(4- piperidin-1-yl-but-1-ynyl)-benzyi]-piperidine-4-carboxylic acid amide; methyl-[3- (4-piperidin-1-yl-but-1-ynyl)-benzyl]-(2-pyridin-2-yl-ethyl)-amine; [2-(3,4- dimethoxy-phenyl)-ethyl]-methyl-{3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine; 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholine; allyl-cyclopentyl-[3-(4- piperidin-1-yl-but-1-ynyl)-benzyl]-amine; 10-[3-(4-piperidin-1 -yl-but-1-ynyl)- benzyl]-1,4,7-trioxa-10-aza-cyclododecane; 1-[4-(3-thiazolidin-3-ylmethyl- phenyl)-but-3-ynyl]-piperidine; [2-(1 H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidin-1- yl-but-1-ynyl)-benzyl]-amine; 1-{1-[3-(4-piperidin-1-yl-but-1 -ynyl)-benzyl]- piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one; phenyl-[3-(4-piperidin-1-yl-but- 1-ynyl)-benzyl]-amine; 1-[4-(3-pyrrolidin-1 -yimethyl-phenyl}-but-3-ynyl]- piperidine; and 1-[3-(4-piperidin-1-yi-but-1 -ynyl)-benzyl]-azacyclotridecane.
Further examples include: dimethyl-[4-(4-piperidin-1 -ylmethyl-phenyl)- but-3-ynyl}-amine; dimethyl-[4-(4-piperidin-1-yl-but-1 -ynyl)-benzyl}-amine; phenyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl}-amine; 1 -[4-(3-aziridin-1-ylmethyl- phenyl)-but-3-ynyl]-piperidine; 2-{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl}- piperidin-4-yloxy}-pyrimidine; {1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]- piperidin-4-yl}-pyridin-2-yl-amine; 4-[4-(3-morpholin-4-ylmethyl-phenyl)-but-3- ynyt]-morpholine; 4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl}-morpholine; 4- [3-(4-piperidin-1-yl-but-1-ynyl)-benzyl}-thiomorpholine; 4-[4-(3-thiomorpholin-4- yimethyl-phenyl)-but-3-ynyl]-morpholine; 4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)- benzyl}-thiomorpholine; 4-{4-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-but-3- ynyl}-morpholine; 4-{4-[3-(4-methyl-piperazin-1 -ylmethyl)-phenyl]-but-3-ynyl}- thiomorpholine; 1-methyl-4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine; 1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol; 1 -[3-(4-morpholin-4-yl- but-1-ynyl)-benzyl}-piperidin-4-ol; 1-[3-(4-thiomorpholin-4-yl-but-1 -ynyl)-benzyl}- piperidin-4-ol; 1-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}- piperidine; 4-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}- morpholine; and 4-{4-[3-(4-methoxy-piperidin-1-ylmethyi)-phenyl]-but-3-ynyl}- thiomorpholine.
The invention also provides compounds that are useful as synthetic intermediates of the compounds of the invention. Such compounds, which themselves may or may not have pharmaceutical activity, include those provided in the schemes and synthetic examples.
The invention also contemplates compounds isotopically-labelled to be detectable by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) useful for studying Hi-mediated disorders.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. In addition, compounds of the invention may be modified by using protecting groups; such compounds, precursors, or prodrugs are also within the scope of the invention. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", ed. J.F.W. McOmie, Plenum
Press, 1973: and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic
Synthesis", 3" ed., John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
HYDROXYL PROTECTING GROUPS
Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl, methyithiomethyl, t-butyithiomethyl, (phenyldimethylsilylymethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2- methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1- [(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8- trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2- chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1- methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydry!, 5-dibenzosuberyl, triphenylmethyl, a- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'- bromophenacyloxy)phenyldiphenylmethyl, 4,4’,4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4 4' 4"-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4 ',4"'- dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, S-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Examples of silyl ethers include trimethylsilyl, triethylsilyl, trisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyithexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butyimethoxyphenylsilyl.
Esters
In addition to ethers, a hydroxyl group may be protected as an ester.
Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P- phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4- (ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate(mesitoate)
Carbonates
Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2 2- trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2- (triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-
methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4- (methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.
Miscellaneous Esters
Examples of miscellaneous esters include 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3- tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, o- naphthoate, nitrate, alkyl N,N,N’,N'-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate
Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
PROTECTION FOR 1,2- AND 1,3-DIOLS
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include methylene, ethylidene, 1-t- butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2- trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4- dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
Cyclic Ortho Esters
Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1- ethoxyethylidine, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, a-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.
Silyl Derivatives
Examples of silyl derivatives include di- t-butylsilylene group, and 1,3- (1,1,3,3-tetraisopropyldisiloxanylidene) derivative.
AMINO PROTECTING GROUPS
Protection for the amino group includes carbamates, amides, and special —NH protective groups.
Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
Carbamates
Examples of methyl and ethyl carbamates include methyl and ethyl, 9- fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7- di-t-butyl-[9-(10,10-dioxo-10,10,10, 10-tetrahydrothioxanthyl)jmethyl, and 4- methoxyphenacyl.
Substituted Ethyl
Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethy|-2- haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and 4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N- hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-
bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9- anthrylmethyl and diphenylmethyl.
Assisted Cleavage
Examples of assisted cleavage include 2-methyithioethyl, 2- methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)jmethyl, 4- methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2- triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyi.
Urea-Type Derivatives
Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl, and N'- phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3- (N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2- furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(p’- methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1- cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p- phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.
Examples of amides include:
Amides
N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N- phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'- dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o- nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o- phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o- nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5- dimethylpyrrolyl, N-1,1,4 4-tetramethyldisilylazacyclopentane adduct, 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4- pyridonyl.
SPECIAL — NH PROTECTIVE GROUPS
Examples of special NH protective groups include:
N-Alkyl and N-Aryl Amines
N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]jmethyl, N-3-acetoxypropyl,
N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N- benzyl, N-4-methoxybenzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,
N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-
2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine
N’-oxide.
Imine Derivatives
N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,
N-diphenyimethylene, N-[(2-pyridyl)mesityllmethylene, and N-(N' ,N'- dimethylaminomethylene).
PROTECTION FOR THE CARBONYL GROUP
Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2- trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include 1,3-dioxanes, 5- methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4- phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl- 1,3-dioxolane, O,0’-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.
Acyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include S,S'-dimethyl,
S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl, S,S’-dipentyl, S,S'-diphenyl, S,S’- dibenzyl and S,S’'-diacetyl.
Cyclic Dithio Acetals and Ketals
Examples of cyclic dithio acetals and ketals include 1,3-dithiane, 1,3- dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include O-trimethyisilyl-
S-alkyl, O-methyl-S-alkyl or -S-phenyl and O-methyl-S-2-(methyilthio)ethyl.
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include 1,3- oxathiolanes.
MISCELLANEOUS DERIVATIVES
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydrins include O-acetyl, O- trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrazones
Examples of substituted hydrazones include N,N-dimethyl and 2,4- dinitrophenyl.
Oxime Derivatives
Examples of oxime derivatives include O-methyl, O-benzyl and O- phenylthiomethyl.
Imines
Substituted Methylene Derivatives, Cyclic Derivatives
Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1’-hydroxyalkyl)imidazoles, N,N’- dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.
MONOPROTECTION OF DICARBONYL COMPOUNDS
Selective Protection of a-and p-Diketones
Examples of selective protection of a-and p-diketones include enamines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and trimethylsilyl.
Cyclic Ketals, Monothio and Dithio Ketals
Examples of cyclic ketals, monothio and dithio ketals include bismethylenedioxy derivatives and tetramethylbismethylenedioxy derivatives.
PROTECTION FOR THE CARBOXYL GROUP
Esters
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl. 2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, o-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methyithioethyl, 1,3- dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyh)ethyi, 2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyi-1-phenylethyl, t- butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yi, cinnamyl, a-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.
Substituted Benzyl Esters
Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(S,10- dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6- chromylmethyl, 2,4 6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p- nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methyisulfinyl)benzyl, 4- sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
Silyl Esters
Examples of silyl esters include trimethylsilyl, triethylsilyl, t- butyldimethyisilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t- butylmethyisilyl.
Activated Esters
Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles, 2-alkyi-1,3- oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(lil) complex.
Stannyl Esters
Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.
AMIDES AND HYDRAZIDES
Amides
Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6- dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4- tetrahydroquinolyl, and p-P-benzenesulfonamides.
Hydrazides
Examples of hydrazides include N-phenyl and N,N’-diisopropyl.
The compounds of the invention can be prepared according to the methods described in the next section.
C. Synthesis
The compounds of the invention can be prepared according to traditional synthetic organic methods and matrix or combinatorial chemistry methods, as shown in Schemes 1 — 5 below and in Examples 1-76. A person of ordinary skill will be aware of variations and adaptations of the schemes and examples provided to achieve the compounds of the invention.
One skilled in the art will recognize that synthesis of the compounds of the present invention may be effected by purchasing intermediate or protected intermediate compounds described in any of the Schemes disclosed herein.
Throughout the schemes when the reacting functionality is located at R®, one skilled in the art will recognize that the choice of R3 is illustrative only and that the reacting functionality could also be located at R* and R® also.
One skilled in the art will further recognize that during any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic
Chemistry", ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &
P.G.M. Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Throughout the schemes when the reacting functionality is located at R®, one skilled in the art will recognize that the choice of R® is illustrative only and that the reacting functionality could also be located at R® and/or R*.
Compounds of formula (V) may be prepared according to the processes outlined in Scheme 1.
Scheme 1.
R?
R'—NH sec (Iv)
R?
HO «1 R'—NH % _ J a. _ 2 ____ R-N = n step A = n step B _ J - n {1} (nr) (IV) (V)
A compound of formula (V) is prepared as outlined in Scheme 1 from a compound of formula (ll). A compound of formula (ll) is reacted with a reagent capable of converting a hydroxyl function into a leaving group X' under hydroxyl activation conditions.
Leaving group X' is a suitable leaving group in a nucleophilic substitution reaction with an amine, such as amine R'R®NH. In a preferred embodiment, leaving group X' is a sulfonate ester, obtained by reacting a compound of formula (If) with an alkyl or arylsulfonyl chloride in a non-acoholic solvent in the presence of an organic or inorganic base at temperature from — 78°C to 50°C. Examples of such solvent are benzene, DCM, DCE, THF, DMF, acetonitrile, hexamethylphosphoramide (HMPA), hexane, pentane, and mixtures thereof. Examples of organic bases are pyridine, TEA, and mixtures thereof. Examples of inorganic bases are, KOH, NaOH, Na,CO3, K,COjor mixtures thereof.
In a particularly preferred embodiment, a compound of formula (Il) is reacted with p-toluenesulfonyl chloride or methanesulfony! chloride in DCM in the presence of TEA at a temperature between 0°C and room temperature.
A compound of formula (V) is obtained from a compound of formula (li) by reacting a compound of formula (IV) with a compound of formula (lll) under nucleophilic displacement conditions, either neat or in a solvent in the presence or absence of a base at a temperature from 0°C to 100°C. Examples of such solvent are methanol, ethanol, propanol, n-butanol, DMF, DMSO, DME, and compatible mixtures thereof. Examples of such base, when present, are sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, tetramethylguanidine, and compatible mixtures thereof.
The use of a high polarity solvent may increase the rate and reduce by- product formation in these reactions. Such high polarity solvent is provided in some embodiments as a mixture of a first solvent with a cosolvent that increases the dielectric constant of the mixture with respect to the dielectric constant of such first solvent. For example, one of ordinary skill in the art will recognize in light of this disclosure that the use of water as such cosolvent may increase the rate and reduce by-product formation in these reactions. In a preferred embodiment the solvent is water, ethanol, or a mixture of water and ethanol and/or propanol, the base is sodium or potassium carbonate or absent, and the temperature is room temperature to 80°C.
In a particularly preferred embodiment, the solvent is ethanol, no exogenous base is used, and the temperature is 0°C to room temperature.
A compound of formula (V) may also be obtained from a compound of formula (I) by reaction of a compound of formula (IV) in the presence of a trialkylphosphonium halide, such as (cyanomethyl)trimethylphosphonium iodide and a base such as DIPEA in a solvent such as propionitrile at 90°C.
Compounds of formula (I) may be prepared according to the processes outlined in Scheme 2.
Scheme 2.
R2
R'—N — J 0 step A }
Vv)
R2
R'—N
Wa w= n
R* R? R* R® (Vi) {1
HO R? step X R'—NH step R2
B | = 1_n n step D |R'—NH
E
(nm (IV) (IV)
HO x!
J— —_—
R= =" | _ RS— —— q step C
RY R® R® R° (vin) (vii)
A compound of formula (1) is prepared from a compound of formula (VI) as shown in Scheme 2.
Group X2, such as group X2 in compound (V1), denotes a suitable leaving group for a coupling reaction with an alkyne, wherein “alkyne” in this definition refers to a chain, whether substituted or unsubstituted, that has a triple carbon-carbon bond. Examples of such leaving group include halo, such as iodo, bromo, and chloro, and sulfonate, such as trifluoromethanesulfonate.
A compound of formula (VI) is reacted with a compound of formula (ll) under
Sonogashira conditions in the presence of a palladium-containing catalyst, such as palladium on carbon, Pd(PPh3)2Cla, Pdx(dba)s, Pdz(dba)seCHCI3,
Pd(P'Bus)z, Pdz(dba)seCHCly/ Pd(PBua)z, Pd(OAC)2, PA(PhCN),Clz, and PdCl,,
and a base, such as triethylamine, DIEA, di-iso-propylamine, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof in a solvent such as THF, DME, dioxane, DCE, DCM, toluene, acetonitrile, and mixtures thereof at a temperature from 0°C to 100°C.
A copper compound is used as a catalyst in this reaction, such as Cu(l) compound. Such Cu(l) catalyst is preferably incorporated in the reaction medium as substoichiometric quantities of a copper salt, such as Cul or
CuBrMe,S. Theuse of phosphine ligands, such as PPh; or P('Bu)s, ispart fo the methodology of some embodiments of the present invention.
As in other process steps in the context of embodiments of this invention, the use of a high polarity solvent may increase the rate and reduce by-product formation in these reactions. Such high polarity solvent is provided in some embodiments as a mixture of a first solvent with a cosolvent that increases the dielectric constant of the mixture with respect to the dielectric constant of such first solvent. For example, one of ordinary skill in the art will recognize in light of this disclosure that the use of water as such cosolvent may increase the rate and reduce by-product formation in these reactions. in a preferred embodiment, the palladium source is Pdz(dba);eCHCly/
Pd(P'Bus)z, Pd(PPh;).Cl,, or palladium on carbon, the base is triethylamine or potassium carbonate, the solvent is THF, or a mixture of DME and water, and the temperature is between room temperature and 80°C. In a particularly preferred embodiment, the palladium source is Pd(PPh;).Cl,, the base is triethylamine, the solvent is THF, a catalytic quantity of Cul or CuBrMe;S is used, and the reaction temperature is room temperature to reflux temperature.
A compound of formula (I) is obtained from a compound of formula (VII) in analogy with Scheme 1, steps A and B, or by analogy with Scheme 1 step C.
A compound of formula (I) may also be obtained directly from a compound of formula (VI) by reaction with a compound of formula (V) under Sonogashira conditions.
Compounds of formula (XII) may be prepared according to the processes outlined in Scheme 3.
Scheme 3 _p! od a NH
J @ _R R20 —_— RZ ~ N o step A Nan step B L21 (1X) (X) (XI) (Xi)
A compound of formula (X11) is prepared as outlined in Scheme 3 from a compound of formula (IX). One skilled in the art will be capable of selecting a suitable protecting group P’ for the compound of formula (IX). A compound of formula (IX) is reacted with a compound of formula (X) under reductive amination conditions in the presence of a reducing agent such as NaBH(OAc)s in a solvent such as DCE, THF, and mixtures thereof at a temperature from 0 °C to 80 °C. Amine (X) reacts in this reductive amination with aldehyde (IX) to form an iminium ion. According to this disclosure, one skilled in the art will recognize that the addition of an acid, such as acetic acid, may accelerate this reaction and decrease byproduct formation. The iminium ion thus formed is subsequently reduced by NaBH(OAc); to the desired product. In a particularly preferred embodiment, a compound of formula (IX) is reacted with a compound of formula (X) in the presence of NaBH(OAc); and acetic acid in DCE at room temperature.
A compound of formula (XII) is obtained from a compound of formula (XI) by removal of the protecting P! under conditions familiar to one skilled in the art. Selection and removal of protecting group P' is within the ordinary skill in the art in light of, for example, reference material cited herein (for example, works by Greene, et al., and McOmie), and description of protecing groups provided herein.
Compounds of formula (XVI) may be prepared according to the processes outlined in Scheme 4.
Scheme 4 cr R22y3 R22 oy R22 J@
HO step A ie! step B o (XI) (XIV) (XV) (XVI)
A compound of formula (XVI) is prepared as outlined in Scheme 4 from a compound of formula (XIII). As noted above, one skilled in the art will be capable of selecting a suitable protecting group P? for the compound of formula (Xt).
A compound of formula (XII) is reacted with a compound of formula (XIV), where x3 is a leaving group such a halogen or an activated ester, in the presence of a base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, DBU, triethylamine, and butyllithium in a solvent such as DMF, THF, toluene, DMAC, acetonitrile, and mixtures thereof, at a temperature from room temperature to 140 °C.
Alternatively, a compound of formula (XII) is reacted with a compound of formula (XIV), where x2 is hydroxyl and R?* is an aromatic group, under
Mitsunobu conditions. A compound of formula (XVI) is obtained from a compound of formula (XV) by removal of the protecting P? under conditions familiar to one skilled in the art.
Compounds of formula (XXVI) may be prepared according to the processes outlined in Scheme 5.
Scheme 5
HO R9—NH HO 0) RS — ) _— = ———
H n step D R—N n rR R RER* R13 (XXVIII) (XXIV) (XXIX)
HO step step n 0)
R2
R'—N R?
RO—NH ) R'-N 0) R® =), xX X—————= =)
H stepA poy step BRo_N n
R* R® RER* R® RER* R3 (XXHI) (XXIV) (XXV) (Vv) (XXXVI)
R2
R'—N R? 9_ ) R'-N R Ne == Jn 0) == step F H step G
R* R® (V) (XXVIII) (XXIV)
A compound of formula (XXVI) is prepared from a compound of formula (XX) as outlined in Scheme 5. The group X2 in the compound of formula (XXII) denotes a leaving group, as defined in Scheme 2.
A compound of formula (XXVIII) is obtained by reacting a compound of formula (XXIII) with a compound of formula (Il) under Sonogashira conditions, as outlined in Scheme 2, step A. A compound of formula (XXIX) is obtained by reacting a compound of formula (XXVIII) with a compound of formula (XXIV) under reductive amination conditions as outlined in Scheme 3, step A. One skilled in the art will recognize that a substituted or unsubstituted nonaromatic heterocycle containing secondary amine functionality, for example piperidine derivatives, such as compounds (XII) and (XVI), may be used in place of the compound of formula (XXIV).
A compound of formula (XXVI) is obtained by reacting a compound of formula (XXIX) under the conditions described in Scheme 1, step C, or
Scheme 1, steps A and B. Alternatively, compound of formula (XXVI) is obtained by reacting a compound of formula (XXV) with a compound of formula (V) under Sonogashira conditions, as described in Scheme 2, step A.
Compound of formula (XXV) is obtained by reacting a compound of formula (XX) under reductive amination conditions, as described in Scheme 3, step
A. Alternatively, compound of formula (XXVI) is obtained by reacting a compound of formula (XXVI1) with a compound of formula (XXIV) under reductive amination conditions, as described in Scheme 3, step A. Compound of formula (XXVH) is obtained by reacting a compound of formula (XXIII) with a compound of formula (V) under Sonogashira conditions, as described in
Scheme 2, step A.
Substituent X° and the aldehyde group are shown in a p-arrangement with respect to each other in compound (XXHI). Other schemes similar to
Scheme 5 with substituent X? and the aldehyde group in arrangements o- and m- with respect to each other are not shown explicitly in the form of additional schemes. It is understood in light of the description provided herein that embodiments of this invention include schemes in which compound (XXIHl) is analogous to that shown in Scheme 5 with substituent X? and the aldehyde group in o-arrangement with respect to each other. Similarly, it is also understood that embodiments of this invention include schemes in which compound (XXIII) is analogous to that shown in Scheme 5 with substituent x? and the aldehyde group in m-arrangement with respect to each other. Specific examples with such m-arrangement are provided herein because of the different reactivity under m-substitution conditions as compared with those under o- and p-substitution conditions.
Examples of additional embodiments of compound (XXIl) with various types of subsitutional arrangements are illustrated by suitably substituted formulae (XXHIw), (XXillow), and (XXIlimw):
RS x? w x2 4
RY R3 R WwW (XXilw) (XXIllow) ' la
Ww R3 (XXImw).
In addition to the methods of making the compounds of this invention that are described herein as implemented in light of the present disclosure and the ordinary skill in the art, embodiments of methods of making compounds according to this invention include the following.
Some embodiments include methods of making compounds of formula (1), a pharmaceutically acceptable salt, ester, or amide thereof, comprising at least one of the steps : reacting a compound of formula (V1) with a compound of formula (V) rR? /
R'—N ~ )
R4 RS ) n (VI) Vv); and x1
RS ms n
R* R3
(vin performing a nucleophilic substitution of X; in compound of formula (Vili) with an organic base R' R2NH, wherein X? is a suitable leaving group in a coupling : reaction with an alkyne, and x! is a suitable leaving group in a nucleophilic substitution with an amine. More specifically, additional embodiments include : those methods wherein NR'R? taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino, more specifically, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, and still more specifically, wherein NR'R? taken together form piperidinyl or pyrrolidinyl.
Additional embodiments include methods wherein one of R* and R% is G, more specifically, wherein R* is G, or wherein R® is G. Additional embodiments include methods wherein n is 1. Additional embodiments include methods wherein Q is a saturated N-linked nitrogen-containing heterocyclyl, more specifically, wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl; or wherein substituted Q is selected from N-(C 1. alkyl) piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8- aza-spiro[4.5]decyl; or wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8- triaza-spiro[4.5)decan-4-one, piperidine-3-carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3bipyridinyl, 4-(3-trifluoromethyi-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2- pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)- pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine; or wherein Q is selected from N-morpholinyl and N-piperidinyl, optionally . substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C1. alkyl, 5-9 membered heterocyclyl, N(C+. alkyl)(5-9 . membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)Ci.3 alkylene, C 1.2-hydroxyalkylene,O(5-9 membered heterocyclyl), C1.6 alkoxy, (Ca. cycloalkyl)-O-, phenyl, (phenyl)Ci.3 alkylene,

Claims (109)

1. A method of making a compound of formula (1) . R! / RZ—N R® — — — ), R* R® ) wherein n is an integer from 0 to 1; R' and R? are independently selected from C 1.3 alkyl, allyl, and C 3.5 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N; one of R®, R*, and R® is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro; Gis LQ; L? is methylene; Q is NRER® wherein R® is independently selected from hydrogen, C 1 alkyl, C
) 2.6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5- 9-membered heterocyclyl)C.¢ alkylene, and (phenyl) C1.¢ alkylene; and Ris independently selected from C 1.6 alkyl, C 3.6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1. alkylene, and (phenyl) C16 alkylene;
or i Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain ) between 1 and 3 additional heteroatoms independently selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1.3 alkyl; and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C1.6 alkyl, 5-9-membered heterocyclyl, N(C1.6 alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)Cs.3 alkylene, phenyl, C1.2-hydroxyalkyiene, Ca.s alkoxy, (Cas cycloalkyl)-O-, phenyl, (phenyl)Ci.3 alkylene, and (pheny!)C1.3 alkylene-O- and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising at least one of the following steps: reacting a compound of formula (VI) with a compound of formula (V) R2 RIN = ) Ré R3 - ) n (VI) Vv); and x1 R® = n R4 R3 A211) performing a nucleophilic substitution of X; in compound of formula (VIII) with an organic base R'R?NH, wherein X? is a suitable leaving group in a coupling reaction with an alkyne, and X' is a suitable leaving group in a nucleophilic substitution with an amine.
2. A method according to claim 1, wherein NR'R? taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino.
3. A method according to claim 2, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino.
4. A method according to claim 3, wherein NR'R? taken together form piperidinyl or pyrrolidinyl.
5. A method according to claim 1, wherein one of R* and R® is G.
6. A method according to claim 5, wherein R* is G.
7. A method according to claim 5, wherein R® is G.
8. A method according to claim 1, wherein nis 1.
: 9. A method according to claim 1, wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.
10. A method according to claim 9, wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
11. A method according to claim 10, wherein substituted Q is selected from : N-(C 1.5 alkyl) piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza- spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl.
12. A method according to claim 9, wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3- carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3'|bipyridinyl, 4- (3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl- cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4- yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yi-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.
13. A method according to claim 11, wherein Q is selected from N- morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C4.¢ alkyl, 5-9 membered heterocyclyl, N(C_¢ alkyl)(5-9 membered heterocyclyl), NH(5- 9 membered heterocyclyl), (5-9 membered heterocyclyl)C1.; alkylene, C 1-2-hydroxyalkylene,O(5-9 membered heterocyclyl), C1 alkoxy, (Cas cycloalkyl)-O-, phenyl, (phenyl)C1.3 alkylene, and (phenyl)C;.; alkylene- O- where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halo, nitro, cyano, and C4; alkyl.
.
14. A method according to claim 11, wherein Q is substituted with a substituent comprising a C4. heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C.¢ alkylene, oxazolyl,
thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C1s alkylene, tetrazolyl, (triazolyl)C4.¢ alkylene, triazolyl, (pyrrolyl)C1. alkylene, and pyrrolyl.
15. A method according to claim 14, wherein Q is a substituted or : unsubstituted N-morpholinyl.
16. A method according to claim 1, wherein n is 1; R' and R? are independently selected from C; alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N; one of R%, R* and R® is G and the two remaining are H; Gis LQ; L? is methylene; Q is NR®R® wherein R® is independently selected from hydrogen, Ci. alkyl, C3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C. alkylene, and (phenyl) C alkylene; and R® is independently selected from C;.; alkyl, C5 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C. alkylene, and (phenyl) Cz alkylene;
. or : Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and “ optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 4.3 alkyl; and wherein substituents of Q can be further selected from tert- butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C »- hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl.
17. A method according to claim 1, wherein (a) NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, and (b) Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
18. A method according to claim 1, wherein said organic base R'R?NH is piperidine and said nucleaphilic substitution is performed at room temperature.
19. A method according to claim 1, wherein said nucleophilic substitution is performed at room temperature with 10 equivalents of piperidine in the presence of ethanol.
20. A method according to claim 1, wherein said nucleophilic substitution is . performed at room temperature with 10 equivalents of piperidine in the presence of ethanol and X' is mesylate, to yield a mixture of a substituted base and an elimination product.
21. A method according to claim 20, further comprising exposing said mixture to HCI to yield a saline solution, selectively precipitating and , crystallizing form said saline solution a phenylalkyne dihydrochloride salt.
. 22. A method according to claim 21, wherein said phenylalkyne dihydrochloride salt is 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyljmorpholine dihydrochloride.
23. A method according to claim 1, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, nis 1, and Q is selected from morpholinyl and piperidinyl.
24. A method according to claim 1, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholinyl or substituted morpholinyl.
25. A method according to claim 1, wherein n= 1, R¥is H, R%is H, R* is LQ, with Q being morpholinyl, L? as defined in claim 1, and NR'R? taken together form piperidinyl.
26. A method according to claim 1, wherein said organic base R'R*NH is piperidine.
27. A method according to claim 1, wherein said nucleophilic substitution is performed in the presence of ethanol at room temperature.
28. A method according to claim 1, wherein said nucleophilic substitution is performed in the presence of ethanol at room temperature and said organic base R'R’NH is piperidine.
29. A method according to claim 28, wherein the amount of said piperidine is 10 equivalents.
30. A method according to claim 1, wherein n= 1, R®is H, R®is H, Ris L2Q, with Q being morpholinyl, L2 as defined in claim 1, said organic base R'R2NH is piperidine, and said nucleophilic substitution is performed in the presence of ethanol at room temperature.
31. A method according to claim 1, wherein said nucleophilic substitution yields a mixture of a substitution product and an elimination product and is performed in an alcoholic medium at a temperature such that said substitution product is obtained in at least 80%.
32. A method according to claim 1, wherein said nucleophilic substitution yields a mixture of a substitution product and an elimination product and is performed in the presence of ethanol at room temperature, and said organic base R'R?NH is piperidine, further comprising treating said mixture with an acid to obtain a saline solution, and selectively precipitating and crystallizing said saline solution to obtain a salt.
33. A method according to claim 32, wherein said acid is HCL
34. A method according to claim 32, wherein diethyl ether and ethanol are used in said crystallization.
35. A method according to claim 34, whereinn=1, R%is H, Rois H, R*is
L2Q. with Q being morpholinyl, L? as defined in claim 1, and NR'R® taken together form piperidinyl, said substitution product is 4-[3-(4-piperidin-1-yl-but- 1-ynyl)-benzyl}-morpholine and said salt is the dihydrochloride salt of said substitution product.
36. A method according to claim 28, further comprising converting an : alcohol of formula (VII) to said compound of formula (VII).
37. A method according to claim 36, further comprising the reductive amination of a compound of formula (VIla) with an amine R?R’NH, wherein one of R¥, R*, and R® is C(O)H and the other two are selected from H, chioro and bromo, to give a compound of formula (VI), wherein one of R®, R?, and Ris NRER?® and the other two are selected from H, chloro and bromo, : : HO - ) n RY RY (Via).
38. A method according to claim 37, wherein said amine is morpholine.
39. A method according to claim 37, further comprising the coupling in the presence of a palladium-containing catalyst and a copper salt of a compound of formula (11) with a disubstituted benzene, wherein one of said benzene substitutents is C(O)H and the other of said benzene substitutents is selected from chloro and bromo, to yield a compound of formula (Vlla).
40. A method of making a compound of formula (1) R' / RZ—N : RS J RB a ), R® R® (1) wherein n is an integer from 0 to 1; R' and R? are independently selected from C 1.3 alkyl, allyl, and C 3.5 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N; one of R® and R%is G, one of the remaining and R* is H, and the other is selected from hydrogen, fluoro, and chloro; Gis L’Q; L? is methylene; Q is NR®R® wherein R® is independently selected from hydrogen, C 1. alkyl, C
1.6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5- 9-membered heterocyclyl)C1.s alkylene, and (phenyl) Cy. alkylene; and RY is independently selected from C 1.6 alkyl, C 3.6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)Ci.¢ alkylene, and (phenyl) C1.6 alkylene; or
Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1.3 alkyl; and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
Ci. alkyl, 5-9-membered heterocyclyl, N(C4.s alkyl)}(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)Cy.3 alkylene, phenyl, C4.2-hydroxyalkylene, C,. alkoxy, (Cs.¢ cycloalkyl)-O-, phenyl, (phenyl)C4.; alkylene, and (phenyl)C1.3 alkylene-O- and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting at least one of the compounds of formulae (XX1IHw) and (XXIllow) with a compound of formula (V) RS x? Ww ~ 4 R4 R3 R Ww (XXIw) (XXlllow), wherein W is C(O)H or G, and X? is a suitable leaving group in a coupling reaction with an alkyne. }
41. A method according to claim 40, wherein said W is C(O)H, further comprising performing a reductive amination of said W with an organic base RPR®NH.
42. A method according to claim 40, wherein NR'R? taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, : methylethylamino, ethylpropylamino, or dipropylamino.
43. A method according to claim 42, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino.
44. A method according to claim 43, wherein NR'R? taken together form piperidinyl or pyrrolidinyl.
45. A method according to claim 40, wherein R®is G.
46. A method according to claim 40, wherein R® is G.
47. A method according to claim 40, wherein nis 1.
48. A method according to claim 40, wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.
49. A method according to claim 40, wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
50. A method according to claim 49, wherein substituted Q is selected from N-(C 1 alkyl) piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl.
.
51. A method according to claim 48, wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, : thiazolidine, 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3- carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3'Ibipyridinyl, 4-(3- trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-
carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy- phenyl)-ethyl]-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, [2-(1H- indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2- one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.
52. A method according to claim 40, wherein Q is selected from N- morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxyl, carboxamide, C+.¢ alkyl, 5-9 membered heterocyclyl, N(C4.¢ alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)Cy.3 alkylene, C 1.2- hydroxyalkylene,O(5-9 membered heterocyclyl), C.¢ alkoxy, (Cs. cycloalkyl)-O- , phenyl, (phenyl)C,.; alkylene, and (phenyl)C1.3 alkylene-O- where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halo, nitro, cyano, and Ci. 3 alkyl.
53. A method according to claim 40, wherein Q is substituted with a substituent comprising a C4.¢ heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C4.¢ alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C4.¢ alkylene, tetrazolyl, (triazolyl)C1.¢ alkylene, triazolyl, (pyrrolyl)C4.¢ alkylene, and pyrrolyl.
54. A method according to claim 40, wherein Q is a substituted or unsubstituted N-morpholinyl.
55. A method according to claim 40, wherein n is 1; R' and R? are independently selected from C; alkyl, or taken together
. with the nitrogen to which they are attached, they form a non-aromatic 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N;
one of R® and R% is G, and the remaining and R* are H; . Gis L%Q; L? is methylene; Q is NRER® wherein R® is independently selected from hydrogen, C1.2 alkyl, C; alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C, alkylene, and (phenyl) C; alkylene; and R® is independently selected from Cy. alkyl, C; alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C. alkylene, and (phenyl) Cz alkylene; or Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 13 alkyl; and wherein substituents of Q can be further selected from tert . butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6- membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2-
. hydroxyalkylene, hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally substituted with trifluoromethyl.
56. A method according to claim 40, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, and ] Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
57. A method according to claim 40, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is selected from morpholinyl and piperidinyl.
58. A method according to claim 40, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholiny! or substituted morpholinyl.
59. A method according to claim 40, wherein nis 1, R* is H, one of R® and R%is H, the other one of R® and R® is L?Q, with Q being morpholinyl, and L? as defined in claim 40, and NR'R? taken together form piperidinyl.
60. A method of making a compound of formula (1) R! / R® — B a ), R* rR? 0) wherein n is an integer from 0 to 1; R' and R? are independently selected from C 13 alkyl, allyl, and C 3 5 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N; one of R®, R*, and R® is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro; Gis LQ; L? is methylene; Q is NR°R® wherein R® is independently selected from hydrogen, C 1.6 alkyl, C
3.6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5- g-membered heterocyclyl)C1. alkylene, and (phenyl) C1. alkylene; and R® is independently selected from C 16 alkyl, C 3.6 alkenyl, 6-9 membered . carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1.s alkylene, and (phenyl) C,.¢ alkylene; or
Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S,
. and N; ‘ wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 1.3 alkyl, and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C1. alkyl, 5-9-membered heterocyclyl, N(C1.¢ alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocycly!)C1.3 alkylene, phenyl, Cy.o-hydroxyalkylene, Cz alkoxy, (Css cycloalkyl)-O-, phenyl, (phenyl)C4.3 alkylene, and (phenyl)Ci.3 alkylene-O- and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting a compound of formula (VII) HO RS ——— n R? R3 (VII) with an organic base R'R?NH in the presence of a trialkylphosphonium halide and a base.
61. A method according to claim 60, wherein said trialkylphosphonium halide is (cyanomethyl)trimethylphosphonium iodide, and said base is DIPEA.
62. A method according to claim 60, wherein NR'R? taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or dipropylamino.
63. A method according to claim 60, wherein NR'R? taken together form ‘ piperidinyl, pyrrolidinyl, or diethylamino.
64. A method according to claim 60, wherein NR'R? taken together form piperidinyl or pyrrolidinyl.
65. A method according to claim 60, wherein one of R* and R® is G.
66. A method according to claim 65, wherein R*is G.
67. A method according to claim 66, wherein R® is G.
68. A method according to claim 60, wherein n is 1.
69. A method according to claim 60, wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.
70. A method according to claim 60, wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
71. A method according to claim 60, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, and Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
. 72. A method according to claim 60, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, nis 1, and Q is selected from morpholinyl and piperidinyl.
73. A method according to claim 60, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, n is 1, and Q is morpholinyl or substituted
. morpholinyl.
74. A method according to claim 60, wherein n= 1, Ris H, Ris H, R* is L?Q, with Q being morpholinyl, L as defined in claim 60, and NR'R? taken together form piperidinyl.
75. A method of making a compound of formula (1) R!
/ . R?—N R® mem RB — ), R* R® ) wherein n is an integer from 0 to 1; : R' and R? are independently selected from C 4.3 alkyl, allyl, and C 34 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non- aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N; R* is G, one of the remaining R® and R®is hydrogen, and the other is selected from hydrogen, fluoro, and chloro; Gis L%Q; L? is methylene; Q is NR8R® wherein R® is independently selected from hydrogen, C 1.6 alkyl, C
3.6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5- g-membered heterocyclyl)C1.¢ alkylene, and (phenyl) C1 alkylene; and Ris independently selected from C 1.6 alkyl, C 36 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered . heterocyclyl)C1.s alkylene, and (phenyl) C1.¢ alkylene; i or
Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N; a wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C 4.3 alkyl; : and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C1. alkyl, 5-9-membered heterocyclyl, N(C1.¢ alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C.; alkylene, phenyl, C4_>-hydroxyalkylene, C,.¢ alkoxy, (Ca. cycloalkyl)-O-, phenyl, (phenyl)C4.; alkylene, and (phenyl)Cy.3 alkylene-O- and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a pharmaceutically acceptable salt, ester, or amide thereof, comprising: reacting a compound of formula (XXIlimw) with a compound of formula (V). x2 __/ Ww <7 R* R3 (XXillmw) wherein W is C(O)H or G, and X? is a suitable leaving group in a coupling reaction with an alkyne.
76. A method according to claim 75, wherein said W is C(O)H, further comprising performing a reductive amination of said W with an organic base R°R°NH.
77. A method according to claim 75, wherein NR'R? taken together form piperidinyl, methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino, . methylethylamino, ethylpropylamino, or dipropylamino. "
78. A method according to claim 75, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino.
79. A method according to claim 75, wherein NR'R? taken together form piperidinyl or pyrrolidinyl.
80. A method according to claim 75, wherein nis 1.
81. A method according to claim 75, wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.
82. A method according to claim 75, wherein Q is selected from substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
83. A method according to claim 75, wherein substituted Q is selected from N-(C 1. alkyl) piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl.
84. A method according to claim 75, wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, piperidine-3- carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-[2,3"]bipyridinyl, 4-(3- . trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4- - carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, [2-(3,4-dimethoxy- : phenyi)-ethyl]-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, [2-(1H- indol-3-yl)-ethyl]-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-
one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.
85. A method according to claim 75, wherein Q is selected from N- morpholinyl and N-piperidinyl, optionally substituted with between 1 and 3 ’ substituents selected from hydroxyl, carboxamide, C1. alkyl, 5-9 membered heterocyclyl, N(C1.s alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)Ci.3 alkylene, C 1.2- hydroxyalkylene,O(5-9 membered heterocyclyl), C1. alkoxy, (Cs. cycloalkyl)-O- , phenyl, (phenyl)C1.; alkylene, and (phenyl!)Ci.3 alkylene-O- where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halo, nitro, cyano, and Ci. 3 alkyl.
86. A method according to claim 75, wherein Q is substituted with a substituent comprising a C1. heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C1.s alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)Ci.6 alkylene, tetrazolyl, (triazolyi)C1.¢ alkylene, triazolyl, (pyrrotyl)C1.¢ alkylene, and pyrrolyl.
87. A method according to claim 75, wherein Q is a substituted or unsubstituted N-morpholinyl.
88. A method according to claim 75, wherein nis 1; R' and R? are independently selected from C; alkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic
. 5-6 membered heterocyclyl optionally including an additional heteroatom independently selected from O, S, and N; R3 and R® are H;
Gis LQ; L? is methylene; Q is NR®R® wherein R® is independently selected from hydrogen, C1.2 alkyl, C3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C; alkylene, and (phenyl) C, alkylene; and R® is independently selected from C12 alkyl, Cs alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)Cz alkylene, and (phenyl) C2 alkylene; or Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms selected from O, S, and N; wherein each of the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and carbocycly!l groups may each be independently and optionally substituted with between 1 and 3 substituents selected from methoxy, halo, amino, nitro, hydroxyl, and C 1.3 alkyl; and wherein substituents of Q can be further selected from tert- butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl, NH(6- ° membered heterocyclyl), O(6-membered heterocyclyl), phenyl, C 2 hydroxyalkylene, hydroxy, benzyl and, where each of above . heterocyclyl, phenyl, and alkyl substituent groups of Q may be optionally ) substituted with trifluoromethyl.
89. A method according to claim 75, wherein NR'R? taken together form piperidinyl, pyrrolidinyl, or diethylamino, and
Q is selected from substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
.
90. A method according to claim 75, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, nis 1, and Q is selected from morpholinyl and = piperidinyl.
91. A method according to claim 90, wherein NR'R? taken together form piperidinyl or pyrrolidinyl, nis 1, and Q is morpholinyl or substituted morpholinyl.
92. A method according to claim 75, wherein nis 1, R® is H, R® is H, and R* is L%Q, with Q being morpholinyl, and L? as defined in claim 75, and NR'R? taken together form piperidinyl.
93. A method according to claim 75, wherein nis 1, Ris H, R%is H, W is C(O)H, and X? is choloro or bromo, and compound of formula (V) is 1-but-3- ynyl-piperidine, to form a phenylalkyne.
94. A method according to claim 93, wherein said reacting is performed in the presence of pyrrolidine and at a temperature of about 50°C to form a phenylalkayne.
95. A method according to claim 94, wherein said reacting is performed in the presence of a palladium-containing catalyst and a copper salt.
96. A method according to claim 93, wherein X2is bromo, and said reacting is performed under conditions such that the yield of said phenylalkyne is at least 80%.
. 97. A method according to claim 93, further comprising a reductive amination with R’R°NH of said phenylalkyne to yield a base.
98. A method according to claim 97, wherein said R®*R°NH is morpholine and said base is 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl}-morpholine.
99. A method according to claim 97, further comprising forming a saline + solution with HCI.
100. A method according to claim 99, further comprising obtaining a dihydrochloride salt of said base by crystallization.
101. A method according to claim 100, wherein said base is 4-[3-(4-piperidin- 1-yl-but-1-ynyl)-benzyl]-morpholine.
102. A method according to claim 40, wherein nis 1, R*is H, R¥is H, R® is C(O)H, NR'R? taken together form a piperidinyl, wherein said reacting is performed at room temperature.
103. A method according to claim 40, wherein nis 1, R*is H, R%is H, R% is C(O)H, NR'R? taken together form a piperidinyl, wherein said reacting is performed at room temperature in the presence of a plaadadium-containing catalyst and a copper salt, and said reacting yields a phenylalkyne.
104. A method according to claim 40, wherein nis 1, R*is H, R%is H, R% is C(O)H, NR'R? taken together form a piperidinyl, X? is bromo, wherein said reacting is performed at room temperature in the presence of a palladium- containing catalyst and a copper salt, and said reacting yields a phenylalkyne.
105. A method according to claim 40, wherein nis 1, R*is H, Ris H, R%is C(O)H, NR'R? taken together form a piperidinyl, wherein said reacting is performed at room temperature in the presence of a plaadadium-containing ) catalyst and a copper salt, and said reacting yields a phenylalkyne, further
. comprising a reductive amination with R’R°NH of said phenylalkyne to yield a base.
106. A method according to claim 105, wherein said R*R°NH is morpholine and said base is 4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine :
107. A method according to claim 105, further comprising forming a saline solution with HCI.
108. A method according to claim 107, further comprising obtaining a dihydrochloride salt of said base by crystallization.
109. A method according to claim 108, wherein said base is 4-[4-(4-piperidin- 1-yl-but-1-ynyl)-benzyl}-morpholine.
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