ZA200601175B - Cyclopropyl derivatives as NK3 receptor antagonists - Google Patents

Cyclopropyl derivatives as NK3 receptor antagonists Download PDF

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ZA200601175B
ZA200601175B ZA200601175A ZA200601175A ZA200601175B ZA 200601175 B ZA200601175 B ZA 200601175B ZA 200601175 A ZA200601175 A ZA 200601175A ZA 200601175 A ZA200601175 A ZA 200601175A ZA 200601175 B ZA200601175 B ZA 200601175B
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methyl
phenyl
amide
compound
salt
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ZA200601175A
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Kehler Jan
Hansen Tore
Poulsen Anders
Bjoernholm Berith
Ruhland Thomas
Noergaard Morten Bang
Soeren Moeller Nielsen
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Lundbeck & Co As H
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Description

CYCLOPROPYL DERIVATIVES AS NK3 RECEPTOR ANTAGONISTS h
FIELD OF THE INVENTION
The present invention relates to novel compounds which are NK3 receptor antagonists and as such useful for treatment of diseases where the NK3 receptor is implicated.
BACKGROUND OF THE INVENTION
Three tachykinins, Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are widely distributed throughout the peripheral and central nervous systems. The biological effects of these neuropeptides are primary mediated via binding to and subsequent activation of the three neurokinin receptors, NK1, NK2 and NK3. Substance P is considered to be the endogenous ligand for the NK1 receptor and likewise NKA and NKB for the NK2 and NK3 receptors, respectively. However, recent data indicates that there exist cross- reactivity within the tachykinin system, which might be of physiological relevance as both
NKA and NKB potently are able to bind and activate the NK1 receptor (for review see
Maggi, CA et al: Trends Pharmacol Sci. 1997, 18, p351-5). The three receptor subtypes belong to the G-protein-coupled receptor super family and have been cloned in various species including mice, rats and humans (Nakanishi S: Annu Rev Neurosci. 1991, 14, p123- 36).
The three tachykinin receptors are expressed both centrally and in the periphery. The NK3 receptor is mainly expressed centrally in regions including cortex, striatum, substantia nigra compacta, ventral tegmental area, hypothalamus, amygdala and hippocampus (Stroessl AJ et al: Brain Res. 1990, 534, p1-7, Koutcherov Y et al: Neuroreport. 2000, 11, p3127-31). In the periphery, the NK3 receptor is expressed in regions including colon, kidney, lungs and the urinary bladder (Regoli D et al: Trends Pharmacol Sci. 1988 Aug;9(8): 290-5, Kamali F:
Curr Opin Investig Drugs. 2001 Jul;2(7):950-6). Centrally, the NK3 receptor is expressed on cholinergic (Chen LW et al: Neuroscience. 2001;103(2):413-22), noradrenergic (references within Oury-Donat F et al: J Pharmacol Exp Ther. 1995, 274, p148-54) and dopaminergic neurons (Keegan KD et al: Br. J. Pharmacol. 1992, 105, p3-5). In agreement with these results, activation of the NK3 receptor has been reported to be implicated in the regulation of various monoamine transmitters, e.g. dopamine and acetylcholine (Marco N et al: Neuropeptides. 1998, 32, p481-8, Stoessl AJ et al: Brain Res. 1990, 517, p111-6),
noradrenaline (Jung M et al: Neuroscience. 1996, 74, p403-14) and serotonine (Stoess! AJ et al: Brain Res. 1990, 517, p111-6).
The NK3 receptor-mediated regulation of monoamine systems supports that the NK3 receptor is involved in diverse functions including memory, learning, cortical processing and behavioral control (Yip J et al: Br J Pharmacol. 1997, 122, p715-25, Ding YQ et al: J
Comp Neurol. 1996, 364, 290-310, Mileusnic D et al: Neurobiol Aging. 1999, 20, p19-35) and that it is target for various psychological and neurological disorders (Emonds-Alt X et al: Can J Physiol Pharmacol. 2002, 80, p482-8, Kamali F, Curr Opin Investig Drugs. 2001, 2, p950-6, Langlois X et al: J Pharmacol Exp Ther. 2001, 299, p712-7). Indeed, the NK3 receptor has been reported to be implicated in modulation of anxiety (Ribeiro SJ et al:
Neuropeptides. 1999, 33, p181-8).
Further, it has been reported that the NK3 receptor antagonist SR142801 has effect against schizophrenia, in particular positive symptoms. SR142801 is described in, e.g., EP 673928.
The structure of SR142801 is outlined below (Kamali F: Curr Opin Investig Drugs. 2001,
Jul;2(7):950-6). lo}
So 8 X NL a
In vivo, NK3 receptor activation centrally has been reported to mediate hypertension and tachycardia (Nagashima A et al: Brain Res. 487, 1989, p392-396, Takano Y et al: Brain
Res. 1990, 528, p231-7, Picard P et al: Br J Pharmacol. 1994, 112, p240-9) whereas NK3 receptor activation in the periphery mediates hypotension and bradycardia (Couture R et al:
Naunyn Schmiedebergs Arch Pharmacol. 1989, 340, p547-57). Additional in vivo studies have indicated that NK3 receptor activation decrease water, salt and alcohol intake (Massi
Met al: Brain Res Bull. 1991 26 p155-60, Massi M et al: Neurosci Lett. 1988, 92, p341-6 and Ciccocioppo R et al: Brain Res Bull. 1994, 33, p71-7) which together with the localization of the NK3 receptor on MCH neurons support a role of the NK3 receptor in the. regulation of food intake (Griffond B et al: J Chem Neuroanat. 1997, 12, p183-9). Further in vivo studies have shown that the NK3 receptor is implicated in renal control of water and electrolyte homeostasis (Yuan YD: Br J Pharmacol. 1997, 120, p785-96). Activation of the
NK3 receptor has been reported to inhibit gastric acid secretion (Improta G et al: Peptides. 1991, 12, p1433-4), induce oral dyskinesia (Liminga U et al: Pharmacol Biochem Behav. 1991, 38, p617-20) and oedema (Inoue H et al: Inflamm Res. 1996, 45, p316-23).
In vitro NK3 activation has been reported to have proconvulsive effect (Maubach KA et al:
Neuroscience. 1998, 83, p1047-62) and to mediate hyperexcitability in ischemic injury (Stumm R et al: J Neurosci. 2001, 21, p798-811).
Selective high affinity non-peptide NK3 receptor antagonists have been shown to be antinociceptic (Fioramonti J et al: Neurogastroenterol Motil. 2003, 15, p363-9, Couture R et al: Life Sci. 2000, 66, p51-65, Julia V et al: Gastroenterology. 1999, 116, p1124-31,
Coudore-Civiale MA: European Journal of Pharmacology 1998, 361, p175-184) and analgesic (Houghton AK et al: Neuropharmacology. 2000, 39, p133-40). In addition, studies demonstrate consistent effect of a NK3 receptor antagonist against visceral pain encouragingly precluding constipation (Mayer EA et al: Gastroenterology. 1999, 116, p1250-2, Julia V et al: Gastroenterology. 1999 116 p1124-31). Similarly inhibition of the
NK3 receptor is stated to prevent gut inflammation highlighting effect against inflammatory bowel disease (Mazelin L et al: Life Sci. 1998, 63, p293-304), cough, airway hyperresponsiveness, microvascular hypersensitivity and reduction of bronchoconstriction (Daoui S et al: Am J Respir Crit Care Med. 1998, 158, p42-8 , Rumsey WL et al: J
Pharmacol Exp Ther. 2001, 298, p307-15, Daoui S et al: Pulm Pharmacol Ther. 1997 10 p261-70). Inhibition of the NK3 receptor as therapeutic strategy for Parkinsons disease has been substantiated in several reports (Arenas E: J Neurosci. 1991, 11, p2332-8, Kemel ML et al: J Neurosci. 2002, 22, p1929-36).
Accordingly, pre-clinical, in vivo and in vitro studies support that NK3 receptor antagonists are of relevance for the treatment or prevention of various disorders including: schizophrenia, depression, anxiety, Parkinson's disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, gut inflammation, inflammatory bowel disease, hypertension, imbalances in water and electrolyte homeostasis, ischemia, oedema and plasma extravasation.
Hence, there is a desire for NK3 receptor antagonists. The present inventors have now found such compounds with a strong affinity for the NK3 receptor.
Several patent applications relate to compounds disclosed as NK receptor antagonist, e.g.
EP 474561, EP 512901 and WO 03/051869. In particular, some patent applications relate to compounds disclosed as NK3 receptor antagonist, e.g. WO 9710211, US 5434158 and EP 673928. US 5750549 disclose cyclopentane derivatives as NK1 receptor antagonist.
The compounds of the present invention are all cyclopropyl derivates. As described in the following, some patent applications relate to different cyclopropane derivatives. However, none of these patent applications relates to the NK3 receptor or others of the NK receptors.
JP 03056415 describes cyclopropane derivatives of the following formula (R)n la CH2NR3R4
Omm CNRIR2 I for treatment of cerebral ischemia.
EP 68999 describes cyclopropane derivatives of the following formula
AST on
R3NR4CH? ONR1R2 1 for treatment of depression.
SUMMARY OF THE INVENTION
The objective of the present invention is to provide compounds that are antagonists at the
NK3 receptor. Some of the compounds may also have affinity for the NK1 and/or NK2 receptor. :
Accordingly, in one aspect the present invention relates to a compound having the general formulal:
R? rR R' i” 0) 5 n-Q
R y o 6. \
R R wherein the substituents are as defined herein, or a salt thereof, in particular a 5 pharmaceutically acceptable acid addition salt thereof. The invention in particular provides the (1S,2R)-isomer of such compounds.
Moreover, the invention provides a pharmaceutical composition comprising a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof. Accordingly, the invention provides a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof for use in medicine.
The invention also provides the use of a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases selected from the group consisting of: schizophrenia, psychotic disorders, depression, anxiety, Parkinson’s disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, gut inflammation, inflammatory bowel disease, hypertension, imbalances in water and electrolyte homeostasis, ischemia, oedema and plasma extravasation.
Further, the invention also provides a method for the treatment of diseases selected from the group consisting of: schizophrenia, psychotic disorders, depression, anxiety, Parkinson’s disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, gut inflammation, inflammatory bowel disease, hypertension, imbalances in water and electrolyte homeostasis, ischemia, oedema and plasma extravasation, comprising administering a therapeutically effective amount of a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION Definitions
The term “halogen” means fluoro, chloro, bromo or iodo.
The expression “Cys-alk(en/yn)yl” means a C¢-alkyl, a C¢-alkenyl or a C;4-alkynyl group.
The term “Cj. alkyl” refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1- butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
The term “Cs, alkenyl” designates such groups having from two to six carbon atoms, including one double bond, including but not limited to ethenyl, propenyl, and butenyl.
The term “Cs alkynyl” designates such groups having from two to six carbon atoms, including one triple bond, including but not limited to ethynyl, propynyl and butynyl.
The expression “Cs g-cycloalk(en)yl” means a C3 g-cycloalkyl or a C3g-cycloalkenyl group.
The term “Cs.g-cycloalkyl” designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term “Cs.g-cycloalkenyl” designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and one double bond, including but not limited to cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.
In the expression “Csg-cycloalk(en)yl-C,¢-alk(en/yn)yl”, the terms “Cjg-cycloalk(en)yl” and “C;4-alk(en/yn)yl” are as defined above.
The term “C,¢-alk(en/yn)yloxy” refers to groups of the formula C;¢-alk(en/yn)yl-O-, wherein C,_¢-alk(en/yn)yl is as defined above.
The terms “C,-alk(en/yn)yl-carbonyl”, “C;.¢-alk(en/yn)yl-aminocarbonyl” and “di-(Ci- alkyl)aminocarbonyl” refer to groups of formula C,¢-alk(en/yn)yl-CO-, C,¢-alk(en/yn)yl-
NH-CO- and (Ci¢-alk(en/yn)yl),-N-CO-, respectively, wherein C;¢-alk(en/yn)yl is as defined above.
In the expressions “Ci¢-alk(en/yn)yl-amino”, “diH(Cis-alkyl)amino”, “Cis- alk(en/yn)ylthio”, *halo-Ci¢-alk(en/yn)yl”, “halo-Ci.¢-alk(en/yn)yl-sulfonyl”, ‘“halo-C,.- alk(en/yn)yl-sulfanyl”, “C¢-alk(en/yn)ylsulfonyl”, and “C,¢-alk(en/yn)ylsulfanyl” etc., the terms “C,¢-alk(en/yn)yl” and “halo” are as defined above.
As used herein, the term “acyl” refers to formyl, C;¢-alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C, ¢-alk(en/yn)ylcarbonyl, C;s-cycloalk(en)ylcarbonyl or a Css-cycloalk(en)yl-C;- alk(en/yn)yl-carbonyl group, wherein C,s-alk(en/yn) and Cs.¢-cycloalk(en)yl are as defined above and aryl is as defined below.
The term "thioacyl" is the corresponding acyl group, in which the carbonyl group is replaced with a thiocarbonyl group.
The term "aryl" refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl and includes both substituted or unsubstituted carbocyclic aromatic groups. Thus, the aryl is optionally substituted with one or more substituents selected from the substituent list as defined below. Accordingly, the term aryl as used herein means an optionally substituted carbocyclic aromatic group, e.g. phenyl or naphthyl, such that said aromatic group is substituted with one or more substituents selected from the substituent list defined below, e.g., C;¢-alkyl or halogen. The aryl is preferably mono- or bicyclic.
The term “heteroaryl” refers to an aromatic group containing at least one carbon atom and one or more heteroatoms selected from O, S or N. As used herein the term "heteroaryl" refers to a mono- or bicyclic heterocyclic group including but not limited to indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, in particular pyrimidyl, indolyl, and thienyl. The term heteroaryl as used herein includes both substituted or unsubstituted heteroaryl. Thus, the heteroaryl is optionally substituted with one or more substituents selected from the substituent list as defined below, e.g., Cis-alkyl or halogen.
The term “monocyclic heteroaryl” as used herein refers to 5- to 6- membered aromatic systems containing 1 to 5 carbon atoms and one or more heteroatoms selected from O, S or
N.
Accordingly, the term "heteroaryl" refers to 5-membered monocyclic rings such as, but not limited to, 1H-tetrazolyl, 3H-1,2,3-oxathiazolyl, 3H-1,2,4-oxathiazolyl, 3H-1,2,5- oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4-oxathiazolyl, 1,4,2-oxathiazolyl, 3H-1,2,4- dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 3H-1,2,3-dithiazolyl, 3H-1,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 H-imidazolyl, 1H-pyrazolyl, 1 H-pyrrolyl, furanyl, thienyl, 1H-pentazole.
Further, the term "heteroaryl" refers to 6-membered monocyclic rings such as, but not limited to, 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4H-1,3,5-oxathiazinyl, 1,4,2-oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4H-1,3,2- dioxazinyl, 4H-1,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-1,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl, 4H-1,3,2-dithiazinyl, 4H-1,3,5-dithiazinyl, 1,4,2-dithiazinyl, 2H-1,5,2- dithiazinyl, 2H-1,2,3-oxadiazinyl, 2H-1,2,4-oxadiazinyl, 2H-1,2,5-oxadiazinyl, 2H-1,2,6- oxadiazinyl, 2H-1,3,4-0xadiazinyl, 2H-1,3,5-oxadiazinyl, 2H-1,2,3-thiadiazinyl, 2H-1,2,4- thiadiazinyl, 2H-1,2,5-thiadiazinyl, 2H-1,2,6-thiadiazinyl, 2H-1,3,4-thiadiazinyl, 2H-1,3,5- thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2-oxazinyl, 2H-1,3- oxazinyl, 2H-1,4-oxazinyl, 2H-1,2-thiazinyl, 2H-1,3-thiazinyl, 2H-1,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl.
Finally the term "heteroaryl" also refers to bicyclic rings such as, but not limited to, 3H- 1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3H-1,2,3-benzodithiazolyl, 1,3,2- benzodithiazolyl, benzfurazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3- benzothiadiazolyl, 1H-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, 1H-
benzimidazolyl, 1H-indazolyl, 3H-1,2-benzoxathiolyl, 1,3-benzoxathiolyl, 3H-2,1- benzoxathiolyl, 3H-1,2-benzodioxolyl, 1,3-benzodioxolyl 3H-1,2-benzodithiolyl, 1,3- benzodithiolyl, 1H-indolyl, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothienyl, 1H-2,1-benzoxazinyl, 11-2,3-benzoxazinyl, 2H-1,2-benzoxazinyl, 2H-1,3- benzoxazinyl, , 2H-1,4-benzoxazinyl, 2H-3,1-benzoxazinyl, 1H-2,1-benzothiazinyl, 1H-2,3- benzothiazinyl, 2H-1,2-benzothiazinyl, 2H-1,3-benzothiazinyl, 2H-1,4-benzothiazinyl, 2H-3,1-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, quinolyl, 1H-2-benzopyranyl, 2H-1-benzopyranyl, = 1H-2-benzothiopyranyl or 2H-1-benzothiopyranyl.
The expression "substituent list" means substituents selected from the group consisting of: halogen, cyano, nitro, C.s-alkyl (e.g methyl), C;¢-alkylamino, di-(C;.¢s-alkyl)amino, Ci4- alkylcarbonyl, aminocarbonyl, C,.¢-alkylaminocarbonyl, di<(C;.s-alkyl)aminocarbonyl, C1.- alkoxy, C;s-alkylthio, alkylsulphonyl, hydroxy, trifluoromethyl, trifluoromethylsulfonyl,
Cig-alkylcarbonylamino and C,¢-alkylcarbonylC;.¢-alkylamino".
The term "treatment" as used herein in connection with a disease or disorders includes also prevention as the case may be.
Compounds of the invention and salts thereof
The present invention relates to compounds of formula I which are antagonists at the NK3 receptor. These products may therefore be useful in the treatment of certain diseases such as, e.g., schizophrenia, psychotic disorders, depression, anxiety, or Parkinson’s disease.
In one aspect, the invention relates to compounds of formula I,
RZ rR? R'
R* 5 n Q
R \ 0 6.~"\
R R7 or a salt thereof, such as a pharmaceutically acceptable salt; wherein - RR’ are independently selected from hydrogen, halogen, cyano, nitro, C;.6- alk(en/yn)yl (e.g C1¢-alkyl, C2s-alkenyl, or C,¢-alkynyl; such as methyl), Cs.s- cycloalk(en)yl (e.g. Css-cycloalkyl), C;.s-cycloalk(en)yl-Cys-alk(en/yn)yl (e.g. Css cycloalkyl-C; ¢-alkyl), amino, C,.¢-alk(en/yn)ylamino (e.g. Cy.¢-alkylamino), di-(Ci.¢- alk(en/yn)yl)amino (.e.g. di-(Cis-alkyl)amino), Ci.s-alk(en/yn)ylcarbonyl (e.g C1-6- alkylcarbonyl), aminocarbonyl, C,s-alk(en/yn)ylaminocarbonyl (e.g.
C.¢-alkylaminocarbonyl), di-(Cy.s-alk(en)yl)aminocarbonyl (e.g. di-(Ci- alkyl)aminocarbonyl)), hydroxy, Ci-¢-alk(en/yn)yloxy (e.g. C1-¢-alkoxy; such as methoxy), C;_¢-alk(en/yn)ylthio (e.g. Cys-alkylthio, such as methylthio), halo-C¢- alk(en/yn)yl (e.g, halo-C, s-alkyl, such as trifluoromethyl), halo-C,.- alk(en/yn)ylsulfonyl (e.g trifluoromethylsulfonyl), halo-C, ¢-alk(en/yn)ylsulfanyl (.c.g trifluoromethylsulfanyl)), and C,-alk(en/yn)ylsulfonyl (e.g. C,s-alkylsulfonyl); - RS is selected from hydrogen, halo-C;.¢-alk(en/yn)yl (e.g. trifluoromethyl), C;.6- alk(en/yn)yl (e.g. C)s-alkyl, such as methyl, C;s-alkenyl, or C;s-alkynyl), C.¢- cycloalk(en)yl (e.g. Cs.3-cycloalkyl), and Cs ¢-cycloalk(en)yl-Ci.¢-alk(en/yn)yl (e.g.
Cs.g-cycloalkyl-Cy-alkyl); - R’ is an ary or a heteroaryl; or R is a group aryl-CR®R’-, wherein R® and R® are independently selected from hydrogen, C;.s-alk(en/yn)yl ( e.g. Cy ¢-alkyl, C;.¢-alkenyl, or C;¢-alkynyl; such as methyl), C3 s-cycloalk(en)yl (e.g. Cs¢-cycloalkyl), and Cs.g- cycloalk(en)yl-C,.¢-alk(en/yn)yl (e.g. Css-cycloalkyl-C,s-alkyl); - nis 0, 1, or 2;
Q is selected from (i)-(vii), the arrow indicating the attachment point: —-— N= - NN N-r" - ‘Gu _/ R" (i) : (ii) ; (iii)
fo) 0)
N N
= N 4 ) ~—N ’ N
N
(iv) a i v) R40 ; > i. —Y 0 wa -—N R® hs o IN R* R® i) re, OM) R® R* wherein R'is an optionally substituted aryl; wherein R'! is selected from an optionally substituted aryl or optionally substituted benzyl, halo-C,¢-alk(en/yn)ylsulfonyl (e.g. trifluoromethylsulfonyl), C,.¢- alk(en/yn)ylsulfonyl (e.g. Ci¢-alkylsulfonyl), arylsulphonyl, arylacyl, Ci alk(en/yn)ylcarbonyl (e.g. C,.¢-alkylcarbonyl), aminocarbonyl, C;s alk(en/yn)ylaminocarbonyl (e.g. C;.s-alkylaminocarbonyl), and di-(Ci4- alk(en)yl)aminocarbonyl (e.g. di-(C,s-alkyl)aminocarbonyl); wherein R'? is an optionally substituted aryl; wherein R'? is hydrogen, hydroxy, cyano, or amino, or one of the following groups: -NHC, ¢-alk(en/yn)yl (e.g. -NHC,¢-alkyl, -NHC,s-alkenyl, or -NHC, s-alkynyl, such as methyl);
N(Cis-alk(en/yn)yl), (e. g -N(Ci.¢-alkyl)); -NR'COR"®, wherein R' is hydrogen or C;s-alk(en/yn)yl and R"’ is C;.¢- alk(en/yn)yl or C;_s-cycloalk(en)yl; -NR'®*COCONR!'R'®, wherein R'® is hydrogen or C;.¢-alk(en/yn)yl and R'7 and R'® are selected independently from hydrogen and C;¢-alk(en/yn)yl (e.g. C,s-alkyl) or Cs.g-cycloalkyl; or R'? and R'® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholiny] are optionally substituted (i.e. unsubstituted or substituted) with a C;.¢-alk(en/yn)yl.
NR’ CONR®R?!, wherein R'? is hydrogen or C, salk(en/yn)yl and R* and R*' are selected independently from hydrogen and C, ¢-alk(en/yn)yl or Cy ¢-cycloalkyl; or R? and R?' together with the nitrogen to which they are attached form a piperidinyl, piperaziny! or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl are optionally substituted (i.e. unsubstituted or substituted) with a Cy s-alk(en/yn)yl;
NRZS0,R®, wherein R? is hydrogen or C.c-alk(en/yn)yl or Cs.s-cycloalkyl and
R? is amino, C,-alk(en/yn)yl or Cj g-cycloalkyl; -COR*, wherein R* is Cs-alk(en/yn)yl or Cs g-cycloalkyl; -CONR®R?S, wherein R? and R?® independently are selected from hydrogen, C,- alk(en/yn)yl and C3 gcycloalkyl, or R* and R* together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholiny] are optionally substituted (i.e. unsubstituted or substituted) with a C;4-alk(en/yn)yl, in particular C,_¢-alkyl; -NHCOOR*, wherein R*? is C,s-alk(en/yn)yl or Cs.scycloalk(en)yl; wherein X, Y, and Z are selected independently from a bond; O; NR*’; CR®*R? and
S(O)m, whereinm is 0, 1 or 2; wherein R* is selected from hydrogen, Cy.s-alk(en/yn)yl (such as Cy-alkyl, C.¢- alkenyl, or C,.¢-alkynyl), Cs3-cycloalkyl, Cs gcycloalkyl-C,.¢-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl; or
R? is a group R*’SO., R*®OCO- or R**SCO-, wherein R* is C,.s-alk(en/yn)yl (such as Cy¢-alkyl, C,¢-alkenyl, or Cy¢-alkynyl), Csg-cycloalkyl, or Cs.g-cycloalkyl-
C,¢-alkyl; or
R? is a group R*R*?NCO- or R*'R*’NCS-, wherein R*' and R* are independently selected from hydrogen, C,s-alk(en/yn)yl (such as C,¢-alkyl, C,¢-alkenyl, or
C,.s-alkynyl), Cs.g-cycloalkyl, Cs g-cycloalkyl-C;¢-alkyl and aryl, wherein said aryl is optionally substituted (i.e. unsubstituted or substituted), e.g. with one or more substituents selected from Cy.-alkyl or halogen; or wherein R*! and R* together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group;
wherein R® and R% are independently selected from hydrogen, halo such as fluoro,
C.s-alk(en/yn)yl (such as C,¢-alkyl, C alkyl, C;¢-alkenyl, or C; ¢-alkynyl),
C;.s-cycloalkyl, and Cj.g-cycloalkyl-C, ¢-alkyl; wherein R**-R* are independently selected from hydrogen, halogen, cyano, nitro, C;- ¢-alk(en/yn)yl (such as Cy ¢-alkyl, C;¢-alkenyl, or C;¢-alkynyl), C3 g~cycloalkyl,
Cs g-cycloalkyl-alkyl, amino, C,¢-alkylamino, di~(C.s-alkyl)amino, C;4- alkylcarbonyl, aminocarbonyl, C, s-alkylaminocarbonyl, di-(C;s- alkyl)aminocarbonyl, C;-alkoxy, C;¢-alkylthio, hydroxy, halo-C;s-alk(en/yn)yl, preferably trifluoromethyl, trifluoromethylsulfonyl and C; ¢-alkylsulfonyl; wherein R>’-R* are either both hydrogen or are fused together in an ethylene chain
CH?-CH?- forming an aza-bicyclo[3.2.1]octane-yl; wherein R*°-R*! are independently selected from hydrogen and the substituent list as defined herein; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S.
To further illustrate the invention, without limitation, the following embodiments of RR’ are within the scope of the invention, in particular for the compounds or salt thereof: R'-R® are independently selected from hydrogen, halogen, cyano, C;s-alkyl, C;.s-cycloalkyl, C;.¢- cycloalkyl-C¢-alkyl, Ci-alkyloxy, Ci-s-alkylthio, and trifluoromethyl; RR’ are independently selected from a hydrogen and C,.¢-alkyl; R'-R® are independently selected from hydrogen, Cl, F, cyano, methyl, methoxy, methylthio, and trifluoromethyl; R'-R® are hydrogen; R'-R? are independently selected from hydrogen and halogen; R'-R® are independently selected from hydrogen, chloro and fluoro; R'-R® are independently selected from hydrogen and chloro; R!-R’ are independently selected from hydrogen and fluoro; R? is chloro and R? is hydrogen, R* and R? are chloro, R? is fluoro and R® is hydrogen, or R? and R? is fluoro, where the rest of R'-R® may, e.g., be hydrogen or they may also be substituted from the list above; at least one R'-R%is F or Cl], such as a compound of the invention for which R® is F or CI; R'-R’ is selected independently from H and cyano; R'-R’ are selected independently from H and Cy.¢-alk(en/yn)yl; R'-R® are selected independently from H and C)s-alkyl, such as methyl or ethyl; R'-R® are selected independently from H and C,_s-alk(en/yn)yloxy, preferably C,_¢-alkoxy, such as methoxy; R'-R> are selected independently from H and C,_¢-alkylthio, such as methylthio; R'-R° are selected independently from H and trifluoromethyl; at least 3 of R'-R® are hydrogen, such as 3, 4 or all of R'-R° are hydrogen; 1 of R'-R® is substituted, such as in the positions R? or R’, e.g. with a halogen (e.g. F or Cl), C-alkyl (e.g. methyl), C_¢-alkoxy (e.g. methoxy) while the rest of R'-R° being hydrogen; 2 of R'-R° sre substituted, e.g. in the positions R? and R®, e.g. selected independently from the group consisting of a halogen (e.g. F or CI), Ci¢-alkyl (e.g. methyl), C)-s-alkoxy (e.g. methoxy) while the rest of R!-R’ being hydrogen.
To further illustrate the invention, without limitation, the following embodiments of RC are within the scope of the invention, in particular for the compounds or salt thereof: Réis selected from hydrogen, halo-C;.¢-alkyl, Cy¢-alkyl, C3 s-cycloalkyl, and C3 s-cycloalkyl-C,. s-alkyl; Ris selected from hydrogen and C).¢-alk(en/yn)yl; R® is hydrogen; R® is a Ci4- alkyl; R® is methyl; R® is ethyl.
When R’ is aryl or heteroaryl, it is understood that the aryl and heteroaryl are as defined herein and may be selected among these.
The invention in one aspect, relates to compounds of Formula (I) wherein R is an aryl as defined herein. To further illustrate the invention, without limitation, the following embodiments of R’, for which R’ is an aryl, are within the scope of the invention, in particular for the compounds or salt thereof: R’ is an unsubstituted phenyl; R’ is phenyl substituted with one or more substituents, e.g. mono or disubstituted, selected independently from the substituent list as defined herein, including, e.g., halogen and C,¢-alkyl; R” is an unsubstituted phenyl and R® is hydrogen; R’ is an unsubstituted phenyl and R is methyl.
To further illustrate the invention, without limitation, the following embodiments of R’, for which R’ is a group aryl-CR®R’-, are within the scope of the invention, in particular for the compounds or salt thereof: R® and R? are independently selected from hydrogen, Cy.¢-alkyl,
Cs-cycloalkyl and C;.g-cycloalkyl-C;¢-alkyl; R® and R® are independently selected from hydrogen and C, s-alkyl; R® and R® are independently selected from hydrogen and methyl;
RPandR’are hydrogen; R%is hydrogen and Ris methyl; R® and R® are methyl.
It is understood that for R’ being "aryl-CR*R®", the aryl of aryl-CR®R’- is as defined herein, i.e. it may, e.g., have one or more of the following characteristic: the aryl is monocyclic or bicyclic; the aryl is unsubstituted; the aryl is phenyl; the aryl is naphthalene, the aryl is substituted with one or more substituents, preferably selected from the group consisting of halogen, cyano, nitro, Cy.¢-alkyl, C¢-alkenyl, C2 ¢-alkynyl, C3 g-cycloalkyl, C;.s-cycloalkyl-
C1s-alkyl, amino, C;.s-alkylamino, di-(C)s-alkyl)amino, C,s-alkylcarbonyl, aminocarbonyl, C;¢-alkylaminocarbonyl, di-(Ci.s-alkyl)aminocarbonyl, Ci- alkylcarbonylamino, C.s-alkylcarbonyl C,s-alkylamino, C,¢-alkoxy (e.g. methoxy), Ci- alkylthio, hydroxy, trifluoromethyl! , difluoromethyl, fluoromethyl and trifluoromethylsulfonyl; the aryl, e.g. phenyl, is an optionally substituted phenyl; the aryl, e.g. phenyl, is mono- or poly-substituted, e.g. di-substituted, e.g. with a halogen, such as fluoro or chloro, and/or e.g. with a Cy_¢-alkoxy (e.g. methoxy).
In a preferred embodiment, R” is an aryl-CR®R’- selected from benzyl or substituted benzyl, e.g. halogen substituted benzyl, e.g. 4-halo benzyl, such as 4-fluorobenzyl, or 2-halo-benzyl, such as 2-chloro-benzyl, or 3,4-dichloro-benzylamide, 3,4-dimethoxy-benzylamide methyl- 1-phenyl-ethyl, methyl-1-(4-methoxyphenyl)-ethyl, or naphthalen-1-ylmethyl.
Further embodiments of the invention relates to compounds of formula I wherein RS is hydrogen or methyl.
Further aspects of the invention relate to compounds of formula I wherein Q is (i). One aspect of the invention relates to embodiments of the invention where Q is (i) and the aryl of
R'is selected from the aryls as defined herein.
In further embodiments, the invention relates to a compound or salt of the invention wherein
Qs (ii). Preferably R'' is selected from an optionally substituted (i.e. substituted or not) aryl or optionally substituted (i.e. substituted or not) benzyl, trifluoromethylsulfonyl, C;.¢- alkylsuifonyl, arylsulphonyl, arylacyl, C,¢-alkylcarbonyl, aminocarbonyl, C.s- alkylaminocarbony! and di-(C,.¢-alkyl)aminocarbonyl), wherein said aryl is selected from the aryls as defined herein. The benzyl may be substituted with one ore more substituent selected from the substituent list as defined herein.
In further embodiments, the invention relates to a compound or salt of the invention wherein
Q is (iii).
To further illustrate the invention, without limitation, the following embodiments of R'? are within the scope of the invention, in particular for the compounds or salt thereof: R'? is an aryl as defined herein; R'? is unsubstituted phenyl; R'? is a phenyl substituted with one or more substituents, e.g. mono or di-substituted, preferably selected from the substituent list as defined herein; the aryl, e.g. phenyl, in R! is substituted with one or more, e.g. one or two substituents selected from a halogen and trifluoromehtyl; the aryl, e.g. phenyl, in R%is substituted with at least one chloro or at least one fluoro and at least one trifluoromethyl; the aryl, e.g. phenyl, in R'? is substituted with one C1 and one trifluoromehtyl; R'2 is 4-chloro- 3-trifluromethyl-phenyl.
The following embodiments of the compound of the invention for which Q is (iii) are also within the scope of the invention: R'? is an aryl substituted with one or more substituents selected from a halogen and aminoacyl and R" is hydrogen; R'? is phenyl substituted with one or more substituents, e.g. mono or di-substituted, selected from a halogen and aminoacyl and R'? is hydrogen.
In one embodiment when Q is (iii) the group R'? is hydroxy. In a preferred embodiment R'? is 4-chloro-3-trifluromethyl-phenyl and R' is hydroxy.
In further embodiments of (iii) the R'* is -NR'*COR'?, where R' and R'* are as defined herein. To further illustrate the invention, without limitation, the following embodiments of
R'? are within the scope of the invention, in particular for the compounds or salt thereof: R** is hydrogen; R'* is methyl; R* is methyl; R' is hydrogen or C,¢-alkyl and R"’ is C,¢-alkyl or Cag-cycloalkyl; R'is H or CHs, R'® is CHj; R" is hydrogen and R'® is methyl; R'* and
RY are methyl,
In further embodiments of (iii), the R'* is -NR'® COCONR''R'®, wherein R', R!” and R'® is as defined herein. To further illustrate the invention, without limitation, the following embodiments of R'? are also within the scope of the invention, in particular for the compounds or salt thereof: R'® is hydrogen or C)¢-alkyl and wherein R!? and R'® are selected independently from hydrogen, Cy.s-alkyl and Cs s-cycloalkyl; R'® is hydrogen or
Ci-alkyl and where R'” and R'® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, where said piperidinyl, piperazinyl and morpholiny] are optionally substituted with a C,.¢-alkyl, e.g. methyl; R', R' and R'® are hydrogen(i.e. oxalamide, -NHCOCONH;); R'S is Cy s-alkyl, and R'” and R'® are hydrogen (i.e. N- C)¢-alkyl oxalamide); R'® and R"" are hydrogen and Ris is Cy-alkyl (i.e. NC alkyl-N-oxalamide); R'® and R'’ are C;¢-alkyl and R'® is hydrogen (i.e. N -C,s-alkyl-N- C,. ¢-alkyl oxalamide); R'® is hydrogen and R'” and R'® are C,s-alkyl, e.g. methyl, (i.e. N,N" di-(C,¢-alkyl)-N-oxalamide); R'S is hydrogen and R'” and R'® are methyl; R'S, R" and R" are C ¢-alkyl (i.e. N’,N’-di-(C,¢-alkyl)-N- C,-alkyl oxalamide).
In further embodiments of (iii) the R'? is -NR'’CONR?’R?', wherein R'®, R? and R? are as defined herein. To further illustrate the invention, without limitation, the following embodiments of R'* are also within the scope of the invention, in particular for the compounds or salt thereof: R'%, R? and R?! are independently selected from hydrogen, Cy.5- alkyl and Cs gcycloalkyl; R'’, R? and R*' are independently selected from hydrogen and
Cis-alkyl; R', Ryo and Ry are hydrogen; R'® is a Cy.s-alkyl and R? and R*! are hydrogen;
Rus and Ryo are hydrogen and R?' is a C;_s-alkyl; R'® and R? are independently selected from a C, ¢-alkyl and R?' is H; R" is H, and R*® and R?! are independently selected from a
Cis-alkyl; or RY, R® and R?! are independently selected from a C,-alkyl; R'® is H and R*® and R?' are independently selected from the group consisting of hydrogen, Me, Et, Bu, and i-Pr.
In further embodiments of (iii) the R'* is -NR*SO,R**, wherein R* and R? are as defined herein. To further illustrate the invention, without limitation, the following embodiments of
R" are also within the scope of the invention, in particular for the compounds or salt thereof: R* is hydrogen or a C,.s-alkyl or Cs.g-cycloalkyl and R* is amino, C,¢-alkyl or Cs. g-cycloalkyl; R* is hydrogen and R? is a C) ¢-alkyl, e.g. methyl (i.e. N(Cy.¢- * alkylsulphonamide) or R* and R* are independently selected from a Cy-alkyl, e.g. methyl i.e. N- C4-alkyl (C¢-alkylsulphonamide); R* is hydrogen; R? is methyl; R?* and R* are methyl; R? is hydrogen and R? is methyl.
In further embodiments of (iii) the R' is -COR*, wherein R* is as defined herein. The following embodiments of R'? are also within the scope of the invention without limitation, in particular for the compounds or salt thereof: R* is a Cys-alkyl; R* is methyl.
In further embodiments of (iii) the R** is -CONR*R?, wherein R* and R?® are as defined herein. To further illustrate the invention, without limitation, the following embodiments of
R'3 are also within the scope of the invention, in particular for the compounds or salt thereof: R* and R?® are independently selected from hydrogen, C,¢-alkyl and C;.5- cycloalkyl; R? and R* are independently selected from hydrogen and methyl; R? and R*® are hydrogen; R? and R are methyl; R> is methyl and R? is hydrogen; R* and R* together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl are optionally substituted with a C,¢-alkyl, in a preferred embodiment the piperidinyl, piperazinyl and morpholinyl are not substituted; R® and R together with the nitrogen to which they are attached form a piperidinyl, wherein the piperidinyl is optionally substituted with a Cy¢- alkyl, however preferably the piperidinyl is unsubstituted.
In further embodiments, the invention relates to a compound or salt of the invention wherein
Q is (vii) as described above.
RY
X—=Y -—N R® “2
R® R® (vii) R® R*
To further illustrate the invention, without limitation, the following embodiments of (vii) are within the scope of the invention: Y is a bond and X and Z are selected independently from 0, NR?, and CR*®R? and S(O)m, provided that X and Z may not at the same time be selected from O and S; Y is a bond and X and Z are selected independently from CR¥®R” and NR”; X is CR*R”, Y is a bond and Z is NR”; X is CR*R”, Y is a bond and Z is O; X isO,Yisabond and Z is CR®R%, R? and R? are hydrogen; R? is an acyl, e.g. C1. alkylcarbonyl; Z is NR?” where R?’ is a C ¢-alkylcarbonyl, e.g. -COCHa; X is CR¥*R? where R?® and R? are hydrogen, Y is a bond, and Z is -NR?’ where said R”’ is -COCH3; RY is selected from the group R**SO,-, R*®0CO- and R*SCO-; R* is R**S0O,; R* is C; ¢-alkyl,
e.g. methyl; X is CR™R”, Y is a bond and Z is NR? preferably R”* and R” are hydrogen,
R? is the group R*'R*2NCO- or R¥R*'NCS-; Y is a bond; R*-R* are independently selected from hydrogen and halogen, e.g. chloro or fluoro; R*>-R*® are all hydrogen;
R* and 3® are both hydrogen; R*’-R* are fused together in an ethylene chain CH2-CH2- forming an aza-bicyclo[3.2.1]octane-yl as shown in the figure below.
X—=Y -—N “2
R® R*
R® R*
In further embodiments of Compound (I), Q is (iv). To further illustrate the invention, without limitation, the following embodiments of (iv) are within the scope of the invention:
Ris selected from the group consisting of hydrogen and halogen; R* is hydrogen in all positions, i.e. the corresponding phenyl group is unsubstituted; the corresponding phenyl group is substituted in only one or two positions with a substituent R* selected from the "substituent" list as defined herein, e.g. a halogen.
In further embodiments of Compound (I), Q is (v). To further illustrate the invention, without limitation, the following embodiments of (v) are within the scope of the invention:
R™ is selected from the group consisting of hydrogen or halogen; R* is hydrogen in all positions, i.e. the corresponding phenyl group is unsubstituted; the corresponding phenyl group is substituted in only one or two positions with a substituent R* selected from the "substituent list" as defined herein, e.g. a halogen.
In further embodiments of Compound (I), Q is (vi). To further illustrate the invention, without limitation, the following embodiments of (vi) are within the scope of the invention:
R* is selected from the group consisting of hydrogen and halogen.; R*' is hydrogen in all positions, i.e. the corresponding benzyl group is unsubstituted; the corresponding benzyl group is substituted in only one or two positions with a substituent R*! selected from the substituent list as defined herein, e.g. with a halogen. :
The compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, i.e. a mixture of stereoisomeres, are included within the scope of the invention.
The compounds of the general formula I exist as optical isomers thereof and such optical isomers are also embraced by the invention. In particular, the compounds of the invention possessing the absolute stereochemistry (1S,2R) are within the invention, either as enantiomers or as mixtures containing compounds of the invention possessing the absolute stereochemistry (1S,2R).
Accordingly, an important aspect of the invention is a compound or salt of the invention as described herein, wherein the compound of formula I is the (1S,2R)-isomer i.e. the compound with absolute configuration as shown in formula IA.
R2
RY R' 5 n-Q
R y 0 87 \
R SY a)
The compound of the invention of formula I or the salt thereof may be part of a racemic mixtures comprising the (1S,2R)-isomer, i.e. the compound shown in formula IA or it may be present as the enantiomer, i.e. without the 3 others stereoisomers.
The invention in further embodiment relates to a compound of formula I which compound is the (1R,2R)-isomer.
The invention in further embodiment relates to a compound of formula I which compound is the (1R,2S)-isomer.
The invention in further embodiment relates to a compound of formula I which compound is the (18,2S)-isomer.
In this context is understood that when specifying the enantiomeric form, then the compound is in a preferred embodiment in enantiomeric excess.
Accordingly, one embodiment of the invention relates to a compound of the invention having an enantiomeric excess of at least 60% (60% enantiomeric excess means that the ratio of Va to its enantiomer is 80:20 in the mixture in question), at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.
The expression "mixture of stereoisomeres comprising the (1S,2R)-isomer of formula 1" implies that in further embodiments, the compound of the invention, i.e. product, may be any one of the following mixture of stereoisomeres: a (1S,2R)-isomer and a (1R,2R)-isomer of formula 1; a (15,2R)-isomer and a (1R,2S)-isomer of formula 1; a (1S,2R)-isomer and a (1S,2R)-isomer of formula 1; a (1S,2R)-isomer and a (1S,2S)-isomer of formula 1; a (1S,2R)-isomer and a (1R,2R)-isomer of formula 1, i.e. consisting of 2, 3 or 4 of the corresponding stereoisomers.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization. The compounds of the present invention may also be resolved by the formation of diastereomeric 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 Resolutions”, John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.
Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted

Claims (1)

1. A compound of formula I R? R? R' R* n-Q R \ 0
8. \ R R 5 m or a salt thereof, such as a pharmaceutically acceptable salt; wherein - R!-R® are independently selected from hydrogen, halogen, cyano, nitro, C;.s- alk(en/yn)yl, Cs.gs-cycloalk(en)yl, Cs.gcycloalk(en)yl-C, ¢-alk(en/yn)yl, amino, C,5- alk(en/yn)ylamino, di-(C,-alk(en/yn)yl)amino, C,-alk(en/yn)ylcarbonyl, aminocarbonyl, Ci_¢-alk(en/yn)ylaminocarbonyl, di-(C-alk(en)yl)aminocarbonyl, hydroxy, Ci¢-alk(en/yn)yloxy, C,—s-alk(en/yn)ylthio, halo-C, s-alk(en/yn)yl, halo-C;. s-alk(en/yn)ylsulfonyl, halo-C,¢-alk(en/yn)ylsulfanyl, and C;.¢-alk(en/yn)ylsulfonyl; - R® is selected from hydrogen, halo-C,.¢-alk(en/yn)yl, C;.s-alk(en/yn)yl, C;_g- cycloalk(en)yl, and Cs g-cycloalk(en)yl-C; ¢-alk(en/yn)yl ; - R'is an aryl or a heteroaryl; or R is a group aryl-CR®R’-, wherein R® and R® are independently selected from hydrogen, C;-alk(en/yn)yl, Csg-cycloalk(en)yl, and Cs. g-cycloalk(en)yl-C ¢-alk(en/yn)yl; - nis 0,1, or2; Qs selected from (i)-(vii), the arrow indicating the attachment point: 12 ~—N R' - /\ on - R ()- ANA R N 13 R 0) : (ii) : (ii)
3 o — ? -—N ) \ (iv) oe} v) ay RY XY 0 va -—N R® 2 = ON R* R®
: (vi) RY vi) R® R® wherein R'%is an aryl;
wherein R!! is selected from an aryl or benzyl, halo-C, ¢-alk(en/yn)ylsulfonyl, C;.¢-
alk(en/yn)ylsulfonyl, arylsulphonyl, arylacyl, C,.¢-alk(en/yn)ylcarbonyl, aminocarbonyl, C,.¢-alk(en/yn)ylaminocarbonyl, and di-(C;¢- alk(en)yl)aminocarbonyi;
wherein R'? is an aryl; wherein R"? is hydrogen, hydroxy, cyano, or amino, or one of the following groups: -NHC,) ¢-alk(en/yn)y}; -N(Ci¢-alk(en/yn)yl); -NR'COR'?, wherein R' is hydrogen or C;-alk(en/yn)yl and R" is C.¢- : alk(en/yn)yl or Cs.s-cycloalk(en)yl; : -NR'SCOCONR''R'®, wherein R'® is hydrogen or Cy s-alk(en/yn)yl and R'” and R'® are selected independently from hydrogen, C,¢-alk(en/yn)yl and C;.3- cycloalkyl; or R'7 and R'® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl are optionally substituted with a C;¢-alk(en/yn)yl, -NR'"’CONR¥R*, wherein R" is hydrogen or C;¢-alk(en/yn)yl and R? and R*! are selected independently from hydrogen and C;¢-alk(en/yn)yl or Cs_s-cycloalkyl; or R?® and R?! together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholiny! is optionally substituted with a C,_s-alk(en/yn)yl;
-NR*S0,R?, wherein R* is hydrogen, C,¢-alk(en/yn)yl or C3.g-cycloalkyl and R* are amino, C,.¢-alk(en/yn)yl or Cs_g-cycloalkyl; -COR?, wherein R* is C, ¢-alk(en/yn)yl or Cs.g-cycloalkyl; -CONR*R%, wherein R** and R? independently are selected from hydrogen, C.s- alk(en/yn)yl and Cj g-cycloalkyl; or R? and R? together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl is optionally substituted with a C;. s-alkyl; -NHCOOR®, wherein R* is C, ¢-alk(en/yn)yl or Cs g-cycloalk(en)yl; wherein X, Y, and Z are selected independently from a bond; O; NR*’; CR*®R? and S(O)m, whereinm is 0, 1 or 2; wherein R?’ is selected from hydrogen, C;.g-alk(en/yn)yl , Cs.g-cycloalkyl,
Cs.s-cycloalkyl-C, s-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl; or + R¥isagroup R*¥S0,-, R¥OCO- or R**SCO-, wherein R* is Cy ¢-alk(en/yn)yl,
Cs.g-cycloalkyl, or C;¢-cycloalkyl-C; ¢-alkyl; or R? is a group R¥R*NCO- or R*R*>NCS-, wherein R*! and R*? are independently selected from hydrogen, C;s-alk(en/yn)yl, Cs.s-cycloalkyl, Cs.s3-cycloalkyl-C; ¢- alkyl and aryl; or wherein R*' and R* together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; wherein R?® and R? are independently selected from hydrogen, fluoro, Ci.¢- alk(en/yn)yl, Cs.g-cycloalkyl, and C;_g-cycloalkyl-C;.¢-alkyl; wherein R*-R* are independently selected from hydrogen, halogen, cyano, nitro, Ci. ¢-alk(en/yn)yl, Css-cycloalkyl, Cs.g-cycloalkyl-alkyl, amino, C;.s-alkylamino, di- (Ci¢-alkyl)amino, C,¢-alkylcarbonyl, aminocarbonyl, C,.¢-alkylaminocarbonyl, di-(C,s-alkyl)aminocarbonyl, C,s-alkoxy, C;¢-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C,.¢-alkylsulfonyl; wherein R*’-R*® are either both hydrogen or are fused together in an ethylene chain CH2-CH?- forming an aza-bicyclo[3.2.1]octane-yl; wherein R*-R*! are independently selected from the group consisting of hydrogen and halogen; provided that no more than one of X, Y and Z may be a bond, and provided that two adjacent groups X, Y or Z may not at the same time be selected from O and S.
2. The compound or salt of claim 1, wherein R'-R® are independently selected from hydrogen, halogen, cyano, C,s-alk(en/yn)yl, Cs g-cycloalk(en)yl, Cs.s-cycloalk(en)yl-C;.s- alk(en/yn)yl, C,¢-alk(en/yn)yloxy, C;-s-alk(en/yn)ylthio, and halo-C, s-alkyl, .e.g trifluoromethyl.
3. The compound or salt of claim 1, wherein R'-R’ is hydrogen.
4. The compound or salt of claim 1, wherein R!-R® are independently selected from hydrogen and halogen.
5. The compound or salt of claim 1, wherein R'-R? are independently selected from hydrogen and chloro. : 10 6. The compound or salt of claim 1, wherein R'-R’ are independently selected from hydrogen and fluoro.
7. The compound or salt of claim 5, wherein R? is chloro and R® is hydrogen.
8. The compound or salt of claim 5, wherein R? and R? are chloro.
9. The compound or salt of claim 6, wherein R? is fluoro and R? is hydrogen.
10. The compound or salt of claim 6, wherein R? and R? are fluoro.
11. The compound or salt of any of claims 7-10, wherein R!, R* and R® are hydrogen.
12. The compound or salt of any of claims 1-11, wherein R® is selected from hydrogen, Ci-s-alkyl, Cs ¢-cycloalkyl, and C;g-cycloalkyl-C,¢-alkyl. 13 The compound or salt of any of claims 1-11, wherein R® is selected from hydrogen and C,¢-alk(en/yn)yl.
14. The compound or salt of any of claims 1-11, wherein RS is hydrogen.
15. The compound or salt of of any of claims 1-11, wherein R® is a C; s-alkyl.
16. The compound or salt of claim 15, wherein R® is methyl.
17. The compound or salt of any of claims 1-16, wherein R’ is the group [aryl-CR*R’-].
18. The compound or salt of claim 17, wherein R® and R® are independently selected from hydrogen, C,.s-alkyl, C3g-cycloalkyl and Cs ¢-cycloalkyl-C, s-alkyl.
19. The compound or salt of claim 17, wherein R® and R’ are independently selected from hydrogen and C, ¢-alkyl.
20. The compound or salt of claim 17, wherein R® and R® are independently selected from hydrogen and methyl.
21. The compound or salt of claim 17, wherein R® and R® are hydrogen.
22. The compound or salt of claim 17, wherein R® is hydrogen and R’ is methyl.
23. The compound of any of claims 1-16, wherein R is an aryl or a heteroaryl.
24. The compound or salt of any of claims 17-23, wherein said aryl or heteroaryl is monocyclic or bicyclic.
25. The compound or salt of any of claims 17-24, wherein said aryl or heteroaryl is unsubstituted.
26. The compound or salt of any of claims 17-24, wherein said aryl or heteroaryl is substituted with one or more substituents.
27. The compound or salt of claim 26, wherein said aryl or heteroaryl is substituted with one or more substituents selected from halogen, cyano, nitro, C,¢-alkyl, C,¢-alkenyl, C,- alkynyl, C;.3-cycloalkyl, C;¢-cycloalkyl-C.¢-alkyl, amino, C;¢-alkylamino, di-(C,.¢- alkyl)amino, C;s-alkylcarbonyl, aminocarbonyl, C;.¢-alkylaminocarbonyl, di-(C;.¢- alkyl)aminocarbonyl, Cis-alkylcarbonylamino, C,¢-alkylcarbonyl C,.¢-alkylamino, C,s-alkoxy, C;¢-alkylthio, hydroxy, trifluoromethyl , difluoromethyl, fluoromethyl and trifluoromethyisulfonyl.
28. The compound or salt of any of claims 24-27, wherein R’ is the group aryl-CR®R’- as defined in any of claims 17-22, and the aryl of said group aryl-CR®R’- is as defined in any of claims 24-27.
29. The compound or salt of claim 28, wherein said aryl is an optionally substituted phenyl.
30. The compound or salt of claim 28 or 29, wherein said aryl is mono- or poly- substituted, e.g. di-substituted, with a halogen, e.g. fluoro or chloro.
31. The compound of claim 17, wherein R’ is the group aryl-CR®R’- and R’ is selected from benzyl, or halogen substitued benzyl, e.g. 4-halo benzyl, such as 4-flucrobenzyl, or 2- halo-benzyl, such as 2-chloro-benzyl.
32. The compound or salt of any of claims 1-31, wherein Q is (i).
33. The compound or salt of claim 32, wherein RI! is an aryl as defined in any of claims 24-30.
34. The compound or salt of any of claims 1-31, wherein Q is (ii).
35. The compound or salt of claim 34, wherein R'! is selected from an optionally substituted aryl or optionally substituted benzyl, trifluoromethylsulfonyl, C,.s-alkylsulfonyl, arylsulphonyl, arylacyl, C,s-alkylcarbonyl, aminocarbonyl, C;_¢-alkylaminocarbony! and di- (Ci ¢-alkyl)aminocarbonyl).
36. The compound or salt of claim 34 or 35, wherein R'! is an aryl as defined in any of claims 24-30.
37. The compound or salt of claim 34, wherein R'! is an arylsulphonyl or an arylcarbonyl, wherein the aryl part of said arylsulphonyl or arylacyl is as defined in any of claims 24-30. 38 The compound or salt of any of claims 1-31, wherein Q is selected from (iii-vii).
39. The compound or salt of claim 38, wherein Q is (iii).
40. The compound or salt of claim 39, wherein R'? is an aryl as defined in any of claims 24-30.
41. The compound or salt of claim 39, wherein R'? is a phenyl.
42. The compound or salt of claim 39, wherein R'? is a phenyl substituted with one or more substituents.
43. The compound or salt of claim 40 or 42, wherein said aryl in R'? is substituted with one or more substituents selected from a halogen and trifluoromehtyl.
44. The compound or salt of claim 39, wherein R%is 4-chloro-3-trifluromethyl-phenyl.
45. The compound or salt of any of claims 39-44, wherein R"* is selected from hydroxy, -NR'“COR", -NR'*COCONR'R'®, -NR'’CONR?R?!, -NR®SO,R%, -COR?, and - CONR*R?.
46. The compound or salt of any of claims 39-44, wherein R'? is hydroxy.
47. The compound or salt of claim 46, wherein R'? is as defined in claim 44.
48. The compound or salt of any of claims 39-44, wherein R'? is -NR'*COR"®.
49. The compound or salt of claim 48, wherein R'* is hydrogen or Cy.-alkyl and R" is Cis-alkyl or Cs g-cycloalkyl.
50. The compound or salt of claim 48 or 49, wherein R'* is hydrogen or methyl.
51. The compound or salt of any of claims 48-50, wherein R'* is methyl.
52. The compound or salt of claim 48, wherein R'* is hydrogen and R'* is methyl; or R' and R'® is methyl.
53. The compound or salt of any of claims 39-44, wherein R'? is -NR'COCONR!’R®.
54. The compound or salt of claim 53, wherein R'® is hydrogen or C, ¢-alkyl and wherein R'7 and R'® are selected independently from hydrogen, C;.s-alkyl and Cs.g- cycloalkyl.
55. The compound or salt of claim 53, wherein R'® is hydrogen or C,4-alkyl and wherein R'” and R"® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholiny] are optionally substituted with a C;.s-alkyl.
56. The compound or salt of claim 53, wherein said R', R'” and R'® are hydrogen; R'® is C.¢-alky], and R” and R'® are hydrogen; R'S and R' are hydrogen and R'® is C, s-alkyl; R'S and R, are C,5-alkyl and Ryg is hydrogen; R'® is hydrogen and R'” and R'® are C,.¢- alkyl; or R'S, R'” and R'® are C, s-alkyl.
57. The compound or salt of any of claims 39-44, wherein R" is -NR'°CONR?R?'.
58. The compound or salt of claim 57, wherein R'’, R? and R*' are independently selected from hydrogen, C,s-alkyl and Cs g-cycloalkyl.
59. The compound or salt of claim 57, wherein R', R? and R? are independently selected from hydrogen and C;4-alkyl.
60. The compound or salt of claim 57, wherein R'® is a C; ¢-alkyl and R? and R?' are hydrogen; R'® and R are hydrogen and R*' is a C,¢-alkyl; R" and R?® are independently selected from a C;¢-alkyl and R* is H; R' is H, and R” and R*' are independently selected from a C,¢-alkyl; or R', R? and R?' are independently selected from a Cy salkyl. -
61. The compound or salt of claim 59, wherein R'?, R?® and R* are hydrogen.
62. The compound or salt of any of claims 57-60, wherein R'® is H.
63. The compound or salt of any of claims 57-60, wherein R?° and R?' are independently selected from the group consisting of hydrogen, Me, Et, Bu, and i-Pr.
64. The compound or salt of claim 63, wherein R'? is H.
65. The compound or salt of any of claims 39-44, wherein R'? is -NR*2SO,R%.
66. The compound or salt of claim 65, wherein R* ig hydrogen, a C,s-alkyl or Cs.3- cycloalkyl and R? is amino, C,.¢-alkyl or Cs.¢-cycloalkyl.
67. The compound or salt of claim 65 or 66, wherein RZ is hydrogen and R> is a C.4- alkyl or R? and R® are independently selected from a C;¢-alkyl.
68. The compound or salt of any of claims 65-66, wherein R* is hydrogen.
69. The compound or salt of any of claims 65-68, wherein R?* is methyl.
70. The compound or salt of any of claims 65-67, wherein R?? and R?* are methyl.
71. The compound or salt of any of claims 65-67, wherein R?? is hydrogen and R® is methyl.
72. The compound or salt of any of claims 39-44, wherein R'? is -COR*.
73. The compound or salt of claim 73, wherein R?* is a Cy.s-alkyl.
74. The compound or salt of claim 72, wherein R** is methyl.
75. The compound or salt of any of claims 39-44, wherein R'? is -CONR®R.
76 The compound or salt of claim 75, wherein R* and R are independently selected from hydrogen, C; ¢-alkyl and C;.g-cycloalkyl.
77. The compound or salt of claim 75, wherein R?* and R?® are independently selected from hydrogen and methyl.
78. The compound or salt of claim 75, wherein R?* and R?® together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholiny! are optionally substituted with a C; s-alkyl.
79. The compound or salt of claim 75, wherein R*® and R? together with the nitrogen to which they are attached form a piperidinyl, wherein said piperidinyl is optionally substituted with a C,¢-alkyl.
80. The compound or salt of any of claims 1-31, wherein Q is (vii).
81. The compound or salt of claim 80, wherein Y is a bond and X and Z are selected independently from O; NR?’; and CR*R? and S(O)m, provided that X and Z may not at the same time be selected from O and S. 1s 82. The compound or sait of claim 80, wherein Y is a bond and said X and Z are selected independently from CR**R” and NR?
83. The compound or salt of claim 80, wherein X is CR®R*, Y is a bond and Z is NR?"
84. The compound or salt of claim 83, wherein R?® and R* are hydrogen.
85. The compound or salt of claim 81, wherein X is CR*R”® and said R”® and R®® are hydrogen.
86. The compound or salt of any of claims 80, wherein X is CR’*R?, Y is a bond and Z is O. :
87. The compound or salt of claim 86, wherein R?® and R? are hydrogen.
88. The compound or salt of claim 80, wherein X is O, Y is a bond and Z is CR™*R”.
89. The compound or salt of claim 88, wherein R?® and R? are hydrogen.
90. The compound or salt of any of claims 80-89, wherein said R?’ is an acyl.
91. The compound or salt of claim 90, wherein said R* is a Cy-alkylearbonyl.
92. The compound or salt of claim 83, wherein Z is NR? and said R¥ is a C\.4- alkylcarbonyl.
93. The compound or salt of claim 92, wherein said R¥ is -COCHs.
94. The compound or salt of any of claims 83, wherein X is CR*®R?, said R?® and R? are hydrogen; Y is a bond; and Z is -NR¥, said R?’ is -COCH;.
95. The compound or salt of any of claims 80-89, wherein said R?’ is selected from the group R*S0,-, R*°0CO- and R*¥SCO-.
96. The compound or salt of any of claims 80-89, wherein R*’ is R**SO,.
97. The compound or salt of claim 96, wherein R* is C;¢-alkyl.
98. The compound or salt of claim 96, wherein R*’ is methyl.
99. The compound or salt of any of claims 96-98, wherein X is CR®R”, Y is a bond and ZisNR?.
100. The compound or salt of claim 99, wherein R* and R” are hydrogen.
101. The compound or salt of any of claims 80-89, wherein R*’ is the group R*'R*>NCO- or R®RNCS-.
102. The compound or salt of any of claims 80-102, wherein at Y is a bond.
103. The compound or salt of any of claims 80-102, wherein R*-R3¢ are independently selected from hydrogen and halogen. 103a. The compound or salt of any of claims 80-103, wherein R*’-R* are both hydrogen.
104. The compound or salt of of claim 1, wherein R'? is as defined in any of claims 3-11, and R® is as defined in claim 13.
105. The compound or salt of of claim 1, wherein R'” is as defined in any of claims 3-11, and R® is as defined in claim 15, e.g. R® is methyl.
106. The compound or salt of claim 1, wherein R® is as defined in claim 14 or 15, e.g. RS is methyl and R’ is as defined in claim 31.
107. The compound or salt of any of claims 102-106, wherein Q is (iii) and said R'? is as defined in claim 41.
108. The compound or salt of any of claims 1-107, wherein n=0.
109. The compound of or salt of any of the preceding claims, wherein the compound of formula I is the (15,2R)-isomer, i.e. said compound with absolute configuration as shown in formula IA.
R? rR R' ne N oO RS V7 aa)
110. The compound or salt of any of claims 1-108, wherein the compound of formula I is a racemic mixture comprising the (1S,2R)-isomer as defined in claim 109.
111. The compound or salt of any of claims 1-108, wherein the compound of formula I is a mixure of stereoisomeres of said compound, which mixture comprises the (1S,2R)-isomer as defined in claim 109.
112. The compound or salt of claim 1 selected from:
la. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)- cyclopropanecarboxylic acid benzyl-methyl-amide;
2a. (1S,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
3a. (18,2R)-2-[1-acetyl-spiro[2,3-dihydro- 1H-indol-3-yl-3,4'-piperidine-1'-yl-methyl]-1- (3,4-dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
4a. (18,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1 H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(3,4-dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
5a. (1S,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4"-piperidine-1'-yl-methyl]-1- (3,4-dichlorophenyl)-cyclopropanecarboxylic acid methyl-([S]-1-phenyl-ethyl) amide;
6a. (18,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(3,4-dichlorophenyl)-cyclopropanecarboxylic acid methyl<([S]-1-phenyl- ethyl) amide;
7a. (1S,2R)-1-Phenyl-2-[4-phenyl-4-(piperidine- 1-carbonyl)-piperidin- 1 -ylmethy]]- cyclopropanecarboxylic acid benzyl-methyl-amide;
8a. (18,2R)-2-[1-methanesulphonyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'- yl-methyl]-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide;
9a. (18,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ylmethyl)-1-phenyl- cyclopropanecarboxylic acid benzyl-methyl-amide;
10a. (1S,2R)-2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1- ylmethyl]-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide;
11a. (1S,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'"-piperidine-1'-yl- methyl]-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide;
12a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(4-chloro-phenyl)- cyclopropanecarboxylic acid benzyl-methyl-amide;
13a. (18,2R)-1-(4-Chloro-phenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin-1- ylmethyl]-cyclopropanecarboxylic acid benzyl-methyl-amide;
14a. (1S,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(4-chloro- phenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
15a. (1S,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ylmethyl)-1-(4-chioro-phenyl)- cyclopropanecarboxylic acid benzyl-methyl-amide;
16a. (1S,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(4-chlorophenyl)}-cyclopropanecarboxylic acid benzyl-methyl-amide;
17a. (1S,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4"-piperidine-1'-yl- methyl]-1-(4-chlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
18a. (18,2R)-2«(4-Acetylamino-4-phenyl-piperidin- 1-ylmethyl)-1-(3,4-difluoro- phenyl)-cyclopropanecarboxylic acid methyl-(1-phenyl-ethyl)-amide;
19a. (1S,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin- 1-ylmethyl]-1-(3,4- difluoro-phenyl)-cyclopropanecarboxylic acid methyl-([S]-1-phenyl-ethyl)-amide;
20a. (15,2R)-2-1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(3,4-difluorophenyl)-cyclopropanecarboxylic acid methyl<([S]-1-phenyl- ethyl) amide;
2la. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-phenyl- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
22a. (18,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-phenyl- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
23a. (18,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-phenyl-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
24a. (18,2R)-2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1- ylmethyl]-1-phenyl-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
25a. (18,2R)-2-[1-acetyl-S-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-phenyl-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
26a. (1S,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethy1]-1-(4-chloro- phenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
27a. (1S,2R)-2-[1-acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3,3'-(8'-aza- bicyclo[3.2.1]octane-8'-yl)]-1-(4-chlorophenyl)-cyclopropanecarboxylic acid (4- fluoro-benzyl)-methyl-amide;
28a. (1S,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ylmethyl)-1-(4~chloro-phenyl)- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
29a. (1S,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl)-1-(4-chlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl- amide;
30a. (1S,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(4-chlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl- amide;
31a. (1S,2R)-1-(4-Fluoro-phenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin-1- ylmethyl]-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
32a. (18,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'"-piperidine-1'-yl- methyl]-1-(4-fluorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl- amide;
33a. (15,2R)-1-(3,4-Difluoro-phenyl)-2-{4-phenyl-4-(piperidine-1-carbonyl)-piperidin- 1-ylmethyl]-cyclopropanecarboxylic acid -methyl-amide;
34a. (1S,2R)-2-[1-acetyl-5-fluoro-spirof2,3-dihydro-1H-indol-3,3'(8'-aza- bicyclo[3.2.1]octane-8'-y1)]-1-(3,4-difluorophenyl)-cyclopropanecarboxylic acid (4- fluoro-benzyl)-methyl-amide;
35a. (185,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(3,4-fluorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)- methyl-amide;
36a. (1S,2R)-1-(3,4-Dichlorophenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin- 1-ylmethyl}-cyclopropanecarboxylic acid benzyl-methyl-amide;
37a. (1S,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)- cyclopropanecarboxylic acid benzyl-methyl-amide;
38a. (1S,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4"-piperidine-1'-yl- methyl]-1-(4-fluorophenyl)-cyclopropanecarboxylic acid methyl-([S]-1-phenyl- cthyl) amide;
39a. (18S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid methyl-(1-phenyl-ethyl)-amide;
40a. (1S,2R)- 1-(3,4-Dichloro-phenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)- piperidin-1-ylmethyl]-cyclopropanecarboxylic acid methyl<([S]-1-phenyl-ethyl) amide;
4la. (1S,2R)-2-[4-(Acetyl-methyl-amino)4-phenyl-piperidin-1-ylmethyl]}-1-(3,4- . dichlorophenyl)-cyclopropanecarboxylic acid methyl-([S]-1-phenyl-ethyl)-amide;
42a. (18,2R)-1-Phenyl-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin-1-ylmethyl]- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
43a. (18,2R)-1-(4-Chloro-phenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin-1- ylmethyl]-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
44a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(4-chloro-phenyl)- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
45a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1<(4-chloro-phenyl)- cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
46a. (1S,2R)-1-+(4-Chloro-phenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin-1- ylmethyl}-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
47a. (1S,2R)-2-[4Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(4-chloro- phenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
48a. (1S,2R)-2-[1-acetyl-5-fluorospiro[2,3-dihydro-1H-indol-3-yl-3,4"-piperidine-1'-y1- : methyl)-1-(4-chlorophenyl)-cyclopropanecarboxylic acid (2-chlorobenzyl)-methyl- amide;
49a. (1S,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(4-fluoro- phenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
50a. (18S,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(3,4- difluoro-phenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
5la. (15,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
52a. (18,2R)-1<3,4-Dichlorophenyl)-2-[4-phenyl-4-(piperidine- 1-carbonyl)-piperidin- 1-ylmethyl]-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
53a. (18,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
54a. (1S,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl}-1-(3,4-dichlorophenyl)-cyclopropanecarboxylic acid (2-chlorobenzyl)- methyl-amide;
55a. (1S,2R)-1<3,4-Dichlorophenyl)-2-(4-phenyl-piperidin-1-ylmethyl)- cyclopropanecarboxylic acid benzyl-methyl-amide;
56a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (1-methyl-1-phenyl-ethyl)-amide.
57a. (1S,2R)- 2<(4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)- cyclopropanecarboxylic acid benzyl-ethyl-amide
58a. (18,2R)- 2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide <([R]-1-phenyl- ethyl) amide
59a. (1R,2S)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
60a. (1R,2R)- 2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide; and
61a. (1S,2S)- 2-(4-Acetylamino-4-phenyl-piperidin-1-yimethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
62a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid methyl-([R]1-phenyl-ethyl)-amide;
63a. (18,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin-1-ylmethyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid methyl-([R]-1-phenyl-ethyl)-amide;
64a. (18S,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(3,4-dichlorophenyl)-cyclopropanecarboxylic acid methyl-([R]-1-phenyl- ethyl) amide;
65a. (15,2R)-2-[1-acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3-y1-3,4'- piperidine-1'-yl-methy1]-1-(3,4-dichlorophenyl)-cyclopropanecarboxylic acid methyl-([R]-1-phenyl-ethyl) amide;
66a. (15,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-phenyl- cyclopropanecarboxylic acid benzyl-methyl-amide;
67a. (18,2R)-1~(3,4-Dichlorophenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)- piperidin-1-ylmethyl]-cyclopropanecarboxylic acid methyl-([S]-1-phenyl-ethyl)- amide;
68a. (18,2R)-2-[1-acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3-yl-3,4'- piperidine-1'-yl-methyl]-1-(3,4-dichlorophenyl)-cyclopropanecarboxylic acid methyl-([S]-1-phenyl-ethyl) amide;
69a. (18,2R)-1-Phenyl-2-[4-phenyl-4-(piperidine-1-carbonyl)-piperidin-1- ylmethyl]-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
70a. (1S,2R)-2-(4-Acetyl-4-phenyl-piperidin- 1-ylmethyl)-1-phenyl- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
71a. (18,2R)-2-[1-methanesulphonyl-spiro[2,3-dihydro- 1 H-indol-3-y1-3,4'- piperidine-1'-yl-methyl}-1-(4-fluophenyl)-cyclopropanecarboxylic acid (4-fluoro- benzyl)-methyl-amide;
72a. (18,2R)-2-[4-(Acetyl-methyl-amino)-4-phenyl-piperidin- 1-ytmethyl]-1-(4- fluorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
73a. (18,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ytmethyl)-1-(4-fluorophenyl)- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
74a. (18,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4"-piperidine-1'-yl- : methyl]-1-(4-flurophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl- amide;
75a. (18,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ylmethy1)-1-(3,4-difluorophenyl)- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
76a. (1S,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl}-1-(3,4-diflurophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)- methyl-amide;
77a. (18,2R)-1-(4-Fluoro-phenyl)-2-{4-phenyl-4-(piperidine- 1-carbonyl)- piperidin-1-ylmethyl]-cyclopropanecarboxylic acid methyl-([S]1-phenyl-ethyl)- amide;
78a. (18,2R)-2-(4-Acetyl-4-phenyl-piperidin-1-ylmethyl)-1-(4-chlorophenyl)- cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
79a. (18,2R)-2-[1-acetyl-spiro[2,3-dihydro-1H-indol-3-yl-3,4'-piperidine-1'-yl- methyl]-1-(4-chlorophenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl- amide;
80a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethy])-1-(4- fluorophenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
8la. (1S,2R)-1-(4-Fluoro-phenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)- piperidin-1-ylmethyl}-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
82a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- difluorophenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
83a. (1S,2R)-1-(3,4-Difluorophenyl)-2-[4-phenyl-4-(piperidine-1-carbonyl)- piperidin- 1-ylmethyl]-cyclopropanecarboxylic acid (2-chloro-benzyl)-methyl-amide;
84a. (1S,2R)-2-[ 1-acetyl-spiro[2,3-dihydro-1 H-indol-3-yl-3,4"-piperidine-1'-yl- methyl]-1-(3,4-diflurophenyl)-cyclopropanecarboxylic acid (2-chloro-benzyl)- methyl-amide;
85a. (1S,2R)-2-[1-acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3-y1-3,4'- piperidine-1'-yl-methyl}- 1-(3,4-diflurophenyl)-cyclopropanecarboxylic acid (2- chloro-benzyl)-methyl-amide;
86a. (18,2R)-1-(3,4-Dichlorophenyl)-2-(4-phenyl-piperidin-1-ylmethyl)- cyclopropanecarboxylic acid 3,4-dichloro-benzylamide;
87a. (18,2R)-1-(3,4-Dichlorophenyl)-2-(4-phenyl-piperidin-1-ylmethyl)- cyclopropanecarboxylic acid 3,4-dimethoxy-benzylamide;
88a. (1S,2R)-2-(4-Acetylamino4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid phenylamide;
89a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (1-methyl-1-phenyl-ethyl)-amide;
90a. (1S,2R)-1-Phenyl-2-[4-(3-trifluoromethylphenyl)-piperazin-1-ylmethyl]- cyclopropanecarboxylic acid benzyl-methyl-amide;
91a. (1S,2R)-2-(4-Benzyl-piperazin-1-ylmethyl)-1-(4-chlorophenyl)- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
92a. (1S,2R)-1-(4-chlorophenyl)-2-[4-(3-triflucromethylphenyl)-piperazin-1- ylmethyl]-cyclopropanecarboxylic acid 4-flucrobenzyl-methyl-amide;
93a. (1S,2R)-2-(4-Benzyl-piperazin-1-ylmethyl)-1-(4-chlorophenyl)- cyclopropanecarboxylic acid benzyl-methyl-amide;
9a. (1S,2R)-2-(4-Benzyl-piperazin-1-ylmethyl)-1-phenyl- cyclopropanecarboxylic acid benzyl-methyl-amide;
95a. (18,2R)-1-(4-chlorophenyl)-2-[4-(3-trifluoromethylphenyl)-piperazin-1- ylmethyl]-cyclopropanecarboxylic acid benzyl-methyl-amide;
96a. (1S,2R)-1-phenyl-2-[4-(3-trifluoromethylphenyl)-piperazin-1-ylmethyl]- cyclopropanecarboxylic acid 4-fluorobenzyl-methyl-amide;
97a. (1S,2R)-2~(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichloro- : phenyl)-cyclopropanecarboxylic acid benzyl amide;
98a. (1S,2R)-2-[1-acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3-yl-3,4'- piperidine-1'-yl-methyl}-1-(3,4-diflurophenyl)-cyclopropanecarboxylic acid (2- fluoro-benzyl)-amide;
99a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid methyl-[1-(4-methoxyphenyl)-ethyl]- amide; 100a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4~dichloro- phenyl)-cyclopropanecarboxylic acid (2-chlorobenzyl) amide; 101a. (1S,2R)-2~(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichloro- phenyl)cyclopropanecarboxylic acid (3,4-dichlorobenzyl) amide; 102a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichloro- phenyl)-cyclopropanecarboxylic acid methyl-phenyl-amide; 103a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(4-methoxy- phenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 104a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-p-tolyl- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 105a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-m-tolyl- cyclopropanecarboxylic acid benzyl-methyl-amide; 106a. (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-m-tolyl- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 107a. (1S,2R)-2-(4- Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3-methoxy- phenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 108a. (18,2R)-2-(4- Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(4-methoxy- phenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide; 109a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin- 1-ylmethyl)-1-p-tolyl- cyclopropanecarboxylic acid benzyl-methyl-amide; 110a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3-methoxy- phenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide;
lila (1S,2R)-1-Phenyl-2-(4-phenyl-4-ureido-piperidin- 1-ylmethyl)- cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 112a. (18,2R)-1-(3,4-Dichlorophenyl)-2-(4-phenyl-4-ureido-piperidin-1-ylmethyl)- cyclopropanecarboxylic acid -benzyl-methyl-amide; 113a. (1S,2R)-1-Phenyl-2-[4-(3-methyl-ureido)-4-phenyl-piperidin-1-ylmethyl]- cyclopropanecarboxylic acid (4-fluorobenzyl)-methyl-amide; 114a. (1S,2R)-2-[4«3-Methyl-ureido)-4-phenyl-piperidin- 1-ylmethyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid benzyl-methyl-amide; 115a, (1S,2R)-N-(1-{2-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-phenyl- cyclopropylmethyl}-4-phenyl-piperidin-4-yl)-oxalamide; 116a. (1S,2R)-N-(1-{2-[benzyl-methyl-carbamoyl]-2-(3,4-dichlorophenyl)- cyclopropylmethyl}-4-phenyl-piperidin-4-yl)-oxalamide; 117a. (1S,2R)-1-Phenyl-2-(4-methanesulfonylamino-4-phenyl-piperidin-1- yimethyl)-cyclopropanecarboxylic acid -(4-fluorobenzyl)-methyi-amide; 118a. (1S,2R)-2-(4-Methanesulfonylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid -benzyl-methyl-amide; 119a. (1S,2R)-{1-[2«((4-fluoro-benzyl)-methyl-carbamoyl)-2-phenyl- cyclopropylmethyl]-4-phenyl-piperidin-4-yl} -carbamic acid methyl ester 120a. (1S,2R)~(1- {2-benzyl-methyl-carbamoyl]-2-(3,4-dichlorophenyl)- cyclopropylmethyl}-4-phenyl-piperidin-4-yl)-carbamic acid methyl ester 121a. (1S,2R)-1-(3,4-Dichloro-phenyl)-2-[4-(3,3-dimethyl-ureido)-4-phenyl- piperidin-1-ylmethyl]-cyclopropanecarboxylic acid benzyl-methyl-amide; 122a. (1S,2R)-1-phenyl-2-[4~(3,3-dimethyl-ureido)-4-phenyl-piperidin-1- ylmethylj-cyclopropanecarboxylic acid (4-fluorobenzyl)-methyl-amide; 123a. (1S,2R)-2-[2-(4-Acetylamino-4-phenyl-piperidin-1-yl)-ethyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 124a. (1S,2R)-2-[3-(4-Acetylamino-4-phenyl-piperidin-1-yl)-propyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 125a. (1S,2R)-2-[4-(2-Acetylamino-5-fluorophenyl)-piperidin-1-ylmethyl]-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 126a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dimethylphenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide;
127a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4- dichlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 128a. (18,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3- chlorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 129a. (18,2R)-2+(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3- fluorophenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide; 130a. (18, 2R)-1-(3,4-Dichlorophenyl)-2-(4-phenyl-piperidin-1-ylmethyl)- cyclopropanecarboxylic acid methyl-naphthalen-1-ylmethyl-amide; 131a. (18, 2R)-1-(3,4-Dichloropheny1)-2-{ 1-acetyl-5-fluoro-spiro[2,3-dihydro-1H- indol-3-yl-3,4"-piperidine-1'-yl-methyl]-cyclopropanecarboxylic acid methyl- naphthalen-1-ylmethyl-amide; 132a. (18, 2R)-1-(3,4-Dichlorophenyl)-2-(4-Acetylamino-4-phenyl-piperidin-1- ylmethyl)-cyclopropanecarboxylic acid methyl-naphthalen-1-ylmethyl-amide; or a salt thereof.
113. A pharmaceutical composition comprising a compound as defined in any of claims 1-112. : 114. Use of a compound as defined in any of claims 1-112 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases selected from the group consisting of: psychotic disorders, schizophrenia, depression, anxiety, Parkinson’s disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, gut inflammation, inflammatory bowel disease, hypertension, imbalances in water and electrolyte homeostasis, ischemia, oedema, plasma extravasation and obesity.
115. Use of a compound as defined in any of claims 1-112 or a salt thereof for the preparation of a medicament for treatment of schizophrenia.
116. Use according to claim 115 for treatment of the positive symptoms of schizophrenia.
117. Use of a compound as defined in any of claims 1-112 or a salt thereof for the manufacture of a pharmaceutical preparation for treatment of a disorder in the central nervous system.
118. A method for the treatment of diseases selected from the group consisting of: psychotic disorders , schizophrenia, depression, anxiety, Parkinson’s disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, gut inflammation, inflammatory bowel disease, hypertension,
imbalances in water and electrolyte homeostasis, ischemia, oedema, plasma extravasation and obesity, comprising administering a therapeutically effective amount of a compound as defined in any of claims 1-112 or a pharmaceutically acceptable salt thereof.
119. The method of the preceding claim, wherein the disease is schizophrenia.
120. A method for treatment of a disorder in the central nervous system comprising administering a therapeutically effective amount of a compound as defined in any of claims 1-112 or a salt thereof.
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