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Title:
SUBSTITUTED 3- AND 4- AMINOMETHYLPIPERIDINES FOR USE AS BETA-SECRETASE IN THE TREATMENT OF ALZHEIMER’S DISEASE
Document Type and Number:
WIPO Patent Application WO/2004/002483
Kind Code:
A1
Abstract:
The invention relates to novel compounds, which are substituted chiral or achiral derivatives of 3- or 4- aminomethylpiperidine of the general formula (I). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of general formula (I) and especially their use as inhibitors of beta-secretases for the treatment of Alzheimer’s disease.

Inventors:
BOSS CHRISTOPH (CH)
BUR DANIEL (CH)
FISCHLI WALTER (CH)
JENCK FRANCOIS (FR)
WELLER THOMAS (CH)
Application Number:
PCT/EP2003/006674
Publication Date:
January 08, 2004
Filing Date:
June 25, 2003
Export Citation:
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Assignee:
ACTELION PHARMACEUTICALS LTD (CH)
BOSS CHRISTOPH (CH)
BUR DANIEL (CH)
FISCHLI WALTER (CH)
JENCK FRANCOIS (FR)
WELLER THOMAS (CH)
International Classes:
A61P25/28; C07D211/26; C07D401/06; C07D401/12; C07D405/06; C07D405/12; (IPC1-7): A61K31/445; A61P25/28; C07D211/26; C07D401/12; C07D401/06; C07D405/06; C07D405/12
Domestic Patent References:
WO2001081308A22001-11-01
WO1992002501A11992-02-20
WO2000033788A22000-06-15
WO2001072741A22001-10-04
Foreign References:
US5192775A1993-03-09
Other References:
VILLALOBOS A ET AL: "NOVEL BENZISOXAZOLE DERIVATIVES AS POTENT AND SELECTIVE INHIBITORS OF ACETYLCHOLINESTERASE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 17, 1994, pages 2721 - 2734, XP001073613, ISSN: 0022-2623
GASTER L M ET AL: "N-U(1-BUTYL-4-PIPERIDINYL)METHYL-3,4-DIHYDRO-2H-U1,3OXAZINO U3,2-ALPHAINDOLE-10-CARBOXAMIDE HYDROCHLORIDE: THE FIRST POTENT AND SELECTIVE 5-HT4 RECEPTOR ANTAGONIST AMIDE WITH ORAL ACTIVITY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 38, no. 24, 24 November 1995 (1995-11-24), pages 4760 - 4763, XP002046521, ISSN: 0022-2623
CLARK ET AL: "Antihypertensive 9-substituted 1-0xa-4,9-diazaspiro[5.5]undecan-3- ones", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 26, no. 6, 1983, pages 855 - 861, XP002082529, ISSN: 0022-2623
BOYFIELD I ET AL: "Design and synthesis of 2-naphthoate esters as selective dopamine D4 antagonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 39, no. 10, 1996, pages 1946 - 1948, XP002105883, ISSN: 0022-2623
ITOH K ET AL: "Synthesis and pharmacological evaluation of carboxamide derivatives as selective serotoninergic 5-HT4 receptor agonists", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 34, no. 4, April 1999 (1999-04-01), pages 329 - 341, XP004178575, ISSN: 0223-5234
LOPEZ-RODRIGUEZ, M.L. ET AL.: "Benzimidazole derivatives. Part I: Synthesis and structure-activity relationships of new benzimidazole-4-carboxamides and carboxylates as potent and selective 5-HT4 receptor antagonists", BIOORG. MED. CHEM., vol. 7, 1999, pages 2271 - 2281, XP002253669
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Claims:
Claims:
1. Compounds of the general formula I, wherein the substitutent is attached either to position 3 or position 4 of the central piperidinering R3 o2 R \ k (H2C) m (H2C))/N\X R4 41 3 4 3 General Formula I Ri wherein R1 represents lower alkyl ; lower alkenyllower alkyl ; lower alkynyllower alkyl ; cycloalkyl ; cycloalkenyllower alkyl ; heterocyclyl ; aryl ; heteroaryl ; R represents hydrogen; lower alkyl ; lower alkenyllower alkyl ; lower alkynyllower alkyl ; cycloalkyl ; cycloalkenyllower alkyl ; heterocyclyl ; aryl ; heteroaryl ; R3 represents hydrogen; lower alkyl ; lower alkenyllower alkyl ; lower alkynyllower alkyl ; cycloalkyl ; cycloalkenyllower alkyl ; heterocyclyl ; aryl ; heteroaryl ; R4 represents lower alkyl ; cycloalkyl ; cycloalkenylCH2 ; heterocyclyl ; aryl ; heteroaryl ; X represents (CH2)nCH2(CH2)j; (C=O)(CH2)p;(C=O)(CH2)pNH(CH2)q; (C=O)(CH2) f*0(CH2) p;(C=0)(CH=CH);(S02)(CH2) p;(S02)NH(CH2) p; (SO2)(CH=CH); Z represents a bond ; ( (CH2)nCH2(CH2)j); ((CH2)(CH=CH); (CH2)gNH(CO); (CH2) gNH (CO)O ; (CH2) gNH (CO)NH ; (CH2) g0 (CH2) m ; n and j represent the whole numbers 0,1 or 2 and may be the same or different; m represents the whole numbers 0 or 1 ; k, p and q represent the whole numbers 0, 1, 2,3 or 4 and may be the same or different; f represents the whole numbers 1, 2,3 or 4; g represents the whole numbers 2,3 or 4; and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
2. Compounds of the general formula I according to claim 1, wherein R', R2, Z, X, m and k are as defined in general formula I above and R3 and R4 are chosen from the structural units given below and may be the same or different wherein R5 represents lower alkyl ; hydroxylower alkyl ; aryl ; aryllower alkyl ; heteroaryl ; heteroaryllower alkyl ; heterocyclyl ; heterocyclyllower alkyl ; cycloalkyl ; cycloalkyllower alkyl ; R6 represents lower alkyl ; lower alkynyl ; aryl ; heteroaryl ; heterocyclyl ; arylamino ; heteroarylamino; cycloalkylamino ; aryllower alkylamino ; heteroaryllower alkylamino ; heterocyclyllower alkylamino ; cycloalkyllower alkyl amino; aryloxy; heteroaryloxy ; cyloalkyloxy ; aryllower alkyloxy ; heteroaryllower alkyloxy ; heterocyclyllower alkyloxy ; cycloalkyllower alkyloxy ; R7 represents aryl ; heteroaryl ; heterocyclyl ; cycloalkyl ; arylamino ; heteroarylamino ; cycloalkylamino ; aryllower alkylamino ; heteroaryllower alkylamino ; heterocyclyllower alkylamino ; cycloalkyllower alkyl amino; aryloxy ; heteroaryloxy ; aryllower alkyloxy ; heteroaryllower alkyloxy ; and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
3. Compounds of the formula II R3 k (H2C) \ JHC) N R' Formula 11 N N wherein Rl, R2, R3, R4, m, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
4. Compounds of the formula II according to claim 3, wherein RI, R3, R4, k, X and Z are as defined in general formula I above and wherein m represents the whole number 1 and R2 represents cyclohexyl ; phenyl ; 3, 5difluorophenyl ; 3, 5dimethylphenyl ; 3, 5dichlorophenyl and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
5. Compounds of the formula III R3 k (H2c) 4 X X Formula III N I wherein Rl, R3, R4, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
6. Compounds of the formula IV R2 R3 (CH2) m 1 1 (CHo) k N Formula IV \R1 wherein Rl, R2, R3, R4, m, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
7. Compounds of the formula IV according to claim 6, wherein R', R3, R, k, X and Z are as defined in general formula I above and wherein m represents the whole number 1 and R2 represents cyclohexyl ; phenyl ; 3, 5difluorophenyl ; 3, 5dimethylphenyl ; 3,5 dichlorophenyl and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
8. Compounds of the formula V: R3 (CHo). N Formula V XRa wherein R', R3, R4, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the mesoform and cisand transisomers of carboncarbon double bonds and pharmaceutically acceptable salts thereof.
9. Pharmaceutical compositions for treatment, prevention or delaying the onset of central nervous system disorders comprising compounds according to any one of the claims 1 to 8.
10. Pharmaceutical compositions containing one or more compounds as claimed in any of the claims 1 to 8 and any inert excipients.
11. Pharmaceutical compositions containing one or more compounds as claimed in any of the claims 1 to 8 and any inert excipients in combination with one or more therapeutic agents selected from the group consisting of antioxidants, antiinflammatory agents, y secretase inhibitors, statins, LDL lowering agents, an amyloid (3peptide derivative and an antiamyloidßpeptide antibody, steroidhormones, antidepressant and antipsychotic agents, neurotrophic factors, metal ion chelators, insulinsensitizers and acetylcholine esterase inhibitors.
12. Pharmaceutical compositions according to any of the claims 9 to ll for treatment, prevention or delaying the onset or the progression of diseases requiring the inhibition of aspartic proteases.
13. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or the progression of disorders associated with the role of secretase (BACE1) and which require selective inhibition of ßsecretase (BACE 1).
14. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or the progression of diseases and disorders selected from the group consisting of Alzheimer's disease, mild cognitive impairment (MCI), Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutchtype, cerebral amyloid angiopathy, other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration or diffuse Lewy body type of Alzheimer's disease and the like.
15. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of Alzheimer's disease.
16. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of mild cognitive impairment.
17. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of Down's syndrome.
18. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of cerebral hemorrhage with amyloidosis of the Dutchtype.
19. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of cerebral amyloid angiopathy.
20. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of degenerative dementias.
21. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of Lewy body type of Alzheimer's disease.
22. Pharmaceutical compositions according to any of the claims 9 to 11 for treatment, prevention or delaying the onset or progression of diseases characterized by deposites of amyloidßpeptides in the brain.
23. A method for inhibiting psecretase activity by exposing said (3secretase in vitro (isolated enzyme assay), in a cell, in an animal, or in humans to an effective inhibitory amount of a compound according to any of the claims 1 to 8 or a pharmaceutical composition according to any of the claims 9 to 11.
24. A method for inhibiting the production of amyloidppeptides (A (3) in vitro (isolated enzyme assay), in a cell, in an animal, or in humans by administering an effective inhibitory amount of a compound according to any of the claims 1 to 8 or a pharmaceutical composition according to any of the claims 9 to 11.
25. A method for inhibiting the production of amyloidppeptide plaques in an animal, or in humans by administering an effective inhibitory amount of a compound according to any of the claims 1 to 8 or a pharmaceutical composition according to any of the claims 9 to 11.
26. A process for the preparation of a pharmaceutical composition according to any of the claims 9 to 22, characterized by mixing one or more active ingredients according to any of the claims 1 to 8 with inert excipients in a manner known per se.
27. A process for the preparation of a pharmaceutical composition according to any of the claims 9 to 22, characterized by mixing one or more active ingredients according to any of the claims 1 to 8 with inert excipients and one or more additional active ingredients selected from the group consisting of antioxidants, antiinflammatory agents, «secretase inhibitors, statins, LDL lowering agents, an amyloid (3peptide derivative and an antiamyloidß peptide antibody, steroidhormones, antidepressant and antipsychotic agents, neurotrophic factors, metal ion chelators, insulinsensitizers and acetylcholine esterase inhibitors, in a manner known per se.
28. Use of at least one of the compounds of general formula I for the treatment, prevention or delaying the onset or progression of diseases.
29. Method of treating a patient suffering from central nervous system disorders by administering a pharmaceutical composition as claimed in any one of claims 9 to 22.
30. Method according to claim 29 by administering a pharmaceutical composition containing a compound as claimed in any one of claims 1 to 8 in a dose of 1 mg to 1000 mg.
31. Method according to claim 29 by administering a pharmaceutical composition containing a compound as claimed in any one of claims 1 to 8 in a dose of 2 mg to 500 mg.
32. Method according to claim 29 by administering a pharmaceutical composition containing a compound as claimed in any one of claims 1 to 8 in a dose of 5 mg to 250 mg.
Description:
SUBSTITUTED 3-AND 4-AMINOMETHYLPIPERIDINES FOR USE AS BETA-SECRETASE IN THE TREATMENT OF ALZHEIMER'S DISEASE The invention relates to novel substituted amino-aza-cycloalkane derivatives of the general formula I, which are (3-secretase inhibitors useful for prevention or treatment of diseases related to the formation and aggregation of amyloid-p-peptide (A (3). More particularly, the compounds and compositions are useful for treating or preventing Alzheimer's disease, other age-associated dementias as well as related Ap dependent diseases (e. g. ß amyloid angiopathy, Down's syndrome or inclusion body myositis). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of general formula I and especially their use as inhibitors of the transmembrane bound aspartic protease BACE 1 or other related aspartic proteases.

Background of the invention: [1] The World Health Organization (WHO) emphasized the importance of mental disorders in the World Health Report 2001 [2] by giving a comprehensive analysis of the world's fastest growing disease group. With increasing life expectancy and a prevalance of 5. 5% of the population above 60 years of age, Alzheimer's disease (AD) has been recognized as a major social and financial burden for the coming decades [3]. A few years ago patients suffering from Alzheimer's disease had only little cause for hope to receive more effective therapies.

At the present time the therapeutic situation has improved with respect to treatment of symptoms such as depression, sleeplessness or agitation but no treatment is available being able to halt progression or even cure Alzheimer's disease.

AD is a major degenerative disease of the brain, which is primarily-but not exclusively- associated with aging and presents clinically by progressive loss of memory, cognition, reasoning, judgement, but also emotional instability that gradually leads to profound mental deterioration and death. The exact cause of AD is still unknown, but increasing evidence

indicates a central role for Ap in the pathogenesis of the disease [4-12]. A robust genetic association exists between the early-onset familial forms of AD and the abundance of A (3 in the brain. Mutations can be identified in a variety of loci including the amyloid precursor protein (APP) gene. Individuals with AD exhibit characteristic neuropathological markers such as neuritic plaques (and in p-amyloid angiopathy, deposits in cerebral blood vessels) as well as neurofibrillary tangles detected in the brain at autopsy. AP is a major component of neuritic plaques in AD brains and increasing evidence supports that Ap neurotoxicity and fibrillar assembly are key pathogenic features of AD. Smaller numbers of neurotoxic lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not display clinical AD. In addition, amyloid deposits and vascular amyloid angiopathy also characterize individuals with Down's syndrome (trisomy 21), hereditary cerebral hemorrhage of the Dutch type and other neurodegenerative disorders.

Increase in brain levels of soluble or fibrillar forms of A (3 in AD might be due to overexpression of the amyloid precursor protein (APP), altered cleavage of APP to Ap or decreased clearance of A (3 from the brain. Ap is generated from APP which is a ubiquitously expressed type I protein with a large N-terminal domain, a single transmembrane domain and a short cytoplasmic domain coded by a gene located on human chromosome 21 (Price et al. , Annu Rev Neurosci 21: 479-505,1998 ; Selkoe, Trends Cell Biol 8: 447-453,1998). APP can undergo several proteolytic events near and within its membrane domain.

A proteolytic activity named P-secretase initially cleaves APP to form two products: a secreted peptide named APPsp and the membrane bound C99 fragment of APP. C99 is the substrate of a second proteolytic activity called y-secretase, which cleaves at position 711 (40) or 713 (42) to form Aßl 40 and Aß 42. ln an alternative, non-amyloidogenic processing pathway, cleavage of APP by a-secretase within the amyloid domain results in the release of the large soluble fragment, APPsa, and generation of a lOkDa membrane anchored C- terminal fragment, C83. It can be argued that a gradual and chronic imbalance between production and clearance of Ap proteins leads to a slow rise in its steady-state levels in the brain tissue, resulting in Ap accumulation and subsequently in plaque formation as well as complex molecular and cellular changes in the brain. It has also become increasingly clear

that all the hereditary familial forms of AD currently known alter either the metabolism or the generation ofAp [13-15].

The integrated functions of APP and its fragments in normal situations remain largely unknown. The processing of APP is similar to that of other proteins that undergo regulated intramembrane proteolysis such as Notch (Niwa et al., Cell 99: 691-702,1999 ; Mumm et al., Dev Biol 228: 151-165,2000) to generate fragments which play a role as transcription factors. Ap naturally arises in the endoplasmatic reticulum, the Golgi apparatus or the endosomal-lysosomal system and most is secreted as Ap 1-40 or Ap 1-42 (5-10%).

However, intracellular aggregates of Ap also accumulate in brains of AD patients, Down's syndrome patients and aging monkeys. This precedes the appearance of neurofibrillary tangles and senile plaques in the hippocampus and entorhinal cortex of affected individuals.

In 1999 the identification of (3-site APP cleaving enzyme (BACE1), also called memapsin-2 or Asp2, was described by using different approaches [16-18]. BACE1 is a membrane- bound aspartic protease with all the known functional properties and characteristics of ß- secretase. It is a 501 amino acid sequence peptide most closely related to the pepsin aspartic protease family. Two aspartic protease active-site motifs with the sequence DTGS (residues 93-96) and DSGT (289-292) are present, mutation of either aspartic acid abolishes the catalytic acitivity of the enzyme. BACE1 has a single predicted C-terminal transmembrane domain (455-480) with a luminal active site. This is the correct topological orientation for APP cleavage. Six cysteins are present in the catalytic domain to form three intramolecular disulfide bonds. The number of dislufide bridges is identical to other aspartic proteases such as pepsin. While the bond spanning between Cys330-380 appears conserved, the positions of two cysteine bridges (Cys278-443, Cys 216-420) are quite different when compared to pepsin, without changing the shape of the catalytic domain. Most cell types produce Ap, indicating broad expression of p-secretase. However, considerably more Ap is generated in primary brain cultures than in peripheral cells (Seubert et al., Nature 361: 260-3,1993) and neurons display more P-secretase activity than astrocytes (Zhao et al., J Biol Chem 271: 31407-11,1996). The expression of BACE1 is highest in pancreas and brain, and significantly lower in most other tissues. The high expression level in pancreas can be

attributed to a catalytically inactive splice variant of BACE1, lacking part of exon 3. p- secretase activity has been found in several cellular compartments including endosomes, lysosomes, Golgi and endoplasmic reticulum. Parallel to BACE1, a second homologous aspartyl protease named BACE2 was found to have (3-secretase activity in vitro and is expressed at low levels in most peripheral organs, although not significantly in the brain.

Down-regulation of BACE1 protein expression with antisense oligonucleotides suppresses APPsp production in cells transfected with APPsw2. On the other hand, overexpression of BACE1 in cells leads to an increase of (3-secretase activity: levels of C99 and APPsp are increased several-fold compared to untransfected cells. In mice, expressing huBACE1 in addition to human APP wild-type or carrying the Swedish mutation, the induction of APP processing results in increased brain levels of (3-amyloid peptides Aßl40 and Aßl 12 at steady state. BACE knock-out mice are fully viable. Ap production is significantly decreased in the brain of these animals, even when the BACE null mutation is introduced in transgenic mice overexpressing APP (Luo et al., Nature Neurosci. 4: 231-232,2001). However, no deleterious side-effects due to the loss of BACE function was observed in these animals.

The healthy phenotype of BACE1 knockouts gives 3-secretase significant therapeutic potential although, as with y-secretase, substrates other than APP may exist. The positive results from the knockout mice suggest that a potential mechanism-based toxicity might not be a major issue for BACEI specific inhibitors.

Prior Art: Today, at least according to our knowledge, no low-molecular-weight non-peptide, non- substrate related BACE1-inhibitor is published in the scientific literature. In the patent literature only a few documents dealing with low-molecular weight non-peptide compounds have been found by database searches (Takeda Chemical Industries: WO 01/87293A1 and WO 00/187293; Vertex Pharmaceuticals : WO 02/088101; Elan Pharmaceuticals : WO 02/076440 [claiming renin inhibitors from WO 97/09311 to F. Hoffmann-LaRoche, as BACE-inhibitors] and WO 03/000261 [claiming HIV-1 protease inhibitors from US 5,846, 978 to Merck & Co. as BACE-inhibitors] ). Several patents dealing with peptidomimetic BACEI inhibitors have been published so far (Elan Pharmaceuticals : WO

00/77030; WO 01/70672 ; WO 02/02520; WO 02/02512; WO 02/02506, WO 02/02505; WO 02/085877; WO 02/094768; WO 02/100399; WO 02/100856; WO 02/100820; WO 03/002122; WO 03/006453; WO 03/006423; WO 03/006021; WO 03/006013; WO 03/037325; WO 03/030886; WO 03/040096; WO 03/039454; US 6,552, 013; 03/45378; WO 03/47576; WO 03/43987; WO 03/43975; WO 03/43618; Pfizer Products Inc.: EP 1233021; Neurologic Inc.: WO 02/096897; US 6,562, 783; Sumitomo Pharmaceutical Co Ltd.: JP 14173448; Oklahoma Medical Research Foundation: WO 02/053594; WO 01/00665 ; GlaxoSmithKline : WO-03/45913; WO 03/45903).

No reports or publications were found about pre-clinical or even clinical investigations with compounds contemplated in the patents listed above.

The present invention relates to the identification of novel low molecular weight non- peptidic inhibitors of BACEI of the general formula I (exhibiting a different binding mode to the protein compared to substrate derived inhibitors) to treat and/or prevent Alzheimer's Disease and other CNS-disorders associated with amyloid deposition in the brain.

The compounds of general formula I were tested against BACE1, plasmepsin II, plasmepsin IV, human cathepsin D, human cathepsin E, human renin and HIV-protease.

Assay conditions to determine inhibition of BACE1 activity: The proteolytic activity of human BACE1 (Sinha, S. , et al. (1999), Nature 402: 537-540) was determined in a FRET-based assay, with a peptide-substrate whose sequence corresponds to the cleavage site of (3-secretase in the Swedish variant of the amyloid precursor protein.

Commercial source of the BACE1-assay : PanVera Corporation Madison WI 53719 USA (www. panvera. com) Descriptions of the assays against the other aspartic proteases can be found in WO 02/24649 and WO 02/38534.

References and Notes: [1] S. Roggo; Curr. Top. Med. Chem. ; 2002,2, 359.

[2] www. who. int/whr/.

[3] K. Alloul ; L. Sauriol ; W. Kennedy; C. Laurier; G. Tessier; S. Novosel ; A.

Contandriopoulous ; Arch. Gerontol. Geriatr. ; 1998, 27, 189.

[4] D. B. Schenk; R. E. Rydel et al ; J. Med. Chem. ; 1995, 21, 4141.

[5] M. Rachi; S. Govoni; Trends Pharmacol. Sci. ; 1999,20, 418.

[6] C. Soto; Mol. Med. Today ; 1999, 5, 343.

[7] M. N. Sabbagh; D. Galasko et al ; J. Alzheimer's Dis. ; 2000,2, 231.

[8] F. Checler; J. Neurochem. ; 1995, 65, 1431.

[9] D. Selkoe; Ann. N. Y. Acad. Sci. ; 2000, 924, 17.

[10] Ch. M. Coughlan ; K. C. Breen; Pharm. Ther. ; 2000, 86, 111.

[I I] R. Vassar; M. Citron ; Neuron ; 2000, 27, 419.

[12] D. J. Selkoe; Physio. Rev. ; 2001, 81, 741.

[13] J. Hardy; Proc. Natl. Acad. Sci. USA ; 1997, 94, 2095.

[14] D. J. Selkoe ; Science ; 1997, 275, 630.

[15] D. J. Selkoe; J. Alzheimer's Dis. ; 2001,3, 75.

[16] R. Vassar; B. D. Bennertt et al ; Science ; 1999, 286, 735.

[17] R. Yan; M. J. Bienkowski et al ; Nature ; 1999, 402, 533.

[18] S. Sinha; J. P. Anderson et al; Nature ; 1999, 402, 537.

[19] S. L. Roberds, J. Anderson et al ; Human Mol. Gen. ; 2001, 10, 1317.

[20] V. Bigl, S. Rossner; Curr. Med. Chem. ; 2003, 10, 871.

[21] B. Schmidt; ChemBioChem ; 2003, 4, 366.

The present invention relates to novel, low molecular weight organic compounds which are substituted piperidines of the general formula I, wherein the substituent is attached either to position 3 or position 4 of the central piperidine-ring: Ra k (H2c) mH2) X-R4 4 3 3 General Formula I ZON Z R1 wherein R'represents lower alkyl ; lower alkenyl-lower alkyl ; lower alkynyl-lower alkyl ; cycloalkyl ; cycloalkenyl-lower alkyl ; heterocyclyl ; aryl ; heteroaryl ; R2 represents hydrogen; lower alkyl ; lower alkenyl-lower alkyl ; lower alkynyl-lower alkyl ; cycloalkyl ; cycloalkenyl-lower alkyl ; heterocyciy) ; aryl ; heteroaryl ; R3 represents hydrogen; lower alkyl ; lower alkenyl-lower alkyl ; lower alkynyl-lower alkyl ; cycloalkyl ; cycloalkenyl-lower alkyl ; heterocycty) ; aryl ; heteroaryl ; R4 represents lower alkyl ; cycloalkyl ; cycloalkenyl-CH2-; heterocyclyl ; aryl ; heteroaryl ;

X represents-(CH2) n-CH2-(CH2) j-;-(C=O)-(CH2) p-;-(C=O)-(CH2) p-NH-(CH2) q-; <BR> <BR> <BR> -(C=0)-(CH2) f"0-(CH2) p-;-(C=0)-(CH=CH)-;-(S02)-(CH2) p-;-(S02)-NH-(CH2) p-;<BR> <BR> <BR> <BR> <BR> - (S02)- (CH=CH)- ; Z represents a bond ;- ( (CH2) n-CH2- (CH2) j)- ;- ( (CH2)- (CH=CH))- ;- (CH2) g-NH- (CO)- ; - (CH2) g-NH- (CO)-O- ;- (CH2) g-NH- (CO)-NH- ;- (CH2) g-O- (CH2),-., n and j represent the whole numbers 0,1 or 2 and may be the same or different; m represents the whole numbers 0 or 1 ; k, p and q represent the whole numbers 0,1, 2,3 or 4 and may be the same or different; f represents the whole numbers 1,2, 3 or 4; g represents the whole numbers 2,3 or 4; and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

In the definitions of the general formula I-if not otherwise stated-the expression lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms which may optionally be substituted with hydroxy or lower alkoxy. Examples of lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, n-heptyl and the like. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy; iso-butoxy, sec. -butoxy and tert. -butoxy and the like. Examples of lower alkynyl groups are ethinyl, propynyl, butynyl, pentynyl, hexynyl and the like which may be optionally substituted by hydroxy or lower alkoxy. Examples of lower alkynyloxy groups are 3-methoxy-prop-1-ynyl and the like. Lower alkylendioxy- groups as substituents of aromatic rings onto two adjacent carbon atoms are preferably

methylen-dioxy and ethylen-dioxy. Lower alkylen-oxy groups as substituents of aromatic rings onto two adjacent carbon atoms are preferably ethylen-oxy and propylen-oxy.

Examples of lower alkanoyl-groups are acetyl, n-propanoyl and n-butanoyl. Lower alkenylen means e. g. vinylen, allylen, propenylen and butenylen.

The expression cycloalkyl, alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 6 carbon atoms, e. g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be mono-or di-substituted with lower alkyl ; lower alkoxy ; aryl- lower alkoxy ; heteroaryl-lower alkoxy ; aryl-lower alkyl-amino ; heteroaryl-lower alkyl- amino; lower alkyl-amino ; bis-(lower alkyl)-amino ; aryl-lower alkoxy-lower alkyl ; heteroaryl-lower alkoxy-lower alkyl ; aryl-lower alkyl-amino-lower alkyl ; heteroaryl-lower alkyl-amino-lower alkyl ; aryl-sulfonyl-amino-lower alkyl ; heteroaryl-sulfonyl-amino-lower alkyl ; cycloalkyl-sulfonyl-amino-lower alkyl ; heterocyclyl-sulfonylamino-lower alkyl ; aryl- lower alkyl-sulfonyl-amino-lower alkyl ; heteroaryl-lower alkyl-sulfonyl-amino-lower alkyl ; cycloalkyl-lower alkyl-sulfonyl-amino-lower alkyl ; heterocyclyl-lower alkyl-sulfonylamino- lower alkyl ; lower alkyl-sulfonyl-amino-lower alkyl ; aryl amino-carbonyl-lower alkyl ; heteroaryl-amino-carbonyl-lower alkyl ; cycloalkyl-amino-carbonyl-lower alkyl ; heterocyclyl-amino-carbonyl-lower alkyl ; lower alkyl-amino-carbonyl-lower alkyl ; aryl- ureido-lower alkyl ; heteroaryl-ureido-lower alkyl ; cycloalkyl-ureido-lower alkyl ; lower alkyl-ureido-lower alkyl ; aryl-lower alkyl-ureido-lower alkyl and in case the substituent on the cycloalkyl contains aryl-or heteroaryl-units those may again be mono-, di or tri- substituted with substituents as outlined herein before.

The expression cycloalkenyl, alone or in combination, means an unsaturated cyclic hydrocarbon ring system with 5 to 7 carbon atoms, e. g. cyclopentenyl, cyclohexenyl and cycloheptenyl which may be substituted with lower alkyl groups or lower alkoxy groups.

The expression heterocyclyl, alone or in combination, means a saturated or unsaturated (but not aromatic) five-, six-or seven-membered ring containing one or two heteroatoms chosen from nitrogen, oxygen or sulfur which may be the same or different and which rings may be substituted with lower alkyl ; lower alkenyl ; aryl ; heteroaryl ; aryl-lower alkoxy ; aryl-lower

alkoxy-lower alkyl ; aryl-oxy ; heteroaryl-lower alkoxy ; heteroaryl-lower alkoxy-lower alkyl ; heteroaryl-oxy ; amino; bis-(lower alkyl)-amino ; alkanoyl-amino ; halogen; hydroxy; hydroxy-lower alkyl ; lower alkoxy ; phenoxy; examples of such rings are morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1, 4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like, and substituted derivatives of such type rings with substituents as outlined hereinbefore.

The expression heteroaryl, alone or in combination, means six-membered aromatic rings containing one to four nitrogen atoms; benzofused six-membered aromatic rings containing one to three nitrogen atoms; five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom and benzo-fused derivatives thereof ; five-membred aromatic rings containing two nitrogen atoms and benzo-fused derivatives thereof ; five membered aromatic rings containig one oxygen and one nitrogen atom and benzo-fused derivatives thereof ; five membred aromatic rings containing one sulfur and one nitrogen atom and benzo fused derivatives thereof ; five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring; examples of such rings are furanyl, <BR> <BR> <BR> <BR> thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyrazolyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the like, whereby such ring systems may be mono-, di-or tri-substituted with heterocyclyl ; heterocyctyt-iower alkyl-amino ; cycloalkyl ; cycloalkyl-amino ; cycloalkyl-lower alkyl-amino ; aryl ; heteroaryl ; aryloxy ; aryl-lower alkoxy ; heteroaryl-lower alkoxy ; aryl-lower alkyl-amino ; heteroaryl- lower alkyl-amino ; lower alkyl ; lower alkenyl ; lower alkynyl ; lower alkyl-carbonyl, amino; lower alkyl-amino ; aryl-amino ; heteroaryl-amino ; bis-(lower-alkyl)-amino ; bis-aryl-amino ; (aryl) (heteroaryl)-amino ; lower alkanoyl-amino ; aryl-carbonyl-amino ; heteroaryl-carbonyl- amino; lower alkyl-sulfonyl-amino ; aryl-sulfonyl-amino ; heteroaryl-sulfonyl-amino ; aryl- lower alkyl-sulfonyl-amino ; heteroaryl-lower alkyl-sulfonyl-amino ;-amino-lower alkyl ; halogen ; hydroxy; carboxyl ; lower alkoxy-carbonyl ; lower alkoxy ; vinyloxy ; allyloxy ; co- hydroxy-lower alkyl ; cyano; amidino; trifluoromethyl ; lower alkyl-sulfonyl and the like and in case the substituent on the heteroaryl contains aryl or heteroaryl, those units may again be mono-, di-or tri-substituted with substituents as outlined herein before.

The expression aryl, alone or in combination, means six membered aromatic rings and condensed systems like naphthyl or indenyl and the like, whereby such ring systems may be mono-, di-or tri-substituted with cycloalkyl ; heterocycty) ; aryl ; heteroaryl; aryloxy; aryl- lower alkoxy; heteroaryl-lower alkoxy; lower alkyl ; lower alkenyl; lower alkynyl; lower alkenylen ; lower alkyl-carbonyl; aryl-carbonyl; heteroaryl-carbonyl ; cycloalkyl-carbonyl; heterocyclyl-carbonyl ; amino; lower alkyl-amino; aryl-amino; heteroaryl-amino ; bis- (lower- alkyl)-amino ; bis-aryl-amino ; lower alkanoyl-amino ; aryl-carbonyl-amino ; heteroaryl- carbonyl-amino ; lower alkyl-sulfonyl-amino ; cycloalkyl-sulfonyl-amino ; cycloalkyl-lower alkyl-sulfonyl-amino ; aryl-sulfonyl-amino ; heteroaryl-sulfonyl-amino ; aryl-lower alkyl- sulfonyl-amino ; c3-amino-lower alkyl ; halogen ; hydroxy; carboxyl ; lower alkoxy-carbonyl ; lower alkoxy ; vinyloxy ; allyloxy ; m-hydroxy-tower alkyl ; co-hydroxy-lower alkoxy ; cyano; amidino; trifluoromethyl ; lower alkyl-sulfonyl and the like and in case the substituent on the aryl contains aryl or heteroaryl, those units may again be mono-, di-or tri-substituted with substituents as outlined herein before. The expression halogen means fluorine; chlorine ; bromine and iodine but fluorine, chlorine and bromine are preferred.

The expression halogen means fluorine; chlorine; bromine and iodine but fluorine, chlorine and bromine are preferred.

In addition to the definitions given above for substituents R3 and R4, the following structural formulae represent structural moieties for substituents R3 and R4 of special interest and are a preferred aspect of the invention:

wherein R5 represents lower alkyl ; hydroxy-lower alkyl ; aryl ; aryl-lower alkyl ; heteroaryl ; heteroaryl-lower alkyl ; heterocyclyl ; heterocyclyl-lower alkyl ; cycloalkyl ; cycloalkyl-lower alkyl ; R6 represents lower alkyl ; lower alkynyl ; aryl ; heteroaryl ; heterocyclyl ; aryl-amino ; heteroaryl-amino ; cycloalkyl-amino ; aryl-lower alkyl-amino ; heteroaryl-lower alkyl-amino ; heterocyclyl-lower alkyl-amino ; cycloalkyl-lower alkyl amino; aryloxy ; heteroaryloxy ; cyloalkyloxy ; aryl-lower alkyloxy ; heteroaryl-lower alkyloxy ; heterocyclyl-lower alkyloxy ; cycloalkyl-lower alkyloxy ; R represents aryl ; heteroaryl ; heterocyclyl ; cycloalkyl ; aryl-amino ; heteroaryl-amino ; cycloalkyl-amino ; aryl-lower alkyl-amino ; heteroaryl-lower alkyl-amino ; heterocyclyl-lower alkyl-amino ; cycloalkyl-lower alkyl amino; aryl-oxy ; heteroaryl-oxy ; aryl-lower alkyl-oxy ; heteroaryl-lower alkyl-oxy ; It is understood that the substituents outlined relative to the expressions cycloalkyl, heterocyclyl, heteroaryl and aryl have been omitted in the definitions of the formulae I to V and in claims 1 to 8 for clarity reasons but the definitions in formulae I to V and in claims 1 to 8 should be read as if they are included therein.

The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e. g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.

The compounds of general formula I can be transformed to suitable produrgs like carboxylic acid esters, phosphonic acid esters, sulfuric acid esters, acetales, ketales, phenyl carbamates, amino acid amides, Mannich bases, Schiff bases, oximes, enolesters, oxazolidines,

thiazolidines and the like if necessary and advantageous. All forms of produrgs leading to an active component comprised in general formula I are included in the present invention.

The compounds of the general formula I can contain one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates and mixtures of diastereomeric racemates and the meso-form. The compounds of general formula I may also contain one or more partially or fully substituted carbon-carbon double bond (s), which may be Z-or E-substituted.

The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i. e. by column chromatography, thin layer chromatography, HPLC, crystallization and the like.

The compounds of the general formula I and their pharmaceutically acceptable salts may be used as therapeutics e. g. in form of pharmaceutical compositions. They may especially be used in prevention or treatment of CNS-disorders related to amyloid-ß-peptide-deposition in the brain, like Alzheimer's disease, Down's Syndrome, Inclusion Body Myositis and other age-associated dementias as well as other amyloid-p-peptide-dependent diseases. These compositions may be administered in enteral or oral form e. g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectally in form of suppositories. These compounds may also be administered in intramuscular, parenteral or intraveneous form, e. g. in form of injectable solutions.

These pharmaceutical compositions may contain the compounds of general formula 1 as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols and the like may be used. For the preparation of solutions and sirups e. g. water, polyols saccharose, glucose and the like are used. Injectables are prepared by using e. g. water, polyols, alcohols,

glycerin, vegetable oils, lecithin, liposomes and the like. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols and the like.

The compositions may contain in addition preservatives, stability improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants and the like.

The compounds of general formula I may also be used in combination with one or more other therapeutically useful substances e. g. with other medicaments used for the treatment of symptoms of Alzheimer's disease such as acetylcholine esterase inhibitors, medicaments for the treatment of depression, agitation or sleeplessness, with other medicaments/substances which halt or retard the formation of amyloid-plaques in the brain such as other BACEl-inhibitors or y-secretase-inhibitors, with antioxidants such as vitamin E, with LDL lowering agents such as HMG-CoA-reductase inhibitors and the like.

The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given in oral form should daily be between about 1 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in I to 3 doses per day, which are of equal weight. As usual, children should receive lower doses which are adapted to body weight and age.

A group of preferred compounds are compounds of the formula 11 : 3 R2 k (H2C) m (H2C) >N\ zR4 T Formula 11 N N wherein Rl, R2, R3, R4, m, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

A group of especially preferred compounds according to formula II are compounds wherein Rl, R3, R4, k, X and Z are as defined in general formula I above and wherein m represents the whole number 1 and R represents cyclohexyl or aryl and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of the formula III : R3 k (H2c) 1 4 N, R4 C \X Formula III N Ri wherein R', R3, R4, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of the formula IV: 3 (CH2) m IR 1 (CHo) k 1 'N Formula Il I Z R1

wherein R', R2, R3, R4, m, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

A group of especially preferred compounds according to formula IV are compounds wherein R', R3, R4, k, X and Z are as defined in general formula I above and wherein m represents the whole number 1 and R represents cyclohexyl or aryl and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of the formula V: R3 , (CH2) k N Formula V cr 4 Z\R1 wherein R', R3, R4, k, X and Z are as defined in general formula I above and pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-form and pharmaceutically acceptable salts thereof.

The compounds of the general formula I of the present invention may be prepared according to the procedures and general sequences of reactions outlined below, wherein R', , R3, R4, m, k, X and Z are as defined in general formula I above (for simplicity and clarity reasons, only parts of the synthetic possibilities which lead to compounds of formulae I-V are described): For general methods of certain steps see also pages 33-37 and WO 02/24649.

Scheme 1 : Synthesis of the 4-aminomethyl-piperidine templates : O NH2 O NH2 CN CN t Boc20, dioxane POCI3, DCM Nez NMO H N N I I so Boc 3 Boc Benzaldehyde LAH Na (OAc) 3BH THF t f t f 0 NH2 CN NH2 POC13, DCM U----"kJ J N N N Boc 4 fjYMgC ! \ [ ! j N L J 1 0 X S 0 MgCI / C N L-CH2 N'J N CsHs 7 8 Benzylamine C6H5 H2/Pd-C Benzylamine Hz/Pd-C H2' tNt X N C6H5 N 9 C6H5 C6H5

The ring nitrogen atom of isonipecotamide 1 (commercially available from Aldrich) was Boc-protected in 95% isolated yield by using Boc20 in dioxane and NMO as the base.

Dehydration was achieved by reaction of 2 with POC13 in DCM at rt overnight in yields of 70-90%. Reduction of the cyano group to the aminomethyl group by LAH in THF or diethylether at rt gave template 4 in 50-60% yield after column chromatography.

Benzylprotection of 1 to give 5 was achieved in 70-80% yield by reductive amination with benzaldehyde and sodium triacetoxyborohydride as the reducing agent in DCM as the solvent. Dehydration to the cyano compound 6 was performed under the same conditions as given for the preparation of 3. Subsequently, compound 6 was reacted with either benzylmagnesiumchloride or phenylmagnesiumchloride at rt overnight, followed by hydrolysis with 2M sulfuric acid to give the ketones 7 and 8, respectively, which were reductively aminated with benzylamine in ethanol in the presence of Pd/C (10%) at 3bar hydrogen pressure overnight in yields of 60-80% to the templates 9 and 10, respectively, which were used as racemates in the following synthetic steps.

Scheme 2 gives an overview of the preparation of the templates 14,19 and 20 from nipecotamide 10 via the same synthetic pathway as described above for the preparation of templates 4,9 and 10. There was no remarkable difference observed in reactivity or physicochemical properties between the regioisomeric templates.

Template 14 was always used as racemate in further transformations. Templates 19 and 20 were used as mixtures of diastereomeric racemates in the following synthetic steps.

Scheme 2: Synthesis of the 3-aminomethyl-piperidine templates : NH2 0 NH2 CN CN Boc2O, dioxane f POCI3, DCM t NH NMO N kNH NMO L N. k. N NH NMO \Boc XBoc 1l 12 13 Benzaldehyde Na (OAc) 3BH LAH THF v O NH2 CN NH2 POCI3, DCM Boc Boc 15 C6H5 16 C6H5 14 6 5 C6H5 0 0 MgCI O C 17 18 Benzylamine k H2/Pd-C Benzylamine X r/\ H2/Pd-C nu2 NH2 \ nez / 19 20 N C6H5 20 '"CeHs Scheme 3 : Preparation of the fully substituted 4-amino-methyl-piperidine derivatives: H 3 R4 0 NH2 \/\S 0t HXR3 c 4 NR H OR O O NR3 CIR4 Boy Boc O NJ NJ or HO R4 4 O 21 Boc HXR t 4 22 OCN-R4 oc-ruz a H R N 0 R4 N R3 s N R3 N R R4 O 3 Toc 26 Boc Boc Boc \viz H 0 O Same pathway to H R FINAL COMPOUNDS as described for 22 via 26 to 27 N R 3 C 27 N N

Preparation of the fully substituted final target compounds (Scheme 3 gives a graphical survey of the sequence applied for 4-aminomethyl-piperidine based structures) started at the exocyclic aminogroup. The first substituent R3 was introduced via reductive amination [Ahmed F. Abdel-Magid et al ; J. Org. Chem. ; 1996, 61, 3849; Clinton F. Lane; Synthesis ; 1975,135] by refluxing the aldehyde and the amine in methanol for 4 h. Then the reaction mixture was cooled to rt and sodium borohydride was slowly added followed again by refluxing for 2 h. Water was added and the product was extracted either by EtOAc or DCM.

The organic layers were dried and the solvents were evaporated. Purification of the product was usually achieved by column chromatography on silicagel with an appropriate mixture of EtOAc/hexane or by recrystallization from diethylether or methyl-tert.-butyl ether to give derivatives 21 in moderate to good yields. Compounds 21 were subsequently acylated by either acid chlorides, carboxylic acids (+ activation reagent like PyBOP or 1-chloro-N, N, 2- trimethylpropenylamine [Acros Organics 30027] ) for the preparation of derivatives 22, or sulfonyl chlorides for the preparation of derivatives 25, in solvents like DCM, chloroform or 1,2-dichloroethane at rt or slightly elevated temperatures in the presence of a base like Hunig's base, TEA or NMM. Reactions usually run for 4 to 24 h followed by aqueous work up with saturated sodium carbonate solution. The combined organic phases were dried and the solvents were evaporated. Purification of the compounds was achieved by column chromatography on silica gel with an appropriate solvent mixture depending on the polarity of the products or by recrystallization. Compounds 21 were also reacted with isocyanates for the preparation of derivatives 24, in solvents like DCM, chloroform or 1, 2-dichloroethane at rt or slightly elevated temperatures. Reactions usually run for 4 to 24 h. The reaction mixtures were concentrated in vacuo and the products purified by column chromatography on silica gel with an appropriate solvent mixture depending on the polarity of the products or by recrystallization. Finally the intermediates 21 were submitted for a second reductive amination step on the exocyclic amino group either by an aldehyde or a ketone to give derivatives 23. If aldehydes were used, the reaction was performed in DCM or 1,2- dichloroethane in the presence of sodium triacetoxyborohydride at rt for 6 to 12 h followed by aqueous work up with saturated sodium carbonate solution. The combined organic layers were dried and concentrated in vacuo. The products were purified by column chromatography on silica gel with an appropriate solvent mixture depending on the polarity

of the products or by recrystallization. If ketones were used, the reaction was performed by first stirring the ketone and the amine in titanium (IV) isopropoxide at rt for 4 to 8 h followed by addition of methanol and sodium borohydride. The reaction was usually complete within 1 h and aqueous work up was performed by addition of saturated sodium carbonate solution, filtration and extraction with DCM. The combined organic layers were dried and evaporated in vacuo. The products were purified by column chromatography on silica gel with an appropriate solvent mixture depending on the polarity of the products or by recrystallization [J. G. Breitenbucher et al ; Tetrahedron Lett. ; 1998, 39, 8207; Ahmed F. Abdel-Magid et al ; J. Org. Chem. ; 1996, 61, 3849]. Boc-deprotection on the intermediates 22,23, 24 and 25 was achieved by addition of a 4 M solution of hydrogen chloride in dioxane to a solution of the respective Boc-protected intermediate in dioxane at rt. The reaction was usually finished within 1 to 3 h. The solvent was evaporated and the amine hydrohloride intermediates were dried at HV [P. J. Kocienski, Protecting Groups, Thieme, 1994; T. W. Greene, P. G. M.

Wuts; Protective Groups in Organic Synthesis, John Wiley & sons 1991.]. The final compounds (e. g. 27) were prepared by reductive amination of the ring nitrogen atom with aldehydes or ketones. The reactions were performed as described before for the preparation of 23.

Exactly the same set of reactions was applied to prepare the compounds depicted in Scheme 4, based on 3-aminomethylpiperidine.

Scheme 4 : Preparation of the fully substituted 3-amino-methyl-piperidine derivatives: N Ra \/R4X° NHZ NR3 XBoc Boc or Jk 0 H0 R4 X N I P I 0 " n r H R ciA R4 I I 0 Boc Boc or HO R4 14 29 HO R4 Boc p 0 30 ß \/N R3 4 cul A H OCN-R R 4 H 4 0 N R s N R3 6t 6t R4 O 3 NR NBoc Nw NBoc Boc 31 32 33 34 Nez 0 O Same pathway to FINAL COMPOUNDS as described for 30 via 34 to 35 N R 3 N t 35 Scheme 5 : Core units used to prepare final compounds via the pathways described in Scheme 3 and Scheme 4: In Scheme 5 templates with an additional centre of chirality are depicted. Usually the racemates (in case of intermediates 9 and 10) and the mixtures of diastereomeric racemates (in case of intermediates 19 and 20) were used. As protecting groups the benzyl group (hydrogenolytic cleavage if necessary), the p-methoxybenzyl group (oxidative cleavage by cer ammonium nitrate) or the Boc-group (cleavage by HCI, TFA or iodo-trimethyl silane) were used. The templates 9,10, 19 and 20 were submitted to the same sequence of reactions (except the deprotection step if PG was not Boc) as depicted in Scheme 3 and 4 to prepare final compounds 37 to 51 as depicted in Scheme 6 (for more detailed experimental descriptions see experimental section).

Scheme 6 : Final compounds via the pathways described in Scheme 3 and Scheme 4: Scheme 6 (continued) : Final compounds via the pathways described in Scheme 3 and Scheme 4: Scheme 7 : Further Variations:

In Scheme 6 only limited possibilities are depicted, especially with respect to R2. But further compounds of type 52 wherein R2 is different from a phenyl-or a benzyl-group can be prepared via the same synthetic procedures as described before (See Scheme 7,53).

The following examples illustrate the invention but do not limit the scope thereof. All temperatures are stated in °C.

List of abbreviations: Boc20 di-tert. -butyl-di-carbonat Boc or boc tert.-butyloxycarbonyl BSA bovine serum albumine Cbz benzyloxycarbonyl DBU 1, 8-diazabicyclo [5.4. 0] undec-7-ene (1, 5-5) DCM dichloromethane DMF dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate HO hydrogen chloride HV high vacuum LAH lithium aluminium hydride M molar NMM N-methylmorpholine PG protecting group POC13 phosphorous oxychloride <BR> <BR> <BR> <BR> PyBOP Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate Rt or rt room temperature TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran tR or tR retention time

General Procedures and Examples: The following compounds were prepared according to the procedures described for the synthesis of compounds encompassed by the general formulae hereinbefore. All compounds were characterized by'H-NMR (300MHz) and occasionally by 13C-NMR (75MHz) (Varian Oxford, 300MHz ; chemical shifts are given in ppm relative to the solvent used; multiplicities : s = singlet, d = doublet, t = triplet; m = multiplet), by LC-MS: A: 0.3 min < tR < 3.2 min; (Waters Micromass; ZMD-platform with ESI-probe with Alliance 2790 HT; Colum : 4. 6x50mm, Zorbax Extended C18,3. 5, um, 120A; Gradient: 5-95% acetonitril in water, 1.4 min, with 0.05% formic acid, flow: 2. 5ml/min ; tR is given in min. ), B: 0.1 min < tR < 1.5 min; (Finnigan AQA with ESI-probe with HP 110 DAD and HP 110 binary pump; column: Develosil RP-AQUEOUS, 5tm, 4.6 mm x 50 mm; gradient: 5-95% acetonitril in water (0.04% TFA), 1 min. , 95% acetonitril in water (0.04% TFA) 0.4 min. , 4.5 ml/min ; tR is given in min.), C : 2 min < tR < 10 min; (Waters Micromass; ZMD-platform with ESI- probe with Alliance 2790 HT; Colum: 2x30mm, Gromsil ODS4, 3pm, 120A; Gradient: 0- 100% acetonitril in water, 6 min, with 0.05% formic acid, flow: 0. 45min ; tR is given in min. ), by TLC (TLC-plates from Merck, Silica gel 60 F254) and occasionally by melting point. a) General Procedures : Typical procedure A) for the reductive amination : The amine and the aldehyde (1.5 eq. ) (which are used as starting materials, are known compounds or the synthesis is described in the Reference Examples), are mixed in anhydrous methanol and refluxed for 4 h. The mixture is cooled to rt and then treated with sodium borohydride (1. 5 eq. ) and again stirred for 2 h at reflux temperature. The reaction mixture is concentrated in vacuo and water is slowly added followed by extraction with DCM (3x). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude compound is purified by column chromatography on silica gel by an appropriate mixture of EtOAc/hexane containing 1% TEA or by recrystallization from a suitable solvent.

Tvnical procedure B) for the acylation (with acid chlorides or sutfonylchlorides) : To a solution of the secondary amine in anhydrous DCM is added Hunig's base (10 eq) or another suitable base followed by the addition of the carboxylic acid chloride or the sulfonylchloride (1.5 eq. ). The reaction mixture is stirred for 4 to 12 h at rt. Then saturated sodium carbonate solution was added and the mixture was extracted with DCM (3x). The combined organic layers were washed with 1 N HCI and brine, dried over magnesium sulfate, filtered and evaporated. The crude compound is purified by column chromatography on silica gel by an appropriate mixture of EtOAc/hexane or by recrystallization from a suitable solvent to give the pure amide intermediates.

Typical Procedure C) for the reaction with isocyanates : To a solution of the secondary amine in DCM was added the isocyanate (1.5 eq) and the reaction mixture was stirred at rt for 4 to 12 h. The reaction mixture was directly concentrated in vacuo and the crude material was purified by column chromatography on silica gel by an appropriate mixture of EtOAc/hexane or by recrystallization from a suitable solvent to give the pure urea intermediates.

Typical Procedure D) for the second reductive amination with aldehydes : To a solution of the secondary amine in DCM was added the aldehyde (1.5 eq) and sodium triacetoxy borohydride (4 eq). Stirring was continued for 6 to 12 h. Water was added and the mixture was extracted with DCM (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo and the crude material was purified by column chromatography on silica gel by an appropriate mixture of EtOAc/hexane or by recrystallization from a suitable solvent to give the pure tertiary amine intermediates.

Typical Procedure E) for the second reductive amination with ketones : To a solution of the secondary amine in neat titanium tetra-isopropoxide was added the ketone (1.5 eq). The mixture was stirred for 4 h at rt followed by addition of methanol and sodium borohydride (4 eq). Stirring was continued for 1 hour. Water was added and the mixture was extracted with DCM (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo and the crude material was purified by column chromatography on silica gel by an appropriate mixture of EtOAc/hexane or by recrystallization from a suitable solvent to give the pure tertiary amine intermediates.

Typical procedure F) for the Boc-deprotection : To a solution of the Boc-protected amine in dioxane at rt was added a solution of 4 M HCI in dioxane (commercially available from Aldrich). Stirring was continued for 1 to 5 h. The mixture was evaporated and dried at HV to give the pure HCI salt of the secondary amine which were used without further purification.

Typical procedure G) for the reductive amination of the ring-nitrogen atom of the piperidine system : - If aldehydes were used, the method described as Typical Procedure D) was applied : - If ketones were used, the method described as Typical Prodedure E) was applied.

-If ketones were used, the reaction could also be performed as follows : To a solution of the secondary amine in methanol was added the ketone (1. 5 eq) and sodium cyano borohydride (6 eq) and some drops of acetic acid or hydrochloric acid. Stirring was continued for 6 to 12 h. Water was added and the mixture was extracted with DCM (3x) or EtOAc (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo and the crude material was purified by column chromatography on silica gel by an appropriate mixture of EtOAc/hexane or by recrystallization from a suitable solvent to give the pure tertiary amines as final compounds.

Typical procedure H) for the Suzuki coupling with arylbromides : To a solution of arylbromide in toluene is added the boronic acid (1. 1 eq. ) in isopropanol and a 2M aqueous solution of potassium carbonate (5 eq. ). The mixture is purged with nitrogen for 10 min and tetrakis (triphenylphosphine) palladium (0.03 eq. ) is added. After heating under reflux for 6 h, water is added to the cooled reaction mixture and the product is extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. The solvent is evaporated to give the crude aldehyde, which is purified by flash chromatography (EtOAc/heptane gradient).

Typical procedure I) for the Suzuki coupling with arylchlorides : The arylchloride, the boronic acid (1.5 eq) and potassium phosphate (K3PO4 ; 3 eq) ) were added subsequently to dioxane (5 ml/mmol arylchloride). While heating to 100°C, nitrogen is bubbled through the mixture. Then a solution of 2'-(dimethylamino)-2-biphenylyl- palladium (II)-chloride dinorbornylphosphine-complex (from Solvias or Fluka 36037; 0.01 eq) ) was added to the hot reaction mixture and stirring was continued for 6 to 18 h. The reaction mixture is cooled to rt, water is added and the product extracted with EtOAc. The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (EtOAc/heptane gradient).

Typical Procedure K) for the Sonogashira coupling of terminal acetylenes with aryliodides : Stephan Thorand, Norbert Krause, J. Org. Chem., 1998, 63, 8551-8553.

D. Trachsel, Helv. Chim. Acta., 2003, in press.

Typical Procedure L) for the Sonogashira coupling of terminal acetylenes with arylbromides : G. Reginato, A. Mordini, M. Caracciolo ; J. Org Chem. ; 1997, 62, 6187-6192.

Typical Procedure M) for the preparation of alkyl substituted aryl-and heteroaryl units : A. Furstner, A. Leitner, M. Mendez, H. Krause; J. Am. Chem. Soc. ; 2002, 124, 13856- 13863. b) Referential Examples : Referential Example 1: a) Isonipecotamide (28 g) was dissolved in water (100 ml) and cooled to 0°C. A 1 M solution of NaOH (318 ml) was added, followed by the addition of Boc20 (47.2 g) in dioxane (100 ml) within 15 min. Stirring was continued for 12 h by slowly warming the reaction mixture to rt. The mixture was extracted with EtOAc (2x). The combined organic layers were subsequently washed with 1 M NaOH and water, dried with magnesium sulfate, filtered and evaporated to give 4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (39.77 g) which was used without further purification. b) 4-Carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (46.0 g) was dissolved in DCM (500 ml) and cooled to 0°C. TEA (57 mi) was added followed by slow addition of a solution of POC13 (20.7 mi) in DCM (100 ml) at 0°C to 5°C. The reaction mixture was stirred at rt for lh. Then a saturated sodium hydrogen carbonate solution (-300 ml) was carefully added until no more gas formation was observed. The organic layer was separated in a separation funnel and the water phase was extracted once more with DCM. The combined organic layers were subsequently washed with a 10% citric acid solution and brine, dried with

magnesium sulfate, filtered and concentrated in vacuo to give 4-cyano-piperidine-1- carboxylic acid tert-butyl ester (41.73 g). The crude material crystallized while drying at HV and was used without further purification. c) LAH (15.43 g) was suspended in diethylether (300 ml) and cooled to-5°C. To this suspension 4-cyano-piperidine-l-carboxylic acid tert-butyl ester (41.73 g) dissolved in 200 ml diethylether, was slowly added at-5°C to 0°C. The suspension was stirred for 2 h at 0°C followed by very slow addition of water (15.5 ml), 15% NaOHaq (15.5 ml) and again water (46.5 ml). The precipitate was filtered off and washed with diethylether. The combined organic phases were evaporated and the crude product was purified by column chromatography over silicagel with DCM/methanol = 9/1 to give 4-aminomethyl- piperidine-l-carboxylic acid tert-butyl ester (20.3 g).

Referential Example 2: 0 0 Y"NH2 THs N N ! NH2 NH2 nu nu H Nipecotamide ! ° if NH2 CN J-nu zea O''O O O 3-Aminomethyl-piperidine-1- carboxylic acid tert-butyl ester The exact same three step procedure was applied to prepare 3-aminomethyl-piperidine-1- carboxylic acid tert-butyl ester from nipecotamide.

Referential Example 3: OqzNH2 OqNH2 CN CON H H Isonipecotamide H2N, + O v U NON 1- (1-Benzyl-piperidin-4-yl)-2-phenyl-ethylamine a) To a solution of isonipecotamide (12.8 g) and benzaldehyde (11.7 g) in DCM (500 ml), sodium triacetoxyborohydride (63.6 g) was added. The mixture was stirred at rt for 48 h. Water (500 ml) was added and the layers were separated. The aqueous layer was extracted with DCM (2x 100 ml). The combined organic layers were dried with sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give 1-benzyl- isonipecotamide (18.45 g) as a white solid. b) To a solution of 1-benzyl-isonipecotamide (10.9 g) in DCM (125 ml) containing TEA (14.2 ml) was added a solution of POCl3 (5.13 ml) in DCM (25 ml) at 0°C to 5°C. The mixture was warmed to rt and stirred for 16 h. Then saturated sodium hydrogencarbonate solution (-450 ml) was added with caution. After gas evolution stopped, the layers were separated. The aqueous layer was extracted again with DCM (I x 100 ml). The combined

organic layers were dried with sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give l-benzyl-4-cyano-piperidine (9.6 g) as a brown viscous oil. c) To a solution of l-benzyl-4-cyano-piperidine (9.3 g) in THF (90 ml) was added a solution of benzylmagnesiumchloride (1. 3 M in THF, 57 ml ; Fluka) at rt. Copper bromide was added (150 mg) and the reaction mixture was warmed to 60°C for 8 h. The mixture was quenched by the addition of water (10 ml) and 15% sulfuric acid (65 ml) and stirring continued for 30 min. The THF was evaporated and 15% sodium hydroxide solution was added until the pH of the aqueous phase reached 8. The product was extracted with ether (2 x) to give crude material (10.8 g) which was purified by bulb-to-bulb destillation to give l- (l-benzyl- piperidin-4-yl)-2-phenyl-ethanone (5.1 g) as a colorless, viscous liquid. d) 1- (l-Benzyl-piperidin-4-yl)-2-phenyl-ethanone (2.6 g) and ammonium acetate (6.72 g) were dissolved in methanol (175 ml) and sodium cyanoborohydride (440 mg) was added.

Stirring was continued for 24 h. The mixture was acidified by conc. HCI to pH = 2 and the methanol was evaporated. The residue was dissolved in water, neutralized with sodium hydroxide and extracted with diethylether (3 x). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed at reduced pressure to give 1- (1- benzyl-piperidin-4-yl)-2-phenyl-ethylamine (2.27 g).

Referential Example 4: 0 0 NH2 NH2 CN NJ-NJ NJ H Nipecotamide t r NH2 O N N 1- (1-Benzyl-piperidin-3-yl)-2-phenyl-ethylamine According to the procedure described in Referential Example 3, 1- (1-benzyl-piperidin-3-yl)- 2-phenyl-ethylamine can be prepared from nipecotamide.

Referential Example 5: NH2 0 NH2 CN ON U-0 N N N H Isonipecotamide zizi HzN \ O \ H2N"'JX o N C- (1-Benzyl-piperidin-4-yl)-C-phenyl-methylamine According to the procedure described in Referential Example 3, C- (l-benzyl-piperidin-4-yl)- C-phenyl-methylamine can be prepared from isonipecotamide.

Referential Example 6: 0 0 CN XNH2 XNH2 u N N Na H Nipecotamide c N. N Nu2 0 \ \ N N C- (1-Benzyl-piperidin-3-yl)-C-phenyl-methylamine According to the procedure described in Referential Example 3, C- (l-benzyl-piperidin-3-yl)- C-phenyl-methylamine can be prepared from nipecotamide.

Referential Example 7: -Ar-B (OH) 2 + Br-Ar >'-Ar-Ar yield (%) H H a) >63B (oH) 2 Bre 58 C CL /58 OCF3 OCF3 26 H H C) >3B (oH) 2 Br SCN =CN 67 - e) 62 B (OH) 2 H 0-0- H H f) B (OH) 2 Br 63 OH H V'OH 50 98 COOMe H COOMe C F j) (OH) 2 Br-b 71 k) nB (OH) 2 Br SF z, rF 32 CF3 CF3 CF3 CF3 n n H H M) B (OH) 2 Br N N 27 H H \ H 27 m) XB (OH) 2 Br<N\ < N\ 27 95 Referential Example 7 (continued): 0 0 SAr-Br + (HO) 2BAr SArAr yield (%) H H 0 a)-Br 71 S S S S H 99 H (HO) 2B Br 0 IO O o Q ) Br H \ H )--Ar-B (OH) 2 + Br-Ar O-Ar-Ar yield (%) H H H H N 0 N 98 n D H N C e) S B (OH) 2 BrX3 H<3 H N H c) HB (OH) 2 BrX/) H< Nk 98 d) X B (OH) 2 Br {> < 9 H H H< B (OH) 2 Br<O ~ O 4

Referential Example 7 (continued): 0 0 SAr-B (oH) 2 + Br-Ar O-Ar-Ar yield (%) H H H H a) OHC- {/-B (OH) 2 Br » > OHC H » ; 98 N N b) B (OH) 2 Br \ : N 86 N P--\C N OHM-OHM OHC OHC b) B (OH) 2 Br 84 N N c) X B (OH) 2 BrX » >, +" ») 84 CHO CHO Biaryl-carboxylic acids:

The commercially not available biaryl-, heteroaryl-aryl-, aryl-heteroaryl-and heterobiaryl- substituents can be prepared according to Typical Procedures H) and 1) or according to methods described in [WO 02/24649 or A. F. Littke and G. C. Fu; Angew. Chem. ; 1998, 110, 3586 and references cited there]. Referential Example 7 only gives an illustrative overview of such substituents and does not limit the invention towards the structures depicted above. For the preparation of the biaryl-carboxylic acids see also [Y. Gong and H.

W. Pauls; Synlett, 2000,829.] According to the Typical Experimental Procedures given above, Examples 1-179, were prepared: With respect to enzyme inhibition, some of the compounds are classified as follows: IC5o < 3uM Activity Class A 3pM < IC50 < 7µM Activity Class B ICso > 7uM Activity Class C c) Examples : Example 1: Hs l NH2 CN N X j (J" I I N boc boc I Boc Boc ! Boc Boc Boc Intermediate 2 Intermediate 1 c) u LJ C5H, l C5H, l N \ I N \ I d) N N H fi" Example 1 Intermediate 3 a) I-Boc-4-aminomethyl-piperidine was reacted with 4-biphenylcarboxaldehyde according to Typical Procedure A) to give intermediate 1. b) Intermediate I was reacted with 4-pentyl-benzoylchloride according to Typical Procedure B) to give intermediate 2. c) Intermediate 2 was deprotected according to Typical Procedure F) to give intermediate 3. d) Intermediate 3 was reacted with phenylacetaldehyde according to Typical Procedure G) to give Example 1 {N-Biphenyl-4-ylmethyl-4-pentyl-N- (1-phenethyl-piperidin-4-ylmethyl)- benzamid} ; LC: tR = 4.71 min; MS: ES+ = 559.46. (Method C)

Example 2: LJ C5H11 X \ I o/\ I xi NEZ I Example 2 N-Biphenyl-4-ylmethyl-4-pentyl-N [1- (3-phenyl-propyl)-piperidin-4-ylmethyl]- benzamide Example 2 was prepared according to the procedures described in Example 1 except by using 3-phenylpropionaldehyde instead of phenylacetaldehyde in step d); LC: tR = 4.73 min; MS: ES+ = 573.66. (Method ç

Example 3:

Example 3 N-Biphenyl-4-ylmethyl-N- (1- (4-methoxy-benzyl)- piperidin4-ylmethyl]-4-pentyl-benzamide Example 3 was prepared according to the procedures described in Example 1 except by using 4-methoxy-benzaldehyde instead of phenylacetaldehyde in step d); LC: tR = 4.63 min; MS: ES+ = 575.87. (Method g) Example 4:

Example 4 N-Biphenyl-4-ylmethyl-4-pentyul-N-[1-(4-pentyl-benzyl)- piperidin-4-ylmethyl]-benzamide Example 4 was prepared according to the procedures described in Example 1 except by using 4-pentyl-benzaldehyde instead of phenylacetaldehyde in step d); LC : tR = 5.44 min; MS: ES+ = 615. 38. (Method C) Example 5 :

N-Biphenyl-4-ylmethyl-N- [1- (3-methyl-butyl)-piperidin- 4-ylmethyl]-4-pentyl-benzamide Example 5 was prepared according to the procedures described in Example 1 except by using isovaleraldehyde instead of phenylacetaldehyde in step d); LC: tR = 4.68 min; MS: ES+ = 525.74. (Method C) Example 6:

1-Biphenyl-4-ylmethyl-3-(4-butyl-phenyl)-1-(1-phenethyi- piperidin-4-ylmethyl)-urea Example 6 was prepared according to the procedures described in Example 1 except by using 4-butyl-phenylisocyanate instead of 4-pentyl-benzoic acid in step b) (Typical Procedure C)) ; LC: tR = 4.59 min; MS: ES+ = 560.70. (Method C) Example 7: 1-Biphenyl-4-ylmethyl-3-(4-butyl-phenyl)-1-[1-(3-phenyl- propyl)-piperidin-4-ylmethyl]-urea Example 7 was prepared according to the procedures described in Example 6 except by using 3-phenylpropionaldehyde instead of phenylacetaldehyde in step d); LC: tR = 4.80 min; MS: ES+ = 574. 31. (Method ç Example 8:

1-Biphenyl-4-ylmethyl-3- (4-butyl-phenyl)-1- [1- (4-methoxy-benzyl)<BR> -piperidin-4-ylmethyl]-urea Example 8 was prepared according to the procedures described in Example 6 except by using 4-methoxy-benzaldehyde instead of phenylacetaldehyde in step d); LC: tR = 4.68 min; MS: ES+ = 576.37. (Method C)

Example 9:

1-Biphenyl-4-ylmethyl-3- (4-butyl-phenyl)-1- [1- (4-pentyl-benzyl)<BR> -piperidin-4-ylmethyl]-urea Example 9 was prepared according to the procedures described in Example 6 except by using 4-pentyl-benzaldehyde instead of phenylacetaldehyde in step d); LC: tR = 5.28 min; MS: ES+ = 616.48. (Method f) Example 10:

1-Biphenyl-4-ylmethyl-3- (4-butyl-phenyl)-1- [1- (3-methyl-butyl)- piperidin-4-ylmethyl]-urea Example 10 was prepared according to the procedures described in Example 6 except by using isovaleraldehyde instead of phenylacetaldehyde in step d); LC: tR = 4.62 min; MS: ES+ = 526. 34. (Method 52)

The following Examples 11 to 46 were prepared by applying the suitable procedure chosen from the Typical Procedures A to M described above, in the same way as for Examples 1 to 10.

Chart 1: (LC-MS by Method ç 0-1 ion N Example 11" tR = 5. 17 ES+ = 652. 21 /) /CsHi \/I/O zain I Example 12 p tR = 4. 46 w /ES+ = 674. 19 / / N zon I Example 13 tir=4. 16 6N ES+ = 610. 40 N . J r° Example 14 N tR = 4. 74 ES+ = 688. 17 \/ Chart 2: (LC-MS by Method C) i Example 15 tR = 4. 58 ES+ 668. 25 ES+ = 668. 25 u NJ i IN 1-C5H, l I Example 16 0 tR = 4. 39 ES+ = 690. 47 ¢D, 0N X, 0 zon N Example 17 gX O r tR ;-- 4. 19 N ES+ = 626. 31 zu \ /I/I W IN N Example 18 0 tR = 4. 73 ES+ = 704. 42 ° / Chart 3: (LC-MS by Method B) Ex. Nr Rii R22 LC-MS "C5H, 1 tR = 1. 20 19 ES+ = 583. 29 "C5H, l tR = 1. 21 ES+ = 597. 30 21 Cl-I 0"C5H, l tR = 1. 20 ES+ = 599. 28 22 lAl < CsH11 tR = 1. 27 ES+ = 639. 31 /sH » ~<°C H tR = 1. 20 ES+ = 549. 29 24 'I tR=1. 21 24 ES+ = 583. 29 tR = 1. 22 /OCSH ES+-597. 30 26 tR = 1. 21 C5H, l ES+ = 599. 29 T"1 t-1 M 27 ! ! ! tp-1. 28 27 ES+ = 639. 35 CSH O C5H, l tR = 1. 21 28 ES+ = 549. 32 Chart 4: (LC-MS by Method C) Ex. Nr | R11 R22 LC-MS tR = 5. 62 29 ES+ = 751. 25 C5H, l tir = 5. 64 30 ES+ = 737. 41 tau tR = 5. 50 31 ES+ = 787. 20 8 5 ; 32 \ tR = 5. 69 (3,-C4H9 ES+ = 753. 39 o 33 0"C6H5 tR = 5. 47 ES+ = 773. 49 34 tR = 5. 43 ES+ = 695. 36 35-I tR = 5. 07 ES+ = 709. 70 /, 36 tR = 4. 63 ES+ = 591. 37 / Chart 5 : (LC-MS by Method B) Ex. Nr R p22 LC-MS vCF3 tR = 0 93 Eus+ = 493. 14 38 H____'I CSH tR = 0. 99' p/ES+ = 49923 tR = 0. 95 0 H---. ' I/C4H9 Eg+-485. 22 O 40 H 0 tR = 0. 93 ES+ = 475. 17 41 tR = 1. 24 0 0. 1 C4H9 ES+ = 645. 32 42 CsHi tR= 1. 26 0 ES+ = 659. 33 d, CF3 tR = 1. 18 ES+ = 653. 25 44 0 tR = 1. 05 ES+ = 497. 24 45 tir = 1. 13 ES+ = 559. 26 46 tR = 1. 17 01117 ES+ = 587. 29

If not otherwise indicated in Chart 6 to Chart 22, the LC-MS data were accumulated by using method B.

Chart 6: tR = retention time in minutes M = [M+H] + Ex. No. 47 48 49 50 51 52 o, :'Vo CN cii Con F CSH LC MS tR : 0. 9 tR : 0. 88 tR : 0. 92 tR : 0. 90 tR : 0. 91 tR : 0. 91 M : 583. 4 M : 572. 4 M : 617. 5 M : 577. 5 M : 561. 5 M : 591. 4 Activity C B A A A A Class Chart 7: tR = retention time in minutes M = [M+H]+ Ex No. 53 54 55 56 57 58 "q I Ac"0 CgH '- CSH, i LC-MS tR : 1. 06 tR : 1 00 tR : 1. 02 tR : 1. 00 tR : 1. 00 tR : 1. 01 M : 631. 6 M : 642. 5 M : 589. 5 M : 605. 5 M : 591. 5 M : 605. 6 Activity A A A A A B Class Ex No. 59 60 61 62 "'I i LC-MS tR : 0. 98 tR : 1-01 tR : 1-00 tR : 1. 00 M : 586. 5 M : 601. 4 M : 575. 5 M : 591. 4 Activity Clans Chart 8: Ex. No. R » R22 Activity LC-MS Class 63 'WS tR = 1. OS 5H, l ES+ = 641. 57 64 CF3 A 64---H'/I \ A tR = 1. 24 ES+-689. 47 0'CH2 ES+-709. 66 ES+ = 1. 14 ohm 66--.'ES+ = 709. 65 67 5HIl A tR = 1. 04 ES+ = 643. 55 N 68 0 tR = 727. 63 69 0 A tR = 1. 05 69 -aci ES+ = 679. 39 0 CON (C3H7) 2 tir=1. 06 70 A ES+ = 778. 67 ES+ = 778. 67 0 tR = 1. 03 CI \ B ES+ = 651. 28 ci-0 ES+ = 651. 28 CI--. CH3 C Eg+-589. 56 Chart 9: Ex No R11 R22 AS. @ LC-MS Class 73...../\/0 A tR = 1. 24 CI ES+ = 731. 41 CF3 74... H ' I A tR=1. 19 ES+ = 719. 38 75.-_.,, tR = 1. 16 CI A ES+ = 689. 36 76. _. H :' v tR = 1. 17 ES+-669. 42 77... I A tR = 1. 15 U) o A ES+ = 683. 39 0 cri 78. _., , \ CI tR = 1. 17 ES+ = 689. 36 /'''A/°j tp=1. 24 ci cl ES+ = 753. 35 CICI 80... tR = 1. 22 ao SCsH11 y < (A esfi \ tR = 1. 21 81. _. ES+ = 717. 40 82. I tR = 1. 15 es+ = 653. 47 Chart 10: tR = retention time in minutes M = [M+H]+ Ex No 83 84 85 86 87 0 0 0 0 cri R 22 XC7 H 1 5 as H 1 1 T C 5 H X X. LC-MS tR : 1-11 tR : 1. 07 tR : 1. 07 tR : 1. 08 tR : 1. 05 M : 681. 67 M : 653. 62 M : 653. 62 M : 653. 66 M : 645. 53 Activity A A A B B Class Chart 11: tR = retention time in minutes M = [M+H]+ Ex. No. 88 89 90 91 92 w T)/---\/'Ti ! 9 ) ) CsHi O LC MS tR : 1. 11 tR : 1. 08 tR : 1. 06 tR : 1. 08 tR : 1. 08 M : 667. 5 M : 675. 6 M : 661. 6 M : 705. 6 M : 705. 5 Activity A A A A A Class Chart 12: ag I Class 93 tir = 1. 02 OC H A ES+ = 635. 5 8 17 OH » ES+ = 635. 5 ES+ = 635. 5 JJ"ES+=621. 5 95 A ES+ = 621. 5 96--tR = 1. 00 ES+ = 555. 5 tR = 0. 99 97 ES+ = 593. 5 tR = 0. 98 97 OC H B ES+ = 593. 4 uueHu tR = tR=0. 98 99 99 OC5H, l B ES+ = 593. 5 s » tR = 0. 97 B ES+ = 579. 5 _ Chart 13: 101'"r A'' Ex. No. R22 Activity LC-MS Class 101 A tR = 1. 01 , OC H A ES+ = 593. 4 6 13 OCBHi tR = 1. 02 102 'I A ES+ = 599. 4 //tR = 0. 9$ 103 \OCsH1, ES+ = 579 4 104-9C6Hr3 11 tR = 1. 03 105, OC, H. tR = 1. 00 ES+ = 585. 4 tR = . 97 ES+ = 557. 4 ES+ = 5 7. 4 tR = 0. 97 107 OC H B ES+ ° 557. 4 6 13 tir = 0. 98 109/==\ tR=0. 99 i 109 tR = 0. 99 \ Hn C ES+=513. 3 110 r 0-0 es+ = 525. 52 Chart 14: Ex. No. 22 Activity Class 1. 06 A tu 7 15 / 112 I A tR=1. 02 OC6Hl3 ES+ = 599. 62 U6''13 11'4 ES+ = 599. 56 A ES+ = 599. 56 O 114 B tR = 0. 98 ES+ = 591. 45 ci 115 g ES+ = 599. 56 tR = 1. 02 116 ES+ = 599. 58 cl3 CF3 117 B tR = 0-98 ES+ = 579. 53 118 tR = 0. 98 118',., ;- ( C ES+ = 557. 49 Chart 15 : R Ex. No R22 Activity LC-MS Clashs 119 A tR = 1. 02 ES+ = 671. 37 OC6 i 3 C6Hl3 ES+ = 605. 4 OH ES+ = 605. 4 15 tR = 1. 03 121 A ES+ = 663. 4 \ 122.---- -CShi A tR = 1. 02 ES+ = 597. 4 tir = 0. 98 /k A ES+=635. 4 s » tR = 1. 00 'aOC6Hl3 ES+ = 635. 4 6 3 /OC6H3 tR = 1. 01 ES+ = 635. 4 ES+ = 635. 4 tir = 0. 99 126 ES+ = 621. 4 Chart 16: Ex. No. R"Activity LC-MS Class 127 0 OMe A tR = 0. 96 H-i-QOMe ES+ = 686. 35 O 128 w-. N p, tR = 0. 96 \/C ES+ = 660. 35 O H H-\-ES+ = 621. 82 H H ES+ = 621. 82 O 130 ./N /Br A tR = 0. 97 ES+ = 706. 2 tR = 0. 94 131'w-./ A ES+ = 644. 34 132 tR = 0. 96 N0 A ES+ = 622. 24 O F 133 tR = 0. 97 ES+ = 662. 33 134'. -/. =°8 A ES+ = 597. 24 135 OMe A tR = 0-99 135 OMe Eg+ = 599. 16 l Chart 17: Ex. No. Activity Class 136 A 137 A tR = 1-10 ES+ = 629. 58 tir = 1. 16 1. 39 Eg+ = 708. 39 zea 140 '. A tR = 1. 10 ES+ = 595. 54 OMe 141't1 A ' ES+ = 631. 52 142 A =' 142 I A tR = 1. 13 ES+ = 707. 50 Br 143 A tR = 1-10 _____ ES+ = 695. 19 144 I q tR = 1. 04 OMe ES+ = 597. 5 Br 145 q tR = 1. 09 ES+ = 695. 22 Chart 18: Ex. No. zz Activity Class 146..... Br A tR = 1-54 ES+ = 661. 43 caf3 147 _____ \/, 4 tR =1. 08 ci cl ES+ = 1. 10 CI 149.... ztcl A tR = 1-09 ES+ = 649. 13 CI 150 __... A tR = 1. 13 ES+ = 637. 4 151 tR = 1-06 A ES+ = 611. 24 152..... A tR = 1-11 Es+ 637. 3 CF3 153..... tR = 1. 11 CF3 3 154 A tR = 1. 08 .. \/Eg+ = 595. 2 155... B tR = 1-08 ES+ = 595. 3 Chart 19: Ex. No. 22 Activity Class 156. _ tR = 1. 08 ES+ = 605. 4 157 _. __. p tR = 1. 06 ES+ = 571. 4 158 ____. A tR = 1. 08 ES+ = 585. 4 159 __ tR = 1. 00 Eus+ = 606. 25 N Chart 20: Clashs . / \ C.3 ci CI 161 A tR = 1. 08 ES+= 721. 47 0-Ct 162----- ES+ = 671. 49 --~ < A ÈOe = t2] 4 Z tR = 1. 06 163 163 ES+=689. 39 cog Chart 21 : Cash11 \/ t H11 OC6Hr3 Ex. No. :/CF3 Ex. No. : nu if N N + tR : 1. 05 ; [M+H] : 629. 5 Activity Class : A Activity Class : A OMe sX C5H11 Ex. No. : N O 165 1 Ex. No. : 169 N H ."""C 5 H 1 H "Hii J H t !, - tR : 1. 06 ; [M+H] + : 585. 5 Me 0 ß SNJt CsH11 Activity Class : A tR : 1. 07 ; [M+H] + : 591. 5 OMe Activity Class : A a0a 0 ß O v O Ex. No. : N 166 HO N eux. No. : tR : 0. 98 ; [M+H] + : 627. 4 170 N Activity Class : A Met MeO tR : 1. 02 ; [M+H] + : 547. 5 F 0 Activity Class : B Ex. No. : 167 \ / tR : 0. 98 ; [M+H] + : 511. 4 0 Activity Class : B Ex. No. : 171 N H, 1 MeO tR : 1. 00 ; [M+H] + : 541. 5 Activity Class : B Chart 22: Ex. No. 22 Activity Clashs 172. _. tR = 1. 05 ES+ = 585. 4 \ \ tR = 1. 07 o,, C5H, l ES+ = 651. 5 u tR = 1. 02 ci ES+ = 621. 4 CI 175 CF3 tR = 1. 01 ES+ = 609. 4 '"t ! A =609. 4 176 0.......... A tR = 1. 07 ES+ = 591. 5 177-\ CsH » tR = 1. 02 ES+ = 615. 5 178..... A tR = 1. 02 ES+ = 591. 4 tir = 0. 97 ES+ = 603. 4