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HK1205115B - Alpha2 adrenoceptor agonists - Google Patents

Alpha2 adrenoceptor agonists Download PDF

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Publication number
HK1205115B
HK1205115B HK15105661.0A HK15105661A HK1205115B HK 1205115 B HK1205115 B HK 1205115B HK 15105661 A HK15105661 A HK 15105661A HK 1205115 B HK1205115 B HK 1205115B
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HK
Hong Kong
Prior art keywords
dihydro
imidazole
methylisochroman
alkyl
hydrochloride
Prior art date
Application number
HK15105661.0A
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Chinese (zh)
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HK1205115A1 (en
Inventor
Tuula Koskelainen
Tero Linnanen
Anna MINKKILÄ
Mikko MÄKELÄ
Antti POHJAKALLIO
Original Assignee
Orion Corporation
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Priority claimed from PCT/FI2013/000013 external-priority patent/WO2013150173A1/en
Publication of HK1205115A1 publication Critical patent/HK1205115A1/en
Publication of HK1205115B publication Critical patent/HK1205115B/en

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Description

Alpha 2 adrenoceptor agonists
Technical Field
The present invention relates to pharmacologically active isochroman and isothiochroman derivatives or pharmaceutically acceptable salts and esters thereof, pharmaceutical compositions containing them and their use as alpha 2 adrenoreceptor agonists, particularly as alpha 2A agonists.
Background
α 2-adrenoceptor (α)2) Are G-protein coupled cell membrane receptors widely distributed in humans, subdivided into three subtypes, α 2A, α 2B, and α 2C (Bylund et al, mol. Pharmacol.,1992,42, 1-5). α 2 adrenergic receptors have diverse biological functions, and compounds acting on these receptors are attractive targets for various diseases (Goodman)&Gilman's The Pharmacological Basis of Therapeutics, 12 th edition, 2011, Chapter 12; Brede et al biol. cell 2004,96, 343-.
U.S. patent No. 3,438,995 discloses certain isochroman and isothiochroman derivatives and discloses their use as rubber accelerators, antioxidants, corrosion inhibitors, Central Nervous System (CNS) depressants and anti-inflammatory agents. WO 2007/085558 discloses various imidazole derivatives useful as TAAR ligands for the treatment of a variety of disorders including a variety of CNS disorders.
Summary of The Invention
It is an object of the present invention to provide novel compounds having agonist activity at the adrenergic α -receptor, in particular the α 2A receptor, which compounds are useful for the treatment of disorders, conditions or diseases such as delirium (e.g. hyperactive delirium), insomnia, ADHD, benzodiazepines(or alcohol or opioid or tobacco) withdrawal, premature ejaculation, hypertension, tachycardia, restless leg syndrome, muscle spasticity, hot flashes, anxiety, post traumatic stress disorder, pain, chronic pelvic pain syndrome and breakthrough cancer pain, as well as other possible conditions treatable with adrenergic α 2 agonist, especially α 2A agonist.
The compounds of the invention are orally active, brain penetrating selective alpha 2A agonists. They have improved α 2A activity and/or α 2A agonistic selectivity and/or increased potency relative to other α receptors and improved metabolism in liver cells in vitro, all of which provide a modest duration of action in vivo. In addition to the above pharmacological effects, the compounds of the present invention have fewer side effects due to small CYP interactions.
The above and other features and advantages of the present teachings will be more fully understood from the following description and appended claims.
Detailed Description
The present invention relates to novel isochroman and isothiochroman derivatives having the general formula I:
wherein
X is O or S;
R1is hydroxy, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, Ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, cyano, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkenyloxy (C)2-C6) Alkenyl, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy-halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy-halo (C)1-C6) Alkoxy, carboxyl, (C)1-C6) Alkyl- (C ═ O) -, (C)1-C6) Alkoxy- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-, halo (C)1-C6) Alkyl- (C ═ O) -, halo (C)1-C6) Alkoxy- (C ═ O) -, (R)6)2N-、(R6)2N-(C1-C6) Alkyl, (R)6)2N-(C＝O)-、R6-(C＝O)-N(R6)-(C＝O)-、R6-(O＝S＝O)-N(R6)-(C＝O)-、 R6-(C＝O)-N(R6)-(O＝S＝O)-、R6-(O＝S＝O)-N(R6)-(O＝S＝O)-、(R6)2N-N-、 (R6)N＝N-、(R6)2N-O-、(R6)O-N(R6)-、(C1-C6) alkyl-S-, (C)2-C6) alkenyl-S- (C)2-C6) An alkenyl group,Hydroxy (C)1-C6) alkyl-S-, hydroxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, halo (C)1-C6) alkyl-S-, halo (C)1-C6) alkyl-S- (C)1-C6) Alkyl, halo (C)1-C6) alkyl-S-halo (C)1-C6) Alkyl radical, R6-(O＝S)-、(R6)2N-(O＝S)-、 R6-(O＝S＝O)-、(R6)2N- (O ═ S ═ O) -, phenyl-O-, heteroaryl-O-, phenyl-N (R ═ O) -, and phenyl-N6) -, heteroaryl-N (R)6) -or heteroaryl (C)1-C6) An alkyl group;
R2is H, hydroxy, oxo, fluoro, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, Ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, cyano, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkenyloxy (C)2-C6) Alkenyl, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy-halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy-halo (C)1-C6) Alkoxy, carboxyl, (C)1-C6) Alkyl- (C ═ O) -, (C)1-C6) Alkoxy- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-, halogenGeneration (C)1-C6) Alkyl- (C ═ O) -, halo (C)1-C6) Alkoxy- (C ═ O) -, (R)6)2N-、(R6)2N-(C1-C6) Alkyl, (R)6)2N-(C＝O)-、R6-(C＝O)-N(R6)-(C＝O)-、R6-(O＝S＝O)-N(R6)-(C＝O)-、 R6-(C＝O)-N(R6)-(O＝S＝O)-、R6-(O＝S＝O)-N(R6)-(O＝S＝O)-、(R6)2N-N-、 (R6)N＝N-、(R6)2N-O-、(R6)O＝N-、(C1-C6) alkyl-S-, (C)2-C6) alkenyl-S- (C)2-C6) Alkenyl, hydroxy (C)1-C6) alkyl-S-, hydroxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, halo (C)1-C6) alkyl-S-, halo (C)1-C6) alkyl-S- (C)1-C6) Alkyl, halo (C)1-C6) alkyl-S-halo (C)1-C6) Alkyl radical, R6-(O＝S)-、(R6)2N-(O＝S)-、R6-(O＝S＝O)-、(R6)2N- (O ═ S ═ O) -, phenyl-O-, heteroaryl-O-, phenyl-N (R ═ O) -, and phenyl-N6) -, heteroaryl-N (R)6) -or heteroaryl (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl or cyclic (C)3-C6) An alkyl group;
R4is H, hydroxy, halogen, (C)1-C2) Alkyl or halo (C)1-C2) An alkyl group;
R5is H, hydroxy, halogen, (C)1-C6) Alkyl, halo (C)1-C2) Alkyl, ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, phenyl or heteroaryl; and is
R6Independently at each occurrence is H, (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl hydroxy (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, or R6And R6Together with the atoms to which they are attached form a fused (condensed)4, 5,6 or 7 membered saturated or unsaturated carbocyclic ring or a fused 4,5,6 or 7 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, oxo, halogen, (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl or halo (C)1-C6) Alkyl-;
or R1And R2Together with the carbon ring atoms to which they are attached form a fused 4,5,6 or 7 membered saturated or unsaturated carbocyclic ring or a fused 4,5,6 or 7 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, oxo, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl or halo (C)1-C6) An alkyl group;
or R2And R3Together with the carbon ring atoms to which they are attached form a fused 4,5,6 or 7 membered saturated or unsaturated carbocyclic ring or a fused 4,5,6 or 7 membered saturated or unsaturated ring containing 1 or 2 members of the group(iii) heterocycle of a heteroatom from N, O and S, wherein the carbocycle or heterocycle is unsubstituted or substituted with 1 or 2 substituents, each substituent independently being hydroxy, oxo, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl or halo (C)1-C6) An alkyl group.
Within a possible sub-group of the compounds of the formula I,
R1is hydroxy, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, Ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, cyano, (C)1-C2) Alkoxy (C)1-C2) Alkyl, hydroxy (C)1-C2) Alkoxy, halo (C)1-C2) Alkoxy (C)1-C2) Alkyl, halo (C)1-C2) Alkoxy-halo (C)1-C2) Alkyl, (C)1-C2) Alkoxy-halo (C)1-C2) Alkoxy, carboxyl, (C)1-C3) Alkyl- (C ═ O) -, (C)1-C3) Alkoxy- (C ═ O) -, halo (C)1-C3) Alkyl- (C ═ O) -, halo (C)1-C3) Alkoxy- (C ═ O) -, (R)6)2N-(C1-C2) Alkyl, (R)6)2N-(C＝O)-、(C1-C6) alkyl-S-, R6-(O＝S)-、R6-(O＝S＝O)-、(R6)2N- (O ═ S ═ O) -, phenyl-O-, heteroaryl-O-, or heteroaryl (C)1-C2) An alkyl group;
R2is H, hydroxy, oxo, fluoro, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy or cyano;
R3is H, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl or cyclic (C)3-C6) An alkyl group;
R4is H, fluorine, (C)1-C2) Alkyl or halo (C)1-C2) An alkyl group;
R5is H, hydroxy, halogen, (C)1-C6) Alkyl, halo (C)1-C2) Alkyl, ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, phenyl or heteroaryl; and is
R6Independently at each occurrence is H, (C)1-C3) Alkyl, or R6And R6Together with the atoms to which they are attached form a fused 5,6 or 7 membered saturated or unsaturated carbocyclic ring or a fused 5,6 or 7 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, oxo, halogen, (C)1-C2) Alkyl or halo (C)1-C2) Alkyl-;
or R1And R2Together with the carbon ring atoms to which they are attached form a fused 5,6 or 7 membered saturated or unsaturated carbocyclic ring or a fused 5,6 or 7 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, oxo, halogen, (C) C1-C2) Alkyl, (C)1-C2) Alkoxy, hydroxy (C)1-C2) Alkyl or halo (C)1-C2) An alkyl group.
In a further possible subgroup of the compounds of the formula I,
R1is hydroxy, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, Ring (C)3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, cyano, (R)6)2N-(C＝O)-、(C1-C6) alkyl-S-or heteroaryl; and/or
R2Is H or (C)1-C6) An alkyl group; and/or
R3Is H, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) An alkyl group; and/or
R4Is H or (C)1-C2) An alkyl group; and/or
R5Is H, hydroxy, halogen, (C)1-C6) Alkyl or (C)1-C6) An alkoxy group; and/or
R6Is H; and/or
R1And R2Together with the carbon ring atoms to which they are attached form a fused 6-or 7-membered saturated or unsaturated carbocyclic ring; for example
R1Is hydroxy, halogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)1-C3) Alkoxy, halo (C)1-C3) Alkoxy or hydroxy (C)1-C3) An alkyl group; and/or
R2Is H or (C)1-C2) An alkyl group; and/or
R3Is H, (C)1-C3) Alkyl or halo (C)1-C3) An alkyl group; and/or
R4Is H or methyl; and/or
R5Is H, halogen or (C)1-C2) An alkyl group; and/or
R1And R2Together with the carbon ring atoms to which they are attached form a fused 6-or 7-membered saturated or unsaturated carbocyclic ring; for example
R1Is hydroxy, halogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)1-C3) Alkoxy, halo (C)1-C3) Alkoxy or hydroxy (C)1-C3) An alkyl group; and/or
R2Is H or (C)1-C2) An alkyl group; and/or
R3Is H, (C)1-C3) Alkyl or halo (C)1-C3) An alkyl group; and/or
R4Is H or methyl; and/or
R5Is H, halogen or (C)1-C2) An alkyl group; for example
R1Is halogen, (C)1-C2) Alkyl, halo (C)1-C2) Alkyl, (C)1-C2) Alkoxy or halo (C)1-C2) An alkoxy group; and/or
R2Is H; and/or
R3Is H or (C)1-C2) An alkyl group; and/or
R4Is H; and/or
R5Is H.
In a further possible subgroup of the compounds of formula I, X is O.
In another possible subgroup of the compounds of formula I, the compounds are 2- (5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carbonitrile, 2- (5-allylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-vinyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-ethyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-ethyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate, 2- (5-ethyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole fumarate, 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-ol, (1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-yl) methanol, 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-chloro-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) -1-methylisochroman-5-yl) -2, the slower eluting isomer of 2-dimethylpropan-1-ol, the faster eluting isomer of 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) -1-methylisochroman-5-yl) -2, 2-dimethylpropan-1-ol, 2- (5-ethynylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3-ethyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (1-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2-dimethylpropan-1-ol, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate, 2- (5-iodoisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3-methyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, and mixtures thereof, 2- (5-bromo-4-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, the faster eluting isomer of 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, the slower eluting isomer of 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -1,3, 5-trimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-cyclopropylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, or mixtures thereof, 2- (3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloro-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3-methyl-isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2-methyl-1-, 2- (1,3, 5-trimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3S) -5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3S) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3S) -3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-isopropylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-fluoroisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- ((3R) -5-ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate, 2- (3-ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2-methyl-3-ethyl-3-methylisochroman-1-yl-imidazole hemifumarate, 2- (3-ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2,2- ((3R) -3, 5-diethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate, 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate, 2- ((3R) -3-methyl-5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-fluoro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-ethoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, and pharmaceutically acceptable salts thereof, 2- ((3S) -5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (furan-3-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (prop-1-yn-1-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carboxamide, 2- (3,7,8,9,10,10 a-hexahydro-1H-cyclohepta [ de ] isochromen-3-yl) -4, 5-dihydro-1H-imidazole, the slower eluting isomer of 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-yl) ethanol, 2- (5, 7-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (7-bromo-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (7-methoxy-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3, 5-dimethylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromoisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-1-methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5, 7-dibromo-3-ethylisothroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, enantiomer hydrochloride of 2-5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxy-1-methylisothroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxyisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-methoxy-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, salts of the same, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same, 2- (5- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-ethyl-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methyl-3- (methoxymethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (4, 5-dihydro-1H-imidazol-2-yl) -5-methylisochroman-7-ol hydrobromide, 1- (4, 5-dihydro-1H-imidazol-2-yl) -3-ethylisochroman-5-ol Hydrochloride, enantiomer-2 of 2- (5-methoxy-3- (2,2, 2-trifluoroethyl) methylisothroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (1, 5-dimethylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, enantiomer-1 hydrochloride of 2- (3-ethylisothroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3- (2-fluoroethyl) -5-methylisothroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer, 2-5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (7-methoxy-3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3) -5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (5- (methylthio) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3) -5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- ((3R) -3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, enantiomer-2 hydrochloride of 5-dihydro-1H-imidazole, 2- (5- (difluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- ((3R) -3-ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, enantiomer-1 hydrochloride of 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5- (difluoromethoxy) -3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, salts of the same, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same, 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-1 hydrochloride, 2- (3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (1-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (difluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (1-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, an enantiomer of 5-dihydro-1H-imidazole, 2- (3-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (3-ethyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, or an enantiomer of 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole.
The terms used herein have the meanings indicated below. The term "at least one" used in the following sense means one or several, for example one. For example, the term "at least one halogen" refers to one or several halogens, e.g., three, two, or one halogen, such as three halogens.
The term "hydroxy" as used herein, by itself or as part of another group, refers to an-OH group.
The term "halo" or "halogen", as employed herein by itself or as part of another group, refers to fluorine, chlorine, bromine or iodine.
The term "(C) as used herein1-C6) Alkyl group "," (C)1-C4) Alkyl group "," (C)1-C3) Alkyl "by itself or as part of another group refers to a saturated straight or branched carbon chain having 1-6, 1-4, 1-3, and 1-2 carbon atoms, respectively. (C)1-C6) Alkyl, (C)1-C4) Alkyl, (C)1-C3) Alkyl and (C)1-C2) Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.
The term "(C) as used herein2-C6) Alkenyl "and" (C)2-C3) Alkenyl ", by itself or as part of another group, refers to a straight or branched carbon chain having 2 to 6 and 2 to 3 carbon atoms, respectively, and containing at least one carbon-carbon double bond. (C)2-C6) Alkenyl and (C)2-C3) Representative examples of alkenyl groups include, but are not limited to, vinyl and prop-2-en-1-yl.
The term "(C) as used herein2-C6) Alkynyl, by itself or as part of another group, means a straight or branched chain carbon having 2,3,4, 5 or 6 carbon atoms and containing at least one carbon-carbon triple bondAnd (3) a chain. (C)2-C6) Representative examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-yn-1-yl, and prop-2-ynyl.
The term "Ring (C) as used herein3-C6) Alkyl "by itself or as part of another group, refers to a saturated hydrocarbon group having a cyclic moiety and containing 3,4,5 or 6 carbon atoms. Ring (C)3-C6) Representative examples of alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "(C) as used herein1-C6) Alkoxy "and" (C)1-C4) Alkoxy "by itself or as part of another group, respectively, means (C) as defined herein1-C6) Alkyl or (C)1-C4) The alkyl group is attached to the parent molecular moiety through an oxygen atom. (C)1-C6) Alkoxy and (C)1-C4) Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-dimethylpropoxy, 3-methylbutoxy, and n-hexyloxy.
The term "halo (C) as used herein1-C6) Alkyl ", by itself or as part of another group, means that at least one halogen as defined herein passes through (C) as defined herein1-C6) An alkyl group is attached to the parent molecular moiety. When there are several halogens, the halogens may be attached to the same or different carbon atoms and the halogens may be the same or different. Halo (C)1-C6) Representative examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2, 2-trifluoroethyl, 1,2, 2-trifluoroethyl, 2-chloropropyl, 3-fluoropropyl, 3-bromopropyl, 1, 3-difluoropropyl, and 3,3, 3-trifluoropropyl.
The term "halo (C) as used herein1-C6) Alkoxy ", by itself or as part of another group, means that at least one halogen passes through (C) as defined herein1-C6) The alkoxy group is attached to the parent molecular moiety. When there are several halogens, the halogens may be attached to the same or different carbon atoms and the halogens may be the same or different. Halo (C)1-C6) Representative examples of alkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, trifluoromethoxy, 2-bromoethoxy, 2,2, 2-trifluoroethoxy, 3-fluoropropoxy, 2-chloropropoxy, 3,3, 3-trifluoropropoxy, and 4-fluorobutoxy.
The term "halo (C) as used herein1-C6) Alkoxy (C)1-C6) Alkyl ", by itself or as part of another group, means halo (C) as defined herein1-C6) Alkoxy is defined by (C)1-C6) An alkyl group is attached to the parent molecular moiety.
The term "halo (C) as used herein1-C6) Alkoxy-halo (C)1-C6) Alkyl ", by itself or as part of another group, means halo (C) as defined herein1-C6) Alkoxy is through halo (C) as defined herein1-C6) An alkyl group is attached to the parent molecular moiety.
The term "(C) as used herein1-C6) Alkoxy-halo (C)1-C6) Alkoxy ", by itself or as part of another group, means (C) as defined herein1-C6) Alkoxy is through halo (C) as defined herein1-C6) The alkoxy group is attached to the parent molecular moiety.
The term "carboxy", as used herein, by itself or as part of another group, refers to a-COOH group.
The term "cyano", as employed herein, by itself or as part of another group, refers to the group — CN.
The term "oxo", as employed herein, by itself or as part of another group, refers to an ═ O group.
The term "hydroxy (C) as used herein1-C6) Alkyl "by itself or as part of another group, means that at least one hydroxyl group as defined herein passes through (C) as defined herein1-C6) An alkyl group is attached to the parent molecular moiety. Hydroxy (C)1-C6) Representative examples of alkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, 1-hydroxy-1-methylpropyl, and 1-hydroxy-2, 2-dimethyl-propan-1-yl.
The term "hydroxy (C) as used herein2-C6) Alkenyl ", by itself or as part of another group, means that at least one hydroxyl group as defined herein passes through (C) as defined herein2-C6) An alkenyl group is attached to the parent molecular moiety. Hydroxy (C)2-C6) Representative examples of alkenyl groups include, but are not limited to, 1-hydroxyvinyl, 2-hydroxyvinyl, and 1-hydroxyprop-2-enyl.
The term "(C) as used herein1-C6) Alkoxy (C)1-C6) Alkyl ", by itself or as part of another group, means at least one (C) as defined herein1-C6) Alkoxy is defined by (C)1-C6) An alkyl group is attached to the parent molecular moiety. There are a plurality of (C)1-C6) When it is an alkoxy group, (C)1-C6) The alkoxy groups may be the same or different. (C)1-C6) Alkoxy (C)1-C6) Representative examples of alkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-dimethoxyethyl, 1-methyl-2-propoxyethyl, 1-methoxy-1-methylethyl, and 4-methoxybutyl.
The term "hydroxy (C) as used herein1-C6) Alkoxy "by itself or as part of another group, means that at least one hydroxyl group as defined herein passes through (C) as defined herein1-C6) The alkoxy group is attached to the parent molecular moiety. Hydroxy (C)1-C6) Representative examples of alkoxy groups include, but are not limited to, hydroxymethoxy, dihydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxybutoxy, and 2-hydroxy-1-methylethoxy.
The term "hydroxy (C) as used herein1-C6) Alkoxy (C)1-C6) Alkyl ", by itself or as part of another group, means hydroxy (C) as defined herein1-C6) Alkoxy is defined by (C)1-C6) An alkyl group is attached to the parent molecular moiety.
The term "(C) as used herein1-C6) Alkoxy (C)1-C6) Alkoxy "by itself or as part of another group, means at least one (C) as defined herein1-C6) Alkoxy is defined by (C)1-C6) The alkoxy group is attached to the parent molecular moiety. (C)1-C6) The alkoxy groups may be the same or different. (C)1-C6) Alkoxy (C)1-C6) Representative examples of alkoxy groups include, but are not limited to, methoxymethoxy, propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy, 2-dimethoxyethoxy, 1-methyl-2-propoxyethoxy, 2-methoxypropoxy, and 4-methoxybutoxy.
The term "(C) as used herein1-C6) Alkoxy (C)1-C6) Alkoxy (C)1-C6) Alkyl ", by itself or as part of another group, means (C) as defined herein1-C6) Alkoxy (C)1-C6) Alkoxy is defined by (C)1-C6) An alkyl group is attached to the parent molecular moiety.
The term "phenyl", as employed herein, by itself or as part of another group, refers to a 6-membered aromatic carbocyclic ring, which may be unsubstituted or substituted by 1 or 2Substituted with substituents each independently being hydroxy, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy or halo (C)1-C4) An alkyl group.
The term "heteroaryl", as used herein by itself or as part of another group, refers to a3 to 7 membered aromatic monocyclic ring system containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. The heteroaryl group may be unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, halogen, oxo, (C)1-C4) Alkyl, (C)1-C4) Alkoxy or halo (C)1-C4) An alkyl group. Representative examples of heteroaryl groups include, but are not limited to, furyl, thienyl, and pyrazolyl.
The term "heteroaryl (C) as used herein1-C6) Alkyl ", by itself or as part of another group, means heteroaryl as defined herein through (C) as defined herein1-C6) An alkyl group is attached to the parent molecular moiety.
The term "(C) as used herein2-C6) Alkenyloxy "by itself or as part of another group, means (C) as defined herein2-C6) The alkenyl group is attached to the parent molecular moiety through an oxygen atom. (C)2-C6) Representative examples of alkenyloxy include, but are not limited to, vinyloxy, prop-2-enyloxy, but-2-enyloxy, and hex-3-enyloxy.
The term "(C) as used herein2-C6) Alkenyloxy (C)2-C6) Alkenyl "means at least one (C) as defined herein2-C6) Alkenyloxy is defined by (C) as defined herein2-C6) The alkenyl group is attached to the parent molecular moiety. There are a plurality of (C)2-C6) In the case of alkenyloxy radicals, (C)2-C6) The alkenyloxy groups may be the same or different. (C)2-C6) Alkenyloxy (C)2-C6) Representative examples of alkenyl groups include, but are not limited to, vinyloxyMonovinyl and prop-2-enyloxyethylene groups.
The expression "compound of the invention" as used herein refers to a compound of formula I.
"pharmaceutically acceptable salts" according to the invention include the therapeutically active, non-toxic base and acid salt forms, which the compounds of formula I are capable of forming with organic and inorganic bases and acids. Representative examples of pharmaceutically acceptable base addition salt forms, e.g., metal or amine salts, include, but are not limited to, ammonium, lithium, sodium, potassium, calcium, magnesium, aluminum, and zinc salts, salts with organic bases such as N-methyl-D-glucosamine, hydrabamine salts and salts with amino acids such as arginine, lysine, and the like. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chloride, bromide, sulfate, nitrate, phosphate, sulfonate, methanesulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate, acetate, oxalate, fumarate, hemi-fumarate, and succinate.
Pharmaceutically acceptable esters, where applicable, may be prepared by known methods using pharmaceutically acceptable acids which are conventional in the pharmaceutical art and retain the pharmacological properties of the free form. Non-limiting examples of such esters include esters of aliphatic or aromatic alcohols. Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and benzyl esters.
The present invention includes within its scope all possible geometric isomers of the compounds, such as the Z and E isomers (cis and trans isomers), as well as all possible optical isomers of the compounds of the present invention, such as diastereomers and enantiomers. In addition, the present invention includes within its scope individual isomers and any mixtures thereof, such as racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting materials, or they may be separated after preparation of the final compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers, from mixtures thereof, conventional resolution methods, e.g. fractional crystallization or preparative chiral chromatography, may be applied.
Compounds of formula I may be prepared by a variety of synthetic routes analogous to or according to methods known in the literature using appropriate starting materials, for example by reacting 2-phenylethanol or 2-phenylethanol with an aldehyde or acetal or according to other known methods (Larghi et al, Synthesis,2006,2, 187-220; Ishibashi et al, J. Heterocyclic Chem 1985,22, 1527-1529). Imidazolenes can be prepared, for example, by reacting ethane-1, 2-diamine with an ester or aldehyde (Gentili et al, J.Med.chem., 2003,46, 2169-.
The starting materials described below are commercially available or can be prepared by synthetic routes known in the literature, for example by reducing carboxylic acids, carboxylic esters or ketones, by opening the corresponding epoxides with metallated aromatics, by enzymatic hydrolysis or by chiral separation of the racemic alcohols (Bunnet et al, J.org.chem., 1962,27, 3836-3843; Mangas-S-nchez et al, Organic Lett.,2010,12, 3498-3501;et al Tetrahedron Lett.,2000,41, 1171-.
In general, compounds of formula I can be prepared analogously or according to scheme 1 below:
scheme 1.
Wherein a) SOCl2、MeOH，b)NaBH4C) TFA, 2-dihydroxyacetic acid, d) ethylenediamine, Me3Al，e)Pd(PPh3)4、HOCH2SnBu3。
One skilled in the art will recognize that any of the starting materials or intermediates in the reactions described above, if desired, may be protected in a manner known in the art. Subsequently, any protected functional groups may be deprotected in a manner known in the art.
The synthetic routes described above are intended to illustrate the preparation of the compounds of the formula I and are in no way limited thereto, i.e. to the general knowledge of the person skilled in the art, there are other possible synthetic methods.
The compounds of formula I may be converted, if desired, into their pharmaceutically acceptable salt or ester forms using methods known in the art.
The present invention will be explained in more detail by the following examples. The examples are for illustrative purposes only and do not limit the scope of the invention as defined in the claims.
The following general abbreviations are used: EtOAc, DCM, HCl, MeOH, methanol, TFA, trifluoroacetic acid, THF, tetrahydrofuran, Et2O-ethyl ether, SiO2Commercial silica (CAS 112926-00-8 or similar), hrs hour, RT room temperature for chromatographic purposes. Microwave heating was carried out using a Biotage microwave reactor. The structure of the product is composed of1H NMR confirmed.1H NMR resonance was measured with a Bruker Avance II 400MHz spectrometer and chemical shifts quoted as parts per million (ppm) shift of the selected compound to low field relative to tetramethylsilane as an internal standard.
Separation Process A
The reaction mixture is diluted with an organic solvent (typically DCM or EtOAc) and washed with water or aqueous base (typically NH)4OH、NaHCO3Or NaOH) and washed with a drying agent (typically Na)2SO4Or K2CO3) Dried, filtered and evaporated.
Separation method B
The reaction mixture is diluted with an organic solvent (typically DCM or EtOAc) and washed with water or aqueous acid (typically HCl or KHSO)4Aqueous solution) and washed with a drying agent (typically Na)2SO4Or K2CO3) Dried, filtered and evaporated.
Separation method C
The crude product is dissolved in an organic solvent (typically DCM or EtOAc) and added in a solvent (typically EtOAc or Et)2O) and evaporating the solvent or filtering the precipitated solid.
Separation method D
The precipitated solid is filtered, washed in a defined solvent or solvent mixture or recrystallised to yield the title compound.
Separation method E
The crude product was passed through a column (commercial SiO2Or CombiFlash instruments with disposable Redisep columns from Teledyne ISCO) are eluted with a solvent mixture, typically EtOAc in heptane or MeOH in DCM, eventually containing triethylamine, ammonia or other basic modifiers, in a ratio of 0/100/0 to 45/45/10, typically 5/94/1.
Separation method F
The reaction mixture was applied to an acidic ion exchange column and the column was washed with MeOH. With a composition containing 10% NH3The compound was eluted with aqueous solution, triethylamine or similar amine base in MeOH, filtered and evaporated.
Separation Process G
The crude product was eluted with a solvent mixture through a reverse phase column (combiFlash instrument with a disposable Redisep Rf18 column, typically from Teledyne ISCO). Typically, a gradient of water/acetonitrile or methanol containing 0.1% ammonia or formic acid is used as eluent.
Separation Process H
The separation was accomplished by preparative HPLC using an Agilent HPLC/UV purification system set-up equipped with a Chiracel 1A column or an OD-H column. Typically, iso-propanol/heptane or hexane containing 0.1% diethylamine or 0.1% TFA in isocratic runs of ratios 70/30 to 99/1 was used as eluent.
Separation method I
The residue is taken up in an aqueous solution (typically NH)4OH、NaHCO3Or NaOH) and the solution is washed with an organic solvent (typically EtOAc, DCM or Et)2O) washing. The aqueous phase is then made acidic by addition of an acid (typically HCl) and treated with an organic solvent (typically Et)2O, EtOAc or DCM). The extract is dried (typically Na)2SO4Or K2CO3) Filtered and evaporated.
Separation method J
The residue is taken up in aqueous acidic solution (typically HCl) and the solution is taken up in organic solution (typically EtOAc, DCM or Et)2O) washing. The aqueous phase is then purified by addition of an aqueous alkaline solution (typically NH)4OH、NaHCO3Or NaOH) and with an organic solvent (typically Et)2O, EtOAc or DCM). The extract is dried (typically Na)2SO4Or K2CO3) Filtered and evaporated.
Separation method K
The reaction mixture was evaporated to dryness and dissolved in MeOH. This was applied to a pre-washed (MeOH) thiourea column. The compound was eluted with MeOH and evaporated.
Separation Process L
The enantiomers were separated using a preparative HPLC/UV purification system equipped with a Phenomenex LUX amyloase-2 column. Typically, an isocratic run of n-hexane/ethanol/formic acid 70/30/0.1 was used as eluent, and the fractions were collected and immediately acidified with aqueous HCl.
Separation method M
The separation was accomplished using a thumb SFC 80 preparative supercritical fluid HPLC system typically equipped with a Chiralpak AD-H column. Typically, carbon dioxide/methanol 93/7 to 90/10 run at equal degrees are used as eluents.
Preparation of the Compounds of the invention
Example 1 2- (5-Methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis Process A
Synthesis method A1 of 5-methylisochroman-1-carboxylic acid
A mixture of 2- (2-methylphenyl) ethanol (2g), TFA (10ml) and 2, 2-dihydroxyacetic acid (1.5g) was refluxed for 23hrs and the volatiles were evaporated. Isolation method I provided the title compound (2.6g) as an off-white solid. Alternatively, sulfuric acid can be used in the cyclization.
Synthesis method A2 methyl 5-methylisochroman-1-carboxylate
A mixture of 5-methylisochroman-1-carboxylic acid (1g), methanol (20ml) and trimethylchlorosilane (2ml) was stirred for 1.5hrs and the volatiles were evaporated. Isolation of method E provided the title compound (0.5g) as a yellowish oil. Or sulfuric acid can be used instead of trimethylchlorosilane.
Synthesis method A3 2- (5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
To a stirred solution of ethylenediamine (0.29ml), trimethylaluminum (2M in heptane, 2.2ml) and toluene (10ml) cooled in a 10 minute ice bath was added a mixture of methyl 7-bromoisochroman-1-carboxylate (0.5g) and toluene (10ml) and the reaction mixture was refluxed for 6 hrs. Water (2ml), methanol (5ml) and DCM (5ml) were added, the mixture was refluxed for 15min and the precipitate was filtered off. The organics were evaporated and the title compound (0.38g) was isolated by isolation D (2-methoxy-2-methylpropane/MeOH).
1H NMR(CDCl3)ppm 7.16(s,1H),7.02(s,2H),5.42(s,1H),4.20(ddd, 1H),3.94(br s,1H),3.84(td,2H),3.39(br s,2H),3.03(ddd,1H),2.68(d,1H), 2.30(s,3H).
Example 2- (5-Bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (2-bromophenyl) ethanol (200mg) using the procedure of Synthesis A and isolation of methods A and E. (yield 80 mg).
1H NMR(CDCl3)ppm 7.45(d,1H),7.30(d,1H),6.99-7.10(m,1H), 5.72(s,1H),4.19(ddd,1H),3.67-3.84(m,5H),2.69-2.93(m,2H).
Example 3 2- (1, 5-Dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of NaH (0.77g), methyl 5-methylisochroman-1-carboxylate (3g, Synthesis A), and THF (40ml) was stirred at ice bath temperature for 75min, methyl iodide (2.3ml) was added and the mixture was stirred at ambient temperature for 3 hrs. Intermediate methyl 1, 5-dimethylisochroman-1-carboxylate (2.5g) was purified by isolation method a and the title compound was synthesized using the procedure of synthesis method a, step 3 and isolation method D (2-propanol/heptane). (yield 1.0 g).
1H NMR(CD3OD)ppm 7.00-7.18(m,3H),3.99(t,2H),3.54(br s,4H), 2.62-2.87(m,2H),2.24(s,3H),1.70(s,3H).
Example 4- (5-Chloroisoprochrome-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method B
A mixture of 2- (2-chlorophenyl) ethanol (1.0g), ethyl 2, 2-diethoxyacetate (1.7g), titanium (IV) chloride (2.0ml) and 1, 2-dichloroethane (15ml) was refluxed for 1 hr. The intermediate ethyl 5-chloroisochroman-1-carboxylate (0.41g) was purified by separation methods B and E and the title compound was synthesized using the procedure of synthesis method a 3. Alternatively, boron trifluoride etherate can be used instead of titanium (IV) chloride. (yield 0.36 g).
1H NMR(CDCl3)ppm 7.20-7.40(m,2H,CHCl3),7.09-7.20(m,1H), 5.41(s,1H),4.23(ddd,1H),3.77-4.00(m,3H),3.28-3.51(m,2H),2.77- 3.01(m,2H).
Example 5 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carbonitrile
A mixture of 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole (50mg), dicyano zinc (25mg), bis (tri-tert-butylphosphino) palladium (0) (3mg) and DMF (2ml) was stirred in a microwave reactor at 160 ℃ for 30 minutes. The title compound was purified using separation methods F and G. (yield 22 mg).
1H NMR(CD3OD)ppm 7.63(dd,1H),7.53(d,1H),7.35(t,1H),4.26 (ddd,1H),3.92(ddd,1H),3.51-3.72(m,4H),3.07-3.22(m,1H),2.89-3.03 (m,1H).
Example 6 2- (5-Allylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method C
To a mixture of 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole (50mg), allyltributyltin (69.9mg), CsF (70.6mg), and bis (tri-tert-butylphosphino) palladium (3.24mg) was added dioxane (2ml) and DMF (0.5 ml). The reaction mixture is treated with N2Degassed and heated in a microwave oven at 160 ℃ for 30 min. The title compound was purified by applying methods F and G. (yield 5.8 mg).
1H NMR(CD3OD)ppm 6.96-7.21(m,3H),5.94(ddt,1H),4.92-5.08 (m,2H),4.22(ddd,1H),3.81(ddd,1H),3.52(s,4H),3.34-3.35(m,2H),2.93 (ddd,1H),2.72(dt,1H).
Example 7 2- (5-Vinylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (100mg) using the procedure of synthesis method C and purified using isolation methods F and G. (yield 5 mg).
1H NMR(CDCl3)ppm 7.38-7.48(m,1H),7.15-7.30(m,1H,CHCl3), 6.80-7.05(m,2H),5.74(dd,1H),5.35(dd,1H),4.25(ddd,1H),3.50-3.85(m, 5H),2.80-3.10(m,1H),2.72–2.85(m,1H).
Example 8 2- (5-Ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method D
To a solution of 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (100mg), ethylboronic acid (56.2 mg), (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium (II) and CH2Cl2Dioxane (4ml) and DMF (1ml) were added to a mixture of complex (1:1) (13mg) and CsF (108 mg). Mixing the mixture with N2Degassed and heated in a microwave oven at 100 ℃ for 30min and at 150 ℃ for 30 min. The title compound was purified by separation methods J and G. (yield 6.1 mg).
1H NMR(CD3OD)ppm 6.96-7.17(m,3H),5.39(s,1H),4.24(ddd,1H), 3.77-3.89(m,1H),3.49-3.69(m,4H),2.87-3.01(m,1H),2.73(dt,1H), 2.63(q,2H),1.20(t,3H).
Example 8HCl salt 2- (5-Ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride
Salt formation method A
To a solution of the compound from example 8 (1g) in ethanol (15ml) was added 4M hydrogen chloride in dioxane (160mg) and the mixture was heated under reflux, cooled and evaporated to give the title compound (1.1 g). Or other solvents, temperatures and hydrogen chloride sources can be used, or the product filtered from solution or washed with other organic solvents.
1H NMR(DMSO-d6)ppm 10.72(s,2H),7.14–7.24(m,3H),5.91(s, 1H),4.16–4.21(m,1H),3.78-3.90(m,5H),2.89–2.96(m,1H),2.69-2.78(m, 1H),2.60(q,2H),1.51(tr,3H).
Example 8 sulfate salt 2- (5-Ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate
Salt formation method B
To an ethanol (30ml) solution of the compound (1.5g) of example 8 was added a solution of sulfuric acid (440mg) in ethanol (7.5ml) and the mixture was heated under reflux, cooled, evaporated and washed with acetone to give the title compound (1.4 g). Or other solvents and temperatures can be used, or the product filtered from solution or washed with other organic solvents.
1H NMR(DMSO-d6)ppm 7.13-7.25(m,2H),7.05(dd,1H),5.61(s, 1H),4.08-4.19(m,1H),3.71(br.s,4H),3.78-3.93(m,1H),2.78-2.90(m, 1H),2.68-2.78(m,1H),2.59(q,2H),1.07-1.21(m,3H).
EXAMPLE 8 fumarate 2- (5-Ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole fumarate
Salt formation method C
To an ethanol (15ml) solution of the compound (2.3g) of example 8 was added an ethanol (5ml) solution of fumaric acid (1.16g), and the mixture was heated under reflux, cooled, evaporated and washed with TBME to give the title compound (3.0 g). Or other solvents and temperatures can be used, or the product filtered from solution or washed with other organic solvents.
1H NMR(DMSO-d6)ppm 7.15–7.20(m,2H),7.05–7.09(m,1H), 6.48(s,2H),5.72(s,1H),4.14–4.19(m,1H),3.80–3.86(m,1H),3.71(s,4 H),2.83–2.91(m,1H),2.67-2.75(m,1H),2.58(q,2H),1.15(tr,3H).
Example 9 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-ol
A mixture of 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (720mg), bis (pinacolato) diboron (715mg), bis (tri-tert-butylphosphine) palladium (0) (39mg), potassium acetate (503mg), dioxane (9ml) and DMF (0.75ml) was stirred in a microwave reactor under an inert atmosphere at 160 ℃ for 30 minutes. Bis (tri-tert-butylphosphine) palladium (0) (21mg) was added and heating was continued for 15 min. Intermediate 2- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole (680mg) was purified by isolation method a and stirred with EtOAc (2ml), water (2ml) and hydrogen peroxide (35%, 0.07ml) for 2hrs at ice bath temperature. The title compound was purified using separation methods a and E. (yield 45 mg).
1H NMR(DMSO-d6)ppm 9.44(s,1H),6.78-7.08(m,1H),6.62(d,1H), 6.67(d,1H),5.22(s,1H),4.05–4.15(m,1H),3.70-3.78(m,1H),3.18-3.42 (m,4H,H2O),2.53-2.69(m,2H).
Example 10 (1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-yl) methanol
The title compound was prepared from 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (50mg) and (tributyltin-yl) methanol (86mg) by using tetrakis (triphenyl-phosphine) palladium (10.28mg) as a catalyst and employing the procedure of synthesis method C and isolation methods F and G. (yield 6.2 mg).
1H NMR(CD3OD)ppm 7.31(d,1H),7.11-7.22(m,2H),5.42(s,1H), 4.62(s,2H),4.22(td,1H),3.86(dd,1H),3.54-3.69(m,4H),2.93-3.05(m, 1H),2.75-2.86(m,1H).
Example 11 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of NaH (0.024g), ethyl 5-bromoisochroman-1-carboxylate (0.2g, FIG. B) and THF (5ml) was stirred at ice bath temperature for 90min, and iodine was addedMethane (0.06ml) and the mixture was stirred at ambient temperature for 16 hrs. Intermediate ethyl 5-bromo-1-methylisochroman-1-carboxylate (0.11g) was purified by isolation A and Synthesis A3 and isolation E (DCM/EtOAc/Et)3N) the title compound was synthesized. (yield 0.07 g).
1H NMR(CDCl3)ppm 7.45-7.47(m,1H),7.39-7.41(m,1H),7.07- 7.11(m,1H),4.70-5.20(br s,1H),3.94-4.05(m,2H),3.22-3.87(m,2H), 2.83-2.87(m.2H),1.77(s,3H).
Example 12- ((3R) -5-chloro-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2-chlorophenyl) butan-2-ol (400mg) using the procedures of Synthesis methods B and A3. The intermediate ethyl (3R) -5-chloro-3-ethylisochroman-1-carboxylate was purified using separation method B (EtOAc/heptane) and E. (yield 235 mg).
1H NMR(DMSO-d6)ppm 7.28-7.43(m,1H),7.11-7.26(m,2H),6.12 (br s,1H),5.35(s,1H),3.53-3.80(m,3H),3.12-3.29(m,2H),2.73-2.92(m, 1H),1.67(m,2H),0.99(t,3H).
Example 13 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) -1-methylisochroman-5-yl) -2, 2-dimethylpropan-1-ol, the slower eluting isomer
To a solution of 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (example 2,0.075g) in 2ml of THF was added 0.33ml of a solution of tetrabutyllithium in pentane (1.7M) followed by 1.2ml of a solution of 20.8M trimethylacetaldehyde in THF at-78 ℃. After stirring at-78 ℃ for 15min, the reaction was quenched with ice. The title compound was isolated using isolation methods a and G. (yield 0.003 g).
1H NMR(CDCl3)ppm 7.43-7.45(m,1H),7.34-7.36(m,1H),7.22- 7.24(m,1H),4.73(s,1H),3.88-4.05(m,2H),3.61(br s,4H),2.84-2.91(m, 2H),1.78(s,3H),0.97(s,9H).
Example 14 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) -1-methylisochroman-5-yl) -2, 2-dimethylpropan-1-ol, faster eluting isomer
The title compound was isolated using isolation methods a and G in the synthesis of example 13. (yield 0.007 g).
1H NMR(CDCl3)ppm 7.46(d,1H),7.50(d,1H),7.18-7.35(m,3H), 4.72(s,1H),4.04(s,1H),3.59-3.81(m,3H),2.81-3.02(m,2H),2.05(d,1H), 1.89(s,3H),0.86-1.05(m,9H).
Example 15 2- (5-ethynylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
To degassed 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (300mg) in Et3To a solution of N (10ml) and ethynyltrimethylsilane (210mg) was added tetrakis (triphenylphosphine) -palladium (37 mg). Mixing the mixture with N2Degassed and heated in a microwave oven at 120 ℃ for 60 min. The reaction mixture was concentrated in vacuo and purified using isolation method K. Will K2CO3Add to the crude reaction (in MeOH) and stir the mixture at rt for 4 h. The title compound was isolated using isolation method G. (yield 6.2 mg).
1H NMR(CDCl3)ppm 7.42-7.37(m,2H),7.17(t,1H),5.42(s,1H), 4.78(s,1H),4.26-4.21(m,1H),4.00-3.73(m,4H),3.08-2.93(m,2H).
Example 16 2- ((3R) -3-Ethyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1 (R) -1- (2- (trifluoromethyl) phenyl) butan-2-ol
2-iodotrichlorotoluene (3g) was dissolved in THF (18ml) and cooled to-78 ℃. n-BuLi (2.5M in hexane, 13.23ml) was added dropwise to the reaction mixture. 1After h, a solution of (R) - (+) -1, 2-epoxybutane (1.4ml) in THF (18ml) was added. The reaction temperature was slowly raised to rt. The mixture was poured into ice-water (100ml) and the product was extracted with heptane. The organic phase was washed with brine and water and dried (Na)2SO4) Evaporated under vacuum. The title compound was obtained using isolation method E. (yield 1.05 g).
Step 2- ((3R) -3-Ethyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2- (trifluoromethyl) phenyl) butan-2-ol (570 mg) using the procedures of synthesis methods B and a 3. The intermediate ethyl (3R) -5-trifluoromethyl-3-ethylisochroman-1-carboxylate was purified using separation method B (EtOAc/heptane) and E. (yield 360 mg).
1H NMR(CD3OD)ppm 7.59(d,1H),7.50(d,1H),7.25-7.42(m,1H), 5.49(s,1H),3.46-3.72(m,5H),2.98(d,1H),2.82(dd,1H),1.59-1.84(m, 2H),0.97-1.18(m,3H).
EXAMPLE 17 Synthesis of 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole method E
To 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (200mg), 2- (di-tert-butylphosphino) biphenyl (5.31mg), palladium (II) acetate (3.19mg), and Cs2CO3(348mg) methanol (1ml) and toluene (2ml) were added to the mixture. Mixing the mixture with N2Degassed and then heated at 120 ℃ for 40min and at 130 ℃ for 30 min. Alternatively, other Pd-ligand complexes and reaction conditions can be used in C-O formation. The title compound was purified using separation methods E and G. (yield 5 mg).
1H NMR(CD3OD)ppm 7.14(t,1H),6.80(d,1H),6.83(d,1H),5.34(s, 0.3H),4.16-4.31(m,1H),3.74-3.89(m,4H),3.50-3.68(m,4H),2.61-2.90 (m,2H).
Example 17HCl salt 2- (5-Methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride
The title compound (Et) was prepared from the compound of example 17 (263mg) as described in example 82O, yield 148 mg).
1H NMR(CD3OD)ppm 7.28(t,1H),6.97(d,1H),6.80(d,1H),5.72(s, 1H),4.12-4.19(m,1H),3.99(br.s,4H),3.87-3.95(m,1H),3.86(s,3H),2.78- 2.84(m,2H).
Example 17 sulfate salt 2- (5-Methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate
The title compound was prepared from the compound of example 17 (50mg) as described in example 8 (EtOH, yield 41.5 mg).
1H NMR(DMSO-d6)ppm 9.37-10.57(br,2H),7.27(t,1H),6.99(d,1H), 6.79(d,1H),5.75(s,1H),4.03-4.20(m,1H),3.85-3.94(m,5H),3.82(s,3H), 2.65-2.79(m,2H).
EXAMPLE 17 hemifumarate 2- (5-Methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate
The title compound (EtOH, yield 38mg) was prepared from the compound of example 17 (50mg) as described in example 8.
1H NMR(DMSO-d6)ppm 7.16(t,1H),6.88(d,1H),6.79(d,1H),6.43 (s,1H),5.47(s,1H),4.07-4.16(m,1H),3.73-3.82(m,4H),3.40-4.75(br.s, 4H),2.58-2.75(m,2H).
Example 18 2- (5-Iodoisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (2-iodophenyl) ethanol (1.5g) using the procedure of Synthesis B and isolation D. (yield 510 mg).
1H NMR(CD3OD)ppm 7.72-7.84(m,1H),7.24(d,1H),6.94(t,1H), 4.21(ddd,1H),3.83(ddd,1H),3.46-3.68(m,4H),2.80-2.95(m,1H),2.56- 2.74(m,1H).
Example 19 2- ((3R) -3-methyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2- (trifluoromethyl) phenyl) propan-2-ol (570 mg) using the procedures of synthesis methods B and a 3. The starting material, (R) -1- (2- (trifluoromethyl) phenyl) propan-2-ol (1.0g) was prepared from 2-iodotrifluorotoluene and (R) - (+) -propylene oxide in a similar manner to that described in example 16. The intermediate ethyl (3R) -5-trifluoromethyl-3-ethylisochroman-1-carboxylate was purified using separation method B (EtOAc/heptane) and E. (yield 340mg).
1H NMR(CD3OD)ppm 7.59(d,1H),7.50(d,1H),7.29-7.43(m,1H), 5.51(s,1H),3.83-3.97(m,1H),3.49-3.72(m,4H),2.99(d,1H),2.82(dd, 1H),1.25-1.48(m,3H).
Example 20 2- (5-bromo-4-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (2-bromophenyl) propan-1-ol (1.55g) using the procedure of Synthesis B and isolation E. (yield 70mg).
1H NMR(CD3OD)ppm 7.43-7.55(m,1H),7.27(d,0.6H),7.04-7.15 (m,1.4H),5.34(s,0.5H),3.98-4.10(m,1H),3.75-3.92(m,1H),3.53-3.67 (m,4H),2.94-3.06(m,1H),1.45(d,1.9H),1.33(d,1.1H).
Example 21 faster eluting isomer of 2- (1, 5-Dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (example 3,70mg) using the procedure of isolation method H. (yield 22 mg).
1H NMR(CDCl3)ppm 7.19-7.40(m,1H,CHCl3),7.02-7.19(m,2H), 3.90-4.15(m,2H),2.66-2.81(m,2H),2.24(m,3H),1.79(s,3H).
Example 22 2- (1, 5-Dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, the slower eluting isomer
The title compound was prepared from 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (example 3,70mg) using the procedure of isolation method H. (yield 9mg).
1H NMR(CDCl3)ppm 7.21-7.36(m,1H,CHCl3),7.01-7.18(m,2H), 3.91-4.15(m,2H),2.60-2.83(m,2H),2.24(s,3H),1.79(s,3H).
Example 23- ((3R) -1,3, 5-trimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl (3R) -3, 5-dimethylisochroman-1-carboxylate (454mg, example 33 intermediate) using the procedure of example 11 and isolation method E (DCM/EtOAc/Et 3N). (yield 232 mg).
1H NMR(DMSO-d6)ppm 7.12-7.23(m,1H),6.93-7.12(m,2H),6.15 (s,0.5H),5.83(s,0.5H),3.87-4.02(m,0.5H),3.61-3.86(m,1H),3.40- 3.61(m,1.5H),3.04-3.29(m,2H),2.53-2.71(m,1H),2.27-2.48(m,1H), 2.18(s,1.5H),2.16(s,1.5H),1.64(s,1.5H),1.56(s,1.5H),1.23-1.38(m,3H).
Example 24 2- (5-Cyclopropylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (example 11,0.15g), sodium carbonate (0.27g), bis (triphenylphosphine) palladium (II) chloride (0.02g), cyclopropylboronic acid (0.09g), water (1ml) and acetonitrile (2ml) was heated in a microwave oven at 120 ℃ for 15 min. The title compound was purified using separation methods a and G. (yield 8 mg).
1H NMR(CDCl3)ppm 7.26-7.28(d,1H),7.11-7.15(tr,1H),6.92- 6.94(d,1H),4.03-4.06(m,2H),3.62(br s,4H),2.95-2.98(m,2H),1.80(s, 3H),0.87-0.96(br m,2H),0.58-0.69(br m,2H).
Example 25 2- (3, 5-Dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 1-o-tolylpropan-2-ol (800 mg) using the procedure of Synthesis B and isolation methods E and D. (yield 19.2 mg).
1H NMR(CD3OD)ppm 6.98-7.11(m,3H),5.43(s,1H),3.88(dd,1H), 3.49-3.67(m,4H),2.64-2.76(m,1H),2.57(d,1H),2.23(s,3H),1.39(d, 3H).
Example 26 2- (5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method A and isolation methods A and D (Et)2O, heptane) the title compound was prepared from 1- (2-chlorophenyl) propan-2-ol (1.0 g). (yield 0.077 g).
1H NMR(DMSO-d6)ppm 7.32-7.37(m,1H),7.14-7.23(m,2H),6.23 (br s,1H),5.36(s,1H),3.83-3.91(br m,1H),3.43(br s,4H),2.82-2.89(m, 1H),2.46-2.53(m,1H),1.29-1.34(dd,3H).
Example 27 2- (3-Ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 1-o-tolylbutan-2-ol (1g) using the procedure of Synthesis B and isolation methods E and D. (yield 16.4 mg).
1H NMR(CD3OD)ppm 6.93-7.11(m,3H),5.41(s,1H),3.45-3.72(m, 6H),2.71(dd,1H),2.55(dd,1H),2.17-2.26(m,3H),1.62-1.78(m,2H), 0.98-1.14(m,3H).
Example 28 2- (5-chloro-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of NaH (0.36g), methyl 5-chloro-3-methylisochroman-1-carboxylate (1.1g, Synthesis A), and THF (20ml) was stirred at ice bath temperature for 60min, iodomethane (0.9ml) was added and the mixture was stirred at ambient temperature for 16 hrs. Intermediate methyl 5-chloro-1, 3-dimethylisochroman-1-carboxylate (0.95g) was purified by isolation method a and the title compound was synthesized using the procedure of synthesis method a and isolation method a. (yield 0.1g).
1H NMR(DMSO-d6)ppm 7.16-7.33(m,3H),6.14(br s,1H),3.72- 4.02(br m,1H),3.40-3.47(br s,2H),2.76-2.86(br s,1H),2.35-2.54(br m, 1H),1.60-1.66(d,3H),1.30-1.32(dd,3H).
Example 29 2- (5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 1- (2-bromophenyl) propan-2-ol (2.5g) using the procedure of synthesis a (43% of prepared methyl 5-bromo-3-methyl-isochroman-1-carboxylate in the last step) and isolation D. (yield 447 mg).
1H NMR(CD3OD)ppm 7.42-7.55(m,1H),7.24(d,0.8H),7.02-7.17 (m,1.2H),5.41(s,0.7H),4.08(s,0.2H),3.81-3.95(m,0.8H),3.50-3.70(m, 4H),2.82-2.93(m,1H),2.40-2.64(m,1H),1.38-1.44(m,2.3H),1.34(d, 0.7H).
Example 30 2- (1,3, 5-trimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Except that isolation methods A and D (Et) were used in the final synthesis step2O and heptane) the title compound was prepared from 1-O-tolylpropan-2-ol (0.9g) using the method described for example 12 (yield 0.012g).
1H NMR(DMSO-d6)ppm 7.27-7.29(d,1H),7.13-7.17(tr,1H),7.05- 7.07(d,1H),4.85(br s,1H),3.82-3.90(m,1H),3.64(br s,4H),2.59-2.64(m, 1H),2.44-2.51(m,1H),2.21-2.23(m,3H),1.72(s,3H),1.37-1.38(d,3H).
Example 31 2- (5-bromo-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 1- (2-bromophenyl) propan-2-ol (2.5g) using the procedure of synthetic method A. After the first two steps, 43% (500mg) of the prepared methyl 5-bromo-3-methyl-isochroman-1-carboxylate was dissolved in THF (5 ml). NaH (140mg) was added to the solution, and the mixture was stirred at ice-bath temperature. After 60min, iodomethane (0.325ml) was added and the mixture was stirred at ambient temperature for 48 hrs. The intermediate methyl 5-bromo-1, 3-dimethylisochroman-1-carboxylate (168mg) was purified by isolation methods a and E and the title compound was synthesized using the procedures of synthesis method a (step 3) and isolation method D. (yield 24 mg).
1H NMR(CD3OD)ppm 7.41-7.54(m,1H),7.25-7.37(m,1H),7.03- 7.17(m,1H),4.04(ddd,0.2H),3.76-3.90(m,0.8H),3.44-3.64(m,4H),2.78 -2.95(m,1H),2.37-2.62(m,1H),1.74(s,0.6H),1.68(s,2.4H),1.32-1.41 (m,3H).
Example 32- ((3R) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2-bromophenyl) propan-2-ol (400mg) using the procedure of Synthesis A and isolation D (heptane). (yield 75 mg).
1H NMR(CD3OD)ppm 7.49(d,1H),7.24(d,1H),7.02-7.18(m,1H), 5.42(s,1H),3.76-3.97(m,1H),3.51-3.72(m,5H),2.75-2.96(m,1H),2.58 (dd,1H),1.22-1.51(m,3H).
Example 33- ((3R) -5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method A and isolation methods A and D (Et)2O and heptane) the title compound was prepared from (R) -1- (2-chlorophenyl) propan-2-ol (0.3 g). (yield 0.03 g).
1H NMR(DMSO-d6)ppm 7.35-7.37(d,1H),7.17-7.23(m,2H),6.14 (br s,1H),5.36(s,1H),3.83-3.91(m,1H),3.6(br m,2H),3.10-3.30(br s, 2H),2.82-2.86(d,1H),2.46-2.53(d,1H),1.33-1.34(d,3H).
Example 34 2- ((3S) -5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method A and isolation methods A and E (Et)2O and heptane) the title compound was prepared from (S) -1- (2-chlorophenyl) propan-2-ol (0.3 g). (yield 0.03 g).
1H NMR(CDCl3)ppm 7.34-7.36(d,1H),7.28-7.30(d,1H),7.11- 7.15(tr,1H),5.54(br s,1H),3.86-3.94(m,1H),3.56-3.76(br m,4H),2.89- 2.94(dd,1H),2.54-2.61(m,1H),1.37-1.43(m,3H).
Example 35- ((3S) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Using Synthesis method A and isolation method D (Et)2O) and G the title compound was prepared from (S) -1- (2-bromophenyl) propan-2-ol (200 mg). (yield 23 mg).
1H NMR(CD3OD)ppm 7.38-7.60(m,1H),7.23(d,1H),7.03-7.18(m, 1H),5.42(s,1H),4.03-4.13(m,0.3H),3.79-3.98(m,0.7H),3.43-3.71(m, 4H),2.81-2.97(m,1H),2.58(dd,0.7H),2.46(dd,0.3H),1.34-1.40(m, 3H).
Example 36- ((3R) -3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -o-tolylpropan-2-ol (400mg) using the procedure of Synthesis A and isolation E. (yield 40mg)
1H NMR(CD3OD)ppm 6.99-7.11(m,3H),5.43(s,1H),3.88(ddd,1H), 3.53-3.66(m,4H),2.72(dd,1H),2.47-2.61(m,1H),1.39(d,3H).
Example 37- ((3S) -3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (S) -o-tolylpropan-2-ol (400mg) using the procedure of Synthesis A and isolation methods E and D. (yield 40mg).
1HNMR(CD3OD)ppm 6.99-7.13(m,3H),5.43(s,1H),3.82-3.93(m, 1H),3.53-3.66(m,4H),2.66-2.79(m,1H),2.48-2.62(m,1H),1.39(d,3H).
Example 38 2- (5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (200mg) using the procedure of synthesis E and isolation methods K and G. (yield 5.8 mg).
1H NMR(CD3OD)ppm 7.07-7.18(m,1H),6.76-6.87(m,2H),5.41(s, 1H),3.76-3.87(m,4H),3.55-3.67(m,4H),2.83(dd,1H),2.42(dd,1H),1.31 -1.41(m,3H).
Example 39 2- (5-Ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (200mg) using the procedure of synthesis D and isolation methods J and G. (yield 18.4 mg).
1H NMR(CD3OD)ppm 7.04-7.14(m,2.6H),6.96-7.01(m,0.4H), 5.45(s,0.7H),4.11(s,0.2H),3.87(ddd,0.8H),3.51-3.66(m,4H),2.75-2.89 (m,1H),2.54-2.70(m,3H),1.37-1.43(m,2.3H),1.33(d,0.7H),1.20(t,3H).
Example 40 2- (5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Adopts a synthesis method B (Lewis acid catalyst BF)3*Et2O) the title compound was prepared from 1 (-2-bromophenyl) pentan-2-ol (only 50% of the prepared ester was used in the final step). (yield 400 mg).
1H NMR(CD3OD)ppm 7.41-7.54(m,1H),7.23(d,1H),7.03-7.14(m, 1H),5.39(s,1H),3.74(td,1H),3.50-3.68(m,4H),2.85(d,1H),2.58(dd,1H), 1.45-1.75(m,4H),0.92-1.04(m,3H).
Example 41 2- (5-Isochroman-1-yl) -4, 5-dihydro-1H-imidazole
To a solution of 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (0.25g, synthesis a), palladium (II) acetate (0.01g), tri-tert-butylphosphine (0.044ml) and toluene (3ml) was added 6.22ml of a 0.5M solution of isopropylzinc bromide in THF at ice bath temperature and stirred at ambient temperature for 3 hrs. The reaction was quenched with dilute hydrochloric acid and the organic phase was separated. The aqueous phase was made basic with 1M NaOH and purified by separation methods a and G to provide the title compound. (yield 2 mg).
1H NMR(CDCl3)ppm 7.20(br s,3H),5.48(s,1H),4.22-4.27(m,1H), 3.85-3.91(m,1H),3.63(br s,4H),3.05-3.12(m,1H),2.91-2.99(m,1H), 2.75-2.80(m,1H),1.21-1.23(m,6H).
Example 42 2- (5-Fluoroisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (2-fluorophenyl) ethanol (0.4g) using the procedure of Synthesis B. The final product was purified by washing the evaporation residue with cold water. (yield 0.09 g).
1H NMR(DMSO-d6)ppm 7.17-7.23(m,1H),7.03–7.08(m,2H),6.31 (br s,1H),5.32(s,1H),4.10-4.15(m,1H),3.79-3.85(m,1H),3.43-3.75(br s,2H),3.09-3.30(br s,2H),2.67-2.83(m,2H).
Example 43 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 1- (2-bromophenyl) butan-2-ol (600mg) using the procedure of Synthesis B (boron trifluoride etherate instead of titanium (IV) chloride) and isolation D. (yield 480mg)
1H NMR(CD3OD)ppm 7.40-7.53(m,1H),7.24(d,1H),7.09(q,1H), 5.39(s,1H),3.52-3.70(m,5H),2.80-2.92(m,1H),2.58(dd,1H),1.56-1.80 (m,2H),0.99-1.10(m,3H).
Example 44- ((3R) -5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- ((3R) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (200mg) using procedure synthesis E (using 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) and isolation procedures J and G. (yield 31.4 mg).
1H NMR(CD3OD)ppm 7.08-7.20(m,1H),6.79-6.85(m,1.7H),6.73 -6.75(d,0.3H),5.40(s,0.7H),4.07-4.10(m,0.2H),3.80-3.92(m,3.8H), 3.46-3.68(m,4H),2.74-2.90(m,1H),2.28-2.47(m,1H),1.35-1.41(m, 2.3H),1.31(d,0.7H).
Example 45 2- ((3R) -5-Ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2-ethylphenyl) propan-2-ol (2.2g) using the procedure of Synthesis method A. Intermediate (3R) -5-ethyl-3-methylisochroman-1-carboxylic acid methyl ester was purified by isolation method E. (yield 146 mg).
1H NMR(CD3OD)ppm 7.01-7.21(m,3H),5.44(s,1H),4.06-4.17(m, 0.15H),3.77-3.96(m,0.85H),3.49-3.69(m,4H),2.75-2.91(m,1H),2.54- 2.69(m,3H),1.26-1.46(m,3H),1.19(t,3H).
Example 45HCl salt 2- ((3R) -5-Ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride
The title compound (IPA, yield 71mg) was prepared from the compound of example 45 (100mg) as described in example 8.
1H NMR(DMSO-d6)ppm 10.63(br.s.,2H),7.13-7.38(m,2H),6.94- 7.13(m,1H),5.87(br.s.,1H),3.88(br.s.,4H),3.61-3.74(m,1H),2.66-2.82 (m,1H),2.42-2.65(m,1H),2.14-2.32(m,3H),1.60-1.83(m,2H),0.79-1.07 (m,3H).
EXAMPLE 45 hemifumarate 2- ((3R) -5-Ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate
The title compound was prepared from the compound of example 45 (940mg) as described in example 8 (ethanol, yield 1.16 g).
1H NMR(DMSO-d6)ppm 6.97-7.20(m,3H),6.43(s,1H),5.59(s, 0.7H),5.49(s,0.3H),4.04–4.08(m,0.3H),3.80-3.92(m,0.7H),3.59(br.s., 4H),3.55(s,1H),2.77(m,2H),2.56-2.63(m,1H),1.26-1.37(m,3H),1.15(t, 3H).
Example 46 2- (3-Ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 1- (2-bromophenyl) butan-2-ol (1.1g) using the procedure of synthesis B (using boron trifluoride etherate complex instead of titanium (IV) chloride) and E (using 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) (C-O coupling reaction to intermediate 5-bromo-3-ethylisochroman-1-carboxylic acid ethyl ester, only 60% of the preparation was used in this step). This C-O coupling reaction gives the free acid, which is further methylated before the final reaction step (method A). The title compound was obtained by concentrating the reaction mixture. (yield 186 mg).
1H NMR(CD3OD)ppm 7.12(t,1H),6.82(d,2H),5.38(s,1H),3.82(s, 3H),3.48-3.69(m,5H),2.73-2.90(m,1H),2.41(dd,1H),1.70(dt,2H),0.96 -1.10(m,3H).
Example 47 2- ((3R) -3, 5-diethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1 (R) -1- (2-ethylphenyl) butan-1-ol
1-bromo-2-ethylbenzene (2.0g) was dissolved in dry THF and the mixture was cooled to-78 ℃. 1.6M n-BuLi (20.26ml) was slowly added to the reaction mixture, and the mixture was stirred at-78 ℃. After 1h, (R) - (+) -1, 2-epoxybutane (1.1g) in 10ml of THF was added. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction was quenched with ice-water and the product was extracted with heptane and finally purified using isolation method E to afford the title compound (1.1 g).
Step 2- ((3R) -3, 5-diethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2-ethylphenyl) butan-1-ol (1.1g) using the procedure of Synthesis A and isolation D. (yield 660 mg).
1H NMR(CD3OD)ppm 6.99-7.19(m,3H),5.43(s,1H),3.49-3.68(m, 5H),2.74-2.86(m,1H),2.55-2.66(m,3H),1.54-1.79(m,2H),1.19(t,3H), 0.95-1.11(m,3H).
Example 48 2- ((3R) -3-Ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (o-tolyl) butan-2-ol (463mg) using the procedure of Synthesis method B. Intermediate ethyl (3R) -3-ethyl-5-methylisochroman-1-carboxylate was purified by isolation method E using boron trifluoride etherate instead of titanium (IV) chloride. The title compound was isolated using isolation method D using MTBE-heptane as solvent (yield 287 mg).
1H NMR(DMSO-d6)ppm 6.95-7.12(m,3H),5.98(br s,1H),5.32(s, 1H),3.49-3.81(m,3H),3.20(br s,2H),2.66(d,1H),2.40-2.47(m,1H),2.19 (s,3H),1.54-1.76(m,2H),0.99(t,3H).
Example 48HCl salt 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride
The title compound (IPA, yield 72mg) was prepared from the compound of example 48 (100mg) as described in example 8.
1H NMR(DMSO-d6)ppm 10.60(br.s.,2H),7.15-7.28(m,2H),7.03- 7.14(m,1H),5.89(s,1H),3.90(br.s.,4H),3.08(s,1H),2.82(d,1H),2.55- 2.70(m,3H),1.36(d,3H),1.15(t,3H).
Example 48 sulfate salt 2- ((3R) -3-Ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-Imidazol sulfate
The title compound (ethanol, yield 2.0g) was prepared from the compound of example 48 (1.5g) as described in example 8.
1H NMR(DMSO-d6)ppm 10.32(s,2H),7.16-7.22(m,2H),7.00–7.02 (m,1H),5.78(s,1H),3.87–3.93(m,5H),2.74(dd,1H),2.50-2.59(m,1H), 1.66–1.74(m,2H),1.10(t,3H),1.01(t,3H).
EXAMPLE 48 hemifumarate 2- ((3R) -3-Ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate
The title compound (ethanol, yield 102.3mg) was prepared from the compound of example 48 (100mg) as described in example 8.
1H NMR(DMSO-d6)ppm 7.09-7.19(m,2H),6.99-7.07(m,1H),6.43 (s,1H),5.60(s,0.7H),5.50(s,0.3H),4.05–4.08(m,0.3H),3.81-3.92(m, 0.7H),3.60(s,4H),2.77(dd,1H),2.56-2.64(m,1H),2.44-2.53(m,2H), 1.25-1.37(m,3H),1.15(t,3H).
Example 49 2- ((3R) -3-methyl-5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1 (R) -1- (2- (trifluoromethoxy) phenyl) propan-2-ol
To a solution of trifluoromethoxybenzene (5.29mL) and N, N, N ', N' -tetramethylethylenediamine (5.96mL) in tetrahydrofuran (80mL) was added sec-butyllithium (32mL,1.4M solution) over 50 minutes at-78 ℃. After 2 hours, a cooled (-78 deg.C) solution of (R) - (+) -propylene oxide (4.20mL) in tetrahydrofuran (20mL) was added over 15 minutes, followed by boron trifluoride etherate (1.89 mL) over 20 minutes. After stirring the reaction mixture at-78 ℃ for 2 hours, H was added2SO4Aqueous solution (0.3M,50 mL) and water (10 mL). After warming the mixture to room temperature, it was extracted with ether (2 × 100 mL). The combined organic phases were washed with brine, washed with Na2SO4Drying and concentrating. The evaporation residue was purified by separation method E (ethyl acetate-heptane). (yield 1.40 g).
1H NMR(DMSO-d6)ppm 7.24-7.44(m,4H),4.67(d,1H),3.80-3.92(m, 1H),2.74(dd,1H),2.65(dd,1H),1.04(d,3H).
Step 2- ((3R) -3-methyl-5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2- (trifluoromethoxy) phenyl) propan-2-ol (110mg) using the procedure of synthesis B. Boron trifluoride etherate was used instead of titanium (IV) chloride. (yield 36mg).
1H NMR(CD3OD)ppm 7.31-7.16(m,3H),5.45(s,1H),4.12-4.02(m, 0.25H),4.94-4.83(m,0.75H),3.70-3.54(m,4H),2.95-2.85(m,1H),2.59 (dd,0.8H),2.48(dd,0.3H),1.40(d,2.4H),1.34(d,0.9H).
Example 50 2- ((3R) -5-fluoro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -1- (2-fluorophenyl) propan-2-ol (170mg) using the procedure of synthesis B. Boron trifluoride etherate was used instead of titanium (IV) chloride. The crude product was triturated with heptane to purify the title compound. (yield 67 mg).
1H NMR(CD3OD)ppm 7.22-7.14(m,1H),7.05(d,1H),7.01-6.93(m, 1H),5.43(s,1H),4.14-4.04(m,0.1H),3.93-3.83(m,0.9H),3.70-3.52(m, 4H),2.93-2.83(m,1H),2.56(dd,0.9H),2.46(dd,0.1H),1.40(d,2.6H),1.33 (d,0.5H).
Example 51 2- (5-Ethoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1: 5-Ethoxyisochroman-1-carboxylic acid
A mixture of ethyl 5-bromoisochroman-1-carboxylate (1.0g, syntheses A1 and A2), cesium carbonate (4.57g), 3,4,7, 8-tetramethyl-1, 10-phenanthroline (332mg), copper (I) iodide (134mg) and ethanol (10ml) was heated in a microwave reactor at 160 ℃. The methanol was evaporated and the title compound was isolated and purified using isolation method B. (yield 400 mg).
Step 2,2- (5-ethoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared using the procedures of synthesis methods a2 and A3 and purified using isolation method D (heptane). (yield 150mg).
1H NMR(CD3OD)ppm 7.11(t,1H),6.80(t,2H),4.11-4.26(m,1H), 4.05(qd,2H),3.79(td,1H),3.51-3.66(m,4H),2.62-2.91(m,2H),1.40(t, 3H).
Example 52 2- (5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1:4,4, 4-trifluoro-1- (o-tolyl) butan-2-ol
To a dichloromethane/water (15/0.5mL) mixture of 2,2, 2-trifluoroethylamine hydrochloride (0.271g) at 0 deg.C was added sodium nitrite (0.166g) and the resulting yellow solution was stirred at 0 deg.C for 1 hour. The reaction mixture was then cooled to-78 ℃ and 2-o-tolylacetaldehyde (0.134g) and then zirconium (IV) tetrachloride were added. After stirring at-78 deg.C for 2hrs, cooling was stopped and methanol (3mL) and saturated NaHCO were added3(10mL) of the solution. The mixture was extracted with dichloromethane and the extracts were dried and concentrated. The evaporation residue (194mg) was dissolved in methanol (3ml) and the solution was cooled to 0 ℃. Sodium borohydride (44mg) was added and the reaction mixture was stirred for 25 min. Will K2CO3Solution (2M,5mL) was added to the reaction mixture, water (5mL) was added after 5min, and the resulting solution was extracted with EtOAc. The extracts were dried and concentrated, and the residue was purified using separation method E (EtOAc/heptane). (yield 121 mg).
1H NMR(CDCl3)ppm 7.23-7.12(m,4H),4.26-4.17(m,1H),2.90(dd, 1H),2.80(dd,1H),2.45-2.27(m,2H),2.34(s,3H),1.86(d,1H).
Step 2- (5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 4,4, 4-trifluoro-1- (o-tolyl) butan-2-ol (121mg) using the procedure of synthetic method B. Using boron trifluoride diethyl etherateThe complex replaces titanium (IV) chloride. By separation method E (dichloromethane-MeOH-NH)4OH) purification of the title compound. (yield 11 mg).
1H NMR(CD3OD)ppm 7.13-7.04(m,2.6H),6.99-6.93(m,0.3H), 5.47(s,1H),4.41-4.33(m,0.3H),4.15-4.07(m,0.7H),3.63-3.51(m,4H), 2.87-2.46(m,4H),2.25(s,3H).
Example 53 2- ((3S) -5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- ((3S) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (200mg) using the procedure for synthesis method E (using 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -phenyl) and isolation method G. (yield 16.3 mg).
1H NMR(CD3OD)ppm 7.10-7.24(m,1H),6.82-6.90(m,1.6H),6.78 (d,0.4H),5.44(s,0.7H),4.05-4.15(m,0.3H),3.80-3.93(m,3.7H),3.53- 3.70(m,4H),2.80-2.92(m,1H),2.31-2.50(m,1H),1.41(d,2.1H),1.34(d, 0.9H).
Example 54 2- (5- (furan-3-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
To a mixture of 2- (2-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (100mg), bis (tri-tert-butylphosphine) palladium (9mg), furan-3-boronic acid (80mg) and cesium carbonate (202mg) were added ethylene glycol dimethyl ether (4ml), ethanol (2ml) and water (1 ml). The reaction mixture is treated with N2Degassed and heated in a microwave oven at 100 ℃ for 30 min. The title compound was purified by applying methods J and G. (yield 19mg).
1H NMR(CD3OD)ppm 7.60-7.67(m,1H),7.52-7.60(m,1H),7.10- 7.33(m,3H),6.49-6.70(m,1H),4.18(ddd,1H),3.71-3.84(m,1H),3.55- 3.67(m,4H),2.97-3.19(m,1H),2.64-2.81(m,1H).
Example 55 2- (5- (prop-1-yn-1-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (2-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (100mg) using the procedure of synthesis C and isolation methods F and G. (yield 3.7 mg).
1H NMR(CD3OD)ppm 7.27(dd,1H),7.12(m,2H),5.34(s,0.2H),4.22 (ddd,1H),3.83(ddd,1H),3.59(m,4H),2.94(m,2H),2.07(s,3H).
Example 56 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carboxamide
A mixture of 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carbonitrile (example 5,75mg), acetamide (39mg), zinc chloride (zink) (45mg), THF (0.5ml) and water (0.5ml) was heated in a microwave reactor at 320W for 50 seconds. The title compound was purified using method a. (yield 15 mg).
1H NMR(CDCl3)ppm 8.06(d,1H),7.57(d,1H),7.32(t,1H),5.17(s, 1H),4.16-4.41(m,1H),3.75-4.03(m,1H),2.93-3.44(m,4H),2.77-2.93 (m,2H).
Example 57 2- (3,7,8,9,10,10 a-hexahydro-1H-cyclohepta [ de ] isochromen-3-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (6,7,8, 9-tetrahydro-5H-benzo [7] annulen-5-yl) methanol (300mg) using the procedure of Synthesis A and isolation of methods F and G. (yield 3 mg).
1H NMR(CDCl3)ppm 6.96-7.24(m,3H),5.32-5.48(m,1H),3.74- 4.03(m,3H),3.39-3.60(m,4H),2.65-2.98(m,2H),1.84-2.11(m,2H), 1.52-1.82(m,2H),1.19-1.42(m,2H).
Example 58 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-yl) ethanol, a slowly eluting isomer
The title compound was prepared from 2- (2-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole (300mg) using the procedure of example 13 and purified using isolation method G. (yield 2 mg).
1H NMR(CD3OD)ppm 7.48(d,1H),7.26(m,2H),5.06(q,1H),3.99 (m,2H),3.74(s,4H),2.96(dt,1H),2.84(dt,1H),1.78(d,3H).
Example 59 2- (5, 7-Dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (2, 4-dimethylphenyl) ethanol (0,5g) using the procedure of Synthesis A. Intermediate 5, 7-dimethylisochroman-1-carboxylic acid was isolated using isolation procedure I and intermediate 5, 7-dimethylisochroman-1-carboxylic acid methyl ester was purified using isolation procedure E. The title compound was isolated using isolation method G. (yield 27 mg).
1H NMR(CD3OD)ppm 8.45(br.s.,1H),7.04(s,1H),6.85(s,1H),5.68 (s,1H),4.11-4.19(m,1H),3.87-4.02(m,5H),2.76-2.88(m,1H),2.64- 2.76(m,1H),2.20-2.35(m,6H).
Example 60 2- (7-bromo-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2- (4-bromo-2-methylphenyl) ethanol (4,5g) using the procedure of synthesis a (using 4-methylbenzenesulfonic acid in methanol in step a2) and isolated using isolation method D using MTBE-heptane as the solvent. (yield 242 mg).
1H NMR(DMSO-d6)ppm 7.29(s,1H),7.20(s,1H),6.32(br.s.,1H), 5.28(s,1H),4.09(dt,1H),3.82(ddd,1H),3.63(dt,2H),3.18-3.27(m,2H), 2.57-2.72(m,2H),2.20(s,3H).
Example 61 2- (7-methoxy-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl 7-methoxy-5-methylisochroman-1-carboxylate (0.25G) using the procedure of synthesis a3 and isolated using isolation method G. (yield 113 mg).
1H NMR(DMSO-d6)ppm 6.65-6.75(m,1H),6.54-6.65(m,1H),6.18 (br.s.,1H),5.23(s,1H),3.98-4.25(m,1H),3.71-3.86(m,1H),3.66(s,3H), 3.20-3.30(m,4H,H2O),2.52-2.72(m,2H),2.17(s,3H).
Example 62- (3, 5-Dimethylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl 3, 5-dimethylisothiochroman-1-carboxylate (0.44G) using the procedure of synthetic method A3 and isolated using isolation method G. (yield 10 mg).
1H NMR(CD3OD)ppm 6.93-7.23(m,3H),3.38-3.68(m,5H),2.98- 3.19(m,1H),2.48(dd,1H),2.19-2.37(m,3H).
Example 63 2- (5-bromo-3-methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl 5-bromo-3-methylisothiochroman-1-carboxylate (0.5g, synthesis a1 and a2) using the procedure of synthesis A3 and isolated using isolation method E. (yield 72 mg).
1H NMR(CD3OD)ppm 7.53(d,1H),7.03-7.25(m,2H),3.47-3.69(m, 5H),3.37-3.46(m,1H),2.57(dd,1H),1.17-1.46(m,3H).
Example 64 2- (5-Methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl 5-methyl-isothiochroman-1-carboxylate (1.3g, synthesis F) using the procedure of synthesis a3 and isolated using isolation method D using EtOAc/EtOH as the solvent. (yield 110 mg).
1H NMR(CDCl3)ppm 6.90-7.17(m,3H),4.63(s,1H),3.52-3.75(m, 4H),3.08-3.25(m,1H),2.80-3.02(m,3H).
Example 65 2- (5-Bromoisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis method F
Synthesis method F1 methyl 2- ((2-bromophenylethyl) thio) acetate
Methyl 2-mercaptoacetate (2.2g), 2-bromophenylethyl methanesulfonate (5.7g), 2,3,4,6,7,8,9, 10-octahydropyrimido [1,2-a ] was added]Aza derivatives(3.7g) and THF (30ml) were stirred at ambient temperature for 1.5hrs and methods A and E were isolated to provide the title compound (4.4 g).
Synthesis method F2 methyl 2- ((2-bromophenylethyl) thio) -2-chloroacetate
A mixture of methyl 2- ((2-bromophenylethyl) thio) acetate (4.4g), 1-chloropyrrolidine-2, 5-dione (2g) and carbon tetrachloride (2.4g) was stirred in an ice bath for 2.5hrs, filtered and evaporated to give the title compound (4.7 g).
Synthesis method F3 of 5-bromoisothiochroman-1-methyl formate
A mixture of methyl 2- ((2-bromophenylethyl) thio) -2-chloroacetate (4.7g), aluminum trichloride (2g) and DCM (15ml) was stirred in an ice bath and warmed to ambient temperature and stirred for 3.5 hrs. Isolation methods B and E provided the title compound (2.9 g).
Synthesis method F4 2- (5-bromoisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl 5-bromo-isothiochroman-1-carboxylate (0.5g) using the procedure of synthetic method a3 and isolated using isolation methods E and D (2-propanol, yield 21 mg).
1H NMR(DMSO-d6)ppm 7.52(dd,1H),7.02-7.19(m,2H),4.65(s, 1H),3.77(td,1H),3.17-3.60(br.s.,4H),2.96-3.09(m,1H),2.75-2.95(m, 2H).
Example 66 2- (5-bromo-1-methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from methyl 5-bromoisothiochroman-1-carboxylate (1.6g) using the procedures of the synthetic methods for example 11 and a3 and was isolated using isolation method E. (yield 30mg).
1H NMR(CDCl3)ppm 7.46-7.56(m,1H),7.21-7.39(m,1H,CHCl3), 7.02-7.16(m,1H),3.17-4.0(m,4H),2.70-3.10(m,3H),1.48-2.01(m,4H).
Example 67 2- (5, 7-dibromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
Step 1,5, 7-dibromo-3-ethylisochroman-1-carboxylic acid ethyl ester
Di-mu-methoxybis (1, 5-cyclooctadiene) diiridium (I) (5.0mg), 4 '-dimethoxy-2, 2' -bipyridyl (3.2mg), bis (pinacolato) diboron (93mg) and 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (157mg, example 43) were loaded in a dry microwave tube and the tube was evacuated in vacuo/N2The flushing is circulated for a plurality of times. Tetrahydrofuran (1mL) was added and the solution was heated to 80 ℃ in a closed tube. After 4 hours the heating was stopped and the reaction mixture was concentrated. The evaporation residue was dissolved in methanol (6mL) and CuBr was added2Water (6 mL). The resulting heterogeneous mixture was heated to 80 ℃ in a closed tube. After 8 hours, the reaction mixture was cooled to room temperature and extracted with ether. The combined organic phases were washed with brine, washed with Na2SO4Dried and concentrated. The evaporation residue was purified by separation method E (ethyl acetate-heptane). (yield 94mg))。
1H NMR(CDCl3)ppm 7.63-7.67(m,1H),7.55-7.58(m,0.33H),7.38 -7.44(m,0.63H),5.31-5.36(m,0.11H)5.28-5-31(d,0.89H),4.19-4.38(m, 2H),4.00-4.09(m,0.37H),3.50-3.60(m,0.63H),2.72-2.83(m,1H),2.56 (ddd,0.64H),2.39(dd,0.36H),1.66-1.90(m,2H),1.30-1.36(m,3H), 1.02-1.13(m,3H).
Step 2,2- (5, 7-dibromo-3-ethyl isochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride,
the title compound was synthesized using synthesis method a3 and converted to the HCl-salt using salt formation method a. (yield 60mg).
1H NMR(DMSO-d6)ppm 10.59(s,1.57H),10.08(s,0.36H),7.93-7.96 (m,1H),7.59(d,0.19H),7.48-7.51(m,0.77H),5.92(br s,0.19H),5.90(br s, 0.78H),3.84-4.00(m,4H),3.63-3.78(m,1H),2.74-2.84(m,1H),2.50-2.57 (m,1H),1.61-1.77(m,2H),0.94-1.02(m,3H).
Example 68 enantiomer of 2-5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
Step 1:1- (2-bromophenyl) -4,4, 4-trifluorobutan-2-one
To a solution of 2,2, 2-trifluoroethylamine hydrochloride (27.1g,200mmol) in DCM (400ml) and water (50ml) at 0 deg.C was added NaNO2(15.43g,241mmol) and stirred for 1 h. Then cooled to-78 deg.C and then 2- (2-bromophenyl) acetaldehyde (20g,100mmol) and ZrCl were added4(30.4g,130 mmol) and stirred for 2 h. The reaction mixture was quenched with MeOH (30 ml). The title compound was purified by separation methods a and E. (yield 13.0g).
Step 2 enantiomer of (1- (2-bromophenyl) -4,4, 4-trifluorobutan-2-ol
To a solution of 1- (2-bromophenyl) -4,4, 4-trifluorobutan-2-one (7.0g,24.9mmol) in MeOH (150ml) at 0 deg.C was added NaBH4(1.23g,32.3mmol) and stirred at RT for 1 h. Then theThe reaction mixture was quenched with MeOH and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation method A, E and H. (yield 1.6g of enantiomer-1 and 1.4g of enantiomer-2). Using Chiralcel OD-H (4.6X250mm) 5. mu.g, hexane: 2-PrOH: TFA (90:10:0.1),1ml/min, enantiomer-1 showed tr5.67min and enantiomer-2 shows tr＝9.57min。
Step 3 enantiomer of 2-5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
The title compound was prepared by synthesis method B from enantiomer-1 of ethyl 1- (2-bromophenyl) -4,4, 4-trifluorobutan-2-ol (500mg) and isolated using isolation method E. The resulting base was subjected to salt formation method A (Et of HCl)2O and DCM solution as solvents) to HCl salt (yield 192 mg).
1H NMR(DMSO-d6) ppm 10.73(br.s.,1.95H),10.26(br.s.,2.05H), 7.70 (overlapping dd,2H),7.20-7.42 (overlapping m,4H),5.99(br.s,1.02H),5.98(br. s,0.98H),4.16-4.33 (overlapping m,2H),3.81-3.96(m,8H),2.59-3.09(m,8H).
Example 69 2- (5-methoxy-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A solution of ethyl glyoxylate (50% in toluene, 11.66ml) and 2-methoxyphenethanol (12.73ml) was stirred for 1hr to give ethyl 2-hydroxy-2- (2-methoxyphenethoxy) acetate. By passing1H NMR detected the formation of ethyl 2-hydroxy-2- (2-methoxyphenylethoxy) acetate and the reaction mixture was cooled on an ice bath and treated with pyridine (48.4ml), 4-dimethylaminopyridine (0.44g), acetyl chloride (12.85 ml). After stirring for 1hr at +7 ℃, heptane (50ml) was added and the ice bath removed to cool the reaction mixture to ambient temperature, then filtered. The filtrate was washed with MTBE (3 × 50ml) and the combined solvents were washed with NaHCO3(saturated aqueous solution), water and NaCl (saturated aqueous solution), and washed with Na2SO4Dried and filtered. Will haveThe organic was evaporated, toluene was added and evaporated. The by-products and residual solvent were distilled (0mbar-1mbar/72 ° -105 ℃) and the residue was dissolved in ethyl acetate, silica gel and activated carbon were added, the solution was stirred for 10 minutes and filtered. Evaporation of the organics gave ethyl 2-acetoxy-2- (2-methoxyphenylethoxy) acetate (12.3g), which was used in the next step.
A solution of ethyl 2-acetoxy-2- (2-methoxyphenylethoxy) acetate (12.3g) in dichloromethane (415ml) was treated with AlCl at-20 deg.C3(5.5g) and stirred for 1 hr. Mixing AlCl3(5.5g) was added to the solution and stirred for 3.5hrs, poured into ice-water (400 ml). Using separation method A, the crude product was then distilled (1-2 mbar/120-.
A mixture of NaH (0.68g), ethyl 5-methoxyisochroman-1-carboxylate (1g) and DMF (10ml) was stirred at ice bath temperature for 2 hrs. Methyl iodide (2.6ml) was added and the mixture was stirred at ambient temperature for 16 hrs. Intermediate ethyl 5-methoxy-1-methylisochroman-1-carboxylate (0.7g) was purified by isolation method a and the title compound was synthesized using the procedure of synthesis method a, step 3 and isolation method D (diethyl ether). (yield 0.1g).
1H NMR(DMSO-d6)ppm 7.10(tr,1H),6.83(dd,2H),6.08(s,1H),3.85 (m,2H),3.77(s,3H),3.44–3.70(br m,2H),3.07–3.28(br s,2H),2.62(tr, 2H),1.60(s,3H).
Example 70 2- (5-Methoxyisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from 2-methoxyphenethyl methanesulfonate (3.58g) using the procedure of Synthesis F. The title compound was purified using isolation method E. (yield 60mg).
1H NMR(CD3OD)ppm 7.11(t,1H),6.84(d,1H),6.73(d,1H),3.82(s, 3H),3.46-3.66(m,4H),3.03-3.17(m,2H),2.75-2.87(m,2H).
Example 71- ((3R) -5-methoxy-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of NaH (0.17g), (3R) -5-methoxy-3-methylisochroman-1-carboxylic acid ethyl ester (0.3g) and DMF (7ml) was stirred at ice bath temperature for 2 hrs. Methyl iodide (0.7ml) was added and the mixture was stirred at ambient temperature for 16 hrs. Intermediate (3R) -5-methoxy-1, 3-dimethylisochroman-1-carboxylic acid ethyl ester (0.4g) was purified by isolation method A and the title compound was synthesized using the procedure of Synthesis method A, step 3 and isolation method E (EtOAc/DCM/triethylamine 10/20/1). (yield 0.3g).
1H NMR(CDCl3)ppm 7.01–7.24(m,2H),6.71–6.76(m,1H),3.97- 4.24(m,1H),3.80–3.84(m,3H),3.37–3.77(br,3H),2.77–2.90(m,1H), 2.32–2.42(m,1H),1.77(d,3H),1.35-1.41(m,3H),1.24–1.29(m,1H).
Example 72 2- (5- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1:2- (2- (2,2, 2-trifluoroethyl) phenyl) oxirane
Bromo-2- (2,2, 2-trifluoroethyl) benzene (0.5g) was dissolved in degassed toluene and tributyl (vinyl) tin (0.67mL), Pd were added2(dba)3(0.096g) and tri-tert-butylphosphine (0.25mL,1M solution). The reaction mixture was heated to 40 ℃. After 4 hours the heating was stopped and a1: 1 solution of diethyl ether and pentane (10ml) was added followed by potassium fluoride (1.0 g). After stirring the mixture for 30 minutes, it was filtered through a pad of silica gel and the filtrate was gradually concentrated under a vacuum of 500 mbar. The evaporation residue was purified by column chromatography (ether-pentane) and the fractions containing the product were concentrated by House vacuum distillation. The evaporated residue containing toluene (0.389g) and the desired styrene product were dissolved in dichloromethane (12mL) and 3-chloroperoxybenzoic acid (0.70g) was added. The reaction mixture was stirred at room temperature overnight. It was diluted in dichloromethane (20mL) and Na was added2SO3Solution (10mL, 1M). The two-phase mixture was stirred for 30 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (3 × 10 mL). All organic phases were combined and saturated NaHCO was used3Washing with solution, over Na2SO4Dried and concentrated (300mbar pressure). The evaporation residue was purified by separation method E (ether-pentane). (yield 220 mg).
1H NMR(CDCl3)ppm 7.26-7.38(m,4H),4.01-4.07(m,1H), 3.42-3.69(m,2H),3.17(dd,1H),2.69(dd,1H).
Step 2,2- (2- (2,2, 2-trifluoroethyl) phenyl) ethanol
The flask was loaded with Pd (0) EnCat 30NP (0.136g, washed with ethanol and ethyl acetate prior to use) and a solution of 2- (2- (2,2, 2-trifluoroethyl) phenyl) oxirane (0.110g) in ethyl acetate (1.5mL) was added followed by triethylamine (0.33mL) and formic acid (90. mu.L). After the mixture was stirred at room temperature for 26 hours, it was filtered. The precipitate was washed with ethyl acetate and the filtrate was concentrated. The evaporation residue was purified by separation method E (ethyl acetate-heptane). (yield 70mg).
1H NMR(CDCl3)ppm 7.19-7.34(m,4H),3.87(td,2H),3.50(q,2H), 2.96(t,2H).
Step 3 2- (5- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was synthesized from 2- (2- (2,2, 2-trifluoroethyl) phenyl) ethanol (70mg) using the procedure of synthesis method B. Boron trifluoride etherate was used instead of titanium (IV) chloride. (yield 53 mg).
1H NMR(CD3OD) ppm 7.16-7.28(m,3H),5.40(s,0.1H, exchangeable protons), 4.23(ddd,1H),3.84(ddd,1H),3.46-3.66(m,5H),3.46-3.53(m,1H), 2.99(ddd,1H),2.80(dt,1H).
Example 73 2- ((3R) -5-Ethyl-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Synthesis Process G
A mixture of NaH (0.39g), (3R) -5-ethyl-3-methylisochroman-1-carboxylic acid ethyl ester (0.6g) and DMF (7ml) was stirred at ice bath temperature for 2 hrs. Methyl iodide (1.5ml) was added and the mixture was stirred at ambient temperature for 16 hrs. Intermediate (3R) -5-Ethyl-1, 3-dimethylisochroman-1-carboxylic acid ethyl ester (0.5g) was purified by isolation method A and the title compound was synthesized using the procedure of Synthesis method A, step 3 and isolation method E (EtOAc/DCM/triethylamine 10/20/1). (yield 0.06 g).
1H NMR(CDCl3)ppm 7.30–7.07(m,3H),4,89(br,1H),3.81–4.10(M, 1H),2.47–2.77(m,4H),1.73–1.83(d,3H),1.38(tr,3H),1.21(td 3H).
Example 74- (5-methyl-3- (methoxymethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared by synthesis method a from ethyl 3- (methoxymethyl) -5-methylisochroman-1-carboxylate (200mg) and isolated by isolation method D. (yield 134 mg).
1H NMR(CD3OD)ppm 7.00-7.14(m,3H),5.45(s,1H),3.96(dd,1H), 3.50-3.67(m,6H),3.40-3.46(m,3H),2.63-2.74(m,2H),2.24(s,3H).
Example 75 1- (4, 5-dihydro-1H-imidazol-2-yl) -5-methylisochroman-7-ol, hydrobromide
2- (7-methoxy-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole (example 61,100 mg) was dissolved in hydrobromic acid (1.5mL,47 w-% in water) and the mixture was heated to reflux, after 5.5H, the mixture was cooled to room temperature. The solvent was evaporated and the evaporation residue was triturated with ethanol to obtain the title compound. (yield 27 mg).
1H NMR(D2O)ppm 6.84(d,1H),6.57(d,1H),5.76(s,1H),4.06(t,2H), 4.00(s,4H),2.74(t,2H),2.23(s,3H).
Example 76 1- (4, 5-dihydro-1H-imidazol-2-yl) -3-ethylisochroman-5-ol, hydrochloride
Step 1 methyl 3-ethyl-5-hydroxyisochroman-1-carboxylate
To a mixture of ethyl 5-bromo-3-ethyl isochroman-1-carboxylate (500mg) and KOH (358mg) were added dioxane (4.5ml) and water (1.5 ml). 2-di-tert-butyl-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4', 6 '. triisopropyl-1 ', 1 ' -biphenyl (38mg), tris (dibenzylideneacetone) dipalladium (0) and Pd2(dba)3(73mg) were added, and the mixture was heated at 100 ℃ for 2.5 h. After the reaction, the reaction mixture was evaporated to dryness and used directly in the next step.
The crude reaction was dissolved in MeOH (15 ml). Chlorotrimethylsilane (5.9ml) was added and the reaction mixture was stirred at rt overnight. The mixture was evaporated to dryness. The title compound was purified by isolation method E. (yield 90mg).
Step 21- (4, 5-dihydro-1H-imidazol-2-yl) -3-ethylisochroman-5-ol, hydrochloride
3-Ethyl-5-hydroxyisochroman-1-carboxylic acid methyl ester (90mg) was dissolved in dichloromethane (1mL) and 3, 4-dihydro-2H-pyran (52. mu.L) and p-pyridinium tosylate were addedSalt (9.6 mg). After 28 hours, more 3, 4-dihydro-2H-pyran (102. mu.L) and p-pyridinium tosylate were addedSalt (10mg) and the mixture was stirred for a further 24 hours. 3, 4-dihydro-2H-pyran (200. mu.L) was then added and the mixture was stirred overnight, then it was diluted with ether (5ml) and saturated NaHCO3-solution washing. The organic phase is treated with Na2SO4Dried and concentrated. The evaporation residue was purified by column chromatography (ethyl acetate-heptane) to yield 37mg of oil, which was purifiedSynthesis procedure A3 was used to convert 2- (3-ethyl-5- ((tetrahydro-2H-pyran-2-yl) oxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole (13 mg). The crude product of this procedure was dissolved in methanol (1ml) and HCl in ether (2M, 39. mu.L) was added. After 2.5 hours, the reaction mixture was concentrated and the residue was taken up in water (10 mL). The solution was washed with ethyl acetate and the aqueous layer was concentrated in a freeze-dryer to obtain the title compound. (yield 6mg).
1H NMR(DMSO-d6)ppm 10.43(s,1.3H),9.92(s,0.45H)9.80(s,0.9H), 7.03-7.14(m,1H),6.78-6.88(m,1H),6.58-6.70(m,1H),5.78(s,0.11H), 5.75(s,0.61H),3.84-3.93(m,4H),3.61-3.74(m,1H),2.77(d,1H),2.28- 2.44(m,1H),1.53-1.76(m,2H),0.92-1.03(m,3H).
EXAMPLE 77 enantiomer of 2- (5-methoxy-3- (2,2, 2-trifluoroethyl) methyl-isochroman-1-yl) -4, 5-dihydro-1H-imidazole-2
Step 1 (R) -4,4, 4-trifluoro-1- (2-methoxyphenyl) butan-2-ol
To a solution of 4,4, 4-trifluoro-1- (2-methoxyphenyl) butan-2-one (6g,25.8mmol, as synthesized in example 52, step 1) in MeOH (100ml) at 0 deg.C was added NaBH4(1.47g, 38.7mmol) and stirred at RT for 1 h. The reaction mixture was then quenched with MeOH and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation method A, E and H, yield (1.7 g). Using Chiralpak 1A (4.6X250mm) 5. mu.l, hexane: 2-PrOH: TFA (90:10:0.1),1ml/min, the enantiomer showed tr＝12.8min。
Step 2 enantiomer-2 of 2- (5-methoxy-3- (2,2, 2-trifluoroethyl) methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared by synthesis method G from enantiomer-2 of 4,4, 4-trifluoro-1- (2-methoxyphenyl) butan-2-ol (900mg) and isolated by isolation method E. (yield 30mg).
1H NMR(CD3OD)ppm 7.14-7.26(m,2H),6.85(t,1H),5.46(s,1H), 4.06(dd,1H),3.81-3.88(m,3H),3.48-3.69(m,4H),2.93(dd,1H),2.45- 2.70(m,2H).
Example 78 2- (1, 5-Dimethylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was synthesized using the procedures of 1, 5-dimethylisothiochroman-1-carboxylic acid ethyl ester and synthesis method a, step 3 and isolation methods D (diethyl ether), E (EtOAc/DCM/triethylamine 10/18/1) and D (diethyl ether/heptane), respectively. (yield 0.06 g).
1H NMR(DMSO-d6)ppm 7.04(m,3H),5.91(s,1H),3.45–3.70(br, 2H),3.18–3.30(br,2H),3.03–3.12(m,1H),2.92–2.81(m,3H),2.20(s, 3H),1.77(s,3H).
Example 79 2- (5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
The title compound was prepared from 1- (2- (2- (trifluoromethoxy) phenyl) ethanol (2,2g) using the procedure of Synthesis method B (using boron trifluoride etherate instead of titanium (IV) chloride and only 1/3 intermediate ethyl 5- (trifluoromethoxy) isochroman-1-carboxylate for the last step.) the resulting base was used in salt formation method A (Et of HCl)2O and DCM solution as solvents) to HCl salt (yield 192 mg).
1H NMR(DMSO-d6)ppm 10.64(s,2H),7.27-7.56(m,3H),5.94(s, 1H),4.17(dt,1H),3.83-3.96(m,1H),3.90(br.s,4H),2.75-2.99(m,2H).
EXAMPLE 80 enantiomer of 2- (3-Ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole-1, HCl salt
The title compound was prepared from the compound of example 8 (500mg) using isolation method L, the faster eluting enantiomer (138 mg).
1H NMR(CD3OD)ppm 7.26(d,2H),7.06(t,1H),5.76(s,1H),4.14- 4.25(m,1H),3.89-4.02(m,5H),2.79-3.02(m,2H),2.68(q,2H),1.22(t, 3H).
Example 81 2- (3- (2-fluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
Step 1:1- (2- (benzyloxy) pent-4-enyl) -2-methylbenzene
To a suspension of NaH (4.9g,127.8mmol) in THF (150ml) was added 1-o-tolylpent-4-en-2-ol (15g in THF, 85.22mmol) at 0 deg.C and stirred for 30 min. Benzyl bromide (17.85g,102.2mmol) was then added at 0 ℃ and the reaction mixture was stirred at room temperature for 16 h. Then using ice-cold H2O quench and concentrate under reduced pressure to afford crude compound. The title compound was isolated by separation methods-a and E. (yield 13.0g).
Step 2 3- (benzyloxy) -4-o-tolylbutanal
To a solution of 1- (2- (benzyloxy) pent-4-enyl) -2-methylbenzene (5.0g,18.72mmol) in DCM (100ml) at-78C was passed O3Gas for 3 h. The reaction mixture was quenched with TEA (5ml) at-78 ℃ and stirred at room temperature for 5 h. The title compound was purified by separation methods a and E. (yield 2.0 g).
Step 3-3- (benzyloxy) -4-o-tolylbutan-1-ol
To a solution of 3- (benzyloxy) -4-o-tolylbutanal (4.0g,14.81mmol) in MeOH (50ml) at 0 deg.C was added NaBH4(1.13g,29.62mmol) and stirred at room temperature for 2 h. The reaction mixture was quenched with water and concentrated under reduced pressure to obtain crude compound. The title compound was purified by separation methods a and E. (yield 3.0g).
Step 4:1- (2- (benzyloxy) -4-fluorobutyl) -2-methylbenzene
To 3- (benzyloxy) -4-o-tolylbutan-1-ol (3.0g,11.11 mmo) at 0 deg.Cl) in DCM (50ml) DAST (2.9ml,22.22mmol) was added and stirred at room temperature for 5 h. Then cooled to 0 ℃ and treated with NH4Cl (10ml) quench. The title compound was purified by separation methods a and E. (yield 1.5g).
Step 5 4-fluoro-1-o-tolylbutan-2-ol
To a solution of 1- (2- (benzyloxy) -4-fluorobutyl) -2-methylbenzene (3.0g,11.03mmol) in MeOH (50ml) under nitrogen was added 10% Pd/C (0.3g) and stirred at 40psi for 5 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain crude compound. The title compound was purified by isolation method E. (yield 1.5g).
Step 6 Ethyl 3- (2-fluoroethyl) -5-methylisochroman-1-carboxylate
The title compound was prepared by Synthesis method A from 4-fluoro-1-o-tolylbutan-2-ol (3.0g,16.48mmol) and purified by separation methods A and E (yield 1.0 g).
Step 7 2- (3- (2-fluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
The title compound was prepared from 3- (2-fluoroethyl) -5-methylisochroman-1-carboxylate (200mg) by synthetic method a and salt formation method a and isolated by isolation method D. (yield 50mg).
1H NMR(CD3OD)ppm 7.15-7.34(m,2H),7.01-7.12(m,1H),5.83(s, 1H),4.53-4.81(m,2H),3.94-4.10(m,5H),2.30(s,3H),2.79-2.94(m,1H), 2.59-2.79(m,1H),1.98-2.27(m,2H).
Example 82 enantiomer of 2- (5-Methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from the compound of example 17 (160mg) using separation method L, the faster eluting enantiomer, (77 mg).
1H NMR(DMSO-d6)ppm 10.54(br.s,2H),7.27(t,1H),6.99(d,1H), 6.85(d,1H),5.83(br.s.,1H),4.10-4.17(m,1H),3.87(br.s,4H)3.82-3.86 (m,1H),3.81(s,3H),2.65-2.81(m,2H).
EXAMPLE 83 enantiomer of 2-5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, HCl-salt
The title compound was prepared by synthesis method B from enantiomer-2 of ethyl 1- (2-bromophenyl) -4,4, 4-trifluorobutan-2-ol (500mg, example 68, step 2) and isolated by isolation method E. The resulting base was subjected to salt formation method A (Et of HCl)2O and DCM solution as solvent) to HCl salt (yield 290 mg).
1H NMR(DMSO-d6) ppm 10.61(br.s.,1.24H),10.50(br.s,0.76H), 7.61-7.79 (overlapping m,1H),7.21-7.39 (overlapping m,2H),5.98(br.s,0.62H),5.97 (bs.s,0.38H),4.24(dd,1H),3.83-3.95(m,4H),2.60-3.08(m,4H).
Example 84 2- (3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
Step 1:1- (2- (benzyloxy) -4, 4-difluorobutyl) -2-methylbenzene
To a solution of 3- (benzyloxy) -4-o-tolylbutan-1-ol (10g,37.04mmol, example 81, step 3) in DCM (100ml) was added DAST (10ml, Wt/V) at 0 ℃ and stirred at room temperature for 5 h. Then cooled to 0 ℃ and treated with NH4Cl (50ml) extraction. The title compound was purified by separation methods a and E. (yield 7.0 g).
Step 2, 4-difluoro-1-o-tolylbutan-2-ol
To a solution of 1- (2- (benzyloxy) -4, 4-difluorobutyl) -2-methylbenzene (10g,34.48mmol) in MeOH (150ml) under nitrogen was added 10% Pd/C (1.0g) and stirred at 40psi for 5 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain crude compound. The title compound was purified by isolation method E. (yield 6.0 g).
Step 3 Ethyl 3- (2, 2-difluoroethyl) -5-methylisochroman-1-carboxylate
The title compound was prepared by Synthesis method A from 4, 4-difluoro-1-o-tolylbutan-2-ol (5.0g,25.0mmol) and purified by separation methods A and E. (yield 1.5g).
Step 4 2- (3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, HCl salt
The title compound was prepared from ethyl 3- (2, 2-difluoroethyl) -5-methylisochroman-1-carboxylate (200mg) by synthetic method a and salt formation method a and was isolated by isolation method D. (yield 130 mg).
1H NMR(CD3OD)ppm 7.15-7.31(m,2H),7.05(d,1H),6.03-6.30(m, 1H),5.83(s,1H),4.09(ddd,1H),3.96-4.04(m,4H),2.86(dd,1H),2.73(dd, 1H),2.19-2.40(m,5H).
Example 85 2- (7-methoxy-3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of 2-bromo-5-methoxytoluene (2g) and THF (10ml) was treated with n-butyllithium (8.8 ml of a 2.5M heptane solution) at-78 deg.C and stirred for 15min before a solution of propylene oxide (0.9ml) in THF (5ml) was added. After stirring at-78 ℃ for 30min, the reaction mixture was brought to ambient temperature and the intermediate 1- (4-methoxy-2-methylphenyl) propan-2-ol was purified using isolation methods a and E (EtOAc/heptane), respectively. A mixture of ethyl 2, 2-diethoxyacetate (0.6ml), 1- (4-methoxy-2-methylphenyl) propan-2-ol (0.5g) and DCE (4ml) was stirred at the temperature of an ice bath, and boron trifluoride etherate (0.7ml) was added, followed by refluxing for 4 hrs. Intermediate 7-methoxy-3, 5-dimethylisochroman-1-carboxylic acid ethyl ester (0.05g) was purified using isolation procedures B and E (ethyl acetate/heptane), respectively. The title compound was synthesized using the procedure of synthesis a, step 3 and isolation D (ether/heptane). (yield 0.01g).
1H NMR(CDCl3)ppm 6.74(dd,2H),5.45(d,1h),3.83–3.92(m,1H), 3.75(d,3H),3.40–3.71(br,3H),2.368–2.68(m,2H),2.2(s,3H),1.37(dd, 3H).
Example 86 enantiomer of 2- ((3) -5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, hydrochloride
Step 1 enantiomer of (4,4, 4-trifluoro-1-o-tolylbutan-2-ol
To a solution of 4,4, 4-trifluoro-1-o-tolylbutan-2-one (7.0g,32.4mmol, example 52, step 1) in MeOH (150ml) at 0 deg.C was added NaBH4(1.84g,48.6mmol) and stirred at RT for 1 h. The reaction mixture was then quenched with MeOH and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation method A, E and H. Yield (1.4 g). Using Chiralcel OD-H (4.6X250mm) 5. mu.g, hexane: 2-PrOH: TFA (90:10:0.1),1ml/min, enantiomer showed tr＝7.0min。
Step 2 enantiomer of 2- ((3) -5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, hydrochloride
The title compound was synthesized from enantiomer-2 of 4,4, 4-trifluoro-1-o-tolylbutan-2-ol (1.19g) as in example 52 and converted to the HCl salt according to salt formation method A. (yield 74 mg).
1H NMR(DMSO-d6)ppm 10.52(br s,1.5H),10.13(br.s,2H),7.16- 7.29(m,2H),7.05-7.13(m,1H),5.93(s,0.75H),5.89(s,0.22H),4.14-4.28 (m,1H),3.83-3.93(m,4H),2.61-2.91(m,4H),2.23(s,3H).
Example 87- (5- (methylthio) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1,3, 4-dihydro-5- (methylthio) -1H-isochromene-1-carboxylic acid ethyl ester
A solution of ethyl 5-bromoisochroman-1-carboxylate (syntheses A1 and A2,0.5g,1.75mmol), NaSMe (0.18,3.3mmol) and CuBr (0.435g,1.8mmol) in DMF (10ml) was heated to 90 ℃ under microwave radiation and reacted for 15 min. The title compound was purified by separation methods D and E. (yield 100 mg).
Step 2- (5- (methylthio) isochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from ethyl 5- (methylthio) isochroman-1-carboxylate (490mg) by synthetic method a and isolated by isolation method G. (yield 380 mg).
1H NMR(CDCl3)ppm 7.17-7.22(m,2H),7.08-7.13(m,1H),5.44(s, 1H),4.24(ddd,1H),3.89(ddd,1H),3.45-3.82(m,4H),2.70-2.93(m,2H), 2.46(s,3H).
Example 88 enantiomer of 2- ((3) -5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, hydrochloride
Step 1 enantiomer-2 of 1- (2-bromophenyl) pentan-2-ol
To a solution of 2- (2-bromophenyl) acetaldehyde (16g,80.8mmol) in THF (100ml) was added propylmagnesium bromide (48ml (2.0M) in THF) at 0 deg.C, 97mmol), followed by stirring at room temperature for 5 h. The reaction mixture was quenched with ammonium chloride and the title compound was purified by separation method A, E and H. (yield 740 mg). Using Chiralcel OD-H (4.6X250mm) 5. mu.g, hexane: 2-PrOH: TFA (90:5:0.1),1ml/min, this enantiomer-2 showed tr＝5.70min。
Step 2 enantiomer, hydrochloride salt of 2- ((3) -5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound (yield 510mg) was synthesized from enantiomer-2 (1.0g) of 1- (2-bromophenyl) pentan-2-ol using the procedures of Synthesis B and salt formation A. Boron trifluoride etherate was used instead of titanium (IV) chloride.
1H NMR(DMSO-d6)ppm 10.73(br s,1.8H),10.16(br s,0.1H), 7.70-7-63(m,1H),7.21-7.34(m,2H),5.92(br s,1H),3.78-3.94(m,5H), 2.78-2.88(m,1H),2.61(dd,1H),1.59-1.72(m,2H),1.35-1.57(m,2H),0.93 (m,3H).
EXAMPLE 89 enantiomer-2 hydrochloride of 2- (-3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1 enantiomer of 1- (2- (benzyloxy) -4, 4-difluorobutyl) -2-methylbenzene
Racemic 1- (2- (benzyloxy) -4, 4-difluorobutyl) -2-methylbenzene (example 84, step 2) was separated into the enantiomers using separation method H (retention time 8.6min,1ml/min, Chiralcel OJ-H,4.6X250mm,90:10:0.1 hexane: iPrOH: TFA) (yield 4.0g).
Step 2 enantiomer of 2- (-3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, hydrochloride
The title compound was synthesized from enantiomer of ethyl (3) -3- (2, 2-difluoroethyl) -5-methylisochroman-1-carboxylate-2 (250mg) using the procedure of synthesis method a3 and salt formation method a. (yield 100 mg).
1H NMR(DMSO-d6)ppm 10.67(s,2H),7.09-7.23(m,3H),6.14-6-45 (tt,1H),5.93(s,1H),3.97-4.08(m,1H),3.85-3.92(m,4H),2.81(dd,1H), 2.63-2.74(m,1H),2.24-2.37(m,2H),2.23(s,3H).
Example 90- (5- (difluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
The title compound was synthesized from ethyl 5- (difluoromethoxy) isochroman-1-carboxylate (220mg) using the procedures of synthesis method a3 and salt formation method a. (yield 180 mg).
1H NMR(DMSO-d6)ppm 10.41(s,2H),7.38(t,1H),7.27(t,1H),7.22 (d,1H),7.15(d,1H),5.85(s,1H),4.14(td,1H),3.83-3.95(m,5H),2.72- 2.90(m,2H).
Example 91 2- ((3R) -3-Ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from (R) -5-bromo-3-ethylisochroman-1-carboxylic acid ethyl ester (700mg) by synthetic method E (refluxing with 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) and a. The C-O coupling reaction (E) gives the free acid, which is further methylated before the last step (Synthesis method A). The title compound was obtained by concentrating the reaction mixture. (yield 169mg).
1H NMR(CD3OD)ppm 7.00-7.22(m,1H),6.76-6.85(m,2H),5.38(s, 1H),3.82(s,3H),3.45-3.71(m,4H),2.82(dd,1H),2.41(dd,1H),1.53-1.81 (m,2H),0.95-1.12(m,3H).
EXAMPLE 92 enantiomer of 2- (5-Chloroisoproman-1-yl) -4, 5-dihydro-1H-imidazole-1, HCl salt
The title compound was prepared from the compound of example 8 (500mg) by isolation method L, the faster eluting enantiomer, (43 mg).
1H NMR(DMSO-d6)ppm 10.50(br.s,2H),7.51(d,1H),7.35(t,1H), 7.25(d,1H),5.86(br.s.,1H),4.13-4.22(m,1H),3.83-3.99(m,5H),2.78- 2.96(m,2H).
Example 93 2- ((3R) -5- (difluoromethoxy) -3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
Step 1 (R) -1- (2-bromophenyl) propan-2-ol
To a solution of 1- (2-bromophenyl) propan-2-one (30g,140mmol) in MeOH (100ml) at 0 deg.C was added NaBH4(6.09g,210mmol) and stirred at room temperature for 2 h. The reaction mixture was quenched with water and concentrated under reduced pressure to obtain crude compound. The title compound was purified by separation method A, E and M (yield 28.0 g). Using Chiralcel OD-H (4.6X250mm) 5. mu.l, hexane: 2-PrOH: TFA (90:5:0.1),1ml/min, this enantiomer-1 showed tr＝7.86min。
Step 2 (3R) -5-bromo-3-methylisochroman-1-carboxylic acid ethyl ester
The title compound was prepared from R-2- (2-bromophenyl) by synthetic methods a1 and a2 and purified by isolation methods a and E. (yield 2.0g)
Step 3 (3R) -5-hydroxy-3-methylisochroman-1-carboxylic acid ethyl ester
To a solution of ethyl (3R) -5-bromo-3-methylisochroman-1-carboxylate (2.0g,5.95mmol) in dioxane (50ml) and water (10ml) at room temperature were added KOH (1.37g,35.7mmol), tetramethyl di-tert-butyl XPhos (0.28g,0.06mmol) and Pd2(dba)3(0.06g,0.06 mmol). Then the reaction mixture is treated with N2Degassed three times and stirred at 100 ℃ for 16 h. The reaction mixture was quenched with MeOH and concentrated under reduced pressure to afford crude compound. The crude product was dissolved in EtOH (80ml) and H was added2SO4(1.0ml) was then stirred at 80 ℃ for 5 h. The solvent was evaporated to give crude compound. The title compound was purified by separation methods a and E. (yield 100 mg).
Step 4 (3R) -5- (difluoromethoxy) -3-methylisochroman-1-carboxylic acid ethyl ester
To a solution of (3R) -5-bromo-3-methylisochroman-1-carboxylic acid ethyl ester (0.25g,1.05mmol) in DMF (5.0 ml) was added K2CO3(0.184g,1.35 mmol). Then flushed with difluoro-chloro-methane gas at room temperature for 2h and stirred at 50 ℃ for 4 h. The reaction mixture was quenched with water. The title compound was purified by separation methods a and E. (yield 40mg). Using Chiralcel OD-H (4.6X250mm) 5. mu.l, hexane: 2-PrOH: TFA (90:5:0.1),1ml/min, the enantiomer-1 (i.e. (R) shows tr＝4.71min.
Step 5 2- ((3R) -5- (difluoromethoxy) -3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
The title compound was synthesized from ethyl (3R) -5- (difluoromethoxy) -3-methylisochroman-1-carboxylate (250mg) using the procedures of synthesis method a3 and salt formation method a. (yield 200mg).
1H NMR(DMSO-d6) ppm 10.81(s,1.75H),10.22(s,0.14H),7.36(t, 1H),7.29(t,1H),7.17-7.23(m,2H),5.98(s,0.07H),5.96(s,0.88H), 3.84-4.00(m,5H, and H)2O signal overlap), 2.81-2.92(m,1H),2.57(dd,0.89H), 2.45(dd,0.09H),1.36(d,2.65H),1.33(d,0.29H).
EXAMPLE 94 enantiomer of 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
Step 1 enantiomer of 1- (2-bromophenyl) butan-2-ol
To a solution of 2- (2-bromophenyl) acetaldehyde (15g,75.37mmol) in THF (100ml) at 0 deg.C was added propylmagnesium bromide (1.0M in THF) (15.13g,113.6mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was quenched with ammonium chloride and the title compound was purified by separation methods A, E and M. (yield 7.0 g). Using Chiralcel OJH (4.6X250mm) 5. mu.l, hexane: ethanol (98:02),1ml/min, the enantiomer showed tr＝13.6min。
Step 2 enantiomer of 2- (-5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared by synthesis method a from the enantiomer of ethyl 3- (2, 2-difluoroethyl) -5-methylisochroman-1-carboxylate (500mg) and isolated by isolation method E. (yield 470mg).
1H NMR(CD3OD)ppm 7.44-7.58(m,1H),7.24(d,1H),7.00-7.16(m, 1H),5.39(s,1H),3.49-3.73(m,5H),2.82-2.90(m,1H),2.42-2.64(m,1H), 1.54-1.82(m,2H),0.92-1.12(m,3H).
EXAMPLE 95 enantiomer of 2- (5-Chloroisoproman-1-yl) -4, 5-dihydro-1H-imidazole-1, HCl salt
The title compound was prepared from example 2(130mg) by separation method L, the faster eluting enantiomer, (28 mg).
1H NMR(DMSO-d6)ppm 10.44(br.s.,2H),7.61-7.77(m,1H),7.17- 7.34(m,2H),5.85(br.s.,1H),4.08-4.22(m,1H),3.81-4.03(m,5H),2.70- 2.93(m,2H).
Example 96 enantiomer of 2- (3-Ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole-2
The title compound was prepared from the compound of example 8 (500mg), the slower eluting enantiomer, (110mg) by separation method L.
1H NMR(CD3OD)ppm 7.26(d,2H),7.06(t,1H),5.76(s,1H),4.14- 4.25(m,1H),3.89-4.02(m,5H),2.79-3.02(m,2H),2.68(q,2H),1.22(t, 3H).
EXAMPLE 97 enantiomer of 2- (5-Methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, HCl salt
The title compound was prepared from the compound of example 17 (160mg), the slower eluting enantiomer, (77mg) by separation method L.
1H NMR(DMSO-d6)ppm 10.45(br.s,2H),7.27(t,1H),6.99(d,1H), 6.83(d,1H),5.81(br.s.,1H),4.10-4.17(m,1H),3.87(br.s,4H)3.82-3.86 (m,1H),3.81(s,3H),2.65-2.80(m,2H).
Example 98- (1-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole
A mixture of NaH (0.18g), 1, 3-dihydrobenzo [ de ] isochromene-1-carboxylic acid methyl ester (0.5g) and DMF (2ml), toluene (2ml) and THF (6ml) was stirred at ice bath temperature, methyl iodide (0.7ml) was added and the mixture was stirred at ambient temperature for 3 hrs. Intermediate methyl 1-methyl-1, 3-dihydrobenzo [ de ] isochromene-1-carboxylate (0.3g) was purified by separation methods a and E (EtOAc/heptane) and the title compound was synthesized using the procedure of synthesis method a, step 3 and separation method E (EtOAc/DCM/triethylamine 10/20/1). (yield 0.1g).
1H NMR(CDCl3)ppm 7.77(td,2H),7.41–7.53(m,3H),7.21(dd,1H), 5.14(q,2H),4.92(br,1H),3.14-4.19(br,4H),1.90(s,3H).
Example 99- (5- (difluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
Step 1:5- (difluoromethyl) isochroman-1-carboxylic acid ethyl ester
To a solution of ethyl 5-formylisochroman-1-carboxylate (200mg) in dichloromethane (1mL) was added diethylaminosulfur trifluoride (275mg), and the solution was stirred at room temperature for 22 hours. The solvent was evaporated and the crude product was purified by separation method E (EtOAc-heptane). (yield 153 mg).
1H NMR(CDCl3)ppm 7.53(d,1H),7.46(d,1H),7.24-7.33(m,1H), 6.72(t,1H),5.36(s,1H),4.21-4.38(m,3H),4.01-4.11(m,1H),2.90-3.06 (m,2H),1.32(t,3H).
Step 2- (5- (difluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
The title compound (yield 87mg) was synthesized from ethyl 5- (difluoromethyl) isochroman-1-carboxylate (153mg) using the procedures of Synthesis method A3 and salt formation method A.
1H NMR(DMSO-d6)ppm 10.51(br.s,2H),7.58(t,1H),7.42-7.48(m, 2H),7.21(t,1H),5.93(s,1H),4.11-4.20(m,1H),3.82-3.94(m,5H),2.87- 3.11(m,2H).
EXAMPLE 100 enantiomer of 2- (5-Chloroisomerin-1-yl) -4, 5-dihydro-1H-imidazole-2, HCl salt
The title compound was prepared from the compound of example 8 (500mg), the slower eluting enantiomer, by separation method L, (40mg)
1H NMR(DMSO-d6)ppm 10.50(br.s,2H),7.51(d,1H),7.35(t,1H), 7.25(d,1H),5.86(br.s.,1H),4.13-4.22(m,1H),3.83-3.99(m,5H),2.78- 2.96(m,2H).
Example 101 enantiomer of 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole-2, HCl salt
The title compound was prepared from the compound of example 2(130mg), the slower eluting enantiomer, (22mg) by separation method L.
1H NMR(DMSO-d6)ppm 10.44(br.s.,2H),7.61-7.77(m,1H),7.17- 7.34(m,2H),5.85(br.s.,1H),4.08-4.22(m,1H),3.81-4.03(m,5H),2.70- 2.93(m,2H).
Example 102 2- (1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
At 0 ℃ to 1, 3-dihydrobenzo [ de ]]To a solution of isochromen-1-ol (100mg) in acetonitrile (3mL) was added zinc (II) iodide (86mg) and the suspension was stirred at 0 ℃ for 10 min. Trimethylsilyl cyanide (672 μ L) was added and the reaction mixture was stirred at room temperature overnight. Saturated NaHCO was added3Solution (10mL) and the mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic phases were washed with brine and Na2SO4And (5) drying. Evaporation of the solvent gave 110mg of 1, 3-dihydrobenzo [ de ]]Isochromene-1-carbonitrile, which was mixed with ethylenediamine mono-p-toluenesulfonate (157mg), and the mixture was heated to 200 ℃. After 3 hours, the reaction mixture was cooled to room temperature and taken up in dichloromethane (10ml) and NaHCO3Aqueous solution (1:1 saturated solution/water) mixture. Separating the phases and subjecting the aqueous phase to a treatment with dichloro-methaneMethane (5mL) was extracted. The combined organic phases were washed with Na2SO4Dried and concentrated. By separation method E (aq. NH)3MeOH-dichloromethane) purification of the evaporation residue. The resulting 2- (1, 3-dihydrobenzo [ de ] was reacted using salt formation method A]Isochromen-1-yl) -4, 5-dihydro-1H-imidazole was converted into the title compound.
1H NMR(DMSO-d6)ppm 10.56(s,2H),7.99(d,1H),7.91(d,1H), 7.53-7.62(m,2H),7.41(d,2H),6.25(s,1H),5.22(AB q,2H),3.90-4.05(m, 4H).
EXAMPLE 103 enantiomer of 2- (1-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from the compound of example 98 (1.2g) by separation method H, the slower eluting enantiomer, (10mg)
1H NMR(CDOD3) ppm 7.81(dd,1H),7.77(d,1H), 7.41-7.53 (m,3H), 7.24(dd,1H),5.14(s,2H),4.76-4.84(m,4H, methanol), 1.85(s,3H).
Example 104 2- (3-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
At-78 deg.C over 25 minutes to 3-methylbenzo [ de ]]To a solution of isochromen-1 (3H) -one (1.38g) in dichloromethane (34mL) was added diisobutylaluminum hydride (10.5mL, 20% in toluene). After 2 hours, 10% aqueous citric acid (20mL) was added and the mixture was stirred at room temperature for 25 minutes. To the resulting suspension were added water (20mL) and dichloromethane (20mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 20mL) and the combined organic phases were washed with brine, washed with Na2SO4Dried and concentrated. The evaporation residue solidified in the refrigerator was purified by trituration with heptane. The obtained 3-methyl-1, 3-dihydrobenzo [ de ]]Isochromen-1-ol (0.92g, mixture of diastereomers) was dissolved in dichloromethane (16mL) and cooled to 0 ℃. Adding intoTrimethylcyanosilane (1.71mL) was added followed by boron trifluoride triethetherate (1.14 mL). After 1.5 hours, saturated NaHCO was added3The solution (10mL) was extracted with dichloromethane. The combined organic phases were washed with brine and dried (Na)2SO4) And concentrated. The evaporation residue was purified by trituration with heptane to give 0.68g of 3-methyl-1, 3-dihydrobenzo [ de ]]Isochromene-1-carbonitrile (a mixture of diastereomers).
3-methyl-1, 3-dihydrobenzo [ de ] isochromene-1-carbonitrile (100mg) was mixed with ethylenediamine mono-p-toluenesulfonate (111mg), and the mixture was heated to 200 ℃. After 3 hours, the reaction was cooled to room temperature. Purification by column chromatography (ethyl acetate-heptane) using neutral alumina afforded 11mg of 2- (3-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole, which was converted to the title compound using salt formation method a. (yield 10 mg).
1H NMR(DMSO-d6)ppm 10.76(s,1H),10.25(s,0.5H),7.88-8.05(m, 2H),7.52-7.66(m,2H),7.30-7.52(m,2H),6.30(s,0.3H),6.27(s,0.6H),5.35 (q,0.6H),3.92(q,0.3H),3.86-4.08(m,4H),1.74(d,2H),1.66(d,1H).
Example 105 2- (3-Ethyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole, hydrochloride
At-78 deg.C to 3-ethylbenzo [ de ]]To a solution of isochromen-1 (3H) -one (0.55g) in dichloromethane (7mL) was added diisobutylaluminum hydride (2.19mL, 20% in toluene). After 3 hours, 10% aqueous citric acid (10mL) was added and the mixture was stirred at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were washed with brine and Na2SO4Dried and concentrated. The evaporation residue was purified by column chromatography (ethyl acetate-heptane) to give 3-ethyl-1, 3-dihydrobenzo [ de ]]Isochromen-1-ol (0.22g, mixture of diastereomers), dissolved in dichloromethane (5 mL). The solution was cooled to 0 ℃ and trimethylsilyl cyanide (0.39mL) was added followed byBoron trifluoride triethetherate (0.26mL) was added. After 2.5 hours saturated NaHCO was added3The solution (10mL) was extracted with dichloromethane. The combined organic phases were washed with brine and dried (Na)2SO4) And concentrated. Will comprise 3-ethyl-1, 3-dihydrobenzo [ de ]]The evaporated residue of the mixture of diastereomers of isochromene-1-carbonitrile (170mg) was combined with dioxane (2mL), 10% aqueous NaOH (1.6mL) was added and the mixture was heated to reflux. After 13 hours, the reaction mixture was cooled to room temperature and water (10mL) and dichloromethane (10mL) were added. The aqueous phase was acidified with 4M HCl and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, washed with Na2SO4Dried and concentrated. Will comprise 3-ethyl-1, 3-dihydrobenzo [ de ]]The evaporation residue of isochromene-1-carboxylic acid (80mg) was converted to the title compound using synthesis methods a2 and A3 and isolation method E in A3. The obtained 2- (3-ethyl-1, 3-dihydrobenzo [ de ]]Isochromen-1-yl) -4, 5-dihydro-1H-imidazole was converted to the title compound using salt formation method a. (yield 5.7mg).
1H NMR(DMSO-d6)ppm 10.73(br s,0.9H),10.42(br s,0.7H),7.99(dd, 1H),7.92(dd,1H),7.53-7.63(m,2H),7.31-7.50(m,2H),6.28(s,0.4H),6.24 (s,0.5H),5.18-5.23(m,0.5H),5.12(t,0.4H),3.90-4.08(m,4H),2.31-2.43(m, 0.5H),1.92-2.24(m,1.4H),1.01-1.12(m,3H).
EXAMPLE 106 enantiomer of 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole
The title compound was prepared from the compound of example 11 (400mg) by isolation method H, the faster eluting enantiomer, (160 mg).
1H NMR(DMSO-d6)ppm 7.49(dd,1H),7.31(dd,1H),7.11(dd,1H), 6.24(s,H),3.79-3.98(m,2H),3.41-3.71(br.s.,2H),3.10-3.73(br.s.,2H), 1.62(s,3H).
As already mentioned above, the compounds of formula I exhibit interesting pharmacological properties, i.e. they exhibit adrenergic propertiesAgonist activity at the α 2 receptor, especially the α 2A receptor, as demonstrated by pharmacological tests provided belowEt al, eur.j.pharmacol.2008,599,65-71) screened for adrenergic α 2 receptor activity the results are shown in table 1 metabolic stability was measured using cryopreserved hepatocytes according to literature methods (Di et al, int.j.pharmaceuticals, 2006,317, 54-60).
TABLE 1 alpha 2A in vitro agonist Activity
The compounds of formula I exhibit adrenergic alpha 2 receptor, particularly alpha 2A receptor, agonistic activity. Accordingly, the present invention provides a compound for use as a medicament. Also provided are compounds for use in the treatment of a condition, disorder or disease in which an alpha 2 agonist, such as an alpha 2A agonist, is indicated to be useful. In addition, methods for treating conditions, disorders or diseases in which an alpha 2 agonist, e.g., an alpha 2A agonist, is indicated to be useful are also provided. In said method, an effective amount of at least one compound of formula I is administered to a mammal, e.g., a human, in need of such treatment. Also provided is the use of a compound of formula I in the manufacture of a medicament for the treatment of a condition, disorder or disease in which an alpha 2 agonist, for example an alpha 2A agonist, is indicated to be useful.
In one embodiment of the invention, the above-described disorder, condition or disease in which an α 2 agonist, e.g., a α 2A agonist, is indicated to be useful is delirium, hyperactive delirium, insomnia, ADHD, benzodiazepinesOr alcohol or opioid or tobacco withdrawal, premature ejaculation, hypertension, tachycardia, restless leg syndrome, muscle spasticity, hot flashes, anxiety, post traumatic stress disorder, pain, chronic pelvic pain syndrome, breakthrough cancer pain or a condition requiring sedation or analgesia; such as hyperactive delirium or insomnia.
The invention also provides compounds of formula I for use as sedatives or analgesics.
The compounds of the present invention may be administered, for example enterally, topically or parenterally, by any pharmaceutical formulation used for said administration and comprising a pharmaceutically acceptable and effective amount of at least one active compound of formula I and pharmaceutically acceptable diluents, carriers and/or excipients known in the art. The preparation of such pharmaceutical formulations is known in the art.
The therapeutic dose administered to an individual in need of such treatment will vary depending on the compound administered, the species, age and sex of the individual being treated, the specifics of the treatment, and the route and method of administration, and will be readily determined by those skilled in the art. Thus, for adult mammals, a typical dose for oral administration is from 10ng/kg to 100mg/kg per day, and a typical dose for parenteral administration is from 1ng/kg to 10 mg/kg.
The compounds of the invention may be administered to an individual as such, or in combination with one or more other active ingredients (each in its own composition, or some or all of the active ingredients combined in a single composition) and/or suitable pharmaceutical excipients. Suitable pharmaceutical excipients include excipients and formulation auxiliaries which are customary in practice, such as, for example, fillers, binders, disintegrants, lubricants, solvents, gel-formers, emulsifiers, stabilizers, colorants and/or preservatives.
The compounds of the present invention are formulated into dosage forms using generally known pharmaceutical manufacturing methods. The dosage form may be, for example, tablets, capsules, granules, suppositories, emulsions, suspensions or solutions. The amount of active ingredient in the formulation may typically vary between 0.01% and 100% by weight depending on the route of administration and galenic form.
Those skilled in the art will appreciate that modifications may be made to the embodiments described herein without departing from the inventive concept. It is also to be understood by those skilled in the art that the present invention is not limited to the particular embodiments disclosed, but is intended to cover modifications of the embodiments within the scope of the present invention.

Claims (18)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein
X is O or S;
R1is hydroxy, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, ring(C3-C6) Alkyl, (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, cyano, (R)6)2N-(C＝O)-、(C1-C6) alkyl-S-or furyl;
R2is H or (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R4is H or (C)1-C2) An alkyl group;
R5is H, hydroxy, halogen, (C)1-C6) Alkyl or (C)1-C6) An alkoxy group;
R6is H;
or R1And R2Together with the carbon ring atoms to which they are attached form a fused 6-or 7-membered saturated or unsaturated carbocyclic ring.
2. The compound of claim 1, wherein R1Is hydroxy, halogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)1-C3) Alkoxy, halo (C)1-C3) Alkoxy or hydroxy (C)1-C3) An alkyl group; and/or
R2Is H or (C)1-C2) An alkyl group; and/or
R3Is H, (C)1-C3) Alkyl or halo (C)1-C3) An alkyl group; and/or
R4Is H or methyl; and/or
R5Is H, halogen or (C)1-C2) An alkyl group; and/or
R1And R2Together with the carbon ring atoms to which they are attached form a fused 6-or 7-membered saturated or unsaturated carbocyclic ring.
3. The compound of any one of claims 1 to 2, wherein R1Is halogen, (C)1-C2) Alkyl, halo (C)1-C2) Alkyl, (C)1-C2) Alkoxy or halo (C)1-C2) An alkoxy group; and/or
R2Is H; and/or
R3Is H or (C)1-C2) An alkyl group; and/or
R4Is H; and/or
R5Is H.
4. The compound of claim 1, wherein X is O.
5. A compound which is 2- (5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carbonitrile, 2- (5-allylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-vinyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-ethyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-ethyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate, 2- (5-ethyliisochroman-1-yl) -4, 5-dihydro-1H-imidazole fumarate, 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-ol, (1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-yl) methanol, 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-chloro-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) -1-methylisochroman-5-yl) -2, the slower eluting isomer of 2-dimethylpropan-1-ol, the faster eluting isomer of 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) -1-methylisochroman-5-yl) -2, 2-dimethylpropan-1-ol, 2- (5-ethynylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3-ethyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (1-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2-dimethylpropan-1-ol, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate, 2- (5-iodoisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3-methyl-5- (trifluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, and mixtures thereof, 2- (5-bromo-4-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, the faster eluting isomer of 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, the slower eluting isomer of 2- (1, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -1,3, 5-trimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-cyclopropylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, or mixtures thereof, 2- (3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloro-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3-methyl-isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2-methyl-1-, 2- (1,3, 5-trimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3S) -5-chloro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3S) -5-bromo-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3S) -3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-isopropylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-fluoroisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- ((3R) -5-ethyl-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate, 2- (3-ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2-methyl-3-ethyl-3-methylisochroman-1-yl-imidazole hemifumarate, 2- (3-ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2,2- ((3R) -3, 5-diethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole sulfate, 2- ((3R) -3-ethyl-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hemifumarate, 2- ((3R) -3-methyl-5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-fluoro-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-ethoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, and pharmaceutically acceptable salts thereof, 2- ((3S) -5-methoxy-3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (furan-3-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (prop-1-yn-1-yl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-carboxamide, 2- (3,7,8,9,10,10 a-hexahydro-1H-cyclohepta [ de ] isochromen-3-yl) -4, 5-dihydro-1H-imidazole, the slower eluting isomer of 1- (1- (4, 5-dihydro-1H-imidazol-2-yl) isochroman-5-yl) ethanol, 2- (5, 7-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (7-bromo-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (7-methoxy-5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3, 5-dimethylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-3-methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromoisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-bromo-1-methylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5, 7-dibromo-3-ethylisothroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, enantiomer hydrochloride of 2- (5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxy-1-methylisothroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methoxyisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-methoxy-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, salts thereof, and pharmaceutically acceptable salts thereof, 2- (5- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5-ethyl-1, 3-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-methyl-3- (methoxymethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 1- (4, 5-dihydro-1H-imidazol-2-yl) -5-methylisochroman-7-ol hydrobromide, 1- (4, 5-dihydro-1H-imidazol-2-yl) -3-ethylisochroman-5-ol Hydrochloride, enantiomer-2 of 2- (5-methoxy-3- (2,2, 2-trifluoroethyl) methylisothroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (1, 5-dimethylisothiochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (trifluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, enantiomer-1 hydrochloride of 2- (3-ethylisothroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (3- (2-fluoroethyl) -5-methylisothroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer, 2- (5-bromo-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (7-methoxy-3, 5-dimethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3) -5-methyl-3- (2,2, 2-trifluoroethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (5- (methylthio) isochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3) -5-bromo-3-propylisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- ((3R) -3- (2, 2-difluoroethyl) -5-methylisochroman-1-yl) -4, enantiomer-2 hydrochloride of 5-dihydro-1H-imidazole, 2- (5- (difluoromethoxy) isochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- ((3R) -3-ethyl-5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole, enantiomer-1 hydrochloride of 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- ((3R) -5- (difluoromethoxy) -3-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, salts of the same, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same, 2- (5-bromo-3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-1 hydrochloride, 2- (3-ethylisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2, 2- (5-methoxyisochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride enantiomer-2, 2- (1-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole, 2- (5- (difluoromethyl) isochroman-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (5-chloroisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (5-bromoisochroman-1-yl) -4, 5-dihydro-1H-imidazole enantiomer-2 hydrochloride, 2- (1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (1-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, enantiomers of 5-dihydro-1H-imidazole, 2- (3-methyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride, 2- (3-ethyl-1, 3-dihydrobenzo [ de ] isochromen-1-yl) -4, 5-dihydro-1H-imidazole hydrochloride or enantiomers of 2- (5-bromo-1-methylisochroman-1-yl) -4, 5-dihydro-1H-imidazole.
6. A compound according to claim 1 for use as a medicament.
7. A compound of claim 1 for use in the treatment of a condition, disorder or disease in which an alpha 2 agonist is indicated to be useful.
8. A compound of claim 1 for use in the treatment of a condition, disorder or disease in which an α 2A agonist is indicated to be useful.
9. The compound of claim 8, wherein the disorder, condition or disease is delirium, insomnia, ADHD, benzodiazepinesOr alcohol or opioid or tobacco withdrawal, premature ejaculation, hypertension, tachycardia, restless leg syndrome, muscle spasticity, hot flashes, anxiety, post traumatic stress disorder, pain, chronic pelvic pain syndrome or a condition requiring sedation or analgesia.
10. Compound according to claim 9, wherein delirium is hyperactive delirium.
11. The compound of claim 9, wherein the pain is breakthrough cancer pain.
12. Use of at least one compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of a condition, disorder or disease in which an alpha 2 agonist is indicated to be useful.
13. Use of at least one compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of a condition, disorder or disease in which an alpha 2A agonist is indicated to be useful.
14. The use of claim 13, wherein the disorder, condition or disease is delirium, insomnia, ADHD, benzodiazepinesOr alcohol or opioid or tobacco withdrawal, premature ejaculation, hypertension, tachycardia, restless leg syndrome, muscle spasticity, hot flashes, anxiety, post traumatic stress disorder, pain, chronic pelvic pain syndrome or a condition requiring sedation or analgesia.
15. Use according to claim 14, wherein delirium is hyperactive delirium.
16. The use of claim 14, wherein the pain is breakthrough cancer pain.
17. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent and/or excipient.
18. The pharmaceutical composition of claim 17, wherein the composition further comprises at least one additional active ingredient.
HK15105661.0A 2012-04-02 2013-03-28 Alpha2 adrenoceptor agonists HK1205115B (en)

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US201261619109P 2012-04-02 2012-04-02
US61/619,109 2012-04-02
PCT/FI2013/000013 WO2013150173A1 (en) 2012-04-02 2013-03-28 New alpha2 adrenoceptor agonists

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HK1205115B true HK1205115B (en) 2018-09-14

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