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    公开号:AU2007256012A1
    申请号:U2007256012
    申请日:2007-06-08
    公开日:2007-12-13
    发明作者:Yun-Xing Cheng；Mehrnaz Pourashraf；Miroslaw Tomaszewski
    申请人:AstraZeneca AB；
    IPC主号:C07D401-14
    专利说明:
    WO 2007/142583 PCT/SE2007/000554 NOVEL COMPOUNDS 23 BACKGROUND OF THE INVENTION 5 1. Field of the invention The present invention relates to agonists of muscarinic receptors. The present invention also provides compositions comprising such agonists, and methods therewith for treating muscarinic receptor mediated diseases. Particularly, the present invention is related to compounds that may be effective in treating pain, Alzheimer's disease, and/or 10 schizophrenia. 2. Discussion of Relevant Technology The neurotransmitter acetylcholine binds to two types of cholinergic receptors: the ionotropic family of nicotinic receptors and the metabotropic family of muscarinic 15 receptors. Muscarinic receptors belong to the large superfamily of plasma membrane bound G protein coupled receptors (GPCRs) and show a remarkably high degree of homology across species and receptor subtype. These MI-M5 muscarinic receptors are predominantly expressed within the parasympathetic nervous system which exerts excitatory and inhibitory control over the central and peripheral tissues and participate in 20 a number of physiologic functions, including heart rate, arousal, cognition, sensory processing, and motor control. Muscarinic agonists such as muscarine and pilocarpine, and antagonists, such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds, thereby making it difficult to assign 25 specific functions to the individual receptors. See, e.g., DeLapp, N. et al., "Therapeutic Opportunities for Muscarinic Receptors in the Central Nervous System," J. Med. Chem., 43(23), pp. 4333-4353 (2000); Hulme, E. C. et al., "Muscarinic Receptor Subtypes," Ann. Rev. Pharmacol. Toxicol., 30, pp. 633-673 (1990); Caulfield, M. P. et al., "Muscarinic Receptors-Characterization, Coupling, and Function," Pharmacol. Ther., 58, pp. 319-379 30 (1993); Caulfield, M. P. et al, International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors," Pharmacol. Rev., 50, pp. 279-290 (1998). The Muscarinic family of receptors is the target of a large number of pharmacological agents used for various diseases, including leading drugs for COPD, asthma, urinary incontinence, glaucoma, schizophrenia, Alzheimer's (AchE inhibitors), 35 and Pain. For example, direct acting muscarinic receptor agonists have been shown to be antinociceptive in a variety of animal models of acute pain (Bartolini A., Ghelardini C., Fantetti L., Malcangio M., Malmberg-Aiello P., Giotti A. Role of muscarinic receptor WO 2007/142583 PCT/SE2007/000554 subtypes in central antinociception. Br. J. Pharmacol. 105:77-82, 1992.; Capone F., Aloisi A. M., Carli G., Sacerdote P., Pavone F. Oxotremorine-induced modifications of the behavioral and neuroendocrine responses to formalin pain in male rats. Brain Res. 830:292-300, 1999.). 5 A few studies have examined the role of muscarinic receptor activation in chronic or neuropathic pain states. In these studies, the direct and indirect elevation of cholinergic tone was shown to ameliorate tactile allodynia after intrathecal administration in a spinal ligation model of neuropathic pain in rats and these effects again were reversed by muscarinic antagonists (Hwang J.-H., Hwang K.-S., Leem J.-K., Park P.-H., 10 Han S.-M., Lee D.-M. The antiallodynic effects of intrathecal cholinesterase inhibitors in a rat model of neuropathic pain. Anesthesiology 90:492-494, 1999; Lee E. J., Sim J. Y, Park J. Y., Hwang J. H., Park P. H., Han S. M. Intrathecal carbachol and clonidine produce a synergistic antiallodynic effect in rats with a nerve ligation injury. Can J Anaesth 49:178-84, 2002. ). Thus, direct or indirect activation of muscarinic receptors 15 has been shown to elicit both acute analgesic activity and to ameliorate neuropathic pain. Muscarinic agonists and ACHE-Is are not widely used clinically owing to their propensity to induced a plethora of adverse events when administered to humans. The undesirable side-effects include excessive salivation and sweating, enhanced gastrointestinal motility, and bradycardia among other adverse events. These side-effects are associated with the 20 ubiquitous expression of the muscarinic family of receptors throughout the body. DESCRIPTION OF THE EMBODIMENTS To date, five subtypes of muscarinic receptors (MI-M5) have been cloned and sequenced from a variety of species, with differential distributions in the body. 25 Therefore, it was desirable to provide molecules would permit selective modulation, for example, of muscarinic receptors controlling central nervous function without also activating muscarinic receptors controlling cardiac, gastrointestinal or glandular functions. There is also a need for methods for treating muscarinic receptor-mediated 30 diseases. There is also a need for modulators of muscarinic receptors that are selective as to subtypes M1-M5. The term "Cm.." or "Cm-n group" refers to any group having m to n carbon atoms. The term "alkyl" refers to a saturated monovalent straight or branched chain 35 hydrocarbon radical comprising 1 to about 12 carbon atoms. Illustrative examples of alkyls include, but are not limited to, C 16 alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1.butyl, 3-methyl-1-butyl, 2 methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1 -2- WO 2007/142583 PCT/SE2007/000554 pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3 dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl, and octyl. An alkyl can be unsubstituted or substituted with one or two suitable substituents. 5 The term "alkenyl" refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms. The double bond of an alkenyl can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to C 2
    -
    6 alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, 10 pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene) pentenyl. An alkenyl can be unsubstituted or substituted with one or two suitable substituents. The term "cycloalkyl" refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. Examples of 15 cycloalkyls include, but are not limited to, C 3 4 7 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl can be unsubstituted or substituted by one or two suitable substituents. Preferably, the cycloalkyl is a monocyclic ring or bicyclic ring. The term "cycloalkenyl" refers to a monovalent ring-containing hydrocarbon 20 radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms. - The term "aryl" refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms. 25 The term "heterocycle" refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, 0, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than 30 one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character. The term "heteroaromatic" refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, 0, P and S, as a 35 part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons). -3- WO 2007/142583 PCT/SE2007/000554 The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or "heterocyclo" refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom. The term "heterocycly" refers a monovalent radical derived from a heterocycle by 5 removing one hydrogen therefrom. The term "heterocyclylene" refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together. The term "heteroaryl" refers to a heterocyclyl having aromatic character. The term "heterocylcoalkyl" refers to a monocyclic or polycyclic ring comprising 10 carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two 15 suitable substituents. Preferably, the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form I to 3 heteroatoms, referred to herein as C 3 -6heterocycloalkyl. The term "heteroarylene" refers to a heterocyclylene having aromatic character. The term "heterocycloalkylene" refers to a heterocyclylene that does not have 20 aromatic character. The term "six-membered" refers to a group having a ring that contains six ring atoms. The term "five-membered" refers to a group having a ring that contains five ring atoms. 25 A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, 0 and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3 thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 30 triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl. A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, 0 and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. 35 Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, -4- WO 2007/142583 PCT/SE2007/000554 morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4 dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro 1H-azepine homopiperazine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide. 5 In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3 oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4 thiadiazole, and 1,3,4- oxadiazole. 10 Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, 15 quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. In addition to the polycyclic heterocycles described above, heterocycle includes 20 polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane. Heterocycly includes, for example, monocyclic heterocyclyls, such as: aziridinyl, 25 oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7 30 tetrahydro-1 H-azepinyl, homopiperazinyl, 1,3-dioxepanyi, 4,7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl. In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl; isoxazolyl, 1,2,3-triazoly, tetrazolyl, 35 1,2,3-thiadiazoyl, 1,2,3-oxadiazolyi, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl. Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, -5- WO 2007/142583 PCT/SE2007/000554 tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 5 pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl. In addition to the-polycyclic heterocyclyls described above, heterocyclyl includes 10 polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl. The term "alkoxy" refers to radicals of the general formula -O-R, wherein R is 15 selected from a hydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. Halogen includes fluorine, chlorine, bromine and iodine. "RT" or "rt" means room temperature. 20 In one aspect, an embodiment of the invention provides a compound of Formula 1, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: (R') Y G
    G
    1 N
    (CH
    2 ) / CH 2 )n 2 m .---N R 0 25 wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; G', G 2 and G 3 are independently selected from hydrogen, halogen, C1.
    6 alkyl, C1. 6 alkoxy, hydroxy-C..
    6 alkyl, -CH 2 -OR, halogenated C1.
    6 alkyl, -CONR 2 ; or any two of G', G 2 -6- WO 2007/142583 PCT/SE2007/000554 and G 3 are linked together to form a C1_alkylene bridge and the other one of G', G 2 and
    G
    3 is as defined above; R' is independently selected from hydrogen, halogen, Cealkyl, C 2
    -
    6 alkenyl, -CN, -C(=O)-OR, -C(=O)-NR 2 , hydroxy, and C1.
    6 alkoxy; 5 R 2 is selected from hydrogen, C 6 alkyl, C 2 p-alkenyl, C1.
    6 alkoxy, CI 6 alkylamino, di
    C,
    6 alkylamino, C 6 .1oaryl, C 6 -.oaryloxy, C2- 9 heteroaryl, C 2 -gheteroaryloxy, C3. 5 heterocycloalkyloxy, C- 5 heterocycloalkyl, C 6 .qoaryl-CO 3 alkoxy, C 6 .1 0 aryl-CO 3 alkyl,
    C
    2
    -
    9 heteroaryl-C, 3 alkoxy, C 2
    -
    9 heteroaryl-Csalkyl, C3- 5 heterocycloalkyl-C..
    3 alkoxy, C3. 5 heterocycloalkyl-C, 3 alkyl, C3- 6 cycloalkyl, C 3
    -
    6 cycloalkyloxy, and C 3
    -
    6 cycloalkyl-C, 3 alkyl, 10 C3- 6 cycloalkyl-COI 3 alkoxy, wherein said C1.
    6 alkyl, C2- 6 alkenyl, C..
    6 alkyl-carbonyl, Cealkylaminocarbonyl, C6-1oaryl, C 2 -eheteroaryl, C 3
    -
    5 heterocycloalkyl, C 6 ,.oaryl-Csalkyl,
    C
    2
    -
    9 heteroaryl-CO 3 alky, C3- 5 heterocycloalkyl-CO 3 alkyl, C3- 6 cycloalkyl, and C 3 -ecycloalkyl
    C
    3 alkyl are optionally substituted with one or more group selected from -CN, -SR, -OR, O(CH 2 )p-OR, R, -C(=O)-R, -CO 2 R, -SO 2 R, -SO 2
    NR
    2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , 15 and -C(=O)-NR 2 ; p is 1, 2, 3 or4; m is 0, 1, or2; n is 1, or2; X, Y and Z are independently selected from C(=O), NH, N-R, N, C, CH 2 , and CH, wherein at least one of X, Y and Z is selected from NH, N-R and N; wherein at most one 20 of X, Y and Z is C(=O); and wherein Z is not C(=O); and each R is independently hydrogen, C1.ralkyl, C2- 6 alkenyl or halogenated C1-ealkyl. In another embodiment, A' and A 2 are independently selected from -CH 2 - and N(R)-, wherein each R is independently hydrogen or C1- 6 alkyl. In another embodiment, one of A' and A 2 is -CH 2 -; and the other one of A' and A 2 25 is -N(R)-. In a further embodiment, A' and A 2 are -CH 2 -. In another embodiment, G', G 2 and G 3 are independently selected from hydrogen, halogen, C1.
    6 alkyl, C1- 6 alkoxy, hydroxy-C 6 alkyl, -CH 2 -OR, halogenated C 6 alkyl, -CONR 2 ; wherein each R is independently hydrogen or C- 6 alkyl. 30 Particularly, G', G2 and G3 are independently selected from hydrogen, fluoro, C. 6 alkyl, C1.
    6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C- 3 alkyl. In a further embodiment, any two of G, G 2 and G 3 are linked together to form a Clalkylene bridge and the other one of G', G 2 and- G 3 is selected from hydrogen, 35 halogen, C 6 alkyl, CI- 6 alkoxy, hydroxy-Ci.alkyl, -CH 2 -OR, halogenated C 6 alkyl, C(=O)NR 2 ; wherein each R is independently hydrogen or C,.
    6 alkyl.. -7- WO 2007/142583 PCT/SE2007/000554 Particularly, G' and G 3 are linked together to form a C2 4 alkylene bridge; and G 2 is selected from hydrogen, fluoro, C 1
    .
    6 alkyl, C 1
    .
    6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C1-salkyl. In another embodiment, G 1 and G 2 are linked together to form a C1-salkylene 5 bridge; and G 3 is selected from hydrogen, fluoro, C 1
    .
    6 alkyl, C 1
    .
    6 alkoxy, hydroxy-methyl, CH 2 -OR, trifluoromethyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C1. 3 alkyl. in a further particular embodiment, R 2 is selected from hydrogen, C 1
    .
    6 alkyl, C3. 6 cycloalkyl, C 3
    -
    6 cycloalkoxy, C3- 6 cycloalkyl-C 1 -alkoxy, C 2
    -
    5 heterocycloalkyl, C 1
    .
    6 alkoxy, 10 C1.
    6 alkylamino, di-C 1 .ealkylamino and benzyloxy, wherein said C 1
    .
    6 alkyl, C 3
    -
    6 cycloalkyl,
    C
    3
    -
    6 cycloalkoxy, C3- 6 cycloalkyl-C 1
    -
    3 alkoxy, C2- 5 heterocycloalkyl, C 1
    .
    6 alkoxy,
    C
    1
    .
    6 alkylamino, di-C 1
    .
    6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, hydroxy, C 1
    .
    6 alkoxy and -CN. In an even further embodiment, R 2 is selected from hydrogen, C1.
    4 alkyl, C 14 alkoxy, C1 4 alkylamino, di 15 C 14 alkylamino, C3- 6 cycloalkyl, pyrrolidinyl, piperdinyl, azetidinyl and benzyloxy. In yet another embodiment, R 2 is selected from methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, benzyl, phenyl, thiophenyl, methoxy, ethoxy, benzyloxy, t-butoxy, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, methylamino, and ethylamino. In another embodiment, R 1 is selected from hydrogen, halogen, methyl, ethyl, 20 -CN, -C(=O)-NH 2 , -C02CH 3 , -C0 2 H, hydroxy and methoxy. In a further embodiment, R 1 is hydrogen. In another embodiment, p is 1. In another embodiment, m, n is 1. In a further embodiment, m is 1 and n is 2. 25 In another embodiment, Z is selected from N, C and CH. In a further embodiment, Y is selected from N and C(=O). In an even further embodiment, X is selected from NH and N-R, wherein R is hydrogen or 01- 3 alkyl. In another embodiment, the invention provides a compound of formula ll, a 30 pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: -8- WO 2007/142583 PCT/SE2007/000554 H R4 N 2 N 2 G 3 1i N 2CH2n (CH2)m -N R 0 Wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; 5 G', G2 and G3 are independently selected from hydrogen, halogen, C1.
    6 alkyl, C 6 alkoxy, hydroxy-C 1
    .
    6 alkyl, -CH 2 -OR, halogenated C 1
    -
    6 alkyl, -C(=O)NR 2 ; or any two of G, G2 and G3 are linked together to form a C 1
    .
    4 alkylene bridge and the other one of G', G2 and G3 is as defined above; R' is independently selected from hydrogen, halogen, C 1
    .
    6 alkyl, C2.
    6 alkenyl, -CN, 10 -C(=O)-OR, -C(=O)-NR 2 , hydroxy, and C 1
    .
    6 alkoxy;
    R
    2 is selected from hydrogen, C 6 alkyl, C 2 -ealkenyl, C 6 alkoxy, Cl-alkylamino, di Cealkylamino, Ce1oaryl, C.
    1 oaryloxy, C 29 heteroaryl, 2- 9 heteroaryloxy, C3. 5 heterocycloalkyloxy, C3 5 heterocycoalkyl, C 6
    .
    1 oaryl-C 1 -alkoxy, C 61 oaryl-CO 3 alkyl,
    C
    2
    -
    9 heteroaryl-C 1
    -
    3 alkoxy, C2-heteroaryl-CO 3 alkyl, C3.
    5 heterocycloalkyl-C 1 3 alkoxy, C3 15 5 heterocycloalkyl--C 1 3 alkyl, C3- 6 cycloalkyl, C 3
    ..
    6 cycloalkyloxy, and C 3
    .
    6 cycloalkyl-COsalkyl,
    C
    3
    -
    6 cycloalkyl-CO 3 alkoxy, wherein said C 1
    .
    6 alkyl, C2- 6 alkenyl, C 16 alkyl-carbonyl,
    C.
    6 alkylaminocarbonyl, Ce- 1 oaryl, C2- 9 heteroaryl, C3-heterocycloalkyl, C 6
    .
    1 oaryl-C 1
    ..
    3 alkyl,
    C
    2 -gheteroaryl-C- 3 alkyl, C3- 5 heterocycloalkyl-CO 3 alkyl, C3.
    6 cycloalkyl, and C3- 6 cycloalkyl
    C
    13 alkyl are optionally substituted with one or more group selected from -CN, -SR, -OR, 20 O(CH 2 )p-OR, R, -C(=O)-R, -CO 2 R, -SO 2 R, -SO 2
    NR
    2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; mis 0, 1, or2; n is 1, 2; and each R is independently hydrogen, C 1 alkyl, C2- 6 alkenyl or halogenated C 16 alkyl. In another embodiment, A' and A 2 are independently selected from -CH 2 - and 25 N(R)-, wherein each R is independently hydrogen or C 1
    .
    6 alkyl. In another embodiment, one of A' and A 2 is -CH 2 -; and the other one of A' and A 2 is -N(R)-. In a further embodiment, A and A 2 are -CH 2 -. -9- WO 2007/142583 PCT/SE2007/000554 In another embodiment, G', G 2 and G 3 are independently selected from hydrogen, halogen, C 1
    .
    6 alkyl, C 1
    .
    6 alkoxy, hydroxy-C 1
    .
    6 alkyl, -CH 2 -OR, halogenated C 1 . 6 alkyl, -CONR 2 ; wherein each R is independently hydrogen or C 1
    .
    6 alkyl. Particularly, G', G 2 and G 3 are independently selected from hydrogen, fluoro, C1. 5 6 alkyl, C 1
    .
    6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C 1 .3alkyl. In a further embodiment, any two of G', G 2 and G 3 are linked together to form a
    C
    1
    .
    4 alkylene bridge and the other one of G', G 2 and G 3 is selected from hydrogen, halogen, C 1
    .
    6 alkyl, C1.
    6 alkoxy, hydroxy-C1.ealkyl, -CH 2 -OR, halogenated C1.
    6 alkyl, 10 C(=O)NR 2 ; wherein each R is independently hydrogen or C1.
    6 alkyl. Particularly, G' and G 3 are linked together to form a C 24 alkylene bridge; and G2 is selected from hydrogen, fluoro, C1.
    6 alkyl, C1.
    6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, -CONR 2 ; wherein each R is independently hydrogen or C 1 -salkyl. In another embodiment, G and G 2 are linked together to form -a C1- 3 alkylene bridge; and 15 G 3 is selected from hydrogen, fluoro, C1.
    6 alkyl, C1.
    6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C1.
    3 alkyl. In a further particular embodiment, R 2 of formula II is selected from hydrogen, C1. 6 alkyl, C 3
    -
    6 cyclOalkyl, C3- 6 cycloalkoxy, C3- 6 cycloalkyl-C 1
    -
    3 alkoxy, C 2
    -
    5 heterocycloalkyl, C 1 . 6 alkoxy, C 1
    -
    6 alkylamino, di-C1- 6 alkylamino and benzyloxy, wherein said C 1
    .
    6 alkyl, C3. 20 ecycloalkyl, C 3
    -
    6 cycloalkoxy, C 3
    -
    6 cycloalkyl-C1- 3 alkoxy, C2- 5 heterocycloalkyl, C 1
    .
    6 alkoxy,
    C
    1 .ealkylamino, di-C, 6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, hydroxy, C1.
    6 alkoxy and -CN. In an even further embodiment, R 2 of formula 11 is selected from hydrogen, C1. 4 alkyl, C1 4 alkoxy, C 14 alkylamino, di-C1 4 alkylamino, C 3
    -
    6 cycloalkyl, pyrrolidinyl, piperdinyl, 25 azetidinyl and benzyloxy. In yet another embodiment, R 2 of formula II is selected from methyl, ethyl, n propyl, isopropyl, 2-methyl-1-propyl, benzyl, phenyl, thiophenyl, methoxy, ethoxy, benzyloxy, t-butoxy, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, methylamino, and ethylamino. 30 In another embodiment, R' of formula II is selected from hydrogen, halogen, methyl, ethyl, -CN, -C(=0)-NH 2 , -CO 2
    CH
    3 , -CO 2 H, hydroxy and methoxy. In an even further embodiment, R1 is hydrogen. In another embodiment, m, n is 1. In a further embodiment, m is 1 and n is 2. 35 In another embodiment, the present invention provides a compound of formula IA, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: -10- WO 2007/142583 PCT/SE2007/000554 x N fCH2)n2 N R 2 0 IA wherein
    R
    2 is selected from hydrogen, C 1
    .
    6 alkyl, C2- 6 alkenyl, C 1 -alkoxy, C 1 .ealkylamino, di 5 C 1 alkylamino, C 6
    .
    1 0 aryl, C-1oaryloxy, C2-gheteroaryl, C 2 .eheteroaryloxy, C3.. 5 heterocycloalkyloxy, C3.sheterocycloalkyl, C 61 oaryl-C 1
    -
    3 alkoxy, CO 61 oaryl-C 1
    .
    3 alkyl, C2-gheteroaryl-C 1 -alkoxy, C 2
    -
    9 heteroaryl-CI.3alkyl, C 3
    .
    5 heterocycloalkyl-C 1
    -
    3 alkoxy, C3 5 heterocycloalkyl-C 1
    -
    3 alkyl, C3- 6 cycloalkyl, C3- 6 cycloalkyloxy, and C3- 6 cycloalkyl-C 1
    -
    3 alkyl, C3- 6 cycloalkyl-C 1
    .
    3 alkoxy, wherein said C 1
    -
    6 alkyl, C2- 6 alkenyl, C 1
    -
    6 alkyl-carbonyl, 10 C 1 -ealkylaminocarbonyl, C..1oaryl, C2-eheteroaryl, C3-sheterocycloalkyl, C- 1 oaryl-C 1
    .
    3 alkyl, C2-eheteroaryl-C 1
    -
    3 alkyl, C3- 5 heterocycloalkyl-C 1
    .
    3 alkyl, C 3
    -
    6 cycloalkyl, and C3- 6 cycloalkyl C1- 3 alkyl are optionally substituted with one or more group selected from phenyl, C3 6 cycloalkyl, C2- 5 heterocycloalkyl, C 2
    -
    5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=O) R, -CO 2 R, -SO 2 R, -SO 2
    NR
    2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; 15 pis1,2,3or4;nis1,2; X, is independently selected from NH, N-R, CH 2 CHR, and CRR'; and each R, R' is independently hydrogen, CO 16 alkyl, C2-6alkenyl or halogenated
    C
    1
    -
    6 alkyl. In a particular embodiment, R 2 of formula IA is selected from hydrogen, C 1
    .
    6 alkyl, 20 C 3 .ecycloalkyl, C- 6 cycloalkoxy, C3.
    6 cycloalkyl-C 1
    -
    3 alkoxy, C2- 5 heterocycloalkyl, C2 5 heterocycloalkyl-C 1
    -
    3 alkyl, phenyl, benzyl, C2- 9 heteroaryl, C 1
    .
    6 alkoxy, C 1
    .
    6 alkylamino, di C1.
    6 alkylamino and benzyloxy, wherein said C 1
    .
    6 alkyl, C3- 6 cycloalkyl, C3- 6 cycloalkoxy, C3 6 cycloalkyl-C 1
    .
    3 alkoxy, C2.
    5 heterocycloalkyl, C2- 5 heterocycloalkyl-C 1
    -
    3 alkyl, phenyl, benzyl, C2-gheteroaryl, C 1 o-alkoxy, C1.
    6 alkylamino, di-C 1
    .
    6 alkylamino and benzyloxy, are optionally 25 substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl,
    C
    3
    -
    6 cycloalkyl, C1.
    6 alkyl, hydroxy, C1.6alkoxy and -CN. - 11 - WO 2007/142583 PCT/SE2007/000554 In another particular embodiment, R 2 of formula IA is selected from hydrogen, C 1 . 6 alkyl, C 14 alkoxy, C 14 alkylamino, di-C 14 alkylamino, C 3
    .
    6 cycIoalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 -salkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy, wherein said C 1
    .
    6 alkyl, C 1 4 alkoxy, C 14 alkylamino, di 5 C 1 4alkylamino, C 3
    -
    6 cycloalkyl, pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-CI 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 .rcycloalkyl, C 1
    .
    6 alkyl, hydroxy, C 16 alkoxy and -CN. In a further embodiment, R 2 of formula IA is selected from methyl, ethyl, n-propyl, 10 isopropyl, n-butyl, isobutyl, tertbutyl, 4-heptyl, 2-methyl-1-propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, ethoxy, isopropoxy, propoxy, benzyloxy, t-butoxy, isopropenoxy, isobutoxy, C 3
    -
    6 cycloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups 15 selected from amino, halogen, phenyl, morpholinyl, CF 3 ,-C(=O) C 1
    .
    6 alkyl, C 3
    .
    6 cycloalkyl,
    C
    1 -alkyl, hydroxy, C1.
    6 alkoxy and -CN. In a further embodiment, n of formula IA is 1. In another embodiment, n of formula IA is 2. In another embodiment, X of formula IA is selected from NH and N-R, wherein R 20 is hydrogen, C 2
    -
    3 alkenyl or C 13 alkyl. In an even further embodiment, the present invention provides a compound of formula IIA, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: H N N N CH2)n N R 2 25 IIA wherein
    R
    2 is selected from hydrogen, C 1
    .
    6 alkyl, C 2
    .
    6 alkenyl, C 16 alkoxy, C 1
    .
    6 alkylamino, di
    C
    1 .ealkylamino, Cs.1oaryl, C 6
    .
    1 oaryloxy, C 2
    -
    9 heteroaryl, C 2
    -
    9 heteroaryloxy, C3 -12- WO 2007/142583 PCT/SE2007/000554 5 heterocycloalkyloxy, Cs.
    5 heterocycloalkyl, C6.1oaryl-C1-3alkoxy, C 6
    -
    1 oaryl-C 1
    -
    3 alkyl,
    C
    2 -gheteroaryl-C 1 -alkoxy, C 2
    -
    9 heteroary-C 1 -salkyl, C3-5heterocycloalkyl-C 1
    .
    3 alkoxy, C3 5 heterocycloalkyl-C 1
    .
    3 alkyl, C3- 6 cycloalkyl, C3- 6 cycloalkyloxy, and C 3 -ecycloalkyl-C 1
    -
    3 alkyl, Cs.
    6 cycloalkyl-C 1 -salkoxy, wherein said C 1
    .
    6 alkyl, C2- 6 alkenyl, C 1
    .
    6 alkyl-carbonyl, 5 C 1
    .
    6 alkylaminocarbonyl, C6o1aryl, C 2
    -
    9 heteroaryl, C 35 heterocycloalkyl, C 6 .1 0 aryl-C 1
    -
    3 alkyl,
    C
    2
    -
    9 heteroaryl-C 1
    -
    3 alkyl, C3- 5 heterocycloalkyl-C 1 -salkyl, C 3
    .
    6 cycloalkyl, and C 3 -ecycloalkyl
    C
    1
    .
    3 alkyl are optionally substituted with one or more group selected from phenyl, C3. 6 cycloalkyl, C2- 5 heterocycloalkyl, C 2
    -
    5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=O) R, -CO 2 R, -SO 2 R, -SO 2
    NR
    2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; 10 p is 1, 2, 3 or 4; n is 1, 2; and each R is independently hydrogen, C1.
    6 alkyl, C 2
    -
    6 alkenyl or halogenated
    C
    1 .ealkyl. In a particular embodiment, R 2 of formula IIA is selected from hydrogen, C 1
    -
    6 alkyl, 15 C 3 -ecycloalkyl, C 3
    .
    6 cycloalkoxy, C3.
    6 cycloalkyl-C 1 -alkoxy, C 2
    -
    5 heterocycloalkyl, C2 5 heterocycloalkyl-C 1
    ..
    3 alkyl, phenyl, benzyl, C 2 -9heteroaryl, C 1
    -
    6 alkoxy, C 1
    .
    6 alkylamino, di
    C
    1
    .
    6 alkylamino and benzyloxy, wherein said C 1 -alkyl, C 3
    -
    6 cycloalkyl, C 3
    -
    6 cycloalkoxy, C3. 6 cycloalkyl-C 1
    .
    3 alkoxy, C 2
    -
    5 heterocycloalkyl, C 2
    .
    5 heterocycloalkyl-C 1 ..alkyl, phenyl, benzyl,
    C
    2 -9heteroaryl, C 1
    .
    6 alkoxy, C 1
    .
    6 alkylamino, di-C 1
    .
    6 alkylamino and benzyloxy are optionally 20 substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C3.ecycloalkyl, C 1 .alkyl, hydroxy, C 1 .ealkoxy and -CN. In a particular embodiment, R 2 of formula IIA is selected from hydrogen, C 1
    -
    6 alkyl,
    C
    1 4alkoxy, C 14 alkylamino, di-C14alkylamino, C3- 6 cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1
    -
    3 alky, phenyl, benzyl, 25 piperdinyl, azetidinyl and benzyloxy, wherein said C 1
    .
    6 alkyl, C14alkoxy, C1 4 alkylamino, di
    C
    14 alkylamino, C3- 6 cycloalkyl, pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1
    .
    3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3
    -
    6 cycloalkyl, C 1 -alkyl, hydroxy, C 1 .ealkoxy and -CN. 30 In a particular embodiment, R 2 of formula IIA is selected from methyl, ethyl, n propyl, isopropyl, n-butyl, isobutyl, tertbutyl, 4-heptyl, 2-methyl-1-propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, ethoxy, isopropoxy, propoxy, benzyloxy, t-butoxy, isopropenoxy, isobutoxy, C3 6 cycloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, 35 azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, CF 3 ,-C(=O) C 1
    .
    6 alkyl, C3 6 cycloalkyl, C 1
    .
    6 alkyl, hydroxy, C 1
    .
    6 alkoxy and -CN. In another particular embodiment, n of formula IIA is 1. - 13 - WO 2007/142583 PCT/SE2007/000554 In a further particular embodiment, n of formula llA is 2. In a further embodiment, the present invention provides a compound of formula X, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture 5 thereof: 0 N N N R 2 NY Xwherein
    R
    2 is selected from hydrogen, C1- 6 alkyl, C 2
    -
    6 alkenyl, C1- 6 alkoxy, C 1
    .
    6 alkylamino, di 10 C 1
    .
    6 alkylamino, C 6
    -
    1 0 aryl, C 6
    .
    1 oaryloxy, C 2
    -
    9 heteroaryl, C 2
    -
    9 heteroaryloxy, C. 5 heterocycloalkyloxy, C 3
    .
    5 heterocycloalkyl, C- 1 oaryl-C 1
    -
    3 alkoxy, C- 1 oaryl-C 1
    .
    3 alkyl,
    C
    2 -gheteroaryl-C 3 alkoxy, C 2
    -
    9 heteroaryl-C 1 3 alkyl, C3- 5 heterocycloalkyl-C 3 alkoxy, C3. sheterocycloalkyl-CIaalkyl, C 3
    -
    6 cycloalkyl, C 3
    -
    6 cycloalkyloxy, and C 3
    .
    6 cycloalkyl-C 1 aalkyl,
    C
    3 -ecycloalkyl-C 1 aalkoxy, wherein said CI- 6 alkyl, C 2
    -
    6 alkenyl, C 16 alkyl-carbonyl, 15 C 1 ealkylaminocarbonyl, C 6
    .
    1 oaryl, C 2
    .
    9 heteroaryl, C 3
    -
    5 heterocycloalkyl, C0 610 aryl-C 1 3 alkyl,
    C
    2
    -
    9 heteroary-C 3 alkyl, C 3
    -
    5 heterocycloalkyl-C 1 aalkyl, C 36 Bcycloalkyl, and C 3
    .
    6 cycloalkyl
    C
    13 alkyl are optionally substituted with one or more group selected from phenyl, C3 6 cycloalkyl, C 2
    -
    5 heterocycloalkyl, C 2
    -
    5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=O) R, -CO 2 R, -SO 2 R, -SO 2
    NR
    2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; 20 pis1,2,3or4;nis1,2; and each R, is independently hydrogen, C 1
    _
    6 alkyl, C 2
    -
    6 alkenyl or halogenated
    C
    1
    .
    6 alkyl. In a further particular embodiment, R 2 of formula X is selected from hydrogen, C 25 6 alkyl, C 3
    -
    6 cycloalkyl, C 3
    -
    6 cycloalkoxy, C 3
    .
    6 cycloalkyl-C 1 salkoxy, C 2
    -
    5 heterocycloalky, C2. 5 heterocycloalkyl-Caalkyl, phenyl, benzyl, C 2 -gheteroaryl, C 1
    .
    6 alkoxy, C 1
    .
    6 alkylamino, di
    C
    1
    .
    6 alkylamino and benzyloxy, wherein said C 1
    .
    6 alkyl, C 3
    -
    6 cycloalkyl, C 3
    -
    6 cycloalkoxy, C3 6 cycloalkyl-C.
    3 alkoxy, C2-heterocycloalkyl, Cz- 5 heterocycloalkyl-Csalkyl, phenyl, benzyl, -14- WO 2007/142583 PCT/SE2007/000554
    C
    2 -9heteroaryl, C 1
    .
    6 alkoxy, C1.
    6 alkylamino, di-C 1
    .
    6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl,
    C
    3
    -
    6 cycloalkyl, C 1
    .
    6 alkyl, hydroxy, C1.6alkoxy and -CN. In a further particular embodiment, R 2 of formula X is selected from hydrogen, C1. 5 6 alkyl, C14alkoxy, C 14 alkylamino, di-C 14 alkylamino, C 3
    -
    6 cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 -alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy, wherein said C 1
    .
    6 alkyl, C 1 4 alkoxy, C 14 alkylamino, di
    C
    1 4alkylamino, C3.
    6 cycloalkyl, pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrroidinyl-C 1
    .
    3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are 10 optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3
    -
    6 cycloalkyl, C 1
    .
    6 alkyl, hydroxy, C 1
    .
    6 alkoxy and -CN. In a further particular embodiment, R 2 of formula X is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, 4-heptyl, 2-methyl-1 -propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, 15 ethoxy, isopropoxy, propoxy, benzyloxy, t-butoxy, isopropenoxy, isobutoxy, C3 6 cycloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, CF 3 ,-C(=O) C 1
    .
    6 alkyl, C3. 6 cycloalkyl, C 16 alkyl, hydroxy, C 1
    .
    6 alkoxy and -CN. 20 In another embodiment, n of formula X is 1. In another embodiment, n of formula X is 2. It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, 25 enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I or 11. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the 30 procedures described thereafter. It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I or 11. It will further be understood that the present invention encompasses tautomers of the compounds of 35 the Formula I or II. It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be -15- WO 2007/142583 PCT/SE2007/000554 understood that the present invention encompasses all such solvated forms of the compounds of the Formula I or 11. Within the scope of the invention are also salts of the compounds of the Formula I or Il. Generally, pharmaceutically acceptable salts of compounds of the present 5 invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCL or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the 10 present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. In one embodiment, the compound of Formula I or 11 above may be-converted to 15 a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate. We have now found that the compounds of the invention have activity as pharmaceuticals, in particular as agonists of M1 receptors. More particularly, the 20 compounds of the invention exhibit selective activity as agonist of the M1 receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which 25 dysfunction of M1 receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, schizophrenia, Alzheimer's disease, anxiety disorders, depression, obesity, gastrointestinal disorders and cardiovascular disorders. In a particular embodiment, the compounds may be used to treat schizophrenia 30 or Alzheimer's disease. In another embodiment, the compounds may be used to treat pain. In another particular embodiment, the compounds may be used to treat neuropathic pain. Compounds of the invention are useful as immunomodulators, especially for 35 autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents. -16- WO 2007/142583 PCT/SE2007/000554 Compounds of the invention are useful in disease states where degeneration or dysfunction of M1 receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). ..5 Compounds of the invention are useful for the treatment of diarrhea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders; panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal 10 disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinsons disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following myocardial infarction, obesity, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension. 15 Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers 20 and opioids. Also within the scope of the invention is the use of any of the compounds according to the Formula I or Il above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject 25 suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I or 11 above, is administered to a patient in need of such treatment. Thus, the invention provides a compound of Formula I or |1 or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. 30 In a further aspect, the present invention provides the use of a compound of Formula I or 11 or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" 35 and "therapeutically" should be contrued accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic -17- WO 2007/142583 PCT/SE2007/000554 therapies for prevention of recurring conditions and continued therapy for chronic disorders. The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, 5 neuropathic pain, back pain, cancer pain, and visceral pain. In a particular embodiment, the compounds are useful in therapy for neuropathic pain. In an even more particular embodiment, the compounds are useful in therapy for chronic neuropathic pain. In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical 10 composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, transdermally, intracerebroventricularly and by injection into the joints. In one embodiment of the invention, the route of administration may be oral, intravenous or intramuscular. 15 The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient. For preparing pharmaceutical compositions from the compounds of this invention, 20 inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table 25 disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. 30 For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, 35 sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like. The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the -18- WO 2007/142583 PCT/SE2007/000554 active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. 5 Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the .10 active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. 15 Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w.(per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition. A therapeutically effective amount for the practice of the present invention may be 20 determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art. Within the scope of the invention is the use of any compound of Formula I or 11 as defined above for the manufacture of a medicament. 25 Also within the scope of the invention is the use of any compound of Formula I or II for the manufacture of a medicament for the therapy of pain. Additionally provided is the use of any compound according to Formula I or 11 for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and 30 visceral pain. A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I or II above, is administered to a patient in need of such therapy. 35 Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I or 1I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. - 19- WO 2007/142583 PCT/SE2007/000554 Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I or IlI or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain. 5 Further, there is provided a pharmaceutical composition comprising a compound of Formula I or HI or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above. In a further embodiment, a compound of the present invention, or a pharmaceutical composition or formulation comprising a compound of the present 10 invention may be administered concurrently, simultaneously, sequentially or separately with one or more pharmaceutically active compound(s) selected from the following: (i) antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, 15 fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (ii) atypical antipsychotics including for example quetiapine and 20 pharmaceutically active isomer(s) and metabolite(s) thereof; amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, lithium, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, 25 prochlorperazine, risperidone, quetiapine, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents thereof; (iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, 30 divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, vaiproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active 35 isomer(s) and metabolite(s) thereof; -20 - WO 2007/142583 PCT/SE2007/000554 (iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, 5 fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (v) anticonvulsants including, for example, carbamazepine, valproate, 10 lamotrogine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (vi) Alzheimer's therapies including, for example, donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; 15 (vii) Parkinson's therapies including, for example, deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; 20 (viii) migraine therapies including, forexample, almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; 25 (ix) stroke therapies including, for example, abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (x) over active bladder urinary incontinence therapies including, for example, darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine 30 and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (xi) neuropathic pain therapies including, for example, gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (xii) nociceptive pain therapies such as celecoxib,.etoricoxib, lumiracoxib, 35 rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; -21- WO 2007/142583 PCT/SE2007/000554 (xiii) insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, choral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, 5 pentobarbital, phenobarbital, propofol, roletamide, triclofos,secobarbital, zaleplon, zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; and (xiv) mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, 10 verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. Such combinations employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the 15 publication reference. In an even further embodiment, a compound of the present invention, or a pharmaceutical composition or formulation comprising a compound of the present invention may be administered concurrently, simultaneously, sequentially or separately with one or more pharmaceutically active compound(s) selected from 20 buprenorphine; dezocine; diacetylmorphine; fentanyl; levomethadyl acetate; meptazinol; morphine; oxycodone; oxymorphone; remifentanil; sufentanil; and tramadol. In a particular embodiment, it may be particularly effective to administrate a combination containing a compound of the invention and a second active compound 25 selected from buprenorphine; dezocine; diacetylmorphine; fentanyl; levomethadyl acetate; meptazinol; morphine; oxycodone; oxymorphone; remifentanil; sufentanil; and tramadof to treat chronic nociceptive pain. The efficacy of this therapy may be demonstrated using a rat FCA-induced heat hyperalgesia model described below. In a further aspect, the present invention provides a method of preparing the 30 compounds of the present invention. In one embodiment, the invention provides a process for preparing a compound of Formula 1, comprising: - 22 - WO 2007/142583 PCT/SE2007/000554 S A 2 (R4) Y G
    G
    3 1 N
    (CH
    2 )m 2 ...--N R O reacting a compound of Formula IlIl with a compound of formula IV, x (R') 2Y 2(OH)
    CH
    2 )n 3 2 m.-N R2 G H 0 5 1i IV wherein A', A 2 , G', G 2 , G3, R', R 2 , m, n, p, X, Y and Z are defined as above. Optionally, the step of reacting a compound of formula III with a compound of formula IV is carried out in the presence of a reducing agent, such as NaBH(OAc) 3 , NaBH 4 or equivalents thereof. 10 In another embodiment, the invention provides a process for preparing a compound of Formula I, comprising: (R') 'Y 2 2
    G
    3 1 N
    'CH
    2 )m CH2)n --N R2 -23- WO 2007/142583 PCT/SE2007/000554 reacting a compound of Formula V with a compound of Q-C(=O)-R 2 , x Ai/ (R') P/Y CCZG2
    G
    3 N
    CH
    2 fCH 2 )n m.-NH V wherein A', A 2 , G', G 2 , G', R', R 2 , m, n, p, X, Y and Z are defined as above; and 5 Q is a halogen or OH. Optionally, the step of reacting a compound of formula V with a compound of Q
    C(=O)-R
    2 , is carried out in the presence of a base, such as diisopropylethylamine, triethylamine or equivalents thereof. In a further embodiment, the present invention provides a process for preparing a 10 compound of Formula IA, comprising: x N N CH2)n N R2 NfY2 0 IA reacting a compound of Formula IlIlA with a compound of formula IV, ax N>O O QfCH2)n N R 2 N H O -24 - WO 2007/142583 PCT/SE2007/000554 lilA IV wherein R 2, n, X, and Q are as defined above. Optionally, the step of reacting a compound of formula IlIl with a compound of formula IV is carried out in the presence of a reducing agent, such as NaBH(OAc) 3 , 5 NaBH 4 or equivalents thereof. In another embodiment, the present invention provides a process for preparing a compound of Formula IA, comprising: x O N. CH2) N R 2 IA 10 reacting a compound of Formula V with a compound of Q-C(=O)-R 2 , x N N < CH2) NH VA wherein R 2 , n, X, and Q are as defined above. Optionally, the step of reacting a compound of formula V with a compound of Q 15 C(=O)-R 2 , is carried out in the presence of a base, such as diisopropylethylamine, triethylamine or equivalents thereof. In a further embodiment, the present invention provides an intermediate of formula VA, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: -25 - WO 2007/142583 PCT/SE2007/000554 x N>=zO N N CH2)n NH VA wherein n is 1, 2; 5 X, is independently selected from NH, N-R, CH 2 CHR, and CRR'; and each R, R' is independently hydrogen, C 1
    .
    6 alkyl, C2- 6 alkenyl or halogenated C 1
    .
    6 alkyl. Compounds of the present invention may also be prepared according to the synthetic routes as depicted in Schemes 1-7. 10 Scheme I (Intermediate I and 2) -26- WO 2007/142583 PCT/SE2007/000554 0 ~NH, OaNH2 HN H
    NH
    2 H CDI N HC NO O NaBH(OAc) 3 N J, N HH N H O NH2 Q NH2N
    NH
    2 CDI HO! N NaBH(OAc) 3 N N Scheme 2 (Examples 1-7, 14-18, 60,61): 0 H H C N e
    CH
    2 ]fl N N 0 R2 N [H] (N N
    [CH
    2 In cis or trans N o R 2 5 Scheme 3 (Examples 8-13, 19-59, 63-68, 75-86): -27- WO 2007/142583 PCT/SE2007/000554 H H H H N N N O )=O ) = a =O a )=O N H ICH 2 I. [CH 2 1,[C cis or trans N [CH 2
    ]
    1 n PG H PR2 0
    NH
    2 NH2 aNH
    NH
    2 N "PG" means "protecting group" N
    ,[CH
    2 1 n PG Scheme 4 (Example 62): (Boc) 2 0 10% Pd/C, H 2 OH MSCI OMs MsC K
    NH
    2 NHBoc NHBoc NHBoc NHBoc O 'J7N-CBz ~Ho NaN 3 N3 10% Pd/C, H 2
    ,NH
    2 NH TFA "NHBoc NHBoc NaBH(OAc) 3 N CBz H NH2 CDI =0 10% Pd/C, H 2 o NaCNBH3 )=0 b 0--CNN N~ NN CBz CBz H 5 Scheme 5 (Examples 69-74): -28- WO 2007/142583 PCT/SE2007/000554 O O base N 6N N PG' PG' cis or trans R - H R R N N N NN
    PG
    2 N N H R2
    PG
    1 and PG2 are protecting groups Scheme 6 (Example 87-89): OH MsCI -- 3NOMs KCN CN NABH 3 CN CN NHBoc Et 3 N, DCM NHBoc NH2 ZnC 2 NH DMSO ketone ON boo NaOH, Ethanol O R2 O HCI/dioxane o DIPEA COOH N A. N -- c-N NH [H] HATU, DMF N N N N H boo boo N R 2 O R2 = OtBu HCl/dioxane N 0 b H > R 0 5 -29- WO 2007/142583 PCT/SE2007/000554 Scheme 7 (Example 90, 91): 0 -- '__ N NN N 0 chiral separation b [H] N N HN O O 0 00 Biological Evaluation 5 Human M1, rat M1, human M3 and human M5 calcium mobilization FLIPRTM assay The compound activity in the present invention (EC50 or ICs 0 ) was measured using a 384 plate-based imaging assay that monitors drug induced intracellular Ca 2 release in whole cells. Activation of hM1 (human Muscarinic receptor subtype 1, 10 gene bank access NM_000738), rM1 (rat Muscarinic receptor subtype 1, gene bank access NM_080773), hM3 (human Muscarinic receptor subtype 3, gene bank access NM_000740NM_000740) and hM5 (human Muscarinic receptor subtype 5, gene bank access NM_0121258), receptors expressed in CHO cells (chinese hamster ovary cells, ATCC) was quantified in a Molecular Devices FLIPR 11 TM instrument as 15 an increase in fluorescent signal. Inhibition of hM3 and hM5 by compounds was determined by the decrease in fluorescent signal in response to 20 nM carbachol activation. CHO cells were plated in 384-black polylysine coated plate (Costar) at 8000 cells/well/50pl for 24 hours or 4000 cells/well for 48 hours in a humidified incubator 20 (5% CO 2 and 37*C) in DMEM/F12 medium without selection agent. Prior to the experiment the cell culture medium was removed from the plates by inversion. A loading solution of 30 pl of Hank's balanced salt solution, 10 mM Hepes and 2.5 mM Probenicid at Ph 7.4 (Cat no. 311-520-VL, Wisent) with 2pM calcium indicator dye (FLUO-3AM, Molecular Probes F14202) was added to each well. Plates were 25 incubated at 37*C for 60 minutes prior to start the experiment. The incubation was terminated by washing the cells four times in assay buffer, leaving a residual 25pl buffer per well. Cell plates were then transferred to the FLIPR, ready for compound additions. The day of experiment, carbachol and compounds were diluted in three-fold 30 concentration range (10 points serial dilution) for addition by FLIPR instrument. For all calcium assays, a baseline reading was taken for 30 seconds followed by the -30- WO 2007/142583 PCT/SE2007/000554 addition of 1 2 .5pl (25pl for hM1 and rM1) of compounds, resulting in a total well volume of 3 7.5pl ( 5 0pl for hM1 and rM1). Data were collected every 1.6 seconds for 300 seconds. For hM3 and hM5 an additional 1 2 .5pl of carbachol (20 nM final) was added at 300 seconds. After this addition of carbachol (producing a final volume of 5 50pl), the FLIPR continued to collect data every 2 seconds.for 240 seconds. The fluorescence emission was read using filter I (emission 520-545 nm) by the FLIPR on board CCD camera. Calcium mobilization output data were calculated as the maximal relative fluorescence unit (RFU) minus the minal value for both compound and agonist 10 reading frame (except for hM1 and rM1 using only the maximal RFU). Data were analyzed using sigmoidal fits of a non-linear curve-fitting program (XLfit version 5.0.6 from ID Business Solutions Limited, Guildford, UK). All EC50 and iC50 values are reported as arithmetic means Qstandard error of mean of 'n' independent experiments. Using the above-mentioned assays, the IC50 and EC50 towards 15 human hM1, ratMi, hM3 and hM5 receptors for most compounds is measured to be in the range 1->30000 nM. The Emax (maximal effect, agonism or antagonist . inhibition) towards human human hM1, ratM1, hM3 and hM5 receptors for most compounds is measured to be in the range of 0 -110 %. 20 hM2 receptor GTPVS binding Membranes produced from Chinese hamster ovary cells (CHO) expressing the cloned human M2 receptor (human Muscarinic receptor subtype 2, gene bank access NM_000739), were obtained from Perkin-Elmer (RBHM2M). The membranes were thawed at 37 0C, passed 3 times through a 23-gauge blunt-end needle, diluted 25 in the GTPyS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgC 2 , pH 7.4, 100 M DTT). The EC 5 o, IC5o and Ema of the compounds of the invention were evaluated from 10-point dose-response curves (three fold concentration range) done in 60pl in 384-well non-specific binding surface plate (Corning). Ten microliters from the dose-response curves plate (5X concentration) 30 were transfered to another 384 well plate containing the following: 1 Ogg of hM2 membranes, 500pg of Flashblue beads (Perkin-Elmer) and GDP in a 25pl volume. An additional 15l containing 3.3X (55000 dpm) of GTPf 35 S (0.4 nM final) were added to the wells resulting in a total well volume of 50pL. Basal and maximal stimulated [a 5 S]GTPTS binding were determined in absence and presence of 30 pM 35 of acetylcholine agonist. The membranes/beads mix were pre-incubated for 15 -31- WO 2007/142583 PCT/SE2007/000554 minutes at room temperature with 25 pM GDP prior to distribution in plates (12.5 pM final). The reversal of acetylcholine-induced stimulation (2siM final) of [ 35 S]GTPYS binding was used to assay the antagonist properties (IC 5 0 ) of the compounds. The plates were incubated for 60 minutes at room temperature with shaking, then 5 centrifuged at 2000rpm for 5 minutes. The radioactivity (cpm) were counted in a Trilux (Perkin-Elmer). Values of EC 50 , IC0 and Emax were obtained using sigmoidal fits of a non linear curve-fitting program (XLfit version 5.0.6 from ID Business Solutions Limited, Guildford, UK) of percent stimulated [ 5 S]GTPyS binding vs. log(molar ligand). 10 All EC50 and IC50 values are reported as arithmetic means ± standard error of mean of 'n' independent experiments. Based on the above assays, the EC 5 0 towards human M2 receptors for most compounds of the invention is measured to be in the range of about between 200 and >30000 nM. The Emax (maximal effect, 15 agonism or antagonist inhibition) towards human M2 receptors for most compounds of the invention were measured to be in the range of about 0-120 %. The IC5o was the concentration of the compound of the invention at which 50% inhibition of acetylcholine [ 5 S]GTPyS binding stimulation has been observed. The IC50 towards human M2 receptors for most compounds of the invention was measured to be in the 20 range of between 40 and >90000 nM. HM4 receptor GTPyS binding Membranes produced from Chinese hamster ovary cells (CHO) expressing the cloned human M4 receptor (human Muscarinic receptor subtype 4, gene bank 25 access NM_000741), were obtained from Perkin-Elmer (RBHM4M). The membranes were thawed at 37 0C, passed 3 times through a 23-gauge blunt-end needle, diluted in the GTPyS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgC 2 , pH 7.4, 100 gM DTT). The EC 50 , IC50 and Emax of the compounds of the invention were evaluated from 10-point dose-response curves (three fold 30 concentration range) done in 60I in 384-well non-specific binding surface plate (Corning). Ten microliters from the dose-response curves plate (5X concentration) were transfered to another 384 well plate containing the following: 104g of hM4 membranes, 500gg of Flashblue beads (Perkin-Elmer) and GDP in a 25[d volume. An additional 15WI containing 3.3X (55000 dpm) of GTP- 5 S (0.4 nM final) were 35 added to the wells resulting in a total well volume of 50pl. Basal and maximal - 32- WO 2007/142583 PCT/SE2007/000554 stimulated [ 35 S]GTPyS binding were determined in absence and presence of 30 pM of acetylcholine agonist. The membranes/beads mix were pre-incubated for 15 minutes at room temperature with 40 pM GDP prior to distribution in plates (20 pM final). The reversal of acetylcholine-induced stimulation (10l.IM final) of [ 35 S]GTPyS 5 binding was used to assay the antagonist properties (IC 50 ) of the compounds. The plates were incubated for 60 minutes at room temperature with shaking, then centrifuged at 2000rpm for 5 minutes. The radioactivity (cpm) were counted in a Trilux (Perkin-Elmer). Values of EC 50 , IC50 and Emax were obtained using sigmoidal fits of a non 10 linear curve-fitting program (XLfit version 5.0.6 from ID Business Solutions Limited, Guildford, UK) of percent stimulated [ 3 S]GTPyS binding vs. log(molar ligand). All EC50 and IC50 values are reported as arithmetic means ± standard error of mean of 'n' independent experiments. Based on the above assays, the EC 50 towards human M4 receptors for most compounds of the invention is measured to be 15 in the range of between 300 and >30000 nM. The Emax (maximal effect, agonism or antagonist inhibition) towards human M4 receptors for most compounds of the invention were measured to be in the range of about 0-120 %. The IC 50 was the concentration of the compound of the invention at which 50% inhibition of acetylcholine [ 3 5 S]GTPyS binding stimulation has been observed. The IC50 towards 20 human M4 receptors for most compounds of the invention was measured to be in the range of between 3000 and >30000 nM. .Certain biological properties of certain compounds of the invention measured using one or more assays described above are listed in Table I below. Table I Certain Biological Properties of the Certain Compounds of the Invention. 25 hMI EC50 hM2 EC50 hM3 EC50 hM4 EC50 hM5 EC50 Compound Structure (nM) (M) (M) (n) (n) H N H 0 a = relative mixture 1000_ -33- WO 2007/142583 PCT1SE2007/000554 0. 12N5 3 2 QN =o K) Chiral N 0 52 730 0 C 90 3 920 N Qj>=o K)Chiral 0N 5 7300>40000 94001 39060 -3H WO 2007/142583 PCT1SE2007/000554 H <6 Chiral 0 0 200>~30000 >40000 >30000 .>40000 6~ Chiral N CH 0 CH 3 _____________4.6 760>40000 13001 36 H OC: o HC __________151 25001>40000 45001 721 -35 - WO 2007/142583 PCT/SE2007/000554 SChiral oN 6.8 500>40000 5100 1600 H 46 >30000 >40000 >30000 >40000 Chiral 0 N 9.2 1000 5400>30000 2400 N Chiral 0 95 2600>40000 >3000 >400 -36- WO 2007/142583 PCT/SE2007/000554 HC CH, Chiral N,
    O-J'
    0
    -'OH
    3 1200 >40000 >40000 CH, Chiral b 0 0- 94 >30000 >40000 >30000 >40000 Chiral N CHa 0 93 >40000 >40000 Chiral 0 N o oCH, 14 1200>40000 4200>40000 -37- WO 2007/142583 PCT/SE2007/000554 H Chiral 2.5 380 1100 S Chiral N N O CH 3 0 a = unknown absolute ISOMER 2 59
    Q
    0 N N N F 81_____ _____ _____ Rat FCA-induced Heat Hyperalgesia Model Twenty four hours before testing, rats are brought to experimental lab. Rats are placed in a plexiglass chamber with 2% isoflurane at a flow rate of 0.8-1 L/hr with 5 oxygen, for approximately 60-90 seconds, until a light-medium depth of anesthesia is attained. A volume of 25pld of FCA is injected into the subcutaneous space of the dorsal aspect of the left hind paw, in the centre of the pads. This creates an inflammation, with accompanying edema and redness, as well as hyperalgesia, -38- WO 2007/142583 PCT/SE2007/000554 which is fully developed'within 24 hours, and remains stable for weeks. In order to assess the degree of hyperalgesia, the animals are placed on a glass surface, and a heat-source is focused onto the plantar surface of the affected paw. The time from the initiation of the heat until the animal withdraws the paw is recorded. A decrease 5 in Paw Withdrawal Latency (PWL) relative to naive animals indicates a hyperalgesic state. Generally, an experiment consists of 5 groups. One group is naive and serves as baseline control. The other 4 groups receive FCA injection. One of the 4 groups serves as the vehicle control and the other receive drug treatment. 10 Drug or vehicle is administered 24h after FCA inoculation. Rats are placed back in their home cage for 30min, then, placed on the plantar apparatus for an additional 30min for habituation. Total time of testing after drug administration is based on Tmax. The degree of reversal effect (heat hyperalgesia) is measured by the ability of a drug to return to normal levels (naive PWL). 15 Statistical significance is determined using one-way ANOVA on raw data followed by a post-hoc Holm-Sidak t-test. The level of statistical significance is set at p s; 0.05. Raw data are normalized using the following formula: % anti-hyperalgesia (PWL(dose)-PWL(vehicle)) / (PWL(naive)-PWL(vehicle)) X 100. Data is expressed as mean ±SEM. 20 A combination containing a compound of the present invention and morphine at a predetermined ratio (e.g., 0.64:1) may be tested using this instant model. The combination drugs may be administered to the rats subcutaneously, orally or combination thereof, simultaneously or sequentially. The results (expressed as ED 0 ) for the combination may be compared with results obtained singly for the compound 25 of the instant invention and morphine at the same or similar dosage range. If the
    ED
    5 0 of the combination is significantly lower than the theoretical ED 5 0 calculated based on the ED 50 measured using the compound of the invention and morphine singly, then a synergy for the combination is indicated. 30 EXAMPLES The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting 35 the invention. -39 - WO 2007/142583 PCT/SE2007/000554 Example 1. Ethyl 4-[(cis (+/-))-2-oxooctahydro-1H-benzimidazol-1-yI]-1,4' bipiperidine-1'-carboxylate H K J H H N NN H racemic racemic 5 To a solution of racemic (cis)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one TFA salt (130 mg, 0.40 mmol) in dichloromethane (4 mL) was added acetic acid (120 gL) followed by ethyl 4-oxopiperidine-1-carboxylate (120 pL) and NaBH(OAc) 3 (250 mg), and the mixture was stirred at 45 0C overnight. The mixture was then quenched with a saturated solution of NaHCO 3 and then diluted in dichloromethane. IN NaOH was added and 10 aqueous phase was extracted several times with dichloromethane. The combined organic phase was dried and concentrated in vacuo. The compound was purified by high pH preparative LCMS to afford the title compound (25 mg). IH NMR (400 MHz, CHLOROFORM-D): 6 ppm 1.09 - 1.19 (m, 1 H), 1.23 (t, J=7.16 Hz, 3 H), 1.29 - 1.46 (m, 3 H), 1.45 - 1.91 (m, 12 H), 2.13 - 2.32 (m, 2 H), 2.33 - 2.46 (m, 1 H), 2.62 - 2.77 (m, 2 15 H), 2.88 (d, J=12.69 Hz, I H), 2.93 (d, J=11.13 Hz, I H), 3.45 - 3.60 (m, 2 H), 3.60 - 3.74 (m, I H), 4.09 (q, J=7.16 Hz, 2 H), 4.12 - 4.30 (m, 2 H). 13C NMR (101 MHz, CHLOROFORM-D): 8 ppm 14.57 (s, I C), 19.63 (s, 1 C), 20.56 (s, I C), 26.26 (s, I C), 27.30 (s, I C), 42.38 (s, I C), 48.43 (s, 1 C), 51.86 (s, I C), 61.77 (s, 1 C), 63.92 (s, 1 C), 154.92 (s, 1 C), 162.48 (s, 1 C). MS: (M+1) 379.3 20 Intermediate 1: (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one -40 - WO 2007/142583 PCT/SE2007/000554 N N O N H Step A: The preparation of tert-butyl 4-{[(1 R,2R)-2-aminocyclohexyl]amino}piperidine-1 carboxylate 5 O NH 2 NH 2
    NH
    2 (N N A mixture of (1R,2R)-cyclohexane diamine (20g, 175mmol) and sodium triacetoxyborohydride (25g, 120mmol) in dichloromethane (550mL) was added with a 10 solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.4g, 92mmol) in dichloromethane (800mL) dropwise over a period of 45 minutes and stirred at room temperature overnight. An aqueous solution of sodium bicarbonate (5%, 200mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2x150mL). The combined organic layers were dried over MgSO 4 , 15 filtered and concentrated in vacuo to afford the crude product which was purified by dry column vacuum chromatography to give the title compound as a pale yellow oil (18.0g, 66%). 1H NMR (300 MHz, METHANOL-D4): 6 ppm 3.99 (td, J=13.3, 3.3Hz, 2H), 2.95 2.70 (m, 3H), 2.40-2.15 (m, 2H), 2.05 (m, 1H), 1.95-1.85 (m, 2H), 1.85-1.65 (m, 3H), 1.44 (s, 9H), 1.95-1,35 (m, 6H) 20 25 Step B: The preparation of tert-butyl 4-[(3aR,7aR)-2-oxooctahydro-1H-benzimidazol-1 yl]piperidine-1 -carboxylate -41- WO 2007/142583 PCT/SE2007/000554 N H 2 N H ONH N '0 (N( A solution of triphosgene (7.2g, 24.2mmol) in dichloromethane (300mL) was added with a solution of tert-buty 4-{[(1R,2R)-2-aminocyclohexyl]amino}piperidine-1-carboxylate (18g, 60mmol) and triethylamine in dichloromethane (600mL) drop wise over a period of 5 1 h and stirred at room temperature for 22h. An additional amount of triphosgene (8g) and triethylamine (13mL) were added and stirred at room temperature for another 22h. An aqueous solution of sodium hydroxide (0.5N 200mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2x100mL). The combined organic layers were dried over Na 2
    SO
    4 , filtered and 10 concentrated in vacuo to afford the crude product which was triturated with diethylether (80mL) to give the title compound as white solid (11.1g, 56%). 1H NMR (300 MHz, METHANOL-D4): 6 ppm 4.25-4.05 (m, 2H), 3.80-3.65 (m, 1H), 3.10-2.90 (m, 2H), 2.85 2.65 (m, 2H), 2.20-1.90 (m, 2H), 1.90-1.55 (m, 4H), 1.55-1.30 (m, 11H) 15 Step C: The preparation of (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one H N H N ON N C N O O H A solution of (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (11.1 g, 34.3mmol) in hydrochloric acid (70mL, 5N in isopropanol) and in methanol (150ml) and 20 stirred at room temperature overnight. The mixture was concentrated in vacuo to give the title compound as a pale yellow solid (8.9g, 100%). 1H NMR (300 MHz, METHANOL D4): 5 ppm 3.73 (tt, J=12.3, 4.1Hz, 1H), 3.55-3.40 (m, 2H), 3.15-2.95 (m, 4H), 2.40-1.70 (m, 8H), 1.50-1.30 (m, 4H). -42- WO 2007/142583 PCT/SE2007/000554 Intermediate 2: (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one O N N H 5 Step A: The preparation of tert-butyl 4-{{(1 S,2S)-2-aminocyclohexyl]amino}piperidine-1 carboxylate 0 + C NH2 ( NH 2 N NH 2 NH N To a solution of (1 S,2S)-cyclohexane-1,2-diamine (4 g, 35.08 mmol) in dichloromethane 10 (80 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (3.49 g, 17.54 mmol) followed by sodium triacetoxy borohydride (11.15 g, 52.60 mmol) and stirred at room temperature for 5 hours. A saturated solution of sodium hydrogen carbonate (10 mL) was then added and the reaction diluted in dichloromethane (100 mL). The phases were separated and aqueous phase was extracted with dichloromethane (2x60 mL). 15 Combined organic layers was washed with brine, dried and concentrated in vacuo. The crude compound was purified by flash chromatography to provide the titled compound as yellow oil (3.5 g). Step B: The preparation of tert-butyl 4-(2-oxooctahydro-1H-benzimidazol-1-yl)piperidine 20 1-carboxylate NH N (N( 0O 0 -43- WO 2007/142583 PCT/SE2007/000554 A solution of tert-butyl 4-{[(1 S, 2
    S)-
    2 -aminocyclohexyllamino}piperidine-1 -carboxylate (3.5 g, 11.78 mmol) in acetonitrile (70 mL) was added with 1,1-carbonyldiimidazole (2.2 g, 13.58 mmol) and stirred at room temperature overnight. The solvent was removed under 5 reduced pressure, taken in dichloromethane (200 mL) and washed with 1N NaOH (10 mL). The organic phase was dried and concentrated in vacuo. The residue was washed with diethyl ether (15 mL), dried and used for the next step without further purification (3.3 g). MS (M+1): 324.24 10 Step C: The preparation of (3aS,7aS)-1-piperidin-4-yioctahydro-2H-benzimidazol-2-one -N -N CN N A solution tert-butyl 4-(2-oxooctahydro-1H-benzimidazol-1-yl)piperidine-1-carboxylate (1 g) in dichloromethane (20 mL) was added with TFA (5 mL) and stirred at room 15 temperature for 1 hour. The solvent was removed under reduced pressure to provide the titled compound as its TFA salt. The salt was then transformed to freebase by MP carbonate and used without any purification. MS (M+1): 224.25 20 Table 1: Examples 2-7 were prepared via reductive amination reactions similar to Example 1, starting from corresponding cis- or trans- 1 -piperidin-4-yloctahydro-2H benzimidazol-2-one (either from the racemic or enantiomerically pure intermediates, Intermediate 1 and Intermediate 2) Structure Name Data (Example) -44- WO 2007/142583 PCT/SE2007/000554 H Ethyl 3-{4-[(cis (+/-))-2- H NMR (400 MHz, CHLOROFORM-D): oxooctahydro-IH-benzimidazol- 5 ppm 1.22 (t, J=7.13 Hz, 3 H), 1.10-1.30 (i, 1 1-yl]piperidin-1-yl}pyrrolidine-1- H), 1.29- 1.43 (i, I H), 1.44- 1.95 (i, 10 H), Ncarboxylate (mixture) 1.95 - 2.19 (m, 3 H), 2.63 - 2.95 (m, 2 H), 2.93 3.15 (m, 2 H), 3.20 - 3.35 (m, I H), 3.40 - 3.74 N -OEt (m, 5 H), 4.09 (q, J=7.10 Hz, 2 H), 4.13-4.20 (m, (2) 1 H), 4.20 - 4.35 (m, I H). MS: 365.3 (M+1). -NH Ethyl 3-{4-[(trans (+/-))-2- 1H NMR.(400 MHz, CHLOROFORM-D): 6 ppm 1.23 N O oxooctahydro-IH-benzimidazol- (t, J=7.03 Hz, 3 H), 1.28 - 1.49 (m, 4 H), 1.58 - 1.89 (* 1-yl]piperidin-1-yl}pyrrolidine-1- (m, 7 H), 1.90 - 1.99 (m, I H), 1.99 - 2.14 (m, 3 H), carboxylate (mixture) 2.23 - 2.33 (m, 1 H), 2.65 - 3.16 (m, 6 H), 3.20 3.36 (m, I H), 3.45 - 3.86 (m, 3 H), 4.10 (q, J=7.03 N OEt Hz, 2 H), 4.44 - 4.60 (m, 1 H). O MS: 365.3 (M+1). (3) Benzyl 3-{4-[(trans (+/-))-2- 1 H NMR (400 MHz, CHLOROFORM-D): N o oxooctahydro-1H-benzimidazol- 6 ppm 1.08- 1.28 (i, 1 H), 1.31 -1.45 (i, 1 H), (*H 1-yl]piperidin-1-yl}pyrrolidine-1- 1.30-1.73 (, 10 H), 1.73-1.88 (i, 3 H), 1.88 carboxylate (mixture) 2.08 (i, 2 H), 2.09 - 2.33 (i, 2 H), 3.28 - 3.89 ~j) (in, 6 H), 4.14 (bs, I H), 4.00 - 4.24 (in, I H), 5.12 N r 0 8 n (s, 2 H), 7.24 - 7.44 (in, 5 H). 0 MS: (M+1) 427.2. N Benzy1 4-[-[(trans (+/-))-2- 1H NMR (400 MHz, CHLOROFORM-D): "N oxooctahydro-1 H-benziiidazol- 6 ppm 1.07 - 1.26 (m, 1 H), 1.29 - 1.47 (m, 3 H), 1 -yj-1,4'-bipiperidine-'- 1.46 - 1.92 (m, 12 H), 2.15 -2.33 (m, 2 H), 2.35 N carboxylate 2.49 (m, I H), 2.66 - 2.82 (m, 2 H), 2.91 (dd, 6 J=20.41, 11.23 Hz, 2 H), 3.52 - 3.60 (in, 2 H), 3.52- 3.70 (i, I H), 4.10-4.35 (m, 2 H), 4.12 (s, (1 2 H), 5.10 (bs, 2 H) 7.27-7.38 (m, 5 H). MS: (M+1) 441.3. (5) -45 - WO 2007/142583 PCT/SE2007/000554 N Ethyl 4-[(3aR,7aR)-2- IH NMR (400 MHz, METHANOL-D4): )=O oxooctahydro-IH-benzimidazol- 6 ppm 1.25 (t, J7.13 Hz, 3 H) 1.32 - 1.50 (i, 4 1-ylj-1,4'-bipiperidine-1'- H) 1.74-2.03 (i, 5 H) 2.13 (d, J=11.72 Hz, 2 H) N carboxylate 2.19 - 2.35 (i, I H) 2.36-2.51 (i, I H) 2.77 2.94 ( t, 2 H) 2.93 - 3.07 (i, 2 H) 3.06 - 3.22 (m, 2 H) 3.35 - 3.49 (m, I H) 3.53 - 3.69 (m, 4 H) 3.60 o6) - 3.67 (m, I H) 3.69 - 3.85 (m, 1 H) 4.11 (q, (6) J=7.16 Hz, 2 H) 4.29 (d, J=1 3.28 Hz, 2 H). MS: (M+1) 379.3. Ethyl 4-[(3aS,7aS)-2- IH NMR (400 MHz, METHANOL-D4): N oxooctahydro-1H-benzimidazol- 6 ppm 1.25 (t, J=7.13 Hz, 3 H) 1.32- 1.50 (i, 4 1-ylj-1,4'-bipiperidine-1'- H) 1.74-2.03 (i, 5 H)2.13 (d, J11.72 Hz, 2 H) N carboxylate 2.19 -2.35 (m, 1 H) 2.36-2.51 (i, I H) 2.77 2.94 (in, 2 H) 2.93 -H3.07 (, 2 H) 3.06 - 3.22 (m, 2 H) 3.35 - 3.49 (m, 1 H) 3.53 - 3.69 (m, 4 H) 3.60 o7) - 3.67 (m, I H) 3.69.- 3.85 (m, 1 H) 4.11 (q, J=7.16 Hz, 2 H) 4.29 (d, J=13.28 Hz, 2 H). MS: (M+1) 379.3. Example 8: (trans (+/-))-1-{1-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]piperidin-4 yl}octahydro-2H-benzimidazol-2-one H N N N 5 0 Step 1: The preparation of tert-butyl 3-(4-((trans (+/-))-2-oxooctahydro-1H-benzimidazol 1-yl]piperidin-1-yl}pyrrolidine-1-carboxylate -46 - WO 2007/142583 PCT/SE2007/000554 H H N N (+1-)(+/-) N N H N 0 mixture of diateroisomers Y Following a similar procedure to that described in Example 1, t-Butyl 3-{4-[(trans (+/-) -2 oxooctahydro-1 H-benzimidazol-1 -yl]piperidin--I-yl}pyrrolidine-1 -carboxylate (2.40 g) was prepared as a mixture of diastereoisomers. 5 Step 2: The preparation of 3-{4-[(trans (+/-))-2-oxooctahydro-1 H-benzimidazol-1 yl]piperidin-1 -yl}pyrrolidine H H N -. N O 1. TFA )'N 2. MP-Carbonate (+/-) (+/-) N N N 0 NH mixture of mixture of diastereoisomers diastereolsomers 10 The crude intermediate (2.4 g) from Step I was dissolved in dichloromethane (10 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature overnight. Removal of solvent and excess TFA yielded the TFA salt (4.2 g) the title compound. The TFA salt was converted to its free base by MP-Carbonate, and purification on flash chromatography (MeOH/DICHLOROMETHANE) to give the title 15 compound (0.70 g). Step 3: The preparation of (trans (+/-))-1-{I-[I-(cyclopentylcarbonyl)pyrrolidin-3 yl]piperidin-4-yl}octahydro-2H-benzimidazol-2-one -47 - WO 2007/142583 PCT/SE2007/000554 H H N rN b O (+/-)(1) N N mixture of mixture of diatereolsomers diatereoisomers NH N 0 To a solution of 3-{4-[(trans (+/-))-2-oxooctahydro-1H-benzimidazol-1-yllpiperidin-1 5 yi}pyrrolidine (mixture of diatereoisomers) (100 mg, 0.34 mmol) in DMF was added diisopropylethylamine (0.16 mmol), cyclopentylcarboxyl chloride (50 AL) at room temperature. The reaction was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with brine. Removal of solvent gave the crude product, which was purified on high pH prep HPLC and 10 converted to HCI salt to afford the title compound as a mixture of diastereoisomers) (36 mg). I H NMR (400 MHz, METHANOL-D4): 5 ppm 1.27 - 1.52 (m, 4 H), 1.55 - 2.05 (m, 13 H), 2.23 - 2.38 (m, 3 H), 2.38 - 2.61 (m, 2 H), 2.83 - 3.08 (m, 3 H), 3.08 - 3.26 (m, 2 H), 3.32-3.37 (m, I H), 3.52 - 4.02 (m, 6 H), 3.65 (s, 1 H), 4.08 - 4.23 (m, 1 H). MS: (M+1) 389.3. 15 Table 2: Examples 9-13 were prepared similar to the procedure described in Example 8, Step 3 Structure Name data (Example) (trans (+/-))-1-{1-[1-(pyrrolidin- 1H NMR (400 MHz, METHANOL-D4): 1-ylcarbonyl)pyrrolidin-3- 6 ppm 1.28 - 1.50 (m, 4 H) 1.68 - 2.06 (m, 10 H) yl]piperidin-4-yl}octahydro-2H- 2.11 - 2.35 (m, 3 H) 2.36 - 2.53 (m, 2 H) 2.92 6NrNfD benzimidazol-2-one (mixture 3.08 (m, 2 H) 3.12 - 3.25 (m, 2 H) 3.32 - 3.75 0 of diastereoisomers) (m, 12 H) 3.65 (s, 1 H) 3.76 - 3.91 (m, 3 H). (9) MS: (M+1). -48- WO 2007/142583 PCT/SE2007/000554 methyl 3-{4-[(trans (+/-))-2- 1 H NMR (400 MHz, METHANOL-D4) HCI salt: oxooctahydro-1H- 8 ppm 1.29 - 1.52 (m, 4 H), 1.58 - 2.07 (m, 8 H), benzimidazol-1-yl]piperidin-1- 2.10-2.35 (m, 4 H), 2.87 - 3.06 (m, 4 H), 3.07 N yl}pyrrolidine-1-carboxylate 3.21 (m, 2 H), 3.23 - 3.40 (m, I H), 3.57 (t, (mixture of diastereoisomers) J=9.77 Hz, I H), 3.59 - 3.75 (m 2 H), 3.67 (s, 3 H). MS: (M+1). N-ethyl-3-[4-[(-[(trans (+/-))- IH NMR (400 MHz, METHANOL-D4): N (2-oxooctahydro-1H- 5 ppm 1.13 (t, J7.13 Hz, 3 H), 1.31 -1.52 (i, 4 benzimidazol-1-yl)piperidin-1- H), 1.73- 2.06 (i, 5 H), 2.24- 2.41 (i, 3 H), N yl]pyrroidine-i-carboxamide 2.40-2.57 (i, 2 H), 2.93 -3.10 (i, 2 H), 3.12 (mixture of diastereoisomers) 3.28 (i, 2 H), 3.22 (q, J=7.23 Hz, 2 H), 3.33 ), 3.46 (in, I H), 3.50 - 3.77 (i, 5 H), 3.77 - 4.03 0 (m, 3 H). (11) MS: (M+1) 364.3. (trans (+/-))-1-{1-[1-(3- 1H NMR (400 MHz, METHANOL-D4) HCl salt: N o methylbutanoyl)pyrrolidin-3- 6 ppm 0.87 - 1.03 (i, 6 H), 1.25 - 1.51 (i, 4 H), (+6 yl]piperidin-4-yl}octahydro-2H- 1.69-2.04 (i, 5 H), 2.02-2.18 (i, 1 H), 2.17 N benziinidazol-2-one (mixture 2.40 (m, 5 H), 2.38 - 2.58 (m, 2 H), 2.89 - 3.07 of diastereoisomers) (m, 2 H), 3.08 - 3.25 (m, 2 H), 3.34 (s, I H), 3.51 - 3.92 (m, 4 H), 3.65 (s, I H), 3.93 - 4.14 (12) (m, 1 H). . MS: (M+1) 377.3. (trans (+/-))-1-[1-(1- 1H NMR (400 MHz, METHANOL-D4): butyrylpyrrolidin-3-yl)piperidin- 8 ppm 0.81 - 1.05 (m, 3 H), 1.27 - 1.51 (m, 4 H), N O 4-yl]octahydro-2H- 1.55 - 1.71 (m, 2 H), 1.73 - 2.06 (m, 5 H), 2.17 benzimidazol-2-one (mixture 2.64 (m, 6 H), 2.90 - 3.10 (m, 2 H), 3.09 - 3.28 N of diastereoisomers) (m, 2 H), 3.52 - 4.16 (m, 9 H), 3.65 (s, I H). N MS (M+1): 363.3. 0 (13) Example 14 and Example 15: Ethyl (3R)- 3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate and ethyl -49- WO 2007/142583 PCT/SE2007/000554 (3S)-3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1 piperidyl]pyrrolidine-1-carboxylate HH H H N N N 0 0 Step A: The preparation of Ethyl 3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H 5 benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate H H N~ O= 6 N mixture of diastereoisomers HN6 0 To a stirred solution of (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one TFA salt (400 mg, 1.24 mmol) in dichloromethane (10 mL) was added acetic acid (0.35 mL, 10 6.12 mmol), ethyl 3-oxopyrrolidine-1-carboxylate (0.35 mL, 2.23 mmol). Sodium triacetoxyoborohydride (0.8 g, 3.77 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with ice water, then diluted with dichloromethane (200 mL) and was washed successively with 1N NaOH (10 mL), water (10 mL) and brine. The solvent was removed under reduced pressure- and the residue 15 was purified by high pH prep LCMS (acetonitrile / water) to provide the mixture of two diastereoisomers (260 mg, 58%). Step B: Separation of diastereoisomers - 50 - WO 2007/142583 PCT/SE2007/000554 H H Chiral Separation N No 0 The two diastereoisomers from Step A were separated by chiral HPLC (OD column, 40% Isopropanol /60% hexane) to provided title compounds as pure enantiomers (Isomer 1 and losmer 2). 5 isomer 1 (72mg): HPLC Retention time = 6.33 min, K': 0.52 (Chiralpak OD column, 4.6 x 250mm, 40% Isopropanol / 60%hexane). IH NMR (400 MHz, CHLOROFORM-D): 8 ppm 1.21 (t, J=7.03 Hz, 3 H), 1.26 - 1.46 (m, 4 H), 1.52 - 1.86 (mi 6 H), 1.93 (d, J=1 0.74 Hz, I H), 1.96 - 2.13 (m, 4 H), 2.25 (d, J=10.74 Hz, I H), 2.60 - 2.80 (m, I H), 2.80 - 2.91 (m, 1 10 H), 2.90 - 3.03 (m, 3 H), 3.06 (q, J=9.57 Hz, I H), 3.17 - 3.34 (m, 1 H), 3.49 (t, J=9.67 Hz, 1 H), 3.52 - 3.64 (m, I H), 3.63 - 3.81 (m, 1 H), 4.08 (q, J=7.03 Hz, 2 H), 4.66 - 4.91 (m, I H). MS (M+1): 365.3. Isomer 2 (32 mg): HPLC Retention time = 6.99 min, K': 0.68 (Chiralpak OD column, 4.6 x 15 250mm, 40%lsopropanol/60%hexane). 1H NMR (400 MHz, CHLOROFORM-D): S ppm 1.21 (t, J=7.03 Hz, 3 H), 1.26 - 1.46 (m, 4 H), 1.52 - 1.86 (m, 6 H), 1.93 (d, J=1 0.74 Hz, I H), 1.96 - 2.13 (m, 4 H), 2.25 (d, J=10.74 Hz, I H), 2.60 - 2.80 (m, I H), 2.80 - 2.91 (m, I H), 2.90 - 3.03 (m, 3 H), 3.06 (q, J=9.57 Hz, 1 H), 3.17 - 3.34 (m, 1 H), 3.49 (t, J=9.67 Hz, 1 H), 3.52 - 3.64 (m, I H), 3.63 - 3.81 (m, I H), 4.08 (q, J=7.03 Hz, 2 H), 4.66 - 4.91 (m, 1 20 H). MS (M+1): 365.3. Example 16 and Example 17: Ethyl (3R)-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate and Ethyl (3S)-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-l-yl]-1 25 piperidyl]pyrrolidine-1-carboxylate -51- WO 2007/142583 PCT/SE2007/000554 H I~ N O& NO N O O 0 Step A: The preparation of ethyl 3-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate H H sO'N Il >=0O N : N mixture of N diastereoisomers H NO 0 5 Following the similar procedure of Step A of the Example 14 and Example 15, ethyl 3-[4 [(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine 1-carboxylate was prepared as a mixture of two diastereoisomers. Step B: Separation of diastereoisomers H H H 0 >=o 02: N>0>=0 + N ON N N, N 0 10 a 0 The two diastereoisomers from Step A were separated by chiral 'HPLC (OD column, 30%lsopropanol/70%hexane) to provided title compounds as pure enantiomers (Isomer I and losmer 2). -52 - WO 2007/142583 PCT/SE2007/000554 Isomer 1: HPLC Retention time = 9.05min, K': 2.34 (Chiralpak AD column, 4.6 x 250mm, 30%lsopropanol/70%hexane). 1H NMR (400 MHz, CHLOROFORM-D): 8 ppm 1.21 (t, J=7.13 Hz, 3 H), 1.26 - 1.48 (m, 4 H), 1.58 - 1.87 (m, 7 H), 1.93 (d, J=10.55 Hz, I H), 1.99 - 2.13 (m, 3 H), 2.25 (d, J=10.94 Hz, I H), 2.65 - 2.79 (m, 1 H), 2.79 - 2.89 (m, I H), 5 2.91 - 3.13 (m, 4 H), 3.16 - 3.34 (m, 1 H), 3.49 (t, J=10.45 Hz, I H), 3.53 - 3.64 (m, I H), 3.65 - 3.83 (m, I H), 4.08 (q, J=7.10 Hz, 2 H), 4.77 (s, I H). MS (M+1): 365.3 Isomer 2: HPLC Retention time = 14.41 min, K': 1.18 (Chiralpak OD column, 4.6 x 250mm, column 30%lsopropanol/70%Hexane). 1H NMR (400 MHz, CHLOROFORM-D): 10 8 ppm 1.22 (t, J=7.13 Hz, 3 H), 1.25 - 1.47 (m, 4 H), 1.56 - 1.87 (m, 7 H), 1.93 (d, J=10.74 Hz, I H), 1.97 - 2.16 (m, 3 H), 2.26 (d, J=10.74 Hz, 1 H), 2.65 - 2.81 (m, 1 H), 2.82 - 2.91 (m, 1 H), 2.91 - 3.02 (m, 3 H), 3.07 (q, J=9.57 Hz, I H), 3.21 - 3.35 (m, I H), 3.39 - 3.64 (m, I H), 3.65 - 3.85 (m, 2 H), 4.09 (q, J=7.10 Hz, 2 H); 4.74 (s, I H). MS (M+1): 365.3 15 Example 18: Tert-butyl 4-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-1-yI]-1-piperidyl]piperidine-1-carboxylate H ON IN >--O N N 20 01, + HCl salt of (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (2 g, 7.72 mmol) was dissolved in MeOH (30 mL) and MP carbonate (12 g) was added. The mixture was stirred for one hour at rt and then filtered and concentrated in vacuo to provide a white solid. To a stirred solution of above freebase and tert-butyl 4-oxopiperidine-1-carboxylate 25 (1.8 g, 9.04 mmol) in MeOH (40 mL) was added a solution of sodium cyanoborohydride (1 g, 14.49 mmol) and zinc chloride (0.73 g, 5.36 mmol) in MeOH (20 mL). The resulting solution was stirred at room temperature over night then concentrated in vacuo. A solution of 1 N NaOH was added and aqueous phase was extracted several times with dichloromethane. The combined organic phases were washed with brine, dried and then -53- WO 2007/142583 PCT/SE2007/000554 concentrated in vacuo. The residue was purified using flash chromatography (linear. gradient starting from 1-12% methanol in dichloromethane) to provide the desired compound as a white solid (2 g, 88%). IH NMR (400 MHz, CHLOROFORM-D): 8 ppm 1.21 - 1.49 (m, 4 H), 1.41 (s, 9 H), 1.57 - 1.67 (m, I H), 1.66 - 1.84 (m, 7 H), 1.93 (d, 5 J=11.13 Hz, 1 H), 2.05 - 2.32 (m, 5 H), 2.29 - 2.43 (m, 1 H), 2.53 - 2.71 (m, 2 H), 2.76 3.05 (m, 4 H), 3.56 - 3.79 (m, 1 H), 3.90 - 4.24 (m, 2 H), 4.76 (s, I H). MS (M+1): 407.3 Example 19: (3aS,7aS)-1-1-(4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-2-one H I H N O NN NN N ( 6N N 10 tert-butyl 4-(2-oxooctahydro-1H-benzimidazo-1-yl)-1,4'-bipiperidine-1'-carboxylate (1.2 g, 2.95 mmol) was dissolved in a mixture of 4M HCI in dioxane (15 mL) and water (5 mL). The mixture was stirred at rt for 1 hour then concentrated in vacuo to provide the title compound as a white solid (0.7 g). IH NMR (400 MHz, CHLOROFORM-D) free base: 8 15 ppm 1.22 - 1.53 (m, 5 H), 1.49 - 1.69 (m, I H), 1.69 - 1.88 (m, 7 H), 1.94 (m, 1 H), 2.04 2.52 (m, 6 H), 2.60 (t, J=11.33 Hz, 2 H), 2.82 - 3.09 (m, 4 H), 3.17 (d, J=12.89 Hz, 2 H), 3.59 - 3.88 (m, 1 H), 4.47 - 4.68 (m, 1 H). MS (M+1): 307.3. 20 Example 20: (3aS,7aS)-1-[1-[1-(cyclopropanecarbonyl)-4-piperidyl]-4-piperidyl] 3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one -54- WO 2007/142583 PCT/SE2007/000554 H H I I N N N N N (N H 0 To a mixture of (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one.2 HCl (0.2 g, 0.53 mmol) in DMF (10 mL) was added diisopropylethylamine (0.28 mL, 1.61 mmol) and cyclopropanecarboxylic acid (0.06 mL, 0.75 mmol) at room temperature. The 5 mixture was then sonicated to help dissolve the starting material. HATU (0.2 g, 0.53 mmol) was then added, and the reaction was stirred at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (80 mL) and the mixture was washed with IN NaOH (10 mL), brine (5 mL) and concentrated in vacuo. The crude product was purified by high pH Prep. LCMS to provide 10 the title compound, which was converted to its HCl salt (0.15 g, 69%). Example 21-47: Examples 21-47 were prepared via HATU coupling method similar to Example 20 starting from (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)octahydro-2H benzimidazol-2-one (either in free base form or salt form) and corresponding 15 carboxylic acid Structure Name Data (Example) (3aS,7aS)-1-[1-[1-(2- 1H NMR (400 MHz, CHLOROFORM-D): Ot=o methylbenzoyl)-4-piperidyll-4- 5 ppm 1.19 - 1.51 (m, 6 H), 1.53 - 1.80 (m, 7 H), piperidyll-3a,4,5,6,7,7a- 1.79 - 1.94 (m, 2 H), 2.06 - 2.31 (m, 3 H), 2.19 hexahydro-3H-benzoimidazol- (s, 3 H), 2.32 - 2.53 (m, I H), 2.68 (t, J=1 2.30 2-one Hz, I H), 2.77 - 3.00 (m, 5 H), 3.42 (d, J=13.87 Hz, I H), 3.55 - 3.75 (m, 1 H), 4.76 (d, J=12.11 Hz, I H), 5.11 (s, I H), 6.98 - 7.24 (m, 4 H). (21) MS (M+1): 425.3 -55- WO 2007/142583 PCT/SE2007/000554 (3aS,7aS)-1-[1-[1- IH NMR (400 MHz, CHLOROFORM-D): N (cyclohexanecarbo nyl)-4- 8ppm 1.16-1.56 (i, 11 H), 1.59- 1.99 (i, 14 (5 piperidyl]-4-piperidyl]- H), 2.12 - 2.33 (i, 3 H), 2.38 - 2.53 (i, 3 H), 3a,4,5,6,7,7a-hexahydro-3H- 2.83 - 3.05 (i, 5 H), 3.65 - 3.79 (i, 1 H), 3.94 N benzoimidazol-2-one (d, J=15.43 Hz, I H), 4.58 (s, I H), 4.65 (d, o~KrjJ=13.48 Hz, I H). MS (M+1): 417.3. (22) (3aS,7aS)-l-1-(2- 1H NMR (400 MHz, CHLOROFORM-D): N fluorobenzoyl)-4-piperidyll-4- 8 ppm 1. 18 -1.45 (mn, 5 H), 1.45 -1.58 (in, I H), (6 piperidyl]-3a,4,5,6,7,7a- 1.59- 1.83 (in, 7 H), 1.85- 1.97 (in, 2 H), 2.14 H hexahydro-3H-benzoimidazol- 2.32 (i, 3 H), 2.48 (t, J 21.03 Hz, I H), 2.73 (t, S 2-one J=12.21, H), 2.82 - 3.10 (i, 5 H), 3.56 (d, SJ=13.48 Hz, I H), 3.64-3.78 ( , I H), 4.64 4.87 (in, 2 H), 6.93 -7.10 (in, I H), 7.11 - 7.21 (23) (in, I H), 7.27 - 7.43 (, 2 H). MS (M+1): 429.3 (3aS,7aS)-1-[1-[1-(4- IH NMR (400 MHz, METHANOL-D4): 8 ppm N methoxybenzoyl)-4-piperidyl]- 1.24- 1.57 (in, 5 H), 1.67 -2.04 (4-, 11 H), 2.19 Nt~ 4-piperidyl]-3a,4,5,6,7,7a- - 2.42 (i, 3 H), 2.65 (t, J=1 1.52 Hz, 1 H), 2.80 hexahydro-3H-benzoimidazol- 3.18 (i, 7 H), 3.55 -3.71 (i, 1 H), 3.82 (s, 3 N 2-one H), 4.53 - 4.72 (i, 1 H), 6.98 (d, J=7.42 Hz, 2 H), 7.37 (d, J=7.42 Hz, 2 H). (24) MS (M+1): 441.3. (3aS,7aS)--[1-[1-(3- 1H NMR (400 MHz, CHLOROFORM-D): NI o methylfuran-2-carbonyl)-4- 8 ppm 1.17 - 1.56 (m, 5 H), 1.56 - 1.88 (m, 9 H), piperidyl]-4-piperidyl- 1.92 (d, J=10.55 Hz, I H), 2.19 (s, 3 H), 2.19 3a,4,5,6,7,7a-hexahydro-3H- 2.34 (m, 3 H), 2.41 - 2.56 (n, I H), 2.60 - 3.02 benzoimidazol-2-one (in, 7 H), 3.60 - 3.77 (i, 1 H), 4.15 -4.63 (, 1 o H), 4.89 (s, H), 6.26 (s, I H), 7.24 - 7.35 (2, 1 H). (25) MS (M+1): 415.3 (3a,7a)-1[1-1-(-56 WO 2007/142583 PCT/SE2007/000554 aH N(3aS,7aS)-l -[1-[1 -(2,6- 1IH NMR (400 MHz, METHANOL-D4)-HCI salt: p=o Ndimethylbenzoyl)-4-piperidylj- 8 ppm 1.27 - 1.57 (in, 6 H), 1.56 - 1.67 (in, I H), 4-pIperidyi]-3a,4,5,6,7,7a- 1.67 - 1.75 (mn, 1 H), 1.74 - 2.02 (mn, 6 H), 2.06 hexahydro-3H-benzoimidazol- (d, J=12.50 Hz, I H), 2.17 (s, 3 H), 2.21 - 2.36 6N2-one (in, 3 H), 2.28 (s, 3 H), 2.55 -2.66 (in, I H), 0 2.77 - 2.90 (in, I H), 2.88 - 3.14 (in, 5 H), 3.36 3.46 (in, 1 H), 3.54 - 3.71 (in, I H), 4.81 (d, (26) J=15.23 Hz, I H), 6.96-7.14 (i, 2 H), 7.13 7.24 (in, I H). MS (M+1): 439.1. H (::):N(3aS,7aS)- -[I-(-butanoyl-4- I H NMR (400 MHz, CHLOROFORM-D): 5 ppm Oo N=o piperidyl)-4-piperidyl]- 0.94 (t, J=7.32 Hz, 3 H), 1.24 - 1.49 (in, 6 H), b 3a,4,5,6,7,7a-hexahydro-3H- 1.52 - 1.68 (in, 3 H), 1.68 - 1.86 (in, 7 H), 1--94 N benzoimidazol-2-one (d, J=10.94 Hz, 1 H), 2.14 - 2.35 (in, 5 H), 2.39 6 - 2.56 (in, 2 H), 2.82 - 3.05 (in, 5 H), 3.62 - 3.78 N 0 (in, I H), 3.88 (d, J=13.28 Hz, I H), 4.61 (mn, 2 (27) H). MS (M+1): 377.3. (3aS,7aS)-1-[1-[1-(2- 1H NMR (400 MHz, CHLOROFORM-D): imethoxybenzoyl)-4-piperidyl]- 5 ppm 1.17-1.57 (m, 5 H), 1.56-2.02 (i, 9 H), 6i~) 4-piperidyl]-3a,4,5,6,7,7a- 2.11 - 2.34 (i, 3 H), 2.41 - 2.53 (i, I H), 2.59 hexahydro-3H-benzoimidazol- 2.78 (i, 1 H) 2.77 - 3.07 (m, 5 H), 3.32 - 3.44 2-one (i, I H), 3.49 (d, J=13.48 Hz, 1 H), 3.59 - 3.75 0 (in, I H), 3.78 (d, J=7.62 Hz, 3 H), 4.69 - 4.88 (in, 2 H), 6.87 (d, J=8.40 Hz, I H), 6.91 - 6.98 (28) (in, I H), 7.17 (d, J=1 6.70 Hz, 1 H), 7.26 -7.36 (in, 1 H). MS (M+I): 441 .1. (3aS,7aS)-1-[1-[1-(3- 1H NMR (400 MHz, CHLOROFORM-D): No imethoxybenzoyl)-4-piperidyl]- 5 ppm 1.26- 1.58 (m, 5 H), 1.58 -2.01 (i, 9 H), b 4-piperidyl]-3a,4,5,6,7,7a- 2.11 - 2.35 (m, 3 H), 2.42 - 2.56 (m, I H), 2.63 hexahydro-3H-benzoimidazol- 2.83 (i, 1 H), 2.86 - 3.09 (m, 5 H), 3.63 - 3.95 2-one (m, 3 H), 3.80 (s, 3 H), 4.47 -4.64 (m, I H), o 0- 4.66 - 4.83 (mn, 1 H), 6.83 -7.00 (in, 3 H), 7.18 H 7.34 ( 40, I H). (.1MS (M+H): 441.3. -57- WO 2007/142583 PCT/SE2007/000554 (3aS,7aS)-1-[1-(1-benzoyl-4- HCI salt-I H NMR (400 MHz, METHANOL-D4): N)=O piperidyl)-4-piperidy]- 5 ppm 1.28- 1.57 (m, 5 H), 1.62-1.89 (i, 4 H), 3a,4,5,6,7,7a-hexahydro-3H- 1.89 -2.13 (i, 4 H), 2.13 -2.34 (i, 3 H), 2.35 N benzoimidazol-2-one 2.53 (i, I H), 2.84 - 3.09 (i, 3 H), 3.09 - 3.25 0 (in, 3 H), 3.47 -3.70 (in, 4 H), 3.69 - 3.83 (in, I N 0 H), 3.84 - 3.99 (in, 1 H), 7.27 - 7.58 (in, 5 H). MS (M+1): 411.2. (30) 2-[4-[4-[(3aS,7aS)-2-oxo- HCI salt-I H NMR (400 MHz, METHANOL-D4): - 3a,4,5,6,7,7a-hexahydro-3H- S ppm 1.30 - 1.54 (m, 5 H), 1.71 - 2.04 (m, 7 H), benzoiidazol-1-yi]-1- 2.05 - 2.47 (m, 5 H), 2.78 - 3.21 (m, 6 H), 3.40 , 3.68 (i, 4 H), 3.67 - 3.85 (i, I H), 7.43 - 7.98 CN carbonyi]benzonitrile (in, 4 H). MS (M+): 436.3 06 (31) 2(3aS,7aS)--[1-[I-(2- oH NMR (400 MHz, METHANOL-D4): aN =O propylpentanoyl)-4-piperidyl]- 5 ppm 0.80 - 1.00 (in, 6 H), 1.11 - 1.35 (in, 4 H), 4-piperidyl-3a,4,5,6,7,7a- 1.32 - 1.48 (n, 6 H), 1.48- 1.67 (, 5 H), 1.75 hexahydro-3H-benzoimidazol- 1.89 (n, 2 H), 1.89 - 2.08 (n, 3 H), 2.13 - 2.33 2-one (in; 4 H), 2.33 -2.52 (n, 1 H), 2.64 (t, J=L 2.30 Hz, I H), 2.78 - 2.93 (m, I H), 2.91 - 3.06 (m, 2 (32) H), 3.07 - 3.24 (m, 3 H), 3.40 - 3.54 (m, I H), 3.56 - 3.71 (i, 2 H), 3.70 - 3.85 (m , 1 H), 4.36 (d, J=13.67 Hz, 1 H), 4.79 (d, J=1 4.06 Hz, I H). (MS (M+1): 433.5. N (3aS,7aS)-1-[1-[1-(2.- I M 40Mz EHNLD C N>o dihydrobenzofuran-7- 8 ppm 1.31 - 1.51 (in, 5 H), 1.65 - 2.30 (in, I11 carbonyl)-4-piperidyl-4- H), 2.34 - 2.48 (i, I H), 2.75 - 2.90 (i, 1 H), -piperidyl]-3a,4,5,6,7,7a- 2.96 - 3.06 (m, 2 H), 3.06 - 3.20 (i, 2 H), 3.25 hexahydro-3H-benzoimidazol- (t, J=8.79 Hz, 2 H), 3.40 - 3.54 (i, I H), 3.55 2-one 3.69 (m, 3 H), 3.68 - 3.87 (i, 2 H), 4.62 (t, (33) J9.37 Hz, 2 H), 4.82 (d, J=12.89 Hz, I H), 6.92 (t, J=7.62 Hz, H), 7.12 (d, J=7.03 Hz, I H), 7.33 (d, J7.42 Hz, I H). MS (M+1): 453.3. -58- WO 2007/142583 PCT/SE2007/000554 N (3aS,7aS)-1-[1-[1-(quinoline- IH NMR (400.MHz, CHLOROFORM-D): >o 4-carbonyl)-4-piperidyll-4- 5 ppm 1.15 - 1.52 (in, 6 H), 1.55 -1.87 (in, 10 r~ piperidyl-3a,4,5,6,7,7a- H), 1.89 -2.11 (mn, 2 H), 2.40 - 2.62 (in, I H), N~ hexahydro-3H-benzoimidazol- 2.77 -3.11 (in, 6 H), 3.38 (d, J=1 3.28 Hz, I H), 62-one 3.73 (s, I H), 4.47 (s, I H), 4.93 (t, J=1 1.72 Hz, N 1 H), 7.27 -7.36 (in, 1 H), 7.59 (q, J=7.81 Hz, 1 N o N (34) M M1:423 )o methylpyrrole-2-carbonyl)-4- 8 ppm 1.25 - 1.55 (mn, 5 H), 1.57 - 1.72 (in, 3 H), 6 piperidyl]-4-piperidyl]- 1.72 - 2.00 (i, 7 H), 2.12 - 2.36 (i, 3 H), 2.53 N 3a,4,5,6,7,7a-hexahydro-3H- (t, J=1 1.33 Hz, 1 H), 2.79 -3.10 (in, 6 H), 3.69 benzoimidazol-2-one 3.83 (in, I H), 3.77 (s, 3 H), 4.43 (s, I H), 4.56 (d, J=1 2.50 Hz, 2 H), 6.04 -6.10 (in, I H), 6.28 H )=o 6.36 (i, I H), 6.68 (s, 1 H). MS (M+1): 414.2. (35) H(3aS,7aS)-1 -[I1-[1 -(1,5- 1H NMR (400 MHz, CHLOROFORM-D): N dimethylpyrrole-2-carbonyl)-4- 5 ppm 1.11 - 1.57 (m, 6 H), 1.62 - 2.01 (m, 10 6 piperidylj-4-piperidyl]- H), 2.23 (s, 3 H), 2.31 (d, J=10.16 Hz, 2 H), N 3a,4,5,6,7,7a-hexahydro-3H- 2.52 (s, I H), 2.74 - 3.16 (i, 6 H), 3.63 (s, 3 H), benzoimidazo!-2-one 3.78 (s, I H), 4.48 (s, I H), 4.58 (d, J=12.89 Hz, 2 H), 5.85 (d, J3.52 Hz, I H), 6.23 (d, J=3.52 Hz, I H). MS (M+1): 428.3. (36) H (3aS,7aS)-1-[[1--(2- IH NMR (400 MHz, METHANOL-D4): cyclohexylbenzoyl)-4- S ppm 1.18 - 1.46 (m, 10 H), 1.46 - 1.67 (m, 3 6' piperidyl]-4-piperidyl]- H), 1.67 - 2.08 (m, 12 H), 2.20 - 2.46 (m, 3 H), 3a,4,5,6,7,7a-hexahydro-3H- 2.53 (t, J=1 0.55 Hz, I H), 2.59 - 2.75 (m, H), benzoimidazol-2-one 2.82 (t, J=1 3.28 Hz, I H), 2.89 -3.16 (i, 5 H), 3.48 (t, J=12.50 Hz, I H), 3.62 (t, J=12.11 Hz, H), 4.77 (t, J=13.67 Hz, I H), 7.06 (d, J7.03 Hz, I H), 7.11 -7.18 (m, I H), 7.17 - 7.27 (m, J=7.42, 7.42 Hz, I H), 7.31 - 7.41 (, I H). MS (M+1): 493.3. -59- WO 2007/142583 PCT/SE2007/000554 (3aS,7aS)-1-[1-[1-(2- 1H NMR (400 MHz, CHLOROFORM-D): morpholin-4-ylbenzoyl)-4- 8 ppm 1.14- 1.61 (i, 4 H), 1.61 -1.89 (i, 8 H), 6 piperidyl]-4-piperidyl]- 1.89 - 2.03 (i, 2 H), 2.18 - 2.41 (m, 3 H), 2.44 3a,4,5,6,7,7a-hexahydro-3H- 2.64 (i, 1 H), 2.66 -2.87 (i, 4 H), 2.88 -3.14 (16) benzoimidazol-2-one (i, 4 H), 3.16 - 3.26 (i, 1 H), 3.28 - 3.38 (i, 1 H), 3.38 - 3.50 (m, I H), 3.67 - 3.92 (m, 5 H), 4.47 (s, I H), 4.85 (t, J=11.72 Hz, I H), 6.95 gj 7.12 (m, 2 H), 7.16 - 7.20 (7.26 - 7.30) (m, I H), (38) 7.35 (t, J=7.81 Hz, I H) MS (M+1): 496.3. (3aS,7aS)-1-[1-[1-(2- IH NMR (400 MHz, CHLOROFORM-D): N phenylbenzoyl)-4-piperidyl]-4- 8 ppm 0.82 - 0.99 (i, 1 H), 1.01 - 1.19 (i, I H), piperidyl]-3a,4,5,6,7,7a- 1.21 - 1.46 (i, 4 H), 1.48 - 1.84 (i, 7 H), 1.84 N hexahydro-3H-benzoimidazol- 1.96 (i, I H), 1.98-2.13 (i, 2 H), 2.16-2.34 2-one (i, 3 H), 2.34-2.54 (i, 2 H), 2.60 (t, J1 1.91 Hz,- H), 2.72 - 2.87 (m, I H), 2.87 - 3.03 (m, 2 H), 3.12 - 3.29 (m, 1 H), 3.54 - 3.74 (m, 1 H), 4.66 - 4.82 (m, 2 H), 7.19 - 7.46 (m, 8 H), 7.52 (39) (d, J=7.81 Hz, I H). MS (M+1): 487.3. N (3aS,7aS)-1-[1-[1-[3-(2- HCI salt-IH NMR (400 MHz, METHANOL-D4): oxopyrrolidin-1-yl)propanoyl]- 8 ppm 1.32 - 1.52 (m, 5 H), 1.54 - 1.73 (m, I H), 4-piperidyl]-4-piperidyl]- 1.73 - 2.03 (m, 6 H), 2.04 - 2.14 (m, 2 H), 2.14 3a,4,5,6,7,7a-hexahydro-3H- 2.27 (m, 2 H), 2.28 - 2.56 (m, 5 H), 2.57 - 2.84 benzoimidazol-2-one (m, 3 H), 2.94 - 3.09 (m, 2 H), 3.10 - 3.25 (m, 3 H), 3.46 - 3.75 (m, 7 H), 3.77 - 3.93 (m, 1 H), 4.14 (d, J=13.67 Hz, 1 H), 4.67 (d, J=1 3.28 Hz, K7L 0 I H). (40) MS (M+1): 446.3. H (3aS,7aS)-1-[1-[1-(2,2- 1H NMR (400 MHz, METHANOL-D4): Q o dimethylpropanoyl)-4- 8 ppm 1.19- 1.30 (i, I H), 1.28 (s, 9 H), 1.33 piperidyl]-4-piperidyl]- 1.50 (i, 4 H), 1.52 - 1.73 (m, 2 H), 1.75 - 1.90 N 3a,4,5,6,7,7a-hexahydro-3H- (i, 2 H), 1.88- 2.10 (i, 3 H), 2.13 -2.34 (i, 4 benzoimidazol-2-one H), 2.35 - 2.52 (i, 1 H), 2.82 -2.95 (i, 2 H), S2.96 - 3.07 (im, 2 H), 3.06 -3.22 (i, 2 H), 3.39 0 3.54 (m, 1 H), 3.55 - 3.70 (m, 2 H), 3.69 - 3.86 (m, I H), 4.60 (d, J=1 1.72 Hz, 2 H). -60 - WO 2007/142583 PCT/SE2007/000554 (41) MS (M+1): 391.2. H (3aS,7aS)-1-[1-[1 (3SaS-1[1[1 I H NMR (400 MHz, METHANOL-D4) HcI salt: N (cyclopentanecarbonyl)-4- 8 ppm 1.28- 1.47 (i, 5 H), 1.51 -2.04 (i, 13 piperidyl]-4-piperidyl]- H), 2.08 - 2.34 (m, 4 H), 2.34 - 2.51 (m, I H), 3a,4,5,6,7,7a-hexahydro-3H- 2.63 (t, J=12.89 Hz, I H), 2.94 - 3.22 (i, 7 H), N benzoimidazol-2-one 3.40 - 3.53 (i, I H), 3.56 - 3.67 (i, 2 H), 3.68 0-1-03.83 (in, 1 H), 4.28 (d, J=14.06 Hz, 1 H), 4.72 (42) (d, J15.62 Hz, I H). MS (M+1): 403.3 (3aS,7aS)-1-[1-[1-(3- 1H NMR (400 MHz, CHLOROFORM-D): N O methoxythiophene-2- 8 ppm 1.27 - 1.57 (i, 6 H), 1.61 - 1.71 (i, 1 H), carbonyl)-4-piperidyl]-4- 1.69- 1.89 (m, 8 H), 1.94 (d, 1=10.55 Hz, I H), N piperidyl]-3a,4,5,6,7,7a- 2.17-2.35 (i, 3 H), 2.42 -2.56 (i, 1 H), 2.77 hexahydro-3H-benzoimidazol- 3.09 (i, 6 H), 3.61 - 3.81 (i, I H), 3.88 (s, 3 2-one H), 4.13 - 4.43 (m, I H), 4.55 (s, I H), 6.75 (d, o
    S
    3=5.27 Hz, I H), 7.30 (d, J=5.47 Hz, 1 H). 0 MS (M+1): 447.3 (43) (3aS,7aS)-1-[1-[1-(thiophene- IH NMR (400 MHz, CHLOROFORM-D): N li N 2-carbonyl)-4-piperidyl]-4- 8 ppm 1.25 - 1.60 (m, 6 H), 1.60 - 2.05 (m, 9 H), 6 piperidyl]-3a,4,5,6,7,7a- 2.11 - 2.33 (m, 3 H), 2.48-2.60 (m, I H), 2.88 N hexahydro-3H-benzoimidazol- 3.10 (m, 6 H), 3.64 - 3.80 (m, I H), 4.25 - 4.62 2-one (i, 2 H), 4.52 (s, I H), 7.02 (d, J=4.98 Hz, I H), o N 7.13- 7.32 (i, I H), 7.41 (d, J=5.08 Hz, 1 H). MS (M+1): 417.3 (44) (3aS,7aS)-I-1-[1-(3- 1H NMR (400 MHz, CHLOROFORM-D): Smethylthiophene-2-carbonyl)- 8 ppm 1.19 - 1.52 (m, 5 H), 1.57 - 1.66 (m, 9 H), 4-piperidyl]-4-piperidyl2- 1.66 - 1.87 (m, 7 H), 1.84 - 2.02 (m, I H), 2.12 N ~3a,4,5,6,7,7a-hexahydro-3H- 2.32 (in, 3 H), 2.21 (s, 3 H ), 2.46 (t, J= 11. 13 6Nbenzoimidazol-2-one Hz, 1 H), 2.74 - 3.04 (i, 6 H), 3.40 (s, I H), S 3.62 -3.78 (m , I H), 4.00 -4.51 (m , 2 H), 4.74 2n4.91 (mi, 1 H), 6.78 (d, J =5.08 Hz, I H), 7.22 (d, .13 J=4.69 Hz, I H). MS (M+1): 431.3 (3aS7aS-1-1-[ - 61- WO 2007/142583 PCT/SE2007/000554 H (3aS,7aS)-1-[1-[1-(2- 1H NMR (400 MHz, CHLOROFORM-D): }=O chlorobenzoyl)-4-piperidyl]-4- 5 ppm 1.24 - 1.49 (i, 4 H), 1.51 - 1.87 (i, 7 H), piperidyl]-3a,4,5,6,7,7a- 1.88- 2.01 (m, 2 H), 2.18-2.36 (m, 3 H), 2.44 N hexahydro-3H-benzoimidazol- 2.60 (i, I H), 2.70 - 2.86 (m, I H), 2.88 - 3.03 2-one (i, 5 H), 3.03-3.16 (m, I H), 3.44 (s, I H), S3.41 -3.55 (m, H), 3.66 - 3.83 (, 1 H), 4.82 (t, J=15.04 Hz, 1 H), 5.04 (s, I H), 7.19 - 7.36 (m, 3 H), 7.37 - 7.46 (m, I H). MS (M+1): 445.3, 446.3 H (3aS,7aS)-1-[1-[1- HCi salt-IH NMR (400 MHz, METHANOL-D4) 8 }= (cyclobutanecarbonyl)-4- ppm 1.30- 1.50 (m, 5 H), 1.53 -1.71 (i, 2 H), piperidyl]-4-piperidyl]- 1.74 - 2.08 (i, 6 H), 2.11 - 2.37 (i, 6 H), 2.36 N 3a,4,5,6,7,7a-hexahydro-3H- 2.51 (i, I H), 2.65 (t, J=12.70 Hz, I H), 2.93 benzoimidazol-2-one 3.20 (i, 6 H), 3.36 - 3.53 (i, 2 H), 3.53 - 3.70 ( in, 3 H), 3.70 - 3.89 ( 2, I H), 3.97 (d, J=14.45 Hz, I H), 4.67 (d, J=1 2.89 Hz, I H). (47) MS (M+1): 389.2 Example 48: Isopropyl 4-[(3aR,7aR)-2-oxooctahydro-1H-benzimidazol-1-yI]-1,4' bipiperidine-1'-carboxylate H N O 5 0 Step A: The preparation of benzyl 4-oxo-1,4'-bipiperidine-1'-carboxylate - 62 - WO 2007/142583 PCT/SE2007/000554 0 MeO oMe 0b N then 1 NHCI Benzyl 4-oxopiperidine-1 -carboxylate (29.5 g, 126 mmol), 4,4-dimethoxypiperidine hydrochloride (20 g, 110 mmol), and trietylamine (16.9 mL, 1121 mmol) were stirred in 1,2-dichloroethane (600 mL). Sodium triacetoxyborohydride (30.4, 143 mmol) was 5 added at 0*C (over 30 minutes) followed by acetic acid (8.2 mL, 143 mmol) and the solution was stirred at room temperature for 24h. IN NaOH (100 mL) was added to the mixture and the solution was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in acetone (300 mL) 10 and HCI (50 mL, 5N to 6N in 2-propanol ) was added and was heated at reflux overnight. The mixture was concentrated in vacuo, diluted with dicloromethane (1 00ml) and extracted with HC I1N (4 x I 00ml). The aqueous extracts were combined and basified with NaOH pallets. The solution was then extracted with dichloromethane (3 x 100 mL), combined organic extracts were dried with anhydrous sodium sulphate, filtered and 15 concentrated in vacuo to afford the titled compound (23 g, 66%) 'H-NMR (300 MHz,
    CD
    3 OD): & 7.30 (5H, m), 5.10 (2H, s) 4.21 (2H, d, J = 13.5 Hz) 2.87 (4H, t, J= 6.2 Hz), 2.77-2.70 (1 H, m) 2.62-2.58 (2H, m), 2.40 (2H, t, J = 6.2 Hz ) 1.86 (2H, d, J = 12.0 Hz), 1.75 (2H, t, J = 5.6 Hz) 1.42 (2H, m). 20 Step B: The preparation of 4-((R,R)-2-amino-cyclohexylamino)-[1, 4']bipiperidinyl-1' carboxylic acid benzyl ester -63- WO 2007/142583 PCT/SE2007/000554 NHNH2 [H] 00 N The (RR)-1,2-diaminocyclohexane (7.2 g, 63.2 mmol), acetic acid (2.71 ml, 47.4 mmol), sodium triacetoxyborohydride (8.71 g, 41.1 mmol) were stirred in a mixture of 1,2 5 dichloroethane (125 mL). N-CBZ-piperidinylpiperidone (10.0 g, 31.6 mmol) solution in dichloromethane (1 25mL) was added at 00C (over 3 hours) and the solution was stirred at room temperature for 3 days. A IN NaOH solution (100 mL) was added to the mixture and was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried with anhydrous sodium sulphate, filtered and concentrated under reduced 10 pressure to give the title product (14.22 g), which was used for next step without purification. Step C: The preparation of 4-((3aR,7aR-2-Oxo-octahydro-benzimidazol-1-yl)-[1,4'] bipiperidinyl-1'-carboxylic acid benzyl ester 15 H NH2 N~>= NH triphosgene N N N N N A solution of triphosgene (4.7 g, 15.8 mmol) and trietylamine (8.8 mL, 63.2 mmol) in anhydrous dichloromethane (300 mL) was added with a solution of N-CBZ-4-(RR)-(2 20 oxo-octahydro-benzoimidazol-1-yi)-piperidine (5.80 g, 19.8 mmol) in dichloromethane -64- WO 2007/142583 PCT/SE2007/000554 (100 mL) dropwise and was stirred at room temperature for 24 h. A 5% aqueous sodium bicarbonate (100 mL) was added to the mixture, the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic portions were washed with 5% aqueous sodium bicarbonate (100 mL), dried with 5 anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by flash-chromatography using 0-40% methanol in AcOEt and was further purified by recrystallization in acetonitrile to provide the titled compound (2.05 g, 14% in 2 steps),H NMR (300 MHz, CD30D): 5 7.3 (5H, m), 5.1 (2H, s) 4.77 (1H, m) 4.21 (2H, m) 3.72 (1H, m) 2.96 (4H, m), 2.74 (2H, t, J = 11.4 Hz) 2.41 (1H, t, J = 11.2 Hz) 2.17-2.29 (3H, m), 10 1.92-1.98 (1H, m) 1.62-1.77 (8H, m), 1.30-1.41 (6H, m). ' 3 C-NMR (75 MHz, CD 3 0D): S 163.9, 155.4, 137.1, 128.7, 128.2, 128.1, 67.3, 62.3, 62.1, 58.9, 51.3, 49.4, 49.1, 43.9, 32.4, 30.7, 29.8, 29.0, 28.4, 28.2, 24.4, 24.0 Step D: The preparation of (3aR,7aR)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol 15 2-one H H2/Pd/C N MeOH N N O- N To a solution of benzyl 4-[(3aR,7aR)-2-oxooctahydro-IH-benzimidazol-1-y]-1,4' bipiperidine-1'-carboxylate- (880 mg, 2.0 mmol) in methanol (25 mL) was added 10% 20 Pd/C (0.1 g), the mixture was hydrogenated at 40 psi for 12 h. Filtration of catalyst and concentration of solvents afforded crude product (600 mg, 98%), which was used for the next step without further purification. MS (M+1): 307.31 Step E: The preparation of isopropyl 4-[(3aR,7aR)-2-oxooctahydro-IH-benzimidazol-1 25 yl]-1,4'-bipiperidine-1'-carboxylate H N ci M H DIPEA N N N 0 -65- WO 2007/142583 PCT/SE2007/000554 The crude product from step A ((3aR,7aR)-1 -(1,4'-bipiperidin-4-yl)octahydro-2H benzimidazol-2-one, 0.25 mmol) was dissolved in dry dichloromethane (5 mL), and cooled to -20'C. A solution of 0.1 N isopropyl chloroformate in dichloromethane (2.2 mL, 0.9 eq.) was added drop wise and the reaction mixture was stirred at -20"C for 10 min. 5 Saturated NaHCO 3 (5 ml) was added followed by dichloromethane (20 mL), the phases were separated and the aqueous was extracted with dichloromethane (2xlOml). The combined organic phases were washed with brine, dried over Na 2
    SO
    4 , filtered, and concentrated in vacuo. The crude produced was purified with high pH prep-LCMS to give the title compound (42 mg, 43%). 1 H NMR (400 MHz, METHANOL-D4): 8 ppm 1.21 (d, .10 J=6.25 Hz, 6 H), 1.30 - 1.49 (m, 6 H), 1.53 - 1.73 (m, 2 H), .1.74 - 2.04 (m, 7 H), 2.17 2.37 (m, 3 H), 2.43 - 2.57 (m, I H), 2.64 - 2.85 (m, 2 H), 2.87 - 3.11 (m, 4 H), 3.50 - 3.73 (m, I H), 4.10 - 4.21 (m, 2 H), 4.74 - 4.84 (m, I H). MS (M+1): 393.2 Example 49: (3aR,7aR)-1-[1'-(cyclopropylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro 15 2H-benzimidazol-2-one HO H HN 0 N 0 - N" HATU N N DIPEA DMF N 0 To the solution of (3aR,7aR)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 20 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO 3 (10 mL) and brine (10 mL) and dried over Na 2
    SO
    4 .The crude product was purified with high pH prep-LCMS to provide the title 25 compound (48 mg, 51%) as white powder. I H NMR (400 MHz, METHANOL-D4): a ppm 0.61 - 0.81 (m, 4 H), 1.16.- 1.43 (m, 6 H), 1.50 - 1.67 (m, 2 H), 1.68 - 1.98 (m, 8 H), 2.13 2.29 (m, 3 H), 2.44 - 2.62 (m, 2 H), 2.80 - 3.10 (m, 5 H), 3.48 - 3.66 (m, I H), 4.31 (d, J=13.28 Hz, I H), 4.47 (d, J=13.28 Hz, I H). MS (M+1): 375.2 -66- WO 2007/142583 PCT/SE2007/000554 Example 50: (3aR,7aR)-1-[1'-(propylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro-2H benzimidazol-2-one HO N O H N /--,N -f00 HATU N N DIPEA N DMF N 0 To the solution of (3aR,7aR)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 5 0.25 mmol) in dry DMF (3 mL) was added butyric acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for I h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO 3 (10 mL) and brine (10 mL), and dried over Na 2
    SO
    4 .The 10 crude product was purified with high pH prep-LCMS to to provide the title compound (53 mg, 56%) as white powder. IH NMR (400 MHz, METHANOL-D4): 8 ppm 0.94 (t, J=7.42 Hz, 3 H), 1.25 - 1.48 (m, 6 H), 1.51 - 1.65 (m, 3 H), 1.68 (d, J=11.72 Hz, I H), 1.74 - 2.01 (m, 7 H), 2.19 - 2.32 (m, 3 H), 2.35 (t, J=7.62 Hz, 2 H), 2.55 (t, J=12.11 Hz, 2 H), 2.89 3.11 (m, 5 H), 3.56 - 3.69 (m, 1 H), 4.01 (d, J=1 3.28 Hz, I H), 4.57 (d, J=13.28 Hz, 1 H). 15 MS (M+1): 377.2 Example 51: (3aR,7aR)-1-[1'-(cyclopentylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro 2H-benzimidazol-2-one H H HO ~ ~ Nr HATU N N N IPEA MF N 0 20 To the solution of (3aR,7aR)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopentanecarboxylic acid (34 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for I h. The reaction was 25 quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO 3 (10 mL) and brine (10 mL) and dried over Na 2 SO4. The crude product was purified with high pH prep-LCMS to yield - 67- WO 2007/142583 PCT/SE2007/000554 (3aR,7aR)-1-[1'-(cyclopentylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro-2H-benzimidazol-2 one (64 mg,63%) as white powder. I H NMR (400 MHz, METHANOL-D4): 8 ppm 1.25 1.49 (m, 6 H), 1.53 - 1.73 (m, 8 H), 1.76 - 2.03 (m, 9 H), 2.18 - 2.36 (m, 3 H), 2.51 - 2.62 (m, 2 H), 2.91 - 3.11 (m, 6 H), 3.56 - 3.68 (m, I H), 4.13 (d, J=13.28 Hz, I H), 4.58 (d, 5 J=13.28 Hz, I H). MS (M+1): 403.3 Example 52: (3aR,7aR)-1 -{1'-[3-(2-oxopyrrolidin-1 -yl)propanoyl]-1,4'-bipiperidin-4 yl}octahydro-2H-benzimidazol-2-one H H HATU N DIPEA N DMF 0 0 10 To the solution of (3aR,7aR)-1 -(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one (0.25 mmol) in dry DMF (3 mL) was added 3-(2-oxopyrrolidin-1-yl)propanoic acid (47 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol). The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 15 mL) was added and washed with saturated NaHCO 3 (10 mL) and brine (10 mL) and dried over Na 2
    SO
    4 . The crude product was purified with High pH prep-LCMS to provide the title compound (53 mg,47%) as white powders. IH NMR (400 MHz, METHANOL-D4): 5 ppm 1.26 - 1.51 (m, 6 H), 1.55 - 1.73 (m, 2 H), 1.75 - 2.08 (m, 9 H), 2.19 - 2.37 (m, 5 H), 2.56 (t, J=1 1.91 Hz, 2 H), 2.64 (t, J=7.03 Hz, 2 H), 2.87 - 3.14 (m, 5 H), 3.43 - 3.55 (m, 4 H), 20 3.55 - 3.69 (m, 1 H), 3.99 (d, J=13.28 Hz, I H), 4.54 (d, J=13.28 Hz, I H). MS (M+1): 446.3 Example 53-57: The examples in the following table was prepared from (3aR,7aR) 1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one or its salt and 25 corresponding acid following the similar procedure described in Example 52 Structure Name Data (Example) -68- WO 2007/142583 PCT/SE2007/000554 N (3aR,7aR)-1-[1-(1-benzoyl-4- 1H NMR (400 MHz, CHLOROFORM-D): N piperidyl)-4-piperidyl- 8 ppm 1.25-1.61 (i, 5 H), 1.62-1.99 (i, 10 3a,4,5,6,7,7a-hexahydro-3H- H), 2.15 - 2.35 (i, 3 H), 2.44 - 2.59 (i, 1 H), benzoimidazol-2-one 2.65- 2.84 (m, I H), 2.87 - 3.08 (i, 5 H), 3.53 6 - 3.95 (in, 2 H), 4.51 (s, I H), 4.61 - 4.87 (in, I N 0 H), 7.30 - 7.50 (in, 5 H). MS (M+1): 411.2 (53) (3aR,7aR)-1-[I-[1 -(2- 1H NMR (400 MHz, CHLOROFORM-D): ON methylbenzoyl)-4-piperidyl]-4- 8 ppm 1.21 - 1.58 (m, 6 H), 1.58 - 1.86 (m, 7 piperidyl]-3a,4,5,6,7,7a- H), 1.87 - 1.99 (m, 2 H), 2.07 - 2.37 (n, 3 H), Nhexahydro-3H-benzoiinidazol- 2.24 (s, 3 H), 2.40 - 2.56 (in, I H), 2.73 (t, 2-one J -12.11 Hz, 1 H), 2.84 - 3.07 (m, 5 H), 3.49 0 ~(d, J=13.87 Hz, I H), 3.64 - 3.84 (in, I H), 4.55 (s, I H), 4.82 (d, J=I 1.91 Hz, 1 H), 7.04 (54) 7.27 , (m, 4 H). MS (M+1): 425.3 HDN >= 0 (3aR,7aR)-1 -[1-[1-(3- H NMR (400 MHz, METHANOL-D4) - HI methoxythlophene-2- salt-a ppm 1.27 - 1.57 (in, 5 H), 1.63 (d, N carbonyl)-4-piperidyl-4- J=12.89 Hz, I H), 1.72 (d, J14.45 Hz, H), N piperidyl]-3a,4,5,6,7,7a- 1.75 - 2.06 (i, 7 H), 2.19 - 2.38 (i, 4 H), 2.51 hexahydro-3H-benzoimidazol- -2.69 (i, 1 H), 2.85 - 3.17 (i, 8 H), 3.54 o N 2-one 3.73 (i, I H), 3.91 (s, 3 H), 6.95 (d, 5.47 Hz, I H), 7.53 (d, J=6.64 Hz, 1 H). MS (M+1): 447.0 (55) H (3aR,7aR)-1-[1-[1-(2- IH NMR (400 MHz, CHLOROFORM-D) II methoxybenzoyl)-4-piperidyll- a ppm 1.17- 1.57 (i, 5 H), 1.56-2.02 (i, 9 S4-piperidyl-3a,4,5,6,7,7a- H), 2.11 -2.34 (i, 3 H), 2.41 -2.53 (i, I H), hexahydro-3H-benzoimidazol- 2.59 -2.78 (i, I H) 2.77 - 3.07 (m, 5 H), 3.32 a2-one -t3.44 (, I H), 3.49 (d, J=53.48 Hz, I H), 01O 3.59 - 3.75 (in, I H), 3.78 (d, J=7.62 Hz, 3 H), 4.69 - 4.88 (i, 2 H), 6.87 (d, J8.40 Hz, 1 H), (56) 6.91 -6.98 (i, I H), 7.17 (d, J16.70 Hz, H), 7.26 - 7.36 (d, J H). MS (M+1): 441.1 -69- WO 2007/142583 PCT/SE2007/000554 :TH (3aR,7aR)-1-[1-[1-(2,6- IH MR (400 MHz, CHLOROFORM-D) N > dimethylbenzoyl)-4-piperidyl]- 8 ppm 1.19-1.55 (i, 5 H), 1.56 -2.02 (i, 10 4-piperidyl]-3a,4,5,6,7,7a- H), 2.12 -2.33 (i, 2 H), 2.17 (s, 3 H), 2.27 (s, hexahydro-3H-benzoimidazol- 3 H), 2.38 -2.52 (i, I H), 2.74 (t, J=12.60 2-one Hz, I H), 2.83 - 3.06 (m, 5 H), 3.34 - 3.47 (m, 1 H), 3.63 - 3.80 (m, I H), 4.49 - 4.69 (m, 2 H), 4.87 (d, J=1 3.67 Hz, 1 H), 6.92 - 7.05 (m, (57) 2 H), 7.07 - 7.20 (m, 1 H). MS (M+1): 439.1 Example 58: (trans (+I-))-l--[1-(thiophene-2-carbonyl)-4-piperidyl]-4-piperidyl) 3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one 5 H N (+1-) N N S Step A: The preparation of tert-butyl 4-[(trans (+/-))-2-oxooctahydro-IH-benzimidazol-I 10 yl]-1,4'-bipiperidine-1'-carboxylate H H -N )=O Q =O_ Q>=o) "I N (+I-) N (+-) H N - 70- WO 2007/142583 PCT/SE2007/000554 To a solution of (±)-(trans)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one. HCI (1.54 g, 5.95 mmol) in dichloromethane (30 mL) was added acetic acid (2 mL) and tert-butyl 4 oxopiperidine-1-carboxylate (2.75 g, 13.82 mmol). To this mixture was then added with sodium triacetoxy borohyrdide (4.4 g, 20.75 mmol) and stirred at room temperature over 5 night. More sodium triacetoxy borohyrdide (0.6 g, 2.83 mmol) was then added and the mixture stirred at room temperature overnight. The mixture was then quenched with water, diluted in dichloromethane (200 mL), washed with IN NaOH (7 mL) and brine (5 mL), dried and concentrated in vacuo. The crude product was then purified over silica gel (dichloromethane/ethylactate then dichloromethane/MeOH gradient) to provide the title 10 compound as a white solid (1 g). MS (M+1): 407.21 Step B: The preparation of (trans (+/-))-1-(1,4'-bipiperidin-4-yl)octahydro-2H benzimidazol-2-one H H Q)=O >=o ""N (+/-) (+1-) CN N N N 15 O O0 To a solution of tert-butyl 4-[(trans (+/-))-2-oxooctahydro-lH-benzimidazol-1-yl]-1,4' bipiperidine-1'-carboxylate (1g) in dichloromethane (20 mL) was added TFA (2 mL) and the mixture was stirred at room temperature over night. More TFA (2 mL) was then added and the mixture stirred for another 2 hours and then concentrated in vacuo to give 20 the titled product. MS (M+1): 307.19 Step B: The preparation of (trans (+/-))-1-[1-[1-(thiophene-2-carbonyl)-4-piperidyl]-4 piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one 25 -71- WO 2007/142583 PCT/SE2007/000554 H H N N >0(+/-) (+/-):N N NN N N0 To a solution of (trans (+/-))-l-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2 one.2TFA (180 mg, 0.31 mmol) in a mixture of dichloromethane and chloroform (1:4) was added diisopropylethylamine (0.2 mL, 1.1 mmol) followed by thiophene-2-carbonyl 5 chloride (0.1 mL, 0.6 mmol) at room temperature. The mixture stirred 48 hours and then quenched with water. Diluted in dichloromethane (60 mL) and washed with 1N NaOH (5 mL) and brine (5 mL) and concentrated in vacuo. The crude was purified by high pH prep LCMS (acetonitrile/water) to provide 26 mg of the title compound as a white solid. IH NMR (400 MHz, CHLOROFORM-D): 6 ppm 1.26 - 1.58 (m, 6 H), 1.59 - 2.03 (m, 9 H), 10 2.12 - 2.34 (m, 3 H), 2.44 - 2.64 (m, I H), 2.82 - 3.06 (m, 6 H), 3.62 - 3.84 (m, 1 H), 4.29 4.57 (m, 2 H), 4.63 (s, I H), 7.01 (d, J=5.08 Hz,1 H), 7.18 - 7.27 (m, 1 H), 7.35 - 7.46 (m, I H). MS (M+I): 417.3 Example 59: (trans (+/-))-1-[1-[1-(2-phenylacetyl)-4-piperidyl]-4-piperidyl] 15 3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one H H N -"'N (+/-) N N H 0 To a solution of (trans (+/-))-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2 20 one.2TFA (180 mg, 0.31 mmol) in a mixture of dichloromethane and chloroform (1:4) was added diisopropylethylamine (0.2 mL, 1.1 mmol) followed by phenylacetyl chloride -72 - WO 2007/142583 PCT/SE2007/000554 (0.1 mL, 0.6 mmol) at room temperature. The mixture stirred 48 hours and then quenched with water. The residue was then diluted in dichloromethane (60 mL) and washed with 1N NaOH (5 mL) and brine (5 mL) and then concentrated in vacuo. Crude was purified by high pH prep LCMS (acetonitrile/water) to provide 32 mg of the HCI salt 5 of the title compound as a white solid. IH NMR (400 MHz, CHLOROFORM-D) 5 ppm 1.00 - 1.53 (m, 6 H), 1.57 - 1.90 (m, 9 H), 1.97 (d, J=10.74 Hz, 1 H), 2.07 - 2.25 (m, 2 H), 2.29 (d, J=1 1.33 Hz, I H), 2.36 - 2.49 (in, I H), 2.49 - 2.64 (m, 1 H), 2.75 - 3.14 (m, 5 H), 3.61 - 3.82 (m, 2 H), 3.91 (d, J=13.09 Hz, I H), 4.52 - 4.86 (m, 2 H), 7.25 (s, 5 H). MS (M+1): 425.3 10 Example 60 and 61: Ethyl 4-[(3aR,7aS)-2-oxooctahydro-IH-benzimidazol-1-yl]-1,4' bipiperidine-1'-carboxylate and Ethyl 4-[(3aS,7aR)-2-oxooctahydro-IH benzimidazol-1-yl]-1,4'-bipiperidine-1'-carboxylate 0 0 HNo HN N N N N O N o 0 0 15 Step A: The preparation of cis (+/-)-ethyl 4-(2-oxooctahydro-I H-benzimidazol-1-yl)-1,4' bipiperidine-1'-carboxylate H 0 SNaBHcN HcI 0/ MeOH W(+-) 0 To a solution of cis-(+/-)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one hydrochloride salt (150 mg, 0.58 mmol) in 5 mL MeOH was added ethyl 4-oxopiperidine 20 1-carboxylate (119 mg, 0.69 mmol) and potassium acetate (1 eq). The mixture was stirred at room temperature for 30 min and sodium cyanoborohydride (182 mg, 2.90 mmol) was added. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in 20 mL DICHLOROMETHANE, and was washed with water. Organic layer was dried over MgSO 4 , filtered and concentrated 25 in vacuo. The crude was purified by High pH prep-LCMS to afford the desired racemic mixture as white solid (102 mg, 46%). MS (M+1): 379.3 Step B: Chiral Separation -73- WO 2007/142583 PCT/SE2007/000554 H H0 N N N o 0 The racemic mixture of cis (+/-)-ethyl 4-(2-oxooctahydro-IH-benzimidazol-1-yl)-1,4' bipiperidine-1'-carboxylate (102 mg) was separated by chiral AD column (20% EtOH/Hex.) to afford both enantiomers, Isomer 1 (30mg) and Isomer 2 (35mg). 5 Isomer 1: HPLC retention time = 5.146min, K: 0.24 (Chiralpak AD column, 4.6 x 250mm column 40%Isopropanol/60%hexane) 1 H NMR (400 MHz, CDCI 3 ): 5 ppm 1.12 - 1.22 (m, IH), 1.25 (t, J = 7.13 Hz, 3H), 1.34 - 1.50 (m, 3H), 1.49 - 1.96 (m, 15H), 2.27 (q, J = 11.72 Hz, 2H), 2.36 - 2.50 (m, 1 H), 2.64 - 2.81 (m, 2H), 2.87 - 3.02 (m, 2H), 3.53 - 3.63 10 (m, IH), 3.62 - 3.75 (m, 1H), 4.00 (s, 1H), 4.12 (q, J = 7.10 Hz, 1H), 4.20 (s, IH). MS (M+1): 379.3 Isomer 2: HPLC retention time = 5.706min, K': 0.37 (Chiralpak AD column, 4.6 x 250mm column 40%lsopropanol/60%hexane). 'H NMR (400 MHz, CDCI 3 ): 8 ppm 1.12 - 1.23 (m, 15 1H), 1.25 (t, J=7.03 Hz, 3H), 1.34 - 1.49 (m, 3H), 1.48 - 2.10 (m, 13H), 2.18 - 2.35 (m, 2H), 2.35 - 2.53 (m, I H), 2.72 (dd, J=1 1.82 Hz, 2H), 2.85 - 3.07 (m, 2H), 3.50 - 3.74 (m, 3H), 3.98 - 4.38 (m, 4H). MS (M+1): 379.3 Example 62: Isopropyl 4-{(3aR,7aS)-2-oxooctahydro-1 H-benzimidazol-1 -yI]-1,4' 20 bipiperidine-1'-carboxylate H 0 N N 0 Step A: The preparation of (1 R, 2R) (2-benzyloxycyclohexyl) carbainic acid tert-butyl ester 25 -74- WO 2007/142583 PCT/SE2007/000554 O (Boc) 2 0 O NH2 K 'NHBoc 2 Et 3 N, CH 2
    C
    2 , rt To a solution of 2-benzyloxycyclohexylamine (5 g, 24.39 mmol) in dichloromethane (60 mL), di-tert-butyldicarbonate (6.4 g, 29.28 mmol) was added followed by the addition of 5 triethylamine (6.75 mL) at 0 0C. The reaction mixture was stirred at room temperature for 4 h, diluted with dichloromethane (80 mL), washed with saturated sodium bicarbonate solution (2 x 100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The crude compound obtained was purified by column chromatography on silica gel using 2% MeOH/ dichloromethane to give the desired 10 compound as a solid (7g, 95 %). MS (M+1): 306.07 Step B: The preparation of (1 R, 2R) (2-Hydroxycyclohexyl)-carbamic acid tert-butyl ester O 10% Pd/C, H2 OH NHBoc EtOAc:MeOH (9:1), 35 psi, 4 h NHBoc 15 To a solution of (1 R, 2R) (2-benzyloxycyclohexyl) carbamic acid tert-buty ester (7 g, .23 mmoles) in a 9:1 mixture of ethyl acetate and methanol (80 mL), 10% Pd-C (1.13 g) was added and hydrogenated at 35 psi for 4 h. The catalyst was removed by filtration through a celite pad. The filtrate was concentrated to give the title compound as an oil (4.7 g, 20 95%). MS: (M+1): 215.95 Step C: The preparation of methanesulphonic acid (1 R, 2R) (2-tert butoxycarbonylaamino)cyclohexyl ester OH MsCI Q OMs "NHBoc EtsN,CH 2
    CI
    2 , 0o C, 30 min NHBoc 25 -75- WO 2007/142583 PCT/SE2007/000554 To a mixture of (1 R, 2R) (2-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (4.7 g, 21.86 mmol) and triethylamine (6.08 mL) in dichloromethane (80 mL), methanesuiphonyl chloride (2.0 mL, 26.23 mmol) was added at 0 0C. The reaction mixture was stirred at 0C for 30 min and then brought to room temperature. Reaction mixture was diluted with 5 dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (80 mL), organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by flash chromatography (Dichloromethane: MeOH = 98:2) to give the tile compound as an oil (5.6 g, 87% ). MS: (M+1): 294.12 10 Step D: The preparation of (1 R, 2S) (2-Azidocyclohexyl-carbamic acid) tert-butyl ester OMs NaN. N3 NHBoc DMF NHBoc 70 OC, 48 h To a solution of (1 R, 2R) methanesulphonic acid (2-tert 15 butoxycarbonylaamino)cyclohexyl ester ( 5.6 g, 19.11mmol) in DMF (60 mL), sodium azide (7.45 g, 114.66 mmol) was added and the reaction mixture was stirred at 70 0C for 18 h. TLC examination indicated the reaction is incomplete, then additional 2.48 g of sodium azide was added, and stirring is continued for 24 h. Solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (100 mL), washed with 20 saturated sodium bicarbonate solution (2 x 35 mL) and brine (2 x 40 mL). The organic layer was collected and dried on sodium sulfate. The solvent was removed under reduced pressure and the product was purified by flash chromatography (Dichloromethane: MeOH = 99:1) to give the title compound as a solid (1.8 g, 40%). MS (M+1): 241.04 25 Step E: The preparation of (1 R, 2S) (2-amino-cyclohexyl)-carbamic acid tert-butyl ester N3 10% Pd/C,
    H
    2 NH 2 3 2 c NH2 NHBoc MeOH ,32 psi, 4 h NHBoc 30 To a solution of compound (1 R, 2S) (2-Azidocyclohexyl-carbamic acid) tert-butyl ester (1.8 g, 7.5 mmol) in methanol (20 mL), 10% Pd-C (360 mg) was added and hydrogenated at 32 psi for 4 h Parr hydrogenator. The reaction mixture was filtered on a -76 - WO 2007/142583 PCT/SE2007/000554 celite pad and the filterate was concentrated to give the tilte compound as a solid .(1.1 g, 69 %), which was used without further purification. MS:(M+1): 215.07 Step F: The preparation of (1S, 2R)-4-(2-tert-butoxycarbonylamino)-piperidine-1 5. carboxylic, acid benzyl ester 0 IN O Oc NHBoc NH NHBoc bCN 1.2 eq
    NH
    2 N NaBH(OAc), 1.6 eq 0 0
    CH
    2 C1 2 , rt, 2 days . To a mixture of (1 R, 2S) (2-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.1 g, 5.14 10 mmol) and N-benzyloxycarbonyl-4-pipeperidone (1.35 g, 6.16 mmol) in dichloromethane (50 mL), sodium triacetoxyborohydride (1.72 g, 8.2 mmol) was added and the reaction mixture was stirred for 2 days at room temperature. Reaction mixture was washed with sat. sodium bicarbonate solution (2 x 30 mL), organic layer was separated and dried over Na 2
    SO
    4 and concentrated under reduced pressure to give the crude product which 15 was further purified by triturating with diethyl ether to give the title compound (2 g, 90%). MS: (ESI) (M+1): 432.17 Step G: The preparation of {4-(2-aminocyclohexylamino)-piperidine-1-carboxylic acid benzyl ester)) C NHBoc NH2 NH TFA-CH 2 Cl 2 NH rt, O/N N CBz 20 CBz -77- WO 2007/142583 PCT/SE2007/000554 To a solution of compound (IS, 2R)-4-(2-tert-butoxycarbonylamino)-piperidine-1 carboxylic acid benzyl ester (2 g, 4.6 mmol) in dichloromethane (45 mL), TFA (5 mL) was added and stirred at room temperature for 18 h. Volatiles were removed under reduced pressure. The product was dissolved in ethyl acetate (60 mL) and washed with 10% 5 sodium carbonate solution (2 x20 ml) and brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.48 g, 96%). MS: (ESI) (M+1): 332.16 Step H: The preparation of 4-(2-oxo-octahydro-benzoimidazol-1-yl)-piperidine-1 10 carboxylic acid benzyl.ester N2 H0 NH CDI N Acetonitrile N CBz rt, O/N CBz To a solution of compound {4-(2-aminocyclohexylamino)-piperidine-1-carboxylic acid benzyl ester)) (1.48 g, 4.47mmoles) in acetonitrile (50 mL), 1,1'-carbonyldilmidazole (0.86g, 5.36mmole) was added and the reaction mixture was stirred at room temperature 15 for 18 h. Reaction mixture was concentrated under reduced pressure, dissolved again in dichloromethane (60 mL) washed with water (2 x 100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a solid (1.45 g, 90%). MS: (M+1): 358.13 20 Step I: The preparation of (1-piperidin-4-yl-octahydro)-benzoimidazol-2-one H
    H
    2 N 31-l bN Pd/C N CBz To a solution of compound 4-(2-oxo-octahydro-benzoimidazo-1-yl)-piperidine-1 carboxylic acid benzyl ester (1.45g, 4.06 mmol) in methanol (25 mL), 10% Pd/C (200 mg) 25 was added and hydrogenated at 32 psi in a Parr hydrogenator for 4 h. The catalyst was removed by filtration on a celite pad and the filtrate was concentrated to give the title compound as a solid (0.9 g, 90.6%). MS (M+1): 224.3 - 78- WO 2007/142583 PCT/SE2007/000554 Step J: The preparation of isopropyl 4 -[(3aR,7aS)-2-oxooctahydro-H-benzimidazol-1-yl] 1,4'-bipiperidine-1'-carboxylate H H N NNaCNBH3, ZnCl2 )=0 )=O MeOH, rt, 2 days Na=CNHZnI N0 N 5 0 O To a mixture of (1-piperidin-4-yl-octahydro)-benzoimidazol-2-one (0.9 g, 4 mmol) and 4 oxo-piperidine-1-carboxylic acid isopropyl ester (1.2 g, 6.48 mmol) in methanol (50 mL), sodium cyanoborohydride (0.750g, 12 mmol) followed by zinc chloride (1.08 g, 8 mmol) were added and the reaction mixture was stirred at room temperature for 2 days. Solvent 10 was removed under reduced pressure; to the residue 30 ml 1 M NaOH solution was added. The product was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried on MgSO 4 , filtered and concentrated under reduced pressure to afford the crude material. The product was purified by flash chromatography (Dichloromethane: MeOH 95:5) to give the title compound as a white solid (0.395g, 15 25%). MS: (M+1): 393.23 Example 63: Isopropyl 4-[(3aS,7aR)-2-oxooctahydro-1H-benzimidazol-1-yl]-1,4' bipiperidine-1'-carboxylate H 0 N Ny 0 20 Step A:The preparation of cis-(+I-)-tert-butyl 4-(2-oxooctahydro-1 H-benzimidazol-1 -yl) 1,4'-bipiperidine-1'-carboxylate -79- WO 2007/142583 PCT/SE2007/000554 N + NaBH 3 CN (---) NH O MeOH ( -HCI o N 0 To a solution of cis-(+/-)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one Hydrochloride salt (263 mg, 1.01 mmol) in MeOH (5 mL) was added tert-butyl 4 oxopiperidine-1-carboxylate (241 mg, 1.21 mmol). The mixture was stirred at room 5 temperature for 30 min before sodium cyanoborohydride (95 mg, 1.52 mmol) was added. The mixture was stirred overnight at room temperature, additional amount of tert-buty 4 oxopiperidine-1-carboxylate and sodium cyanoborohydride (1 eq each) were added and stirred at room temperature for 3 more days. MeOH was concentrated in vacuo, the residue dissolved in dichloromethane (20 mL) and washed with water. The organic layer 10 was dried over MgSO 4 , filtered and concentrated in vacuo. To provide the title compound (244 mg, 59%) MS (M+1): 407.4 Step B: The preparation of cis-(+/-)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2 one hydrochloride salt NHCl Dioxane N 2HCl (+1-) (+/-)H 150 A 4N solution of hydrochloric acid in dioxane (1.0 mL, 4.0 mmol) was added to a solution of cis-(+/-)-tert-butyl 4-(2-oxooctahydro-1 H-benzimidazol-1 -yl)-1,4'-bipiperidine-1' carboxylate (244 mg, 0.60 mmol) from Step A in dioxane (5 mL). The reaction was stirred at room temperature for 7 h and the mixture was concentrated in vacuo. The product 20 (251 mg) was used directly for the next step without further purification. MS (M+1): 307.4 Step C: The preparation of cis-(+/-)-isopropyl 4-(2-oxooctahydro-IH-benzimidazol-1-yl) 1,4'-bipiperidine-1'-carboxylate - 80 - WO 2007/142583 PCT/SE2007/000554 o ci O -2HCi KC0 3 N "O N H A ceto ne (+ -) N (+/-) NHN To a solution of cis-(+/-)-1-(1 ,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one hydrochloride salt from step B (70 mg, 0.18 mmol) in 5 ml acetone was added potassium carbonate (49 mg, 0.36 mmol) followed by 1M isopropyl chloroformate in toluene (0.36 5 mL, 0.36 mmol) and the mixture was stirred at room temperature for 3 h. Removal of solvent gave a residue, which was dissolved in dichloromethane, and then water was added. The mixture was passed through VARIAN CHEM ELUTIM cartridges. The cartridge was rinsed with dichloromethane (2x20 mL). The dichloromethane solution was concentrated in vacuo and the crude product was purified by high pH prep-LCMS H to 10 afford the title compound (40 mg, 56%). 'H NMR (400 MHz, CDCl 3 ): 8 ppm 1.14 - 1.21 (m, I H), 1.23 (d, J = 6.25 Hz, 6H), 1.33 - 1.48 (m, 3H), 1.48 - 1.67 (m, 6H), 1.66 - 1.95 (m, 8H), 2.43 (t, J = 10.94 Hz, 1H), 2.71 (t, J = 12.21 Hz, 2H), 2.95 (dd, J = 21.09, 10.35 Hz, 2H), 3.52 - 3.63 (m, 2H), 3.68 (t, J 12.01 Hz, 1H), 4.02 (s, IH), 4.20 (s, 2H), 4.80 4.98 (m, IH). MS (M+1): 393.3 15 Step D: Chiral Separation The racemic mixture obtained in from step C (35 mng) was separated on chiral OD column (30% EtOH/Hexane) to provide enantiomners, isomer 1 and isomer 2. 20 Isomer 1 (Example 63) (10 mg): (Identified as Example 63 by comparing retention time with Example 62 prepared by independent method described above) HPLC retention time = 7.956min, K': 0.92 (Chiralpak 00 column, 4.6 x 250mm column. 20%Ethanol/80%hexane): 1 H NMR (400 MHz, 0DC13) 8 ppm 1.24 (d, J = 6.25 Hz, 6H), 25 1.33 - 1.46 (mn, 1H), 1.50 -1.66 (in, 15H), 1.65 - 1.78 (in, 2H), 1.75 -2.08 (in, 4H), 2.21 2.56 (mn, 1H) 2.64 -3.13 (in, 2H), 3.49 -3.86 (in, 2H), 4.00 -4.41 (in, J = 67.57 Hz, 2H), 4.84 - 4.96 (mn, 1 H). MS (M+1): 393.2. - 81 - WO 2007/142583 PCT/SE2007/000554 Isomer 2 (Example 62) (10 mg): HPLC retention time = 9.160min (identical retention time as Example 62 prepared by independent method described above), K': 1.21 (Chiralpak OD column, 4.6 x 250mm column 20%Ethanol/80%hexane) 'H NMR (400 MHz, CDC 3 ) 6 5 ppm 0.84 - 1.15 (m, 2H), 1.24 (d, J = 6.25 Hz, 6H), 1.30 - 1.51 (m, 5H), 1.48 - 1.78 (m, 11 H), 1.78 - 1.97 (m, 2H), 1.96 - 2.22 (m, I H), 2.21 - 2.61 (m, I H), 2.61 - 3.09 (m, 2H), 3.18 - 3.82 (m, 3H), 3.89 - 4.46 (m, 2H), 4.83 - 4.97 (m, 1H). MS (M+1): 393.2 Example 64: cis(+/-)-1-(1'-benzoyl-1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol 10 2-one HN SCN CNy (+/-) 0 Step A: The preparation of cis-(+/-)-benzyl-4-(2-oxooctahydro-1 H-benzimidazol-1 -yl)-1,4' bipiperidine-1'-carboxylate H 0 0- N~ S+ bN NaBHCN N NH 0rO- + (+/-) -HoN o MeOH 15 Following the similar procedure described in step A of Example 60 and 61, cis-(+/-) benzyl-4-(2-oxooctahydro-1 H-benzimidazol-1-yl)-1,4'-bipiperidine-1'-carboxylate (800 mg, 94%) was obtained. MS (M+1): 441.4 20 Step B: The preparation of cis-(+/-)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2 one
    H
    2 , 10% Pd/C N EtOH N "1--N -NH -82- WO 2007/142583 PCT/SE2007/000554 To a solution of cis-(+/-)-benzyl-4-(2-oxooctahydro-1 H-benzimidazol-1 -yl)-1,4' bipiperidine-1'-carboxylate (800 mg, 1.82 mmol) in EtOH (50 mL) was added 10% Pd/C (80 mg) and the mixture was hydrogenated at 40 psi for 3 h. Filtration of catalyst on celite and removal of solvent afforded the title compound (372 mg, 67%), which was used 5 without further purification. MS (M+I1): 306.0 Step C: The preparation of cis(+/-)-1-(1'-benzoyl-1,4'-bipiperidin-4-yl)octahydro-2H benzimidazol-2-one H H O H N N- 0 -K N HATUDIPEA NON NH MF N *N (+1-) CN (+1-) -- ; 100 A solution of benzoic acid (21 mg, 0.17 mmol), HATU (63 mg, 0.17 mmol) and diisopropylethylamine (0.06 mL, 0.34 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. Crude cis-(+/-)-1 -(1,4'-bipiperidin-4-yl)octahydro-2H benzimidazol-2-one from Step B: The preparation of B (51 mg, 0.17 mmol) was added to 15 the solution and the mixture was stirred at room temperature for overnight. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (15 mL), washed with saturated NaHCO 3 and brine and dried over Na 2
    SO
    4 .The crude product was purified with high pH prep-LCMS to prvide the title compound (28 mg, 41%). 'H NMR (400 MHz, CDCla): 5 ppm 1.14 - 1.29 (m, 1H), 1.33 - 1.48 (m, 2H), 1.50- 2.00 (m, 13H), 2.19 - 2.36 20 (m, 2H), 2.46 - 2.60 (m, 1H), 2.65 - 2.86 (m, 1H), 2.88 - 3.10 (m, 3H), 3.53 - 3.63 (m, 2H), 3.63 - 3.74 (m, 1H), 3.74 - 3.91 (m, IH), 4.02 (s, IH), 4.77 (d, J = 9.18 Hz, IH), 7.36 7.44 (m, 5H). MS (M+1): 411.2 Example 65: cis (+/-)-1-[1'-(cyclopentylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro-2H 25 benzimidazol-2-one H CO2 H HN N NH N 0 Following the procedure of step C of Example 64, cis (+/-)-1-[1'-(cyclopentylcarbonyl) 1,4'-bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one ( 20 mg, 20%) was obtained. 'H NMR (400 MHz, CDCI 3 ) S ppm 1.07 - 1.27 (m, 1 H), 1.31 - 1.47 (m, 3H), 1.47 - 1.98 (m, - 83 - WO 2007/142583 PCT/SE2007/000554 20H), 2.14 - 2.37 (m, 2H), 2.39 - 2.65 (m, 2H), 2.81 - 3.06 (m, 4H), 3.49 - 3.66 (m, 2H), 3.68 (t, J = 11.91 Hz, 1H), 3.93 - 4.13 (m, 2H), 4.69 (d, J = 13.28 Hz, 1H). MS (M+1): 403.3 5 Exampie 66: cis (+/-)-i-[1'-(3-thienylcarbonyl).1,4'-bipiperdin-4-yl]octahydro-2H benzimidazol-2-one O
    CO
    2 H O NS N N,_ N N NHHATU N N N Following the procedure of step C of Example 64, cis (+/-)-1 -[1'-(3-thienylcarbonyl)-1,4' bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one (17 mg, 19%) was obtained. 1 H NMR 10 (400 MHz, CDCl 3 ) 5 ppm 1.13 -1.30 (m, 1 H), 1.31 - 2.04 (m, 17H), 2.14 - 2.40 (m, 2H), 2.46 - 2.62 (m, IH), 2.65 - 3.16 (m, 3H), 3.53 - 3.63 (m, 2H), 3.63 - 3.75 (m, 1H), 3.94 4.12 (m, 1H), 4.71 (s, 1H), 7.17 (dd, J = 4.98, 1.07 Hz, 1H), 7.33 (dd, J = 5.08, 2.93 Hz, IH), 7.50 (dd, J = 2.83, 0.88 Hz, IH). MS (M+1): 417.3 15 Example 67: cis (+I-)-1-[i'-(2-thienylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro-2H benzimidazol-2-one cO0 2 H HATU N N -) NH (+/-) N 0 Following the procedure of step C of Example 64, cis (+/-)-1-[1'-(2-thienylcarbonyl)-1,4' bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one (39 mg, 33%) was obtained. 1 H NMR 20 (400 MHz, CDCI 3 ): S ppm 1.13 - 1.28 (m, IH), 1.33 - 1.45 (m, 1H), 1.45 - 1.98 (m, 15H), 2.19 - 2.35 (m, 2H), 2.45 - 2.62 (m, IH), 2.85 - 3.08 (m, 4H), 3.53 - 3.63 (m, 2H), 3.63 3.76 (m, 1 H), 4.03 (s, I H), 4.50 (s, I H), 7.04 (dd, J = 4.98, 3.61 Hz, I H), 7.25 - 7.30 (m, IH), 7.43 (dd, J = 4.98, 0.88 Hz, IH). MS (M+1): 417.3 25 Example 68: cis (+/-)-1-(1'-butyryl-1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol 2-one - 84- WO 2007/142583 PCT/SE2007/000554 0-
    N
    HATU N ( )NH (+/) N 0 Following the procedure of step C of Example 64, cis (+/-)-1-(1'-butyryl-1,4'-bipiperidin-4 yl)octahydro-2H-benzimidazol-2-one (20 mg, 18%) was obtained. 'H NMR (400 MHz, CDCla): 8 ppm 0.96 (t, J = 7.32 Hz, 3H), 1.12 - 1.28 (m, IH), 1.30 - 1.97 (m, 17H), 2.16 5 2.37 (m, 4H), 2.39 - 2.60 (rn, 2H), 2.81 - 3.08 (m, 3H), 3.50 - 3.63 (m, 2H), 3.62 - 3.79 (m, 1H), 3.91 (d-, J = 12.50 Hz, IH), 4.01 (s, IH), 4.68 (d, J = 12.89 Hz, IH). MS (M+1): 377.3 Example 69: (3aS,7aS)-1-methyl-3-[1-[1-[3-(2-oxopyrrolidin-1 -yl)propanoyl]-4 piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydrobenzoimidazol-2-one O N N (N 10 0 Step A: The preparation of tert-butyl 4-[(3aS,7aS)-3-methyl-2-oxooctahydro-1 H benzimidazol-1-yllpiperidine-1 -carboxylate H N O N 6 0-2-oxooctahydro--1H To a solution of (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (1.5 g, 4.64 15 mmol) in DMF (30 mL) was added NaH (0.56 g, 14 mmol) and was stirred for one hour at room temperature. Methyl iodide (0.35 mL, 5.65 mmol) was then added dropwise and was stirred for 2 h at room temperature. The reaction was then quenched by slow -85- WO 2007/142583 PCT/SE2007/000554 addition of ice/water and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated NaHCO 3 aqueous solution and then with brine, dried and concentrated in vacuo to give the title compound, which was used for the next step without purification. MS (M+1): 338.3 5 Step B: The preparation of (3aS,7aS)-1-methyl-3-piperidin-4-yloctahydro-2H benzimidazol-2-one I O N C N Crude tert-butyl 4-[(3aS,7aS)-3-methyl-2-oxooctahydro-1 H-benzimidazol-1-yl]piperidine 10 1-carboxylate was dissolved in dioxane (10 mL) and 4 M HCI (5 mL) was then added. The mixture was stirred at room temperature and then concentrated in vacuo to provide a yellow-pale solid (1.38 g). The salt was then trated with MP-carbonate to give the free base of the title compound. MS (M+1): 238.3 15 Step C: The preparation of tert-butyl 4-[(3aS,7aS)-3-methy-2-oxooctahydro-1 H benzimidazol-1-yl]-1,4'-bipiperidine-1'-carboxylate ,N OCN 6N)=N N H (3aS,7aS)-1-methyl-3-piperidin-4-yloctahydro-2H-benzimidazol-2-one (1.13 g, 4.75 20 mmol) was dissolved in MeOH (10 mL) and tert-butyl 4-oxopiperidine-1-carboxylate (1g, 5.02 mmol) was then added. A solution containing sodium cyanoborohydride (0.49 g, 7.10 mmol) and ZnCl2 (0.38 g, 2.79 mmol) in MeOH (2 mL) was added and the mixture and stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane (150 mL). Organic layer was - 86 - WO 2007/142583 PCT/SE2007/000554 washed with IN NaOH (10 mL) and brine (5 mL), dried and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane-MeOH gradient) to provide the title compound as a white solid (1.6 g, 80%). MS (M+1): 421.4. 5 Step D: The preparation of (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)-3-methyloctahydro-2H benzimidazol-2-one N N N CN 0:0 + H Tert-butyl 4-[(3aS,7aS)-3-methyl-2-oxooctahydro-1 H-benzimidazol-1 -yi]-1,4'-bipiperidine 1'-carboxylate (1.6 g, 3.80 mmol) was dissolved in MeOH (20 mL), 4M HCI in dioxane 10 was added (4 mL) and the mixture stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo to provide a yellow-pale solid which was washed with MeOH to give the HCI salt of the title compound as a white solid (1.1g, 60 % for 4 Step B: The preparation of s). MS (M+1): 321.3 15 Step E: The preparation of (3aS,7aS)-1 -methyl-3-[1-[1-[3-(2-oxopyrrolidin-1 yl)propanoyl]-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydrobenzoimidazol-2-one) N N)=0 N N N N O NO H0 To a solution of (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)-3-methyloctahydro-2H-benzimidazol-2 20 one. 2 HCi (71 mg, 0.18 mmol) in DMF (4 mL) was added diisopropylethylamine (0.1 mL, 0.57 mmol) and 3-(2-oxopyrrolidin-1-yl)propanoic acid (34 mg, 0.2 mmol) at room temperature, the mixture was sonicated to dissolve the starting materials and HATU (75 -87- WO 2007/142583 PCT/SE2007/000554 mg, 0.2 mmol) was then added. The solvent was removed under reduced pressure and the mixture was diluted in dichloromethane (60 mL). The mixture was washed with iN NaOH (5 mL) and brine (5 mL) and concentrated in vacuo. The residue was then purified by high pH prep LCMS to provide the title compound as a white solid (44 mg, 49%). HCl 5 salt-1H NMR (400 MHz, METHANOL-D4) 8 ppm 1.24 - 1.53 (m, 4 H), 1.53 - 1.71 (m, 1 H), 1.76 - 2.11 (m, 7 H), 2.10 - 2.37 (m, 4 H), 2.41 (t, J=8.20 Hz, 3 H), 2.55 - 2.81 (m, 4 H), 2.66 (s, 3 H), 2.87 - 3.01 (m, 1 H), 3.05 - 3.22 (m, 3 H), 3.39 - 3.67 (m, 8 H), 3.74 3.89 (m, I H), 4.14 (d, J=14.45 Hz, I H), 4.67 (d, J=13.67 Hz, I H). MS (M+1): 460.2 10 Example 70: (3aS,7aS)-3-[1-[1-(cyclopropanecarbonyl)-4-piperidyl-4-piperidyl]-1 methyl-3a,4,5,6,7,7a-hexahydrobenzoimidazo-2-one =QO )=O N N N N H 0 To a solution of (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)-3-methyloctahydro-2H-benzimidazol-2 one. 2 HCI (71 mg, 0.18 mmol) in DMF (4 mL) was added diisopropylethylamine (0.1 mL, 15 0.57 mmol) and cyclopropanecarboxylic acid (32 gL, 0.4 mmol) at room temperature, the mixture was sonicated to dissolve the starting materials and HATU (75 mg, 0.2 mmol) was then added. The reaction mixture was stirred at room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (60 mL), the mixture was washed with IN NaOH (5 mL) and brine (5 mL) and then 20 concentrated in vacuo. The crude product was then purified by high pH prep- LCMS to provide the title compound as a white solid, which was converted to its HCl salt (60 mg, 78%). 1 H NMR (400 MHz, METHANOL-D4) 5 ppm 0.72 - 0.95 (m, 4 H), 1.24 - 1.53 (m, 6 H), 1.61 (d, J=12.50 Hz, I H), 1.70 (d, J=14.06 Hz, 1 H), 1.79 - 2.02 (m, 7 H), 2.03 - 2.12 (m, I H), 2.21 - 2.38 (m, 3 H), 2.50 - 2.65 (m, 2 H), 2.65 (s, 3 H), 2.87 - 2.98 (m, 1 H), 25 2.99 - 3.12 (m, 2 H), 3.14 (d, J=1 3.28 Hz, I H), 3.34 (s, 1 H), 3.51 - 3.73 (m, 1 H), 4.40 (d, J=13.28 Hz, I H), 4.56 (d, J=12.89 Hz, I H). MS (M+1): 389.2. Example 71: (3aS,7aS)-4-methyl-3-[1-[1-(2-methylbenzoyl)-4-piperidyl]-4-piperidyl] 3a,4,5,6,7,7a-hexahydrobenzoimidazol-2-one -88- WO 2007/142583 PCT/SE2007/000554 N O NN N (N H 0 jN To a solution of (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)-3-methyloctahydro-2H-benzimidazol-2 one. 2 HC1 (71 mg, 0.18 mmol) in DMF (4 mL) was added diisopropylethylamine (0.1 mL, 0.57 mmol) and 2-methylbenzoic acid (30 mg, 0.2 mmol) at room temperature, the 5 mixture was then sonicated to dissolve the starting material and HATU (75 mg, 0.2 mmol) was then added. The reaction mixture was stirred at room temperature and the solvent was removed under reduced pressure. The mixture was dissolved in dichloromethane (60 mL), washed with IN NaOH (5 mL) and brine (5 mL) and then concentrated in vacuo. The residue was then purified by high pH prep. LCMS to provide the title compound as a 10 white solid (44 mg, 51%). (HCI salt)1 H NMR (400 MHz, METHANOL-D4) 6 ppm 1.23 1.56 (m, 5 H), 1.60 (d, J=12.89 Hz, 1 H), 1.69 (d, J=11.72 Hz, I H), 1.74 - 1.96 (m, 6 H), 1.97 - 2.11 (m, 2 H), 2.23 (s, 3 H), 2.15 - 2.38 (m, 3 H), 2.51 - 2.62 (m, 2 H), 2.64 (s, 3 H), 2.83 (t, J=11.91 Hz, 1 H), 2.94 (t, J=10.16 Hz, I H), 3.04 (t, J=11.72 Hz, 3 H), 3.39 - 3.54 (m, I H), 3.57 - 3.71 (m, 1 H), 4.74 (d, J=12.89 Hz, I H), 7.03 - 7.42 (m, 4 H). 15 MS (M+1): 439.3. Example 72: (3aS,7aS)-1-[1-[1-(3-methoxythiophene-2-carbonyl)-4-piperidy]-4 piperidyl]-3-methyl-3a,4,5,6,7,7a-hexahydrobenzoimidazol-2-one N}=O -N N N N 0 S H-9 -89 - WO 2007/142583 PCT/SE2007/000554 To a solution of (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one.2 HCI (71 mg, 0.18 mmol) in DMF (4 mL) was added diisopropylethylamine (0.1 mL, 0.57 mmol) and 3-methoxythiophene-2-carboxylic acid (35 mg, 0.2 mmol) at room temperature, the mixture was then sonicated to to dissolve the starting materials and 5 HATU (75 mg, 0.2 mmol) was then added. The solvent was removed under reduced pressure and the mixture was diluted in dichloromethane (60 mL). The mixture was washed with IN NaOH (5 mL) and brine (5 mL) and concentrated in vacuo. The residue was then purified by high pH prep. LCMS to provide the title compound as a white solid (49 mg, 55%). 1H NMR (400 MHz, CHLOROFORM-D) 5 ppm 1.21 -1.41 (m, 4 H), 1.42 10 1.56 (m, 2 H), 1.57 - 1.67 (m, I H), 1.67 - 1.88 (m, 7 H), 1.99 (d, J=8.98 Hz, 2 H), 2.15 2.34 (m, 3 H), 2.40 - 2.57 (m, 2 H), 2.65 (s, 3 H), 2.78 - 2.89 (m, 2 H), 2.93 (t, J=9.96 Hz, 2 H), 3.43 (s, I H), 3.64 - 3.81 (m, 1 H), 3.85 (s, 3 H), 4.11 - 4.47 (m, 1 H), 6.74 (d, J=5.47 Hz, 1 H), 7.29 (d, J=5.47 Hz, I H). MS (M+1): 461.2. 15 Example 73: Ethyl 4-[4-[(3aS,7aS)-2-oxo-3-prop-2-enyl-3a,4,5,6,7,7a hexahydrobenzoimidazo-1-yI]-1-piperidyl]piperidine-1-carboxylate OKZ -O N N O 0 20 Step A: Preparation of tert-butyl 4-[(3aS,7aS)-3-allyi-2-oxooctahydro-1H-benzimidazol-1 yl]piperidine-1-carboxylate HI N NN - 90- WO 2007/142583 PCT/SE2007/000554 To a solution of (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (0.4 g, 1.24 mmol) in DMF (10 mL) was added NaH (123 mg, 3.1 mmol). The mixture was then stirred for one hour at room temperature. Allyl iodide (0.13 mL, 1.36 mmol) was then added drop wise and the stirring continued for 2 hours. The reaction was quenched by slow addition 5 of ice/water and the solvent was removed under reduced pressure. The residue diluted in dichloromethane (120 mL) and was washed with water (5 mL) and then brine, dried and concentrated in vacuo to prvide the title compound, which was .used for the next step without any purification. MS (M+1): 364.4. 10 Step B: Preparation of (3aS,7aS)-1-allyl-3-piperidin-4-yloctahydro-2H-benzimidazol-2 one N N Tert-butyl 4-[(3aS,7aS)-3-allyl-2-oxooctahydro-1H-benzimidazol-1-yl]piperidine-1 carboxylate was dissolved in methanol (20 mL) and 4 M HCI (7 mL) was then added. The 15 mixture was stirred at room temperature and then concentrated in vacuo. The salt was then converted to freebase by using MP-carbonate. MS (M+1): 264.2. Step C: Preparation of ethyl 4-[(3aS,7aS)-3-allyl-2-oxooctahydro-1H-benzimidazol-1-yl] 1,4'-bipiperidine-1'-carboxylate 6 N NN N. 20 WO 2007/142583 PCT/SE2007/000554 (3aS,7aS)-1-ailyl-3-piperidin-4-yioctahydro-2H-benzimidazol-2-one (183 mg, 0.69 mmol) was dissolved in MeOH (2 mL) and ethyl 4-oxopiperidine-1-carboxylate (100 pL, 0.66 mmol) was added. A solution of sodium cyanoborohydride (82 mg, 1.19 mmol) and zinc chloride (47 mg, 0.34 mmol) in MeOH (1 mL) was then added drop wise at room 5 temperature. The mixture was then stirred for 3 hours and then more sodium cyanoborohydride (40 mg) was added and the mixture stirred at room temperature over night. The solvent was then removed under reduced pressure and the residue was diluted in dichloromethane (80 mL). Washed with IN NaOH (5 mL) and brine, dried and concentrated in vacuo. The residue was purified by high pH prep LCMS to provide the 10 title compound (120 mg). 1H NMR (400 MHz, METHANOL-D4) Sppm 1.24 (t, J=7.03 Hz, 3 H), 1.28 - 1.48 (m, 6 H), 1.53 - 1.64 (m, 1 H), 1.65 - 1.74 (m, I H), 1.77 - 1.99 (m, 6 H), 1.99 - 2.10 (m, 1 H), 2.22 - 2.36 (m, 3 H), 2.42 - 2.58 (m, I H), 2.69 - 2.86 (m, 3 H), 2.89 3.11 (m, 3 H), 3.56 - 3.71 (m, I H), 3.72 - 3.78 (m, 2 H), 4.09 (q, J=7.16 Hz, 2 H), 4.17 (d, J=1 3.28 Hz, 2 H), 5.03 - 5.26 (m, 2 H), 5.62 - 5.84 (m, I H). MS (M+1): 419.2 15 Example 74: Ethyl 4-[(3aS,7aS)-3-isopropyl-2-oxooctahydro-1H-benzimidazol-1-yl] 1,4'-bipiperidine-1'-carboxylate - =O N N Step A: Preparation of tert-butyl 4-[(3aS,7aS)-3-isopropyl-2-oxooctahydro-1H 20 benzimidazol-1 -yl]piperidine-1 -carboxylate H N N)= NO N6 CO O NN To a solution of (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (0.4 g, 1.24 mmol) in DMF (10 mL) was added NaH (123 mg, 3.1 mmol) and the mixture was then - 92- WO 2007/142583 PCT/SE2007/000554 stirred for one hour at room temperature. Isopropyl iodide (0.14 mL, 1.36 mmol) was then added drop wise and the stirring continued for 2 hours. The reaction was quenched by slow addition of ice/water and the solvent was removed under reduced pressure. The residue diluted in dichloromethane (120 mL) and was washed with water (5 mL) and 5 brine, dried and concentrated in vacuo to give the tilte compound, which was used for the next step without any purification. MS (M+1): 366.3. Step B: Preparation of (3aS,7aS)-1-isopropyl-3-piperidin-4-yloctahydro-2H-benzimidazol 2-one N N 10 Tert-butyl 4-[(3aS,7aS)-3-isopropyl-2-oxooctahydro-1H-benzimidazol-1-yl]piperidine-1 carboxylate was dissolved in methanol (20 mL) and 4 M HCI (7 mL) was then added. The mixture was stirred at room temperature and then concentrated in vacuo to provide the title compound. MS (M+1): 266.34 15 Step C: Preparation of ethyl 4-[(3aS,7aS)-3-isopropyl-2-oxooctahydro-1H-benzimidazol I -yl]-1,4'-bipiperidine-1 -carboxylate N)=O N N (3aS,7aS)-1-isopropyl-3-piperidin-4-yloctahydro-2H-benzimidazol-2-one (85 mg, 0.3 20 mmol) was dissolved in MeOH (2 mL) and ethyl 4-oxopiperidine-1-carboxylate (48 pL, 0.32 mmol) was added. A solution of sodium cyanoborohydride (31 mg, 0.45 mmol) and zinc chloride (20 mg, 0.15 mmol) in MeOH (1 mL) was then added drop wise at room - 93 - WO 2007/142583 PCT/SE2007/000554 temperature. The mixture was then stirred for 3 hours and then more sodium cyanoborohydride (40 mg) was added and the mixture stirred at room temperature over night. The solvent was then removed under reduced pressure and the residue was diluted in dichloromethane (80 mL) and was washed with IN NaOH (5 mL), brine and 5 then dried and concentrated in vacuo. The residue was purified by high pH prep LCMS to provide the title compound (30 mg). Free Base-I H NMR (400 MHz, METHANOL-D4): 5 ppm 1.14 (dd, J=6.84, 5.27 Hz, 6 H), 1.20 (t, J=7.23 Hz, 3 H), 1.28 - 1.45 (m, 6 H), 1.54 (d, J=12.50 Hz, I H), 1.61 - 1.69 (m, 1 H), 1.75 - 1.92 (m, 6 H), 2.12 - 2.32 (m, 4 H), 2.38 - 2.52 (m, 1 H), 2.64 - 2.81 (m, 2 H), 2.80 - 2.92 (m, 2 H), 2.92 - 3.05 (m, 2 H), 3.52 - 3.65 10 (m, I H), 3.83 - 3.98 (m, I H), 4.05 (q, J=7.03 Hz, 2 H), 4.13 (d, J=13.28 Hz, 2 H). MS (M+1): 421.4 Example 75: (3aS,7aS)-1-(1'-(1-methylcyclopropanecarbonyl)-1,4'-bipiperidin-4 yl)hexahydro-1 H-benzo[d]imidazol-2(3H)-one H H N N N N N N H 15 HBTU (284 mg, 0.75 mmol) was added to a solution of 1-methylcyclopropanecarboxylic acid (75 mg, 0.75 mmol), N,N-diisopropylethyl amine (194 mg, 1.50 mmol) and (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)hexahydro-1lH-benzo[dimidazol-2(3H)-one (153.22 mg, 0.50 mmol) in DMA (10 mL) and stirred at room temperature for overnight. Concentrated 20 in vacuo, diluted in dichloromethane (50ml) and washed with sat. NaHCO 3 (10mL). The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by high pH Prep LCMS to give the titled compound (40mg, 20.6%). IH NMR (400 MHz, CHLOROFORM-D): S ppm 0.51 - 0.59 (m, 2 H) 0.86 - 0.94 (m, 2 H) 1.30 (s, 3 H) 1.33 - 1.45 (m, 6 H) 1.68 (s, I H) 1.74 - 1.84 (m, 7 H) 1.96 (d, J=10.16 Hz, I 25 H) 2.21 - 2.32 (m, 3 H) 2.48 (t, J=11.13 Hz, 1 H) 2.76 (s, I H) 2.92 - 3.03 (m, 4 H) 3.71 3.81 (m, I H) 4.49 (s, 3 H). MS (M+1): 389.2 - 94- WO 2007/142583 PCT/SE2007/000554 Example 76-81: Examples 76-81 were prepared via HBTU coupling method similar to Example 75, starting from (3aS,7aS)-1-(1,4'-bipiperidin-4-yl)octahydro-2H benzimidazol-2-one and from the corresponding carboxylic acid Structure Name Data (Example) (3aS,7aS)-1-(1'-(2,2- IH NMR (400 MHz, CHLOROFORM-D): NI>=0 difluorocyclopropanecarbonyl)- 8 ppm 1.35 - 1.47 (m, 5 H) 1.61 - 1.72 (m, 2 1,4'-bipiperidin-4-yl)hexahydro- -H) 1.80 (dd, J=19.14, 9.37 Hz, 6 H) 1.87 N I H-benzo[d]imidazol-2(3H)-one 1.99 (m, 2 H) 2.09 - 2.17 (m, I H) 2.21 - 2.33 (mixture of diastereo isomers) (m, 3 H) 2.47 - 2.57 (m, 2 H) 2.62 - 2.69 (m, I H) 2.94 (m, 2 H) 2.97 - 3.05 (m, 2 H) 3.11 (td, J=1 1.72, 6.25 Hz, 1 H) 3.71 - 3.81 (in, I H) (76) 4.07 (d, J=12.11 Hz, 1 H) 4.53 (s, 1 H) 4.57 4.67 (m, I H). MS (M+1) = 411.2 ,~N (3aS,7aS)-1-(1'-(2- IH NMR (400 MHz, CHLOROFORM N methylcyclopropanecarbonyl)- 8 ppm 0.52 - 0.59 (m, 1 H) 1.11 (d, J=5.86 6 . 1,4'-bipiperidin-4-y)hexahydro- Hz, 3 H) 1.15 (d, J=3.52 Hz, I H) 1.33 - 1.45 N 1H-benzo[dimidazol-2(3H)-one (i, 7 H) 1.63-1.73 (i, I H) 1.77 (s, 2H) N (mixture of diastereo isomers) 1.79 (d, J=9.37 Hz, 5 H) 1.96 (d, J10.55 Hz, 1 H) 2.30 (d, J=10.16 Hz, 3 H) 2.47 - 2.59 (i, 2 H) 2.93 - 3.03 (m, 5 H) 3.71 - 3.81 (m, I H) (77) 4.23 (d, J=12.11 Hz, 1 H) 4.59 (s, 1 H) 4.64 (s, I H). MS (M+1) = 389.2 (3aS,7aS)-1-(1'-(1- 1H NMR (400 MHz, CHLOROFORM-D): OLN (trifluoromethyl)cyclopropaneCar 8 ppm 1.12-1.16 (i, 2 H) 1.30-1.35 (i, 2 bonyl)-1,4'-bipiperidin-4- H) 1.36- 1.44 (i, 6 H) 1.60 (s, 1 H) 1.69 (i, N~ yl)hexahydro-IH- I H) 1.74-1.81 (i, 6 H) 1.83 (s, 2 H) 1.96 (d, N benzo[d]imidazol-2(3H)-one J1 1.33 Hz, 1 H) 2.20 - 2.31 (i, 3 H) 2.45 2.51 (m, 1 H) 2.91 - 3.03 (m, 5 H) 3.71 - 3.80 FF F(m, 1 H) 4.41 (s, 2 H) . (78) MS (M+1) = 443.2 -95- WO 2007/142583 PCT/SE2007/000554 (3aS,7aS)-1-[1'-(3- 1H NMR (400 MHz, CHLOROFORM-D): N methyibutanoyl)-1,4'-bipiperidin- 5 ppm 0.92 (d, J=6.64 Hz, 6 H) 1.29 - 1.41 6N 4-ylloctahydro-2H-benzimidazol- (m, 6 H) 1.60 - 1.68 (m, I H) 1.69 - 1.80 (m, 6 2-one H) 1.92 (d, J=1 0.94 Hz, 1 H) 2.02 - 2.11 (m, -J=1 3.48, 7.03, 6.74, 6.74 Hz, I H) 2.15 - 2.27 o (m, 5 H) 2.39 - 2.51 (m, 2 H) 2.87 - 2.99 (m, 6 H) 3.66 - 3.76 (m, I H) 3.88 (d, J=12.89 Hz, 1 (79) H) 4.53 (s, I H) 4.65 (d, J=1 2.89 Hz, I H). MS (M+1) = 391..2 (3aS,7aS)-1-[1'-(1-acetyl-D- IH NMR (400 MHz, CHLOROFORM-D): prolyl)-1,4'-bipiperidin-4- 5 ppm 1.11 - 1.49 (m, 5 H), 1.51 - 1.96 (m, I1 N)=O yloctahydro-2H-benzimidazol-2- H), 1.95 - 2.30 (i, 4 H), 2.01 (s, 3 H), 2.33 S one 2.64 (m, 2 H), 2.75 - 2.99 (m, 5 H), 2.98 - 3.19 (m, 1 H), 3.30 - 3.41 (m, 1 H), 3.40 - 3.52 (m, 1 H), 3.52 - 3.75 (m, 2 H), 3.79 - 4.14 (m, 1 H), 4.52 (d, J=12.50 Hz, 1 H), 4.72 - 4.86 (m, 1 H), 4.87 - 5.06 (m, I H). 0 MS (M+1): 446.3. (80) (3aS,7aS)-1-(1'-isobutyryl-1,4'- 1H NMR (HCl salt) (400 MHz, METHANOL N - bipiperdin-4-y)octahydro-2H- D4): 5 ppm 0.99 - 1.17 (m, 6 H), 1.30 - 1.50 benzimidazol-2-one (m, 4 H), 1.52 - 1.75 (m, 2 H), 1.75 - 1.87 (m, 2 H), 1.92 (d, J=13.67 Hz, I H), 1.98 (d, J=8.59 Hz, 2 H), 2.14 - 2.38 (m, 5 H), 2.39 2.52 (m, 1 H), 2.64 (t, J=12.50 Hz, I H), 2.92 - 3.06 (m, 3 H), 3.08 - 3.25 (m, 3 H), 3.42 (81) ~3.56 (m, 1 H), 3.59 - 3.69 (m, 2 H), 3.83 (t, J=11.52 Hz, I H), 4.23 (d, J=14.45 Hz, 1 H), 4.72 (d, J=12.50 Hz, I H). MS (M+1): 377.2. - 96 - WO 2007/142583 PCT/SE2007/000554 Example 82: Isopropyl 4 -((3aS,7aS)-2-oxooctahydro-1H-benzo[d]imidazol-1-yl)-1,4' bipiperidine-1'-carboxylate Q N= NO NN NN (N CN HCIH 0 O HCI (3aS,7aS)-1 -(1,4'-bipiperidin-4-yl)hexahydro-1 H-benzo[djimidazol-2(3H)-one 5 dihydrochloride (0.68 g, 1.79 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.75 mL, 5.38 mmol) was added. Isopropyl chloroformate (1.792 mL, 1.79 mmol) (solution IM in toluene) was added drop wise at 0 0C. The mixture was stirred for 2 hours then diluted in dichloromethane (60 mL) and the mixture made basic with N NaOH. The phases were separated and aq. phase was extracted with dichloromethane 10 (2x25 mL). The combined organic phases were washed with brine (5 mL) and concentrated under reduced pressure. The crude was then purified by high pH prep LCMS to provide the tilte compound as a white solid (560 mg, 80%). 1H NMR (400 MHz, CHLOROFORM-D): 5 ppm 1.22 (d, J=6.25 Hz, 6 H), 1.26 - 1.49 (m, 6 H), 1.58 - 1.70 (m, 2 H), 1.72 - 1.84 (m, 7 H), 1.94 (d, J=1 1.33 Hz, I H), 2.14 - 2.32 (m, 3 H), 2.33 - 2.47 (m, 15 1 H), 2.69 (t, J=13.09 Hz, 2 H), 2.84 - 2.96 (m, 2 H), 2.96 - 3.06 (m, 1 H), 3.65 - 3.81 (m, 1 H), 4.07 - 4.28 (m, 2 H), 4.43 (s, 1 H), 4.80 - 4.94 (m, I H). MS (M+1): 393.2 Example 83-86: The examples in the following table was prepared from (3aS,7aS) 1-(1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one or its salt and with the 20 corresponding chloroformate following the similar method described in Example 82 Structure Name Data (Example) -97- WO 2007/142583 PCT/SE2007/000554 prop--n2y I-(aa2 1H NMR (400 MHz, CHLOROFORM-D): oxooctahydro-I H-benzo[d]imidazol- 8 ppm 1.36 (d, J=10.55 Hz, I H) 1.40 - 1.48 1-yI)-1 ,4-bipiperidine-1 '-carboxylate (in, 5 H) 1.65 - 1 .72 (in, 1 H) 1.74 - 1.85 (in, 7 N ~H) 1.92 - 2.00 (m, 3 H) 2.22 -2.33 (m, 3 H) 6 ~2.45 (ddd, J1l1.23, 8.11, 3.32 Hz, I H) 2.80 H 0.;4, 0(s, 2 H) 2.92 - 3.04 (mn, 4 H) 3.76 (ddd, K J=16.60, 12.11, 4.10 Hz, 1 H) 4.22 (s, 2 H) (83) 4.52 (s, 1 H) 4.66 (d, J5.47 Hz, 2 H). (MS) (M+1) = 391.2 2-fluoroethyl 4-[(3aS,7aS)-2- 1 H NMR (400 MHz, CHLOROFORM-D) N oxooctahydro-IH-benzimidazol-1-yl]- 5 ppm 1.34 (s, 2 H) 1.37-1.48 (i, 5 H) 1.68 1,4'-bipiperidine-1'-carboxylate (s, 2 H) 1.76 (s, 3 H) 1.79 (d, J=11.72 Hz, 5 i tH) 1.94 (s, H) 2.21 -2.33 (i, 3 H) 2.44 (t, J=10.94 Hz, 1 H) 2.77 (s, 2 H) 2.93 (t, ol'o J=pp 1.52 Hz, 2 H) 3.01 (d, J=6.64 Hz, 2 H) 3.71 - 3.80 (m, H) 4.29 (d, J4.30 Hz, 3 H) (84) 4.36 (s, I H) 4.47 (s, H) 4.51 -4.56 (, 1 H) 4.64 -4.68 (i, I H). MS (M+1) = 397.2 isobuty1 4-[(3aS,7aS)-2- IH NMR (400 MHz, CHLOROFORM-D) N oxoootahydro-I H-benzimidazol--y]- 8 ppm 0.87- (0.96 (i, 6 H) 1.33- 1.45 (i, 5 1,4'-bipiperidine-'-carboxy(ate H) 1.62- 1.72 (i, I H) 1.72 -1.3 (in, 7 H) (I.~ 1.87 - 1.99 (in, J= 13.28, 6.64, 6.64, 6.64, 6.64 -Hz, 2 H) 2.21 - 2.33 ( m, 3 H) 2.43 (ddt, J=1 1.43, 8.11, 3.52 Hz, I H) 2.73 (s, 2 H) (85) 2.93 (t, J= 0.94 Hz, 2 H) 2.98 - 3.03 (in, 2 H) 3.71 - 3.80 (m, I H) 3.85 (d, J=6.64 Hz, 2 H) 4.20 (s, 2 H) 4.56 (s, 1 H). MS (M+1) = 407.3 - 98- WO 2007/142583 PCT/SE2007/000554 102283-1 WO methyl 4-((3aS,7aS)-2-oxooctahydro N I H-benzimiiazol-1-yll-1,4'- IH NMR (400 MHz, CHLOROFORM-D) bipiperidine-1'-carboxylate 8 ppm 1.09 - 1.51 (m, 6 H), 1.55 -1.84 (m, 8 H), 1.92 (d, J=10.16 Hz, I H), 2.09 - 2.31 (m, 3 H), 2.37 (t, J=11.13 Hz, 1 H), 2.58 - 2.78 (m, 2 H), 2.87 (t, J=11.72 Hz, 2 H), 2.92 (86) 3.05 (m, 2 H), 3.62 (s, 3 H), 3.53 - 3.77 (m, 1 H), 3.96 - 4.31 (m, 2 H), 4.97 (bs, I H). MS (M+1): 365.2. Example 87: Ethyl 4-[4-[(3aR,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-indol-1-yI]-1 piperidyllpiperidine-1-carboxylate 5 N N N N Step A: The preparation of {(1 S,2S)-2-[(tert-butoxycarbony)amino]cyclohexyl}methy methanesulfonate 0 OH
    [I
    NH '- NH 10 tert-butyl [(1 S,2S)-2-(hydroxymethyl)cyclohexyllcarbamate (1.3 g, 5.68 mrnmol) was dissolved in dichloromethane (10 mL) and MsCI (0.52 mL, 6.75 mmol) was added drop wise at 0 OC. Triethylamine (1 mL) was then added and the mixture stirred for 2 hours. The reaction mixture was quenched with ice and diluted in dichloromethane. Washed 15 with a saturated solution of NaHCO 3 and brine, dried and concentrated in vacuo to provide the tile compound as brown solid (1.8 g). MS (M+1): 308.16 Step B: The preparation of tert-butyl [(1 S,2R)-2-cyanomethyl)cyclohexyllcarbamate -99- WO 2007/142583 PCT/SE2007/000554 0 O-S- awCN NH NH 00 00 The crude of {(1 S, 2 S)-2-[(tert-butoxycarbonyi)aminocyclohexyl}methy methanesulfonate (1.8 g) was dissolved in dry DMSO and potassium cyanide was added and the mixture 5 was then heated at 90 "C under N 2 for 4 hours. The mixture was cooled and then poured on to water (50 mL) and extracted with ether (30 mLx3). The combined organic phases were washed with brine and concentrated in vacuo to provide the title compound. Step C: The preparation of [(1 R, 2 S)-2-aminocyclohexyl]acetonitrile 10 CN CN NH
    NH
    2 0 0 The crude of tert-buty [(1 S, 2 R)-2-cyanomethyl)cyclohexyl]carbamate was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was added. The mixture stirred 15 for 2 hours the concentrated in vacuo to provide the tile compound as a yellow oil. The mixture was then converted to freebase by MP carbonate work-up (1.1 g). Step D: The preparation of tert-butyl 4-{[(1 S,2R)-2 (cyanomethyl)cyclohexyljamino}piperidine- -carboxylate 20 CN CN
    NH
    2 NH N [(I R,2S)-2-aminocyclohexyl]acetonitrile (1.1 g) was dissolved in MeOH (10 mL) and sodium methoxyde (0.45 mL) was added. The mixture was stirred for 15 minutes then 25 tert-butyl 4 -oxopiperidine-1-carboxylate (0.85 g, 4.27 mmol) was added. A solution containing sodium cyanoborohydride (0.36 g, 5.22 mmol) and zinc chloride (0.35 g, 2.60 mmol) in MeOH (2 mL) was then added drop wise and the mixture stirred at room temperature. The solvent was then removed under reduced pressure and the residue -100- WO 2007/142583 PCT/SE2007/000554 was diluted in dichloromethane and was washed with IN NaOH and brine. The crude was purified by high pH prep LCMS to provide 0.6 g of the title compound. MS (M+1): 322.27 5 Step E: The preparation of ((1R,2S)-2-{[1-(tert-butoxycarbonyl)piperidin-4 yl]amino}cyclohexyl)acetic acid HCN COOH NHH N CN 10 Tert-butyl 4-{[(1 S, 2
    R)-
    2 -(cyanomethyl)cyclohexyllamino)piperidine-1--carboxylate (90 mg, 0.28 mmol) was dissolved in ethanol (1 mL) and I N NaOH was then added and was heated at 80 C for 3 hours. More IN NaOH (I mL) was added and the mixture stirred at room temperature over night. The mixture was concentrated in vacuo and dissolved in water (1 mL). Acidified to pH 3-4 with 2NHCI and the mixture was then concentrated in 15 vacuo. Methanol was added, the precipitate filtered off and the filtrate was concentrated in vacuo to provide the title compound. MS (M+1): 341.3 Step F: The preparation of tert-butyl 4-[(3aR, 7aS)-2-oxooctahydro-1 H-indol-1 20 yllpiperidine-1 -carboxylate COOH O NH N ((I R,2S)-2-{[1 -(tert-butoxycarbonyl)piperidin-4-yl]amino}cyclohexyl)acetic acid was dissolved in DMF (3 mL) and diisopropyl ethylamine (50 uL) and HATU (0.1 g, 0.26 25 mmol) was then added and the mixture stirred at room temperature over night. The solvent was then removed under reduced pressure and the mixture was diluted in dichloromethane. Washed with 1 N NaOH and with brine and the solvent was then removed under reduced pressure to give the tile compound. MS (M+1): 323.24 -101 - WO 2007/142583 PCT/SE2007/000554 Step G: The preparation of (3aR, 7 aS)-1-piperidin-4-yloctahydro-2H-indol-2-one N N O H 0 0 .HCl 5 tert-butyl 4-[(3aR, 7aS)-2-oxooctahydro-1 H-indol-1 -yl]piperidine-1 -carboxylate was dissolved in MeOH (25 mL) and 4M HCl/dioxane (5 mL) was added. The mixture stirred at room temperature then concentrated in vacuo to give the tile compound. MS (M+1): 223.26 10 Step H: The preparation of ethyl 4-[(3aR, 7aS)-2-oxooctahydro-1H-indol-1-yl]-1,4' bipiperidine-1'-carboxylate N N H N O N 15 The crude of (3aR)-1-piperidin-4-yloctahydro-2H-indol-2-one (110 mg) was dissolved in MeOH (3 mL) and sodium methoxide (25 uL) was added followed by ethyl 4 oxopiperidine-1-carboxylate (77 pL, 0.5 mmol. A solution of sodium cyanoborohydride (35 mg, 0.5 mmol) and zinc chloride (29 mg, 0.25 mmol) in MeOH (1 mL) was added 20 drop wise at room temperature and the mixture was stirred at room temperature over night. The solvent was then removed under reduced pressure and the residue dissolved in dichloromethane (60 mL). Washed with IN NaOH (5 mL) and brine, dried and concentrated in vacuo. The residue was purified by high pH Prep LCMS to provide the title compound. I H NMR (400 MHz, METHANOL-D4): 5 ppm 1.24 (t, J=6.45 Hz, 3 H), 25 1.27 - 1.49 (m, 6 H), 1.62 (d, J=12.50 Hz, 2 H), 1.55 - 1.73 (m, 1 H), 1.78 (d, J=9.77 Hz, I H), 1.82 - 2.17 (m, 7 H), 2.18 - 2.33 (m, 3 H), 2.33 - 2.43 (m, I H), 2.49 (t, J=12.11 Hz, 1 - 102 - WO 2007/142583 PCT/SE2007/000554 H), 2.69 - 2.86 (m, 2 H), 3.02 (t, J=10.94 Hz, 2 H), 3.12 (t, J=10.16 Hz, I H), 3.72 - 3.85 (m, I H), 4.09 (q, J=7.03 Hz, 2 H), 4.16 (d, J=12.89 Hz, 2 H). MS (M+1): 378.3 Example 88: Isopropyl 4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]-1,4'-bipiperidine 5 1'-carboxylate )O N N 0 0 Step A: The preparation of tert-butyl 4-[(3aR,7aS)-2-oxooctahydro-1 H-indol-1 -yl]-1,4' bipiperidine-1'-carboxylate 10 '- 0 N O (N N H N tert-butyl 4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]-1,4'-bipiperdine-1'-carboxylate was prepared following similar reductive amination procedure described in Example 87, Step H 15 Step B: The preparation of (3aR,7aS)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-indol-2-one -103- WO 2007/142583 PCT/SE2007/000554 cI )x=o N_ Q0> NN O ON N H To a solution of tert-butyl 4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]-1,4'-bipiperidine-1' carboxylate (180 mg, 0.44 mmol) in MeOH (3 mL) was added 4M HCI (1 mL) and the mixture was stirred at room temperature. The solvents were then removed under reduced 5 pressure to provide the title compound as yellow oil (120 mg). Ms (M+1): 306.3 Step C: The preparation of isopropyl 4-[(3aR,7aS)-2-oxooctahydro-1 H-indol-1 -yl]-1,4' bipiperidine-1'-carboxylate 0 N N N N 10 Following procedure similar to Example 82, the title compound was prepared from (3aR,7aS)-1-(1,4'-bipiperidin-4-yl)octahydro-2H-indol-2-one and isopropyl chloroformate. IH NMR (400 MHz, METHANOL-D4) HCl salt: S ppm 1.24 (d, J=5.86 Hz, 6 H), 1.27 1.53 (m, 4 H), 1.53 - 1.83 (m, 4 H), 1.84 - 2.00 (m, 4 H), 2.04 - 2.17 (m, 3 H), 2.26 (d, J=6.64 Hz, I H), 2.28 - 2.37 (m, I H), 2.35 - 2.68 (m, 2 H), 2.74 - 2.95 (m, 2 H), 3.03 15 3.23 (m, 3 H), 3.34 - 3.46 (m, I H), 3.60 (d, J=12.89 Hz, 2 H), 3.78 - 3.94 (m, I H), 4.29 (d, J=14.06 Hz, 2 H), 4.76 - 4.88 (m, I H). MS (M+1): 392.3 Example 89: (3aR,7aS)-I-[1'-(2-methylbenzoyl)-1,4'-bipiperidin-4-yl]octahydro-2H indol-2-one 20 - 104- WO 2007/142583 PCT/SE2007/000554 O N N 0 Step A: The preparation of 1-(2-methylbenzoyl)piperidin-4-one 0 o + H S H H c o K> H 2 0/DCM N H -HCI 5 To a solution of 2-methylbenzoyl chloride (800 mg, 5.2 mmol) in 5 mL of DICHLOROMETHANE was added a mixture of piperidine-4,4-diol hydrochloride salt 800 mg, 5.2 mmol) and potassium carbonate ( 716 mg, 5.2 mmol) in 5 mL H 2 0 and stirred at room temperature for 2 hours. Layers were separated and aqueous layer was extracted with dichloromethane (3 x 10 mL). Organic layers were combined, dried, 10 filtered and the filtrate was concentrated in vacuo to give the tile compound (1.2 g) as light yellow oil. MS (M+1): 218.0 Step B: The preparation of (3aR,7aS)-1-[1'-(2-methylbenzoyl)-1,4'-bipiperidin-4 yl]octahydro-2H-indol-2-one 15 N I O 0 N O H N HC 0 - 105- WO 2007/142583 PCT/SE2007/000554 To a solution of (3aR,7aS)-1-piperidin-4-yloctahydro-2H-indol-2-one hydrochloride (70 mg, 0.27 mmol) in MeOH (4 mL) was added sodium methoxide (62 p1, 0.27 mmol) followed by 1-(2-methylbenzoyl)piperidin-4-one (60 mg, 0.27 mmol) and the mixture stirred at room temperature for 10 minutes. A solution containing sodium 5 cyanoborohydride (28 mg, 0.41 mmol) and zinc chloride (18 mg, 0.13 mmol) in MeOH (1 mL) was then added and the mixture stirred at room temperature overnight. The reaction was quenched with water and solvents were removed under reduced pressure. The mixture was diluted in dichloromethane (30 mL) and 1N NaOH (7 mL) was added. The phases were separated and aqueous phase was extracted with dichloromethane (2x20 10 mL). The combined organic phases were dried and concentrated in vacuo. The crude compound was purified by high pH prep LCMS (40-60%) to provide the tilte compound as a white solid (37 mg, 37%). 1H NMR (400 MHz, CHLOROFORM-D): 5 ppm 1.12 1.41 (m, 5 H), 1.42 - 1.54 (m, I H), 1.54 - 1.70 (m, 4 H), 1.70 - 1.99 (m, 7 H), 2.11 - 2.39 (m, 4 H), 2.23 (s, 3 H), 2.39 - 2.55 (m, I H), 2.72 (t, J=12.50 Hz, I H), 2.78 - 3.07 (m, 4 15 H), 3.48 (d, J=12.11 Hz, 1 H), 3.83 - 4.01 (m, I H), 4.80 (d, J=12.50 Hz, 1 H), 7.01 - 7.28 (m, 4 H). MS (M+1): 424.2 Example 90 and 91: Ethyl (3S)-3-{4-[(3aR,7aS)-2-oxooctahydro-IH-indol-1 yl]piperidin-1-yl}pyrrolidine-1-carboxylate and ethyl (3R)-3-{4-[(3aR,7aS)-2 20 oxooctahydro-1H-indol-1-yl]piperidin-1-yl}pyrrolidine-1-carboxylate N O NO N b ZN O CN O, 0 0 Step A: The preparation of mixture of two diastereomers: 0 o N ONO NO O AN N N O~. N- O ' 0 25 mixture of diastereo isomers (3aR,7aS)-1-(piperidin-4-yl)hexahydro-1H-indol-2(3H)-one (0.38 g, 1.44 mmol) was dissolved in MeOH (5 ml) and triethylamine (0.200 ml, 1.44 mmol) was added followed by -106- WO 2007/142583 PCT/SE2007/000554 1-N-ethoxycarbonyl-3-pyrrolidinone (0.226 g, 1.44 mmol). After 15 minutes a solution of sodium cyanoborohydride (0.135 g, 2.15 mmol) and zinc chloride (0.098 g, 0-.72 mmol) in methanol (Iml) was added dropwise at room temperature. The mixture was stirred at room temperature over night. The solvent was then removed under reduced pressure 5 and the residue was diluted in dichloromethane (60 mL) and washed with 1N NaOH (10 mL) followed by brine (5 mL) and concentrated under reduced pressure. The crude was then purified by using high pH prep LCMS to provide the mixture of two enantiomers (0.15 g). MS (M+1): 364.26 10 Step B: Separation of diastereomers by chiral HPLC b b + N N 0 0 0 15 The mixture of two diastereo isomers was purified by chiral HPLC AD 30 % isopropanol (ChiralPak AD, 21 x 250 mm, 20 gm particle size) to provide the pure diastereoisomers as Isomer 1 and Isomer 2 as a white solids. Isomer 1: HPLC Retention time = 8.75 min (40% isopropanol, ChiralPak AD, 4.6 x 250 20 mm, 20 um particle size). 1 H NMR (400 MHz, CHLOROFORM-D) 5 ppm 1.07 - 1.45 (m, 3 H), 1.22 (t, J=7.23 Hz, 3 H), 1.50 - 2.17 (m, 13 H), 2.30 (d, J=6.64 Hz, I H), 2.33 (d, J=6.64 Hz, 1 H), 2.62 - 2.88 (m, 2 H), 2.92 - 3.12 (m, 3 H), 3.18 - 3.35 (m, 1 H), 3.50 (t, J=9.57 Hz, 1 H), 3.53 - 3.64 (m, 1 H), 3.64 - 3.73 (m, 1 H), 3.87 - 4.02 (m, I H), 4.09 (q, J=7.03 Hz, 2 H). Ms (M+1): 364.26. 25 Isomer 2: HPLC Retention time = 15.53 min (40% isopropanol, ChiralPak AD, 4.6 x 250 mm, 20 rn particle size. 1H NMR (400 MHz, CHLOROFORM-D): & ppm 1.12 - 1.46 (m, 3 H), 1.21 (t, J=7.23 Hz, 3 H), 1.49 - 2.15 (m, 13 H), 2.29 (d, J=6.64 Hz, I H), 2.33 (d, J=6.25 Hz, 1 H), 2.63 - 2.81 (m, 2 H), 2.80 - 3.02 (m, 2 H), 3.06 (q, J=9.11 Hz, 1 H), 3.19 30 - 3.37 (m, 1 H), 3.49 (t, J=9.77 Hz, I H), 3.32 - 3.63 (m, 1 H), 3.64 - 3.72 (m, 1 H), 3.85 4.00 (m, I H), 4.08 (q, J=7.03 Hz, 2 H). MS (M+1): 364.26. -107-
    权利要求:
    Claims (72)
    [1] 1. A compound of formula 1, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: (R') I Y A2G G 3 N (CH 2 )/ 2)n m.--N Y R2 5 1 Wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; G', G 2 and G 3 are independently selected from hydrogen, halogen, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C1. 6 alkyl, -CONR 2 ; or any two of G 1 , G 2 10 and G 3 are linked together to form a C1. 4 alkylene bridge and the other one of G', G 2 and G 3 is independently selected from hydrogen, halogen, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C 1 . 6 alkyl, -C(=O)NR 2 ; R1 is independently selected from hydrogen, halogen, C1. 6 alkyl, C 2 - 6 alkenyl, -CN, -C(=O)-OR, -C(=O)-NR 2 , hydroxy, and C1.ealkoxy; 15 R 2 is selected from hydrogen, C1. 6 alkyl, C 2 - 6 alkenyl, C1. 6 alkoxy, C 1 . 6 alkylamino, di C1. 6 alkylamino, C 6 1oaryl, C 6 .- oaryloxy, C 2 . 9 heteroaryl, C 2 -gheteroaryloxy, C3 5 heterocycloalkyloxy, C 3 -sheterocycloalkyl, C 6 .1oaryl-C1- 3 alkoxy, C6.1 0 aryl-C1.salkyl, C 2 -eheteroaryl-C1,alkoxy, C 2 ..heteroaryl-C1- 3 alkyl, C3.5heterocycloalkyl-C1. 3 alkoxy, C3. 5 heterocycloalkyl-C1- 3 akyl, C 3 -ecycloalkyl, C3- 6 cycloalkyloxy, and C 3 . 6 cycloalkyl-C1.3alkyl, 20 C 3 .ecycloalkyl-C1. 3 alkoxy, wherein said C.. 6 alkyl, C 2 . 6 alkenyl, C1. 6 alkyl-carbonyl, C1. 6 alkylaminocarbonyl, C 6 .. 1oaryl, C 2 - 9 heteroaryl, C 3 .sheterocycloalkyl, C 6 -.oaryl-C.. 3 alkyl, C 2 -eheteroaryl-C1- 3 alkyl, C3a 5 heterocycloalkyl-C1,3alkyl, C3a. 6 cycloalkyl, and C 3 - 6 cycloalkyl C1- 3 alkyl are optionally substituted with one or more group selected from phenyl, C3. 6 cycloalkyl, C 2 -5heterocycloalkyl, C 2 . 5 heteroaryl, -CN, -SR, -OR, -O(CH2)p-OR, R, -C(=0) 25 R, -C0 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; p is 1,2, 3or4; mis 0, 1, or2; n is 1,2; -108- WO 2007/142583 PCT/SE2007/000554 X, Y and Z are independently selected from C(=0), NH, N-R, N, C, CH 2 , and CH, wherein at least one of X, Y and Z is selected from NH, N-R and N; wherein at most one of X, Y and Z is C(=O); and wherein Z is not C(=O); and each R is independently hydrogen, C 1 .ealkyl, C 2 . 6 alkenyl or halogenated C 1 .ealkyl. 5
    [2] 2. A compound as claimed in claim 1, wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C 3 -ecycloalkyl, C 3 . 6 cycloalkoxy, C3 6cycloalkyl-C- 3 alkoxy, C 2 . 5 heterocycloalkyl, C 2 -5heterocycloalkyl-C 1 . 3 alkyl, phenyl, benzyl, C 2 - 9 heteroaryl, C 1 . 6 alkoxy, C1. 6 alkylamino, di-C 1 .alkylamino and benzyloxy, wherein said 10 C 1 . 6 alkyl, C3. 6 cycloalkyl, C 3 -6cycloalkoxy, C3. 6 cycloalkyl-C 1 -salkoxy, C 2 - 5 heterocycloalkyl, C 2 . 5 heterocycloalkyl-C 1 . 3 alkyl, phenyl, benzyl, C 2 . 9 heteroaryl, C 1 . 6 alkoxy, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C3- 6 cycloalkyl, C 1 .ealkyl, hydroxy, C1. ealkoxy and -CN. 15
    [3] 3. A compound as claimed in claim 1, wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C 14 alkoxy, C14alkylamino, di C14alkylamino, C 3 - 6 cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 13 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy, 20 wherein said C 1 . 6 alkyl, C 1 . 4 alkoxy, C 14 alkylamino, di-C 14 alkylamino, C 3 . 6 cycloalkyl, pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 -salkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 - 6 cycloalkyl, C 1 . 6 alkyl, hydroxy, C 1 . 6 alkoxy and -CN. 25
    [4] 4. A compound as claimed in claim 1, wherein R 2 is selected from methyl, ethyl, n-propyl, isopropyl, butyl, 4-heptyl, 2-methyl-1 propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2 oxopyrrolidinyl-ethyl, methoxy, ethoxy, benzyloxy, t-butoxy, cyclopentyl, cyclohexyl, 30 pyrrolidinyl, piperdinyl, azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 - 6 cycloalkyl, C 1 .ealkyl, hydroxy, C 1 . 6 alkoxy and -CN.
    [5] 5. A compound as claimed in claim 1, wherein 35 R 1 is selected from hydrogen, halogen, methyl, ethyl, -CN, -C(=O)-NH 2 , CO 2 CH 3 , -CO 2 H, hydroxy and methoxy.
    [6] 6. A compound as claimed in claim 1, wherein R' is hydrogen. - 109- WO 2007/142583 PCT/SE2007/000554
    [7] 7. A compound as claimed in claim 1, wherein p is 1.
    [8] 8. A compound as claimed in claim 1, wherein m, n is 1. 5
    [9] 9. A compound as claimed in claim 1, wherein m is I and n is 2.
    [10] 10. A compound as claimed in claim 1, wherein Z is selected from N, C and CH. 10
    [11] 11. A compound as claimed in claim 1, wherein Y is selected from N and C(=O).
    [12] 12. A compound as claimed in claim 1, wherein X is selected from NH and N-R, wherein R is hydrogen, C2- 3 alkenyl or C 1 . 3 alkyl. 15
    [13] 13. A compound as claimed in claim 1, wherein A' and A 2 are independently selected from -CH 2 - and -N(R)-, wherein each R is independently hydrogen or C 1 . 6 alkyl.
    [14] 14. A compound as claimed in claim 1, one of A' and A 2 is -CH 2 -; and the other one of A' and A 2 is -N(R)-. 20
    [15] 15. A compound as claimed in claim 1, A and A 2 are -CH 2 -.
    [16] 16. A compound as claimed in claim 1, G', G 2 and G 3 are independently selected from hydrogen, halogen, C 16 alkyl, CIealkoxy, hydroxy-C 1 .alkyl, -CH 2 -OR, halogenated 25 C 16 alkyl, -C(=0)NR 2 ; wherein each R is independently hydrogen or Ci 6 alkyl.
    [17] 17. A compound as claimed in claim 1, G', G 2 and G 3 are independently selected from hydrogen, fluoro, C 1 . 6 alkyl, CI- 6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, C(=0)NR 2 ; wherein each R is independently hydrogen or C 1 . 3 alkyl. 30
    [18] 18. A compound as claimed in claim 1, any two of G', G 2 and G 3 are linked together to form a C 14 alkylene bridge and the other one of G', G 2 and G 3 is selected from hydrogen, halogen, C 1 . 6 alkyl, C 1 .ralkoxy, hydroxy-C 1 ealkyl, -CH 2 -OR, halogenated C.. 6 alkyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or Ce 6 alkyl. 35
    [19] 19. A compound as claimed in claim 1, G' and G 3 are linked together to form a C2. 4 alkylene bridge; and G 2 is selected from hydrogen, fluoro, C 1 . 6 alkyl, C1.6alkoxy, hydroxy -110- WO 2007/142583 PCT/SE2007/000554 methyl, -CH 2 -OR, trifluoromethyl, -C(=0)NR 2 ; wherein each R is independently hydrogen or C1- 3 alkyl.
    [20] 20. A compound as claimed in claim 1, G 1 and G 2 are linked together to form a C1. 5 3 alkylene bridge; and G 3 is selected from hydrogen, fluoro, C1. 6 alkyl, C1. 6 alkoxy, hydroxy methyl, -CH 2 -OR, trifluoromethyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C1. 3 alkyl.
    [21] 21. A compound of formula 11, a pharmaceutically acceptable salt thereof, 10 diastereomer, enantiomer, or mixture thereof: H R A NG G3 G N CjCH 2 )n 2 (CH2)m N R Wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; 15 G1, G 2 and G 3 are independently selected from hydrogen, halogen, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C1. 6 alkyl, -CONR 2 ; or any two of G1, G 2 and G 3 are linked together to form a C1. 4 alkylene bridge and the other one of G1, G 2 and G 3 is selected from hydrogen, halogen, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C1. 6 alkyl, -C(=O)NR 2 ; 20 R1 is independently selected from hydrogen, halogen, C1..alkyl, C 2 - 6 alkenyl, -CN, -C(=0)-OR, -C(=0)-NR 2 , hydroxy, and C 1 . 6 alkoxy; R 2 is selected from hydrogen, C 1 . 6 alkyl, C 2 - 6 alkenyl, C1-alkoxy, C 1 . 6 alkylamino, di C1. 6 alkylamino, C.1oaryl, C61 oaryloxy, C 2 - 9 heteroaryl, C2- 9 heteroaryloxy, Cs. 5heterocycloalkyloxy, C3.sheterocycloalkyl, Ce. 1 oaryl-C1 3 alkoxy, Cooaryl-C1- 3 alkyl, 25 C 2 -heteroaryl-C1. 3 alkoxy, C2-9heteroaryl-C1-salkyl, C3.sheterocycloalkyl-C1- 3 alkoxy, C3 sheterocycloalkyl-C,.alkyl, C 3 . 6 cycloalkyl, C 3 - 6 cycloalkyloxy, and C 3 - 6 cycloalkyl-C1-salkyl, C3-ecycloalkyl-C1-aalkoxy, wherein said C 1 . 6 alkyl, C2- 6 alkenyl, C 1 . 6 alkyl-carbonyl, C1.ealkylaminocarbonyl, C 6 . 1 0 aryl, C 2 - 9 heteroaryl, C 3 -sheterocycloalkyl, C 6 -.oaryl-C1-salkyl, -1III- WO 2007/142583 PCT/SE2007/000554 C 2 - 9 heteroary-C 1 -salkyl, C3-sheterocycloalkyl-C 1 -salkyl, C 3 - 6 cycloalkyl, and Cs. 6 cycloalkyl C 1 -salkyl are optionally substituted with one or more group selected from phenyl, C3. 6 cycloalkyl, C 2 - 5 heterocycloalkyl, C 2 - 5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=0) R, -CO 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 ),NR 2 , and -C(=O)-NR 2 ; 5 m is 0, 1, or 2; n is 1,2; and each R is independently hydrogen, C 16 alkyl, C 2 - 6 alkenyl or halogenated C 1 . 6 alkyl.
    [22] 22. A compound as claimed in claim 21, wherein R 2 is selected from hydrogen, C 6 alkyl, C 3 . 6 cycloalkyl, C3. 6 cycloalkoxy, C 3 - 6 cycloalkyl-C 1 . 3 alkoxy, C 2 . 5 heterocycloalkyl, C2 10 5heterocycloalkyl-C 3 alkyl, phenyl, benzyl, C 2 . 9 heteroaryl, C 16 alkoxy, C 1 ..alkylamino, di C 1 . 6 alkylamino and benzyloxy, wherein said C 16 alkyl, C 3 - 6 cycloalkyl, C3- 6 cycloalkoxy, C3. 6cycloalkyl-Clsalkoxy, C2. 5 heterocycloalkyl, C 2 - 5 heterocycloalkyl-C 1 3alkyl, phenyl, benzyl, C 2 -9heteroaryl, Ciealkoxy, C 1 . 6 alkylamino, di-Cj. 6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, 15 C 3 -ecycloalkyl, C 1 - 6 alkyl, hydroxy, C1- 6 alkoxy and -CN.
    [23] 23. A compound as claimed in claim 21, wherein R 2 is selected from hydrogen, Cj_ 6 alkyl, Cgalkoxy, C 14 alkylamino, di-C 14 alkylamino, C 3 -cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 . 3 alkyl, phenyl, benzyl, 20 piperdinyl, azetidinyl and benzyloxy, wherein said C 1 6 alkyl, C 14 alkoxy, C 14 alkylamino, di C 1 4 alkylamino, C 3 - 6 cycloalkyl, pyrrolidinyl, furyl, quinoliny, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 3 alkyl, phenyl, benzyl, piperdiny, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 - 6 cycloalkyl, C.s 8 alkyl, hydroxy, C 16 alkoxy and -CN. 25
    [24] 24. A compound as claimed in claim 21, wherein R 2 is selected from methyl, ethyl, n propyl, isopropyl, butyl, 4-heptyl, 2-methyl-1-propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, ethoxy, benzyloxy, t-butoxy, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, azetidinyl, 30 methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C3. 6 cycloalkyl, C 1 ealkyl, hydroxy, C_ 6 alkoxy and -CN.
    [25] 25. A compound as claimed in claim 21, wherein R' of formula II is selected from 35 hydrogen, halogen, methyl, ethyl, -CN, -C(=O)-NH 2 , -CO 2 CH 3 , -CO 2 H, hydroxy and methoxy.
    [26] 26. A compound as claimed in claim 21, wherein R' is hydrogen. -112- WO 2007/142583 PCT/SE2007/000554
    [27] 27. A compound as claimed in claim 21, wherein m, n is 1.
    [28] 28. A compound as claimed in claim 21, wherein m is 1 and n is 2. 5
    [29] 29. A compound as claimed in claim 21, wherein A' and A 2 are independently selected from -CH 2 - and -N(R)-, wherein each R is independently hydrogen or C1. 6 alkyl.
    [30] 30. A compound as claimed in claim 21, one of A' and A 2 is -CH 2 -; and the other one 10 of A' and A 2 is -N(R)-.
    [31] 31. A compound as claimed in claim 21, A' and A 2 are -CH 2 -.
    [32] 32. A compound as claimed in claim 21, G', G 2 and G 3 are independently selected 15 from hydrogen, halogen, C1. 6 alkyl, C1..alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C1. 6 alkyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C1. 6 alkyl.
    [33] 33. A compound as claimed in claim 21, G', G 2 and G 3 are independently selected from hydrogen, fluoro, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-methyl, -CH 2 -OR, trifluoromethyl, 20 C(=O)NR 2 ; wherein each R is independently hydrogen or C1. 3 alkyl.
    [34] 34. A compound as claimed in claim 21, any two of G1, G 2 and G 3 are linked together to form a C1. 4 alkylene bridge and the other one of G', G 2 and G 3 is selected from hydrogen, halogen, C1ealkyl, C1.6alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C1. 25 6 alkyl, -C(=O)NR 2 ; wherein each R is independently hydrogen or C1. 6 alkyl.
    [35] 35. A compound as claimed in claim 21, G1 and G 3 are linked together to form a C2 4 alkylene bridge; and G 2 is selected from hydrogen, fluoro, C 1 . 6 alkyl, C1. 6 alkoxy, hydroxy methyl, -CH 2 -OR, trifluoromethyl, -C(=0)NR2; wherein each R is independently hydrogen 30 or C1.salkyl.
    [36] 36. A compound as claimed in claim 21, G' and G 2 are linked together to form a C1. 3 alkylene bridge; and G 3 is selected from hydrogen, fluoro, C1. 6 alkyl, C1. 6 alkoxy, hydroxy methyl, -CH 2 -OR, trifluoromethyl, -C(=0)NR 2 ; wherein each R is independently hydrogen 35 or C 1 . 3 alkyl.
    [37] 37. A compound of formula IA, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: -113- WO 2007/142583 PCT/SE2007/000554 x N N fCH2)n N R 2 0 IA wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C2- 6 alkenyl, C 1 -ealkoxy, C1.ealkylamino, di 5 C 1 . 6 alkylamino, C6-1 0 aryl, C 6 .1oaryloxy, C 2 - 9 heteroaryl, C2- 9 heteroaryloxy, C3 5 heterocycloalkyloxy, C3- 5 heterocycloalkyl, C 6 i.oaryl-CIsalkoxy, C 6 - 1 oaryl-C 1 - 3 alkyl, C2-gheteroaryl-C 1 - 3 alkoxy, C2-gheteroary-C 1 - 3 alkyl, C3- 5 heterocycloalkyl-C 1 . 3 alkoxy, C3 5 heterocycloalkyl-C 1 . 3 akyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkyloxy, and C3.ecycloalkyl-C 1 . 3 alkyl, C3. 6 cycloalkyl-C 1 -salkoxy, wherein said C 1 - 6 alkyl, C2- 6 alkenyl, C 1 . 6 alkyl-carbonyl, 10 C 16 -alkylaminocarbonyl, C 6 -1 0 aryl, C2- 9 heteroaryl, C3- 5 heterocycloalkyl, C 6 - 1 0 aryl-C 1 .. 3 alkyl, C2.gheteroaryl-C 1 - 3 alkyl, C3- 5 heterocycloalkyl-C 1 - 3 alkyl, C3.ecycloalkyl, and C3- 6 cycloalkyl C1- 3 alkyl are optionally substituted with one or more group selected from phenyl, C3. 6 cycloalkyl, C 2 - 5 heterocycloalkyl, C2. 5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=O) R, -C0 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; 15 p is 1, 2, 3 or 4; n is 1, 2; X, is independently selected from NH, N-R, CH 2 CHR, and CRR'; and each R, R' is independently hydrogen, C 1 -alkyl, C2- 6 alkenyl or halogenated C 1 - 6 alkyl. 20
    [38] 38. A compound as claimed in claim 37, wherein R 2 is selected from hydrogen, C 1 - 6 alkyl, C3- 6 cycloalkyl, C 3 - 6 cycloalkoxy, C3 6 cycloalkyl-O 1 - 3 alkoxy, C 2 -5heterocycloalky, C2- 5 heterocycloalkyl-C 1 -3alky, phenyl, benzyl, C2-gheteroaryl, C 1 - 6 alkoxy, C 1 - 6 alkylamino, di-C 16 -alkylamino and benzyloxy, wherein said C1-ealkyl, C 3 . 6 cycloalkyl, C 3 . 6 cycloalkoxy, C3. 6 cycloalkyl-C 1 -salkoxy, C2- 5 heterocycloalkyl, 25 C2.sheterocycloalkyl-C 1 .salkyl, phenyl, benzyl, C 2 .sheteroaryl, C 1 . 6 alkoxy, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C3-6cycloalkyl, C1- 6 alkyl, hydroxy, C1. 6 alkoxy and -CN. - 114 - WO 2007/142583 PCT/SE2007/000554
    [39] 39. A compound as claimed in claim 37, wherein R 2 is selected from hydrogen, Ci..alkyl, CIAalkoxy, C 14 alkylamino, di C 14 alkylamino, C 3 . 6 cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, 5 pyrrolyl, 2-oxopyrrolidinyl-C 1 - 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy, wherein said C 1 . 6 alkyl, C 14 alkoxy, C 14 alkylamino, di-C 14 alkylamino, C3. 6 cycloalkyl, pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 . 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen; phenyl, morpholinyl, C 3 . 6 cycloalkyl, C 1 . 6 alkyl, 10 hydroxy, C 1 . 6 alkoxy and -CN.
    [40] 40. A compound as claimed in claim 37, wherein R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, 4 heptyl, 2-methyl-I -propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, 15 pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, ethoxy, isopropoxy, propoxy, benzyloxy, t butoxy, isopropenoxy, isobutoxy, C 3 - 6 cycloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, CF 3 ,-C(=O) C 1 . 6 alkyl, C3. 6 cycloalkyl, C 1 . 6 alkyl, hydroxy, C 1 . 6 alkoxy and -CN. 20
    [41] 41. A compound as claimed in claim 37, wherein n is 1.
    [42] 42. A compound as claimed in claim 37, wherein n is 2. 25
    [43] 43. A compound as claimed in claim 37, wherein X is selected from NH and N-R, wherein R is hydrogen, C 2 - 3 alkenyl or C1- 3 alkyl.
    [44] 44. A compound of formula IIA, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: -115- WO 2007/142583 PCT/SE2007/000554 H N O N N N R 2 IIA wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C 2 - 6 alkenyl, C 1 . 6 alkoxy, C.. 6 alkylamino, di 5 Cl6alkylamino, C 6 . 1 oaryl, C6.loaryloxy, C 2 - 9 heteroaryl, C2 9 heteroaryloxy, C 3 5 heterocycloalkyloxy, C 3 - 5 heterocycloalkyl, C6.1oaryl-C 1 -salkoxy, Cs. 10 aryl-C 1 . 3 alkyl, C 2 -9heteroaryl-C 1 - 3 alkoxy, C 2 -gheteroaryl-C 1 -salkyl, C3- 5 heterocycloalkyl-C 1 -salkoxy, C3 5 heterocycloalkyl-C 1 . 3 alkyl, C 3 a 6 cycloalkyl, C 3 . 6 cycloalkyloxy, and C 3 . 6 cycloalkyl-C 1 ..alkyl, C3.6cycloalkyl-C1- 3 alkoxy, wherein said C 1 . 6 alkyl, C 2 - 6 alkenyl, C1- 6 alkyl-carbonyl, 10 C 1 .ealkylaminocarbonyl, C 6 . 1 0 aryl, C 2 - 9 heteroaryl, C3. 5 heterocycloalkyl, C 6 - 1 oaryl-C 1 . 3 alkyl, C 2 -gheteroaryi-C 1 -salkyl, C3- 5 heterocycloalkyl-C1-salkyl, C 3 - 6 cycloalkyl, and C 3 s 6 cycloalkyl C 1 - 3 alkyl are optionally substituted with one or more group selected from phenyl, C3. ecycloalkyl, C 2 .5heterocycloalkyl, C 2 - 5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=O) R, -CO 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=0)-NR 2 ; 15 pis 1,2, 3or4;nis 1,2; and each R is independently hydrogen, C 1 . 6 alkyl, C 2 - 6 alkenyl or halogenated C 1 . 6 alkyl.
    [45] 45. A compound as claimed in claim 44, wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkoxy, C3 20 6 cycloalkyl-C 1 -salkoxy, C2. 5 heterocycloalkyl, C 2 -5heterocycloalkyl-C1.3alkyl, phenyl, benzyl, C 2 . 9 heteroaryl, C 1 . 6 alkoxy, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino and benzyloxy, wherein said C 1 . 6 alkyl, C 3 - 6 cycloalkyl, C3a6cycloalkoxy, C 3 -6cycloalkyl-Cl 3 alkoxy, C 2 -sheterocycloalkyl, C 2 -heterocycloalkyl-C 1 - 3 alkyl, phenyl, benzyl, C2-9heteroaryl, C 1 . 6 alkoxy, C1.ealkylamino, di-C1. 6 alkylamino and benzyloxy are optionally substituted by one or more groups 25 selected from amino, halogen, phenyl, morpholinyl, C 3 . 6 cycloalkyl, C 1 -ealkyl, hydroxy, C1. 6 alkoxy and -CN.
    [46] 46. A compound as claimed in claim 44, wherein - 116 - WO 2007/142583 PCT/SE2007/000554 R 2 is selected from hydrogen, C 1 . 6 alkyl, C1 4 alkoxy, C 14 alkylamino, di CI4alkylamino, C3- 6 cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C1- 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy, wherein said C 1 . 6 alkyl, C1.4alkoxy, C 1 4alkylamino, di-C 14 alkylamino, C 3 secycloalkyl, 5 pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 . 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 - 6 cycloalkyl, C 1 . 6 alkyl, hydroxy, C1. 6 alkoxy and -CN. 10
    [47] 47. A compound as claimed in claim 44, wherein R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, 4 heptyl, 2-methyl-1-propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, ethoxy, isopropoxy, propoxy, benzyloxy, t butoxy, isopropenoxy, isobutoxy, C3. 6 cycloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, 15 cyclohexyl, pyrrolidinyl, piperdinyl, azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, CF 3 ,-C(=O) C 1 . 6 alkyl, C 3 - 6 cycloalky, C 1 . 6 alkyl, hydroxy, C 16 alkoxy and -CN.
    [48] 48. A compound as claimed in claim 44, wherein n is 1. 20
    [49] 49. A compound as claimed in claim 44, wherein n is 2.
    [50] 50. A compound of formula X, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: 25 0 N N CH2) N R 2 Y Xwherein -117- WO 2007/142583 PCT/SE2007/000554 R 2 is selected from hydrogen, C1. 6 alkyl, C 2 - 6 alkenyl, C 1 . 6 alkoxy, Ciealkylamino, di C 16 -alkylamino, C 6 . 1 oaryl, C 6 . 1 oaryloxy, C2- 9 heteroaryl, C 2 -eheteroaryloxy, Cs. 5 heterocycloalkyloxy, C 3 .sheterocycloalkyl, C6-1oaryl-Clsalkoxy, C 6 . 1 oaryl-C 1 aalkyl, C 2 - 9 heteroaryl-C 1 3 alkoxy, C 2 -eheteroary-Cs. 3 alkyl, C 3 -sheterocycloalkyI-Cisalkoxy, Cs. 5 5 heterocycloalkyl-CI 3 alkyl, C 3 - 6 cycloalkyl, Cs-6cycloalkyloxy, and C 3 - 6 cycloalkyl-C 13 alkyl, C 3 - 6 cycloalkyl-Cs. 3 alkoxy, wherein said C 1 ealkyl, C2-ealkenyl, C 1 ealkyl-carbonyl, C 1 alkylaminocarbonyl, C 6 .1oaryl, C 2 . 9 heteroaryl, C 3 . 5 heterocycloalkyl, C 6 . 1 oaryl-C 1 .. 3 alkyl, C 2 .gheteroary-C 3 alkyl, C3-sheterocycloalkyl-C 3 alkyl, C 3 - 6 cycloalkyl, and C3.6cycloalkyl C 13 alkyl are optionally substituted with one or more group selected from phenyl, C 3 10 6 cycloalkyl, C 2 - 5 heterocycoalkyl, C 2 - 5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=O) R, -CO 2 R, -S0 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; pis 1,2,3or4;nis 1,2;and each R is independently hydrogen, C 1 . 6 alkyl, C 2 . 6 alkenyl or halogenated C 16 alkyl. 15
    [51] 51. A compound as claimed in claim 50, wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C 3 - 6 cycloalkyl, C 3 . 6 cycloalkoxy, C 3 6 cycloalkyl-C 13 alkoxy, C 2 - 5 heterocycloalkyl, C 2 - 5 heterocycloalkyl-CI. 3 alkyl, phenyl, benzyl, C 2 - 9 heteroaryl, C 1 . 6 alkoxy, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino and benzyloxy, wherein said C 16 alkyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkoxy, C 3 . 6 cycloalkyl-C 1 salkoxy, C 2 - 5 heterocycloalkyl, 20 C 2 - 5 heterocycloalkyl-C 3 alkyl, phenyl, benzyl, C 2 -eheteroaryl, C 1 ealkoxy, Ce 6 alkylamino, di-Ce 6 alkylamino and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 - 6 cycloalkyl, C 16 alkyl, hydroxy, C 1 6 alkoxy and -CN. 25
    [52] 52. A compound as claimed in claim 50, wherein R 2 is selected from hydrogen, C 16 alkyl, C 1 -alkoxy, Cl-alkylamino, di C1.alkylamino, Coa 6 cycloalkyl, pyrrolidinyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy, wherein said C 16 alkyl, C 14 alkoxy, C 14 alkylamino, di-C 1 -alkylamino, C3- 6 cycloalkyl, 30 pyrrolidinyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-C 1 3 alkyl, phenyl, benzyl, piperdinyl, azetidinyl and benzyloxy are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, C 3 - 6 cycloalkyl, C 1 . 6 alkyl, hydroxy, C 1 - 6 alkoxy and -CN. 35
    [53] 53. A compound as claimed in claim 50, wherein R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, 4 heptyl, 2-methyl-1-propyl, benzyl, phenyl, thienyl, furyl, quinolinyl, dihydrobenzofuranyl, pyrrolyl, 2-oxopyrrolidinyl-ethyl, methoxy, ethoxy, isopropoxy, propoxy, benzyloxy, t -118- WO 2007/142583 PCT/SE2007/000554 butoxy, isopropenoxy, isobutoxy, CS.6cycloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperdinyl, azetidinyl, methylamino, and ethylamino, which are optionally substituted by one or more groups selected from amino, halogen, phenyl, morpholinyl, CF 3 ,-C(=O) C 1 . 6 alkyl, C3-6cycloalkyl, C 1 . 6 alkyl, hydroxy, C 1 . 6 alkoxy and -CN. 5
    [54] 54. A compound as claimed in claim 50, wherein n is 1.
    [55] 55. A compound as claimed in claim 50, wherein n is 2. 10
    [56] 56. A compound selected from Ethyl 4-[(cis (+/-))-2-oxooctahydro-1 H-benzimidazol-1 -yl)-1,4'-bipiperidine-1'-carboxylate Ethyl 3-{4-[(cis (+/-))-2-oxooctahydro-1 H-benzimidazol-1 -yl]piperidin-1 -yl}pyrrolidine-1 carboxylate Ethyl 3-{4-(trans (+/-))-2-oxooctahydro-1H-benzimidazol-1-yl]piperidin-1-yl}pyrrolidine-1 15 carboxylate Benzyl 3-{4-[(trans (+/-))-2-oxooctahydro-1H-benzimidazol-1-yllpiperidin-1-yl}pyrrolidine I -carboxylate Benzyl 4-[-[(trans (+/-))-2-oxooctahydro-IH-benzimidazol-1-yl]-1,4'-bipiperidine-1' carboxylate 20 Ethyl 4-[(3aR,7aR)-2-oxooctahydro-1 H-benzimidazol-i-yll-1,4'-bipiperidine-1' Carboxylate Ethyl 4-[(3aS,7aS)-2-oxooctahydro-I H-benzimidazol-I -yl]-1,4'-bipiperidine-I' Carboxylate (trans (+/-))-1-{1-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]piperidin-4-yi}octahydro-2H 25 benzimidazol-2-one (trans (+/-))-1-{1-[1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yljpiperdin-4-yl}octahydro-2H benzimidazol-2-one methyl 3-{4-[(trans (+/-))-2-oxooctahydro-IH-benzimidazol-1-yl]piperidin-1-yl}pyrrolidine I -carboxylate 30 N-ethyl-3-[4-[(-[(trans (+/-))- (2-oxooctahydro-1 H-benzimidazol-1-yl)piperidin-1 yl]pyrrolidine-I -carboxamide (trans (+/-))-I -{I -[I -(3-methylbutanoyl)pyrrolidin-3-yl]piperidin-4-yl}octahydro-2H benzimidazol-2-one (trans (+/-))-1 -[I -(I -butyrylpyrrolidin-3-yl)piperidin-4-ylloctahydro-2H-benzimidazol-2-one 35 (mixture of diastereoisomers) Ethyl (3R)- 3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-I-yl]-1 piperidyl]pyrrolidine-1-carboxylate - 119 - WO 2007/142583 PCT1SE2007/000554 Ethyl (3S)-3-[4-[(3aR,7aR)-2-0oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1 -ylJ-1 piperidyl]pyrrolidine-1 -carboxylate Ethyl (3R)-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1 -yI]-l piperidyl]pyrrolidine-1 -carboxylate, 5 Ethyl (3S)-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazo-1 -ylI-1 piperidyllpyrrolidine-1 -carboxylate Tert-butyl 4-[4-[(3aS,7aS)-2-oxo-3a,4,5,6 ,7 ,7a-hexahydro-3H-benzoimidazo-1 -yl]II- piperidyl]piperidine-1 -carboxyl ate (3aS,7aS)-1 -[I -(4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2 10 one (3aS,7aS)-1 J -[1 1 -(cyclopropanecarbonyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[I -[1-(2-methylbenzoyl)-4-piperidyl]-4-piperidyi]-3a,4,5,6,7,7a-hexahydro 3H-benzoimidazol-2-one 15 (3aS,7aS)-1 -[1 -[1-(cyciohexanecarbo nyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[I -[I -(2-fluorobenzoyi)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-2-one (3aS,7aS)-1 -[1-[1 -(4-methoxybenzoyl)-4-piperidyll-4-piperidyll-3a,4,5,6,7,7a-hexahydro 20 3H-benzolmidazol-2-one (3aS,7aS)-1 -[1 [1-(3-methylfuran-2-carbonyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[jl-jj-(2,6-dimethylbenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one 25 (3aS,7aS)-1 -[1-(1 -butanoyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-2-one (3aS,7aS)-1 -[1 -[1-(2-methoxybenzoyl)-4-piperidylj-4-piperidyl]-3a,4,5,6,7,7a-hexahydro 3H-benzoimidazoi-2-one (3aS,7aS)-1 -[1 -[1-(3-methoxybenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydro 30 3H-benzoimidazol-2-one (3aS,7aS)-1 -[1 -(1-benzoyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-2-one 2-[4-j4-[(3aS,7aS)-2-oxo-3a, 4,5,627, 7a-hexahydro-3H-benzoimidazol-1-yll-1 piperidyl]piperidine-1 -carbonyllbenzonitrile 35 (3aS,7aS)-1 -[I-[l -(2-propylpentanoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydro 3H-benzoimidazol-2-one (3aS,7aS)-1 -[I -[I -(2,3-dihydrobenzofuran-7-carbonyl)-4-piperidyl]-4-piperidyll 3a,4,5,6,7,7a-hexahydro-3H-benzomidazol-2-one -120- WO 2007/142583 PCT/SE2007/000554 (3aS,7aS)-1-[1-[1-(quinoline-4-carbonyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1-[1-[1-(1-methylpyrrole-2-carbonyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one 5 (3aS,7aS)-1-[1-[1-(1,5-dimethylpyrrole-2-carbonyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1-[I-[1-(2-cyclohexylbenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[1 -[1 -(2-morpholin-4-ylbenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a 10 hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[1-[1 -(2-phenylbenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydro 3H-benzoimidazol-2-one (3aS,7aS)-1 -[1 -[1 -[3-(2-oxopyrrolidin-1 -yl)propanoyl]-4-piperidylj-4-piperidyl] 3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one 15 (3aS,7aS)-1 -[1 -[1 -(2,2-dimethylpropanoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[1 -[1 -(cyclopentanecarbonyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 41 -[1 -(3-methoxythiophene-2-carbonyl)-4-piperidyl]-4-piperidyl] 20 3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-l -[1 -[I -(thiophene-2-carbony)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (3aS,7aS)-1 -[1 -[1 -(3-methylthiophene-2-carbony)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one 25 (3aS,7aS)-1 -[1 -[1 -(2-chlorobenzoyl)-4-piperidyll-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-2-one (3aS,7aS)-1 -[1-[ -(cyclobutanecarbonyl)-4-piperidyl]-4-piperidyi]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one Isopropyl 4-[(3aR,7aR)-2-oxooctahydro-1H-benzimidazol-1-yI]-1,4'-bipiperidine-1' 30 carboxylate (3aR,7aR)-1 -[1'-(cyclopropylcarbonyl)-1,4'-bipiperidin-4-yl]octahydro-2H-benzimidazol-2 one (3aR,7aR)-1 -[1'-(propylcarbonyl)-1,4'-bipiperid in-4-ylioctahydro-2H-benzimidazol-2-one (3aR,7aR)-1 -[1'-(cyclopentylcarbonyl)-1,4'-bipiperidin-4-ylIoctahydro-2H-benzimidazol-2 35 one - 121 - WO 2007/142583 PCT1SE2007/000554 (3aR,7aR)-1 -{1'-[3-(2-oxopyrroiidin-1-yI)propanoyl]-1 ,4.-bipiperidin-4-yl}octahydro-2H be nzimid azo -2- n e (3aR,7aR)-1 -[1 -(1-benzoyl-4-piperidyl)-4-piperidylJ-3a,4,5,6,7,7a-hexahydro-3H benzoimidazol-2-one 5 (3aR,7aR)-1 -[1 -[I -(2-methylbenzoyI)-4-piperidyIJ-4-piperidyij-3a,4,5,6,7,7a-hexahydro 3H--benzoimidazoi-2-one (3aR,7aR)-I J -[ I -(3-methoxythiophene-2-carbonyl)-4-piperidyl]-4-piperidyI 3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (3aR,7aR)-1 -[1 -[1 -(2-methoxybenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahydro 10 3H-benzoirnidazol-2-one (3aR,7aR)-1 -11 J[1 -(2,6-dimethylbenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one (trans (+/-))-1 -[1-[1 -(thiophene-2-carbony)-4-piperidyl]-4-piperidylJ-3a,4,5,6,7,7a hexahydro-3H-benzoimidazol-2-one 15 (trans (+/-))-1 -[1 -[1 -(2-phenylacetyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a-hexahyciro-3H benzoimidazol-2-one Ethyl 4-[(3aR,7aS)-2-oxooctahydro-1 H-benzimidazol-1 -yl]-1 ,4'-bipiperidinie-1 '-carboxylate Ethyl 4-[(3aS,7aR)-2-oxooctahydro-1 H-benzim idazol-1 -yl]-l ,4'-bipiperidine-1 '-carboxylate Isopropyl 4-[(3aR,7aS)-2-oxooctahydro-I H-benzimidazol-1 -yfl-1 ,4'-bipiperidine-l1 20 carboxylate Isopropyl 4-[(3aS,7aR)-2-oxooctahydro-1 H-benzimidazol-1 -yl]-1 ,4'-bipiperidine-1' carboxylate cis(II-)-1 -(1 '-benzoyl-1 ,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one cis (+/-)-I -[1 '-(cyclopentylcarbonyl)-1 ,4'-bipiperidin-4-yl]octahydro-2H--benzimidazol-2-one 25 cis (+I-)-1 -11 -(3-thienylcarbonyl)-1 ,4'-bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one cis (+/-)-I -[I '-(2-thienylcarbonyl)-1 ,4-bipiperidin-4-ylloctahydro-2H-benzimidazol-2-one cis (+/-)-I -(1 '-butyryl-1 ,4'-bipiperidin-4-yI)octahydro-2H-benzimidazol-2-one (3aS,7aS)-1 -methyl-3-[1 -[1-[3-(2-oxopyrrolidin-1 -yI)propanoyl]-4-piperidyl]-4-piperidyl] 3a,4,5,6,7,7a-hexahydrobenzomidazol-2-one 30 (3aS,7aS)-3-[1 -[1 -(cyclopropanecarbonyl)-4-piperidyl]-4-piperidyl]-I -methyl 3a,4,5,6,7,7a-hexahydrobenzoimidazol-2-one (3aS,7aS)-l -methyl-3-jj -[1 -(2-methylbenzoyl)-4-piperidyl]-4-piperidyl]-3a,4,5,6,7,7a hexahydrobenzoimidazol-2-one (3aS,7aS)-1 -[1 -[1 -(3-methoxythiophene-2-carbonyl)-4-piperidyl-4-piperidyl]-3-methyl 35 3a,4,5,6,7,7a-hexahydrobenzoimidazol-2-one Ethyl 4-[4-[(3aS,7aS)-2-oxo-3-prop-2-enyl-3a,4,5,6,7,7a-hexahydrobenzoimidazol-1 -yl]l piperidyl]piperidine-1 -carboxylate -122- WO 2007/142583 PCT/SE2007/000554 Ethyl 4-[(3aS,7aS)-3-isopropyl-2-oxooctahydro-1 H-benzimidazol-1 -yl]-1,4'-bipiperidine-1' carboxylate (3aS,7aS)-1 -(I'-(1 -methylcyclopropanecarbonyl)-1,4'-bipiperidin-4-yl)hexahydro-1 H benzo[d]imidazol-2(3H)-one 5 (3aS,7aS)-1-(1'-(2,2-difluorocyclopropanecarbony)-1,4'-bipiperidin-4-yl)hexahydro-1 H benzo[d]imidazol-2(3H)-one (3aS,7aS)-1-(1'-(2-methylcyclopropanecarbonyl)-1,4'-bipiperidin-4-yl)hexahydro-1H benzo[d]imidazol-2(3H)-one (3aS,7aS)-1 -(1'-(1 -(trifluoromethyl)cyclopropanecarbonyl)-1,4'-bipiperidin-4-yl)hexahydro 10 1 H-benzo[d]imidazol-2(3H)-one (3aS,7aS)-1 -[1'-(3-methylbutanoyl)-1,4'-bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one (3aS,7aS)-1 -[1'-(1 -acetyl-D-prolyl)-1,4'-bipiperidin-4-yf]octahydro-2H-benzimidazol-2-one (3aS,7aS)-1 -(I'-isobutyryl-1,4'-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one Isopropyl 4-((3aS,7aS)-2-oxooctahydro-1 H-benzo[d]imidazol-1-yl)-1,4'-bipiperidine-1' 15 carboxylate Prop-I-en-2-yl 4-((3aS,7aS)-2-oxooctahydro-I H-benzo[d]imidazol-1 -yl)-1,4'-bipiperidine 1'-carboxylate 2-Fluoroethyl 4-[(3aS,7aS)-2-oxooctahydro-1 H-benzimidazol-I -yl]-1,4'-bipiperidine-1' carboxylate 20 Isobutyl 4-[(3aS,7aS)-2-oxooctahydro-I H-benzimidazol-1-yl]-1,4'-bipiperidine-1' carboxylate Methyl 4-[(3aS,7aS)-2-oxooctahydro-I H-benzimidazol-I -yl]-1,4'-bipiperidine-1' carboxylate Ethyl 4-[4-[(3aR,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-indol-1-yl]-1 25 piperidyl]piperidine-1 -carboxylate Isopropyl 4-[(3aR,7aS)-2-oxooctahydro-I H-indol-I -yl]-1,4'-bipiperidine-1'-carboxylate (3aR,7aS)-I-[1'-(2-methylbenzoyl)-1,4'-bipiperidin-4-yl]octahydro-2H-indol-2-one Ethyl (3S)-3-{4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidin-1-yl}pyrrolidine-1 carboxylate 30 Ethyl(3R)-3-{4-[(3aR,7aS)-2-oxooctahydro-IH-indol-1-yl]piperidin-1-yl}pyrrolidine-1 carboxylate; and pharmaceutically acceptable salts thereof.
    [57] 57. A compound according to any one of claims 1-56 for use as a medicament. 35
    [58] 58. The use of a compound according to any one of claims 1-56 in the manufacture of a medicament for the therapy of pain. - 123- WO 2007/142583 PCT/SE2007/000554
    [59] 59. The use of a compound according to any one of claims 1-56 in the manufacture of a medicament for the treatment of Alzheimer's disease.
    [60] 60. The use of a compound according to any one of claims 1-56 in the manufacture 5 of a medicament for the treatment of schizophrenia.
    [61] 61. A pharmaceutical composition comprising a compound according to any one of claims 1-56 and a pharmaceutically acceptable carrier. 10
    [62] 62. A method for the therapy of pain in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-56.
    [63] 63. A method for the therapy of Alzheimer's disease in a warm-blooded animal, 15 comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-56.
    [64] 64. A method for the therapy of schizophrenia in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically 20 effective amount of a compound according to any one of claims 1-56.
    [65] 65. A method for the therapy of anxiety in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-56. 25
    [66] 66. A method for the therapy of depression in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-56. 30
    [67] 67. A process for preparing a compound of Formula I, comprising: - 124- WO 2007/142583 PCT/SE2007/000554 G 3 N .--N R 2 x G2A NY (R'~ A 2 / (CH 2 ) / 1CH On 2 G 3 m--N R G H O 5 111 IV wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; G', G 2 and G 3 are independently selected from hydrogen, halogen, C 1 . 6 alkyl, C 1 .. 6 alkoxy, hydroxy-C 1 . 6 alkyl, -CH 2 -OR, halogenated C 1 - 6 alkyl, -CONR 2 ; or any two of G', G 2 10 and G 3 are linked together to form a C14alkylene bridge and the other one of G', G 2 and G 3 is independently selected from hydrogen, halogen, C 1 . 6 alkyl, C 1 . 6 alkoxy, hydroxy-C 1 . 6 alkyl, -CH 2 -OR, halogenated C 1 - 6 alkyl, -C(=0)NR 2 ; R 1 is independently selected from hydrogen, halogen, C 1 - 6 alkyl, C 26 alkenyl, -CN, -C(=O)-OR, -C(=0)-NR 2 , hydroxy, and C1. 6 alkoxy; 15 R 2 is selected from hydrogen, C1- 6 alkyl, C 2 . 6 alkenyl, C 1 .ealkoxy, C 1 - 6 alkylamino, di C 1 . 6 alkylamino, C 61 oaryl, C 6 .joaryloxy, C 2 -heteroaryl, C 2 - 9 heteroaryloxy, C 3 . 5 heterocycloalkyloxy, C 3 - 5 heterocycloalkyl, C 6 .. 1 oaryl-C 1 - 3 alkoxy, C 6 -1 0 aryl-C 1 - 3 alkyl, C 2 -eheteroaryl-C 1 - 3 alkoxy, C 2 -sheteroaryl-C 1 . 3 alkyl, C 3 ..heterocycloalkyl-C 1 - 3 alkoxy, C 3 . 5 heterocycloalkyl-C 1 ..alkyl, C 3 - 6 cycloalkyl, C 3 . 6 cycloalkyloxy, and C 3 . 6 cycloalkyl-C 1 -salkyl, 20 C 3 .ecycloalkyl-C 1 -salkoxy, wherein said C 1 . 6 alkyl, C 2 . 6 alkenyl, C 1 . 6 alkyl-carbonyl, C 16 -alkylaminocarbonyl, C 6 . 1 oaryl, C.. 9 heteroaryl, C3- 5 heterocycloalkyl, C 6 .1 0 aryl-C 1 . 3 alkyl, C 2 -gheteroaryl-C 1 -salkyl, C 3 - 5 heterocycloalkyl-C 1 - 3 alkyl, C 3 . 6 cycloalkyl, and C 3 . 6 cycloalkyl -125- WO 2007/142583 PCT/SE2007/000554 C1.3alkyl are optionally substituted with one or more group selected from phenyl, C3.. 6 cycloalkyl, C 2 - 5 heterocycloalkyl, C 2 -5heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=0) R, -CO 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; p is 1,2,3 or4; m is 0, 1, or2; n is 1,2; 5 X, Y and Z are independently selected from C(=O), NH, N-R, N, C, CH 2 , and CH, wherein at least one of X, Y and Z is selected from NH, N-R and N; wherein at most one of X, Y and Z is C(=O); and wherein Z is not C(=O); and each R is independently hydrogen, C1. 6 alkyl, C 2 - 6 alkenyl or halogenated C 1 . 6 alkyl. 10
    [68] 68. A process for preparing a compound of Formula 1, comprising: 1 X A / ' (R1) 'Y 2G G 3 GI/ N (CH 2 ) CH2)n m.-N R 2 reacting a compound of Formula V with a compound of Q-C(=O)-R 2 I X A ,' (R) A 2 Y G 1 N (CH 2 )m m---NH 15 V wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; G', G 2 and G 3 are independently selected from hydrogen, halogen, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-C1. 6 alkyl, -CH 2 -OR, halogenated C1. 6 alkyl, -CONR 2 ; or any two of G', G 2 20 and G 3 are linked together to form a C1.4alkylene bridge and the other one of G', G 2 and -126 - WO 2007/142583 PCT/SE2007/000554 G 3 is independently selected from hydrogen, halogen, C 1 . 6 alkyl, C 1 . 6 alkoxy, hydroxy-C 1 . 6 alkyl, -CH 2 -OR, halogenated C 1 . 6 alkyl, -C(=O)NR 2 ; R 1 is independently selected from hydrogen, halogen, C 1 . 6 alkyl, C2- 6 alkenyl, -CN, -C(=O)-OR, -C(=O)-NR 2 , hydroxy, and C 1 . 6 alkoxy; 5 R 2 is selected from hydrogen, C 1 . 6 alkyl, C2-alkenyl, C 1 alkoxy, C 1 . 6 alkylamino, di C 1 . 6 alkylamino, C6. 1 0 aryl, C 6 . 1 0 aryloxy, C2-eheteroaryl, C2-gheteroaryloxy, C3. 5 heterocycloalkyloxy, C3- 5 heterocycloalkyl, C. 1 0 aryl-C. 3 alkoxy, C 6 . 1 0 aryl-C 1 - 3 alkyl, C2-sheteroaryl-C 1 - 3 alkoxy, C 2 .9heteroaryl-C 1 -salkyl, C 3 . 5 heterocycloalkyl-C 1 . 3 alkoxy, C3 5 heterocycloalkyl-C 1 .3alkyl, C3- 6 cycloalkyl, C 3 - 6 cycloalkyloxy, and C 3 - 6 cycloalkyl-C 1 .- 3 alkyl, 10 C3-6cycloalkyl-C 1 salkoxy,.wherein said C 1 . 6 alkyl, C2- 6 alkenyl, C 1 . 6 alkyl-carbonyl, C 1 . 6 alkylaminocarbonyl, Ce.1oaryl, C2-gheteroaryl, C3. 5 heterocycloalkyl, C 6 . 1 oaryl-C 1 .salkyl, C2- 9 heteroaryl-C 1 . 3 alkyl, C3.s 5 heterocycloalkyl-C 1 - 3 alkyl, C 3 . 6 cycloalkyl, and C 3 s 6 cycloalkyl C1- 3 alkyl are optionally substituted with one or more group selected from -CN, -SR, -OR, O(CH 2 )p-OR, R, -C(=O)-R, -CO 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , 15 and -C(=O)-NR 2 ; p is 1, 2, 3 or4; m is 0, ,or2; n =1, 2; X, Y and Z are independently selected from C(=O), NH, N-R, N, C, CH 2 , and CH, wherein at least one of X, Y and Z is selected from NH, N-R and N; wherein at most one of X, Y and Z is C(=O); and wherein Z is not C(=O); 20 Q is a halogen, OH; and each R is independently hydrogen, C 1 . 6 alkyl, C2- 6 alkenyl or halogenated C 1 . 6 alkyl.
    [69] 69. A process for preparing a compound of Formula IA, comprising: Cx N N CH2) < f 2 N R 2 25 IA reacting a compound of Formula lIlA with a compound of formula IV, - 127- WO 2007/142583 PCT/SE2007/000554 _x O O CH2)n N R 2 N H 0 lilA IV wherein R 2 is selected from hydrogen, C 16 alkyl, C 2 - 6 alkenyl, C1. 6 alkoxy, C 16 alkylamino, di 5 C 1 . 6 alkylamino, Cs. 1 oaryl, C61 oaryloxy, C 2 .heteroaryl, C 2 -eheteroaryloxy, C3 5 heterocycloalkyloxy, C 3 . 5 heterocycloalkyl, C 6 . 1 oaryl-C 1 . 3 alkoxy, C 6 - 1 oaryl-C 1 - 3 alkyl, C 2 - 9 heteroary-C 1 . 3 alkoxy, C 2 -gheteroaryl-Csalkyl, C 3 - 5 heterocycloalkyl-C 1 - 3 alkoxy, C3 sheterocycloalkyl-C1-3alkyl, C 3 . 6 cycloalkyl, C 3 - 6 cycloalkyloxy, and C 3 - 6 cycloalkyl-C1. 3 alkyl, C 3 . 6 cycloalkyl-C 1 - 3 alkoxy, wherein said C1. 6 alkyl, C 2 - 6 alkenyl, C 1 . 6 alkyl-carbonyl, 10 C 1 . 6 alkylaminocarbonyl, C6.1oaryl, C 2 - 9 heteroaryl, C 3 - 5 heterocycloalkyl, CB. 1 oaryl-C 1 . 3 alkyl, C 2 .gheteroaryl-C 1 - 3 alkyl, C3. 5 heterocycloalkyl-C 1 - 3 alkyl, C 3 - 6 cycloalkyl, and C3. 6 cycloalkyl C 1 3 alkyl are optionally substituted with one or more group selected from phenyl, C 3 . 6 cycloalkyl, C 2 . 5 heterocycloalkyl, C 2 - 5 heteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=0) R, -C0 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; 15 p is 1, 2, 3 or 4; n is 1, 2; X, is independently selected from NH, N-R, CH 2 CHR, and CRR'; and each R, R' is independently hydrogen, Ci-alkyl, C2- 6 alkenyl or halogenated C 16 alkyl.
    [70] 70. A process for preparing a compound of Formula IA, comprising: x N CH2) N R 20 0 IA reacting a compound of Formula V with a compound of Q-C(=O)-R 2 , - 128- WO 2007/142583 PCT/SE2007/000554 x N NH VA wherein R 2 is selected from hydrogen, C 1 . 6 alkyl, C 2 - 6 alkenyl, C 1 . 6 alkoxy, C 1 . 6 alkylamino, di 5 C 1 -ealkylamino, C6-1oaryl, C 6 e.oaryloxy, C2- 9 heteroaryl, C2- 9 heteroaryloxy, C3 5 heterocycloalkyloxy, C 3 . 5 heterocycloalkyl, C 6 . 1 0 aryI-C 1 - 3 alkoxy, C 6 . 1 0 aryl-C 1 - 3 alkyl, C2.heteroaryl-C 1 . 3 alkoxy, C2- 9 heteroaryl-C 1 - 3 alkyl, C3.sheterocycloalkyl-C 1 - 3 alkoxy, C3 5 heterocycloalkyl-C 1 .3alkyl, Ca. 6 cycloalkyl, C3- 6 cycloalkyloxy, and C 3 - 6 cycloalkyl-C 1 . 3 alkyl, C 3 . 6 cycloalkyl-C 1 . 3 alkoxy, wherein said C 1 . 6 alkyl, C2- 6 alkenyl, C 16 -alkyl-carbonyl, 10 C 1 . 6 alkylaminocarbonyl, C6.1oaryl, C 2 -eheteroaryl, Ca. 5 heterocycloalkyl, CO 61 oaryl-C 1 - 3 alkyl, C 2 .gheteroaryl-C 13 alkyl, C 3 - 5 heterocycloalkyl-C.alkyl, C 3 . 6 cycloalkyl, and C3- 6 cycloalkyl C 1 -alkyl are optionally substituted with one or more group selected from phenyl, C3 6 cycloalkyl, C2- 5 heterocycloalkyl, C 2 -sheteroaryl, -CN, -SR, -OR, -O(CH 2 )p-OR, R, -C(=0) R, -C0 2 R, -SO 2 R, -SO 2 NR 2 , halogen, -NO 2 , -NR 2 , -(CH 2 )pNR 2 , and -C(=O)-NR 2 ; 15 pis 1,2,3or4; nis 1,2; X, is independently selected from NH, N-R, CH 2 CHR, and CRR'; and each R, R' is independently hydrogen, C 1 . 6 alkyl, C2- 6 alkenyl or halogenated C1-ealkyl, and Q is a halogen, or OH. 20
    [71] 71. A compound of formula VA, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: O N N FCH 2 )n NH - 129- WO 2007/142583 PCT/SE2007/000554 VA wherein n is 1, 2; X, is independently selected from NH, N-R, CH 2 CHR, and CRR'; and 5 each R, R' is independently hydrogen, C 1 . 6 alkyl, C2- 6 alkenyl or halogenated C1. 6 alkyl.
    [72] 72. A compound of formula V, a pharmaceutically acceptable salt thereof, diastereomer, enantiomer, or mixture thereof: (R') 'Y P A 2 G 3 1 N (CH 2 ) / 2CH A m.NH 10 V wherein A' and A 2 are independently selected from -CH 2 -, -CH(R)-, -N(R)-, and -0-; 1 2 3 G , G and G 3 are independently selected from hydrogen, halogen, C1. 6 alkyl, C1. 6 alkoxy, hydroxy-C 1 . 6 alkyl, -CH 2 -OR, halogenated C 1 . 6 alkyl, -CONR 2 ; or any two of G', G 2 15 and G 3 are linked together to form a C 1 . 4 alkylene bridge and the other one of G', G 2 and G 3 is independently selected from hydrogen, halogen, C 1 . 6 alkyl, C 1 ..alkoxy, hydroxy-C 1 . 6 alkyl, -CH 2 -OR, halogenated C 1 . 6 alkyl, -C(=0)NR 2 ; R 1 is independently selected from hydrogen, halogen, C 1 . 6 alkyl, C2- 6 alkenyl, -CN, -C(=0)-OR, -C(=0)-NR 2 , hydroxy, and C 1 . 6 alkoxy; 20 pis 1,2,3or4;misO,1,or2;nis 1,2; X, Y and Z are independently selected from C(=0), NH, N-R, N, C, CH 2 , and CH, wherein at least one of X, Y and Z is selected from NH, N-R and N; wherein at most one of X, Y and Z is C(=0); and wherein Z is not C(=O0); and each R is independently hydrogen, C1. 6 alkyl, C 2 - 6 alkenyl or halogenated C1. 6 alkyl. 25 - 130-
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    法律状态:
    2012-03-15| MK5| Application lapsed section 142(2)(e) - patent request and compl. specification not accepted|
    优先权:
    申请号 | 申请日 | 专利标题
    US81220906P| true| 2006-06-09|2006-06-09||
    US60/812,209||2006-06-09||
    PCT/SE2007/000554|WO2007142583A1|2006-06-09|2007-06-08|Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia.|
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