AU2007219509A1 - Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof - Google Patents

Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof Download PDF

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AU2007219509A1
AU2007219509A1 AU2007219509A AU2007219509A AU2007219509A1 AU 2007219509 A1 AU2007219509 A1 AU 2007219509A1 AU 2007219509 A AU2007219509 A AU 2007219509A AU 2007219509 A AU2007219509 A AU 2007219509A AU 2007219509 A1 AU2007219509 A1 AU 2007219509A1
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linear
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mono
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Laura Bettinetti
Hendrick Bothmann
Chiara Ghiron
Simon Haydar
Iolanda Micco
Arianna Nencini
Joanna Quinn
Renza Roncarati
Michela Valacchi
Maurizio Varrone
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Siena Biotech SpA
Wyeth LLC
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Siena Biotech SpA
Wyeth LLC
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Description

WO 2007/098826 PCT/EP2007/000382 1 MODULATORS OF ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS AND THERAPEUTIC USES THEREOF The present invention relates to compounds with a7 nicotinic acetylcholine receptor (a7 nAChR) agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological and psychiatric diseases. 5 Background of the invention A number of recent observations point to a potential neuroprotective effect of nicotine in a variety of neurodegeneration models in animals and in cultured cells, involving excitotoxic insults (1-5), trophic deprivation (6), ischemia (7), trauma (8), AB-mediated neuronal death (9-11) and protein 10 aggregation mediated neuronal degeneration (9;12). In many instances where nicotine displays a neuroprotective effect, a direct involvement of receptors comprising the a7 subtype has been invoked (7;11-15) suggesting that activation of a7 subtype-containing nicotinic acetylcholine receptors may be instrumental in mediating the neuroprotective effects of nicotine. The available 15 data suggest that the a7 nicotinic acetylcholine receptor represents a valid molecular target for the development of agonists/positive modulators active as neuroprotective molecules. Indeed, a7 nicotinic receptor agonists have already been identified and evaluated as possible leads for the development of neuroprotective drugs (16-20). Involvement of a7 nicotinic acetylcholine 20 receptor in inflammatory processes has also recently been described (21). Thus, the development of novel modulators of this receptor should lead to novel treatments of neurological, psychiatric and inflammatory diseases. Known prior art Different compounds carrying an aryl/heteroaryl- ureido or carbamoyl 25 moiety and a basic nitrogen and exhibiting nicotinic and muscarinic rAMCIDM ATIAM rADV WO 2007/098826 PCT/EP2007/000382 2 acetylcholine receptor affinity or claimed for use in Alzheimer disease were found to be described: fused pyridazine derivatives (W003070707); methods for treating an inflammatory condition (US2004127536); aza-bicyclic N biarylamides (W003078431); heterocyclic urea derivatives (W00266468); 5 spirocyclic piperidines (W02004004714); phenyl-substituted indoles and indazoles (WOO 174773); phenyl-subsituted imidazopyridines (WOO 174815); Heterocyclic compounds carrying a basic nitrogen and hexibiting various types of biological activity were found to be described: anti herpes virus compounds (US6288091); 2H-phthalazin-1-one derivatives 10 (W000044726); 1,4-dihydro-2(2H)isoquinolines (DE2406490); pyridine compounds (JP06016638); piperidine amides (WOO198268); 8-amino-aryl substituted imidazopyrazines as kinase inhibitors (US2005009832); Heterocyclic compounds were also disclosed in Heterocycles (1997), 45(4), 723-734: 1-[w[(arylamino)carbonyl]alkyl]-4 15 (benzocycloalkyl)piperazines. These referenced compounds are readily distinguishable structurally from those herein disclosed by either the functionalities, attachment chain or substitution pattern; these prior documents fail to disclose or suggest the unique combination of structural fragments which embody the novel 20 o-aminoalkylureas or carboxamides having activity on the nicotinic alpha7 receptor herein disclosed. Summary of the invention The invention provides novel compounds acting as full or partial agonists at the a7 nicotinic acetylcholine receptor (a7 nAChR), 25 pharmaceutical compositions containing the same compounds and the use thereof for the treatment of diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor such as neurological and psychiatric disorders, in particular Alzheimer's disease and schizophrenia.
WO 2007/098826 PCT/EP2007/000382 3 Description of the invention This invention provides compounds of formula (I) K, x | I ),Oh Q
K
2 R 5 (I) wherein w, h and k are, independently from one another, 0,1,2, or 3 with the condition that 3 w + h + k 5; KI and K2, which are bound to either the same or a different carbon 10 atom where k>1, represent independently from one another hydrogen; halogen; (CI-C 5 ) alkyl, alkoxy, fluoroalkyl, alkylene, fluoroalkylene; hydroxyalkyl; or KI and K2 taken together may form an alkylidene or a fluoroalkylidene group; or KI and K2, taken together with the carbon atom to which they are attached, form a (C 3
-C
6 ) cycloalkyl group; or when k is 2, 15 two Ok carbon atoms may form an unsaturated bond; or when w is 1, 2, or 3, and k is 1, K1 and K2 taken together with the carbon atom to which they are attached may form an oxo group; j is 0, 1 or 2; X is a group of formula 20 25 WO 2007/098826 PCT/EP2007/000382 4 T'p L LZ TN T'P U () Tr N NI N-()q' N- Nn '' 'U' -p T-p N f)s )s)s K PS s T-p NN ) N p i p0 1,2or3 On N On N 5 n is 0,1 or 2; s is 1 or 2; q and q' are, independently from one another, integers from 1 to 4; T' represent, independently from one another, hydroxy; mercapto; amino; cyano; nitro; linear, branched or cyclic (CI-C 6 ) alkyl, trihaloalkyl, 10 hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; mono- or di-, linear, branched or cyclic
(C
1
-C
6 ) alkylamino; linear, branched or cyclic (CI-C 6 ) alkoxy-(C 1
-C
6 ) alkyl, mono- or di- (C 1
-C
6 ) alkylamino-(CI-C 6 ) alkyl, or (C 1
-C
6 ) alkylthio-(CI-C 6 ) alkyl; (CI-C 3 ) alkylsulphonylamino; mono- or di- (CI-C 3 ) 15 alkylaminosulphonyl; sulphamoyl; linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; or, when p is 2 or 3, two T' form a 5- to 8 membered ring with spiro or fused junction; U and U' represent, independently from one another, hydrogen; cyano; hydroxy; amino; a mono- or di-, linear, branched, or cyclic (C 1
-C
6 ) alkylamino 20 group; a linear or branched (CI-C 6 ) alkoxy group; a linear, branched or cyclic
(C
1
-C
6 ) alkyl, azaalkyl, oxaalkyl chain optionally substituted with hydroxy, mercapto, amino, cyano, nitro, oxo, trihalomethyl, trihalomethoxy, carbamoyl, WO 2007/098826 PCT/EP2007/000382 5 sulphamoyl, linear, branched or cyclic (C 1
-C
6 ) alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl, mono- or di- (C 5 -Cio) aryl- or heteroarylaminocarbonyl, 5 (C 5
-C
1 O) aryl- or heteroarylsulphonylamino, (C 1
-C
3 ) alkylsulphonylamino,
(C
5 -CIO) aryl- or heteroarylsulphonyl, (CI-C 3 ) alkylsulphonyl, mono- or di- (C 5
-C
1 o) aryl- or heteroarylsulphamoyl, mono- or di- (C 1
-C
3 ) alkylsulphamoyl, mono- or di-, linear, branched, or cyclic (CI-C 6 ) alkylamino; a linear, branched or cyclic (CI-C 6 ) alkyl, azaalkyl, oxaalkyl chain bearing a 10 5- to 10-membered aryl or heteroaryl group optionally substituted with one or more groups independently selected from hydroxy, mercapto, amino, cyano, nitro, trihalomethyl, trihalomethoxy, linear, branched or cyclic (CI-C 6 ) alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxyxcarbonyl, alkylcarbonylamino, mono- or di-, linear, branched, or 15 cyclic (Ci-C 6 ) alkylamino, linear, branched or cyclic (CI-C 6 ) alkoxy-(C 1
-C
6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(C 1
-C
6 ) alkyl, or (C 1
-C
6 ) alkylthio
(CI-C
6 ) alkyl, carbamoyl, (C 5 -Co) aryl- or heteroarylsulphonylamino, (CI-C 3 ) alkylsulphonylamino, mono- or di- (C 5 -CIO) aryl- or heteroarylsulphamoyl,
(CI-C
3 ) alkylsulphamoyl, sulphamoyl, mono- or di-, linear, branched or cyclic 20 (CI-C 6 ) alkylaminocarbonyl; mono- or di- (C 5
-C
10 ) aryl- or heteroarylaminocarbonyl, a 5 to 10 membered aromatic or heteroaromatic ring optionally substituted with one or more groups independently selected from hydroxy; halogen; mercapto; amino; cyano; nitro; trihalomethyl; trihalomethoxy; linear, branched or cyclic (Ci-C 6 ) alkyl, hydroxyalkyl, 25 aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl-, alkoxyxcarbonyl, alkylcarbonylamino; mono- or di-, linear, branched, or cyclic (CI-C 6 ) alkylamino; linear, branched or cyclic (Ci-C 6 ) alkoxy-(C 1
-C
6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl, or (CI-C 6 ) alkylthio- WO 2007/098826 PCT/EP2007/000382 6
(CI-C
6 ) alkyl; carbamoyl; (C 5 -Cio) aryl- or heteroarylsulphonylamino; (CI-C 3 ) alkylsulphonylamino; mono- or di- (C 5 -CIO) aryl- or heteroarylsulphamoyl; mono- or di- (C 1
-C
3 ) alkylsulphamoyl; sulphamoyl; mono- or di- (C 5 -CIO) aryl- or heteroarylaminocarbonyl; mono- or di-, linear, branched or cyclic 5 (Ci-C 6 ) alkylaminocarbonyl; -Y-Q- is -C(=0)NH-Q- or -NH-C(=O)-NH-Q; Q is a 5 to 10-membered aromatic or heteroaromatic ring; R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: 10 halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic
(CI-C
6 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic
(CI-C
6 ) alkylcarbonylamino, mono- or di- (C 5
-C
10 ) aryl- or heteroarylaminocarbonyl; mono- or di, linear, branched, or cyclic (Ci-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (CI-C 6 ) 15 alkylsulphonylamino; linear, branched, or cyclic (Ci-C 6 ) alkylsulphonyl; mono- or di- (C 5 -CIO) aryl- or heteroarylsulphamoyl; mono- or di- linear, branched, or cyclic (Ci-C 6 ) alkylsulphamoyl; linear, branched or cyclic (Ci-C 6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(Ci-C 6 ) alkyl,
(CI-C
6 ) alkylthio-(CI-C 6 ) alkyl; 20 R' represent, independently from one another when j = 2, halogen; hydroxy; mercapto; cyano; nitro; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 6 ) alkyl, trihaloalkyl, alkoxy, hydroxyalkyl, mercaptoalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphonyl; linear, branched, or cyclic (C 1
-C
6 ) alkylcarbonylamino; mono- or di, linear, branched, 25 or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic
(CI-C
6 ) alkylsulphamoyl; linear, branched or cyclic (Ci-C 6 ) alkoxy-(Ci-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(Ci-C 6 ) alkyl, (CI-C 6 ) alkylthio
(CI-C
6 ) alkyl, WO 2007/098826 PCT/EP2007/000382 7 provided that when k is zero and the sum of w and h is 4, T' is mercapto; amino; trihaloalkyl; hydroxyalkyl; (C1-C6) aminoalkyl; mercaptoalkyl; alkylthio; alkoxycarbonyl; alkylcarbonylamino; mono- or di-, linear, branched or cyclic (Ci-C 6 ) alkylamino; linear, branched or cyclic (Ci-C 6 ) alkoxy-(Ci-C 6 ) 5 alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl, or (CI-C 6 ) alkylthio-(C
C
6 ) alkyl; mono- or di- (CI-C 3 ) alkylaminosulphonyl, orj 7); and that when j is zero, and the sum of w, h and k is 4, then KI and K2 are not both hydrogen; and with the exclusion of the following compounds: 10 1--[4-(2-Amino-thiazol-5-yl)-phenyl]-3-(3-imidazol-1-yl-propyl) urea;1-(Biphenyl-4-yl)-3-(5-(spiro(indane-1,4'-piperidine-10-yl)-pentyl)-urea; 1-(Biphenyl-4-yl)-3-(4-(spiro(indane- 1,4'-piperidine-10-yl)-butyl)-urea;3-{4 [3-(3-Morpholin-4-yl-propyl)-ureido]-phenyl}-1H-indazole-5-carboxylic acid amide;3-{4-[3-(3-Piperidin-1-yl-propyl)-ureido]-phenyl}-1H-indazole-5 15 carboxylic acid amide;1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl) phenyl]-3-(3-morpholin-4-yl-propyl)-urea 1-[4-(8-Cyclopropylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(3 pyrrolidin-1-yl-propyl)-urea;1-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-[4-(8 methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;1-[4-(8 20 Cyclopropylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(3-morpholin-4-yl propyl)-urea;1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(3 pyrrolidin- 1 -yl-propyl)-urea; N-Biphenyl-4-yl-4-piperazin- 1 -yl-butyramide Within compounds of formula I above described, most preferred compounds are those in which X is 25 T'p ()qz U N I ; /N'U WO 2007/098826 PCT/EP2007/000382 8 More preferred group compounds are those for which X is T'p ()q z N-()q'; In one embodiment, this invention provides compounds hereafter 5 referred to as GI, in which: Xis: T'p _'-L T' U N - I 'U' / / I N-()q' ; NE 'I z is selected from CH 2 , N, 0; 10 T' represent, independently from one another when p is greater than 1, hydroxy; amino; cyano; nitro; linear, branched or cyclic (CI-C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; mono- or di-, linear, branched or cyclic (Ci-C 6 ) alkylamino; linear, branched or cyclic (Ci-C 6 ) 15 alkoxy-(Ci-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl, or (Ci-C 6 ) alkylthio-(Ci-C 6 ) alkyl; (C 1
-C
3 ) alkylsulphonylamino; mono- or di- (CI-C 3 ) alkylaminosulphonyl; sulphamoyl; linear, branched or cyclic (Ci-C 6 ) alkylaminocarbonyl; carbamoyl; or when p is 2 or 3, two T' substituents form a 5- to 8-membered ring with spiro or fused junction; 20 U and U' represent, independently from one another, hydrogen; a linear, branched or cyclic (Ci-C 6 ) alkyl, azaalkyl, oxaalkyl chain optionally substituted with hydroxy, oxo, trihalomethyl, trihalomethoxy, carbamoyl, sulphamoyl, pyridyl, linear, branched or cyclic (CI-C 3 ) alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, mono- or di-, linear, branched or cyclic 25 (Ci-C 3 ) alkylaminocarbonyl, (CI-C 3 ) alkylsulphonylamino, (CI-C 3
)
WO 2007/098826 PCT/EP2007/000382 9 alkylsulphonyl, mono- or di- (C 1
-C
3 ) alkylsulphamoyl, mono- or di-, linear, branched, or cyclic (Ci-C 6 ) alkylamino; Q is a 6 to 10-membered aromatic or heteroaromatic ring; R represents a 5 to 10-membered aromatic or heteroaromatic ring optionally 5 substituted with one or more groups independently selected from: halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic (CI-C 6 ) alkyl, trihaloalkyl,. alkoxy or alkylcarbonyl; linear, branched, or cyclic (Ci-C 6 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (CI-C 6 ) 10 alkylsulphonylamino; linear, branched, or cyclic (Ci-C 6 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (Ci-C 6 ) alkylsulphamoyl; linear, branched or cyclic
(CI-C
6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(Ci-C 6 ) alkyl; R' represent, independently from one another when j = 2, halogen; hydroxy; trihalomethyl; trihalomethoxy; linear, branched or cyclic (C 1
-C
3 ) 15 alkyl, trihaloalkyl, alkoxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphonyl; linear, branched, or cyclic (Ci-C 3 ) alkylcarbonylamino; mono or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl;
(CI-C
3 ) alkylsulphonylamino; linear, branched, or cyclic (CI-C 3 ) alkylsulphamoyl; linear, branched or cyclic (CI-C 3 ) alkoxy-(Ci-C 3 ) alkyl, 20 mono- or di- (CI-C 3 ) alkylamino-(Ci-C 3 ) alkyl, (CI-C 3 ) alkylthio-(CI-C 3 ) alkyl; In one aspect of this invention, G1 provides a group of compounds hereafter referred to as Gl a wherein w + h + k = 4. Within Gla, a particular embodiment provides compounds in which k is 0; 25 X is a group of formula: U . N'U' WO 2007/098826 PCT/EP2007/000382 10 U and U' represent, independently from one another, hydrogen; a linear, branched or cyclic (CI-C 6 ) alkyl, azaalkyl, oxaalkyl chain optionally substituted with trihalomethyl, trihalomethoxy, carbamoyl, sulphamoyl, pyridyl; 5 -Y- is a group -C(=O)NH- or -NH-C(=O)NH-; j is 0, or 1; R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (CI-C 6 ) alkyl, trihaloalkyl, 10 alkoxy; linear, branched, or cyclic (C 1
-C
3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C3) alkylaminocarbonyl; carbamoyl; R' represents halogen; trihalomethyl; trihalomethoxy; linear, branched or cyclic (C 1
-C
3 ) alkyl, alkoxy. In another embodiment, this invention provides a group of compounds 15 hereafter referred to as G2 in which: w +h+ k= 4 KI and K2 represent, independently from one another hydrogen; halogen; (CI-C 3 ) alkyl, alkoxy; X is a group of formula: 20 T'p q z N-()q'; z is CH 2 , N, 0; p is 0 or 1; T' represents linear, branched or cyclic (C 1
-C
3 ) alkyl, trihaloalkyl, 25 alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic
(C
1
-C
3 ) alkylaminocarbonyl; carbamoyl; WO 2007/098826 PCT/EP2007/000382 11 R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (C 1
-C
3 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono 5 or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C 1
-C
3 ) alkylsulphonylamino; linear, branched, or cyclic (Ci-C 6 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (CI-C 6 ) alkylsulphamoyl; linear, branched or cyclic (CI-C 6 ) alkoxy-(Ci-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl; 10 R' represent, independently of one another when j = 2, halogen; hydroxy; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 3 ) alkylaminocarbonyl; carbamoyl;
(C
1
-C
3 ) alkylsulphonylamino; linear, branched, or cyclic (Ci-C 3 ) 15 alkylsulphamoyl; linear, branched or cyclic (CI-C 3 ) alkoxy-(CI-C 3 ) alkyl, mono or di- (CI-C 3 ) alkylamino-(CI-C 3 ) alkyl, (C 1
-C
3 ) alkylthio-(Ci-C 3 ) alkyl; Within G2, a particular embodiment defines a group of compounds hereafter referred to as G3 in which: KI and K2 represent, independently from one another hydrogen; 20 halogen; (CI-C 3 ) alkyl; X is a group of formula: T'p I q N--()q' z is CH 2 , N; 25 q and q' are, independently from one another, integers from 1 to 3; T' represents linear, branched or cyclic (CI-C 3 ) alkyl, alkylcarbonyl; WO 2007/098826 PCT/EP2007/000382 12 R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; linear, branched or cyclic (Ci-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, 5 or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; R' represents, independently from one another when j = 2, halogen; trihalomethyl; linear, branched or cyclic (CI-C 3 ) alkyl, alkoxy. In one aspect, G3 provides a subset of compounds hereafter referred to as G4a in which -Y- is a group -C(=O)NH-. 10 Within G4a, a particular embodiment is that in which: Q is a phenyl or pyridyl ring; j is 1 or 2; R represents a phenyl, pyridyl, or pyrazolyl ring, optionally substituted with one or more groups independently selected from: halogen; linear, 15 branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic
(CI-C
3 ) alkylaminocarbonyl; carbamoyl. In another aspect, G3 provides a subset of compounds hereafter referred to as G4b where: 20 -Y- is a group -NH-C(=O)-NH-. Within G4b, a particular embodiment is that in which: KI and K2 represent, independently from one another hydrogen; halogen; (CI-C 3 ) alkyl; X is a group of formula: 25 T'p 0q Lz N-()q' WO 2007/098826 PCT/EP2007/000382 13 z is CH 2 , N; p is 0 or 1; q and q' are, independently from one another, integers from 1 to 3; T' represents linear, branched or cyclic (C 1
-C
3 ) alkyl, alkylcarbonyl; 5 -Y- is a group -NH-C(=O)-NH-; Q is a phenyl or pyridyl; R represents a phenyl, pyridyl or pyrazole ring, optionally substituted with one or more groups independently selected from: halogen; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or 10 cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic
(CI-C
3 ) alkylaminocarbonyl; carbamoyl; Under yet another aspect of invention, GI also provides a group of compounds hereafter referred to as G5, wherein w+ h+ k= 3; 15 X is Iq z N -- ()q'; Within G5, one embodiment provides a group of compounds hereafter referred to as G5a in which: 20 q and q' are, independently from one another, integers from 1 to 3; T' represent, independently from one another when p is greater than 1, hydroxy; cyano; oxo; linear, branched or cyclic (C 1
-C
6 ) alkyl, trihaloalkyl, hydroxyalkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (CI-C 6 ) alkoxy-(CI-C 6 ) alkyl; (CI-C 3 ) 25 alkylsulphonylamino; mono- or di- (CI-C 3 ) alkylaminosulphonyl; sulphamoyl; linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched or cyclic (CI-C 3 ) alkoxy-(Ci-C 3 ) alkyl; (CI-C 3
)
WO 2007/098826 PCT/EP2007/000382 14 alkyl sulphonylamino; mono- or di- (CI-C 3 ) alkylsulphamoyl; (CI-C3) sulphonyl; -Y- is a group -NH-C(=0)-NH-; R represents a 5 to 6-membered aromatic or heteroaromatic ring, 5 optionally substituted with one or more groups independently selected from: halogen; hydroxy; cyano; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (Ci-C 3 ) alkylsulphonylamino; linear, branched, or cyclic 10 (CI-C 3 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (CI-C 3 ) alkylsulphamoyl; linear, branched or cyclic (Ci-C 3 ) alkoxy-(Ci-C 3 ) alkyl; R' represents, independently of one another when j = 2, halogen; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 3 ) alkyl, alkoxy. 15 Within G5a, a particular embodiment is represented by compounds in which k is 0; p is 0, or 1; T' represents, independently from one another when p is greater than 1, 20 linear, branched or cyclic (CI-C 3 ) alkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (CI-C3) alkylaminocarbonyl; carbamoyl; -Y- is a group -NH-C(=O)-NH-; Q is a phenyl or pyridyl; 25 j is 0 or 1; R represents a phenyl or pyridyl ring optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (CI-C 6 ) alkyl, alkoxy; linear, branched, or cyclic (Ci-C 3
)
WO 2007/098826 PCT/EP2007/000382 15 alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; R' represents halogen. The compounds of the invention can be prepared through a number of 5 synthetic routes amongst which the ones illustrated in Schemes 1-5 below: a) Scheme 1 HO, <,NH 2 + RHO O RR 1 2 3 4 Y'= isocyanate Y = -NHCONH + X NaBH(OAc)3 y R R 5 6 According to Scheme 1, an aminoalcohol, for example 3-amino-2,2 10 dimethyl-propan-1-ol when k = 1 and KI = K2 = -CH 3 , is reacted with for example an isocyanate or a carbamoyl chloride, hereby exemplified by an arylisocyanate, in an organic solvent such as for example dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof, until the reaction is complete. The hydroxyurea 3 then oxidised under standard conditions (for 15 example Swern oxidation) and the obtained aldehyde 4 is then reacted with a suitably substituted amine 6 under standard reductive alkylation conditions for example with sodium triacetoxyborohydride - to afford compound Ia. In the case of R being a halogen or a boronic acid ester, Ia can be further processed - for example via a cross-coupling reaction, for example under the 20 conditions of the Suzuki coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds I0.
WO 2007/098826 PCT/EP2007/000382 16 b) Scheme 2
K
1
KN
2 -Br.-. Y X Br ( C 1 + R BrRR 8k C R iK 6 7 8 9 XQk Y X = amine K, K Y = -CONH Ia 10 According to Scheme 2 an ao-haloalkanoyl chloride is reacted with an 5 (hetero)aromatic amine 8 in the presence of an organic base to afford an o-haloalkanoic acid amide 9. This species is reacted with an amine 6 to displace the halogen and afford compounds Ia. In the case of R being a halogen or a boronic acid ester, Ia can be further processed - for example via a cross-coupling reaction, for example under the conditions of the Suzuki 10 coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds 1p. c) Scheme 3
K
1 0 K 1 0 K, Br()w ()h-N / + X ( N ) ( NH BOW N Q OW, Oh OW) Oh 2 K2 0 K 0 K K K, 0 1 H I H I N X ' Owk N 0X Ok..N XN() H 2 + (w ()h' ( ()h 0 K, R (R')j HN " -R HN N gR Ia 1 1f3 1 (R')j (R')j 15 According to Scheme 3, a suitably activated o-haloalkylphthalimide, is reacted with an amine X in an organic solvent such as for example but not limited to 2-butanone or dimethylformamide in the presence of a base such as WO 2007/098826 PCT/EP2007/000382 17 for example triethylamine or potassium carbonate. For example, a mixture of amine (or its hydrochloride salt) and o-haloalkylphthalimide are refluxed in methylethyl ketone in the presence of alkaline carbonate until the reaction is complete, then the reaction mixture is cooled, the insoluble materials removed 5 by filtration, the filtrate washed with chloroform or dichloromethane, and the filtrate and washings concentrated to dryness. In the following step, the o-aminoalkylphthalimide is converted into a o-diamine, for example by refluxing a mixture of the o-aminoalkylphthalimide and hydrazine hydrate in ethanol. The o-diamine is reacted with an activated species such as for 10 example an isocyanate or a carbamoyl chloride in an organic solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof, to give compounds of formula Ia In the case of R being a halogen, a boronic acid or a boronic ester, Ia can be further processed - for example via a cross-coupling reaction, for example under the conditions of the Suzuki 15 coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds of formula I. d) Scheme 4 K K K, K, I I, II IIH 0" .k H OW'()w (hNH2 + O() '_()h 0O ----- N O W()w ()h 0 ()Oh N O
I
2 K QK R' (R')j HN Q R HNN a R I I (R)j K (R')j amineX x H reducing agent x .()k N Ow ()h Ow2 Oh' I a(R')j' N a -R 10(R%')j 1 Q1R 20 According to Scheme 4, a suitable aldehyde precursor, for example an aminoalcohol, for example aminopropanol when k = 1 and KI = K2 = H, is reacted with for example an isocyanate or a carbamoyl chloride, hereby exemplified by an arylisocyanate, in an organic solvent such as for example WO 2007/098826 PCT/EP2007/000382 18 dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof, until the reaction is complete. The aldehyde precursor thus obtained is then converted to the aldehyde, for example oxidised under standard conditions (for example Swern oxidation) in the case of an alcohol, and the aldehyde is 5 then reacted with a suitably substituted amine X under standard reductive alkylation conditions - for example with sodium triacetoxyborohydride - to afford compounds Ia. In the case of R being a halogen, a boronic acid or a boronic acid ester, Ia can be further processed - for example via a cross coupling reaction, for example under the conditions of the Suzuki coupling, 10 with a boronic acid or an aryl or heteroaryl halide - to yield compounds of formula I. e) Scheme 5 K, K, amine X K Br s()w LG + R'k ( base Iw () h NH ()I h BrO O h NH X).O NH R~~ (R(R'0)() K2 K2 R'Q' (R')j R'0,'(R')j Ia K, 1I 0 Ow (Oh NH R'-'(R')j 15 According to Scheme 5 a suitably activated o-haloalkanoic acid (for example where the moiety C(=O)-LG represents an acyl chloride or activated ester or imidazolide) is reacted with an (hetero)aromatic amine in the presence of an organic base to afford an o-haloalkanoic acid amide. This species is further reacted with an amine X to displace the o-halogen atom and afford 20 compounds of formula Ia. In the case of R being a halogen, a boronic acid or a boronic acid ester, Ia can be further processed - for example via a cross-coupling reaction, for example under the conditions of the Suzuki coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds of formula I.
WO 2007/098826 PCT/EP2007/000382 19 f) Scheme 6 K 1i 0 Ki X .0k R')j (R')j w ()h OH + H2N'Q'R N() ( R '2 2K wlO X = amine - 2 According to Scheme 6, an o-aminoalkanoic acid is suitably activated 5 using an agent such for example but not limited to as 1,1'-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford subject matter compounds of formula I. g) Scheme 7 10 Ow Ifi o R) W ()h H + H 2 N' Br Ow Oh N'H r X = amine 1 0 (R')j I (h H
K
2 According to Scheme 7, an o-aminoalkanoic acid is suitably activated using an agent such for example but not limited to as 1,1'-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or 15 mixtures thereof and reacted with a suitable bromoaryl or heteroaryl amine to afford bromoaryl or heteroaryl amides, which are then reacted further under cross-coupling conditions, for example Suzuki conditions, to afford subject matter compounds of formula I. Scheme 8 shows one possible route towards the synthesis of chain 20 substituted acids, precursors to compounds of Formula I WO 2007/098826 PCT/EP2007/000382 20 0 0 1) base ALK HBr 48%, 120 0 C 2) a,w-dihaloalkane Br 0 0 Br OH ALK n= -2 0 O 0 0 amnine X, 0 NaOH aq MeOH, H 2
SO
4 Br . toluene, -O H XOH AX reflux * 0 L ALK ALK AU( According to Scheme 8, an alkyl-substituted malonic acid diester it treated with base, such as for example but not limited to sodium hydride in a solvent such as tetrahydrofurane or dimethylformamide and reacted with an 5 a,o>-dihaloalkane. The disubstituted malonic acid diester thus obtained is hydrolysed and mono-decarboxylated by treatement with a strong acid, such as for example hydrobromic acid. Esterification is then carried out, for example by treatement with methanol and a catalytic amount of acid. Substitution of the uo-halogen may be accomplished by the use of a suitable 10 amine heating in a solvent like toluene, but not limited to this solvent. Finally, hydrolysis of the ester function with an aqueous base affords intermediates which can be activated as described to afford compounds of Formula I. The compounds in this invention can in general be prepared by any of several standard synthetic processes commonly used by those skilled in the art 15 of organic chemistry. In general, the amides can be prepared through a base-catalysed nucleophilic addition between the appropriate carboxylic acid with an appropriately selected amine or via a nucleophilic substitution reaction wherein the appropriate amine reacts with either the selected acyl halide, anhydride or ester to yield the required amine. When coupling the 20 acids to the amines, standard chemical coupling reagents such as carbonyldiimidazole (CDI), 1,3-dicyclohexylcarbodiimide (DCC) or 1-ethyl 3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) can be used in the presence or absence of hydroxybenzotriazole (HOBt). In an alternative procedure the carboxylic acids are converted into the corresponding acyl WO 2007/098826 PCT/EP2007/000382 21 halides by reaction with, for example, thionyl chloride or oxalyl chloride. Subsequently, the acid halide is added to the appropriately selected amine to yield the amide using art-known reaction procedures such as the Schotten Baumann method. 5 The carboxylic acids and the amines are readily available, or may be prepared using methods that are well known in the art. Many compounds are commercially available, for example, from Aldrich Chemicals, or when the compounds are not commercially available, they may be readily prepared from available precursors using straightforward transformations that are well known 10 in the art. For example the carboxylic acids can be prepared by hydrolysis of nitriles, carbonation of organometallic compounds or oxidation of primary alcoholds or aldehydes. In particular branched alkyl nitriles are prepared from the corresponding alkyl acetonitriles by conversion to the dialkyl or spiroalkyl derivative using e.g. sodium hexamethyldisilazane and methyl iodide or 15 dibromobutane, followed by hydrolysis under acidic or basic conditions to the desired carboxylic acid. Appropriate acids and bases in the hydrolysis are for example H2SO4 and KOH. The hydrolysis reaction can be conveniently performed using microwave heating. The compounds of formula I, their optical isomers or diastereomers can 20 be purified or separated according to well-known procedures, including but not limited to chromatography with a chiral matrix and fractional crystallisation. The pharmacological activity of a representative group of compounds of formula I was demonstrated in an in vitro assay utilising cells stably 25 transfected with the alpha 7 nicotinic acetylcholine receptor and cells expressing the alpha 1 and alpha 3 nicotinic acetylcholine receptors and 5HT3 receptor as controls for selectivity. According to a further aspect, the invention is therefore directed to a method of treating neurological and WO 2007/098826 PCT/EP2007/000382 22 psychiatric disorders, which comprises administering to a subject, preferably a human subject in need thereof, an effective amount of a compound of formula I. Neurological and psychiatric disorders that may benefit from the treatment with the invention compounds include but are not limited to senile dementia, 5 attention deficit disorders, Alzheimer's disease and schizophrenia. In general, the compounds of formula I can be used for treating any disease condition, disorder or dysfunction that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor, including but not limited to Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, 10 epilepsy, memory or learning deficit, panic disorders, cognitive disorders, depression, sepsis and arthritis. The dosage of the compounds for use in therapy may vary depending upon, for example, the administration route, the nature and severity of the disease. In general, an acceptable pharmacological effect in humans may be 15 obtained with daily dosages ranging from 0.01 to 200 mg/kg. In yet a further aspect, the invention refers to a pharmaceutical composition containing one or more compounds of formula I, in association with pharmaceutically acceptable carriers and excipients. The pharmaceutical compositions can be in the form of solid, semi-solid or liquid preparations, 20 preferably in form of solutions, suspensions, powders, granules, tablets, capsules, syrups, suppositories, aerosols or controlled delivery systems. The compositions can be administered by a variety of routes, including oral, transdermal, subcutaneous, intravenous, intramuscular, rectal and intranasal, and are preferably formulated in unit dosage form, each dosage containing 25 from about 1 to about 1000 mg, preferably from 1 to 600 mg of the active ingredient. The compounds of the invention can be in the form of free bases or as acid addition salts, preferably salts with pharmaceutically acceptable acids. The invention also includes separated isomers and diastereomers of WO 2007/098826 PCT/EP2007/000382 23 compounds I, or mixtures thereof (e.g. racemic mixtures). The principles and methods for the preparation of pharmaceutical compositions are described for example in Remington's Pharmaceutical Science, Mack Publishing Company, Easton (PA). 5 Experimental Procedures - Synthesis of compounds General Unless otherwise specified all nuclear magnetic resonance spectra were recorded using a Varian Mercury Plus 400 MHz spectrometer equipped with a PFG ATB Broadband probe. 10 HPLC-MS analyses were performed with a Waters 2795 separation module equipped with a Waters Micromass ZQ (ES ionisation) and Waters PDA 2996, using a Waters XTerra MS C18 3.5 m 2.lx5Omm column. Preparative HLPC was run using a Waters 2767 system with a binary Gradient Module Waters 2525 pump and coupled to a Waters Micromass ZQ 15 (ES) or Waters 2487 DAD, using a Supelco Discovery HS C18 5.0 pm 10 x 21.2 mm column. Gradients were run using 0.1% formic acid/water and 0.1% formic acid/acetonitrile with gradient 5/95 to 95/5 in the run time indicated. All column chromatography was performed following the method of 20 Still, C.; J. Org Chem 43, 2923 (1978). All TLC analyses were performed on silica gel (Merck 60 F254) and spots revealed by UV visualisation at 254 nm and KMnO4 or ninhydrin stain. When specified for array synthesis, heating was performed on a Buchi Syncore* system. 25 All microwave reactions were performed in a CEM Discover oven.
WO 2007/098826 PCT/EP2007/000382 24 Abbreviations used throughout the Experimental Procedures CDI NN'-carbonyldiimidazole DCM Dichloromethane DCE 1,2-dichloroethane DMEA NN-dimethylethylamine DMF NN-dimethylformamide DMSO, dmso Dimethylsulphoxide DAM NN-dimethylacetamide SCX strong cation exchanger TEA Triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography LC-MS, LCMS Liquid chromatography - mass spectrometry HPLC High performance liquid chromatography General procedure for aminoalkylamine synthesis - phthalimide route N-(3-Bromopropyl)phthalimide (1 eq) was added to a suspension of 5 amine (1 eq), sodium iodide (0.5 eq) and potassium carbonate (1.1 eq) in 2-butanone (ca. 20 volumes with respect to phthalimide weight). The resulting suspension was stirred for 18h at 85 0 C, then the reaction was filtered and the solvent removed by vacuum distillation; the resulting oil was washed with water and recovered with DCM. The solvent was removed under reduced 10 pressure to yield the amino-phthalimide products pure enough to be used in the next step without further purification. The phthalimides thus obtained (1 eq) were dissolved in EtOH (ca. 7-10 volumes with respect to phthalimide weight) and hydrazine monohydrate (2 eq) was added dropwise. The mixture was heated at 80 0 C for 4 h, after 15 which the reaction was acidified with 37% HCl and the solid which precipitated was removed by filtration. The solution was concentrated under vacuum and taken up with IN HCl. Any residual 2,3-dihydro-phthalazine-1,4- WO 2007/098826 PCT/EP2007/000382 25 dione was removed by filtration. The aqueous solution was evaporated under vacuum to recover pure product. In case of acid sensitive derivatives the reaction mixture was filtered and washed with EtOH, concentrated under vacuum and taken up with toluene 5 and DCM to remove excess 2,3-dihydro-phthalazine-1,4-dione. Solvent removal under reduced pressure afforded the pure product. 1-[4-(3-Amino-propyl)-piperazin-1-yl]-ethanone 2-[3-(4-Acetyl-piperazin-1-yl)-propyl]-isoindole-1,3-dione (5.0 g, 16 mmol) was dissolved in EtOH (50 mL) and hydrazine monohydrate 10 (1.5 mL, 32 mmol) was added. The mixture was heated at 80*C for 1 hour. 1-(4-Bromo-phenyl)-3-(3-piperidin-1-yl-propyl)-urea a) 2-(3-Piperidin-1-yl-propyl)-isoindole-1,3-dione N-(3-Bromopropyl)phthalimide (5.36 g, 20 mmol) was added to a suspension of piperidine (1.98 mL, 20 mmol), sodium iodide (3.9 g, 26 mmol) 15 and potassium carbonate (4.15 g, 21 mmol) in 2-butanone (100 mL). The resulting suspension was stirred for 24 hour at 90'C. The reaction was filtered to remove inorganic salts and the solvent removed by vacuum distillation; the resulting oil was washed with water and recovered with DCM. The solvent was removed under reduced pressure to 20 afford 4.39 g of desired product as a white solid (yield: 81%). C16H20N202 Mass (calculated) [272.35],; found [M+H*]=273 'H-NMR (400 MHz, CDC13) 1.25-1.47(6H, in), 1.76-1.92 (2H, in), 2.14-2.42 (6H, in), 3.63-3.68 (2H, in), 7.63-7.73 (2H, in), 7.76-7.86 (2H, in). b) 3-Piperidin-1-yl-propylamine hydrochloride 25 2-(3-Piperidin-1-yl-propyl)-isoindole-1,3-dione (7.5 g, 18.34 mmol) was dissolved in EtOH (45 mL) and hydrazine monohydrate (1.78 mL, 34.5 mmol) was added. The mixture was heated at 80'C for 1 hour. The reaction was then cooled and acidified with 5 mL of 37% HCl and WO 2007/098826 PCT/EP2007/000382 26 2,3-dihydro-phthalazine-1,4-dione was removed by filtration. The solution was concentrated under vacuum, 10 mL of IN HCl were added and the mixture was filtered again to remove the residual 2,3-dihydro-phthalazine-1,4 dione. The aqueous solution was evaporated under vacuum and 3.0 g (yield 5 48%) of pure product were recovered. C8H18N2 Mass (calculated) [142.25]; (found) [M+H*]=143 NMR (400 MHz, dmso-d6): 1.25-1.45 (2 H, in), 1.57-1.92 (4 H, in), 1.93-2.17 (2H, in), 4.05-5.37 (4H, in). General procedure for urea synthesis 10 To a cooled solution of amine (1 eq) in dichloromethane an equimolar amount of an aryl or heteroaryl isocyanate was added. In the case of the amine being in the form of a hydrochloride or bis-hydrochloride salt, equimolar amounts of TEA were added to free-base the amine. The mixture was left stirring at 0*C for 1-4 hours. The p-bromophenyl 15 ureas generally precipitated out of solution as white solids, were recovered by filtration and if necessary purified further by washing with Et 2 O or by flash chromatography. The m-bromophenylureas were isolated by solvent removal under reduced pressure and purified by crystallisation from an mixture of AcOEt: Et 2 0. 20 Alternatively, to a solution of aniline in DCM (0.32 mmol/mL) cooled at 0*C, triphosgene (1 eq) was added under N 2 flux; a white precipitate formed and NEt 3 (1.1 eq) was added and the mixture generally became a yellow solution. After 30 minutes the amine was added and the reaction was left stirring at 0*C for 2 hours, when LC-MS generally showed complete 25 conversion. If a precipitate was present it was filtered affording the urea product, otherwise the solution was washed with NaOH 10% solution and the organic phase concentrated under reduced pressure. The crude was then purified by crystallization from Et 2 0.
WO 2007/098826 PCT/EP2007/000382 27 1-(4-Bromo-phenyl)-3-(3-piperidin-1-yl-propyl)-urea To a cooled solution of 3-piperidin-1-yl-propylamine dihydrochloride (0.96 g, 4 mmol) in dichloromethane (20 mL) TEA was added (1.11 mL, 8 mmol). 5 p-Bromophenylisocyanate (0.78 g, 4 mmol) was then added and the mixture was stirred at 0 0 C until a white solid precipitated out of solution after 2 hours. The white solid was filtered off and washed with Et 2 0 to give 1.4 g of pure title compound. Cl5H22BrN3OMass (calculated) [340.27]; (found) [M+H*]=340-342 10 Lc Rt (10 min method)= 2.69, 92% NMR (400 MHz, dmso-d6): 1.26-1.63 (8H, in); 2.14-2.36 (4H, in); 2.45-2.51 (2H, m, under DMSO); 3.00-3.13 (2H, m); 6.11-6.26 (1H, m), 7.33 (4H, s), 8.52-8.66(1H,s). 1-(2-Chloro-4-Bromo-phenyl)-3-(4-piperidin-1-yl-butyl)-urea 15 Prepared via the general procedure for urea synthesis (via isocyanate) Yield: 76% NMR (400 MHz, dmso-d6): 1.27-1.52 (10H, in), 2.14-2.37 (6H, in), 3.03-3.4 (2H, in), 7.04 (1H, t), 7.40 (1H, dd), 7.60 (1H, d), 8.50 (1H, s), 8.12 (1H, d). 20 1-(2-Fluoro-4-Bromo-phenyl)-3-(4-piperidin-1-yl-butyl)-urea Prepared via the general procedure for urea synthesis (via isocyanate) Yield: 88% NMR (400 MHz, dmso-d6): 1.22-1.50 (10H, in), 2.12-2.37 (6H, in), 3.00-3.13(2H, in), 6.62 (1H, t), 7.25 (1H, d), 7.47 (1H, dd), 8.10 (1H, t), 8.33 25 (1H, s). 1-(2,6 difluoro-4-Bromo-phenyl)-3-(4-piperidin-1-yl-butyl)-urea Prepared via the general procedure for urea synthesis (via isocyanate) Yield: 67% WO 2007/098826 PCT/EP2007/000382 28 C16H22BrF2N30 Mass (calculated) 390; (found) [M+H*]= 390-392 Lc Rt= 2.04 (100%), 10' NMR (400 MHz, dmso-d6): 1.31-1.51 (10H, n), 2.17-2.37 (6H, n), 2.98-3.09 (2H, in), 6.36 (1H, t), 7.44 (1H, d), 7.82 (1H, s). 5 1-(2-Fluoro-4-Bromo-phenyl)-3-(3-piperidin-1-yl-propyl)-urea Prepared via the general procedure for urea synthesis (via isocyanate) Yield: 86% C15H21BrFN30 Mass (calculated) 358; (found) [M+H*]= 358-360 Lc Rt= 2.18 (100%), 10' 10 NMR (400 MHz, dmso-d6): 1.31-1.40 (2H, in), 1.41-1.49 (4H, in), 1.50-1.57 (2H, in), 2.17-2.35 (6H, in), 3.07 (2H, q, J=5.8Hz), 6.59 (1H, t), 7.25 (1H, dt), 7.46 (1H, dd), 8.08 (lH, t), 8.34 (1H, s). 1-(2-Chloro-4-Bromo-phenyl)-3-(3-piperidin-1-yl-propyl)-urea Prepared via the general procedure for urea synthesis (via isocyanate) 15 Yield: 78% C15H21BrClN30 Mass (calculated) 374; (found) [M+H*]= 374-376 Lc Rt= 2.46 (98%), 10' NMR (400 MHz, dnso-d6): 1.30-1.39 (2H, m),1.42-1.49 (4H, in), 1.50-1.60 (2H, in), 2.16-2.37 (6H, in), 3.08 (2H, q, J=4.7), 7.01(1H, t), 7.40 20 (1H, dd), 7.62 (1H, d), 8.48 (1H, s), 8.11 (1H, d). General procedure for amide synthesis from co-haloalkanoyl chlorides Br C H2N Br N BH2 H oN Br H R2 WO 2007/098826 PCT/EP2007/000382 29 One-pot with low molar excess of amine R1R2NH In a round-bottom 2-neck flask, triethylamine (1 eq) was added to a solution of aryl or heteroaryl amine (1 eq) in a volume of DCE such as to obtain a 1.2 M solution of amine; 5-bromovaleryl chloride (0.95 eq) was then 5 added dropwise as a solution in 1.2 M solution in DCE and the reaction was stirred at room temperature for 1 hour 30 minutes. A 1.8 M solution of amine R1R2NH (3 eq) and triethylamine (1 eq) in DCE were then added and the reaction mixture strirred at 55*C for a time between 4 and 16 h, until LCMS monitoring showed reaction completion. After this period the reaction mixture 10 was partitioned between water and DCM; the organic layer was washed with saturated NaCI and dried over Na 2
SO
4 . The crude amides obtained after solvent evaporation at reduced pressure were purified by trituration from Et 2 O or by flash chromatography. One-pot with high molar excess of amine R]R2NH 15 Alternatively, a solution of aniline (1 eq) and triethylamine (1 eq) in dichloromethane (0.2 mmol/mL) was cooled at 0*C under nitrogen atmosphere. 5-Bromo-pentanoyl chloride (1 eq) in dichloromethane (0.3 mmol/mL) was slowly added. The mixture was stirred at room temperature for 1.5 hours, after which the amine R1R2NH (5 eq) and 20 triethylamine (1 eq) were added at once and the reaction was stirred at room temperature for further 40 hours. The organic solution was washed with brine, dried and the solvent removed. The product were triturated by hexane/diethyl ether 1/1 or purified by flash chromatography. One-pot, high molar excess of amine R1R2NH - array method 25 To a solution of aniline (1 eq for each molar equivalent of amine R1R2NH used) and triethylamine (1 eq for each molar equivalent of amine R1R2NH used) in dichloromethane (0.3 mmol/mL for each amine R1R2NH used) 5-bromo-pentanoyl chloride (1 eq for each molar equivalent of amine WO 2007/098826 PCT/EP2007/000382 30 R1R2NH used) was slowly added and the mixture stirred at room temperature for 2 hours. The solution was then split in as many aliquotes as many amines used in the array and each portion added to a vial containing an amine R1R2NH (5 eq) and triethylamine (1 eq). The reactions were then shaken at 5 room temperature for 40 hours. The organic solutions were washed with brine, collected, dried (Na 2
SO
4 ) and the solvent evaporated. The products were purified by preparative HPLC. Two steps, using an equimolar amount of amine RJR2NH 5-Bromopentanoic acid-(4-bromophenyl)-amide 10 4-Bromo-aniline (6 g, 0.035 mol) and 0.035 mol of NEt 3 (4.87 mL) were dissolved in 120 mL of dichloromethane and cooled at 0*C. To this solution, 0.038 mol of 5-bromovaleryl chloride (5.4 mL) were slowly added and the resulting mixture was stirred for 1 h at 0*C. When all the starting material was consumed (as monitored by LCMS) 15 the solution was washed with 50 mL of Na 2
CO
3 0.4 M and the organic layer was recovered by extraction and drying over Na 2
SO
4 . The solvent was removed under reduced pressure giving 10 g of the title compound as a white solid (yield 86%). CI 1H13Br2NO Mass (calculated) [335]; (found) [M+H*]=335 20 Lc Rt = 2.64, 100% (5 min method) NMR (400 MHz, CDCl3) 1.70-2.00 (4H, in), 2.35-2.45 (2H, in), 3.38-3.48 (2H, in), 7.30-7.50 (4H, in). 1 eq of the thus prepared alkylating agent was dissolved in butanone (5-10 mL/mmol substrate) and to this 1 eq of Nal and 1.1 eq of the amine 25 R1R2NH were added. The mixture was stirred at 70'C or 24 hours. The mixture was cooled. When the products precipitated as salts, they were taken into water, free-based by addition of NaOH 10% to pH = 10 and extracted with dichloromethane. In the case where no product precipitation occurred, the WO 2007/098826 PCT/EP2007/000382 31 solvent was removed under reduced pressure, the crude was taken into dichloromethane and extracted after adjusting the pH to 10 with NaOH 10%. If necessary, the products were further purified by flash chromatography 5-Azepan-1-yl-pentanoic acid (4-bromo-3-fluoro-phenyl)-amide 5 Following the general procedure for amide synthesis, 3-fluoro-4 bromoaniline (66 mg, 0.35 mmol) and triethylamine (35 mg, 0.35 mmol) were dissolved in DCE (0.5 mL) and 5-bromovaleryl chloride (66 mg, 0.33 mmol) in DCE (0.5 mL) was added dropwise. After 1.5 hours, azepane (118 mg, 0.105 mmol) and triethylamine (35 mg, 0.35 mmol) in DCE (0.5 mL) were 10 added and the reaction mixture heated at 55 0 C for 4 hours. Work-up followed by prep HPLC afforded the title compound (87 mg, 77%) as the formate salt. C17H24BrFN20 Mass (calculated) [371.30]; (found) [M+H*]=371.33/373.35. LC Rt=2.23, 100% (10 min method) 15 NMR (400 MHz, CDCl 3 ): 1.7 (4H, s); 1.88-1.84 (8H, in); 2.44 (2H, mt); 2.98 (2H, in); 3.15 (4H, bs); 7.27 (1H, in); 7.4 (1H, dd, J=8.8,7.6); 7.80 (1H, dd, J=10.8, 2.4); 8.63 (1H, HCOOH,s); 9.8 (1H, bs). 5-Azepan-1-yl-pentanoic acid (4-bromo-3-trifluoromethyl-phenyl) amide 20 Following the general procedure, 4-bromo-3-trifluoromethyl-aniline (82 mg, 0.35 mmol) and triethylamine (35 mg, 0.35 mmol) were dissolved in DCE (0.5 mL) and 5-bromovaleryl chloride (66 mg, 0.33 mmol) in DCE (0.5 mL) was added dropwise. After lh 30 min, azepane (118 mg, 0.105 mmol) and triethylamine (35 mg, 0.35 mmol) in DCE (0.5 mL) were 25 added, and the reaction mixture heated at 55 0 C for 4 hours. Work-up followed by prep HPLC afforded the title compound (29 mg, 20%) as its formate salt. C18H24BrF3N20 Mass (calculated) [421.30]; (found) [M+H*]=421.29/423.29.
WO 2007/098826 PCT/EP2007/000382 32 LC Rt=2.52, 98% (10 min method) 5-[Methyl-(2-pyridin-2-yl-ethyl)-amino]-pentanoic acid (3-bromo phenyl)-amide Prepared according to the general procedure for amide synthesis and 5 purified by preparative HPLC to afford 106 mg (47%) of the title compound as the formate salt. CigH 24
N
3 OBr. HCO 2 H Mass (calculated) [390.33-46.03]; found [M+H*]=390.23, Lc Rt=1.73, 100% 10 NMR (400 MHz, CD 3 0D): 1.73-1.89 (4H, in); 2.46-2.50 (2H, in); 2.91 (3H, s); 3.19-3.27 (4H, in); 3.49-3.55 (2H, in); 7.19-7.24 (2H, in), 7.31 (1H, br dd, J=5.2 Hz, 6.8 Hz); 7.38 (1H, ddd, J=6.8 Hz, 1.6 Hz, 2.0 Hz); 7.80 (1H, ddd, J=8.0 Hz, 7.6 Hz, 1.6 Hz); 7.91 (1H, s); 8.46 (1H, s); 8.51 (1H, br d, J=4.8 Hz). 5-(Methyl-pentyl-amino)-pentanoic acid (4-bromo-phenyl)-amide 15 Prepared according to the general procedure for amide synthesis and purified by preparative HPLC to afford 123 mg (60%) of the title compound as the formate salt.
C
17
H
27
N
2 Obr HCO 2 H Mass (calculated) [355.32-46.03]; found [M+H*]=355.27, 20 Lc Rt=1.98, 100% NMR (400 MHz, CD 3 0D): 0.95 (3H, t, J=6.8 Hz); 1.32-1.44 (4H, in); 1.67-1.81 (6H, in); 2.43-2.49 (2H, in); 2.81 (3H, s); 3.04-3.13 (4H, m); 7.42-7.45 (2H, in), 7.49-7.52 (2H, m),.8.51 (1H, s). General procedure for cross-coupling reaction with boronic acids 25 R1N A NIBr (OH),B R O 2 H Pd(Ph a) 4 R N 2 A k N R2H R A= CH,, N WO 2007/098826 PCT/EP2007/000382 33 Thermal conditions on ureas (A = N) To a degassed solution of aryl or heteroaryl bromide prepared following the general procedure for urea synthesis described above (1 eq), the appropriate boronic acid (1.3 eq) was added dissolved in 40 volumes (i.e. 5 1 mL/g substrate) of acetonitrile/0.4N aqueous Na 2
CO
3 (1/1), Pd[(PPh 3
)]
4 (10% mol). The solution was refluxed overnight under nitrogen either in a round-bottom flask or in a glass test tube in a Buchi SynCore* apparatus. The acetonitrile phase was separated and the desired products purified over a SCX or silica column. Fractions containing the desired product were 10 combined and dried under reduced pressure. Microwave conditions on ureas (A = N) To a degassed solution of bromide prepared following the general procedure for urea synthesis (1 eq), the appropriate boronic acid (1 eq) and Na 2
CO
3 (3 eq) in 20 volumes (i.e. 1 mL/g substrate) of acetonitrile/water 15 (1/1), Pd[(PPh 3
)]
4 (10% mol) were added. The solution was irradiated in a microwave oven using the following parameters: power: 200 watt; ramp time: 1 min; hold time: 20:00 min; temperature: 90 C; pressure: 200 psi. The acetonitrile phase was separated, the solvent was removed under reduced pressure and the crude material purified 20 using SCX column (eluting with a gradient of DCM/MeOH, MeOH,
NH
3 /MeOH). The fractions containing product were combined and dried under reduced pressure. Microwave conditions on amides (A = CH 2 ) To a degassed mixture of 5-alkyl-pentanoic acid aryl-amide (0.1 g, 25 1 eq) aryl boronic acid (1.1 eq) in acetonitrile/sodium carbonate 0.4M solution 1/1 (4 mL), a catalytic amount of Pd[(PPh 3
)]
4 (5 mmol%) was added. The reaction mixture was heated at 901C for 20 minutes under microwave irradiation (150 Watt, pressure max) and then again other 20 minutes. The WO 2007/098826 PCT/EP2007/000382 34 organic layer was separated and concentrated, and further purified by SCX column and/or by preparative HPLC. The solvent was removed under reduced pressure to afford the corresponding product. General procedure for cross-coupling reaction with aryl/heteroaryl 5 bromides R12 A IPRR H Br I R A= CHN To a degassed mixture of co-aminoalkanoic acid [4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-amide (0.16 g, 0.4 mmol,1 eq) (prepared 10 following the general procedures described above) and an aryl/heteroaryl bromide (0.4 mmol, 1 eq) in acetonitrile/sodium carbonate 0.4M solution 1/1 (8 mL) a catalytic amount of Pd[(PPh 3
)]
4 (5 mmol %) was added. The reaction mixture was stirred at 90 0 C for 18 hours under N 2 and monitored for formation of the product by LCMS. The organic layer was separated and 15 filtered on a Celite* pad and the solvent removed under reduced pressure. The crude was purified by preparative HPLC or flash chromatography. General method for the synthesis of 1-(4-aryl-phenyl)-3-(4-aminoalkyl butyl)-ureas via reductive amination and cross-coupling a) 1- (4-Bromo-phenyl) -3- (4, 4-diethoxy-butyl)-urea 20 A solution of 4-aminobutyraldehyde diethyl acetal (0.88 mL, 5 mmol) in dry DCM (10 mL) was added over 30' to a solution of 4-bromophenylisocyanate (1 g, 5 mmol, 1 eq) in dry DCM (25 mL) cooled to 0C (ice/water bath) under N 2 ; after 1 hour a thick white precipitate of the urea formed. The solid was recovered by filtration and washing with Et 2 O 25 (3 X 20 mL) to yield 1-(4-bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea in essentially quantitative yield (1.78 g).
WO 2007/098826 PCT/EP2007/000382 35 C15H23BrN2O3 Mass (calculated) [359.27]; (found) [M+Na+]=38 1.11/383.25 LC Rt=3.54, 100% (10 min method) NMR (400 MHz, dmso-d6): 1.08 (6H, t, J=5.85 Hz); 1.42 (2H, in); 5 1.50 (2H, in); 3.06 (2H, in); 3.41 (2H, q); 3.54 (2H, q); 4.45 (1H, t); 6.19 (1H, t); 7.37 (4H, s); 8.54 (1H, s). b) 1-(4-Bromo-phenyl)-3-(4-aminoalkyl-butyl)-ureas 1-(4-Bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea (0.72 g, 2 mmol, 1 eq) was dissolved in dry DCM (10 mL) at room temperature and Montomorrilonite 10 K-5 (0.145 g) was added. The reaction was stirred at room temperature for 2 hours, when LC-MS showed complete conversion into the aldehyde. The reaction mixture was filtered to remove all solids and the amine (6 mmol, 3 eq) was added, followed by NaBH(OAc) 3 (4 mmol, 2 eq). The reaction was stirred at room temperature for 24 hrs. 15 Upon reaction completion (as monitored by LC-MS), the solvent was removed under reduced pressure and the resulting residue was purified by SCX column, eluting with DCM:MeOH 1:1 and then 2M NH 3 in MeOH. c) 1-(4-aryl-phenyl)-3-(4-aminoalkyl-butyl)-ureas To a degassed mixture of 1-(4-bromo-phenyl)-3-(4-aminoalkyl-butyl) 20 ureas (0.11 g, 1 eq) and a substituted benzeneboronic acid or pinacolboronate ester (1.5 eq) in acetonitrile/sodium carbonate 0.4M solution 1/1 (3 mL) a catalytic amount of Pd[(PPh 3
)]
4 (5 mmol %) was added. The reaction mixture was heated at 90*C for 10 minutes under microwave irradiation (150 Watt) and then again other 10 minutes, if needed. The organic layer was separated 25 and purified by SCX column or by prep HPLC (standard acidic conditions). 1-Methyl-4-piperidin-1-yl-butylamine a) N-Boc-5-methyl-2-pyrrolidinone A solution of di-tert-butyl carbonate (12.1 g; 55.5 mmol) in acetonitrile WO 2007/098826 PCT/EP2007/000382 36 (20 mL) was added dropwise to a solution of 5-methyl-2-pyrrolidinone (5.0 g; 50 mmol) and 4-dimethylamino-pyridine (0.31 g; 5 mol%) in acetonitrile (50 mL) at RT. The mixture was stirred for 7 hrs. The solvent evaporated and the obtained crude dissolved in ethyl acetate and washed with NaHCO 3 sat. 5 solution. The organic layer was collected and dried (Na 2
SO
4 ) and evaporation of the solvent gave the clean product. 9.41 g; 90%
CIOH
17
NO
3 calculated 199; found 126/144 Lc Rt (5 min)= 1.73, 99% 10 NMR (400 MHz, dmso-d6): 1.22 (3H, d, J= 6.4 Hz); 1.43 (9H, s); 1.50-1.57 (1H, m); 2.04-2.14 (1H, m); 2.26 (1H, ddd, J= 3.2 Hz, 9.2 Hz, 17.2 Hz); 2.56 (1H, ddd, J= 9.2 Hz, 10.42 Hz, 17.2 Hz); 4.07-4.15 (1H, m). b) (1-Methyl-4-oxo-4-piperidin-1-yl-butyl)-carbamic acid tert-butyl ester 15 N-Boc-5-methyl-2-pyrrolidinone (0.7 g; 3.52 mmol) and piperidine (1.55 g; 18.2 mmol, 1.8 mL) were mixed and heated at 150'C by MW irradiation for 40 minutes. The mixture was diluted with dichloromethane and the solution washed trice with HCl 1.0 M solution. The organic layer was dried (Na 2
SO
4 ) and the solvent evaporated. The crude product was purified by 20 flash chromatography (cyclohexane: ethyl acetate). 0.522 g; 73%
C
15
H
28
N
2 0 3 calculated 284; found 285 Lc Rt (3 min)= 1.31, 99% NMR (400 MHz, dmso-d6): 0.99 (3H, d, J= 6.8 Hz); 1.35 (9H, s); 1.36 25 1.40 (2H, m); 1.43-1.48 (2H, m); 1.50-1.58 (4H, m); 2.15-2.30 (2H, m); 3.30 3.46 (5H, m); 6.63 (lH, d, J= 8.8 Hz). c) 4-Amino-1-piperidin-1-yl-pentan-]-one (1-Methyl-4-oxo-4-piperidin-1-yl-butyl)-carbamic acid tert-butyl ester WO 2007/098826 PCT/EP2007/000382 37 (3.50 g; 12.3 mmol) was dissolved in CH 2 C1 2 (40 mL) at 0*C and HCl 37% solution (6 mL) were slowly added. After 15 minutes the ice bath was removed and the mixture stirred at RT for 4 hrs. NaOH 2N solution was slowly added to reach pH>8 and the organic layer collected, dried and the 5 solvent evaporated. 2.0 g; 88% CioH 20
N
2 0 calculated 184; found 185 Lc Rt (5 min)= 0.35, 100% NMR (400 MHz, dmso-d6): 0.95 (3H, d, J= 6.4 Hz); 1.32-1.57 (8H, in); 10 2.20-2.36 (2H, in); 2.68-2.76 (1H, in); 3.21 (4H, br in). d) 1-Methyl-4-piperidin-1-yl-butylamine 4-Amino-1-piperidin-1-yl-pentan-1-one (2.0 g, 10.9 mmol) was dissolved in THF (50 mL) at 0*C and a solution of lithium aluminum hydride 1.0 M in THF (22 mL, 22 mmol) was slowly added. The mixture was stirred at 15 0*C for 30 min, then 4 hrs at RT. Water (0.8 mL) was added to the solution and the solvent evaporated. The residue was treated with ether and NaOH 15% solution. The organic layer was collected and dried. Evaporation of the solvent gave a product clean enough to be used without further purification. 1,21 g; 65% 20 CIoH 2 2
N
2 calculated 170; found 171 Lc Rt (5 min)= 0.35, 100% NMR (400 MHz, dmso-d6): 0.89 (3H, d, J= 6.4 Hz); 1.10-1.17 (2H, in); 1.30-1.37 (4H, in); 1.39-1.45 (6H, in); 2.10-2.14 (2H, in); 2.23 (4H, br in); 2.65-2.69 (1H, in). 25 2,2-Difluoro-4-piperidin-1-yl-butylamine a) 3,3-Difluoro-succinamic acid To a solution of 2,2-Difluoro-succinic acid (2.0 g, 13 mmol) in 20 mL of iPrOAc, Trifluoroacetic anhydride (2.2 mL, 15.6 mmol) was added in one WO 2007/098826 PCT/EP2007/000382 38 portion. The solution was stirred under N 2 atmosphere at 50*C for 1 hour. The formation of the 2,2-Difluoro-succinic anhydride was confirmed by LCMS after quenching of a little part with methanol [C 5
H
6
F
2 0 4 calculated 168; found 5 M- 167; Lc Rt (5 min)= 1.05]. The solution was then cooled at room temperature and added dropwise to NH 3 in methanol (7N, 15 mL, 105 mmol) under N 2 atmosphere maintaining the temperature below 20'C. The solvent was then evaporated and the residue dissolved in a small 10 amount of water basified with Na 2
CO
3 (pH 8-9). The aqueous phase was washed with EtOAc, acidified with HCl 6N to pH 1 and the product extracted several time with Et 2 O and CHCl 3 . The organic layers were collected and dried. Evaporation of the solvent gave 0.877 g of crude product used without further purification. 15 Yield: 45%
C
4
H
5
F
2
NO
3 calculated 153; found M- 152 Lc Rt (5 min)= 0.32 NMR (400 MHz, dmso-d6): 3.16 (2H, t, J = 15.4); 7.86 (1H, s); 8.09 (1H, s); 12.90 (1H, s). 20 b) 2,2-Difluoro-4-oxo-4-piperidin-1-yl-butyramide 3,3-Difluoro-succinamic acid (0.18 g, 1.2 mmol) was dissolved in 10 mL of acetonitrile and the mixture was cooled at 0 0 C under N 2 atmosphere. N,N-dicyclohexylcarbodiimide (0.266 g, 1.3 mmol) was added and the mixture was stirred again at 0*C for further 10 minutes. 25 1-Hydroxybenzotriazole hydrate (0.308 g, ca. 2 mmol) was then added and the ice bath removed. After 20 minutes at RT Piperidine (0.115 mL, 1.2 mmol) was added and the reaction was stirred at RT overnight.
WO 2007/098826 PCT/EP2007/000382 39 The solvent was evaporated and the residue dissolved in Dichloromethane. The organic phase was washed with HCl 0.16 N and then with water. The organic solvent was then evaporated and the residue purified by 5 SiO 2 column (eluant: EtOAc:DCM 9:1). 0.113 g of pure product were obtained. Yield: 43%
C
9
HI
4
F
2
N
2 0 2 calculated 220; found M+ 221 Lc Rt (5 min)= 1.16 10 NMR (400 MHz, dmso-d6): 1.35-1.57 (6H, in); 3.25-3.36 (6H, in); 7.71 (1H, s); 7.92 (lH, s). c) 2,2-Difluoro-4-piperidin-1-yl-butylamine To solution of 2,2-Difluoro-4-oxo-4-piperidin- 1 -yl-butyramide (0.323 g, 1.5 mmol) in 10 mL of dry THF was slowly added lithium aluminum 15 hydride solution 1.0 M in THF (5.88 mL, 5.9 mmol) under Nitrogen atmosphere at 0*C. The mixture was stirred for 3 days at RT. The excess of hydride was then quenched with water and the solvent removed. The residue was then diluted with methanol and filtered on Celite* The solution was purified by SCX column and the obtained oil was used without further 20 purification. 0.169 g of product were obtained. Yield: 59%
C
9
HI
8
F
2
N
2 calculated 192; found M+ 193 Lc Rt (5 min)= 0.19 25 19F-HNMR (400 MHz, dmso-d6): -106.16 (quint.) 2,2-Dimethyl-4-piperidin-1-yl-butylamine a) 2,2-Dimethyl-4-oxo-4-piperidin-1-yl-butyric acid To solution of 2,2-dimethylsuccinic anhydride (1.0 g, 7.8 mmol) and WO 2007/098826 PCT/EP2007/000382 40 triethylamine (0.79 g, 078 mmol) in CH 2 Cl 2 (40 mL) was slowly added a solution of piperidine (0.66 g, 7.8 mmol) in CH 2 Cl 2 (10 mL) at RT. The mixture was stirred for 4 hrs. NaOH 1.OM solution was added and the aqueous layer collected and subsequently acidified to pH 4 using HCl 2.0 M solution. 5 Extraction with CHCl 3 and evaporation of the solvent gave a crude product clean enough to be used without further purification. 1.63 g; 98%
C
11
H
19
NO
3 calculated 213; found M+ 214/M- 212 Lc Rt (5 min)= 1.56 10 NMR (400 MHz, dmso-d6): 1.10 (6H, s); 1.32-1.37 (2H, in); 1.40-1.44 (2H, in); 1.50-1.55 (2H, in); 2.50 (2H, s); 3.31-3.35 (4H, in); 11.7 (1H, br s). b) 2,2-Dimethyl-4-oxo-4-piperidin-1-yl-butyramide To a solution of 2,2-dimethyl-4-oxo-4-piperidin-1-yl-butyric acid (2.0 g, 9.4 mmol) in CH 2 Cl 2 (40 mL) was slowly added oxalyl chloride 15 (2.98 g, 23.5 mmol) under nitrogen atmosphere at RT. The mixture was stirred for 3 hrs. After evaporation of the solvent and the excess of oxalyl chloride, the obtained crude product was dissolved in CH 2 Cl 2 (20 mL) and added to a solution of ammonia 0.5 M in dioxane (200 mL). After addition of NaHCO 3 sat. solution, the organic layer was extracted twice, collected and 20 dried. Evaporation of the solvent gave a crude product purified by flash chromatography (CH 2 Cl 2
/CH
3 0H=96/4). 0.93 g; 46%
C
11
H
2 0
N
2 0 2 calculated 212; found M+ 213 Lc Rt (5 min)= 1.32 25 NMR (400 MHz, CD 3 0D): 1.27 (6H, s); 1.48-1.54 (2H, m); 1.56-1.61 (2H, in); 1.63-1.69 (2H, m); 2.64 (2H, s); 3.45-3.49 (4H, m). c) 2,2-Dimethyl-4-piperidin-1-yl-butylamine To solution of 2,2-dimethyl-4-oxo-4-piperidin-1-yl-butyramide (2.0 g, WO 2007/098826 PCT/EP2007/000382 41 9.43 mmol) in THF was slowly added lithium aluminum hydride solution 1.0 M in THF (28.3 mL) at 0*C under nitrogen atmosphere. The mixture was stirred for 6 hrs. Water (1.0 mL) was added to the solution and the solvent evaporated. The residue was treated with ether and NaOH 1.0 M solution, the 5 organic layers collected and dried. Evaporation of the solvent gave 1.4 g of crude product used without further purification. 1.40 g; 80%
C
11
H
24
N
2 calculated 185; found M+ 186 Lc Rt (10 min)= 0.21 10 NMR (400 MHz, dmso-d6): 0.75 (6H, s); 1.26-1.29 (2H, in); 1.32-1.36 (2H, in); 1.41-1.47 (4H, in); 2.13-2.17 (2H, in); 2.25 (4H, br in); 2.26 (2H, br s). 4-Piperidin-1-yl-pentylamine a) 2-(4-Bromo-pentyl)-isoindole-1,3-dione 15 1,4-Dibromo-pentane (2.9 g, 15,7 mmol) was added to a solution of potassium phthalimide in 2-butanone at RT and the mixture stirred at RT 24 hrs, then 10 hrs at 50*C. After cooling the solvent was evaporated and the crude purified by flash chromatography (cyclohexane/ethyl acetate). 4.0 g; 86% 20 NMR (400 MHz, Acetone): 1.68 (3H, d, J= 6.8 Hz); 1.80-1.93 (4H, in); 3.69 (2H, m); 4.26-4.34 (1H, tq, J= 6.8 Hz, 4.8 Hz); 7.85 (4H, br in). b) 2-(4-Piperidin-1-yl-pentyl)-isoindole-1,3-dione A mixture of 2-(4-bromo-pentyl)-isoindole-1,3-dione (0.3 g, 1 mmol), piperidine (0.1 mL, 1 mmol) and potassium carbonate (0.14 g, 1 mmol) in 25 DMF (3 mL) were mixed in a pressure tube at 80*C for 6 hrs. After filtration the solvent was evaporated and the obtained residue purified by flash chromatography (hexane/ethyl acetate). 0.19 g; 62% WO 2007/098826 PCT/EP2007/000382 42 NMR (400 MHz, dmso-d6): 0.82 (3H, d, J= 6.4 Hz); 1.30-1.45 (8H, in); 1.53-1.62 (2H, in); 2.20-2.25 (2H, in); 2.35-2.40 (2H, in); 2.52-2.55 (lH, m); 3.54 (2H, in); 7.80-7.86 (4H, br m). c) 4-Piperidin-1-yl-pentylamine 5 2-(4-Piperidin-1-yl-pentyl)-isoindole-1,3-dione (0.19 g, 0.63 mmol) was dissolved in ethanol. After addition of hydrazine hydrate (0.06 g, 1.27 mmol) the mixture was stirred at reflux for 6 hrs and then left at RT overnight. After filtration of the solid, the organic solution was concentrated in vacuum and the obtained crude product purified by scx-column. 10 0.05 g; 46% NMR (400 MHz, dmso-d6): 0.84 (3H, d, J= 6.4 Hz); 1.28-1.46 (10H, in); 2.25-2.30 (2H, in); 2.37-2.51 (5H, in). General 3-amino-5-aryl/heteroaryl pyrazole synthesis The 3-amino-5-aryl/heteroaryl pirazoles used in the Examples were 15 eithere commercially available os synthesised using the routes shown in the Scheme below: Ar O Al or Albis Ar A0 Ar 1 CNH Ar NH 2 o Cl A B1 B2 CN General procedure for aryl/heteroaryl fi-ketonitrile synthesis (A 1): 20 0 CH 3 CN 0 Ar O NaH, toluene Ar H oCN To a solution of an aryl or heteroaryl methyl carboxylate (6.5 mmol) in dry toluene (6 mL) under N 2 , NaH (50-60% dispersion in mineral oil, 624 mg, 13 mmol) was carefully added. The mixture was heated at 804C and then dry 25 CH 3 CN was added dropwise(1.6 mL, 30.8 mmol). The reaction was heated for WO 2007/098826 PCT/EP2007/000382 43 18 hours and generally the product precipitated from the reaction mixture as Na salt. The reaction was then allowed to cool down to room temperature and the solid formed was filtered and then dissolved in water. The solution was 5 then acidified with 2N HCL solution and at pH between 2-6 (depending on the ring substitution on the aryl/heteroaryl system) the product precipitated and was filtered off. If no precipitation occurred, the product was extracted with DCM. After work-up, the products were generally used in the following step 10 without further purification. The general yield was between 40 and 80%. General procedure for aryl/heteroaryl 8-ketonitrile synthesis (route Albis): 0 0 CHaCN or RCHCN H, R A Ar A Ar BuLi, toluene CN 15 To a solution of dry alkanenitrile in toluene (1 mmol/mL, 5 eq.) cooled down to -78'C under nitrogen, a solution of n-butyllithium in n-hexane (1.6 N, 3.5 eq) was added dropwise. The mixture was left stirring at -78'C for 20 minutes and then a solution of the aryl or heteroaryl methyl carboxylate in toluene (0.75 mmol/mL, 1 eq.) was added and the reaction allowed to reach room 20 temperature. Upon reaction completion, after about 20 minutes, the mixture was cooled down to 0*C and HC1 2N was added to pH 2. The organic phase was recovered, dried over Na 2
SO
4 and concentrated under reduced pressure, affording the title product which was generally used without further purification. General procedure for aryl aminopyrazole synthesis (route A2): 25 0 H Ar T H, R -
NH
2 CN
H,R
WO 2007/098826 PCT/EP2007/000382 44 To a solution of the p-ketonitrile (7.5 mmoL), in absolute EtOH (15 mL) hydrazine monohydrate (0.44 mL, 9.0 mmol) was added and the reaction was heated at reflux for 18 hrs. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced 5 pressure. The residue was dissolved in DCM and washed with water. The organic phase was concentrated under reduced pressure to give a crude product that was purified by SiO 2 column or by precipitation from Et 2 0. Yields were generally between 65 and 90%. 5-(JH-Indol-5-yl)-2H-pyrazol-3-ylamine 10 a) J-Triisopropylsilanyl-JH-indole-5-carboxylic acid methyl ester To a solution of Ig of methyl indole-5-carboxylate (5.7 mmol) in 10 mL of dry DMF 273 mg of NaH (mineral oil dispersion 50-60%, 5.7 mmol) were added and the mixture cooled to 0*C. Triisopropylchlorosilane (1.06 g, 5.7mmol) were added drop wise and after 1 hour LC-MS showed complete 15 conversion of the starting material to the title product. The mixture was diluted with 30 mL of DCM and washed with saturated Na2CO3. The organic phase was dried over Na 2
SO
4 and concentrated under reduced pressure. The crude was purified with SiO 2 column eluting with n-hexane. The title compound was obtained (500 mg, yield 26%). 20 C 19
H
29
NO
2 Si Mass (calculated) [331]; (found) [M+H+]=332 LC Rt=3.39, 100% (5 min method) 1 H-NMR: (dmso-d 6 ): 1.06 (d, 18H, J=7.52), 1.75 (quin, 3H, J=7.52), 6.75 (in, 1H), 7.48 (m, 1H), 7.60 (in, 1H), 7.72 (in, 1H), 8.25 (s, 1H). 25 b) 3-Oxo-3-(1-triisopropylsilanyl-JH-indol-5-yl)-propionitrile To a solution of 393 pL of anhydrous CH 3 CN (7.5 mmol) in 6 mL of dry toluene cooled down to -78'C, 5.35 mLof butyllithium in hexane solution (1.6 N) were added dropwise. The mixture was left stirring at -78*C for WO 2007/098826 PCT/EP2007/000382 45 20 minutes and then a solution of 500 mg of 1-triisopropylsilanyl-1H-indole 5-carboxylic acid methyl ester (1.5 mmol) in 2 mL of dry toluene were added and the reaction allowed to reach room temperature. Upon reaction completion after about 20 minutes the mixture was cooled down to 0 0 C and HC1 2N was 5 added to pH 2. The organic phase was separated, dried over Na 2
SO
4 and concentrated under reduced pressure, affording 490 mg of title product which was used in the next step without further purification (yield = 96%).
C
20
H
28
N
2 OSi Mass (calculated) [340]; (found) [M+H*]=341 [M-H*]=339 10 LC Rt=3.10, 89% (5 min method) 'H-NMR: (dmso-d 6 ): 1.06 (18H,d, J=7.52), 1.76 (3H,quin, J=7.52), 4.76 (1H, d), 7.78-7.81 (1H, in), 7.48-7.52 (1H, in), 7.60-7.73 (2H, m), 8.25 (s, 1H). c) 5-(]H-Indol-5-yl)-2H-pyrazol-3-ylamine To a solution of 3-Oxo-3-(1-triisopropylsilanyl-1H-indol-5-yl) 15 propionitrile (490 mg, 1.44 mmol) in 15 mL of absolute EtOH, 720 pL of hydrazine monohydrate (14.4 mmol) were added and the reaction refluxed for 18 hours. LC-MS showed complete conversion to the aminopyrazole and also silyl deprotection. The mixture was concentrated under reduced pressure, and purified with SiO2 column (eluent gradient from 100% DCM to DCM:MeOH 20 9:1) to afford the title compounds (120mg, yield: 41%). C IHioN4 Mass (calculated) [198]; (found) [M+H*]=199 LC Rt=0.84, 100% (3 min method) 5-Pyridin-3-yl-2H-pyrazol-3-ylamine 25 a) 3-Oxo-3-pyridin-3-yl-propionitrile The product was prepared according to the general procedure for aminopyrazole synthesis (route Al). 'H-NMR (400 MHz, MeOH-d 4 ): 9.07 (1H, d), 8.81 (2H, dd), 8.26 (1H, WO 2007/098826 PCT/EP2007/000382 46 dt), 7.59 (1H, dd), 4.79 (2H, s). b) 5-Pyridin-3-yl-2H-pyrazol-3-ylamine The product was prepared according to general procedure for aminopyrazole synthesis (route A2). 5 The crude product was purified with SiO2 column (5 g) with gradient elution from 100% DCM to DCM-NH3 (2N MeOH solution) 95:5. The title product (371 mg, 68% yield) was obtained. 'H-NMR (400 MHz, MeOH-d 4 ): 8.82 (1H, d), 8.41 (1H, dd), 7.98 (lH, dt), 7.37 (lH, dd), 5.82 (2H, s) 10 3-Imidazo[1,2-a]pyridin-6-yl-3-oxo-propionitrile The product was obtained starting from imidazo[1,2-a]pyridine-6 carboxylic acid methyl ester according to general procedure Al Yield 39% C1OH7N30 Mass (calculated) [185]; (found) [M+H+]=186 [M-H]=184 15 LC Rt=0.23, 100% (3 min method) 1H-NMR: (dmso-d6): 4.72 (2H,s), 7.61-7.65 (2H, in), 7.70 (1H, in), 8.07 (1H, s), 9.40 (s, 1H). 5-Imidazo[1,2-a]pyridin-6-yl-1H-pyrazol-3-ylamine The title compound was synthesized according to general procedure A2 20 starting 3-imidazo[1,2-a]pyridin-6-yl-3-oxo-propionitrile Yield: 84% C1OH9N5 Mass (calculated) [199]; (found) [M+1]= 200 LCMS, (5min method, RT=0.21 min, NMR (1H, 400MHz, MeOH-d 4 ) 3,34 (s, 2H), 5,90 (br s, 1H), 7,57 25 (s, lH), 7,63 (br s, 1H), 7,86 (s, 1H), 8,73 (s, 1H). 5-(3-Fluoro-phenyl)-1H-pyrazol-3-yl-amine a) 3-(3-Fluoro-phenyl)-3-oxo-proprionitrile The product was prepared according to a modification of general route WO 2007/098826 PCT/EP2007/000382 47 Al. To a solution of methyl-3-fluorobenzoate (3 g, 18 mmol) in dry toluene (25 mL) under N 2 , NaH (50-60% dispersion in mineral oil, 1.44 g, 36 mmol) was carefully added. The mixture was heated at 90*C and then dry CH 3 CN was added 5 dropwise (4.45 mL, 85.2 mmol). The reaction was heated for 18 hours and the product precipitated from the reaction mixture as its sodium salt. The reaction was allowed to cool down to room temperature and the solid formed was filtered, then redissolved in water, and the solution was acidified with 2N HCl to pH 5-6, upon which precipitation was observed. Filtration of the solid from 10 the aqueous solution afforded 2.12 g of the title compound (72% yield) which was used directly in the following step. b) 5-(3-Fluoro-phenyl)-]H-pyrazol-3-yl-amine The product was prepared according to a slight modification of route A2. To a solution of 3-(3-fluoro-phenyl)-3-oxo-propionitrile (1.92 g, 15 11.77 mmoL) in absolute EtOH (32 mL) hydrazine monohydrate (0.685 mL, 14.12 mmol) was added and the reaction was heated at reflux for 2 hrs. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The crude was treated with ether and filtered to give 1.71 g of title compound were recovered (82% yield). 20 C 9
H
8
FN
3 Mass (calculated) [177]; (found) [M+H*] =190 LC Rt = 1.13, 69% (5 min method) 5-Pyridin-4-yl-1H-pyrazol-3-ylamine 3-Oxo-3-pyridin-4-yl-propionitrile 25 The product was prepared according to a modification of route Al. To a solution of 3 g (22 mmol) of isonicotinic acid methyl ester in dry toluene (30 mL) under N 2 , NaH (50-60% dispersion in mineral oil, 1.75 g, 44 mmol) was carefully added.
WO 2007/098826 PCT/EP2007/000382 48 The mixture was heated at 90'C and then dry CH 3 CN was added dropwise (5.39 mL, 103 mmol). The reaction was heated for 18 hours and the product precipitated from the reaction mixture as the sodium salt. The reaction was allowed to cool down to room temperature and the solid formed was 5 filtered, then it was dissolved in water and the solution was acidified with 6N HCl solution to pH 5-6 and the product extracted with DCM. The pH of the aqueous phase was adjusted again to 4-5 and another extraction with DCM afforded more product. The organic phases were combined, dried and evaporated. The product 10 was used directly in the following step. Yield of crude product: 58%. b) 5-Pyridin-4-yl-]H-pyrazol-3-ylamine The product was prepared according to a modification of route A2. To a solution of 3-oxo-3-pyridin-4-yl-propionitrile (1.86 g, 12.74 mmoL) in absolute EtOH (35 mL) hydrazine monohydrate (0.74 mL, 15.29 mmol) was 15 added and the reaction was heated at reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The crude product obtained was washed with ether to afford the title compound (yield: 39%).
C
8
H
8
N
4 20 Mass (calculated) [160]; (found) [M+H*] =161 LC Rt = 0.23, 100% (5 min method) 'H-NMR (400 MHz, dmso-d6): 5.02 (2H, s); 5.85 (lH, s); 7.59 (2H, d, J=6 Hz); 8.50 (2H, d, J=6 Hz); 11.93 (lH, s). Chlorocynnamonitrile synthesis (route B]) 25 0 C1 ArAk Ar CN POCl 3 (2 eq with respect to the aryl/heteroaryl acetophenone) were added dropwise to 4 molar equivalents of anhydrous DMF cooled down to 0*C, at such WO 2007/098826 PCT/EP2007/000382 49 a rate that the temperature did not exceed 10*C. The acetophenone (1 eq) was then added dropwise and the reaction was allowed to reach room temperature. The reaction was then stirred for further 30' and then 0.4 mmol of hydroxylamine hydrochloride were added. The reaction was then heated up to 5 50*C, after which heating was removed and additional 4 eq. of hydroxylamine hydrochloride were added portionwise (at such a rate that the temperature never exceeded 120*C). The reaction was then stirred until the temperature of the mixture spontaneously decreased to 25'C. Water (100 mL) were then added and the mixture was extracted with diethyl ether. The organic phase was 10 dried over Na 2
SO
4 and concentrated under reduced pressure. The crude product was used for the next step without further purification. Aryl aminopyrazole synthesis (route B2) CI Ar k NH2 CN Ar 15 To a solution of the chlorocynnamonitrile (0.5 mmol/mL, 1 eq) in absolute EtOH 2 eq of hydrazine monohydrate were added and the reaction was heated at reflux for 4 hrs. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated with Et 2 0, allowing to recover the title compound which 20 was generally used without further purification. 5-(3-Bromo-phenyl)-2H-pyrazol-3-ylamine a) 3-(3-Bromo-phenyl)-3-chloro-acrylonitrile To 30.9 mL of dry DMF (400 mmol) cooled down to 0 0 C 18.3 mL of POC1 3 (200 mmol) were added dropwise so that the temperature was always 25 under 10*C. To the mixture 19.9 g (100 mmol) of 1-(3-bromophenyl)ethanone were added dropwise and the reaction was allowed to reach room temperature. When the addition was complete the reaction was stirred for further 30 minutes and then 2.7 g (40 mmol) of hydroxylamine hydrochloride were WO 2007/098826 PCT/EP2007/000382 50 added and the reaction heated up to 50*C. The heating was then removed and other 27 g (400 mmol) of hydroxylamine hydrochloride were added portionwise (so that the temperature did never exceed 120*C). After the last addition the reaction was left stirring until the temperature 5 of the mixture spontaneously decreased to 25*C. Water (100 mL) was then added and the mixture was extracted with diethyl ether. The organic phase was dried over Na 2
SO
4 andconcentrated under reduced pressure. The crude product was used for the next step without further purification. 10 C 9
H
5 BrClN 1 H-NMR (400 MHz, dmso-d 6 ): 7.03 (s, 1H), 7.44-7.54 m, 1H), 7.72-7.84 (in, 2H), 8.00 (br s, 1H). Yield 68% b) 5-(3-Bromo-phenyl)-2H-pyrazol-3-ylamine 15 To a solution of 3-(3-bromo-phenyl)-3-chloro-acrylonitrile (10 mmoL), in absolute EtOH (20 mL) hydrazine monohydrate (1 mL, 20 mmol) was added and the reaction was heated at reflux for 4 hrs. The reaction mixture was then allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was triturated with Et 2 0, allowing to 20 recover 1.8 g of the title compound as pure product (yield 54%).
C
9
H
8 BrN 3 'H-NMR(400 MHz, dmso-d 6 ): 4.58, 5.03 (1H, 2 tautomeric peaks),5.64, 5.84 (1H, 2 tautomeric peaks), 7.28 (1H, s), 7.35 (lH, s), 7.53-7.65 (1H, in), 7.77 (1H, s), 11.56, 11.97 (1H, 2 tautomeric peaks). 25 WO 2007/098826 PCT/EP2007/000382 51 General method for the synthesis of co-bromo-alkanoic acid (JH-pyrazol-3-yl-5-aryl) -am ides H2N R N-N H 0 Br DIPEA Br 0 Wj nDMA, -10 C N R~ 2hrs H n=1,2,3 5 A solution of o-bromoalkanoyl chloride (15.7 mmol, 1 eq) in dry DMA (35 mL) was cooled to -10 0 C (ice/water bath) under N 2 ; a solution of 5-aryl/heteroaryl-1H-pyrazol-3-ylamine (15.7 mmol, 1 eq) and diisopropylethylamine (15.7 mmol, 1 eq) in dry DMA (15 mL) is added over 30'. After 2 hrs at -10 0 C, completion of the reaction as monitored by LC-MS 10 was generally observed (acylation on the pyrazole ring is also detected). The reaction is then quenched by addition of H 2 0 (ca. 50 mL); the thick white precipitate formed upon addition of water was recovered by filtration. Washing with Et 2 0 (3 X 10 mL) usually efficiently removed the byproduct of acylation on the pyrazole ring. 15 General method for the synthesis of co-amino-alkanoic acid (JH-pyrazol-3-yl-5-aryl)-am ides R1 PH R2 R1 Br 0 R2R\N0 BNR DIPEA, Nal N R N- DMF. +50 CN n=1,2,3 18 hrs N-N o-Bromo-alkanoic acid [5-aryl-1H-pyrazol-3-yl]-amide (0.6 mmol, 20 1 eq) is dissolved in DMF (4 mL), sodium iodide (0.6 mmol, 1.0 eq) is added followed by the secondary amine (1.5 mmol, 2.5 eq) and diisopropylethylamine (0.6 mmol, 1 eq). The reaction is then stirred under N 2 at + 50'C for 18 hrs. Upon reaction completion (as monitored by LC-MS), the solvent is removed 25 at reduced pressure and the resulting oily residue is dissolved in DCM (20 mL), WO 2007/098826 PCT/EP2007/000382 52 washed with sat. Na 2
CO
3 (2 X 20 mL) and sat. NaCl (2 X 20 mL); the organic layer is dried over Na 2
SO
4 and the solvent removed under reduced pressure. The title compounds were purified either by silica column or preparative HPLC. General synthetic method for the one-pot synthesis of co-amino-alkanoic 5 acid (JH-pyrazol-3-yl-5-aryl)-am ides: acylation-nucleophilic substitution 0N R CA Br DIPEA Br N R2NR R2 N R DMA, -10 C N 60-C or rt N-N 2 hrs N-N n=1,2,3 To a solution of co -bromoalkanoyl chloride (0.94 mmol, leq) in DMA (1mL) cooled at 04C is added a solution of 3-amino-5-aryl/heteroarylpyrazole 10 (0.94 mmol, leq) and diisopropylethylamine (1.88 mmol, 2 eq) in DMA (2 mL) and the reaction is stirred for 1 hour at 0*C. The secondary amine (2.35 mmol, 2.5 eq) and Nal (0.94mmol, 1 eq) are then added. For 3-carbon chain derivatives the reaction was generally complete after 2 hours at room temperature. For 4-carbon chain derivatives the reaction mixture was generally 15 heated at 60'C for 24-48 hours. Upon complete conversion of the bromo intermediate (as monitored by LC-MS), the solvent was removed under reduced pressure. The residue was taken up in DCM (2 mL) and washed with Na 2
CO
3 saturated water solution. The organic phase was concentrated under reduced pressure and the crude products were either recrystallised from CH 3 CN, or 20 purified by SiO 2 column (gradient from 100%DCM to DCM-NH3MeOH 2N solution 8:2) or by preparative HPLC (standard acidic conditions). General method for the synthesis of co-amino-alkanoic acid (]H-pyrazol-3-yl-5-aryl)-am ides via the amino acid route
H
2 N R O X 0 NaOH OH N-N H Br,.()n LOEt : X () OBt X On H X ()n N HC0 CDI 0 N-N HCI H 25 n -1, 2,3 WO 2007/098826 PCT/EP2007/000382 53 To a solution of amine X (65 mmol) in toluene (15 mL) ethyl o bromoalkanoate (26 mmol) was added and the reaction mixture was refluxed for 10 hours. The mixture was allowed to cool to room temperature and any solid present was filtered off and washed with ether. The filtrate was 5 concentrated under reduced pressure to give the o-aminoester which was used in the next step without further purification. To a suspension of crude ethyl o-aminoalkanoate from the previous step (about 25 mmol) in 15 mL of water, NaOH (1.4 g, 25 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was then 10 allowed to cool down to room temperature, the solution was acidified at 0 0 C with HCl 6N and concentrated under reduced pressure. The residue was treated with EtOH and the sodium chloride which precipitated was filtered off. Evaporation of the solvent under reduced pressure afforded the co-aminoacid as a white solid. To a suspension of co-aminoacid (7.93 mmol) in 12,2 15 dichloroethane (20 mL), NN'-carbonyldiimidazole (1.2 g, 7.4 mmol) was added and the mixture was stirred at room temperature for 2 hours (when all the aminoacid was activated complete dissolution of the suspension was generally observed). The 3-amino-5 -aryl/heteroarylpyrazole (5.29 mmol) was then added and the reaction was stirred for further 10 hours. Upon reaction 20 completion (as monitored by LC-MS) if the formation of two isomers was observed, the mixture was heated at 50'C until the conversion of the less stable isomer to the title compound was observed (as monitored by LC-MS). The solvent was washed with sat. Na 2
CO
3 solution, extracted and removed under reduced pressure. The crude products were either recrystallised from 25 CH 3 CN, or purified by SiO 2 column or by preparative HPLC.
WO 2007/098826 PCT/EP2007/000382 54 Example 1 5-Azepan-1-yl-pentanoic acid (2-chloro-2',3'-difluoro-biphenyl-4-yl) amide a) 5-Azepan-1-yl-pentanoic acid (4-bromo-3-chloro-phenyl)-amide 5 Following the general procedure, 4-bromo-3-chloroaniline (72 mg, 0.35 mmol) and triethylamine (35 mg, 0.35 mmol) were dissolved in DCE (0.5 mL) and 5-bromovaleryl chloride (66 mg, 0.33 mmol) in DCE (0.5 mL) was added dropwise. After lh 30 min, azepane (118 mg, 0.105 mmol) and triethylamine (35 mg, 0.35 mmol) in DCE (0.5 mL) was added and the 10 reaction mixture heated at +55'C for 4 hours. Work-up followed by preparative HPLC afforded the title compound (23 mg, 17%) as formate. C17H24BrC1N20 Mass (calculated) [387.75]; (found) [M+H+]=389.28. LC Rt=2.34, 100% (10 min method) b) 5-Azepan-1-yl-pentanoic acid (2-chloro-2', 3 '-difluoro-biphenyl-4-yl) 15 amide Following the general procedure for cross-coupling under microwave conditions, 5-azepan-1-yl-pentanoic acid (4-bromo-3-chloro-phenyl)-amide (70 mg, 0.18 mmol) and 2,3-difluorophenyl boronic acid (31 mg, 0.2 mmol) were dissolved in acetonitrile/0.4 M Na 2
CO
3 1/1 (1.5 mL each) and 20 Pd[P(Ph) 3
]
4 (11 mg, 0.01 mmol) was added. After irradiating for 20 minutes, preparative HPLC purification afforded the title compound (23 mg, 27%) as the corresponding formate, as a white solid. C23H27ClF2N20 Mass (calculated) [420.93]; (found) [M+H+]=421.38 LC Rt= 2.04, 100% (10 min method) 25 NMR (400 MHz, CDCl 3 ): 1.63 (4H, s); 1.80 (8H, in); 2.43 (2H, in); 2.94 (2H, m); 3.1 (4H, bs); 6.96 (lH, in); 7.05-7.02 (2H, in); 7.11 (lH, d, J=8); 7.16 (lH, d, J=8.4); 7.53 (1H, d, J=8.4); 7.9 (1H, s); 8.56(lH, s, HCOOH); 9.68 (1H, s, NH).
WO 2007/098826 PCT/EP2007/000382 55 Example 2 4'-(5-[Methyl-(2-pyridin-2-yl-ethyl)-amino]-pentanoylamino}-biphenyl 3-carboxylic acid amide Prepared according to the general procedure for amide synthesis 5 followed by the general procedure for cross-coupling under microwave irradiation to give 0.07 g of title compound (62%).
C
26
H
3 0
N
4 0 2 . Mass (calculated) [430.55]; (found) [M+H*]=431.42 Lc Rt=1.59, 100% NMR (400 MHz, dmso-d6): 1.37-1.45 (2H, m); 1.51-1.59 (2H, m); 2.17 10 (3H, s); 2.28-2.36 (4H, m); 2.62-2.66 (2H, m), 2.81-2.85 (2H, m); 7.14 (1H, br dd, J=7.6 Hz, 4.8 Hz); 7.24 (1H, d, J=8.0 Hz); 7.40 (1H, br s); 7.48 (1H, dd, J=8 Hz, 7.6 Hz); 7.61-7.7.0 (5H, m); 7.78 (2H, m); 8.06 (1H, s); 8.11 (1H, s); 9.96 (1H, s). Example 3 15 1-(2, 2'-Dimethoxy-biphenyl-4-yl)-3-(4-piperidin-1-yl-butyl)-urea 1-(4-Bromo-3-methoxy-phenyl)-3-(4-piperidin-1-yl-butyl)-urea (prepared according to the general procedure for urea synthesis, reaction with isocyanate) was weighed into a microwave vessel (100 mg, 0.26 mmol) and dissolved in acetonitrile (1 mL). To this, 2-methoxyphenylboronic acid (47 20 mg, 0.312 mmol) was added, along with tetrakis(triphenylphosphine)palladium (20 mg, 0.017 mmol) and a solution of sodium carbonate (1 mL, 0.4 M). The reaction mix was then exposed to microwave irradiation at psi 250, at 90'C for 20 minutes. On reaction completion by LCMS, the separated organic phase was removed from the 25 reaction mix and passed through a plug of Celite*. The collected crude was loaded onto an SCX column, eluting the desired compound with a solution of ammonia in methanol (20% ammonia). Fractions containing the desired compound were combined and dried affording the titled compound (30 mg, WO 2007/098826 PCT/EP2007/000382 56 0.073 mmol, 28% yield). C24H33N303 Mass (calculated) [411.55]; (found) [M+H*] =412 LC Rt=2.03, 98% (10 min method) NMR (400 MHz, CDCl 3 ): 1.57-1.67 (11H, m); 2.42-2.50 (5H, m); 3.29 5 (2H, m); 3.77 (6H, s); 5.85 (1H, s); 6.61 (1H, s); 6.75-6.77 (1H, d); 6.95-7.00 (2H, m); 7.15 (1H, d); 7.21-7.22 (1H, m) 7.23-7.33 (2H, m) Example 4 5-Imidazol-1-yl-pentanoic acid (3'-acetylamino-biphenyl-4-yl)-amide a) 5-Bromopentanoic acid- (4-bromophenyl) -amide 10 4-Bromo-aniline (6 g, 0.035 mol) and 0.035 mol of NEt 3 (4.87 mL) were dissolved in 120 mL of dichloromethane and cooled at 0*C. To this solution, 0.038 mol of 5-bromovaleryl chloride (5.4 mL) were slowly added and the resulting mixture was stirred for 1 h at 0*C. When all the starting material was consumed (monitoring by LCMS) the 15 solution was washed with 50 mL of Na 2
CO
3 0.4 M and the organic layer was recovered by extraction and drying over Na 2
SO
4 . The solvent was removed under reduced pressure giving 10 g of the title compound as a white solid (yield 86%). C 1H13Br2NO Mass (calculated) [335]; (found) [M+H*]=335 20 Lc Rt = 2.64, 100% (5 min method) NMR (400 MHz, CDCl3) 1.70-2.00 (4H, m), 2.35-2.45 (2H, m), 3.38-3.48 (2H, m), 7.30-7.50 (4H, m). b) 5-Imidazolyl acid- (4-bromophenyl) -am ide 400 mg (1.19 mmol) of 5-bromopentanoic acid-(4-bromophenyl)-amide 25 and 800 mg of imidazole (11.7 mmol) were suspended in 2 mL of a mixture of Toluene: EtOH 1:1. The reaction mixture was heated at 160'C for 10 minutes under microwave conditions. The solvent was removed under reduced pressure and the crude mixture dissolved in DCM (10 mL) and washed twice with 1M WO 2007/098826 PCT/EP2007/000382 57 NaOH. The solution was dried over Na 2
SO
4 , filtered and the solvent removed to give the desired product as a white powder (240 mg yield 62%). NMR (400 MHz, dmso-d6): 7.65 (1H, s), 7.56-7.52 (2H, in), 7.46-7.42 (2H, in), 7.42 (1H, in), 6.87 (1H, in), 3.95 (2H, t, J = 12 Hz), 2.30 (2H, t, J = 5 7.2 Hz), 1.75-1.68 (2H, m), 1.55-1.45 (2H, in). c) 5-Imidazol-1-yl-pentanoic acid (3'-acetylamino-biphenyl-4-yl)-amide A mixture of 1 mL of 0.4 M solution of Na 2
CO
3 and 1 mL of DMF was added to a microwave tube containing 5-imidazolyl acid-(4-bromophenyl) amide (100 mg, 0.31 mmol), 3-acetoamidophenyl boronic acid (83.4 mg, 0.46 10 mmol) and [Pd(PPh 3
)
4 ] (16 mg, 0.03 mmol). The reaction mixture was heated at 90'C for 20 minutes under microwave conditions. The mixture was diluted with MeOH and the solution passed through a plug of Celite*. The solvent was removed under reduced pressure and the crude mixture dissolved in DCM and washed with IM NaOH. The organic phase was dried over MgSO4, 15 filtered and the solvent removed under reduced pressure. Purification by SCX and after by crystallization from EtOAC/Et 2 O gave 43 ing of pure product (yield 37%). C22H24N402 Mass (calculated) [376]; (found) [M+H*]= 377 Lc Rt 2.11 (10 min) 20 Purity 98% NMR (400 MHz, dmso-d6): 10.03 (lH, s), 8.85 (1H, d, J = 2.0 Hz), 8.50 (1H, dd, J= 4.8 Hz, 1.6 Hz), 8.03 (1H, in), 7.67 (4H, in), 7.63 (1H, s), 7.44 (1H, m), 6.87 (lH, in), 3.98 (2H, t, J = 7.2 Hz), 2.34 (2H, t, J= 7.2 Hz), 1.74 (2H, m), 1.53 (2H, in). 25 Example 5 1-(2,2'-Difluoro-biphenyl-4-yl)-3-(4-piperidin-1-yl-butyl)-urea a) 1-(4-Bromo-3-fluoro-phenyl)-3-(4-piperidin-1-yl-butyl)-urea Prepared via the general procedure for urea synthesis (triphosgene WO 2007/098826 PCT/EP2007/000382 58 activation of aniline). Yield: 71% C16H23BrFN30 Mass (calculated) 372; (found) [M+H*]= 372-374 Lc Rt= 2.26 (100%), 10' 5 NMR (400 MHz, dmso-d6): 128-1.56 (10H, in), 2.16-2.38 (6H, in), 3.00 3.15 (2H, m), 6.30 (1H, t), 6.99 (1H, dd), 7.46 (1H, t), 7.59 (1H, dd), 8.81 (1H, s). b) 1-(2,2'-Difluoro-biphenyl-4-yl)-3-(4-piperidin-1-yl-butyl)-urea To a degassed solution of 1-(4-bromo-3-fluoro-phenyl)-3-(4-piperidin 10 1-yl-butyl)-urea (100 mg, 0.26 mmol) in DME/H 2 0 (1.8 mL/0.3 mL) 2-fluorophenyl boronic acid (55 mg, 0.39 mmol), Na 2
CO
3 (55 mg, 0.52 mmol), Pd(OAc) 2 (6 mg, 10% mol) and tri-o-tolylphosphine (34 mg, 20% mol), were added. The solution was irradiated under microwave conditions for 20 minutes with power 200W. 15 The organic phase was diluted with 1 mL of AcOEt and separated The crude was purified with prep-HPLC (36 mg, 40% yield). Molecular formula: C22H27F2N30 Mass (calculated) [387]; (found) [M+H*]=388 Lc Rt (10 min method)= 399, 97% 20 'H-NMR (400MHz, d 6 -DMSO): 1.27-1.54 (10H, in), 2.25-2.44 (6H, in), 2.94-3.13 (2H, m), 6.33-6.45 (1H, m), 7.09-7.14 (1H, in), 7.21-7.30 (3H, in), 7.34-7.45 (2H, in), 7.48-7.55 (1H, in), 8.16 (1H, s), 8.85 (1H, s). Example 6 3'-Fluoro-4'-[3-(4-piperidin-1-yl-butyl)-ureido]-biphenyl-3-carboxylic 25 acid amide) a) 1-(2-Fluoro-4-bromo-phenyl)-3-(4-piperidin-1-yl-butyl)-urea Prepared via the general procedure for urea synthesis (isocyanate) Yield:88% WO 2007/098826 PCT/EP2007/000382 59 NMR (400 MHz, dmso-d6): 1.22-1.50 (10H, in), 2.12-2.37 (6H, in), 3.00-3.13(2H, in), 6.62 (1H, t), 7.25 (1H, d), 7.47 (lH, dd), 8.10 (1H, t), 8.33 (IH, s) b) 3'-Fluoro-4'-[3-(4-piperidin-1-yl-butyl)-ureido]-biphenyl-3 5 carboxylic acid amide To a degassed solution of 1-(2-fluoro-4-bromo-phenyl)-3-(3-piperidin 1-yl-propyl)-urea (100 mg, 0.27 mmol), the 3-benzamide-phenylboronic acid (66 mg,0.44 mmol) and Na 2
CO
3 (3 eq) in 20 volumes (weight/vol) of acetonitrile/water (1/1), Pd[(PPh 3
)]
4 (10% mol) were added. 10 The solution was irradiated in a microwave oven using the following parameters: power: 200 watt; ramp time: 1 min; hold time: 20:00 min; temperature: 90*C; pressure: 200 psi. The acetonitrile phase was separated, the solvent was removed under 15 reduced pressure and the crude material purified using SCX column (eluting with a gradient of DCM/MeOH, MeOH, NH 3 /MeOH). The fractions containing the desired product were combined and dried under reduced pressure, and then further purified by preparative HPLC (yield 15%). Molecular formula: C22H27F2N30 20 Mass (calculated) [387]; (found) [M+H*]=388 Lc Rt (10 min method)= 399, 97% 'H-NMR (400MHz, CD30D): 1.40-1.67 (10H, in), 2.26-2.58 (6H, in), 3.21-3.27 (2H, in), 7.13-7.20 (1H, in), 7.21-7.28 (1H, in), 7.30-7.39 (1H, in), 7.40-7.51 (2H, in), 7.56 (1H, s,), 8.11-8.16 (1H, in). 25 Example 7 4'-(5-[Methyl-(2-pyridin-2-yl-ethyl)-amino]-pentanoylamino)-biphenyl 3-carboxylic acid amide Prepared according to the general method for aide coupling (one-pot, WO 2007/098826 PCT/EP2007/000382 60 excess amine followed by the general method for cross-coupling with boronic acids, microwave conditions) to give 0.07 g (yield = 62%) of title compound.
C
26
H
3 0
N
4 0 2 . Mass (calculated) [430.55]; (found) [M+H*]=431.42 Lc Rt=1.59, 100% 5 NMR (400 MHz, dmso-d6): 1.37-1.45 (2H, in); 1.51-1.59 (2H, in); 2.17 (3H, s); 2.28-2.36 (4H, in); 2.62-2.66 (2H, in), 2.81-2.85 (2H, in); 7.14 (1H, br dd, J=7.6 Hz, 4.8 Hz); 7.24 (1H, d, J=8.0 Hz); 7.40 (1H, br s); 7.48 (1H, dd, J=8 Hz, 7.6 Hz); 7.61-7.7.0 (5H, in); 7.78 (2H, in); 8.06 (1H, s); 8.11 (1H, s); 9.96 (1H, s). 10 Example 8 1-(4'-Methoxy-biphenyl-4-yl)-3-(1-methyl-4-piperidin-1-yl-butyl)-urea a) 1-(4-Bromo-phenyl)-3-(1-methyl-4-piperidin-1-yl-butyl)-urea To a solution of 1-methyl-4-piperidin-1-yl-butylamine (1.07 g, 6.3 mmol) in CH 2 Cl 2 (15 mL) at 0 0 C was slowly added a solution of 4 15 bromophenyl isocyanate (1.25 g, 6.3 mmol) in CH 2 Cl 2 (15 mL). The mixture was stirred 30 min at OC, then 3 hrs at RT. The solvent was evaporated and the residue purified by SCX column. The obtained solid was washed with ether. 1.57 g; 68%
C
17
H
26 BrN 3 0 calculated 368; found 368/370 20 Lc Rt (5 min)= 1.35, 100% NMR (400 MHz, dmso-d6): 1.02 (3H, d, J= 6.8 Hz); 1.30-1.45 (5H, in); 2.13-2.17 (5H, in); 2.13-2.17 (2H, in); 2.23 (4H, br in); 3.57-3.64 (1H, in); 5.97 (1H, J= 8 Hz); 7.29-7.34 (4H, in); 8.36 (1H, s). b) 1-(4'-Methoxy-biphenyl-4-yl)-3-(1-methyl-4-piperidin-1-yl-butyl) 25 urea To a degassed mixture of 1-(4-bromo-phenyl)-3-(1-methyl-4-piperidin 1-yl-butyl)-urea (0.3 g, 0.81 mmol) and 4-methoxyphenylboronic acid (186 mg, 1.22 mmol) in acetonitrile/sodium carbonate 0.4M solution 1/1 WO 2007/098826 PCT/EP2007/000382 61 (8 mL) a catalytic amount of Pd[(PPh 3
)]
4 (47 mg, 5 mmol %) was added. The reaction mixture was heated at 901C for 20 minutes under microwave condition. After addition of ethyl acetate (1 mL), the organic layer was separated and purified by scx columns. 5 0.27 g; 84%
C
17
H
2 6 BrN 3 0 calculated 395; found 396 Lc Rt (10 min)= 2.23, 100% NMR (400 MHz, dmso-d6): 1.05 (3H, d, J= 6.4 Hz); 1.33-1.47 (10H, in); 2.06-2.18 (2H, in); 2.26 (4H, br in); 3.61-3.67 (1H, in); 3.75 (3H, s); 5.95 10 (1H, J= 8 Hz); 6.95-6.97 (2H, in); 7.39-7.46 (4H, m); 7.50-7.52 (2H, in); 8.30 (1H, s). Example 9 1-(2,2-Dimethyl-4-piperidin-1-yl-butyl)-3-[4-(1-methyl-1H-pyrazol-4 yl)-phenyl]-urea 15 a) 1-(4-Bromo-phenyl)-3-(2,2-dimethyl-4-piperidin-1-yl-butyl)-urea To a solution of 2,2-dimethyl-4-piperidin-1-yl-butylamine (1.4 g, 7.6 mmol) in CH 2 C1 2 (20 mL) at 0*C was slowly added a solution of 4-bromophenyl isocyanate (1.5 g, 7.6 mmol) in CH 2 C1 2 (15 mL). The mixture was stirred 20 min at 0*C, then 4 hrs at RT. The solvent was evaporated and 20 the residue treated with ether and the solid separated. The solution was purified by SCX column. The obtained solid was used without further purification. 0.825 g (28%)
C
18
H
2 8BrN 3 0 calculated 382; found M+ 382/384 25 Lc Rt (5 min)= 1.39 NMR (400 MHz, dmso-d6): 0.80 (6H, s); 1.28-1.34 (4H, m); 1.41-1.46 (4H, in); 2.17-2.21 (2H, in); 2.28 (4H, br in); 2.90 (2H, d, J= 6Hz); 6.15 (lH, t, J= 6 Hz); 7.33-7.35 (4H, m); 8.51 (1H, s).
WO 2007/098826 PCT/EP2007/000382 62 b) 1-(2,2-Dimethyl-4-piperidin-1-yl-butyl)-3-[4-(1-methyl-1H-pyrazol 4-yl)-phenyl]-urea To a degassed mixture of 1-(4-bromo-phenyl)-3-(2,2-dimethyl-4 piperidin-1-yl-butyl)-urea (0.11 g, 0.29 mmol) and 1-methyl-4-(4,4,5,5 5 tetramethyll,3,2-dioxaborolan-4-yl)-1H-pyrazole (90 mg, 0.43 mmol) in acetonitrile/sodium carbonate 0.4M solution 1/1 (4 mL) a catalytic amount of Pd[(PPh 3
)]
4 (17 mg, 5 mmol %) was added. The reaction mixture was heated at 90'C for 20 minutes under microwave condition. After addition of ethyl acetate (1 mL), the organic layer was separated and purified by scx columns 10 followed by preparative HPLC. 0.067 g; 61%
C
2 2
H
3 3
N
5 0 calculated 383; found M+ 384 Lc Rt (10 min)= 1.61 NMR (400 MHz, dmso-d6): 0.82 (6H, s); 1.35-1.40 (4H, in); 1.48-1.54 15 (4H, in); 2.40-2.44 (2H, in); 2.46-2.50 (4H, br m); 2.91 (2H, d, J= 6Hz); 3.81 (3H, s); 6.32 (lH, t, J= 6 Hz); 7.33-7.39 (4H, in); 7.72 (1H, s); 7.97 (1H, s); 8.23 (1H, s); 8.56 (1H, s). Example 10 1-(4-Piperidin-1-yl-pentyl)-3-(4-pyridin-3-yl-phenyl)-urea 20 a) 1-(4-Bromo-phenyl)-3-(4-piperidin-1-yl-pentyl)-urea To a solution of 4-piperidin-1-yl-pentylamine (0.20 g, 1.18 mmol) in
CH
2 Cl 2 (4 mL) at 0 0 C was slowly added a solution of 4-bromophenyl isocyanate (0.23 g, 1.18 mmol) in CH 2 C1 2 (2 mL). The mixture was stirred 5 min at 0 0 C, then 1 hrs at RT. The solvent was evaporated and the residue 25 used without further purification. 0.39 g; 90% NMR (400 MHz, CD 3 0D): 0.96 (3H, d, J= 6.4 Hz); 1.25-1.59 (10H, m); 2.46-2.55 (5H, m); 3.11 (2H, t, J= 6.8 Hz); 7.25-7.28 (2H, in); 7.32-7.36 (2H, m).
WO 2007/098826 PCT/EP2007/000382 63 b) 1-(4-Piperidin-1-yl-pentyl)-3-(4-pyridin-3-yl-phenyl)-urea To a degassed mixture of 1-(4-bromo-phenyl)-3-(4-piperidin-1-yl pentyl)-urea (130 mg, 0.35 mmol) and pyridine-3-boronic acid (65 mg, 0.53 mmol) in acetonitrile/sodium carbonate 0.4M solution 1/1 (4 mL) a catalytic 5 amount of Pd[(PPh 3
)]
4 (17 mg, 5 mmol %) was added. The reaction mixture was heated at 90'C for 10 minutes under microwave condition. After addition of ethyl acetate (1 mL), the organic layer was separated and purified by scx columns followed by preparative HPLC. 0.025 g; 19% 10 C 2 2
H
3 0
N
4 0 calculated 366; found 367 Lc Rt (10 min)= 0.24-0.81 NMR (400 MHz, dmso-d6): 0.82 (6H, d, J= 6.8); 1.24-1.55 (10H, in); 2.46-2.68 (5H, in); 3.05-3.09 (2H, in); 6.38 (1H, t, J= 5.6 Hz); 7.41 (lH, ddd, J= 8.0 Hz, 4.8 Hz, 0.8 Hz); 7.49-7.52 (2H, in); 7.57-7.60 (2H, in); 7.99 (lH, 15 ddd, J= 8.0 Hz, 2.0 Hz, 1.6 Hz); 8.21 (1H, s); 8.47 (1H, dd, J= 4.8 Hz, 1.6 Hz); 8.74 (1H, s); 8.82 (1H, dd, J= 2.0 Hz, 0.8 Hz). Example 11 1-[4-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(3,3,3-trifluoro propylamino)-butyl]-urea 20 a) 1-(4-Bromo-phenyl)-3-[4-(3,3,3-trifluoro-propylamino)-butyl]-urea 1-(4--Bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea (0.72 g, 2 mmol, 1 eq) was dissolved in dry DCM (10 mL) at room temperature and Montomorrilonite K-5 (0.145 g) is added. The reaction was stirred ar room temperature for 2 hours, when LC-MS shows complete conversion into the 25 aldehyde. The reaction mixture was filtered to remove all solids and trifluopropylamine.HCl (0.9 g, 6 mmol, 3 eq) and diisoproylethylamine (1.05 mL, 6 mmol, 3 eq) were added, followed by NaBH(OAc) 3 (1.2 g, 4 mmol, 2 eq,). The reaction was stirred at rt for 24 hrs. Upon reaction WO 2007/098826 PCT/EP2007/000382 64 completion (as monitored by LC-MS), the solvent was removed under reduced pressure and the resulting residue was purified by SCX column, eluting with DCM:MeOH 1:1 and then 2M NH3 in MeOH. 1-(4-Bromo-phenyl)-3-[4 (3,3,3-trifluoropropylamino)-butyl]-urea was obtained (0.33 g, 40% yield). 5 C14H19BrF3N30 Mass (calculated) [382.23]; (found) [M+H*]=381.25 (ESI-) LC Rt=0.63, 90% (10 min method) b) 1-[4-(1-Methyl-JH-pyrazol-4-yl)-phenyl]-3-[4-(3,3,3-trifluoro propylamino)-butyl]-urea 10 To a degassed solution of 1-(4-Bromo-phenyl)-3-[4-(3,3,3 trifluoropropylamino)-butyl]-urea (0.11 g, 0.3 mmol), 31-Methyl-4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.0.94 g, 0.45 mmol) in 3 mL Acetonitrile/ 0.4 M Na 2
CO
3 (50/50) Pd[(PPh 3
)]
4 (0.02 mmol) were added. The solution was irradiated under the microwave conditions described 15 above. The acetonitrile layer was separated and filtered on a Celite* pad. The solution was dried and the product purified by preparative HPLC to yield 20 mg of the title compound as formate salt (0.048 mmol, 16% yield). C18H24F3N50 Mass (calculated) [383.42]; (found) [M+H*]= 384.21 Lc Rt= 1.48 (100%) 20 NMR (400 MHz, dmso-d6): 1.31 (4H, in); 2.43-2.30 (2H, in); 2.57-2.55 (2H, in); 2.75 (2H, in); 3.05 (2H, in); 3.81 (3H, s); 6.17 (lH, bs); 7.38-7.32 (4H, in); 7.72 (lH, s); 7.97 (1H, s); 8.18 (1H, s, HCOOH); 8.43 (1H, s). Example 12 4'-(5-Azepan-1-yl-pentanoylamino)-2'-chloro-biphenyl-3-carboxylic 25 acid amide a) 5-Azepan-1-yl-pentanoic acid (4-bromo-3-chloro-phenyl)-amide 4-bromo-3-chloroaniline (0.72 g, 3.5 mmol), triethylamine (0.48 mL, 3.35 mmol) and 5-bromovaleryl chloride (0.44 mL, 3.32 mmol) are reacted for WO 2007/098826 PCT/EP2007/000382 65 2 hrs at rt in DCE (12 mL): after this time, azepane (1.18 mL, 10.3 mmol) and more triethylamine (0.48 mL, 3.35 mmol) are added and the reaction stirred for +55'C for 4 h. After reaction completion and work-up, the title compound is clean enough (92% purity) for the following step (1.3 g, quant yield). 5 C17H24BrClN20 Mass (calculated) [387.75]; (found) [M+H+]= 387.32/389.28 Lc Rt= 2.83 (92%), 10' b) 4'-(5-Azepan-1-yl-pentanoylamino)-2'-chloro-biphenyl-3-carboxylic acid amide 10 5-Azepan- 1 -yl-pentanoic acid (4-bromo-3-chloro-phenyl)-amide (0.07 g, 0.18 mmol) and benzamide-3-boronic acid (0.044 g, 0.27 mmol) are reacted in acetonitrile/sodium carbonate 0.4M solution 1/1 (3 mL) with a catalytic amount of Pd[(PPh 3
)]
4 (5 mmol %). The title compound is obtained as free base after purification by SCX 15 column (0.045 g, 0.11 mmol, 60% yield) C24H30ClN302 Mass (calculated) [472.98]; (found) [M+H*]= 428.46 Lc Rt= 2.04 (100%), 10' NMR (400 MHz, CDCl 3 ): 1.68-1.55 (8H, in); 1.77 (4H, in); 2.41 (2H, in;, 2.58 (2H, in); 2.67 (2H, in); 2.72 (2H, in); 7.27 (1H, s); 7.49 (2H, in); 7.59 20 (1H, s); 7.8 (2H, m); 7.85 (1H, s); 8.16 (1H, bs). Example 13 5-Azepan-1-yl-pentanoic acid (2-fluoro-2'-methoxy-biphenyl-4-yl) amide a) 5-Azepan-1-yl-pentanoic acid (4-bromo-3-fluoro-phenyl)-amide 25 4-Bromo-3-fluoroaniline (0.66 g, 3.5 mmol), triethylamine (0.48 mL, 3.35 mmol) and 5-bromovaleryl chloride (0.44 mL, 3.32 mmol) are reacted for 2 hrs at rt in DCE (12 mL): after this time, azepane (1.18 mL, 10.3 mmol) and more triethylamine (0.48 mL, 3.35 mmol) are added and the reaction stirred WO 2007/098826 PCT/EP2007/000382 66 for +55*C for 4 h. After reaction completion and work-up, the title compound is clean enough (90% purity) for the following step (1.29 g, quant yield). C17H24BrFN20 Mass (calculated) [371.30]; (found) [M+H+]= 371.33/373.35 5 Lc Rt= 2.23 (90%), 10' b) 5-Azepan-1-yl-pentanoic acid (2-fluoro-2'-methoxy-biphenyl-4-yl) amide 5-Azepan-1-yl-pentanoic acid (4-bromo-3-fluoro-phenyl)-amide (0.093 g, 0.25 mmol) and 2-methoxyphenyl-boronic acid (0.057 g, 0.37 mmol) 10 are reacted in acetonitrile/sodium carbonate 0.4M solution 1/1 (4 mL) with a catalytic amount of Pd[(PPh 3
)]
4 (5 mmol %). The title compound is obtained as formate salt after purification by preparative HPLC (0.025 g, 0.06 mmol, 13% yield). C24H31FN202 Mass (calculated) [398.53]; (found) [M+H+]= 399.18 15 Lc Rt= 2.98 (98%), 10' NMR (400 MHz, CD 3 0D): 1.83-1.72 (8H, in); 1.9 (4H, in); 2.5 (2H, in); 3.18 (2H, m); 3.37 (4H, in); 3.77 (3H, s); 6.99 (1H, m); 7.06 (1H, bs); 7.21 (1H, m); 7.25 (2H, m); 7.35 (1H, m); 7.57 (1H, in); 8.49 (1H, s, HCOOH). Example 14 20 1-(2,2-Difluoro-4-piperidin-1-yl-butyl)-3-(4'-methoxy-biphenyl-4-yl) urea a) 1-(4-Bromo-phenyl)-3-(2,2-difluoro-4-piperidin-1-yl-butyl)-urea To a solution of 2,2-difluoro-4-piperidin-1-yl-butylamine (0.149 g, 0.78 mmol) in CH2Cl2 (4 mL) at 0 0 C a solution of 4-bromophenyl isocyanate 25 (0.153 g, 0.78 mmol) in CH2Cl2 (1 mL) was slowly added. The mixture was stirred at 0*C for 30 min, then at room temperature until the reactants were all consumed. The solution was purified by SCX column. The oil obtained was used without further purification (0.218 g).
WO 2007/098826 PCT/EP2007/000382 67 Yield: 72% C16H22BrF2N30 calculated 390; found M+ 390/392 Lc Rt (5 min)= 1.34 1H-NMR (400 MHz, dmso-d6): 1.43-1.57 (8H, m); 2.02-2.53 (8H, m); 5 7.22-7.43 (6H, m). b) 1-(2,2-Difluoro-4-piperidin-1-yl-butyl)-3-(4'-methoxy-biphenyl-4-yl) urea To a degassed mixture of 1-(4-bromo-phenyl)-3-(2,2-difluoro-4 piperidin-1-yl-butyl)-urea (0.109 g, 0.28 mmol), 4-methoxyphenylboronic 10 (0.051 g, 0.34 mmol) and Na2CO3 (0.042 g, 0.40 mmol) in DME (1.3 mL) and water (0.2 mL) tri-o-tolylphosphine (0.017 g, 20 mmol%) and Pd(OAc)2 (0.003 g, 5% mmol) were added. The reaction mixture was heated at 90*C for 10 minutes under microwave conditions. After addition of ethyl acetate (1 mL), the organic layer was separated and purified by scx columns followed 15 by SiO2 column (gradient from 100%DCM to DCM-NH3 in MeOH 2N solution 9:1) to give 0.010 g of product. Yield: 9% C23H29F2N302 calculated 417; found M+ 418/M- 416 Lc Rt (10 min)= 2.23, 100% 20 NMR (400 MHz, dmso-d6): 1.47-1.62 (6H, m); 2.09-2.22 (2H, m); 2.46-2.62 (6H, m); 3.64 (2H, t, J=14); 3.81 (3H, s); 6.96 (2H, d, J=8.8); 7.40 (2H, d, J=6.8), 7.47-7.51 (4H, m). 19F-HNMR (400 MHz, dmso-d6): -118.90 (quint.) Example 15 25 5-Piperidin-1-yl-pentanoic acid [5-(4-methoxy-phenyl)-4-methyl-2H pyrazol-3-yl]-amide a) 3-(4-Methoxy-phenyl)-2-methyl-3-oxo-propionitrile The product was prepared according to the general procedure for WO 2007/098826 PCT/EP2007/000382 68 aminopyrazole synthesis (route Al). The crude product was purified with SiO2 column (10 g) with gradient elution from 100% Hexane to Hexane-AcOEt 7:3. to give 1.43 g of pure product (yield 3 1%). 5 'H-NMR (400 MHz, MeOH-d 4 ): 7.97 (2H, d), 6.98 (1H, d), 4.31 (1H, q, J = 7.3 Hz), 3.89 (3H, s), 1.63 (3H, d, J = 7.3 Hz). b) 5-(4-Methoxy-phenyl)-4-methyl-2H-pyrazol-3-ylamine The product was prepared according to the general procedure for aminopyrazole synthesis (route A2) 10 The crude product was purified with SiO2 column (10 g) with gradient elution from 100% DCM to DCM-MeOH 8:2. 1.0 g of pure product were obtained (yield 65%). 'H-NMR (400 MHz, CDCl3): 7.37 (2H, d), 6.97 (2H, d), 3.84 (3H, s), 2.03 (3H, s). 15 c) 5-Piperidin-1-yl-pentanoic acid [5-(4-methoxy-phenyl)-4-methyl-2H pyrazol-3-yl]-amide The product was prepared according to the general synthetic method for the one-pot synthesis of o-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl) amides. 20 The crude product was purified with SiO2 column (2 g) with gradient elution from 100% DCM to DCM-NH3 (2N MeOH solution) 95:5. The obtained crude was then purified again by prep-HPLC to give 54 mg of pure product (yield 7%).
C
21
H
30
N
4 0 2 25 Mass (calculated) [370]; (found) [M+H*] =371 LC Rt=1.61, 100% (10 min method) 'H-NMR (400 MHz, dmso-d 6 ): 9.57 (1H, s), 8.12 (1H, s), 7.47 (2H, d), 7.02 (2H, d), 3.78 (3H, s), 2.41 (4H, broad), 2.37 (2H, in), 2.29 (2H, t), 1.91 WO 2007/098826 PCT/EP2007/000382 69 (3H, s), 1.57 (2H, in), 1.50 (6H, in), 1.38 (2H, in). Example 16 N-[5-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-4-piperidin-1-yl-butyramide a) 4-Piperidin-1-yl-butyric acid ethyl ester 5 To a solution of piperidine (5.4 g, 65 mmol) in toluene (15 mL) ethyl 4 bromobutyrate (3.8 mL, 26 mmol) was added and the reaction mixture was refluxed for 10 hours. The mixture was allowed to cool down to room temperature and the white solid present (piperidium bromide) was filtered off and washed with ether. The filtrate was concentrated under reduced pressure 10 to give the title product which was used in the next step without further purification. C IH 21 NO2 Mass (calculated) [199]; (found) [M+H*] =200 LC Rt = 0.2, 100% (5 min method) 15 'H-NMR (400 MHz, MeOH-d 4 ): 1.22-1.25 (3H, in), 1.46-1.47 (2H, in), 1.57-1.63 (4H, in), 1.78-1.84 (2H, in), 2.30-2.35 (4H, in), 2.42 (4H, m, broad), 4.08-4.14 (2H, in). b) 4-Piperidin-1-yl-butyric acid To a suspension of crude 4-piperidin-1-yl-butyric acid ethyl ester from 20 the previous step (about 25 mmol) in 15 mL of water, NaOH (1.4 g, 25 mmol) was added and the mixture was heated at reflux for 16 hours. The reaction was then allowed to cool down to room temperature, the solution was acidified at 0 0 C with HCl 6N and concentrated under reduced pressure. The residue was treated with EtOH and the sodium chloride which precipitated was filtered off. 25 Evaporation of the solvent under reduced pressure afforded 2.8 g of the title compound as a white solid in 58% overall yield of steps a) and b).
C
9
H
17 NO2 Mass (calculated) [171]; (found) [M+H*] =172 WO 2007/098826 PCT/EP2007/000382 70 LC Rt = 0.23, 100% (5 min method) 'H-NMR (400 MHz, dmso-d 6 ): 1.44-1.51 (2H, m); 1.64-1.80 (6H, m); 2.22-2.25 (2H, m); 2.75-2.78 (2H, m, broad); 2.91-2.94 (2H, m, broad); 3.30-3.40 (2H, m). 5 c) N-[5-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-4-piperidin-1-yl-butyramide To a suspension of 4-piperidin-1-yl-butyric acid (1.32 g, 7.93 mmol) in 12,2-dichloroethane (20 mL), NN'-carbonyldiimidazole (1.2 g, 7.4 mmol) was added and the mixture was stirred at room temperature for 2 hours (when all the aminoacid was activated complete dissolution of the suspension was 10 generally observed). 3-Amino-5 -(4-methoxyphenyl)pyrazole (1 g, 5.29 mmol) was then added and the reaction was stirred for further 10 hours. Upon reaction completion (as monitored by LC-MS) the formation of two isomers was observed, and the mixture was heated at 50'C until the conversion of the less stable isomer to the title compound was observed (as monitored by 15 LC-MS). The solvent was washed with sat. Na 2
CO
3 solution, extracted and removed under reduced pressure. The crude was crystallised from acetonitrile to give 1.2 g of the title compound (Yield: 70%).
C
19
H
26
N
4 0 2 Mass (calculated) [342]; (found) [M+H+] =343 20 LC Rt = 1.54, 100% (10 min method) 'H-NMR (400 MHz, dmso-d 6 ): 1.34-1.40 (1H, m); 1.52-1.55 (1H, m); 1.62-1.75 (6H, m); 1.94-1.98 (2H, m); 2.37-2.40 (2H, m); 2.81-2.88 (2H, m); 2.97-3.03 (2H, m); 3.39-3.42 (2H, m); 3.77 (3H, s); 6.77 (1H, s); 6.98 (2H, d, J= 8.8 Hz); 7.61 (2H, d, J= 8.8 Hz); 10.47 (1H, s), 12.66 (1H, s). 25 Example 17 N-[5-(3-Methoxy-phenyl)-1H-pyrazol-3-yl]-4-morpholin-4-yl-butyramide a) 3-(3-Methoxy-phenyl)-3-oxo-propionitrile To a solution of commercially available 3-methoxy-benzoic acid ethyl WO 2007/098826 PCT/EP2007/000382 71 ester (3.2 g, 18 mmol) in dry toluene (25 mL), under N 2 , NaH (50-60% dispersion in mineral oil, 1.44 g, 36 mmol) was carefully added. The mixture was heated at 90'C and anhydrous CH 3 CN was added dropwise (4.45 mL, 85.2 mmol). The reaction was heated for 18 hours and the product precipitated 5 from the reaction mixture as Na salt. The reaction was allowed to cool down to room temperature and the solid formed was filtered and washed with ether, then it was redissolved in water and the solution acidified with 2N HCl solution to pH 3 when precipitation of title compound was observed. Filtration of the solid from the aqueous solution afforded 1.57 g of title product 10 (50% yield). CioH 9 NO2 Mass (calculated) [175]; (found) [M+H*] =176 LC Rt = 1.69, 94% (5 min method) b) 5-(3-Methoxy-phenyl)-2H-pyrazol-3-ylamine 15 To a solution of 3-(3-methoxy-phenyl)-3-oxo-propionitrile (8.96 mmoL) in absolute EtOH (20 mL) hydrazine monohydrate (0.52 mL, 15 mmol) was added and the reaction was heated at reflux for 18 hrs. The reaction mixture was then allowed to cool to room temperature and the solvent was evaporated under reduced pressure. 20 The crude was treated with ether and filtered, to give 1.4 g of title product (83% of yield). CioHI IN 3 0 Mass (calculated) [189]; (found) [M+H*] =190 LC Rt = 1.13, 100% (5 min method) 25 'H-NMR (400 MHz, MeOH-d 4 ): 3.82 (3H, s); -5.93 (1H, s); 6.86-6.88 (1H, in); 7.19-7.31 (3H, in).
WO 2007/098826 PCT/EP2007/000382 72 c) N-[5- (3-Methoxy-phenyl) -1 H-pyrazol-3-yl]-4-morpholin-4-yl butyramide A solution of 4-bromobutyryl chloride (0.104 mL, 0.9 mmol) in dry DMA (1 mL) was cooled to -10*C (ice/water bath) under N 2 ; 5-(3-methoxy 5 phenyl)-2H-pyrazol-3-ylamine (170 mg, 0.9 mmol) and diisopropylethylamine (0.315 mL, 1.8 mmol) in dry DMA (1 ml) were added. Upon complete conversion to the intermediate 4-Bromo-N-[5-(3-methoxy-phenyl)-1H pyrazol-3-yl]-butyramide (as monitored by LC-MS), morpholine (0.079 mL, 0.9 mmol) was added and the mixture was heated at 60'C for 16 hours. The 10 residue was dissolved in DCM (2 mL) and washed with sat. Na 2
CO
3 solution. The organic phase was concentrated under reduced pressure and the crude product was purified by SiO 2 column (gradient from Acetonitrile 100% to MeCN/MeOH, NH 3 90/10). The fractions containing the title compound were collected to afford 17 mg (5.5% of yield). 15 C 18
H
24
N
4 0 3 Mass (calculated) [344]; (found) [M+H*] =345 LC Rt = 1.36, 95% (10 min method) 'H-NMR (400 MHz, MeOH-d 4 ): 1.77-1.85 (2H, in); 2.34-2.40 (8H, m); 3.59-3.62 (4H, in); 3.76 (3H, s); 6.79-6.85 (2H, in); 7.15-7.29 (3H, in). 20 Example 18 4-Azepan-1-yl-N-[5-(3-methoxy-phenyl)-1H-pyrazol-3-yl]-butyramide A solution of 4-bromobutyryl chloride (0.104 mL, 0.9 mmol) in dry DMA (1 mL) was cooled to -10 0 C (ice/water bath) under N 2 ; 5-(3-Methoxy phenyl)-2H-pyrazol-3-ylamine (170 mg, 0.9 mmol) and diisopropylethylamine 25 (0.315 mL, 1.8 mmol) in dry DMA (1 ml) was added. Upon complete conversion to the o>-bromoamide intermediate (as monitored by LC-MS) 0.101 mL of azepine were added to the solution and the mixture was left stirring at 60*C for 16 hours.
WO 2007/098826 PCT/EP2007/000382 73 The residue was dissolved in DCM (2 mL) and washed with saturated Na 2
CO
3 solution. The organic phase was concentrated under reduced pressure and the crude product was purified by SiO 2 column (gradient from acetonitrile 100% to MeCN/MeOH, NH 3 90/10). The fractions containing the 5 title product were collected and a further purification by preparative HPLC was carried out to afford 20 mg of the title compound as its formate salt (5.5% yield).
C
20
H
28
N
4 0 2 Mass (calculated) [356]; (found) [M+H*] =357 10 LC Rt=1.71, 99% (10 min method) 'H-NMR (400 MHz, MeOH-d 4 ): 1.65-1.68 (4H, in); 1.80-1.90 (4H, in); 1.97-2.04 (2H, in); 2.49-2.52 (2H, in); 3.12-3.16 (2H, in); 3.24-3.30 (4H, m, broad); 3.75 (3H, s); 6.76 (lH, s); 6.82-6.85 (1H, in); 6.13-6.15 (2H, in); 6.23-6.27 (LH, m); 8.37 (1H, s, formate) 15 Example 19 4-Azepan-1-yl-N-[5-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-butyramide Prepared following the general synthetic method for the one-pot synthesis of o-amino-alkanoic acid (LH-pyrazol-3-yl-5-aryl)-amides. Starting from commercially available 5-(4-fluoro-phenyl)-2H-pyrazol-3-ylamine and 20 following the procedure, 25 mg of title compound were recovered as its formate salt after preparative HPLC purification (7% yield).
C
20
H
28
N
4 0 2 Mass (calculated) [344]; (found) [M+H*] =345 LC Rt=1.69, 100% (10 min method). 25 1 H-NMR (400 MHz, MeOH-d 4 ): 1.66-1.69 (4H, in); 1.80-1.90 (4H, m, broad); 1.97-2.05 (2H, in); 2.52-2.54 (2H, in); 3.12-3.18 (2H, in); 3.25-3.30 (4H, in, broad); 6.67 (1H, s, broad); 7.08-7.12 (2H, in); 7.59-7.63 (2H, in); 8.43 (1H, s, formate).
WO 2007/098826 PCT/EP2007/000382 74 Example 20 N-[5-(6-Methyl-pyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-yl butyramide a) 3-(6-Methyl-pyridin-3-yl)-3-oxo-propionitrile 5 The oxopropionitrile was synthesised following the general method for 3-oxopropionitriles (route Al).
C
9
H
8
N
2 0 Mass (calculated) [160]; (found) [M+H*] =161 LC Rt = 0.63, 100% (5 min method) 10 1 H-NMR (400 MHz, dmso-d 6 ): 2.55 (3H, s); 4.65 (2H, s); 7.43-7.45 (in, 1); 8.13-8.16 (lH, in); 8.94-8.95 (lH, in). b) 5-(6-Methyl-pyridin-3-yl)-1H-pyrazol-3-ylamine The aminopyrazole was synthesised following the general method described in route A2. 15 C 9 H1ON 4 Mass (calculated) [174]; (found) [M+H*] =175 LC Rt = 0.23, 100% (5 min method) c) N-[5-(6-Methyl-pyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-yl butyramide 20 Prepared following the general synthetic method for the one-pot synthesis of o-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides to afford 19 mg (6% yield) of title compound as its formate salt after preparative HPLC purification. CI 8
H
25
N
5 0 25 Mass (calculated) [327]; (found) [M+H*] =328 LC Rt = 0.33, 100% (10 min method) 'H-NMR (400 MHz, MeOH-d 4 ): 1.40-1.90 (6H, in); 2.30-2.54 (5H, m); 3.05-3.09 (4H, in); 3.20-3.24 (2H, in); 6.72 (lH, s, broad); 7.30 (1H, d J= WO 2007/098826 PCT/EP2007/000382 75 8.0 Hz); 7.92-7.94 (1H, in); 8.35 (1H, s, formate); 8.67 (1H, s). Example 21 N-[5-(5-Methyl-pyridin-3-yl)-]H-pyrazol-3-yl]-4-piperidin-1-yl butyramide 5 a) 3-(5-Methyl-pyridin-3-yl)-3-oxo-propionitrile The oxopropionitrile was synthesised following the general method for 3-oxopropionitriles (route Al).
C
9
H
8
N
2 0 Mass (calculated) [160]; (found) [M+H+] =161 10 LC Rt = 0.63, 100% (5 min method) 1 H-NMR (400 MHz, MeOH-d 4 ): 2.55 (3H, s); 4.65 (2H, s); 7.43-7.45 (in, 1); 8.13-8.16 (1H, in); 8.94-8.95 (lH, in). b) 5-(5-Methyl-pyridin-3-yl)-]H-pyrazol-3-ylamine The aminopyrazole was synthesised following the general method 15 described in route A2.
C
9 H1ON 4 Mass (calculated) [174]; (found) [M+H*] =175 LC Rt = 0.23, 100% (5 min method) c) N-[5-(5-Methyl-pyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-yl 20 butyramide Prepared following the general synthetic method for the one-pot synthesis of o-amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides to afford 25 mg of the title compound as its formate salt (7.4% yield) after preparative HPLC purification. 25 C 18
H
25
N
5 0 Mass (calculated) [327]; (found) [M+H*] =328 LC Rt = 0.33, 100% (10 min method) 'H-NMR (400 MHz, MeOH-d 4 ): 1.52-1.70 (2H, m, broad); 1.72-1.84 WO 2007/098826 PCT/EP2007/000382 76 (4H, m, broad); 1.98-2.06 (2H, in); 2.45 (3H, s); 2.48-2.54 (2H, in); 3.04-3.10 (4H, in); 3.20-3.24 (2H, m, broad); 6.74 (1H, s, broad); 7.88 (1H, s); 7.28 (1H, s); 8.37 (1H, s, formate); 8.67 (lH, s). Example 22 5 4-(4-Acetyl-[1,4]diazepan-1-yl)-N-[5-(6-methoxy-naphthalen-2-yl)-1H pyrazol-3-yl]-butyramide a) 6-Methoxy-naphthalene-2-carboxylic acid methyl ester To a solution of 6-methoxy-naphthalene-2-carboxylic acid (1.01 g, 5 mmol) in methanol (10 mL), a catalytic amount of sulphuric acid was added. 10 The mixture was then heated at 80'C for 8 hours. Upon reaction completion (as monitored by LcMS), the solution was slowly cooled and the precipitation of the product was observed. Filtration of the white solid afforded 1.01 g (94% yield) of title compound.
C
13
H
1 203 15 Mass (calculated) [216]; (found) [M+H*] =217 LC Rt = 2.43, 100% (5 min method) b) 3-(6-Methoxy-naphthalen-2-yl)-3-oxo-propionitrile To a solution of 6-methoxy-naphthalene-2-carboxylic acid methyl ester (1.0 g, 4.7 mmol) in dry toluene (8 mL), NaH (0.55 mg, 9.4 mmol) were added 20 and the mixture was heated at 90'C. To the hot solution, acetonitrile (1.2 mL) was added dropwise. The reaction was then heated for 18 hours and the product precipitated from the reaction mixture as its sodium salt. The reaction was allowed to cool down to room temperature and the solid formed was first filtered and washed with ether, then it was dissolved in 25 water and the solution was acidified with HCl 2N to pH 3, upon which precipitation of the title compound was observed. Filtration of the solid from the aqueous solution afforded 1.1 g of title compound (100% of yield).
C
1 3
H
1 2 0 3 WO 2007/098826 PCT/EP2007/000382 77 Mass (calculated) [225]; (found) [M+H*] =226 LC Rt = 2.13, 90% (5 min method) c) 5-(6-Methoxy-naphthalen-2-yl)-1H-pyrazol-3-ylamine To a solution of 3-(6-methoxy-naphthalen-2-yl)-3-oxo-propionitrile 5 (1.1 g, 4.8 mmoL) in absolute EtOH (10 mL) hydrazine monohydrate (0.96 mL, 19.2 mmol) was added and the reaction was heated at reflux for 18 hrs. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The crude was treated with ether and filtered to afford 0.95 g of title compound (83% of yield). 10 C 1 4
H
13
N
3 0 Mass (calculated) [239]; (found) [M+H*] =240 LC Rt = 1.49, 90% (5 min method) d) 4-(4-Acetyl-[1,4]diazepan-1-yl)-N-[5-(6-methoxy-naphthalen-2-yl) ]H-pyrazol-3-yl]-butyramide 15 Following the general method for the synthesis of o-bromo-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides and the general method for the synthesis of o amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides, purification by preparative HPLC afforded 15 mg (3% yield) of title compound as its formate salt.
C
25
H
31
N
5 0 3 20 Mass (calculated) [449]; (found) [M+H*] =450 LC Rt = 1.91, 100% (10 min method) 'H-NMR (400 MHz, MeOH-d 4 ): 1.88-2.0 (4H, in); 2.06 (3H, s); 2.48-2.52 (2H, in); 2.94-3.02 (2H, m); 3.08-3.18 (4H, in); 3.52-3.58 (2H, in); 3.64-3.72 (2H, in); 3.82 (3H, s); 6.78-6.82 (1H, *m); 7.04-7.10 (1H, m); 25 7.16-7.18 (1H, in); 7.62-7.78 (3H, in); 7.98-8.02 (1H, in); 8.28 (lH, s, formate). Example 23 6-(4-Acetyl-[1,4]diazepan-1-yl)-hexanoic acid [5-(4-methoxy-phenyl)- WO 2007/098826 PCT/EP2007/000382 78 JH-pyrazol-3-yl]-amide The product was prepared according to the general synthetic method for the one-pot synthesis of co-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl) amides. A solution of 5-bromohexanoyl chloride (0.144 mL, 0.94 mmol) in 5 dry DMA (1 mL) was cooled to -10 0 C (ice/water bath) under N 2 ; 5-(4 methoxy-phenyl)-1H-pyrazol-3-ylamine (178 mg, 0.94 mmol) and diisopropylethylamine (0.324 mL, 1.88 mmol) were added in dry DMA (1 ml). The reaction was left stirring for lh at 0*C and then 1-[1,4]diazepan-1 yl-ethanone (0.310 mL, 2.35 mmol,) and NaI (0.94mmol, 1 eq) were added. 10 The reaction mixture was heated at 60*C until LC-MS analysis showed complete conversion of the bromo-intermediate, at which point the reaction was cooled down and the solvent was removed under reduced pressure. The residue was dissolved in DCM (2 mL) and washed with saturated Na 2
CO
3 solution. 15 The organic phase was concentrated under reduced pressure and half of the crude was purified by SiO 2 column (gradient from 100% DCM to DCM-NH3MeOH 2N solution 8:2). The fractions containing the title compound were collected (35 mg).
C
23
H
33
N
5 0 3 20 Mass (calculated) [427]; (found) [M+H*] =428 LC Rt = 1.61, 96% (10 min method) 'H-NMR (400 MHz, dmso-d6): 1.24-1.29 (2H, in); 1.36-1.44 (2H, in); 1.54-1.58 (2H, in); 1.62-1.76 (2H, in); 1. 94-1.96 (3H, m); 2.25-2.28 (2H, in); 2.35-2.41 (2H, in); 2.51-2.54 (2H, in); 2.60-2.62 (1H, in); 3.38-3.44 (5H, in); 25 3.77 (3H, s); 6.73 (1H, s); 6.98 (2H, d, J=8.8 Hz); 7.61 (2H, d, J=8.8); 10.32 (1H, s). Example 24 N-[5-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-2-methyl-4-piperidin-1-yl- WO 2007/098826 PCT/EP2007/000382 79 butyramide a) Methyl-4-bromo-2-methyl-butyric acid 4-Bromo-2-methyl-butyric acid (2.16 g, 1 eq, prepared according to the procedure described in J.Am.Chem.Soc. 1990, 112, 2755) was dissolved 5 in MeOH (10 mL) and a few drops of conc. H 2
SO
4 were added. The reaction was stirred at reflux for 16 hours. After reaction completion, as monitored by LC-MS, MeOH was removed under reduced pressure, the oily residue was diluted with water, the pH adjusted to 9 with 10% NaOH, and the product was extracted with Et 2 O (2 X 20 mL) and dried over Na 2
SO
4 . The title 10 compound was obtained as a colourless oil (1.29 g, 55% yield) after solvent removal. NMR (400 MHz, CDCl3); 1.19 (3H, d); 1.94-1.89 (2H, m); 2.29-2.23 (2H, in); 3.43-3.40 (1H, m); 3.69 (3H, s). b) 2-Methyl-4-piperidin-1-yl-butyric acid. HCl 15' Methyl-4-bromo-2-methyl-butyric acid (1.29 g, 1 eq) was dissolved in toluene (15 mL) and piperidine (1.07 mL, 3 eq) was added; the reaction was stirred for 3 hours. After reaction completion, as monitored by LC-MS, toluene was removed under reduced pressure and the crude ester was dissolved in IM NaOH (14 mL, 1.1 eq) and MeOH (2 mL). The reaction was 20 stirred at reflux for 16 hours; after hydrolysis was complete, the reaction was concentrated under reduced pressure and the pH adjusted to 4 with 6N HCl. EtOH was added to help precipitation of NaCl. The organic phase was filtered and EtOH removed under reduced pressure. The resulting oil was treated with 2M HCl in Et 2 0 to obtain 2-methyl-4-piperidin-1-yl-butyric acid. HCl (0.96 g, 25 66% yield).
CIOH
19 NO2 Mass (calculated) [185.27]; (found) [M+H+]=186.27 LC Rt=0.23, 95% (5 min method) WO 2007/098826 PCT/EP2007/000382 80 c) N-[5-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-2-methyl-4-piperidin-1 yl-butyramide 2-Methyl-4-piperidin-1-yl-butyric acid. HCl (0.45 g, 1.2 eq) was suspended in 1,2-DCE (15 mL) and triethylamine (0.29 mL, 1.2 eq) was 5 added: 1,1'-carbonyldiimidazole (0.303 g, 1.1 eq) was added in one portion and the reaction was stirred at room temperature for 2 hours. 5-(4-Methoxy phenyl)-2H-pyrazol-3-ylamine (0.325 g, 1 eq) was then added and the reaction stirred at room temperature for further 16 hours. After reaction completion, as monitored by LC-MS, the solvent was removed under reduced pressure and 10 the crude amide was purified by column chromatography (Flash-SI 10 g;
CH
3 CN:MeOH 9:1, CH 3 CN:2N NH 3 MeOH 9:1) to give the title compound as thick colourless oil (0.120 g, 0.33 mmol).
C
20
H
28
N
4 0 2 Mass (calculated) [356.48]; (found) [M+H*]=357.25 15 LC Rt=1.67, 97% (10 min method) NMR (400 MHz, dmso-d6); 1.18 (3H, d); 1.35-1.31 (2H, m); 1.46 1.41 (4H, m); 1.77-1.72 (lH, m); 2.19-2.16 (2H, m); 2.27-2.23 (4H, m); 2.61-2.58 (2H, m); 3.76 (3H, s); 6.76 (1H, s); 6.92 (2H, d); 7.61 (2H, d); 10.33 (1H, s). 20 Example 25 N-[4-(4-Methoxy-phenyl)-]H-imidazol-2-yl]-4-piperidin-1-yl butyramide To a suspension of 4-piperidin-1-yl-butyric acid (200 mg, 1.17 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL), NN'-carbonyldiimidazole (179.9 mg, 25 1.11 mmol, 0.95 eq) was added and the mixture was stirred at room temperature for 1 hour until complete activation of the aminoacid and dissolution of the suspension. 4-(4-Methoxy-phenyl)-1H-imidazol-2-ylamine (prepared according to the procedure reported in JOC 1994, 59, 24, 7299; WO 2007/098826 PCT/EP2007/000382 81 110.5 g, 0.58 mmol, 0.50 eq) was added and the reaction stirred for 1 day at 50*C. The slow conversion was monitored by LC-MS. Another aliquote of activated acid (4-piperidin-1-yl-butyric acid, 200 mg and carbonyldiimidazole, 179.9 mg in 2 mL of 1,2-dichloroethane) were added and the reaction stirred 5 for further two days at 50'C. The solvent was evaporated under reduced pressure and the crude mixture purified by preparative HPLC to obtain a 9:1 mixture of the product and unreacted 4-(4-methoxy-phenyl)-1H-imidazol-2-ylamine. The crude was purified by treatment with isocyanate resin and SCX column to give 78.0 mg 10 (Yield: 39%) of the title compound as a white solid. C19H26N402 Mass (calculated) [342]; (found) [M+H*] =343 LC Rt = 1.00 (and solvent front), 99% (10 min method) 'H-NMR (400 MHz, DMSO): 1.30-1.36 (2H, in); 1.43-1.49 (4H, in); 1.67-1.75 (2H, in); 2.22-2.34 (8H, in); 3.73 (3H, s, -OCH3); 6.87 (2H, d, J=8.8 15 Hz); 7.10 (1H, s); 7.60 (2H, d, J= 8.8 Hz); 11.26 (1H, s, NHCO), 11.52 (1H, s, NH). 13 C-NMR (400 MHz, DMSO): 21.54 (IC); 23.63 (IC); 24.92 (2C); 33.24 (IC); 53.6 (IC, -OCH3); 55.02 (2C); 57.46 (1C); 113.88 (2C); 125.18 (2C), 141.13 (IC); 157.67 (IC); 162.33 (2C); 163.66 (IC); 171.15 20 (1C, CO). Table 1- Examples 26-171 Table 1 shows a selection of the compounds synthesised, which were prepared according to the method indicated in the last column of the table and discussed in detail in the Experimental Procedures with the synthesis of 25 Examples 1-25. When the compound is indicated as the HCl salt, the salt was formed by dissolution of the free base in methanol and addition of 1 eq 1M HC in ether followed by evaporation of the solvents. When the compound is WO 2007/098826 PCT/EP2007/000382 82 indicated as HCOOH (formic acid) salt, the compound was purified by preparative HPLC.
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0 z LI. Iz zz 0 0 oz 0 WO 2007/098826 125 PCT/EP2007/000382 to 0 v -o . ~ 0-~. > > E" 0 om, 00U o 0 000 '4 0 0 u LjUL MIz 0 m zz Oz 0 WO 2007/098826 PCT/EP2007/000382 126 0 - -n u o 0 coo 000 00 "ll:l 00 C Cl1 0 LLm Li-4 0 00 WO 2007/098826 127 PCT/EP2007/000382 0 w -0 a y a boo 00 00 000 C11 C14 o 0 u u 0 z -%Z 00 z WO 2007/098826 PCT/EP2007/000382 128 t~ 0 'SC', 0) 0p -q to;~ ~~ o OR I-q In 00N 000 ClC zz I-) TC-) zz Ifz Z2 WO 2007/098826 PCT/EP2007/000382 129 2 3z 5 o 0up b 10 000 zmz 00L zz -'P 0 01 WO 2007/098826 PCT/EP2007/000382 130 to r-. I 0 t cn 0E2 0 .-;. 0 :-c o 0 0 00 c C> Cl en Cl) 00 00 * Cl) m r-00 00 cl) zz zmz ZZI 09 0 N 00 WO 2007/098826 PCT/EP2007/000382 131 to t 000 000 0 0 e'4 ~z ON 0 0N WO 2007/098826 PCT/EP2007/000382 132 -o ON ON ON 0 zm z WO 2007/098826 PCT/EP2007/000382 133 Biological activity Cloning of alpha7 nicotinic acetylcholine receptor and generation of stable recombinant alpha7 nAChR expressing cell lines Full length cDNAs encoding the alpha7 nicotinic acetylcholine receptor 5 were cloned from a rat brain cDNA library using standard molecular biology techniques. Rat GH4C1 cells were then transfected with the rat receptor, cloned and analyzed for functional alpha7 nicotinic receptor expression employing a FLIPR assay to measure changes in intracellular calcium concentrations. Cell clones showing the highest calcium-mediated 10 fluorescence signals upon agonist (nicotine) application were further subcloned and subsequently stained with Texas red-labelled a-bungarotoxin (BgTX) to analyse the level and homogeneity of alpha7 nicotinic acetylcholine receptor expression using confocal microscopy. Three cell lines were then expanded and one characterised pharmacologically (see Table 2 15 below) prior to its subsequent use for compound screening. Table 2 - Pharmacological characterisation of alpha7 nAChR stably expressed in GH4CJ cells using the functional FLIPR assay Compound EC 50 [microM] Acetylcholine 3.05 ± 0.08 (n=4) Choline 24.22 ± 8.30 (n=2) Cytisine 1.21 ± 0.13 (n=5) DMPP 0.98 ± 0.47 (n=6) Epibatidine 0.0 12± 0.002 (n=7) Nicotine 1.03 + 0.26 (n=22) Development of a functional FLIPR assay for primary screening and 20 concentration-response analysis A robust functional FLIPR assay (Z' = 0.68) employing the stable recombinant GH4C1 cell line was developed to screen the alpha7 nicotinic WO 2007/098826 PCT/EP2007/000382 134 acetylcholine receptor. The FLIPR system allows the measurements of real time Ca 2+-concentration changes in living cells using a Ca2+ sensitive fluorescence dye (such as Fluo4). This instrument enables the screening for agonists and antagonists for alpha 7 nAChR channels stably expressed in 5 GH4C1 cells. Cell culture GH4C1 cells stably transfected with rat- alpha7-nAChR (see above) were used. These cells are poorly adherent and therefore pretreatment of flasks and plates with poly-D-lysine was carried out. Cells are grown in 10 150 cm 2 T-flasks, filled with 30ml of medium at 37*C and 5% CO 2 Data analysis
EC
50 and IC 50 values were calculated using the IDBS XLfit4.1 software package employing a sigmoidal concentration-response (variable slope) equation: Y= Bottom + ((Top-Bottom)/(1+((EC 50 /X) ^HillSlope)) 15 Assay validation The functional FLIPR assay was validated with the alpha7 nAChR agonists nicotine, cytisine, DMPP, epibatidine, choline and acetylcholine. Concentration-response curves were obtained in the concentration range from 0.001 to 30 microM. The resulting EC 50 values are listed in Table 2 and the 20 obtained rank order of agonists is in agreement with published data (Quik et al., 1997)(22). The assay was further validated with the specific alpha7 nAChR antagonist MLA (methyllycaconitine), which was used in the concentration range between 1 microM to 0.01 nM, together with a competing nicotine 25 concentration of 10 microM. The IC 50 value was calculated as 1.31+0.43 nM in nine independent experiments. Development offunctional FLIPR assays for selectivity testing Functional FLIPR assays were developed in order to test the selectivity WO 2007/098826 PCT/EP2007/000382 135 of compounds against the alphal (muscular) and alpha3 (ganglionic) nACh receptors and the structurally related 5-HT3 receptor. For determination of activity at alphal receptors natively expressed in the rhabdomyosarcoma derived TE 671 cell line an assay employing membrane potential sensitive 5 dyes was used, whereas alpha3 selectivity was determined by a calcium monitoring assays using the native SH-SY5Y cell line. In order to test selectivity against the 5-HT3 receptor, a recombinant cell line was constructed expressing the human 5-HT3A receptor in HEK 293 cells and a calcium-monitoring FLIPR assay employed. 10 Screening of compounds The compounds from Examples 1-171 described showed agonist activity in the functional FLIPR primary screening assay employing the stable recombinant GH4C 1 cell line expressing the alpha7 nAChR. The most potent hits identified were validated further by generation of concentration-response 15 curves. The potency of compounds from Examples 1-153 as measured in the functional FLIPR screening assay was found to range between 10 nM and 30 microM, with the majority showing a potency ranging between 10 nM and 10 microM. The best exemplified compounds were also demonstrated to be selective 20 against the alphal nACh, alpha3 nACh and 5HT3 receptors.
WO 2007/098826 PCT/EP2007/000382 136 REFERENCES 1. Prendergast, M. A., Harris, B. R., Mayer, S., Holley, R. C., Pauly, J. R., Littleton, J. M. (2001) Nicotine exposure reduces N-methyl-D-aspartate 5 toxicity in the hippocampus: relation to distribution of the alpha7 nicotinic acetylcholine receptor subunit. Med.Sci.Monit. 7, 1153-1160. 2. Garrido, R., Mattson, M. P., Hennig, B., Toborek, M. (2001) Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons. J.Neurochem. 76, 10 1395-1403. 3. Semba, J., Miyoshi, R., Kito, S. (1996) Nicotine protects against the dexamethasone potentiation of kainic acid- induced neurotoxicity in cultured hippocampal neurons. Brain Res. 735, 335-338. 4. Shimohama, S., Akaike, A., Kimura, J. (1996) Nicotine-induced 15 protection against glutamate cytotoxicity. Nicotinic cholinergic receptor-mediated inhibition of nitric oxide formation. Ann.N. Y.Acad.Sci. 777, 356-361. 5. Akaike, A., Tamura, Y., Yokota, T., Shimohama, S., Kimura, J. (1994) Nicotine-induced protection of cultured cortical neurons against N- methyl-D 20 aspartate receptor-mediated glutamate cytotoxicity. Brain Res. 644, 181-187. 6. Yamashita, H., Nakamura, S. (1996) Nicotine rescues PC12 cells from death induced by nerve growth factor deprivation. Neurosci.Lett. 213, 145-147. 7. Shimohama, S., Greenwald, D. L., Shafron, D. H., Akaika, A., Maeda, 25 T., Kaneko, S., Kimura, J., Simpkins, C. E., Day, A. L., Meyer, E. M. (1998) Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Res. 779, 359-363. 8. Socci, D. J., Arendash, G. W. (1996) Chronic nicotine treatment WO 2007/098826 PCT/EP2007/000382 137 prevents neuronal loss in neocortex resulting from nucleus basalis lesions in young adult and aged rats. Mol.Chem.Neuropathol. 27, 285-305. 9. Rusted, J. M., Newhouse, P. A., Levin, E. D. (2000) Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and 5 Parkinson's disease. Behav.Brain Res. 113, 121-129. 10. Kihara, T., Shimohama, S., Sawada, H., Kimura, J., Kume, T., Kochiyama, H., Maeda, T., Akaike, A. (1997) Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity. Ann.Neurol. 42, 159-163. 11. Kihara, T., Shimohama, S., Sawada, H., Honda, K., Nakamizo, T., 10 Shibasaki, H., Kume, T., Akaike, A. (2001) alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3- kinase to block A beta-amyloid induced neurotoxicity. J.Biol.Chem. 276, 13541-13546. 12. Kelton, M. C., Kahn, H. J., Conrath, C. L., Newhouse, P. A. (2000) The effects of nicotine on Parkinson's disease. Brain Cogn 43, 274-282. 15 13. Kem, W. R. (2000) The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21). Behav.Brain Res. 113, 169-181. 14. Dajas-Bailador, F. A., Lima, P. A., Wonnacott, S. (2000) The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against 20 NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism. Neuropharmacology 39, 2799-2807. 15. Strahlendorf, J. C., Acosta, S., Miles, R., Strahlendorf, H. K. (2001) Choline blocks AMPA-induced dark cell degeneration of Purkinje neurons: potential role of the alpha7 nicotinic receptor. Brain Res. 901, 71-78. 25 16. Jonnala, R. R., Terry, A. V., Jr., Buccafusco, J. J. (2002) Nicotine increases the expression of high affinity nerve growth factor receptors in both in vitro and in vivo. Life Sci. 70, 1543-1554. 17. Bencherif, M., Bane, A. J., Miller, C. H., Dull, G. M., Gatto, G. J.
WO 2007/098826 PCT/EP2007/000382 138 (2000) TC-2559: a novel orally active ligand selective at neuronal acetylcholine receptors. Eur.J.Pharmacol. 409, 45-55 Ref Type: Journal. 18. Donnelly-Roberts, D. L., Xue, I. C., Arneric, S. P., Sullivan, J. P. (1996) In vitro neuroprotective properties of the novel cholinergic channel 5 activator (ChCA), ABT-418. Brain Res. 719, 36-44. 19. Meyer, E. M., Tay, E. T., Zoltewicz, J. A., Meyers, C., King, M. A., Papke, R. L., De Fiebre, C. M. (1998) Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties. J.Pharmacol.Exp.Ther. 284, 1026-1032. 10 20. Stevens, T. R., Krueger, S. K., Fizsimonds, R. M. and Picciotto, M. R. (2003) Neuroprotection by nicotine in mouse primary cortical cultures involves activation of calcineurin and L-type calcium channel inactivation. J. Neuroscience 23, 10093-10099. 21. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, 15 Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384-388. 22. Quik M, Philie J. and Choremis J. (1997). Modulation of alpha7 nicotinic receptor-mediated calcium influx by nicotinic agonists. Mol. 20 Pharmacol., 51, 499-506.

Claims (8)

1. A compound of formula (I) K, x I OW (I), Oh Q (R')j K2 R (I) 5 wherein: w, h and k are, independently from one another, 0, 1, 2, or 3 with the condition that 3 w + h + k 5; KI and K2, which are bound to either the same or a different carbon atom where k>1, represent, independently from one another, hydrogen; 10 halogen; (CI-C 5 ) alkyl, alkoxy, fluoroalkyl, alkylene, fluoroalkylene; hydroxyalkyl; or KI and K2 taken together form an alkylidene or a fluoroalkylidene group; or KI and K2 taken together with the carbon atom to which they are attached form a (C 3 -C 6 ) cycloalkyl group; or when k is ;>2, two Ok carbon atoms may form an unsaturated bond; or when w is 1, 2, or 3, 15 and k is 1, K1 and K2 taken together with the carbon atom to which they are attached, may form an oxo group; j is 0, 1 or 2; X is a group of formula T'p L I r N N N-()q'-n 20 WO 2007/098826 PCT/EP2007/000382 140 Tp Tp N PS P T'p -N - 0 -N A x L, SOn ~ N On~ On T-p T p N ) N On On Z is CH 2 , N, 0, S, S(=0), or S(=0)2; p is 0, 1, 2 or 3; n is 0, 1 or 2; 5 s is 1 or 2; q and q' are, independently from one another, integers from 1 to 4; T' represent, independently from one another, hydroxy; mercapto; amino; cyano; nitro; linear, branched or cyclic (C 1 -C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, 10 alkoxycarbonyl, alkylcarbonylamino; mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylamino; linear, branched or cyclic (C 1 -C 6 ) alkoxy-(C 1 -C 6 ) alkyl, mono- or di- (C 1 -C 6 ) alkylamino-(C 1 -C 6 ) alkyl, or (C 1 -C 6 ) alkylthio-(C 1 -C 6 ) alkyl; (C 1 -C 3 ) alkylsulphonylamino; mono- or di- (C 1 -C 3 ) alkylaminosulphonyl; sulphamoyl; linear, branched or cyclic (C 1 -C 6 ) 15 alkylaminocarbonyl; carbamoyl; or, when p is 2 or 3, two T' substituents form a 5- to 8-membered ring with spiro or fused junction; U and U' represent, independently from one another, hydrogen; cyano; hydroxy; amino; a mono- or di-, linear, branched, or cyclic (C 1 -C 6 ) alkylamino group; a linear or branched (C 1 -C 6 ) alkoxy group; a linear, branched or cyclic 20 (C 1 -C 6 ) alkyl, azaalkyl, oxaalkyl chain optionally substituted with hydroxy, mercapto, amino, cyano, nitro, oxo, trihalomethyl, trihalomethoxy, carbamoyl, sulphamoyl, linear, branched or cyclic (C 1 -C 6 ) alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, WO 2007/098826 PCT/EP2007/000382 141 alkylcarbonylamino, mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl, mono- or di- (C 5 -C 1 o) aryl- or heteroarylaminocarbonyl, (C 5 -Cio) aryl- or heteroarylsulphonylamino, (C 1 -C 3 ) alkylsulphonylamino, (C 5 -CIO) aryl- or heteroarylsulphonyl, (CI-C 3 ) alkylsulphonyl, mono- or di 5 (Cs-CIO) aryl- or heteroarylsulphamoyl, mono- or di- (CI-C 3 ) alkylsulphamoyl, mono- or di-, linear, branched, or cyclic (C 1 -C 6 ) alkylamino; a linear, branched or cyclic (CI-C 6 ) alkyl, azaalkyl, oxaalkyl chain bearing a 5- to
10-membered aryl or heteroaryl group optionally substituted with one or more groups independently selected from hydroxy, mercapto, amino, cyano, nitro, 10 trihalomethyl, trihalomethoxy, linear, branched or cyclic (CI-C 6 ) alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxyxcarbonyl, alkylcarbonylamino, mono- or di-, linear, branched, or cyclic (CI-C 6 ) alkylamino, linear, branched or cyclic (C 1 -C 6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (C 1 -C 6 ) alkylamino-(C 1 -C 6 ) alkyl, or (CI-C 6 ) alkylthio-(C1 15 C) alkyl, carbamoyl, (C 5 -Cio) aryl- or heteroarylsulphonylamino, (CI-C 3 ) alkylsulphonylamino, mono- or di- (C 5 -Cio) aryl- or heteroarylsulphamoyl, (C 1 -C 3 ) alkylsulphamoyl, sulphamoyl, mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl; mono- or di- (C 5 -CIO) aryl- or heteroarylaminocarbonyl, a 5 to 10 membered aromatic or heteroaromatic ring 20 optionally substituted with one or more groups independently selected from hydroxy; halogen; mercapto; amino; cyano; nitro; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 6 ) alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl-, alkoxyxcarbonyl, alkylcarbonylamino; mono- or di-, linear, branched, or 25 cyclic (CI-C 6 ) alkylamino; linear, branched or cyclic (C 1 -C 6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (C 1 -C 6 ) alkylamino-(C 1 -C 6 ) alkyl, or (CI-C 6 ) alkylthio-(Ci C 6 ) alkyl; carbamoyl; (C 5 -Cio) aryl- or heteroarylsulphonylamino; (Ci-C 3 ) alkylsulphonylamino; mono- or di- (C 5 -CIO) aryl- or heteroarylsulphamoyl; WO 2007/098826 PCT/EP2007/000382 142 mono- or di- (CI-C 3 ) alkylsulphamoyl; sulphamoyl; mono- or di- (C 5 -C 10 ) aryl- or heteroarylaminocarbonyl; mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl; -Y-Q- is -C(=0)NH-Q- or -NH-C(=O)-NH-Q; 5 Q is a 5 to 10-membered aromatic or heteroaromatic ring; R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic (CI-C 6 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic 10 (C 1 -C 6 ) alkylcarbonylamino, mono- or di- (C 5 -CIO) aryl- or heteroarylaminocarbonyl; mono- or di, linear, branched, or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C 1 -C 6 ) alkylsulphonylamino; linear, branched, or cyclic (C 1 -C 6 ) alkylsulphonyl; mono- or di- (C 5 -CIO) aryl- or heteroarylsulphamoyl; mono- or di- linear, 15 branched, or cyclic (C 1 -C 6 ) alkylsulphamoyl; linear, branched or cyclic (CI-C 6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl, (CI-C 6 ) alkylthio-(CI-C 6 ) alkyl; R' represent, independently from one another when j = 2, halogen; hydroxy; mercapto; cyano; nitro; trihalomethyl; trihalomethoxy; linear, 20 branched or cyclic (Ci-C 6 ) alkyl, trihaloalkyl, alkoxy, hydroxyalkyl, mercaptoalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphonyl; linear, branched, or cyclic (CI-C 6 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C 1 -C 6 ) alkylsulphamoyl; linear, branched or cyclic (CI-C 6 ) alkoxy-(CI-C 6 ) 25 alkyl, mono- or di- (C 1 -C 6 ) alkylamino-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylthio-(Cl C) alkyl; provided that when k is zero and the sum of w and h is 4, T' is mercapto; amino; trihaloalkyl; hydroxyalkyl; (CI-C 6 ) aminoalkyl; WO 2007/098826 PCT/EP2007/000382 143 mercaptoalkyl; alkylthio; alkoxycarbonyl; alkylcarbonylamino; mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylamino; linear, branched or cyclic (C 1 -C 6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl, or (CI-C 6 ) alkylthio-(CI-C 6 ) alkyl; mono- or di- (CI-C 3 ) alkylaminosulphonyl, 5 or j 7); and that when j=0, and the sum of w, h and k is 4, then KI and K2 are not both hydrogen; and with the exclusion of the following compounds: 1-[4-(2-Amino-thiazol-5-yl)-phenyl]-3-(3-imidazol-1-yl-propyl)-urea; 1 -(Biphenyl-4-yl)-3-(5-(spiro(indane- 1,4'-piperidine- 1 0-yl)-pentyl)-urea; 10 1-(Biphenyl-4-yl)-3-(4-(spiro(indane-1,4'-piperidine-10-yl)-butyl)-urea; 3-{4 [3-(3-Morpholin-4-yl-propyl)-ureido]-phenyl}-1H-indazole-5-carboxylic acid amide;3-{4-[3-(3-Piperidin-1-yl-propyl)-ureido]-phenyl}-1H-indazole-5 carboxylic acid amide;1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl) phenyl]-3-(3-morpholin-4-yl-propyl)-urea; 15 1-[4-(8-Cyclopropylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(3 pyrrolidin- 1 -yl-propyl)-urea; 1-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-[4-(8 methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea; 1-[4-(8 Cyclopropylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(3-morpholin-4-yl propyl)-urea; 1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(3 20 pyrrolidin- 1 -yl-propyl)-urea; N-Biphenyl-4-yl-4-piperazin- 1 -yl-butyramide. 2. A compound according to claim 1 wherein: w, h, k, KI, K2, j, p, q, q' and Y are as described in claim 1 Xis Tp L T'p U N N-()q' ;N- ' 25 z is selected from CH 2 , N, 0; T' represent, independently from one another when p is >1, hydroxy; WO 2007/098826 PCT/EP2007/000382 144 amino; cyano; nitro; linear, branched or cyclic (C 1 -C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; mono- or di-, linear, branched or cyclic (CI-C 6 ) alkylamino; linear, branched or cyclic (CI-C 6 ) alkoxy-(CI-C 6 ) alkyl, 5 mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl, or (CI-C 6 ) alkylthio-(C 1 -C 6 ) alkyl; (CI-C 3 ) alkylsulphonylamino; mono- or di- (C 1 -C 3 ) alkylaminosulphonyl; sulphamoyl; linear, branched or cyclic (C 1 -C 6 ) alkylaminocarbonyl; carbamoyl; or, when p is 2 or 3, two T' substituents form a 5- to 8-membered ring with spiro or fused junction; 10 U and U' represent, independently from one another, hydrogen; a linear, branched or cyclic (C 1 -C 6 ) alkyl, azaalkyl, oxaalkyl chain optionally substituted with hydroxy, oxo, trihalomethyl, trihalomethoxy, carbamoyl, sulphamoyl, pyridyl, linear, branched or cyclic (C 1 -C 3 ) alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, mono- or di-, linear, branched or cyclic 15 (CI-C 3 ) alkylaminocarbonyl, (C 1 -C 3 ) alkylsulphonylamino, (CI-C 3 ) alkylsulphonyl, mono- or di- (CI-C 3 ) alkylsulphamoyl, mono- or di-, linear, branched, or cyclic (C 1 -C 6 ) alkylamino; Q is a 6 to 10-membered aromatic or heteroaromatic ring; R represents a 5 to 10-membered aromatic or heteroaromatic ring 20 optionally substituted with one or more groups independently selected from: halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic (C 1 -C 6 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic (C 1 -C 6 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (CI-C 6 ) 25 alkylsulphonylamino; linear, branched, or cyclic (C 1 -C 6 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (C 1 -C 6 ) alkylsulphamoyl; linear, branched or cyclic (C 1 -C 6 ) alkoxy-(CI-C 6 ) alkyl, mono- or di- (C 1 -C 6 ) alkylamino-(CI-C 6 ) alkyl; WO 2007/098826 PCT/EP2007/000382 145 R' represent, independently of one another when j = 2, halogen; hydroxy; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy, hydroxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphonyl; linear, branched, or cyclic (C 1 -C 3 ) alkylcarbonylamino; mono 5 or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; (C 1 -C 3 ) alkylsulphonylamino; linear, branched, or cyclic (C 1 -C 3 ) alkylsulphamoyl; linear, branched or cyclic (C 1 -C 3 ) alkoxy-(CI-C 3 ) alkyl, mono- or di- (C 1 -C 3 ) alkylamino-(CI-C 3 ) alkyl, (CI-C 3 ) alkylthio-(CI-C 3 ) alkyl. 10 3. A compound according to claim 2, wherein: K1, K2, j, p, q, q', T', U, U', Q, R, R' and Y are as defined in claim 2 w, h and k are, independently from one another, 0, 1, 2, or 3 with the condition that w + h + k = 4; Xis T'p U ()qL ' ; N 15 / z is selected from CH 2 , N, 0. 4. The compounds of claim 3 wherein: h, w, Q, and Y are as defined in claim 3 k is 0 20 X is a group of formula: U U and U' represent, independently from one another, hydrogen; a linear, branched or cyclic (CI-C 6 ) alkyl, azaalkyl, oxaalkyl chain optionally substituted with trihalomethyl, trihalomethoxy, carbamoyl, sulphamoyl, 25 pyridyl; WO 2007/098826 PCT/EP2007/000382 146 j is 0, or 1; R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (Ci-C 6 ) alkyl, trihaloalkyl, 5 alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; R' represents halogen; trihalomethyl; trihalomethoxy; linear, branched or cyclic (Ci-C 3 ) alkyl, alkoxy. 5. A compound according to claim 3 wherein: 10 j, q, q', Q, and Y are as defined in claim 3; KI and K2 represent, independently from one,another hydrogen; halogen; (CI-C 3 ) alkyl, alkoxy; X is a group of formula: T'p Iq z N-()q' 15 z is CH 2 , N, 0; p is 0 or 1; T' represents linear, branched or cyclic (Ci-C 3 ) alkyl, trihaloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; 20 R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic (Ci-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 3 ) 25 alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C 1 -C 3 ) alkylsulphonylamino; linear, branched, or cyclic (CI-C 6 ) alkylsulphonyl; WO 2007/098826 PCT/EP2007/000382 147 mono- or di- linear, branched, or cyclic (Ci-C 6 ) alkylsulphamoyl; linear, branched or cyclic (Ci-C 6 ) alkoxy-(Ci-C 6 ) alkyl, mono- or di- (CI-C 6 ) alkylamino-(CI-C 6 ) alkyl; R' represents, independently from one another when j = 2, halogen; 5 hydroxy; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; (CI-C 3 ) alkylsulphonylamino; linear, branched, or cyclic (CI-C 3 ) alkylsulphamoyl; linear, branched or cyclic 10 (CI-C 3 ) alkoxy-(CI-C 3 ) alkyl, mono- or di- (CI-C 3 ) alkylamino-(Ci-C 3 ) alkyl, (CI-C 3 ) alkylthio-(Ci-C 3 ) alkyl. 6. A compound according to claim 5, wherein: j, Q, and Y are as defined in claim 5; Ki and K2 represent, independently from one another, hydrogen; 15 halogen; (CI-C 3 ) alkyl; X is a group of formula: T'p 0q N-()q'; z is CH 2 , N; q and q' are, independently from one another, integers from 1 to 3; 20 T' represents linear, branched or cyclic (Ci-C 3 ) alkyl, alkylcarbonyl; R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; linear, branched or cyclic (C 1 -C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (C 1 -C 3 ) alkylcarbonylamino; mono- or di, linear, branched, 25 or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; R' represents, independently from one another when j = 2, halogen; WO 2007/098826 PCT/EP2007/000382 148 trihalomethyl; linear, branched or cyclic (CI-C 3 ) alkyl, alkoxy. 7. A compound according to claim 6 in which Q, j and R are as defined in claim 6; Y is -C(=O)NH-. 5 8. A compound according to claim 7 in which Q is a phenyl or pyridyl ring; j is 1 or 2; R represents a phenyl, pyridyl, pyrazolyl ring, optionally substituted with one or more groups independently selected from: halogen; linear, 10 branched or cyclic (Ci-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl; 9. A compound according to claim 6 in which Q and R are as defined in claim 6 15 Y is -NH-C(=O)-NH-. 10. A compound according to claim 9 in which Q is a phenyl or pyridyl; R represents a phenyl, pyridyl or pyrazole ring optionally substituted with one or more groups independently selected from: halogen; linear, 20 branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (Ci-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (CI-C 3 ) alkylaminocarbonyl; carbamoyl.
11. A compound according to claim 2 wherein: j, T', q, q' p, R, R', Q and Y are as defined in claim 2; 25 w, h and k are, independently from one another, 0,1,2, or 3 with the condition that w+ h+ k= 3 X is WO 2007/098826 PCT/EP2007/000382 149 Oq Iq z N--()q';
12. A compound according to claim 11 wherein: w, h, k, j, p and Q are as defined in claim 11 q and q' are, independently from one another, integers from 1 to 3; 5 T' represent, independently from one another when p >1, hydroxy; cyano; oxo; linear, branched or cyclic (C 1 -C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (CI-C 6 ) alkoxy-(Ci-C 6 ) alkyl; (C 1 -C 3 ) alkylsulphonylamino; mono- or di- (CI-C 3 ) alkylaminosulphonyl; sulphamoyl; 10 linear, branched or cyclic (CI-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched or cyclic (C 1 -C 3 ) alkoxy-(C 1 -C 3 ) alkyl; (CI-C 3 ) alkylsulphonylamino; mono- or di- (CI-C 3 ) alkylsulphamoyl; (CI-C3) sulphonyl; -Y- is -NH-C(=O)-NH-; 15 R represents a 5 to 6-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; cyano; linear, branched or cyclic (CI-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (CI-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 3 ) alkylaminocarbonyl; carbamoyl; linear, 20 branched, or cyclic (Ci-C 3 ) alkylsulphonylamino; linear, branched, or cyclic (CI-C 3 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (CI-C 3 ) alkylsulphamoyl; linear, branched or cyclic (CI-C 3 ) alkoxy-(CI-C 3 ) alkyl; R' represents, independently of one another when j = 2, halogen; trihalomethyl; trihalomethoxy; linear, branched or cyclic (CI-C 3 ) alkyl, 25 alkoxy;
13. A compound according to claim 12 wherein: WO 2007/098826 PCT/EP2007/000382 150 k is 0 p is 0, or 1; T' represents, independently from one another when p is greater than 1, linear, branched or cyclic (C 1 -C 3 ) alkyl, alkylcarbonyl, alkoxycarbonyl, 5 alkylcarbonylamino; linear, branched or cyclic (C 1 -C 3 ) alkylaminocarbonyl; carbamoyl; Q is a phenyl or pyridyl; j is 0 or 1; R represents a phenyl or pyridyl ring optionally substituted with one or 10 more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (C 1 -C 6 ) alkyl, alkoxy; linear, branched, or cyclic (C 1 -C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (C 1 -C 3 ) alkylaminocarbonyl; carbamoyl; R' represents halogen. 15 14. A pharmaceutical composition containing a compound according to claims 1-13 with a pharmaceutically acceptable carrier or excipient.
15. The use of a compound according to claims 1-13 for the preparation of a medicament for the treatment of neurological, psychiatric, cognitive, immunological and inflammatory disorders. 20 16. The use according to claim 15, for the treatment of a neurodegenerative disease, particularly Alzheimer's disease.
17. A method for the treatment or prevention of diseases, conditions, or dysfunctions involving the alpha 7 nAChR, which comprises administering to a subject in need thereof an effective amount of a compound according to 25 claims 1-13.
18. A method according to claim 17, for the prevention or treatment of a psychiatric or neurodegenerative disease, particularly senile dementia, attention deficit disorders, Alzheimer's disease and schizophrenia.
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