NZ617367B2 - Positive allosteric modulators of nicotinic acetylcholine receptor - Google Patents

Positive allosteric modulators of nicotinic acetylcholine receptor Download PDF

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Publication number
NZ617367B2
NZ617367B2 NZ617367A NZ61736712A NZ617367B2 NZ 617367 B2 NZ617367 B2 NZ 617367B2 NZ 617367 A NZ617367 A NZ 617367A NZ 61736712 A NZ61736712 A NZ 61736712A NZ 617367 B2 NZ617367 B2 NZ 617367B2
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New Zealand
Prior art keywords
amide
phenyl
ethyl
hydroxy
cyclopropanecarboxylic acid
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NZ617367A
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NZ617367A (en
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J Rgen Eskildsen
Ask Puschl
Anette Graven Sams
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H Lundbeck A/S
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Priority to NZ710003A priority Critical patent/NZ710003B2/en
Priority claimed from PCT/EP2012/063219 external-priority patent/WO2013007621A1/en
Publication of NZ617367A publication Critical patent/NZ617367A/en
Publication of NZ617367B2 publication Critical patent/NZ617367B2/en

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Abstract

Disclosed are compounds of formula (I) wherein R1, R2, R3, R4 and R5 are H; R6 is methoxymethyl; A7 is C-R7, A8 is N and A9 is C-R9; R7, R9, R10 and R11 are selected independently of each other from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy and OR12; wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C; and pharmaceutically acceptable salts thereof, which are positive allosteric modulators (PAMs) of the nicotinic acetylcholine ?7 receptor and are therefore useful in the treatment of conditions including schizophrenia, psychosis and other cognitive disorders. Compounds of formula I include (1S,2S)-2-phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxyethyl]-amide; (1S,2S)-N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenylcyclopropanecarboxamide; (1S,2S)-N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenylcyclopropanecarboxamide; and (1S,2S)-2-phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide. rated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C; and pharmaceutically acceptable salts thereof, which are positive allosteric modulators (PAMs) of the nicotinic acetylcholine ?7 receptor and are therefore useful in the treatment of conditions including schizophrenia, psychosis and other cognitive disorders. Compounds of formula I include (1S,2S)-2-phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxyethyl]-amide; (1S,2S)-N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenylcyclopropanecarboxamide; (1S,2S)-N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenylcyclopropanecarboxamide; and (1S,2S)-2-phenyl-cyclopropanecarboxylic acid {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide.

Description

[Annotation] sak TITLE POSITIVE ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTOR FIELD OF THE INVENTION The present invention relates to compounds useful in therapy, to itions com- prising said compounds, and to s of treating diseases comprising administration of said compounds. The compounds referred to are positive eric modulators (PAMs) of the nicotinic choline o7 receptor.
BACKGROUND OF THE INVENTION Nicotinic acetylcholine receptors (nAChRs) belong to the super family of ligand gated ionic channels, and gate the flow of cations ing calcium. The nAChRs are endogenously activated by acetylcholine (ACh) and can be divided into nic receptors of the neuromus- cularjunction and neuronal nicotinic receptors (NNRs). The NNRs are widely expressed throughout the central nervous system (CNS) and the eral nervous system (PNS). The NNRs have been suggested to play an important role in CNS function by modulating the re- lease of many neurotransmitters, for example, ACh, norepinephrine, dopamine, nin, and GABA, among others, resulting in a wide range of physiological effects.
Seventeen subunits of nAChRs have been reported to date, which are identified as 012-0110, [51-84, v, 6 and a. From these subunits, nine subunits, (12 through (17 and [32 through [34, prominently exist in the mammalian brain. Many onally distinct nAChR complexes exist, for example five (17 subunits can form a receptor as a homomeric functional pentamer or combinations of different subunits can form heteromeric receptors such as (1482 and (1384 ors (Gotti, C. et al., Prog. Neurobiol., 2004, 74: 363-396; Gotti, C. et al., Biochemical Pharmacology, 2009, 78: 703—71 1) The homomeric d7 receptor is one of the most abundant NNRs, along with (1482 re- ceptors, in the brain, wherein it is heavily expressed in the hippocampus, , thalamic nu- clei, ventral tegmental area and substantia nigra (Broad, L. M. et al., Drugs of the Future, 2007, 32(2): 161-170, Poorthuis RB, m Pharmacol. 2009, 1;78(7):668—76).
The role of (17 NNR in neuronal signalling has been actively investigated. The (17 NNRs have been demonstrated to regulate interneuron excitability and modulate the release of excitatory as well as inhibitory neurotransmitters. In addition, (17 NNRs have been reported to be involved in neuroprotective effects in experimental models of cellular damage - hama, 8., Biol Pharm Bull. 2009, 32(3):332-6).
[Annotation] sak Studies have shown that (17 subunits, when expressed recombinant in-vitro, activate and de- sensitize rapidly, and exhibit relatively higher calcium bility compared to other NNR combinations (Papke, R.L. et al., J Pharmacol Exp Ther. 2009, 329(2):791-807).
The NNRs, in general, are involved in s cognitive functions, such as learning, memory and attention, and therefore in CNS disorders, i.e., Alzheimer's disease (AD), son's e (PD), attention deficit hyperactivity disorder (ADHD), Tourette's syn- drome, schizophrenia, bipolar disorder, pain and tobacco dependence r, J. J. et al., Be- hav. Brain Res. 2005, 162: 143-52; Haydar, S.N. et al., Curr Top Med Chem. 2010;10(2):144- 52).
The G7 NNRs in particular, have also been linked to cognitive disorders including, for example, ADHD, autism spectrum disorders, AD, mild cognitive impairment (MCI), age asso- ciated memory impairment (AAMI) senile ia, frontotemporal lobar degeneration, HIV associated dementia (HAD), HIV ated cognitive ment (HIV-Cl), Pick's disease, dementia associated with Lewy bodies, cognitive impairment associated with Multiple Sclero- sis, Vascular Dementia, cognitive impairment in Epilepsy, ive impairment associated with e X, cognitive impairment associated with Friedreich’s , and dementia associ- ated with Down's syndrome, as well as cognitive impairment associated with schizophrenia.
In addition, o7-NNRs have been shown to be involved in the neuroprotective effects of nico- tine both in vitro (Jonnala, R. B. et al., J. Neurosci. Res., 2001, 66: 565- 572) and in vivo (Shimohama, 8., Brain Res., 1998, 779: 359-363) as well as in pain signalling. More particularly , neurodegeneration underlies several progressive CNS disorders, including, but not lim- ited to, AD, PD, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bod- ies, as well as diminished CNS function resulting from traumatic brain injury. For example, the impaired function of (17 NNRs by beta-amyloid peptides linked to AD has been implicated as a key factor in pment of the cognitive deficits associated with the disease (Liu, Q.-S., et al., PNAS, 2001,98: 4734-4739). Thus, modulating the activity of (17 NNRs trates promising potential to prevent or treat a variety of diseases indicated above, such as AD, other dementias, other neurodegenerative diseases, schizophrenia and neurodegeneration, with an underlying pathology that involves cognitive function including, for example, aspects of learning, memory, and attention (Thomsen, M.S. et al., Curr Pharm Des. 2010 Jan;16(3):323-43; , A. et al., Arch Gen Psychiatry. 2006, 63(6):630-8; Deutsch, S.|., Clin harmacol. 2010, 33(3):114-20; Feuerbach, D., Neuropharmacology. 2009, 56(1): 254-63) The NNR ligands, ing (17 ligands, have also been ated in weight control, diabetis inflammation, obsessive-compulsive disorder (OCD), angiogenesis and as ial analgesics (Marrero, M.B. et al., J. Pharmacol. Exp. Ther. 2010, 332(1):173-80; Vincler, M., [Annotation] sak Exp. Opin.lnvest. Drugs, 2005, 14 (10): 1191-1 198; Ballina, M., J. Intern Med. 2009 265(6):663-79; Arias, H.R., Int. J. Biochem. Cell Biol. 2009, 41(7):1441-51; Tizabi, Y., Biol Psychiatry. 2002, 51 (2):164-71).
Nicotine is known to enhance attention and cognitive performance, reduced anxiety, enhanced sensory gating, and analgesia and neuroprotective effects when administered.
Such effects are mediated by the non-selective effect of nicotine at multiple nicotinic or subtypes. However, nicotine also exerts adverse events, such as cardiovascular and gastro- intestinal problems (Karaconji, |.B. et al., Arh Hig Rada Toksikol. 2005, 56(4):363-71). Con- sequently, there is a need to identify subtype-selective compounds that retain the cial effects of ne, or an NNR ligand, while eliminating or decreasing e effects.
Examples of reported NNR ligands are or? NNR agonists, such as DMXB-A, SSR180711 and ABT-107, which have shown some beneficial effects on cognitive processing both in rodents and humans (H312: 1213-22; Olincy, A. et al., Arch Gen Psychiatry. 2006 63(6):630-8; Pichat, P., et al., Neuropsychopharmaco/ogy. 2007 32(1):17-34; Bitner, R.S., J Pharmacol Exp Ther. 2010 1;334(3):875-86). In addition, modulation of or? NNRs have been reported to improve negative symptoms in patients with phrenia (Freedman, R. et al., Am J Psychiatry. 2008 165(8):1040-7).
Despite the beneficial effects of NNR ligands, it remains uncertain whether chronic treatment with agonists affecting NNRs may provide suboptimal benefit due to sustained acti- vation and desensitization of the NNRs, in particular the o7 NNR e. In contrast to ago- nists, stering a positive allosteric tor (PAM) can reinforce endogenous choliner- gic transmission without directly stimulating the target receptor. nic PAMs can selec- tively modulate the activity of ACh at NNRs, preserving the activation and deactivation kinet- ics of the receptor. ingly, o7 lective PAMs have emerged (Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2):99—106).
Consequently, it would be beneficial to increase or? NNR function by enhancing the ef- fect of the endogenous neurotransmitter acetvlcholine via PAMs. This could reinforce the en- dogenous cholinergic neurotransmission t directly activating o7 NNRs, like agonists.
Indeed, PAMs for enhancing channel activity have been proven clinically successful for GABAa receptors where iazepines and barbiturates, behave as PAMs acting at dis- tinct sites (Hevers, W. et al., Mol. Neurobiol., 1998, 18: 35-86).
To date, only a few NNR PAMs are known, such as 5-hydroxyindole (5-Hl), ivermec- tin, galantamine, and 1, a peptide derived from acetylcholinesterase (AChE). Gen- istein, a kinase inhibitor was also reported to increase or? responses. PNU-120596, a urea derivative, was ed to increase the potency of ACh as well as improve ry gating deficits induced by amphetamine in rats. Also, NS1738, JNJ-1930942 and compound 6 have [Annotation] sak been reported to potentiate the response of ACh and exert beneficial effect in experimental models of sensory and cognitive sing in s. Other NNR PAMs include tives of quinuclidine, , benzopyrazole, thiazole, and benzoisothiazoles (Hurst, R. S. et al., J.
Neurosci. 2005, 25: 405; Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2):99—106; mann, D.B., J. Pharmacol. Exp. Ther. 2007, 323(1):294-307; Ng, H.J. et al., Proc.
Natl. Acad. Sci. U SA. 2007, 8;104(19):8059—64; Dinklo, T., J. Pharmacol. Exp. Ther. 2011, 336(2):560-74.). s compounds of the overall structure N NZ R1 R2 which compounds are said to be PAMs of the o7 NNR.
The (17 NNR PAMs presently known generally demonstrate weak activity, have a range of non-specific effects, or can only achieve limited access to the central nervous sys- tem where (17 NNRs are abundantly expressed. Accordingly, it would be beneficial to identify and provide new PAM compounds of (17 NNRs and compositions for treating diseases and disorders wherein o7 NNRs are involved. It would further be particularly beneficial if such compounds can provide improved efficacy of treatment while ng adverse effects asso- ciated with compounds targeting neuronal nicotinic receptors by selectively modulating o7 NNRs. recites compounds of the overall structure R2 0 Y / (R)v N (Ci)q-(O)r-Ar p R5 R1 2/ ( R3)w as calcium or sodium channel blockers. Compound examples disclosed in are not intended to be ed in the present invention.
Particularly the compounds (1 S,2S)Phenyl-cyclopropanecarboxylic acid {(S)—1-[5- (2,2,2-trifluoro-ethoxy)—pyridinyl]—ethy|}-amide, (1 S,2S)(2-Chlorofluoro-phenyl)- cyclopropanecarboxylic acid {(S)—1-[5-(2,2,2-trifluoro-ethoxy)—pyridinyl]-ethyl}-amide and (1 S,2S)(2-F|uoromethoxy-phenyl)-cyc|opropanecarboxylic acid {(S)—1-[5-(2,2,2-trifluoroethoxy )-pyridinyl]-ethyl}-amide are disclosed in WO 37351 are disclaimed from the present invention SUMMARY OF THE INVENTION The objective of the present invention is to provide compounds that a positive allosteric modulators (PAMs) of the nicotinic acetylcholine erceptor subtype α7.
Disclosed herein are compounds defined by a (I) below: 10249033 According to an aspect of the present invention, there is provided a nd according to formula [I] R3 R5 R6 R2 N A R1 A R11 9 wherein R1, R2, R3, R4 and R5 are selected independently of each other from H, C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, C1-6alkoxy, cyano and halogen, wherein said C1-6alkyl, C2-6alkenyl and C2- 6alkynyl is ally substituted with one or more substituents independently selected from chlorine and fluorine; R6 is hydroxymethyl; A7 is C-R7, A8 is N and A9 is C-R9; R7, R9, R10 and R11 are selected independently of each other from H, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C1-6alkoxy, cyano, NR12R13, C1-6alkylsulfonyl and halogen, wherein said C1-6alkyl, C2- 6alkenyl, C2-6alkynyl or C1-6alkoxy is optionally substituted with one or more tuents selected from chlorine, ne, C1-6alkoxy, cyano and 3; R12 and R13 independently represent hydrogen, C1-6alkyl, C2-6alkenyl and C2-6alkynyl; and pharmaceutically acceptable salts thereof. 10249033 [Annotation] sak memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia asso- ciated with Lewy ; ia associated with Down's syndrome; Huntington's Disease; Parkinson’s disease (PD); obsessive-compulsive er (OCD); traumatic brain injury; epi- lepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disor- ders, reduced angiogenesis; amyotrophic lateral sclerosis and pain, which method comprises the administration of a therapeutically effective amount of a compound according to formula [I], and pharmaceutically acceptable salts thereof.
In one embodiment, the invention relates to the use of a compound according to for- mula [I], and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer’s disease (AD); mild cognitive im- nt (MCI); age associated memory impairment (AAMI); senile dementia; AIDS demen- tia; Pick's disease; dementia ated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson’s disease (PD); obsessive-compulsive disorder (OCD); tic brain ; epilepsy; post-traumatic ; Wernicke-Korsakoff me (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, matory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
Definitions In the present context, "optionally substituted" means that the indicated moiety may or may not be substituted, and when substituted is mono-, di-, or tri-substituted, such as with 1, 2 or 3 substituents. In some instances, the substituent is independently selected from the group consisting of C1_6alkyl, 02-5alkenyl, 02-5alkynyl, , C1_5alkoxy, hydroxy and halo- gen. It is tood that where no substituents are indicated for an nally tuted" moiety, then the on is held by a hydrogen atom.
In the present context, "alkyl" is intended to indicate a ht, branched and/or cyclic saturated hydrocarbon. In particular "C1-6a|kyl" is intended to indicate such hydrocarbon hav- ing 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of C1_6alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-methylpropyl and tert-butyl. Examples of substituted C1-5a|ky| include e.g. fluoromethyl and hy- droxymethyl.
In the present t, "alkenyl" is intended to indicate a non-aromatic, ht, branched and/or cyclic arbon comprising at least one carbon-carbon double bond. In [Annotation] sak particular "02-6alkenyl" is intended to indicate such hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms. Examples of 02-5alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and nyl and cyclohexenyl.
In the present context, yl" is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon triple bond and optionally also one or more carbon-carbon double bonds. In particular "02-6alkynyl" is in- tended to indicate such hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms. Examples of CZ- ealkynyl e ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 5-but enynyl.
In the present context, "hydroxy" is intended to indicate —OH.
In the present context, "alkoxy" is ed to indicate a moiety of the formula —OR’, wherein R’ indicates alkyl as defined above. In particular "C1-6a|koxy" is intended to indicate such moiety wherein the alkyl part has 1, 2, 3, 4, 5 or 6 carbon atoms. es of "C1- salkoxy" include methoxy, , n-butoxy and tert-butoxy.
In the t context, "alkylsulfonyl" is ed to indicate —S(O)2alkyl In particular C1-5alkylsulfonyl is intended to indicate such a moiety wherein the alkyl part has 1, 2, 3, 4, 5 or 6 carbon atoms. Particular n is made of methylsulfonyl.
In the present context, a "monocyclic moiety" is intended to cyclic moiety comprising only one ring, said cyclic moiety can be saturated or unsaturated.
In the present context, the terms "halo" and "halogen" are used interchangeably and refer to fluorine, chlorine, e or iodine.
In the present context, the term "cyano" indicates the group -CEN, which consists of a carbon atom triple-bonded to a nitrogen atom.
In the t context, "ring atom" is intended to indicate the atoms tuting a ring, and ring atoms are selected from C, N, O and 8. As an example, e and toluene both have 6 carbons as ring atoms whereas pyridine has 5 carbons and 1 nitrogen as ring atoms.
In the present context, "heteroatom" means a nitrogen, oxygen or sulfur atom.
In the present context, "deuterium" indicates the atomic e of en consisting of one proton and one neutron in its nucleus, and thus having an approximate weight of two (2). Deuterium is represented as D, d or 2H. An example of a substituent comprising deute- rium is (2,2,2-d3)-ethoxy wherein three of the hydrogens in ethoxy are the 2H isotopes.
In the present context, "enantiomeric excess" represents the % excess of a compound in a mixture of compound enantiomers. If for example an enantiomeric excess is 90% then the ratio of the compound to its enantiomer is 95:5 and if an enantiomeric excess is 95% then the ratio of the compound to its omer is 97.525 Likewise, "diastereomeric excess" represents % excess of a compound in a mixture of compound diastereomers.
[Annotation] sak In the present t, pharmaceutically able salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alky- lated ammonium salts. Acid addition salts include salts of nic acids as well as organic acids.
Examples of suitable inorganic acids include hloric, hydrobromic, odic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
Examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroace- tic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, ic, oxalic, picric, c, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, c, palmitic, EDTA, ic, p-aminobenzoic, glutamic, benzenesul- fonic, enesulfonic acids, theophylline acetic acids, as well as the 8—halotheophyllines, for example 8—bromotheophylline and the like. Further examples of pharmaceutical acceptable inorganic or organic acid addition salts include the ceutically acceptable salts listed in Berge, SM. et al., J. Pharm. Sci. 1977,66,2, which is incorporated herein by reference.
Examples of metal salts include m, sodium, ium, magnesium salts and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, l-, n-butyl-, sec-butyl-, tert-butyl-, tetrame- thylammonium salts and the like.
In the present t, pharmaceutical carriers include inert solid ts or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lac- tose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, poly- oxyethylene and water. Similarly, the carrier may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
In the present context, the term "therapeutically effective " of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administra- tion of said compound. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective s for each purpose will depend on the severity of the dis- ease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by con- [Annotation] sak structing a matrix of values and testing different points in the matrix, which is all within the or- dinary skills of a trained physician.
In the present context, the term "treatment" and "treating" means the management and care of a patient for the purpose of combating a condition, such as a disease or a disor- der. The term is ed to include the full um of treatments for a given condition from which the patient is ing, such as administration of the active compound to alleviate the ms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be under- stood as the management and care of a patient for the purpose of combating the disease, ion, or disorder and includes the administration of the active nds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and thera- peutic (curative) treatments are two separate aspects of the present invention. The patient to be d is preferably a mammal, in particular a human being.
In the present context, the term tive disorders" is intended to indicate disorders characterized by abnormalities in aspects of perception, problem solving, language, learning, working memory, , social recognition, attention and pre-attentional processing, such as by not limited to ion Deficit Hyperactivity Disorder (ADHD), autism spectrum disor- ders, Alzheimer’s disease (AD), mild cognitive impairment (MCI), age associated memory im- pairment (AAMI), senile dementia, ar dementia, frontotemporal lobe dementia, Pick's disease, dementia ated with Lewy bodies, and dementia ated with Down's syn- drome, cognitive impairment ated with Multiple Sclerosis, cognitive ment in epi- lepsy, cognitive impairment associated with fragile X, cognitive impairment associated with ibromatosis, cognitive impairment associated with Friedreich’s Ataxia, progressive su- pranuclear palsy (PSP), HIV associated dementia (HAD), HIV associated cognitive impair- ment (HIV-Cl), Huntington's Disease, Parkinson’s disease (PD), obsessive-compulsive dis- order (OCD), traumatic brain , epilepsy, post-traumatic stress, Wernicke-Korsakoff syn- drome (WKS), post-traumatic amnesia, cognitive deficits associated with depression as well as cognitive impairment associated with schizophrenia.
The cognitive enhancing properties of a compound can be assessed eg. by the atten- tional set-shifting paradigm which is an animal model allowing assessment of executive func- tioning via intra-dimensional (lD) versus extra-dimensional (ED) shift discrimination learning.
The study can be performed by testing r the compound is attenuating "attentional per- formance impairment" induced by subchronic PCP administration in rats as described by Rodefer, J.S. et al., Eur. J. Neurosci. 2005, 21:1070-1076.
[Annotation] sak In the present context, the term "autism spectrum disorders" is intended to indicate disorders characterized by widespread abnormalities of social ctions and verbal and non-verbal communication, as well as restricted interests, repetitive behavior and attention, such as by not limited to autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise ied (PDD-NOS), Rett syndrome, Angelmann syndrome, fragile X, ge syndrome and ood Disintegrative Disorder.
In the t context, the term "inflammatory disorders" is intended to indicate disor- ders characterized by abnormalities in the immune system such as by not limited to, allergic reactions and myopathies resulting in abnormal inflammation as well as non-immune diseases with etiological origins in inflammatory processes are thought to include but not be limited to cancer, sclerosis, osteoarthritis, rheumatoid arthritis and ischaemic heart disease.
DETAILED PTION OF THE INVENTION The present inventors have found that certain new compounds are positive allosteric modulators (PAMs) of NNRs, and as such may be used in the ent of various ers.
PAMs of NNRs may be dosed in combination with other drugs in order to achieve more efficacious ent in certain patient populations. An (17 NNR PAM may act synergis- tically with another drug, this has been described in animals for the combination of com- pounds affecting nicotinic receptors, including (17 NNRs and D2 antagonism (Wiker, 0., Int. J.
Neuropsychopharmacol. 2008, 11(6):845-50).
Thus, compounds of the present invention may be useful treatment in the combination with another drug e.g. selected from acetylcholinesterase inhibitors, glutamate receptor an- tagonists, dopamine transport inhibitors, enalin transport inhibitors, D2 antagonists, D2 partial agonists, PDE10 antagonists, 5-HT2A antagonists, 5-HT6 antagonists and KCNQ an- tagonists, lithium, sodium channel blockers, GABA signalling enhancers.
In one embodiment, compounds of the t invention are used for treatment of pa- tients who are already in treatment with another drug selected from the list above. In one em- bodiment, compounds of the present invention are adapted for stration simultaneous with said other drug. In one embodiment compounds of the present invention are adapted for administration sequentially with said other drug. In one embodiment, compounds of the pre- sent ion are used as the sole medicament in treatment of a patient. In one ment, compounds of the present invention are used for treatment of patients who are not already in treatment with r drug selected from the list above.
Embodiments according to the invention [Annotation] sak In the following, embodiments of the invention are disclosed. The first ment is denoted E1, the second embodiment is denoted E2 and so forth.
E1. A nd according to formula [I] N \As H I / [L9 wherein R1, R2, R3, R4 and R5 are selected independently of each other from H, C1-5alkyl, 02-5alkenyl, Cz_6alkynyl, C1_5alkoxy, cyano and halogen, wherein said C1_6alkyl, 02-5alkenyl and Cz_6alkynyl is optionally substituted with one or more tuents independently ed from chlorine and fluorine; R6 is selected from C1-6a|ky|, Cz_6a|keny|, Cz_6a|kyny| and C1_6alkoxy, wherein said ky|, Cz_6alkeny| and Cz_6alkynyl is optionally tuted with one or more substituents independ- ently selected from hydroxy, C1-5alkoxy and fluorine; A7 is C-R7 or N, A8 is C-R8 or N and A9 is C-R9 or N, provided that at least one of A7, A8 or and 9 is N and no more than two of A7, A8 and A9 is N; R7, R8, R9, R10 and R11 are selected independently of each other from H, C1_6alkyl, CZ- ealkenyl, Cz_6alkynyl, C1_6alkoxy, cyano, NR12R13, C1-5alkylsulfonyl, halogen and OR14, wherein said C1-5alkyl, 02-5alkenyl, Cz_6alkynyl or C1_6alkoxy is optionally substituted with one or more substituents selected from chlorine, fluorine, C1_6alkoxy, cyano and NR12R13; R12 and R13 independently represent hydrogen, C1_6alkyl, 02-5alkenyl and Cz_6alkynyl; R14 represents a monocyclic ted ring moiety having 4-6 ring atoms n one of said ring atoms is O and the others are C; or R9 and R10 may be linked together to form the moiety indicated below O\l-/]n wherein n is 1, 2 or 3; and pharmaceutically acceptable salts thereof; ation] sak with the proviso that the compound of formula [I] is other than (1 S,28)Phenyl-cyclopropanecarboxylic acid {(S)—1-[5-(2,2,2-trifluoro-ethoxy)—pyridinyl]— ethy|}-amide; (1 S,28)(2-Chlorofluoro-phenyl)-cyclopropanecarboxylic acid {(S)—1-[5-(2,2,2-trifluoroethoxy )—pyridinyl]-ethyl}-amide; (1 S,28)(2-F|uoromethoxy-phenyl)-cyclopropanecarboxylic acid {(S)—1-[5-(2,2,2-trifluoro- )—pyridinyl]-ethyl}-amide.
E2. The compound ing to embodiment 1, wherein R1, R2, R3, R4 and R5 are se- lected ndently of each other from H, methyl, fluorine and chlorine; R6 is selected from methyl, hydroxymethyl, methoxymethyl and fluoromethyl; R7, R8, R9, R10 and R11 are selected independently of each other from H, C1_4alkyl, C1- 4alkoxy, cyano, -N(CH3)2, methylsulfonyl, fluorine, chlorine and OR14, wherein said C1_4alkyl or C1.4a|koxy is optionally substituted with one or more substituents selected from fluorine, C1- 4a|koxy and cyano; R14 represents a clic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the others are C; or R9 and R10 may be linked together to form the moiety ted below O\l-/]n wherein n is 1 or 2.
E3. The compound according to any of embodiments 1-2, wherein R1, R2, R3, R4 and R5 are selected independently of each other from H, methyl, fluorine and chlorine.
E4. The compound according to any of embodiments 1-3, wherein four or more of R1, R2, R3, R4 and R5 are H.
E5. The nd according to embodiment 4, wherein all of R1, R2, R3, R4 and R5 are E6. The compound according to any of embodiments 1-5, wherein R6 is selected from methyl , hydroxymethyl, methoxymethyl and fluoromethyl.
[Annotation] sak E7. The nd according to embodiment 6, wherein R6 is .
E8. The compound according to embodiment 6, wherein R6 is hydroxymethyl.
E9. The compound according to embodiment 6, wherein R6 is methoxymethyl.
E10. The compound according to embodiment 6, wherein R6 is fluoromethyl.
E11. The compound according to any of ments 1-10, wherein R7, R8, R9, R10 and R11 are selected ndently of each other from H, C1_4alkyl, C1_4alkoxy, cyano, -N(CH3)2, methylsulfonyl, fluorine, ne and OR14, wherein said C1_4alkyl or koxy is optionally substituted with one or more substituents selected from fluorine, koxy and cyano; R14 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the others are C; or R9 and R10 may be linked together to form the moiety indicated below O\l-/]n wherein n is 1 or 2; E12. The nd according to any of embodiments 1 and 3-11, wherein R7, R8, R9, R10 and R11 are selected independently from H, C1_6alkyl, 02-5alkenyl, 02.6alkynyl, C1_6alkoxy, cyano or halogen, n said C1_6alkyl, 02-6alkenyl, 02-6alkynyl or C1_6alkoxy is optionally substituted with one or more substituents selected from fluorine, C1.6alkoxy and cyano.
E13. The compound according to any of embodiments 1-12, wherein R7, R8, R9, R10 and R11 are selected independently from H, C1_4alkyl, Cz_4alkenyl, Cz_4alkynyl, C1_4alkoxy, cyano and halogen, wherein said C1_4alkyl, Cz_4alkenyl, Cz_4alkynyl or C1_4alkoxy is optionally substi- tuted with one or more substituents selected from fluorine and koxy.
E14. The compound according to any of embodiments 1-13, wherein one or more of the hydrogen atoms are represented by deuterium.
E15. The compound according to embodiment 14, wherein one or more of the hydrogen atoms in R7, R8, R9, R10 and R11 are represented by deuterium.
[Annotation] sak E16. The nd according to any of embodiments 14-15, wherein at least about 85% of the compound has a deuterium atom at each position designated as deuterium, and any atom not designated as deuterium is present at about its natural isotopic abundance.
E17. The compound according to embodiment 16, wherein at least about 90% of the com- pound has a deuterium atom at each on designated as deuterium, and any atom not designated as ium is present at about its natural isotopic abundance.
E18. The compound according to any of embodiments 1-17, wherein no more than one of A7, A8 or A9 is N.
E19. The compound according to any of embodiments 1-18, wherein A7 is N, A8 is C-R8 and A9 is C-R9.
E20. The compound according to ment 19, wherein R8, R10 and R11 all represent E21. The compound according to any of embodiments 1-18, wherein A8 is N, A7 is C-R7 and A9 is C-R9.
E22. The compound according to embodiment 21, wherein R7, R10 and R11 all represent E23. The compound according to any of embodiments 19-22, wherein R9 is selected from methyl, C1_4alkoxy or cyano, wherein said methyl is optionally substituted with C1_4alkoxy or one or more fluorine.
E24. The compound according to embodiment 23, wherein R9 represents C1.4alkoxy and one or more of the hydrogen atoms in said C1.4alkoxy are represented by deuterium.
E25. The compound according to any of embodiments 19-22, wherein R9 is OR14, n R14 represents a clic ted ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the others are C.
[Annotation] sak E26. The compound according to any of embodiments 1-18, wherein A9 is N, A7 is C-R7 and A8 is C-R8.
E27. The compound according to embodiment 26, wherein R7, R8 and R11 all ent H.
E28. The compound according to any of embodiments 26-27, wherein R10 is selected from methyl, C1_4alkoxy or cyano, wherein said methyl is optionally substituted with C1_4alkoxy or one or more fluorine.
E29. The compound according to embodiment 28, wherein R10 ents C1_4a|koxy and one or more of the hydrogen atoms in said C1.4a|koxy are ented by deuterium.
E30. The compound according to any of embodiments 1-17, wherein two of A7, A8 or A9 are N.
E31. The nd according to any of ments 1-30 having a diastereomeric ex- cess of at least 80% such as at least 85%, such as at least 90%, such as at least 95%.
E32. The compound according to embodiment 1 selected from 1 : (1 S, 2S)Phenyl—cyclopropanecarboxylic acid [(S)(6-isopropoxy—pyridinyl)-ethyl]— amide; 2: (1 S, 2S)Phenyl—cyclopropanecarboxylic acid [(S)(5-methyl—pyridiny/)-ethyl]—amide; 3: (1 S, 28)Phenyl—cyclopropanecarboxylic acid [(S)(6-methoxy—pyridinyl)-ethy/]—amide; 4: (1 S, Phenyl—cyclopropanecarboxylic acid [(S)(6-methyl—pyridin-3—y/)-ethyl]—amide; 5: (1 S, 2S)-2—Phenyl—cyclopropanecarboxylic acid [(S)(6-cyano-pyridinyl)-ethyl]—amide; 6: (1 S, 28)Phenyl—cyclopropanecarboxylic acid [(S)(6-trifluoromethyl—pyridinyl)-ethyl]- amide; 7: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid -(6-ethoxy-pyridin-3—y/)-ethyl]—amide; 8: (1 S, 28)Phenyl—cyclopropanecarboxylic acid [(S)(6-ethyl-pyridinyl)-ethy/]—amide; 9: (1 S, 28)Phenyl—cyclopropanecarboxylic acid [(S)(6-methoxymethyl-pyridinyl)-ethyl]— amide; 1 0: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid {(S)-1 -[6-(2, 2, 2-trifluoro-ethoxy)-pyridin-3— y/]-ethyl}-amide; 1 1 : (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(S)[6-(2-methoxy-ethoxy)-pyridinyl]— ethyl}-amide; 12: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(S)(2-ethoxy-pyridiny/)-ethyl]—amide; [Annotation] sak 13: (1 S, Phenyl-cyclopropanecarboxy/ic acid ((S){6-[(S)—(tetrahydro-furanyl)oxy]- pyridiny/}-ethyl)—amide; 14: (1 S, 2S)Phenyl-cyclopropanecarboxy/ic acid ((S){6-[(R)—(tetrahydro-furanyl)0ny- pyridinyl}-ethyl)-amide; : (1 S, 28)-2—Phenyl—cyclopropanecarboxy/ic acid ((S)[1, 3]dioxo/o[4, 5-b]pyridinyl—ethyl)- amide; 16: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(S)(2, 3-dihydro-[1, 4]dioxino[2, 3- b]pyridin- 7-y/)-ethyl]—amide; 17: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(S)(2-ethoxy-pyrimidiny/)-ethyl]— amide; 1 8: (1 S, 2S)Phenyl-cyclopropanecarboxy/ic acid [(S)(6-chloro-pyridiny/)-ethyl]—amide; 19: (1 S, 2S)Phenyl-cyclopropanecarboxy/ic acid {(8)[6-(oxetanyloxy)—pyridinyl]— ethyl}-amide; : (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(S)(6-cyanomethoxy-pyridinyl)— -amide; 21 : (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)hydroxy(6-propoxy-pyridiny/)- ethy/J-amide; 22: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)hydroxy(6-trifluoromethyl-pyridin- 3-yl)-ethy/]—amide; 23: (1 S, Phenyl—cyclopropanecarboxy/ic acid [(R)(5-cyano-pyridin-2—yl)—2—hydroxy- ethy/J-amide; 24: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)hydroxy(6-methoxy-pyridinyl)— ethy/J-amide; : (1 S, 28)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)hydroxy(6-methyl—pyridinyl)— ethy/J-amide; 26: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)hydroxy(6-isopropoxy-pyridin y/)-ethy/]-amide; 27: (1 S, 2S)(3-Fluoro-phenyl)-cyclopropanecarboxy/ic acid [(R)(6-ethoxy-pyridiny/)—2— y-ethy/]—amide; 28: (1 S, 2S)(4-Fluoro-phenyl)-cyclopropanecarboxy/ic acid [(R)(6-ethoxy-pyridiny/)—2— y-ethy/]—amide; 29: (1 S, 2S)(3-F/uoro-phenyl)—cyclopropanecarboxy/ic acid [(R)hydroxy(6-propoxy- pyridiny/)-ethyl]—amide; : (1 S, 2S)-2—(4-F/uoro-phenyl)—cyclopropanecarboxy/ic acid [(R)hydroxy(6-propoxy- pyridiny/)-ethyl]—amide; [Annotation] sak 31 : (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(R)-1 -(6-(2, 2, 2-d3)-ethoxy-pyridin-3—yl)—2- hydroxy-ethy/]—amide,' 32: (1 S, 2S)(3-Fluoro-phenyl)-cyclopropanecarboxy/ic acid [(R)(6-(1, 1 -d2)-ethoxy-pyridin- 2-hydroxy-ethy/]—amide,' 33: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(R)(6-ethoxy-pyridin-3—y/)hydroxy- -amide; 34: (1 S, 2S)(4-Fluoro-phenyl)-cyclopropanecarboxy/ic acid [(R)(6-(1, 1, 2, 2, 2-d5)-ethoxy- pyridinyl)hydroxy-ethyl]—amide,' : (1 S, 2S)(4-Fluoro-phenyl)-cyclopropanecarboxy/ic acid [(R)-1 -(6-(2, 2, 2-d3)-ethoxy- nyl)hydroxy-ethyl]—amide,' 36: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(R)(6-(1, 1 -d2)-ethoxy-pyridin-3—yl)—2- y-ethy/]—amide,' 37: (1 S, 2S)(4-Fluoro-phenyl)-cyclopropanecarboxy/ic acid [(R)(6-(1, 1 -d2)-ethoxy-pyridin- 3—yl)hydroxy-ethy/]—amide,' 38: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(R)(6-(1, 1, 2, 2, 2-d5)-ethoxy-pyridin y/)hydroxy-ethy/J—amide,‘ 39: (1 S, 2S)(3-F/uoro-phenyl)—cyclopropanecarboxy/ic acid [(R)(6-(2, 2, 2-d3)-ethoxy- pyridinyl)hydroxy-ethyl]—amide,' 40: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid [(R)(6-cyc/obutoxy-pyridin-3—yl)—2- hydroxy-ethy/]—amide,' 41 : (1 S, (3-F/uoro-phenyl)—cyclopropanecarboxy/ic acid [(R)(6-cyc/obutoxy-pyridin-3— y/)hydroxy-ethy/J—amide,‘ 42: (1 S, 2S)(4-F/uoro-phenyl)-cyc/opropanecarboxy/ic acid [(R)(6-cyc/obutoxy-pyridin-3— y/)hydroxy-ethy/J—amide,‘ 43: (1 S, 2S)Phenyl—cyclopropanecarboxylic acid ((R)hydroxy{6-[(R)-(tetrahydro-furan- 3—yl)oxy]-pyridin-3—yl}-ethy/)-amide,' 44: (1 S, 28)-N-[(1 R)hydroxy[6-[(38)-tetrahydrofuran-3—y/Joxypyridyljethyl]—2-phenyl— cyc/opropanecarboxamide,‘ 45: (1 S, 28)—2-((Z)Methy/ene—pem‘a-2, 4-dienyl)-cyclopropanecarboxy/ic acid {(R) hydroxy[6-(tetrahydro-pyranyloxy)—pyridiny/]-ethy/}-amide,' 46: (1 S, 2S)Phenyl—cyc/opropanecarboxylic acid [(R)(6-ethoxy-pyridin-3—y/)methoxy- ethy/J-amide; 47: (1 S, [(1R)—2-methoxy[6-[(3R)-tetrahydrofuran-3—yl]oxy-3—pyridyl]ethy/J—2-phenyl- cyc/opropanecarboxamide,‘ 48: (1 S, 2S)-N-[(1R)—2-methoxy[6-[(3S)-tetrahydrofuran-3—yl]oxy-3—pyridy/]ethy/J—2-phenyl— cyc/opropanecarboxamide,‘ [Annotation] sak 49: (1 S, 2S)-2—Phenyl—cyclopropanecarboxylic acid {(R)-2—methoxy[6-(tetrahydro-pyran -pyridinyl]-ethyl}-amide; 50: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid {(8)[6-(oxetanyloxy)-pyridinyl]— ethyl}-amide; 51 : (1 S, 2S)Phenyl-cyclopropanecarboxy/ic acid [(S)(6-ethanesulfonyl -pyridinyl)-ethyl]—amide; 52: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)(5-ethoxy-pyridin- 2-yl)hydroxy-ethy/]—amide; and pharmaceutically acceptable salts of any of these compounds.
E33. A compound according to any of embodiments 1-32, for use as a medicament.
E34. A compound according to any of embodiments 1-32, for use in y.
E35. A nd according to any of embodiments 1-32, for use in the treatment of a dis- ease or disorder ed from Psychosis; Schizophrenia; cognitive disorders; cognitive im- pairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); au- tism spectrum disorders, Alzheimer’s disease (AD); mild cognitive impairment (MCI); age as- sociated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; de- mentia associated with Lewy bodies; dementia associated with Down's syndrome; Hunting- ton's Disease; Parkinson’s disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic ; Wernicke-Korsakoff me (WKS); post- traumatic amnesia; cognitive deficits associated with sion; diabetes, weight control, matory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
E36. The compound according to embodiment 35, wherein said a disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sis; gton's disease; dementia associated with Lewy bodies and pain.
E37. The compound according to embodiment 36, n said disease or disorder is se- lected from schizophrenia; AD; ADHD and autism um disorders.
E38. The compound according to embodiment 37, wherein said disease or disorder is se- lected from negative and/or cognitive symptoms of schizophrenia.
[Annotation] sak E39. The compound according to any of embodiments 1-32, for use itantly or se- quentially with a therapeutically effective amount of a compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine ort inhibitors; noradrenalin transport tors; D2 nists; D2 partial agonists; PDE10 an- tagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium chan- nel blockers and GABA signaling enhancers in the treatment of a disease or disorder accord- ing to any of embodiments 35-38.
E40. A pharmaceutical composition comprising a compound according to any of - ments 1-32, and one or more pharmaceutically able carrier or excipient.
E41. The composition according to ment 40, which composition additionally com- prises a second compound selected from the list ting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibi- tors; D2 antagonists; D2 partial agonists; PDE10 nists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling en- hancers.
E42. The composition according to embodiment 41, wherein said second compound is an acetylcholinesterase inhibitor.
E43. A kit comprising a nd according to any of embodiments 1-32, er with a second compound selected from the list consisting of acetylcholinesterase inhibitors; gluta- mate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antago- nists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
E44. The kit according to embodiment 43, wherein said second compound is an cho- linesterase inhibitor.
E45. A method for the treatment of a disease or disorder selected from Psychosis; Schizo- phrenia; cognitive disorders; ive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, mer’s disease (AD); mild cognitive ment (MCI); age associated memory impairment (AAMI); senile demen- tia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associ- ated with Down's syndrome; gton's Disease; Parkinson’s disease (PD); obsessive- [Annotation] sak compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic ; Wernicke- Korsakoff syndrome (WKS); raumatic amnesia; cognitive deficits associated with de- pression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; o- phic lateral sclerosis and pain, which method comprises the administration of a therapeuti- cally effective amount of a compound according to any of embodiments 1-32 to a patient in need thereof.
E46. The method according to embodiment 45, n said e or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain.
E47. The method ing to embodiment 46, wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
E48. The method according to embodiment 47, wherein said ent comprises the treat- ment of negative and/or cognitive symptoms of schizophrenia.
E49. The method according to any of embodiments 45-48, wherein said treatment further comprises the administration of a therapeutically ive amount of a second compound se- lected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antago- nists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antago- nists; m; sodium channel blockers and GABA signaling enhancers.
E50. The method ing to embodiment 49, wherein said second compound is an ace- tylcholinesterase inhibitor.
E51. Use of a compound according to any of embodiments 1-32, for the manufacture of a medicament for the treatment of a disease or disorder selected from Psychosis; Schizophre- nia; cognitive disorders; cognitive impairment associated with schizophrenia; ion t ctivity Disorder (ADHD); autism spectrum disorders, Alzheimer’s disease (AD); mild cognitive impairment (MCI); age associated memory ment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson’s disease (PD); obsessive- compulsive disorder (OCD); traumatic brain injury; epilepsy; raumatic stress; Wernicke- Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with de- [Annotation] sak pression; diabetes, weight l, inflammatory disorders, reduced angiogenesis; amyotro- phic lateral sclerosis and pain.
E52. The use according to embodiment 51, wherein said e or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain.
E53. The use according to embodiment 52, n said disease or disorder is selected from schizophrenia; AD; ADHD and autism um disorders.
E54. The use according to embodiment 53, wherein said disease is the positive, negative and/or cognitive symptoms of schizophrenia.
E55. The use according to any of embodiments 51-54, wherein said cture further comprises the use of a second compound selected from the list consisting of acetylcholi- nesterase inhibitors; glutamate or antagonists; dopamine transport inhibitors; noradrenalin ort inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5- HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
E56. The use according to embodiment 55, wherein said second compound is an acetyl- cholinesterase inhibitor.
The compounds of the invention may exist in unsolvated as well as in solvated forms in which the solvent les are selected from pharmaceutically acceptable solvents such as water, ethanol and the like. In general, such solvated forms are considered equivalent to the unsolvated forms for the es of this invention.
Included in this invention are also isotopically labeled compounds, which are identical to those claimed in a [I], wherein one or more atoms are represented by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (e.g., 2H, 3H, 11C, 130, 15N, 18F and the like). ular mention is made of 2H substituted compounds i.e. compounds n one or more H atoms are represented by deuterium. In one embodiment of the invention one or more of the hydro- gen atoms of the compound of formula [I] are represented by ium. It is recognized that elements are present in natural isotopic abundances in most synthetic compounds, and result in inherent incorporation of deuterium. However, the natural isotopic abundance of hydrogen [Annotation] sak isotopes such as deuterium is immaterial (about 0.015%) relative to the degree of stable iso- topic substitution of nds indicated herein. Thus, as used herein, designation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural nce of ium. Any atom not designated as a particular isotope is intended to represent any stable isotope of that atom, as will be apparent to the or- dinarily skilled artisan.
In one embodiment, designation of a on as "D" in a compound has a m deuterium incorporation of greater than about 60% at that position such as greater than about 70% at that position such as greater than about 80% at that position such as greater than about 85% at that position. In a further embodiment, designation of a position as "D" in a compound has a minimum deuterium incorporation of greater than about 90% at that position such as greater than about 95% at that position such as greater than about 97% at that posi- tion such as greater than about 99% at that position.
The compounds of the present invention have three asymmetric centers with fixed stereochemistry indicated by the arrows below.
The compounds of the present invention can be manufactured from two chiral inter- es with one and two asymmetric centers, respectively, as illustrated by the examples below.
In this context is understood that when specifying the enantiomeric form of the inter- e, then the ediate is in enantiomeric excess, e.g. essentially in a pure, mono- enantiomeric form. Accordingly, the resulting nds of the invention are having a di- astereomeric excess of at least 80%. One embodiment of the invention relates to a com- pound of the ion having a diastereomeric excess of at least 80% such as at least 85%, such as at least 90%, ably at least 95% or at least 97% with reference to the three as- symetric centers indicated above.
Dependent on the individually substituents R1-R14, the compounds of the present in- n may furthermore have one or more additional asymmetric centers. It is intended that any optical isomers (i.e. enantiomers or diastereomers), in the form of separated, pure or par- tially purified optical isomers and any mixtures thereof including racemic mixtures, Le. a mix- ture of stereoisomers, which have emerged because of asymmetric centers in any of sub- stituents , are included within the scope of the invention.
[Annotation] sak Racemic forms can be resolved into the optical antipodes by known methods, for ex- ample by separation of diastereomeric salts thereof with an optically active acid, and liberat- ing the lly active amine compound by treatment with a base. r method for resolv- ing racemates into the l des is based upon chromatography of an optically active matrix. The nds of the present invention may also be resolved by the formation of di- astereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A.
Collet and S. Wilen in "Enantiomers, Racemates, and tions", John Wiley and Sons, New York . Optically active compounds can also be prepared from optically active starting materials.
Furthermore, when a double bond or a fully or lly ted ring system is pre- sent in the molecule geometric isomers may be formed. It is intended that any ric iso- mers, as separated, pure or partially purified geometric isomers or mixtures thereof are in- cluded within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
The compounds of the present invention may be stered alone as a pure com- pound or in combination with pharmaceutically acceptable carriers or excipients, in either sin- gle or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and ce of Pharmacy, 19 Edition, Gennaro, Ed., Mack Pub- lishing 00., , PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including sub- cutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, es, s and granules. Where appropriate, they can be prepared with coatings.
[Annotation] sak Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical itions for eral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be tituted in sterile injectable solutions or dispersions prior to use.
Other suitable administration forms include itories, sprays, ointments, cremes, gels, inhalants, dermal patches, ts, etc.
In one embodiment, the compound of the present invention is administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day. In par- ticular, daily dosages may be in the range of 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The exact dosages will depend upon the frequency and mode of administra- tion, the sex, the age the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.
A typical oral dosage for adults will be in the range of 0.1-1000 mg/day of a compound of the present invention, such as 1-500 mg/day, such as 1-100 mg/day or 1-50 .
Conveniently, the compounds of the invention are administered in a unit dosage form contain- ing said compounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg of a nd of the t invention.
For parenteral administration, solutions of the compound of the invention in sterile aqueous on, aqueous propylene , aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if ary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are par- ticularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administra- tion. The sterile aqueous media employed are all readily available by standard ques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid ts or fillers, sterile aqueous solution and various organic solvents. es of solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, o lipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compound of the invention and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms le for the sed routes of administration.
Formulations of the present invention suitable for oral administration may be pre- sented as discrete units such as capsules or tablets, each containing a predetermined [Annotation] sak amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or sus- pension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tablet, e.g. placed in a hard gelatine capsule in powder or pellet form or in the form of a troche or loz- enge. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g.
If a liquid r is used, the preparation may be in the form of a syrup, emulsion, soft gela- tine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or ts followed by the ssion of the mixture in a conventional tabletting ma- chine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, mag- nesium stearate, gelatine, e, gums, and the like. Any other nts or additives usu- ally used for such es such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
All references, including ations, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each refer- ence were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), less of any sepa- rately ed incorporation of particular documents made elsewhere herein.
The use of the terms "a" and "an" and "the" and similar referents in the t of de- scribing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by t. For example, the phrase "the compound" is to be understood as referring to various "compounds" of the invention or par- ticular described aspect, unless othenNise indicated.
The description herein of any aspect or aspect of the ion using terms such as "comprising", "having," "including," or "containing" with nce to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "consists essentially of", or "substantially comprises" that particular element or elements, unless othenNise stated or clearly dicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a compo- sition consisting of that element, unless otherwise stated or clearly contradicted by context).
It should be understood that the various aspects, embodiments, implementations and es of the invention mentioned herein may be claimed separately, or in any combination.
[Annotation] sak The compounds of formula I may be ed by methods described below, together with synthetic s known in the art of c chemistry, or modifications that are familiar to those of ry skill in the art. The starting materials used herein are available commer- cially or may be prepared by routine methods known in the art, such as those method de- scribed in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. l-Xll" (published with Wiley-lnterscience). Preferred methods include, but are not limited to, those described below.
The schemes are representative of methods useful in synthesizing the nds of the present ion. They are not to ain the scope of the invention in any way.
Methods of ation of the Compounds of the Invention.
The compounds of the invention with formula I can be prepared from intermediate Ill and II as described in Scheme 1.
Scheme 1 If X is a hydroxyl, the carboxylic acid II and the amine Hi can be condensed to form the amide I using standard peptide coupling chemistry, e.g. as described in the textbook Syn- thetic Peptides A user’s Guide (Edited by Gregory A. Grant, W H. Freeman and company (1992) ISBN 07009-1) or as described in the textbook -Wey/ Volume E22a Synthesis of es (George Thiemes Ver/ag Stuttgart (2003) 4th ed.). One example of this amide formation is the use of the coupling reagent HATU (O-(benzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate). lly, one eq. of II is reacted with one eq. of HATU in the presence of two eq. of a tertiary amine e.g. triethylamine in a suitable solvent e.g. DMF. After a short period of time (e.g. five minutes) this mixture is reacted with one eq. of III to form |. Another example of this amide formation uses 1-hydroxybenzotriazole together with the water soluble carbodiimide EDC (CAS 259528) and triethyl amine in a suitable solvent e.g. THF. These reactions are usually performed at room temperature or between 0 0C and 50 0C.
[Annotation] sak If X is a chloride (e.g. prepared from the carboxylic acid ll, X = OH, using thionyl chloride) lll can be reacted with II to form | in the presence of a tertiary amine in a suitable solvent. Alter- natively, the carboxylic acid chloride (ll, X = Cl) can be reacted with N-hydroxy succinimide to produce the HOSU ester which can be isolated and then reacted with I" to produce |.
Methods of Preparation of the Intermediates of the Invention.
The Intermediates of the invention with formula II are either commercially available or can be prepared as bed in Scheme 2.
R4 R4 R3 R5 R3 R5 R2 0 R2 0 R1 R1 K racemic-trans-ll ethylester R3 R5 SFC separation R2 OH racemic trans || " Scheme 2. ation of the (1S, 2S) enantiomer of formula II.
Ethyldiazoacetate can be reacted with the styrene in Scheme II to produce the race- mic-trans ll ethyl ester. This ester can then be hydrolyzed to racemic trans II which can then be separated into the two enantiomers using SFC. Alternatively, racemic trans II can be re- solved into the two enantiomers by known methods as bed in the textbook "Enanti- omers, Racemates and Resolutions" (J. Jaques, et al., John Wiley and sons, New York (1981)).
Another preparation of the compounds with a II is described in Scheme 3. This method has been bed in detail in W02012/O37258 [Annotation] sak R4 R4 R3 R5 OEt R3 R5 EtO\ I OtBU —S— NaH LiOH + PW I H —» H / OtBu —> —’ R2 0 O Toluene R2 NaOtBu R1 0 R1 0 DMSO R3 R5 R2 OH Separation racemic trans ll " Scheme 3. Preparation of the (1S, ZS) enantiomer of formula II.
The benzaldehyde shown in Scheme 3 can be reacted with the anion of (Diethoxy- phosphoryl)—acetic acid tert-butyl ester to produce the unsaturated ester shown. Cylopropana- tion followed by ysis then produces Racemic trans II, which can be separated as de- scribed above.
The lntermediates of the invention with formula III are either commercially ble or can be prepared as described in Scheme 4 in which R5 is CHZOH.
Br A" / is9 0 H OSITBS ' 0 R10 S\NH + O _> g —> / / 2 OSiTBS tBU \N BuLi OSiTBS OSITBS OH i '/ i s A s A A t /Bu \N 7¢ + / As Bu \N 7¢ 7? I A I As H2N As H H A _. I / /A 9 / 9 9 R11 R11 R11 R10 R10 R10 Scheme 4. Preparation of the chiral amines of a III, with R5 = CHZOH. The method is described in: Barrow, J. C. et al. Tetrahedron Letters (2001) 2051.
[Annotation] sak )methylpropanesulfinamide can be reacted with (tertbutyldimethylsilyloxy ldehyde as described in the literature (Barrow, J. C. et al. e- dron Letters (2001) 2051) to produce the sulfinimine shown in Scheme 4. 1,2- addition of an organometallic (e.g. a Grignard reagent or an thiumreagent (shown in Scheme 4) re- agent to this sulfinyl imines then gives the two reomeric protected amino alcohols shown in scheme 4. These isomers can be separated e.g. by silica gel chromatography and the protecting groups are then removed under acidic conditions.
Another method using enantiopure tert-butanesulfinamide is shown in Scheme 5 (Robak, M., Herbage, M., Ellman, Chem. Rev. 2010, 110, 3600-3740 and references cited herein). For simplicity, the method is only illustrated for R5 = CH3, but the method is not lim- ited to R5 = CH3.
I I8 Reduction X8\ + _, —> NHz 9 0 o t t /l A \N 7\\ + A /l A B" As B" \N 7C 7C As HZN As H —» I H I I /l 9 /l /l 9 9 R11 R11 R11 R10 R10 R10 Minor isomer Major isomer Scheme 5. Preparation of the chiral amines of formula III, with R5 = CH3. The method is de- scribed in: Robak, M., Herbage, M., Ellman, Chem. Rev. 2010, 110, 3600-3740 and refer- ences cited herein.
(R)—(+)methylpropanesulfinamide can be reacted with a le ketone and titanium (lV)ethoxide in a suitable solvent e.g. THF under heating conditions to produce the sulfinyl imine shown in scheme 5. This imine can be reduced, with some selectivity using a reducing agent (e.g. L-selectride) in a suitable solvent (e.g. THF) at a suitable temperature (e.g. -70 0C) to produce the major and the minor isomer shown in Scheme 5. The major iso- mer can be isolated by e.g. silica gel tography and the chiral auxiliary can then be re- moved with acid (e.g. HCI in water to produce lll).
EXAMPLES ation] sak The invention will be illustrated by the following non-limiting examples.
Abbreviations AcOH = acetic acid. OLD = specific optical on. Aq = Aqueous. BBr3 = boron tribromide (used as DCM solution; Aldrich 17,893-4). Boc20 = Boc anhydride / di-t—butyl dicarbonate (e.g. Aldrich 19,913-3). Brine = saturated aqueous solution of sodium chloride. CDCI3 deuter- ated form (e.g. Aldrich 225789). Celite = filter-aid. CH3| = methyl iodide / iodomethane (e.g. Aldrich 28,956-6). Cs2C03 = cesium carbonate (Aldrich 441902). DCM = dichloro- methane. DMF = yl formamide. DMSO = yl sulfoxide. O = ated dimethyl sulfoxide (e.g. Aldrich 296147). ELSD = evaporative light scattering detection. Et3N = triethyl amine. EtOAc = ethyl e. 99% EtOH = absolute ethanol. EtZO = diethyl ether. h = hours. HATU = O-(7-Azabenzotriazoly|)-N,N,N’,N’-tetramethyluronium ouruphos- phate. HBTU = 2-(1H-Benzotriazolyl)—1,1,3,3-tetramethyluronium hexaflourophosphate. i= iso. K2C03 = potassium carbonate (e.g. Aldrich 20,961-9). LDA = lithium di-i-propylamide (used as a THF/heptane/ethylbenzene solution; Fluka 62491 ). LC/MS = erformance liquid chromatography / mass spectrometer. LAH = lithium aluminium hydride (used as a 1M THF solution; Aldrich 21,277-6). MeOH = methanol. min = minutes. NaCNBH3 = sodium cyanoborohydride (Aldrich 15,615-9). NaH = sodium hydride (used as a 60% dispersion; Aldrich 45,291-2). NaOH = gueous solution of sodium hydroxide. Pd/C = palladium-on- al (e.g. Aldrich 20,569-9). PTSA = para-toluene sulfonic acid e (e.g. Aldrich 40,288—5). rt = room temperature. RT = retention time. sat. NaHCOs = saturated aqueous so- lution of sodium hydrogen carbonate. sat. NH4C| = saturated aqueous solution of ammonium chloride. SFC = supercritical flash chromatography. TFA = trifluoroacetic acid. THF = tetrahy- drofuran (dried over 4A molecular sieves). TLC = thin layer chromatography. al names were obtained using the software MDL ISIS/DRAW 2.5 from MDL informa- tion systems Spectroscopic methods.
Method A: LC-MS were run on a Sciex AP|150EX equipped with APPl-source operating in positive ion mode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps, SPD-M20A PDA or (operating at 254 nm) and SCL-10A system controller. Autosampler was Gilson 215, Column oven was a Jones Chromatography 7990R and ELS detector was a Sedere Sedex 85.
[Annotation] sak LC-conditions: The column was a Waters Symmetry C-18, 4.6x30 mm, 3.5 pm operating at 60°C with 3.0 mL/min of a binary gradient consisting of water + 0.05% TFA (A) and methanol + 0.05% TFA (B).
Gradient: 0.01 min 17% B 0.27 min 28% B 0.53 min 39% B 0.80 min 50% B 1.07 min 59% B 1.34 min 68% B 1.60 min 78% B 1.87 min 86% B 2.14 min 93% B 2.38 min 100% B 2.40 min 17% B 2.80 min 17% B Total run time: 2.8 min.
The retention times (tR) are expressed in minutes based on ce at 254 nm.
Method B: LC-MS were run on Waters Acquity UPLC-MS consisting of Waters y including column mamager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector, and SQD-MS equipped with APPl-source operating in ve ion mode.
LC-conditions: The column was y UPLC BEH C18 1.7um ; 2.1x50mm operating at 60°C with 1.2 ml/min of a binary gradient consisting of water + 0.05 % trifluoroacetic acid (A) and acetonitrile + % water + 0.035 % trifluoroacetic acid.(B) Gradient: 0.00 min 10% B 1.00 min 100% B 1.01 min 10% B 1.15 min 10% B Total run time: 1.2 min.
The retention times (tR) are expressed in minutes based on UV-trace at 254 nm.
[Annotation] sak Method C: ative supercritical fluid chromatography (SFC) was med on a Berger Multigram ll operating at 50 mL/min at 35°C and 100 bar backpressure using stacked injections. The col- umn was a ChiralpakAD 5 u, 250x21 mm. The eluent was C02 (70%) and ethanol (30%).
Method D: Preparative supercritical fluid chromatography (SFC) was performed on a Thar SFC-80 oper- ating at 60 g/min at 35°C and 140 bar backpressure using stacked injections. The column was a ChiralPakAD-H 0 mm). The eluent was C02 (88%) and Ethanol (12%).
Method E: Preparative ritical fluid chromatography (SFC) was performed on a Thar SFC-200 op- erating at 100 g/min at 35°C and 140 bar backpressure using stacked injections. The column was a PakAD-H 0 mm). The eluent was C02 (90%) and Ethanol (10%).
Method F: Enantiomeric excess (ee) was determined on an Aurora Fusion A5 SFC system operating at 3 ml/min at 40 °C and 100 bar backpressure. The column was a Chiralpak AD .6 mm).
The eluent was C02 (70%) and ethanol + 0.1% l amine (30%). 1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX-500 instrument at T=303.3 K or at 600 MHz on a Bruker Avance AV-lll-600 instrument. Chemical shift values are expressed in ppm-values relative to tetramethylsilane unless noted otherwise. The follow- ing abbreviations or their combinations are used for multiplicity of NMR signals: s = singlet, d = doublet, m = multiplet and br = broad.
Preparation of intermediates Pre aration of bromo ridines.
IM1 : 5-Bromo-2—isopropoxy—pyridine BraI k\ 60% NaH in 0" (15:1, Sodium hydride:Minera| Oil, 5.20 g) was added in two portions to iso- propyl alcohol (150 mL) at room temperature under N2. The mixture was stirred at 60°C for 30 min. 5-bromochloropyridine (10.00 g, 51.96 mmol) was added in two portions and the mix- ture was stirred at reflux 4h and then at 80°C overnight. The solution was concentrated in [Annotation] sak vacuo. Water (50 mL) and EtOAc (50 mL) was added and the layers were ted. The aqueous layer was ted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was d in vacuo. The crude prod- uct was subjected to flash chromatography (silica, 0-50% EtOAc in es) to give the title compound as a clear oil (8.74 g, 78%). 1H NMR (600 MHz, DMSO) 6 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H), 1.33 (s, 6H).
IM2: 5-Bromo(2, 2, 2-trifluoro-ethoxy)-pyridine Prepared analogously to IM1 to give the title compound as a colorless liquid (2.78 g, 54%) sufficiently pure for the next step.
IM3: 5-Bromopropoxy—pyridine Potassium tert—butoxide (1.85 g, 16.5 mmol) was added to a mixture of 5-bromo chloropyridine (2.89 g, 15.0 mmol) and 1-propanol (1.230 mL, 16.5 mmol) in THF (15 mL).
The reaction mixture was heated at 120°C for 30 minutes in a microwave reactor. The mixture was poured into a mixture of water (50 mL) and EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (sil- ica, 0-20% EtOAc in heptanes) gave the title compound as a yellow oil (3.13 g, 97%) suffi- ciently pure for the next step.
IM4: 5-Bromo(2, 2, 2-d3)-ethoxy-pyridine [Annotation] sak Prepared analogously to IM3 using commercially available 2,2,2-d3-ethanol (Sigma-Aldrich, catalog no ) to give the title compound as a colorless oil (2.53 g, 82%) sufficiently pure for the next step.
IM5: 5-Bromo-2—(1 , 1, 2, 2, 2-d5)-ethoxy-pyridine Prepared analogously to IM3 using commercially available 1,1,2,2,2-d5-ethanol (Sigma- h, catalog no 489336) to give the title compound as a colorless oil (1.16 g, 87%) suffi- ciently pure for the next step.
IM6: 5-Bromo-2—(1 1 -d2)-ethoxy-pyridine Prepared analogously to IM3 using commercially available 1,1-d2-ethanol (Sigma-Aldrich, catalog no 347434) to give the title compound as a colorless oil (2.61 g, 85%) sufficiently pure for the next step.
IM7: 5-Bromo-2—(2—methoxy—ethoxy)-pyridine 2-Methoxyethanol (5.12 mL, 65.0 mmol) was dissolved in 1,4-dioxane (125 mL). Potassium tert—butoxide (7.00 g, 62.4 mmol) was added under N2. The e was stirred for 10 min- utes. 5-Bromochloropyridine (10.0 g, 52.0 mmol) was added and the ing mixture was refluxed for 2 hours. The mixture was poured into brine and extracted with EtOAc. The or- ganic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Purification by flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (8.74 g, 73%) iently pure for the next step.
IM8: 5-Bromomethoxymethyl-pyridine ation] sak \' 0\ To a solution of opyridinecarbaldehyde (5.00 g, 26.9 mmol) dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was added sodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45 minutes 0.5 mL water was added and the mixture and evaporated to dryness. The oily residue was subjected to flash tography (silica, EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridinyl)—methanol (4.81 g, 86%) as pale-yellow oil.
A solution of this (5-bromo-pyridinyl)—methanol (4.80 g, 23.0 mmol) in DMF (25 mL) was added drop wise over 5 minutes to a slurry of sodium hydride (1.10 g, 27.6 mmol) in DMF (50 mL) at 0 °C under N2. The mixture was stirred for 15 minutes before the drop wise addition of a solution of methyl iodide (1.57 mL, 25.3 mmol) in DMF (25 mL). The mixture was allowed to reach room temperature and was then stirred ght. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were thoroughly washed with brine, dried over MgSO4 and evaporated to dryness to give the title nd as a yellow oil (4.77 g, 98%) sufficiently pure for the next step.
IM9: ocyc/obutoxy—pyridine Prepared analogously to IM3 using commercially available cyclobutanol to give the title compound as a clear oil (2.72 g, 80%) sufficiently pure for the next step.
IM1 0: 5-Bromo[(R)-(tetrahydro-furanyl)oxy]—pyridine To a solution of 5-bromochloropyridine (10 g, 52.1 mmol) in 100 mL of DMF was added cially available )—3-hydroxytetrahydrofuran (6.87 g, 78.1 mmol) and Cs2C03 (33.85 g, 0.104 mol), the resulting mixture was heated 90 °C for 36 hours. The solvent was concentrated and the residue was extracted with EtOAc (500ml), washed with water (200ml).
The organic layer was dried over NaZSO4, concentrated and purified by chromatography on silica gel (eluting with Petrol ether: EtOAc = 100:1) to afford 5-Bromo[(R)-(tetrahydro-furan- 3-yl)oxy]—pyridine (5.9 g, yield: 47%) as a solid. 1HNMR (CDCI3 400MHz): 68.15 (d, J = 2.4 Hz, 1 H), 7.61-7.64 (m, 1 H), 6.64 (d, J: 8.8 Hz, 1 H), 5.47-5.50 (m, 1 H), 3.85-4.02 (m, 4 H), 2.07-2.28 (m, 2 H). [a1D20 = +18.5 (C=0.189, CHCI3).
[Annotation] sak IM1 1 : 5-Bromo-2—[(S)-(tetrahydro-furanyl)ony-pyridine Bra 0 \ u' Prepared analogously to IM10 using commercially available (S)-(+)hydroxytetrahydrofuran to afford 5-Bromo[(S)-(tetrahydro-furany/)oxy]-pyridine (9.62 g, yield: 51%) as a solid. 1HNMR (CDCI3400MHz): 68.16 (d, J = 2.4 Hz, 1 H), 7.62- 7.65 (m, 1 H), .66 (m, 1 H), 5.48-5.52 (m, 1 H), 3.99-4.03 (m, 2 H), 3.86-3.97 (m, 2 H), 2.20-2.29 (m, 1 H), 2.08-2.15(m, 1 H). [011020 = -20.7 (c=0.21, CHCI3).
IM12: 5-Bromo(tetrahydro-pyranyloxy)-pyridine Prepared analogously to IM3 using commercially available tetrahydropyranol to give the title compound iently pure for the next step.
IM1 3: 6-Bromo-[1, 3]dioxolo[4, 5-b]pyridine Br Br / IN / + N Br/\Br I \ \ OH 0 OH 0J To a suspension of o-pyridine-2,3-diol (10.0 g, 52.63 mmol, commercially ble, CAS 34206-49—0) in NMP (100 mL) was added K2C03 (21.97 g, 158 mmol) and dibromo methane (10.97 g, 63.16 mmol). The reaction mixture was heated to 90 °C for 16 h. EtOAc was added and the salts were filtered off. Water was added, the phases were separated and the aq layer was extracted with more ethyl acetate. The combined organic layers was dried over anhydrous NaZSO4 and concentrated under vacuo to get the crude nd. The crude compound was purified by silica gel chromatography (eluent 5 % ethyl acetate in petrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2.2 g (21%) pure by 1H NMR (400 MHz, DMSO) 6 7.71 (d, 1H, J = 2 Hz), 7.55 (d, 1H, J = 2 Hz), 6.20 (s, 2H). Mp 69-71 C.
IM1 4: 7-Bromo-2, 3-dihydro-[1, 4]dioxino[2, 3-b]pyridine [Annotation] sak Br Br / IN + Br/W / ; IN \ \ OH 3, 0 To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol, commercially available, CAS 34206-49—0) in DMF (150 mL) was added K2C03 (21.78 g, 158 mmol) and 1,2-dibromo ethane (11.87 g, 63.2 mmol). The reaction mixture was heated to 100 °C for 5 h. The on mixture was cooled to rt and poured into ice cold water EtOAc was added and the phases were separated and the aq layer was ted with more ethyl acetate. The combined or- ganic layers was dried over anhydrous NaZSO4 and concentrated under vacuo to get the crude compound. The crude compound was purified by silica gel chromatography (eluent 10 % ethyl acetate in petrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2.2 g (18 %) pure by 1H NMR (400 MHz, DMSO) 6 7.85 (d, 1H, J = 2 Hz), 7.59 (d, 1H, J = 2 Hz), 4.41 (m, 2H), 4.27 (m, 2H).
Acetylation of pyridines.
IM15: 1-(6-Ch/oro-pyridin-3—y/)-ethanone A round bottomed flask was charged with 5-bromochloropyridine (5.30 g, 27.6 mmol) in THF under N2 and cooled at 0°C. A solution of 1 M iso-propylmagnesiumchloride - lithium chloride complex in THF (40 mL) was added drop wise over 15 min. After 70 min N-methoxy- N-methylacetamide (4.1 mL, 38 mmol) was added drop wise. After stirring for 5 min at 0 °C the cooling bath was removed. The mixture was left ng overnight and was then quenched by the addition of 100 mL saturated s NH4CI solution. The mixture was ex- tracted with 3x100 mL EtOAc. The combined organic layers were washed with water followed by brine and dried over MgSO4. ation of the volatiles at 80 °C, 10 mbar for 1h gave the title compound (3.596 g, 84) sufficiently pure for the next step.
IM16: 1 -(6-Iso-propoxy—pyridinyI)-ethanone [Annotation] sak A round-bottomed flask was charged with 5-bromoiso-propoxypyridine (IM1) (5.00 g, 23.1 mmol) in THF (100) under N2 and cooled in an acetone/dry-ice bath to -66 °C (internal temperature ). A solution of2.5 M n-butyllithium in hexane (10.1 mL, 25.3 mmol) was added drop wise over 10 minutes at keeping the internal temperature below -55 °C. The mixture was stirred at -65 °C for 15 minutes. N-methoxy-N-methylacetamide (3.07 mL, 28.9 mmol) dis- solved in THF (10 mL) was then added drop wise over 10 s while g the internal temperature below -65 °C. After stirring for 1 h the mixture was allowed to reach room tem- perature. The mixture was poured into saturated s NH4CI solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evapo- rated to dryness. Flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (3.20 g, 77%) iently pure for the next step.
IM17: 1 -(6-Methoxymethyl-pyridinyl)-ethanone \ 0\ Prepared analogously to IM16 from IM8 to give the title compound as a colorless liquid (0.379 g, 17%) sufficiently pure for the next step.
IM1 8: 1-[6-(2, 2, 2— Trifluoro-ethoxy)-pyridinyl]—ethanone \ F O/\F'< Prepared analogously to IM16 from IM2 to give the title compound as a colorless liquid (1.234 g, 48%) iently pure for the next step.
IM1 9: 1 -[6-(2-Methoxy—ethoxy)-pyridinyl]—ethanone Prepared analogously to IM16 from IM7 to give the title compound as a colorless liquid (2.13 g, 57%) sufficiently pure for the next step.
IM20: 1-(2-Ethoxy-pyridinyl)-ethanone [Annotation] sak Prepared analogously to IM16 from commercially ble 4-bromoethoxy-pyridine, Synchem OHG catalog no CT091 to give the title compound as a colorless liquid (1.20 g, 49%) sufficiently pure for the next step.
IM21 : 1-[1, 3]Dioxolo[4, ridiny/—ethanone A round-bottomed flask was charged with 6-Bromo-[1,3]dioxolo[4,5-b]pyridine IM13 (1.74 g, 8.61 mmol) in DMF (25 ml) under N2 and tributyl(1-ethoxyvinyl)tin (3.65 ml, 10.8 mmol) was added. Tetrakistriphenylphosphinepalladium(0) (0.50 g, 0.43 mmol) was added and the solu- tion was stirred at 65 °C overnight. The e was added to water and EtOAc and the phases were separated. The org phase was washed with brine, dried (MgSO4) filtered and was rotovaped. The residue was dissolved in THF (100 ml), and a mixture of water (15 ml) and conc. HCI (2.5 ml) was added and the solution was stirred at rt 5 min. The solution was added to brine and sat NaHC03 solution was added until the on was slightly alkaline.
The org Phase was extracted with EtOAc and the phases were separated. The org phase was washed with brine, dried (MgSO4) filtered and was rotovaped. The residue was redis- solved in THF (10 ml) EtOAc (20 ml) and heptanes (20 ml). The e was concentrated until 25 ml remained and cooled in ice. A solid precipitated and was collected by filtration.
Yield: 0.942 g (66%) of IM21. 1H-NMR (500 MHz, DMSO) 6 8.47 (s,1H), 8.54 (s, 1H), 6.27 (s, 2H), 2.53 (s, 3H).
IM22: 1 -(2, 3-Dihydro-[1 , 4]dioxino[2, 3—b]pyridiny/)-ethanone [Annotation] sak Prepared ously to IM21 from with 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (3.00 g, 13.9 mmol) to give the title nd as a white powder (1.84 g, 74%). 1H-NMR (500 MHz, DMSO) 6 8.47 (s, 1H), 8.54 (s, 1H), 6.27 (s, 2H), 2.53 (s, 3H).
IM23: 1-(6-Ethyl—pyridin-3—yl)-ethanone A dry round bottomed flask was charged with 1-(6-chloropyridinyl)—1-ethanone (IM15) (3.596 g, 23.11 mmol) and [1 ,1'-bis(dipheny|phosphino)ferrocene]-dichloropalladium(ll) (1.694 g, 2.315 mmol) in THF (100 mL) under N2. A1 M solution of diethyl zinc in hexane (35 mL, 35 mmol) was added drop wise to this mixture followed by N,N-dimethylaminoethanol (0.50 mL, 5.0 mmol). The mixture was heated to reflux for 30 minutes. The mixture was cooled to room temperature and then quenched by the addition of ted aqueous NH4C| solution (100 mL). The mixture was filtered through a plug of celite. The aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layers were washed with water, brine and then dried over Mg2804. Flash Chromatography (120 g silica, 0-40% EtOAc in hep- tanes) gave the title compound as a yellow oil (0.699 g, 20%) sufficiently pure for the next step.
Preparation of chiral amines.
Chiral amines were made, if not commercially available, according to well-described proce- dure for either 1,2-stereoselective reduction of sulfinyl imines or 1,2-stereoseelctive on of organometallic reagents to sulfinyl imines. These methods have been described by Chel- lucci, G., Baldino, 8., Chessa, 8., Pinna, G., ini, 8., Tetrahedron Asymmetry 2006, 17, 3163-3169, Evans, J., Ellman, J., J. Org. Chem. 2003, 68, 9948-9957 and Robak, M., Herb- age, M., Ellman, J., Chem. Rev. 2010, 110, 3600-3740 and references cited herein.
IM24: (8)(6-Isopropoxy—pyridin-3—yI)-ethy/amine [>le mI k\ Ste 1: Formation of sulfin l imine: so-propoxy-pyridinyl)-ethanone IM16 (3.20 g, 17.8 mmol) was ved in THF (55 mL) under N2. R(+)methylpropanesulfinamide (2.21 g, 18.2 mmol) and tita- [Annotation] sak nium(|V)ethoxide (7.40 mL, 35.7 mmol) was added. The mixture was refluxed for 24 hours.
The mixture was allowed to reach room temperature. The mixture was diluted with EtOAc (200 mL) and poured into ice/brine. The resulting slurry was filtered through Celite. The or- ganic layer was washed with brine, dried over M9804 and evaporated to dryness. Flash chromatography (silica, heptanes/EtOAc 2:1) gave (R)—2-methyl-propanesulfinic acid [1-(6- isopropoxy-pyridinyl)-ethy|idene]-amide (4.04 g, 80%) as a yellow oil sufficiently pure for the next step.
Step 2: ion of the imine: A round-bottomed flask was charged with methyl-propanesulfinic acid [1-(6-iso— propoxy-pyridinyl)—ethylidene]—amide (4.00 g, 14.2 mmol) in THF (50 mL) under N2 and cooled to -66°C (internal temperature). A 1.00 M solution of L-Selectride in THF (29.0 mL, 29.0 mmol) was added drop wise over 15 minutes. The mixture was stirred at -70°C for 1 hour. The cold mixture was poured into saturated aqueous NH4CI solution. The e was extracted with EtOAc. The combined organic layers were washed with brine, dried over M9804 and evaporated to dryness. Flash chromatography (silica, EtOAc) gave (R)—2-methyl- propanesulfinic acid [(S)—1-(6-isopropoxy-pyridinyl)—ethyl]—amid (2.91 g, 72%) as a color- less powder. reomeric excess >95% based on 1H NMR.
Step 3: Removal of chiral auxiliaLy: (R)—2-Methyl-propanesulfinic acid [(S)—1-(6-isopropoxy-pyridinyl)—ethyl]—amide (2.90 g, 10.2 mmol) was dissolved in methanol (48 mL). A e of 12.0 M HCI in water (4.25 mL) and water (4.25 mL) was added drop wise over 3 minutes. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The oily residue was sub- jected to flash tography (silica, EtOAc/EtOH/triethylamine 90:5:5) on a short column to give (S)—1-(6-isopropoxy-pyridinyl)—ethylamine IM24 (1.71 g, 93%) as a pale-yellow oil suf- ficiently pure for the next step. The overall yield from 1-(6-isopropoxy-pyridinyl)—ethanone IM16 was 54%.
IM25: (S)(6-Ethyl—pyridinyl)-ethylamine ed analogously to IM24 from IM23 to give the title compound sufficiently pure for the next step.
IM26: (S)(6-Methoxymethyl-pyridinyI)-ethy/amine [Annotation] sak Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM27: (S)-1 -[6-(2, 2, 2- Trifluoro-ethoxy)-pyridinyl]—ethy/amine ed analogously to IM24 to give the title nd sufficiently pure for the next step.
IM28: (S)[6-(2-Methoxy-ethoxy)-pyridiny/]-ethylamine Q‘Hz \ O/\/O\ Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM29: (S)(2-Ethoxy—pyridinyl)-ethy/amine E‘Hz Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM30: (S){6-[(S)-(Tetrahydro-furany/)oxy]-pyridiny/}-ethylamine /N O \I L) Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM31 : (S){6-[(R)—(Tetrahydro-furanyl)oxy]-pyridinyl}-ethy/amine [Annotation] sak Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM32: (S)[1, 3]Dioxolo[4, 5-b]pyridiny/-ethylamine Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM33: (S)(2, 3-Dihydro-[1,4]dioxino[2, 3-b]pyridin- 7-yl)-ethy/amine Prepared analogously to IM24 to give the title compound sufficiently pure for the next step.
IM34: (S)(2-Ethoxy-pyrimidinyl)-ethy/amine ed ously to IM24 to give the title compound sufficiently pure for the next step.
IM35: 2—[5-((S)Amino-ethyl)-pyridin-2—yloxy]-ethanol E‘Hz o3 JOH|\ 0 Prepared analogously to IM24 to give the title nd sufficiently pure for the next step.
[Annotation] sak IM36: (R)Amino(6-propoxy—pyridiny/)-ethanol Br 1 tB) u'L' )(S‘gH / N +> Flash chromatography (silica, 10-100% EtOAc in es) gave (R)—2-Methyl-propane sulfinic acid [(R)—2-(tert-butyl-dimethyl-silanyloxy)—1-(6-propoxy-pyridinyl)—ethy|]-amide, the fastest eluding isomer, as a clear oil (2.33 g, 48%) sufficiently pure for the next step. Di- astereomeric excess >95% based on 1H NMR.
A 2.00 M solution of hydrogen chloride in diethyl ether (28 mL, 56 mmol) was added to a stirred solution of [(R)—2-(tert-butyl-dimethyl-silanyloxy)—1-(6-propoxy-pyridinyl)-ethy|]-amide (2.33 g, 5.62 mmol) dissolved in MeOH (11 mL) at 0°C under Ar. After the addition was com- pleted the cooling bath was removed and the solution was stirred at room temperature over- night. The mixture was then evaporated to dryness and the residue was suspended in methylene chloride and transferred to a short silica gel . After eluding with EtOAc:EtOH:Et3N (90:5:5) Amino(6-propoxy-pyridinyl)-ethano|, IM36, was ob- tained as an oil (0.813 g, 74%). The overall yield from 5-bromopropoxypyridine IM3 was 36%. 1H NMR (600 MHz, CDCI3) 6 8.61 (s, 1H), 8.60 (dd, 1H), 7.71 (d, 1H), 4.22 (t, 2H), 4.06 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 1.78 (m, 2H), 1.24 (m, 1H), 1.02 (m, 4H).
IM37: (R)Amino-2—(6-isopropoxy—pyridin-3—y/)-ethanol ation] sak '2‘"2 OH \ Prepared analogously to IM36 to give the title compound sufficiently pure for the next step (1.07 g, 36% overall yield from IM1).
IM38: Amino(6-ethoxy-pyridinyI)-ethano/ Q‘Hz OH \ Prepared analogously to IM36 to give the title compound sufficiently pure for the next step (0.360 g, 35% overall yield from commercially available 5-bromoethoxy-pyridine, Apollo catalog no OR13065).
IM39: (R)Amino(6-(1, 1, 2, 2, 2-d5)-ethoxy—pyridinyl)-ethanol OH \ D>H\DD D Prepared analogously to IM36 to give the title compound sufficiently pure for the next step (0.500 g, 22% overall yield from IM5).
IM40: Amino(6-(2, 2, 2-d3)-ethoxy-pyridin-3—y/)-ethanol Q‘Hz Prepared analogously to IM36 to give the title compound sufficiently pure for the next step (0.647 g, 30% overall yield from IM4).
IM41 : (R)Amino(6-(1,1-d2)-ethoxy-pyridiny/)-ethanol [Annotation] sak OH \ Prepared analogously to IM36 to give the title compound sufficiently pure for the next step (0.380 g, 18% overall yield from IM6).
IM42: (R)-2—Amino{6-[(S)-(tetrahydro-furanyl)oxy]—pyridinyl}-ethano/ E‘Hz OH \ [2 Prepared analogously to IM36 to give the title compound sufficiently pure for the next step.
IM43: (R)Amino{6-[(R)-(tetrahydro-furany/)oxy]—pyridinyl}-ethano/ E‘Hz OH \ IL) Prepared ously to IM36 to give the title nd sufficiently pure for the next step.
IM44: (R)Amino-2—(6-cyclobutoxy-pyridiny/)-ethanol m/N D Prepared analogously to IM36 to give the title compound sufficiently pure for the next step.
IM45: (R)Amino-2—[6-(tetrahydro-pyranyloxy)-pyridiny/]-ethanol OH \ Prepared analogously to IM36 to give the title compound sufficiently pure for the next step.
Pre aration of carbox lic acids.
[Annotation] sak IM46: (1 S,2S)Pheny/-cyclopropanecarboxy/ic acid (3 O III"V)\OH Commercially available, racemic trans 2-phenyl-cyclopropanecarboxylic acid (Sigma-Aldrich, catalog no P22354) was subjected to chiral SFC separation, method C to give IM46 as an oil that slowly solidified upon standing. Enantiomeric purity 95% ee d F). Specific optical rotation +300.9° [or]D20 (C = 1% EtOH). (Lit: +389° [or]D20 (C = 0.61, CHCI3) Kozikowski et al., J.
Med. Chem. 2009, 52, 1885-1902), (Lit: +311.7° [or]D20 (C = 1.776, EtOH) Walborsky et al., Tetrahedron 1964, 20, 699.) IM47: (1 S,2S)(3-F/uoro-phenyl)-cyc/opropanecarboxylic acid F OH Fm Step1 F //\n/ \/ —>O + 3N / O Fm LO Q 0 / OH 0 I""V)kOH Step 1: A round-bottomed flask was charged with 3-fluorostyrene (13.0 g, 0.107 mol) in anhydrous methylene chloride (130 mL). To this mixture was added rhodium acetate dimer (1.30 g, cat amount). A solution of ethyldiazoacetate (33.28 g, 0.291 mol) in anhydrous ene chlo- ride (130 mL) was added to the reaction via a syringe pump over 5 h and stirred at room tem- perature for 1h in darkness. The reaction mixture was filtered h a plug of celite, which was washed with water followed by brine. The organic layer was dried over NaZSO4 and ated to dryness. Flash chromatography (silica, EtOAc/petroleum ether 1:9) gave rac- trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 59%) as a colorless liquid sufficiently pure for the next step.
To a solution of ans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 0.062 mol) in MeOH (310 mL) was added a solution of KOH (35.0 g, 0.625 mol) in MeOH [Annotation] sak (150 mL) at 0°C. After addition of the base the reaction mixture was stirred at room tempera- ture for 18 h. The reaction mixture was poured into water and extracted with methylene chlo- ride (2x50 mL). The aqueous layer was ied with 10% HCI. The resulting mixture was ex- tracted with methylene chloride (2x150 mL). The combined organic layers were dried over N82804 and evaporated to dryness to give ans(3-fluoro-phenyl)- cyclopropanecarboxylic acid as colorless crystals (9.5 g, 85%). Separation of the isomers by chiral SFC (Method D) gave the title compound (1S,2S)—2-(3-fluoro-pheny|)- cyclopropanecarboxylic acid IM47 as colorless ls (3.27 g, 17% overall yield from 3- fluorostyrene) sufficiently pure for the next step. ic optical on +263.4° [or]D20 (C = 1% MeOH) IM48: (1 S, 2S)(4-Fluoro-phenyl)-cyclopropanecarboxy/ic acid F : I""V)k0H Prepared analogously to IM48 using SFC method E to give the title compound sufficiently pure for the next step (3.1 g, 13% overall yield from 4-fluorostyrene). ic optical rotation ° MD" (0 = 1% MeOH) Other intermediates.
IM49: (R)Methyl-propanesu/finic acid [2-(terf-butyl-dimethyl-silanyloxy)-ethylidene]— amide K/O;Si/ (R)—(+)methylpropanesulfinamide (8.70 g, 71.8 mmol), pyridinium p-toluenesulfonate (0.902 g, 3.59 mmol) and MgSO4 (43.2 g, 359 mmol) was suspended in methylene chloride (25 mL). A on of (terf-butyldimethylsilyloxy)acetaldehyde (25.0 g, 144 mmol) dissolved in methylene chloride (10 mL) was added drop wise at room temperature. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness. Flash chro- matography (silica, EtOAc/heptanes 1:4) gave the title compound as an oil that slowly solidi- fied upon standing (18.3 g, 92%) sufficiently pure for the next step.
Example 1: Preparation of example compounds of the invention: [Annotation] sak Compound 1: (1 S, 2S)-2—Pheny/—cyclopropanecarboxy/ic acid -(6-isopropoxy—pyridin-3— yl)-ethy/]-amide 'E'HZ I"'-V)kNH VAC" + | k / N 0 AC» k\ Transphenylcyclopropanecarboxylic acid IM46 (0.590 g, 3.64 mmol) was dissolved in DMF (15.0 mL). N,N,N’,N’-tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophos- phate (1.38 g, 3.63 mmol) was added. Triethylamine (1.10 mL, 7.89 mmol) was then added and the mixture was d for 15 minutes at room temperature. This mixture was added drop wise to a solution of (S)—1-(6-isopropoxy-pyridinyl)-ethylamine IM24 (0.655 g, 3.63 mmol) dissolved in DMF (15.0 mL) over 2 minutes. The mixture was stirred at room temperature over night. The mixture was evaporated to s. The residue was transferred to a silica gel column and eluded with EtOAc/heptanes 1:1 to give Compound 1 as a solid. This solid was dissolved in EtOAc (50 mL) and to this solution was slowly added heptanes (50 mL). The mixture was concentrated to approx. 25 mL in vacuo and this on was cooled in an ice/water bath. A white itate formed. The solids was collected by filtration and dried in vacuo to give the title compound as colorless crystals (0.794 g, 67%). LC-MS (m/z) 325.4 (MH+), tR = 1.51 min (method A). 1H NMR (500 MHz, DMSO) 6 8.57 — 8.50 (m, 1H), 8.06 (br s, 1H), 7.65 — 7.57 (m, 1H), 7.30 — 7.24 (m, 2H), 7.20 — 7.14 (m, 1H), 7.10 (d, J = 7.5 Hz, 2H), 6.69 (d, J = 8.5 Hz, 1H), 5.25 — 5.16 (m, 1H), 4.98 — 4.88 (m, 1H), 2.24 — 2.15 (m, 1H), 1.94 — 1.88 (m, 1H), 1.41 — 1.32 (m, 4H), 1.26 (d, J = 6.2 Hz, 6H), 1.20 (ddd, J = 8.5, 6.1, 4.1 Hz, 1H). Diastereomeric excess >95% based on 1H NMR.
Compound 2: (1 S,2S)-2—Pheny/—cyclopropanecarboxy/ic acid [(8)(5-methy/-pyridin-2—y/)- ethyIJ-amide o o 2 VAN" I""V)LOH + N \ l N-(3-Dimethylaminopropyl)—N’-ethylcarbodiimide hydrochloride (0.709 g, 3.70 mmol) and 1- hydroxybenzotriazole (0.667 g, 4.93 mmol) were added to a d mixture of IM46 (0.60 g, 3.70 mmol) and commercially available (S)—1-(5-methyl-pyridinyl)—ethylamine hydrochloride [Annotation] sak (Supplier Netchem Inc, Catalog No 528193) (0.426 g, 2.47 mmol) and N,N- diisopropylethylamine (0.859 ml, 4.93 mmol) in THF (25 ml). The solution was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc (3x80 ml). The com- bined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was evaporated of in vac. The crude product was ed by silica gel chromatography (EtOAc in heptanes 1:1). Yield of Compound 2: 110 mg (16%). LC-MS (m/z) 281.1 (MH+), tR = 0.91 min (method A).
Compound 3: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(S)(6-methoxy—pyridin-B—yD- ethyIJ-amide NHz ,, O NH Ill"V)kOH / IN —> E \ 0/ | \ / Prepared analogously to Compound 1 using IM46 and commercially available (6- methoxy-pyridinyl)-ethylamine (Supplier Netchem Inc, Catalog No 517706). Yield = 0.88 g (66%).1H NMR (500 MHz, DMSO) 6 8.55 (d, 1H), 8.10 (s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.78 (d, 1H), 4.93 (m, 1H), 3.72 (s, 3H), 2.21 (m, 1H), 1.90 (m, 1H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 297.4 (MH+), tR = 1.36 min (method A).
Compound 4: (1 S,2S)-2—Pheny/—cyclopropanecarboxy/ic acid [(S)(6-methyl—pyridin-3—y/)— ethyIJ-amide NHz ,, :VAOH 0QEO NH / N —> E + n\ Prepared analogously to Compound 1 using IM46 and commercially available (S)—1-(6- methyl-pyridinyl)-ethylamine ier Netchem Inc, g No 519526). Yield = 0.27 g (21%).1H NMR (600 MHz, DMSO) 6 8.61 (d, 1H), 8.37 (s, 1H), 7.57 (d, 1H), 7.26 (m, 2H), 7.16 (m, 2H), 7.09 (d, 2H), 4.92 (m, 1H), 2.41 (s, 3H), 2.19 (m, 1H), 1.91 (m, 1H), 1.36 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 281.2 (MH+), tR = 0.86 min (method A).
[Annotation] sak Compound 5: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid [(S)(6-cyano-pyridiny/)— ethyIJ-amide NHz ,, [::j i '" o NH #OH /\©\/ N —> ? / |N \\N \ ed analogously to Compound 2 using IM46 and commercially available 5-((S) amino-ethyl)-pyridinecarbonitrile hloride (Supplier Netchem Inc, Catalog No 549493). Yield = 0.104 g (20%). %). 1H NMR (600 MHz, DMSO) 6 8.76 (d, 1H), 8.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.29 (m, 2H), 7.19 (m, 1H), 7.12 (d, 2H), 5.03 (m, 1H), 2.21 (m, 1H), 1.92 (m, 1H), 1.40 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 292.0 (MH+), tR = 1.31 min (method A).
Compound 6: (1 S,2S)Pheny/—cyclopropanecarboxy/ic acid [(S)(6-trifluoromethyl-pyridin- 3—y/)-ethy/]—amide Ell-l2 ,, O NH "VAOH N —> ? ' / \ F r F \ F F F Prepared analogously to Compound 2 using IM46 and commercially available (6- trifluoromethyl-pyridinyl)—ethylamine hydrochloride. ier Netchem Inc, Catalog No 517662). Yield = 0.33 g (55%). %). 1H NMR (500 MHz, DMSO) 6 8.77 (d, 1H), 8.72 (s, 1H), 7.99 (d, 1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.13 (d, 2H), 5.05 (m, 1H), 2.20 (m, 1H), 1.93 (m, 1H), 1.41 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 335.2 (MH+), tR = 1.59 min (method A).
Compound 7: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid [(S)(6-ethoxy—pyridin-3—yl)- ethyIJ-amide gHZ ----:7/JLNH oowe [Annotation] sak Prepared analogously to Compound 2 using IM46 and commercially ble (S)—1-(6- ethoxy-pyridinyl)—ethylamine hydrochloride (Supplier Sial Gmbh, Catalog No 528261-HCI, Lot no LNA098). Yield = 0.30 g (39%). 1H NMR (500 MHz, DMSO) 6 8.54 (d, 1H), 8.08 (s, 1H), 7.62 (d, 1H), 7.27 (m, 2H), 7.16 (m, 1H), 7.12 (d, 2H), 6.73 (d, 1H), 4.92 (m, 1H), 4.25 (q, 2H), 2.20 (m, 1H), 1.91 (m, 1H), 1.35 (m, 4H), 1.30 (t, 3H), 1.19 (m, 1H). LC-MS (m/z) 311.4 (MH+), tR = 1.45 min (method A).
Compound 8: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(S)(6-ethy/-pyridin-3—yl)- ethyIJ-amide NH2 ,, O NH 1"'V)LOH + IN —> ? \ IN Prepared analogously to Compound 1 using IM46 and IM25. Yield = 0.44 g (65%). 1H NMR (500 MHz, DMSO) 6 8.51 (d, 1H), 8.41 (s, 1H), 7.27-7.14 (m, 4H), 7.10 (d, 2H), 4.96 (m, 1H), 2.72 (q, 2H), 2.20 (m, 1H), 1.92 (m, 1H), 1.38 (m, 4H), 1.21 (m, 4H). LC-MS (m/z) 295.1 (MH+), tR = 0.90 min (method A).
Compound 9: (1 S, Phenyl—cyclopropanecarboxy/ic acid [(S)(6-methoxymethyl— pyridinyl)-ethyl]—amide W12 ,, O NH I""V)LOH + IN —> E \ 0\ IN \ o\ Prepared analogously to Compound 1 using IM46 and IM26. Yield = 0.18 g (40%). 1H NMR (500 MHz, DMSO) 6 8.63 (d, 1H), 8.10 (s, 1H), 7.71 (d, 1H), 7.37 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 4.97 (m, 1H), 3.37 (s, 3H), 2.21 (m, 1H), 1.93 (m, 1H), 1.39 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 311.3 (MH+), tR = 0.98 min (method A). nd 10: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid {(S)[6-(2, 2, 2—trifluoro- ethoxy)-pyridinyl]-ethy/}-amide [Annotation] sak NH2 ,, o '5‘" V» 2 . N OH \ F Io/kF Prepared analogously to Compound 1 using IM46 and IM27. Yield = 0.695 g (50%). 1H NMR (500 MHz, DMSO) 6 8.62 (d, 1H), 8.12 (s, 1H), 7.73 (d, 1H), 7.27 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.95 (d), 4.97 (m, 3H), 2.20 (m, 1H), 1.91 (m, 1H), 1.37 (m,4H), 1.20 (m, 1H). LC-MS (m/z) 365.3 (MH+), tR = 1.78 min (method A).
Compound 1 1 : (1 S,28)-2—Phenyl—cyclopropanecarboxylic acid {(8)[6-(2-methoxy—ethoxy)- pyridin-3—y/]—ethy/}-amide E'HZ """#NH o0 ' Prepared analogously to Compound 1 using IM46 and IM28. Yield = 0.758 g (30%). 1H NMR (500 MHz, DMSO) 6 8.57 (d, 1H), 8.08 (s, 1H), 7.65 (d, 1H), 7.26 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.78 (d, 1H), 4.92 (m, 2H), 4.32 (m, 2H), 3.62 (m, 2H), 3.27 (s, 3H), 2.20 (m, 1H), 1.89 (m, 1H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 341.0 (MH+), tR = 1.33 min d A). nd 12: (1 S, 28)-2—Phenyl—cyclopropanecarboxylic acid [(S)(2-ethoxy—pyridinyl)- ethyIJ-amide Isz K E:- O = O NH K / —> ? + I O OH \ N | Prepared analogously to Compound 1 using IM46 and IM29. Yield = 0.11 g (48%). 1H NMR (500 MHz, DMSO) 6 8.55 (d, 1H), 8.06 (s, 1H), 7.30 (m, 2H), 7.19 (m, 1H), 7.14 (m, 2H), 6.90 (d, 1H), 6.67 (d, 1H), 4.88 (m, 1H), 4.26 (m, 2H), 2.20 (m, 1H), 1.96 (m, 1H), 1.40-1.27 (m, 7H), 1.22 (m, 1H). LC-MS (m/z) 311.4 (MH+), tR = 1.36 min (method A). ation] sak Compound 13: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid ((S){6—[(S)—(tetrahydro- furan-3—yl)ony-pyridin-3—yI}-ethy/)-amide NHz ,, [ 1 O NH / N O _, E / N O OH Q .Q 0‘ \I D Prepared ously to Compound 1 using IM46 and IM30. Yield = 0.983 g (62%). 1H-NMR (500 MHz, DMSO) 6 8.55 (d,1H), 8.09 (s, 1H), 7.64 (d, 1H), 7.27 (m, 2H), 7.16 (m, 1H), 7.11 (d, 2H), 6.78 (d, 1H), 5.48 (m, 1H) 4.96 (m, 1H), 3.92 (m, 1H), 3.85 (m, 1H), 3.74 (m, 2H), 2.21 (m, 2H), 1.95 (m, 2H), 1.37 (m, 4H),1.19 (m, 1H). LC-MS (m/z) 353.3 (MH+), tR = 1.45 min d A).
Compound 14: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid ((S){6—[(R)—(tetrahydro- furan-3—yl)ony-pyridin-3—yI}-ethy/)-amide Prepared analogously to Compound 1 using IM46 and IM31. Yield = 0.696 g (62%). 1H-NMR (500 MHz, DMSO) 6 8.56 (d,1H), 8.08 (s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.78 (d, 1H), 5.47 (m, 1H) 4.92 (m, 1H), 3.91 (m, 1H), 3.84 (m, 1H), 3.73 (m, 2H), 2.20 (m, 2H), 1.95 (m, 2H), 1.37 (m, 4H),1.20 (m, 1H). LC-MS (m/z) 353.3 (MH+), tR =1.45 min (method A).
Compound 15: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid ((S)[1, 3]dioxo/o[4, 5- b]pyridinyI-ethyI)-amide MHZ ,, O NH 1"'V)LOH / + IN a \ IN O \ 04 O Prepared analogously to Compound 1 using IM46 and IM32. Yield = 0.572 g (42%). 1H-NMR (500 MHZ, DMSO) 6 8.54 (d,1 H), 7.52 (s, 1H), 7.27 (m, 2H), 7.20-7.15 (m, 2H), 7.10 (d, 2H), [Annotation] sak 6.11 (s, 2H), 4.91 (m, 1H), 2.20 (m, 1H), 1.88 (m, 1H), 1.35 (m, 4H),1.20 (m, 1H). LC-MS (m/z) 311.1 (MH+), 1R = 0.61 min (method B).
Compound 16: (1 S, 2S)-2—Pheny/—cyclopropanecarboxy/ic acid [(S)(2, 3-dihydro- [1, 4]dioxino[2, 3-b]pyridin- ethyl]—amide Ell-l2 ,, o NH «L + flN —> OH \ o | o¢ 0 ed analogously to Compound 1 using IM46 and IM33. Yield = 0.877 g (39%). 1H-NMR (500 MHz, DMSO) 6 8.52 (d,1H), 7.68 (s, 1H), 7.27 (m, 2H), 7.22 (s, 1H), 7.18 (m, 1H), 7.10 (d, 2H), 4.92 (m, 1H), 4.37 (d, 2H), 4.22 (d, 2H), 2.20 (m, 1H), 1.90 (m, 1H), 1.35 (m, 4H),1.20 (m, 1H). LC-MS (m/z) 325.5 (MH+), 1R = 1.28 min (method A).
Compound 17: (1 S, 28)PhenyI-cyclopropanecarboxy/ic acid [(S)(2-ethoxy-pyrimidin yl)-ethy/]-amide NHz ,, O NH W ; + YINmag fl/ \N o/\ Prepared ously to Compound 1 using IM46 and IM34. Yield = 0.195 g (32%). 1H-NMR (600 MHz, DMSO) 6 8.53 (d,1H), 8.52 (s, 2H), 7.26 (m, 2H), 7.16 (s, 1H), 7.10 (d, 2H), 4.92 (m, 1H), 4.32 (m, 2H), 2.20 (m, 1H), 1.88 (m, 1H), 1.40 (d, 3H), 1.35 (m, 1H), 1.31 (t, 3H),1.20 (m, 1H). LC-MS (m/z) 312.2 (MH+), tR = 0.62 min (method B).
Compound 18: (1 S, 2S)-2—Pheny/—cyclopropanecarboxy/ic acid [(S)(6-ch/oro-pyridinyl)- ethyIJ-amide NHz ,, O NH + /\CNK ' OH \ Cl | [Annotation] sak Prepared analogously to nd 1 using IM46 and commercially available (S)—1-(6- -pyridinyl)-ethylamine (Aurora building blocks catalogue nrA06.814.555). Yield = 1.40 g (71%). 1H-NMR (500 MHz, DMSO) 6 8.68 , 8.36 (s, 1H), 7.78 (d, 1H), 7.48 (d, 1H), 7.28 (m, 2H), 7.18 (m, 1H), 7.11 (d, 2H), 4.99 (m, 1H), 2.20 (m, 1H), 1.92 (m, 1H), 1.37 (m, 4H),1.20 (m, 1H). LC-MS (m/z) 301.2 and 303.1 (MH+), tR = 0.67 min (method B).
Compound 19: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid {(S)[6-(oxetany/oxy)- pyridin-3—y/]—ethy/}-amide © 0 O 0 %w + L —» \I \ Cl 0 (1 S,2S)Phenyl-cyclopropanecarboxylic acid [(S)—1-(6-chloro-pyridinyl)-ethyl]-amide (Compound 18) (2.00 g, 6.65 mmol) was dissolved in DMF (50 ml). Oxetanol (4.00 g, 54 mmol) and dicesium carbonate (16.2 g, 49.9 mmol) were added and the mixture was heated at 100 °C ON. The mixture was poured out into brine and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and was filtered and then evaporated to dry- ness. The residue was transferred to a silica gel column and eluded with EtOAc/heptanes 1:1 to give Compound 19 as a solid. This solid was ved in a mixture of THF (10 ml), EtOAc (20 mL) and es (10 ml).The mixture was concentrated to approx. 15 mL in vacuo and this solution was cooled in an ice/water bath. A white precipitate formed. The solids was col- lected by filtration and dried in vacuo to give the title compound as colorless crystals (0.097 g, 4%). %). 1H-NMR (500 MHz, DMSO) 6 8.55 (d,1H), 8.04 (s, 1H), 7.70 (d, 1H), 7.25 (m,2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.87 (d, 1H), 5.52 (m, 1H), 4.95 (m, 1H), 4.87 (m, 2H), 4.53 (m, 2H), 2.20 (m, 1H), 1.90 (m, 1H), 1.37 (m, 4H),1.21 (m, 1H). LC-MS (m/z) 339.2 (MH+), tR = 0.63 min d B). Mp =151-153 C.
Compound 20: (1 S,28)-2—Pheny/—cyclopropanecarboxy/ic acid [(S)(6—cyanomethoxy— pyridin-3—yl)-ethyl]—amide [Annotation] sak (>11 " 0 = OH / VA'2‘" + IN I _’ = OH Compound 20a G#0630"r ©Vin Compound 20b Compound 20 Compound 20a was prepared analogously to Compound 1 using IM46 and IM35 for the first step. Yield of Compound 20a = 1.50 g (71%). Pure on TLC (Eluent EtOAc, Rf = 0.5). This material (1.50 g, 4.36 mmol) was dissolved in a mixture of DMSO (50 ml) and THF (50 ml) and 1-Hydroxy-1,2-benziodoxol-3(1H)—one e (1.34 g, 4.8 mmol) was added and the mixture was stirred at rt overnight. The mixture was added to a mixture of brine and EtOAc and the phases were separated. The organic phases was dried over MgSO4 and was ro- tovaped. The crude product was purified by silica gel chromatography (Eluent EtOAc). Yield of Compound 20b = 1.08 g (72%). Pure on TLC (Eluent EtOAc, Rf = 0.7). This material (1.05 g, 3.24 mmol) was dissolved in THF (10 ml), and MeCN (50 ml) and added drop wise to a so- lution of oxy-1,2-benziodoxol-3(1H)—one e (1.36 g, 4.86 mmol) in ammonia in water (13 M, 25 ml) and THF (5 ml) and MeCN (5 ml). The mixture was stirred at rt ON.
The organic phases was dried over MgSO4 and was rotovaped. The crude product was puri- fied by silica gel tography (Eluent EtOAc in heptanes 4:1) to give 177 mg impure prod- uct. This material was THF (10 ml) and EtOAc (10 ml) and heptanes (10 ml) were added. The mixture was rotovaped until aprox 10 ml solvent was left and then cooled in an ice bath. A solid precipitated and was collected and dried in vac. Yield of Compound 20 = 0.054 g (5%).
Pure on LCMS and H-NMR. Mp—- 163-165 C. LC-MS (m/z) 322.1 (MH+), tR= 1.03 min (method A). 1H-NMR (500 MHz, DMSO) 6 8.60 (d,1H), 8.17 (s, 1H), 7.75 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.11 (d, 2H), 6.95 (d, 1H), 5.19 (s, 2H), 4.97 (m, 1H), 2.21 (m, 1H), 1.92 (m, 1H), 1.38 (m, 4H),1.21 (m, 1H).
Compound 21: (1 S, 2S)Phenyl—cyclopropanecarboxy/ic acid -hydroxy—1-(6-propoxy— pyridin-3—y/)-ethy/]—amide [Annotation] sak 6 z '- o NH I""V)LOH w y 4 OH \I O OH(U f\ Triethylamine (0.384 mL, 2.75 mmol) was added to a mixture of transphenyl cyclopropanecarboxylic acid IM46 (223 mg, 1.38 mmol) and O-(benzotriazolyl)-N,N,N’,N’- tetramethyluronium uorophosphate (522 mg, 1.38 mmol) suspended in DMF (2mL) in a small vial. The vial was vigorously agitated for 30 seconds and then left for 5 minutes. This e was added drop wise to (R)—2-Amino(6-propoxy-pyridinyl)-ethanol IM36 (270 mg, 1.4 mmol) ved in DMF (3 mL). After 1 h the mixture was poured into a mixture of EtOAc (40 mL) and brine (20 mL). The organic layer was dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, 10-100% EtOAc in es) gave the title com- pound as a white solid (0.134 g, 29%). LC-MS (m/z) 341.0 (MH+), tR = 1.52 min (method A). 1H-NMR (600 MHz, DMSO) 6 8.53 (d, J = 8.2 Hz, 1H), 8.04 (br s, 1H), 7.64 — 7.57 (m, 1H), 7.30 — 7.23 (m, 2H), 7.19 — 7.14 (m, 1H), 7.10 (d, J = 7.3 Hz, 2H), 6.74 (d, J = 8.5 Hz,1H), 4.96 — 4.90 (m, 1H), 4.88 — 4.80 (m, 1H), 4.16 (t, J = 6.7 Hz, 2H), 3.61 — 3.49 (m, 2H), 2.23 — 2.15 (m, 1H), 2.04 — 1.95 (m, 1H), 1.74 — 1.64 (m, 2H), 1.40 — 1.32 (m, 1H), 1.23 — 1.13 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H).
Compound 22: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)hydroxy—1-(6- trifluoromethyl—pyridinyl)-ethyl]-amide NH2 ’1. 6 z '- o NH ""-V)LOH + w 2 ' / OH \ F IN OH \ F N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (0.39 g, 2.03 mmol) and 1- hydroxybenzotriazole (0.366 g, 2.71 mmol) were added to a stirred mixture of IM46 (0.22 g, 1.36 mmol) and commercially available (R)—2-amino(6-trifluoromethyl-pyridinyl)-ethanol hydrochloride (Supplier Netchem Inc, Catalog No 517882) (0.494 g, 2.03 mmol) and N,N- diisopropylethylamine (0.472 ml, 2.71 mmol) in THF (20 ml). The solution was stirred at rt overnight. Water was added and the mixture was ted with EtOAc (3x80 ml). The com- bined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was evaporated of in vac. The crude product was purified by silica gel chromatography ation] sak (EtOAc in heptanes 10:1). Yield of Compound 22 475 mg (78%). 1H-NMR (500 MHz, DMSO) 6 8.77 (d, 1H), 8.74 (s, 1H), 8.00 (d, 1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.18 (m, 1H), 7.13 (d, 2H), 5.04 (m, 2H), 3.64 (m, 2H), 2.22 (m, 1H), 2.07 (m, 1H), 1.37 (m, 1H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 351.1 (MH+), tR = 1.51 min (method A).
Compound 23: (1 S,28)-2—Pheny/—cyclopropanecarboxy/ic acid [(R)(5-cyano-pyridin-2—yl)— 2—hydroxy—ethy/J—amide I l /N OH OH \ \ | \ N OH \ ed analogously to Compound 22 using IM46 and commercially available 6-((R)—1- aminohydroxy-ethyl)-nicotinonitrile (Supplier m Inc., Catalog No 549885). Yield of Compound 23 230 mg (61%). 1H-NMR (500 MHz, DMSO) 6 8.97 (s, 1H), 8.72 (d, 1H), 8.26 (d, 1H), 7.52 (d, 1H), 7.27 (m, 2H), 7.18 (t, 1H), 7.11 (d, 2H), 5.05-4.95 (m, 2H), 3.70 (m, 2H), 2.20 (m, 1H), 2.17 (m, 1H), 1.36 (m, 1H), 1.20 (m, 1H). LC-MS (m/z) 308.1 (MH+), tR = 1.21 min (method A).
Compound 24: (1 S, 28)-2—Phenyl-cyclopropanecarboxy/ic acid [(R)hydroxy—1-(6-methoxy— pyridin-3—yl)-ethyl]—amide MHZ ,, o NH '-V)LOH N s + | / N OH \ 0/ I OH \ / Prepared analogously to Compound 22 using IM46 and commercially available Amino- 2-(6-methoxy-pyridinyl)—ethanol (Supplier Netchem Inc., Catalog No 517926). Yield of Compound 24 = 763 mg (22%). 1H-NMR (500 MHz, DMSO) 6 8.53 (d, 1H), 8.09 (s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.15 (m, 1H), 7.12 (m, 2H), 6.77 (d, 1H), 4.95 (m, 2H), 4.85 (m, 2H), 3.83 (s, 3H), 3.57 (m, 2H), 2.21 (m, 1H), 2.00 (m, 1H), 1.37 (m, 1H), 1.19 (m, 1H). LC- MS (m/z) 313.1 (MH+), tR = 1.53 min (method A).
Compound 25: (1 S,28)-2—Pheny/—cyclopropanecarboxy/ic acid [(R)hydroxy—1-(6-methyl- pyridin-3—yl)-ethyl]—amide [Annotation] sak 0 © o EDC.HCI ©V)kIIIIII#NH'-#NH 5 «k _ _’ —> / N OH N - | I LIOH 0H \ "Q C compound 25a N-(3-Dimethylaminopropyl)—N’-ethylcarbodiimide hydrochloride (0.316 g, 1.65 mmol) and 1- hydroxybenzotriazole (0.223 g, 1.65 mmol) were added to a stirred mixture of IM46 (0.18 g, 1.1 mmol) and commercially available (R)—2-Amino(6-methyl-pyridinyl)-ethanol o- chloride (Supplier Netchem Inc., Catalog No 549945) (0.128 g, 1.21 mmol) and N,N- diisopropylethylamine (0.575 ml, 3.30 mmol) in THF (10 ml). The solution was stirred at rt overnight. Water was added and the mixture was ted with EtOAc. The organic phase was rotovaped to produce 140 mg of Compound 25a. LC-MS (m/z) 441.4 (MH+), tR = 1.44 min d A). Compound 25a was dissolved in THF and LiOH (1 M) was added and the mixture was stirred 30 min. A solid precipitated and was isolated by filtration and dried in vac.
Yield of Compound 25 = 110 mg (34%). 1H-NMR (500 MHZ, DMSO) 6 8.53 (d, 1H), 8.09 (s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.15 (m, 1H), 7.12 (m, 2H), 6.77 (d, 1H), 4.95 (m, 2H), 4.85 (m, 2H), 3.83 (s, 3H), 3.57 (m, 2H), 2.21 (m, 1H), 2.00 (m, 1H), 1.37 (m, 1H), 1.19 (m, 1H).
LC-MS (m/z) 297.3 (MH+), tR = 0.78 min (method A).
Compound 26: (1 2-Pheny/—cyclopropanecarboxy/ic acid [(R)hydroxy—1-(6- isopropoxy—pyridinyI)-ethy/]-amide Prepared analogously to Compound 21 using IM46 and IM37. Yield of Compound 26 = 667 mg (77%). 1H-NMR (600 MHz, DMSO) 6 8.52 (d, 1H), 8.03 (s, 1H), 7.60 (d, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.67 (d, 1H), 5.20 (m, 1H), 4.92 (t, 1H), 4.83 (m, 1H), 3.55 (m, 2H), 2.20 (m, 1H), 2.00 (m, 1H), 1.35 (m, 1H), 1.24 (d, 6H), 1.19 (m, 1H). LC-MS (m/z) 341.0 (MH+), tR = 1.45 min (method A). ation] sak Compound 27: (1 S,2S)(3—F/uoro-pheny/)-cyc/opropanecarboxylic acid [(R)(6-ethoxy- pyridin-3—y/)hydroxy-ethyl]—amide NH2 - 6 g F o 51H I""V)kOH + F OH \' N J )0 OH \ Prepared analogously to Compound 21 using IM47 and IM38. Yield of Compound 27 = 90 mg (19%). 1H-NMR (600 MHz, DMSO) 6 8.53 (d, 1H), 8.05 (s, 1H), 7.62 (m, 1H), 7.28 (m, 1H), 6.97 (m, 3H), 6.73 (d, 1H), 4.83 (m, 1H), 4.24 (m, 2H), 3.55 (m, 2H), 2.22 (m, 1H), 2.03 (m, 1H), 1.37 (m, 1H), 1.28 (t, 3H), 1.22 (m, 1H). LC-MS (m/z) 345.0 (MH+), tR = 0.63 min (method B).
Compound 28: (1 S,2S)(4-F/uoro-pheny/)-cyc/opropanecarboxylic acid [(R)(6-ethoxy- pyridin-3—y/)hydroxy-ethyl]—amide MHZ , VA F ; NH / E OH OH \ O I OH \ J Prepared analogously to Compound 21 using IM48 and IM38. Yield of Compound 28 = 93 mg white solid. (54%). 1H-NMR (600 MHz, DMSO) 6 8.56 (d, 1H), 8.07 (s, 1H), 7.62 (m, 1H), 7.18 (m, 2H), 7.12 (m, 2H), 6.77 (d, 1H), 4.93 (t, 1H), 4.83 (m, 1H), 4.25 (dd, 2H), 3.52 (m, 2H), 2.27 (m, 1H), 1.97 (m, 1H), 1.30 (m, 4H), 1.15 (m, 1H). LC-MS (m/z) 345.0 (MH+), LCMS (m/z) 345.0 (MH+), tR = 1.36 min (method A).
Compound 29: (1 S,2S)(3—F/uoro-pheny/)-cyc/opropanecarboxylic acid [(R)hydroxy (6-propoxy-pyridin-3—yl)-ethyl]-amide JG a F '- o NH 0H + —» / F OH \' O IN OH \ J/ Prepared analogously to Compound 21 using IM47 and IM36. Yield = 150 mg (30%). 1H- NMR (600 MHz, DMSO) 6 8.53 (d, 1H), 8.03 (s, 1H), 7.62 (d, 1H), 7.29 (m, 1H), 6.95 (m, 3H), [Annotation] sak 6.74 (d, 1H), 4.93 (m, 1H), 4.84 (m, 1H), 4.16 (t, 2H), 3.55 (m, 2H), 2.23 (m, 1H), 2.03 (m, 1H), 1.68 (m, 2H), 1.37 (m, 1H), 1.25 (m, 1H), 0.93 (t, 3H). LC-MS (m/z) 359.1 (MH+), tR = 1.57 min (method A).
Compound 30: (1 S, 2S)(4-F/uoro-phenyI)-cyclopropanecarboxy/ic acid -hydroxy (6-propoxy-pyridinyl)-ethyl]-amide F ,, (3 ? o NH W»... mN+ J/ 3 O /, f OH \ Prepared analogously to nd 21 using IM48 and IM36. Yield 176 mg (36%). 1H-NMR (600 MHz, DMSO) 6 8.52 (d, 1H), 8.05 (s, 1H), 7.63 (d, 1H), 7.14 (m, 2H), 7.09 (m, 2H), 6.74 (d, 1H), 4.92 (t, 1H), 4.85 (m, 1H), 4.15 (t, 2H), 3.55 (m, 2H), 2.22 (m, 1H), 1.97 (m, 1H), 1.70 (m, 2H), 1.34 (m, 1H), 1.18 (m, 1H), 0.92 (t, 3H).
Compound 31: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid [(R)(6-(2, 2, 2-d3)-ethoxy- pyridin-3—y/)hydroxy-ethyl]—amide [EH—'2 """#NH #0 a + "Q o / H OH \ O/\)/D ' D Prepared analogously to Compound 21 using IM46 and IM40. Yield = 785 mg (66%). 1H- NMR (600 MHz, CDCI3) 6 8.62 (s, 1H), 7.52 (d, 1H), 7.26 (m, 2H), 7.20 (m, 1H), 7.08 (d, 2H), 6.71 (d, 1H), 6.27 (m, 1H), 5.05 (m, 1H), 4.31 (s, 2H), 3.91 (m, 2H), 2.51 (m, 2H), 1.67 (m, 2H), 1.31 (m, 1H). LC-MS (m/z) 330.3 (MH+), tR = 1.32 min (method A).
Compound 32: (1 S, 2S)(3-F/uoro-phenyI)-cyclopropanecarboxy/ic acid [(R)(6-(1,1-d2)- ethoxy-pyridinyl)hydroxy-ethyl]—amide [Annotation] sak Prepared analogously to Compound 21 using IM47 and IM41. Yield = 104 mg (44%). 1H- NMR (600 MHz, DMSO) 6 8.52 (d, 1H), 8.03 (s, 1H), 7.61 (m, 1H), 7.29 (m, 1H), 6.97 (m, 3H), 6.72 (d, 1H), 4.93 (m, 1H), 4.85 (m, 1H), 3.55 (m, 2H), 2.22 (m, 1H), 2.02 (m, 1H), 1.37 (m, 1H), 1.25 (m, 4H). LC-MS (m/z) 347.2 (MH+), tR = 0.64 min (method A).
Compound 33: (1 S,2S)-2—Pheny/—cyclopropanecarboxy/ic acid -(6-ethoxy—pyridin-3—yl)- 2-hydroxy-ethy/J—amide NH2 ,, o NH '-V)LOH N ? + I / N OH \ /\ O I Prepared analogously to Compound 22 using IM46 and IM38. Yield = 90 mg (28%). 1H-NMR (600 MHz, DMSO) 6 8.53 (d, 1H), 8.06 (s, 1H), 7.52 (m, 1H), 7.26 (m, 2H), 7.16 (m, 1H), 7.10 (d, 2H), 6.73 (d, 1H), 4.95 (t, 1H), 4.87 (m, 1H), 4.25 (m, 2H), 3.55 (m, 2H), 2.20 (m, 1H), 2.02 (m, 1H), 1.36 (m, 1H), 1.28 (t, 3H), 1.20 (m, 1H). LC-MS (m/z) 327.4 (MH+), tR = 0.57 min (method B).
Compound 34: (1 S, 2S)-2—(4-Fluoro-phenyl)-cyc/opropanecarboxy/ic acid [(R)(6-(1, 1,2, 2, 2- d5)-ethoxy-pyridinyl)-2—hydroxy—ethyl]—amide F ,, o 1ng + (\CNKD = D —> 0&0 / N OH OH \ D D Prepared ously to Compound 21 using IM48 and IM39. Yield = 130 mg (41%). 1H- NMR (600 MHz, DMSO) 6 8.53 (d, 1H), 8.06 (s, 1H), 7.62 (m, 1H), 7.14 (m, 2H), 7.10 (m, 2H), 6.73 (d, 1H), 4.95 (br s, 1H), 4.84 (m, 1H), 3.55 (m, 2H), 2.22 (m, 1H), 1.96 (m, 1H), 1.34 (m, 1H), 1.18 (m, 1H). LC-MS (m/z) 350.2 (MH+), tR = 1.41 min (method A).
Compound 35: (1 S,2S)(4-F/uoro-phenyl)-cyc/opropanecarboxylic acid [(R)(6-(2, 2, 2-d3)- ethoxy-pyridinyl)-2—hydroxy—ethyl]—amide [Annotation] sak Prepared ously to Compound 21 using IM48 and IM40. Yield = 144 mg (41%). 1H- NMR (600 MHz, DMSO) 6 8.53 (d, 1H), 8.08 (s, 1H), 7.63 (m, 1H), 7.13 (m, 2H), 7.10 (m, 2H), 6.73 (d, 1H), 4.97 (br s, 1H), 4.86 (m, 1H), 4.24 (s, 2H), 3.57 (m, 2H), 2.23 (m, 1H), 1.97 (m, 1H), 1.37 (m, 1H), 1.20 (m, 1H). LC-MS (m/z) 347.9 (MH+), tR = 1.39 min (method A).
Compound 36: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)(6-(1, 1 -d2)-ethoxy- pyridin-3—y/)hydroxy—ethyl]—amide NHz ,, (3 z O NH / N E + D D I,"-V)LOH I X —> / OH D \ D 0 lN OH \ OX Prepared analogously to nd 21 using IM46 and IM41. Yield = 148 mg (67%). 1H- NMR (600 MHz, DMSO) 6 8.52 (d, 1H), 8.05 (s, 1H), 7.61 (d, 1H), 7.50 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.72 (d, 1H), 4.94 (t, 1H), 4.85 (m, 1H), 3.55 (m, 2H), 2.18 (m, 1H), 1.97 (m, 1H), 1.35 (m, 1H), 1.27 (s, 3H), 1.20 (m, 1H). LC-MS (m/z) 329.2 (MH+), tR = 0.61 min (method B).
Compound 37: (1 S, 2S)-2—(4-F/uoro-phenyI)-cyclopropanecarboxy/ic acid [(R)(6-(1,1-d2)- ethoxy-pyridinyl)-2—hydroxy—ethyl]—amide F ,, o NH [ I"'-V)LOH+C,):\©D>§/ N E D D / O INDD OH \ ox Prepared analogously to Compound 21 using IM48 and IM41. Yield = 123 mg (52%). 1H- NMR (600 MHz, DMSO) 6 8.52 (d, 1H), 8.06 (s, 1H), 7.62 (m, 1H), 7.14 (m, 2H), 7.10 (m, 2H), 6.73 (d, 1H), 4.92 (t, 1H), 4.84 (m, 1H), 3.55 (m, 2H), 2.22 (m, 1H), 1.96 (m, 1H), 1.34 (m, 1H), 1.28 (s, 3H), 1.18 (m, 1H). LC-MS (m/z) 347.2 (MH+), tR = 1.41 min (method B).
[Annotation] sak Compound 38: (1 S, 2S)Pheny/—cyclopropanecarboxy/ic acid -(6-(1, 1,2, 2, 2-d5)- ethoxy-pyridinyl)hydroxy-ethyl]—amide NHZ I «k E D NH O D + N D E D D | —> OH OH \ D O | Prepared ously to Compound 21 using IM46 and IM39. Yield = 98 mg (32%). 1H-NMR (600 MHz, DMSO) 6 8.52 (d, 1H), 8.05 (s, 1H), 7.61 (d, 1H), 7.26 (t, 2H), 7.16 (t, 1H), 7.10 (d, 2H), 6.72 (d, 1H), 4.93 (t, 1H), 4.83 (m, 1H), 3.55 (m, 2H), 2.18 (m, 1H), 1.99 (m, 1H), 1.35 (m, 1H), 1.20 (m, 1H). LC-MS (m/z) 332.2 (MH+), tR = 0.61 min (method B).
Compound 39: (1 S, 2S)(3-F/uoro-phenyI)-cyclopropanecarboxy/ic acid [(R)(6-(2, 2, 2-d3)- ethoxy-pyridinyl)hydroxy-ethyl]—amide '2le O I F D D / [EIH + IN TD - D ’ —> / ND F OH OH \ 0 l OH \ TD Prepared analogously to Compound 21 using IM47 and IM40. Yield = 101 mg (29%). 1H- NMR (600 MHz, DMSO) 6 8.53 (d, 1H), 8.05 (s, 1H), 7.61 (d, 1H), 7.28 (m, 1H), 70-695 (m, 3H), 6.72 (d, 1H), 4.93 (t, 1H), 4.83 (m, 1H), 4.22 (s, 2H), 3.55 (m, 2H), 2.23 (m, 1H), 2.02 (m, 1H), 1.37 (m, 1H), 1.27 (m, 1H). LC-MS (m/z) 348.0 (MH+), tR = 1.43 min (method A).
Compound 40: (1 S,2S)Pheny/—cyclopropanecarboxy/ic acid [(R)(6-cyclobutoxy-pyridin- 3-yl)hydroxy-ethy/]—amide 3‘" z '- o NH «k / N E + (\Ok D —’ / N OH OH \ 0 ' o/D OH \ Prepared analogously to Compound 21 using IM46 and IM44. Yield = 53 mg (30%). 1H-NMR (600 MHz, DMSO) 6 8.50 (d, 1H), 8.03 (s, 1H), 7.61 (d, 1H), 7.25 (m, 2H) 7.16 (m, 1H), 7.10 (m, 2H), 6.71 (d, 1H), 5.09 (m, 1H), 4.90 (t, 1H), 4.82 (m, 1H), 3.55 (m, 2H), 2.37 (m, 2H), [Annotation] sak 2.21 (m, 1H), 2.00 (m, 4H), 1.76 (m, 1H), 1.61 (m, 1H), 1.32 (m, 1H), 1.20 (m, -MS (m/z) 353.1 (MH+), tR = 0.70 min (method B).
Compound 41: (1 S,2S)(3-F/uoro-phenyl)-cyc/opropanecarboxylic acid [(R)(6- cyc/obutoxy-pyridiny/)hydroxy-ethy/]—amide NHz ,, g F o NH "'V)kOH m D/+ N ? I, / O IN E OH \ Prepared analogously to Compound 21 using IM47 and IM44. .Yield = 38 mg (20%). 1H- NMR (600 MHz, DMSO) 6 8.50 (d, 1H), 8.03 (s, 1H), 7.61 (d, 1H), 7.27 (m, 1H), 6.95 (m, 3H), 6.71 (d, 1H), 5.08 (m, 1H), 4.95 (br. s, 1H), 4.82 (m, 1H), 3.55 (m, 2H), 2.37 (m, 2H), 2.22 (m, 1H), 2.02 (m, 4H), 1.75 (m, 1H), 1.61 (m, 1H), 1.37 (m, 1H), 1.27 (m, 1H). LC-MS (m/z) 371.1 (MH+), tR = 0.71 min (method B).
Compound 42: (1 2-(4-F/uoro-phenyl)-cyc/opropanecarboxylic acid [(R)(6- cyc/obutoxy-pyridiny/)hydroxy-ethy/]—amide NH2 , Fo 3 NH ,, + —> O OH \ 0 Prepared analogously to Compound 21 using IM48 and lM44.Yie|d = 84 mg (45%). 1H-NMR (600 MHz, DMSO) 6 8.50 (d, 1H), 8.03 (s, 1H), 7.61 (d, 1H), 7.14 (m, 2H), 7.09 (m, 2H), 6.71 (d, 1H), 5.08 (m, 1H), 4.92 (t, 1H), 4.82 (m, 1H), 3.55 (m, 2H), 2.37 (m, 2H), 2.21 (m, 1H), 2.05-1.95 (m, 4H), 1.75 (m, 1H), 1.61 (m, 1H), 1.32 (m, 1H), 1.17 (m, 1H). LC-MS (m/z) 371.1 (MH+), tR = 0.71 min (method B).
Compound 43: (1 S,28)Pheny/—cyclopropanecarboxylic acid ((R)hydroxy{6-[(R)- (tetrahydro-furany/)oxy]—pyridiny/}-ethyl)-amide O EH2 I"-.V)kNH ©"""" - + / IN 0 —> / N O OH \ ' O OH \ (E) ation] sak Prepared analogously to Compound 21 using IM46 and IM43. Yield = 1.34 g white solid (60%).1H NMR (400 MHz, CDCI3): 6 8.08 (s, 1 H), 7.51 (d, J: 8.4 Hz, 1 H), 7.18-7.25 (m, 3 H), 7.04-7.06 (m, 2 H), 6.68-6.71 (m, 1 H), 6.36-6.39 (m, 1 H), 5.50-5.53(m, 1 H), 5.04- .05(m, 1 H), 3.88-4.01 (m, 6 H), 2.48-2.50 (m, 1 H), 2.21-2.26 (m, 1 H), 2.11-2.13 (m, 1 H), 1.62-1.71 (m, 2 H), 1.27-1.31 (m, 1 H). LC-MS (m/z) 369.2 (MH+), tR = 2.04 min (method WXE-ABO1). [61,30 = 178.6 (C=0.2, CHCI3) Compound 44: (1 S, 2S)-N-[(1R)hydroxy— 1-[6-[(38)-tetrahydrofuranyljoxy pyridyljethy/J—2-phenyl-cyclopropanecarboxamide © 0 VAW / O 3 Prepared analogously to nd 21 using IM46 and IM42. Yield = 2.10 g white solid (50%). 1H NMR (400 MHz, CDCI3): 68.09 (m, 1 H), 7.52-7.55 (m, 1 H), 7.29 (m, 1 H), 7.25- 7.27 (m, 1 H), 7.20-7.21 (m, 1 H), 7.17-7.19 (d, J: 7.2 Hz, 2 H), 6.70-6.73 (d, J: 8.8 Hz, 1 H), 6.34-6.36 (d, J = 7.2 Hz, 1 H), 5.50-5.53(m, 1 H), 5.04-5.05(d, J = 6.8 Hz, 1 H), 3.94-4.03 (m, 2 H), 3.85-3.91 (m, 4 H), 2.48-2.50 (m, 1 H), 2.21-2.26 (m, 1 H), .13 (m, 1 H), 1.62- 1.71 (m, 2 H), 1.27-1.31 (m, 1 H). LC-MS (m/z) 369.2 (MH+), tR = 2.03 min (method WXEABO1 ). [61,30 = 160.9 (c=0.21, CHCI3).
Compound 45: (1 S, 2S)((Z)Methy/ene-penta-2, 4-dienyl)-cyclopropanecarboxy/ic acid {(R)hydroxy—1-[6-(tetrahydro-pyrany/oxy)-pyridinyl]-ethyl}-amide 'E‘Hz O ' + @le / N O : II, —> '- OH OH \' /IN 0 O OH \ Prepared ously to Compound 1 using IM46 and IM45. Yield = 2.5 g white solid (44%). 1H NMR ((400 MHz, CDCI3): 68.09 (s, 1 H), 7.52-7.55 (m, 1 H), 7.27-7.28 (m, 1 H), 7.25-7.26 (m, 1 H), 7.20 (m, 1 H), 7.06-7.08 (t, J: 4.2 Hz, 2 H), .72 (d, J = 8.4 Hz, 1 H), 6.34-6.36 (d, J = 7.2 Hz, 1 H), 5.18-5.21(m, 1 H), .05(d, J: 6.8 Hz, 1 H), 3.62-3.99 (m, 4 H), [Annotation] sak 3.56-3.62 (m, 2 H), 2.46-2.50 (m, 1 H), 2.01-2.06 (m, 2 H), 1.74-1.80 (m, 2 H), 1.62-1.70 (m, 2 H), 1.27-1.30 (m, 1 H). [011020 = 144.3 (c = 0.204 g/100mL, CHCI3).
Compound 46: (1 S,28)Pheny/—cyclopropanecarboxy/ic acid [(R)(6-ethoxy—pyridinyl)- 2-methoxy—ethy/J—amide E: 0 0 1,,1'V)k lélH © 1""?ka Km : / IN NaH (60 % suspension in mineral oil) (2.06 g, 51.5 mmol) was suspended in DMF and the on vessel was cooled in an ice bath. (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-ethoxy-pyridinyl)hydroxy-ethyl]—amide (Compound 33) (15 g, 46 mmol) was dissolved in DMF (50 ml) and added drop wise to the sodium hydride suspension at 5-8 C over 20 minutes. The solution was stirred 30 minutes. Methyl iodide (3.30 ml, 53.0 mmol) dis- solved in DMF (25 ml) was added drop wise at 5-12 C over 10 minutes and the mixture was stirred at 7-8 C for 30 minutes. The mixture was added to a brine solution and ted with EtOAc. The organic layer was washed with more brine, dried (MgSO4) filtered and the sol- vent was evaporated off. The crude product was purified by silica gel chromatography (eluent EtOAc in heptanes 4:1 ). The fractions that ned the t was collected and the sol- vent was removed in vac. The residue was redissolved in THF (50 ml) EtOAc (100 ml) and heptanes (25 ml). The mixture was trated until 40 ml remained and cooled in ice. A white solid precipitated and was ted by filtration. Yield: 6.75 g (43%) of Compound 46.
LC-MS (m/z) 341.2 (MH+), tR = 0.64 min (method B). 1H-NMR (500 MHz, DMSO) 6 8.62 (d,1H), 8.08 (br s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.74 (d, 1H), 5.05 (m, 1H), 4.26 (m, 2H), 3.55 — 3.46 (m, 2H), 3.26 (s, 3H), 2.20 (m, 1H), 1.99 (m, 1H), 1.38 (m, 1H), 1.29 (t, 3H), 1.20 (m, 1H).
Compound 47: (1 S, 2S)-N-[(1R)-2—methoxy—1-[6-[(3R)-tetrahydrofuranyl]oxy—3- pyridy/Jethy/]phenyl-cyc/opropanecarboxamide E: 0 © 0 [1"1,V)LI¥H ,,,,,'V)LNH (\O O / N O I L) I L) OH \ /O \ O 0 ed analogously to Compound 46 using Compound 43 (0.90 g).
[Annotation] sak Yield = 490 mg (53%) as a solid. 1H NMR (400 MHz, CDCI3): 68.12 (d, J = 2.4 Hz, 1 H), 7.54- 7.57 (m, 1 H), .28 (m, 2 H), 7.18-7.21 (m, 1 H), 7.05-7.07 (m, 2 H), 6.68-6.70 (d, J: 8.8 Hz, 1 H), 6.37-6.39 (d, J: 8.0 Hz, 1 H), 5.51-5.54 (m, 1 H), 5.10-5.12(m, 1 H), 3.87-4.04 (m, 4 H), 3.66-3.69 (m, 1 H), .63 (m, 1 H), 3.38 (s, 3 H), 2.45-2.46 (m, 1 H), 2.21-2.26 (m, 1 H), 1.60-1.68 (m, 2 H), 1.25-1.28 (m, 1 H). LC-MS: 1R = 0.53 min (method B), m/z = 383.2 [M + H]+. [011,30 = 188.2 (C=0.176, .
Compound 48: (1 S, 2S)-N-[(1R)methoxy[6-[(3S)-tetrahydrofuran-B—y/Joxy pyridy/Jethy/]—2-phenyl-cyc/opropanecarboxamide © 0 0 _> © ,VjLNH #NH I I OH \ [2 o \ / [2 o 0 ed analogously to Compound 46 using Compound 44 (841 mg).
Yield = 645 mg (44%) as a solid. 1H NMR (400 MHz, CDCI3): 68.10-8.11 (d, J: 2.4 Hz, 1 H), 7.54-7.57 (m, 1 H), 7.25-7.28 (m, 2 H), 7.18-7.21 (m, 1 H), 7.05-7.07 (m, 2 H), 6.68-6.70 (d, J = 8.8 Hz, 1 H), 6.37-6.39 (d, J: 8.0 Hz, 1 H), 5.51-5.54 (m, 1 H), 5.10-5.12(m, 1 H), 3.87- 4.04 (m, 4 H), 3.66-3.69 (m, 1 H), 3.60-3.63 (m, 1 H), 3.38 (s, 3 H), 2.45-2.46 (m, 1 H), 2.21- 2.26 (m, 1 H), 1.60-1.68 (m, 2 H), 1.25-1.28 (m, 1 H). LC-MS: tR = 0.62 min (method B), m/z = 383.2 [M + H]+. [011,30 = 162.5 (C=0.225, CHCI3).
Compound 49: (1 S,2S)Pheny/—cyclopropanecarboxy/ic acid {(R)methoxy—1-[6- (tetrahydro-pyranyloxy)-pyridiny/]-ethyI}-amide Prepared analogously to Compound 46 using Compound 45. Yield = 343 mg (20%) as a solid. 1H NMR (400 MHz, CDCI3): 68.10-8.11 (d, J: 2.4 Hz, 1 H), 7.54-7.57 (m, 1 H), 7.25- 7.29 (m, 2 H), 7.18-7.21 (m, 1 H), .07 (m, 2 H), 6.66-6.68 (t, J: 4.2 Hz, 1 H), 6.38-6.40 (d, J = 7.2 Hz, 1 H), 5.20-5.21 (m, 1 H), .12(m, 1 H), 3.94-3.99 (m, 2 H), 3.57-3.69 (m, 4 H), 3.37 (s, 3 H), .49 (m, 1 H), 2.02-2.08 (m, 2 H), 1.61-1.79 (m, 4 H), 1.25-1.28 (m, 1 H) d1D2° = 1593 (c = 0.198 g/100mL, CHCI3). LC-MS (m/z) 383.15 (MH+), 1R = 0.54 min (method B).
[Annotation] sak Compound 50: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid {(8)[6-(oxetany/oxy)- pyridin-3—y/]—ethy/}-amide © 0 O O VA?" 1",, 1,", + [L NH —> VA HCI \ / / CI [Tl (1 S,2S)Phenyl-cyclopropanecarboxylic acid -(6-chloro-pyridinyl)-ethyl]-amide (Compound 18) (2.00 g, 6.65 mmol) was dissolved in DMF (40 ml). N,N- dimethylhydroxylaminehydrochloride (5.00 g, 51.2 mmol) and dicesium ate (25 g, 76.7 mmol) were added and the e was heated at 95 C 3 days. The mixture was poured out into brine and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and was filtered and then evaporated to dryness. The residue was erred to a silica gel column and eluded with EtOAc to give Compound 50 as a solid. This solid was dissolved in a mixture of THF (10 ml), EtOAc (10 ml) and heptanes (10 ml).The e was concentrated to approx. 10 ml volume and this solution was cooled in an ice/water bath. A white precipitate formed. The solids was collected by filtration and dried in vacuo to give the title compound as a white solid (0.044 g, 2%). 1H-NMR (500 MHz, DMSO) 6 8.43 (d,1H), 8.02 (s, 1H), 7.45 (d, 1H), 7.25 (m,2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.61 (d, 1H), 4.83 (m, 1H), 3.98 (m, 6H), 2.19 (m, 1H), 1.90 (m, 1H), 1.35 (m, 4H),1.21 (m, 1H). LC-MS (m/z) 310.2 (MH+), tR = 0.46 min (method B). Mp =171-181 C.
Compound 51: (1 S, 2S)-2—Phenyl—cyclopropanecarboxylic acid [(S)(6-ethanesulfonyl -pyridinyl)-ethyl]—amide [>le E: ' 0 = / VAIIZ I ""V)kOH + IN : \ / 0 S x IN 8\ \ fif’f’ ed analogously to Compound 1 using IM46 and (S)—1-(6-Methanesulfonyl-pyridin yl)-ethylamine (prepared from 1-(6-Methanesulfonyl-pyridineyl)—ethanone analogously to IM24, which was prepared from commercially available 5-Bromomethanesulfonyl-pyridine CAS 986260). Yield from IM46 = 1.54 g (68%). 1H-NMR (500 MHz, DMSO) 6 8.80 (d,1H), 8.72 (s, 1H), 8.02 (m, 2H), 7.27 (m, 2H), 7.20 (s, 1H), 7.12 (d, 2H), 5.08 (m, 1H), 3.27 ation] sak (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.42 (d, 3H), 1.37 (m, 22 (m, 1H). LC-MS (m/z) 345.1 (MH+), tR = 1.21 min (method A).
Compound 52: (1 S, 2S)-2—Phenyl—cyclopropanecarboxy/ic acid [(R)(5-ethoxy—pyridin- 2-yl)hydroxy—ethy/]—amide MHZ ,. VA 3 NH 0 N . 1"'V)LOH I / OH \ O I Prepared analogously to Compound 21 using IM46 and Amino(5-ethoxy-pyridin yl)-ethanol (prepared from commercially available 2-Bromoethoxy-pyridine CAS 42834 analogously to lM36). Compound 52 was further purified by SFC (Column: Chiralpack OJ250x30 mm, Mobile phase: Supercrital C02/MeOH+NH4OH = 55/45 at 50 mL/min, column temperature: 38°C, Nozzle Pressure: 100 Bar, Nozzle Temp = 60°C, Evaporator temp = 20 C, Trimmer temp =25°C, Detector: 220 nm). Yield = 163 mg. 1H NMR (CDCI3 400MHz, TMS): 6 8.15 (d, J = 2.8 Hz, 1 H), 7.08-7.31 (m, 6 H), 7.06 (d, J = 7.2 Hz, 2 H), 5.11-5.15 (m, 1 H), 4.00-4.08 (m, 3 H), 3.87-3.90 (m, 1 H), 2.47-2.52 (m, 1 H), .76 (m, 3 H), 1.43 (t, J = 7.2 Hz, 3 H), .31 (m, 1 H); [01]20,D = 182.0 (c = 0.234 g/100mL, EtOH) In vitro assays The nicotinic acetylcholine receptor 07 is a calcium-permeable ion channel, whose ac- tivity can be measured by over expression in mammalian cells or oocytes. These two individ- ual assays are described in Example 2 and 3, respectively.
Example 2: 017 NNR flux assay The nicotinic choline receptor 07 is a calcium-permeable ion channel, whose ac- tivity can be measured by over expression in ian cells or oocytes. In this version of the assay, the human 07 receptor is stably expressed in the rat GH4C1 cell line. The assay was used to identify positive allosteric modulators (PAMs) of the 017 receptor. Activation of the channel was measured by loading cells with the calcium-sensitive fluorescent dye Calcium-4 (Assay kit from Molecular Devices), and then measuring real-time changes in fluorescence upon ent with test compounds.
[Annotation] sak The cell line ChanClone GH4C1-nAChRalpha7 from Genionics was seeded from frozen stock in 384-well plates in culture media 2-3 days before experiment to form an approximately 80% confluent layer on the day of experiment.
Cell plating and dye loading The cell culture were split into m x 22.5cm"-plates with approximately 100x103 cells/cm2. After four days incubation in a humidified incubator at 37°C and 5% C02, it had grown to an 80-90% confluent layer, and the cells were harvested.
Culture media: 500 mL DMEM/F12 (Gibco 31331) 50 mL FBS (Gibco 10091-155, lot 453269FD) mL Sodium Pyruvate (Gibco 11360) mL Pen/Strep (Gibco 15140) 0.1 mg/mL G-418(Gibco11811-064) Two or three days before the experiment the cells were seeded in 384 well plates from r bio-one (781946, AT, Poly-D-Lysine, black, uClear).
The media was poured off and the plate washed with PBS and left to drain. 5 mL Trypsin was added, cells were washed and ted (at room temperature) for about 10 seconds. Tryp- sin was poured of quickly and the cells were incubated for 2 minutes at 37°C (if the cells were not y detached). Cells were resuspended in 10 mL culture media and transfered to 50 mL tubes.
The cell suspension was counted (NucleoCounter, total cell count) from the first plates to estimate the total cell number of the whole batch.
The cells were seeded in 384 well plates with 30 uL/well (30000 cells/well) while stirring the cell suspension or otherwise preventing the cells from precipitating.
The plates were incubated at room temperature for 30-45 minutes.
The plates were placed in incubator for two days (37°C and 5% C02).
Loading the Cells The loading buffer was 5% v/v Calcium-4 Kit and 2.5 mM Probenecid in assay . 190 mL assay buffer mL Kit-solution 2 mL 250 mM Probenecid This volume was enough for 3 x 8 cell plates.
Culture media were removed from the cell plates and 20 uL loading buffer was added in each well. The cell plates were placed in trays and incubated 90 minutes in the incubator [Annotation] sak (37°C). Thereafter the plates were incubated 30 minutes at toom temperature, still protected from light.
Now the cell plates were ready to run in the Functional Drug ing System (FDSS).
The assay buffer was HBSS with 20 mM HEPES, pH 7.4 and 3 mM CaClz.
FDSS Ca assay 200 nL 10 mM compound solution in DMSO was diluted in 50 uL assay . The fi- nal test concentrations in the cell plates were 5-2.5-1.25-0.625-0.312-0.156 0.039 uM. Assay buffer and 3 uM PNU-120596 were used for control.
The agonist acetylcholine was added to a final concentration of 20 uM (~EC100).
In the FDSS7000 the Ex480-Em540 was measured with 1 second intervals. The baseline was made of 5 frames before addition of test compounds, and 95 frames more were made before addition of acetylcholine. The measurement stopped 30 frames after the 2nd addition.
Raw data for each well were collected as "the maximum fluorescence count" in the interval 100-131 seconds and as "the e fluorescence count" in the interval 96-100 seconds.
The positive allosteric modulation in the 2nd addition was the enhancement of t re- sponse with test compound compared to agonist alone.
Results were calculated as % modulation of test compound compared to the reference PNU-120596 set to 100%. From these data EC50 curves were generated giving EC50, hill and maximum stimulation.
The compounds of the invention were shown to be PAMs of the o7 receptor. The com- pounds of the t invention characterized in the flux assay lly possess EC50 val- ues below 20.000 nM or less such as below 10.000 nM. Many compounds, in fact have EC50 values below 5.000 nM. Table 1 shows EC50 values for exemplified compounds of the inven- tion.
Table 1 E0000 E0000 E0000 [Annotation] sak Example 3: a7NNR oocyte assay Expression of (17 nACh receptors in Xenopus oocytes.
Oocytes were surgically removed from mature female Xenepus laevis anaesthetized in 0.4% MS—222 for 10 — 15 min. The oocytes were then digested at room temperature for 2-3 hours with 0.5 mg/mL enase (type IA Sigma-Aldrich) in 0R2 buffer (82.5 mM NaCl, 2.0 mM KCI, 1.0 mM MgClz and 5.0 mM HEPES, pH 7.6). Oocytes avoid of the follicle layer were selected and incubated for 24 hours in Modified Barth's Saline buffer (88 mM NaCl, 1 mM KCI, 15 mM HEPES, 2.4 mM NaHCOs, 0.41 mM CaClz, 0.82 mM MgSO4, 0.3 mM Ca(NOs)2) supplemented with 2 mM sodium pyruvate, 0.1 U/l penicillin and 0.1 ug/l streptomycin. Stage IV oocytes were fied and injected with 4.2 - 48 hi of nuclease free water containing 0.1 — 1.2 ng of cRNA coding for human (17 nACh receptors or 3.0 — 32 ng of cRNA coding for rat o7 nACh receptors and incubated at 18°C for 1 — 10 days when they were used for electro- physiological recordings.
Electrophysiological recordings of (17 nACh ors sed in oocytes.
Oocytes were used for electrophysiological recordings 1 — 10 days after injection.
Oocytes were placed in a 1 mL bath and perfused with Ringer buffer (115 mM NaCl, 2.5 mM KCI, 10 mM HEPES, 1.8 mM CaClz, 0.1 mM MgClz, pH 7.5). Cells were impaled with agar plugged 0.2 — 1 M0 electrodes containing 3 M KCI and e clamped at -90 mV by a Ge- neClamp 500B amplifier. The ments were performed at room temperature. Oocytes were continuously perfused with Ringer buffer and the drugs were applied in the ate.
ACh (30 uM) applied for 30 sec were used as the standard agonist for activation of the (17 [Annotation] sak nACh receptors. In the standard screening set-up the new test compound (10 uM or 30 uM) were applied for 1 min of pre-application allowing for evaluation of agonistic activity followed by 30 sec of co-application with ACh (30 uM) allowing for evaluation of PAM activity. The re- sponse of co-application was compared to the agonistic response ed with ACh alone.
The drug induced effects on both the peak response and the total charge (AUC) se were calculated thus giving the effect of drug induced PAM activity as fold tion of the control response.
For more elaborate studies doses-response curves can be performed for evaluation of max-fold modulation and E050 values for both peak and AUC responses.
WE

Claims (19)

CLAIM :
1. A compound according to a [I] R3 R5 R6 R2 N A R1 A R11 9 wherein R1, R2, R3, R4 and R5 are ed independently of each other from H, C1-6alkyl, C2- 6alkenyl, kynyl, C1-6alkoxy, cyano and halogen, wherein said C1-6alkyl, kenyl and C2- 6alkynyl is optionally substituted with one or more substituents independently selected from chlorine and fluorine; R6 is hydroxymethyl; A7 is C-R7, A8 is N and A9 is C-R9; R7, R9, R10 and R11 are selected independently of each other from H, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C1-6alkoxy, cyano, NR12R13, C1-6alkylsulfonyl and halogen, wherein said C1-6alkyl, C2- 6alkenyl, C2-6alkynyl or C1-6alkoxy is optionally substituted with one or more substituents ed from chlorine, fluorine, C1-6alkoxy, cyano and NR12R13; R12 and R13 independently represent hydrogen, C1-6alkyl, kenyl and C2-6alkynyl; and ceutically acceptable salts thereof.
2. The compound according to claim 1, wherein four or more of R1, R2, R3, R4 and R5 are
3. The compound according to claims 1 or 2, wherein R7, R9, R10 and R11 are selected independently of each other from H, C1-4alkyl, C1-4alkoxy, cyano, -N(CH3)2, methylsulfonyl, fluorine and chlorine, wherein said C1-4alkyl or C1-4alkoxy is optionally substituted with one or more substituents selected from fluorine, C1-4alkoxy and cyano.
4. The compound according to any one of claims 1-3, wherein R7, R8, R9, R10 and R11 are selected independently from H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, cyano and halogen, n said C1-4alkyl, C2-4alkenyl, C2-4alkynyl or C1-4alkoxy is optionally substituted with one or more substituents selected from fluorine and C1-4alkoxy. 10249033
5. The compound according to any one of claims 1-4, wherein R7, R10 and R11 all represent
6. The compound according to any one of claims 1-5, wherein R9 is selected from methyl, C1- 4alkoxy or cyano, wherein said methyl is optionally substituted with C1-4alkoxy or one or more fluorine.
7. The compound according to claim 1 selected from 21: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)hydroxy(6-propoxy-pyridinyl)-ethyl]- amide; 22: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)hydroxy(6-trifluoromethyl-pyridinyl)- ethyl]-amide; 24: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)hydroxy(6-methoxy-pyridinyl)- ethyl]-amide; 25: )Phenyl-cyclopropanecarboxylic acid [(R)hydroxy(6-methyl-pyridinyl)-ethyl]- amide; 26: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)hydroxy(6-isopropoxy-pyridinyl)- ethyl]-amide; 27: (1S,2S)(3-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-ethoxy-pyridinyl) hydroxy-ethyl]-amide; 28: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-ethoxy-pyridinyl) hydroxy-ethyl]-amide; 29: (1S,2S)(3-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)hydroxy(6-propoxy-pyridin- 3-yl)-ethyl]-amide; 30: )(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)hydroxy(6-propoxy-pyridin- 3-yl)-ethyl]-amide; 31: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-(2,2,2-d3)-ethoxy-pyridinyl) hydroxy-ethyl]-amide; 32: )(3-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-(1,1-d2)-ethoxy-pyridin yl)hydroxy-ethyl]-amide; 33: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-ethoxy-pyridinyl)hydroxy-ethyl]- amide; 34: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-(1,1,2,2,2-d5)-ethoxy- nyl)hydroxy-ethyl]-amide; 35: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-(2,2,2-d3)-ethoxy-pyridin yl)hydroxy-ethyl]-amide; 10249033 36: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-(1,1-d2)-ethoxy-pyridinyl) hydroxy-ethyl]-amide; 37: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-(1,1-d2)-ethoxy-pyridin hydroxy-ethyl]-amide; 38: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-(1,1,2,2,2-d5)-ethoxy-pyridinyl) hydroxy-ethyl]-amide; 39: )(3-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-(2,2,2-d3)-ethoxy-pyridin yl)hydroxy-ethyl]-amide; 40: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-cyclobutoxy-pyridinyl)hydroxy- ethyl]-amide; 41: (1S,2S)(3-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-cyclobutoxy-pyridinyl) hydroxy-ethyl]-amide; 42: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-cyclobutoxy-pyridinyl) hydroxy-ethyl]-amide; and pharmaceutically acceptable salts of any of these compounds.
8. The compound according to claim 1, which is 21: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)hydroxy(6-propoxy-pyridinyl)-ethyl]- amide; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, which is 27: )(3-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-ethoxy-pyridinyl) hydroxy-ethyl]-amide; or a pharmaceutically acceptable salt thereof.
10. The compound ing to claim 1, which is 28: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid -(6-ethoxy-pyridinyl) hydroxy-ethyl]-amide; or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, which is 30: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)hydroxy(6-propoxy-pyridin- 3-yl)-ethyl]-amide; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, which is 33: (1S,2S)Phenyl-cyclopropanecarboxylic acid [(R)(6-ethoxy-pyridinyl)hydroxy-ethyl]- amide; or a pharmaceutically acceptable salt thereof. 10249033
13. The compound according to claim 1, which is 35: (1S,2S)(4-Fluoro-phenyl)-cyclopropanecarboxylic acid [(R)(6-(2,2,2-d3)-ethoxy-pyridin yl)hydroxy-ethyl]-amide; or a pharmaceutically acceptable salt thereof.
14. A compound according to any one of claims 1-13, for use as a medicament.
15. A compound according to any one of claims 1-13, for use in the treatment of a disease or disorder selected from sis; Schizophrenia; cognitive disorders; cognitive ment ated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer’s disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson’s disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; posttraumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
16. The compound according to any one of claims 1-13, for use concomitantly or sequentially with a therapeutically effective amount of a compound selected from the list consisting of acetylcholinesterase tors; glutamate or antagonists; dopamine transport tors; noradrenalin transport inhibitors; D2 antagonists; D2 l agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ nists; lithium; sodium channel blockers and GABA signaling enhancers in the treatment of a disease or disorder according to claim 15.
17. A pharmaceutical composition comprising a compound according to any one of claims 1- 13, and one or more ceutically able r or excipient.
18. A kit sing a compound according to any one of claims 1-13, together with a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; enalin transport inhibitors; D2 antagonists; D2 l agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium l blockers and GABA ing enhancers.
19. Use of a compound according to any one of claims 1-13 in the preparation of a medicament for the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer’s e (AD); mild cognitive impairment (MCI); age ated memory impairment (AAMI); senile dementia; AIDS 10429733 dementia; Pick's disease; dementia associated with Lewy bodies; dementia ated with Down's syndrome; Huntington's Disease; Parkinson’s disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); raumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced enesis; amyotrophic lateral sis and pain. H. Lundbeck A/S By the Attorneys for the Applicant SPRUSON & FERGUSON Per: 10249033
NZ617367A 2011-07-08 2012-07-06 Positive allosteric modulators of nicotinic acetylcholine receptor NZ617367B2 (en)

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DKPA201100520 2011-07-08
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PCT/EP2012/063219 WO2013007621A1 (en) 2011-07-08 2012-07-06 Positive allosteric modulators of nicotinic acetylcholine receptor

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