AU2006264652A1 - Substituted cyclohexyl derivatives as NK-3 receptor antagonists - Google Patents

Substituted cyclohexyl derivatives as NK-3 receptor antagonists Download PDF

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AU2006264652A1
AU2006264652A1 AU2006264652A AU2006264652A AU2006264652A1 AU 2006264652 A1 AU2006264652 A1 AU 2006264652A1 AU 2006264652 A AU2006264652 A AU 2006264652A AU 2006264652 A AU2006264652 A AU 2006264652A AU 2006264652 A1 AU2006264652 A1 AU 2006264652A1
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alkyl
compound
optionally substituted
optionally
heteroaryl
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AU2006264652A
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Olivier Dirat
Jason Matthew Elliott
Andrew Pate Owens
Duncan Edward Shaw
Francine Sternfeld
Brian John Williams
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Description

WO 2007/003965 PCT/GB2006/050184 Substituted cyclohexyl derivatives as NK-3 receptor antagonists The present invention relates to substituted cyclohexyl derivatives, pharmaceutical compositions comprising them and their use in treating diseases mediated by neurokinin-3 (NK-3) receptors. These 5 compounds can thus be used in methods of treatment to suppress and treat such disorders. Background information on NK-3 receptor antagonists can be found in literature reviews such as Giardina and Raveglia, Exp. Opin. Ther. Patents (1997) 7(4): 307-323 and Giardina et al., Exp. Opin. Ther. Patents (2000) 10(6): 939-960. These references also contain pertinent information on preclinical validation of therapies that can be treated with NK-3 antagonists. 10 Representative examples of compounds prepared in the art as NK-3 antagonists are to be found in WO-A-9719926 (SmithKline Beecham S.p.a.) and US-A-5741910 (Sanofi). Substituted cyclohexyl derivatives are known in the art. For instance, published International applications WO 2004/031137 and WO 2004/031139 (both Merck Sharp & Dohme Limited) disclose cyclohexyl sulfones as gamma-secretase inhibitors useful in the treatment of Alzheimer's disease. 15 However, neither document discloses that substituted cyclohexyl derivatives are useful as NK-3 antagonists and are thus useful in the treatment of diseases such as schizophrenia. The present invention thus provides a compound of Formula (I):
R
5
R
6 7// R A S(O)n-X Z-N RI) R2 Y R B R3 R4 20 wherein: rings A and B are independently aryl or heteroaryl; n is 0, 1 or 2; X and Y are independently selected from a bond, -CH 2 -, -C(CiAalkyl) 2 - and -N(Ci 4 alkyl)-; Z is a bond, -CH 2 - or -C(CiAalkyl) 2 -; 25 R 1 is hydrogen, C 1
-
6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3
-
8 cycloalkyl, hydroxy, C 1
-
6 alkoxy, halogen, CN, C0 2
(C
1
-
6 alkyl) or C(CH 3
)
2 0H, optionally substituted by 1 to 8 halogen atoms;
R
2 is hydrogen, C 1
_
6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3
-
8 cycloalkyl or halogen;
R
3 is hydrogen, C 1
-
6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3
-
8 cycloalkyl, hydroxy, C 1
-
6 alkoxy, halogen or CN, optionally substituted by 1 to 8 halogen atoms; 30 R 4 is hydrogen, C1_ 6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3
-
8 cycloalkyl or halogen; R5 and R6 are independently selected from hydrogen, C1_ 6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3 8 cycloalkyl, hydroxy, C 1
-
6 alkoxy or halogen; WO 2007/003965 PCT/GB2006/050184 2 R7 is hydrogen, CI 6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl, C 3
-
8 cycloalkyl, (CH 2 )o- 2 aryl, (CH 2
)
0 2 heteroaryl or Het, optionally substituted by 1 to 8 halogen atoms, CiAalkyl, hydroxy, CiAalkoxy or heteroaryl, which heteroaryl is optionally substituted by 1 to 3 groups selected from CiAalkyl;
R
8 is hydrogen, CI 6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl or C 3
-
8 cycloalkyl; 5 or R7 and R 8 , together with the nitrogen atom to which they are attached, form a 4- to 7 membered heterocycle, optionally containing 1, 2 or 3 further heteroatoms selected from N, 0 and S, which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from C1- 6 alkyl, C 2 6 alkenyl, C 2
-
6 alkynyl or C 3
-
8 cycloalkyl, hydroxy, oxo, (CH 2 )o- 3
CI
6 alkoxy, (CH 2 )o-30aryl, (CH 2 )o- 3 aryl, 10 (CH 2 )o- 3 heteroaryl, (CH 2 )o- 3 Het, or (CH 2
)
0
-
3 NRaRb, wherein said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from CI 6 alkyl, hydroxy, oxo, CI 6 alkoxy or halogen, which CI 6 alkyl being optionally substituted by hydroxy or 1 to 5 halogen atoms, and where said aryl, heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains 1, 2 or 3 heteroatoms selected from N, 0 or S and which ring is optionally substituted by CiAalkyl, hydroxy, 15 oxo, CiAalkoxy or halogen, and which heterocycle may optionally be fused to heteroaryl, which heteroaryl is optionally substituted by
CI
6 alkyl or trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5- or 10-membered mono- or bi-cyclic ring system optionally containing 1, 2 or 3 heteroatoms selected from N, 0 and S, and further optionally 20 containing 1, 2 or 3 double bonds and also optionally substituted by 1 to 3 groups independently selected from C 1
.
6 alkyl, hydroxy, oxo, phenyl and SO 2
C
1
.
6 alkyl; Ra is hydrogen, C 1
.
6 alkyl, C(O)C 1
.
6 alkyl, C(O)OC 1
.
6 alkyl, C(O)NH(C 1
.
6 alkyl), (CH 2 )o- 3 aryl,
(CH
2 )o- 3 heteroaryl or SO 2
C
1
.
6 alkyl, optionally substituted by C 1
.
6 alkyl; Rb is hydrogen, C 1
.
6 alkyl or aryl; 25 and pharmaceutically acceptable salts thereof. In one embodiment, ring A is phenyl, pyridyl or pyrimidyl. Preferably, ring A is phenyl or pyridyl. In another embodiment, ring B is aryl or pyridyl. Preferably, ring B is phenyl. In another embodiment, n is 1 or 2. Preferably, n is 2. 30 In another embodiment, X is a bond, -CH 2 - or -C(CiAalkyl) 2 -. Preferably, X is a bond or CH 2 -. More preferably, X is a bond. In another embodiment, Y is a bond, -CH 2 - or -C(CiAalkyl) 2 -. Preferably, Y is a bond or CH 2 -. More preferably, Y is a bond. In another embodiment, Z is a bond or -CH 2 -. Preferably, Z is a bond. 35 In another embodiment, R 1 is hydrogen, C 1
.
6 alkyl, hydroxy, C 1
.
6 alkoxy, halogen, CN, C0 2
(C
1 . 4 alkyl) or C(CH 3
)
2 0H, optionally substituted by 1 to 5 halogen atoms. Preferably, R 1 is hydrogen, C 1 . 4 alkyl, Ci 4 alkoxy, halogen, CN, CO 2
CH
3 or C(CH 3
)
2 0H, optionally substituted by 1 to 3 halogen atoms.
WO 2007/003965 PCT/GB2006/050184 3 More preferably, R 1 is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, CN, CO 2
CH
3 or
C(CH
3
)
2 0H. In another embodiment, R 2 is hydrogen or CI 6 alkyl. Preferably, R 2 is hydrogen or methyl. More preferably, R 2 is hydrogen. 5 In another embodiment, R 3 is hydrogen, CI 6 alkyl, hydroxy, CI 6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. Preferably, R 3 is hydrogen, Ci 4 alkyl, Ci 4 alkoxy, halogen or CN, optionally substituted by 1 to 3 halogen atoms. More preferably, R 3 is hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN. In another embodiment, R 4 is hydrogen or halogen. Preferably, R 4 is hydrogen, fluorine or 10 chlorine. In another embodiment, R5 is hydrogen, CI 6 alkyl, hydroxy, CI 6 alkoxy, or halogen. Preferably, R5 is hydrogen, methyl, hydroxy, methoxy or fluorine. More preferably, R5 is hydrogen, hydroxy or fluorine. Most preferably, R5 is hydrogen. In another embodiment, R6 is hydrogen or CI 6 alkyl. Preferably, R6 is hydrogen or methyl. 15 More preferably, R6 is hydrogen. In another embodiment, R7 is hydrogen, CI 6 alkyl, (CH 2 )o- 2 aryl, or Het, optionally substituted by CiAalkyl, CiAalkoxy or heteroaryl, which heteroaryl is optionally substituted by 1 or 2 methyl or ethyl groups. Preferably, R7 is hydrogen, benzyl or piperidinyl, optionally substituted by methoxy or pyrazolyl, which pyrazolyl is optionally substituted by 1 or 2 methyl or ethyl groups. More preferably, R7 is 20 hydrogen, 4-methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl. In another embodiment, R 8 is hydrogen or CI 6 alkyl. Preferably, R 8 is hydrogen or methyl. More preferably, R 8 is hydrogen. In another embodiment, R7 and R 8 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycle, optionally containing 1 or 2 further heteroatoms selected from N 25 and 0, which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from CiAalkyl, oxo,
CH
2 -0-phenyl, phenyl, heteroaryl, CH 2 heteroaryl, Het, NH 2 , (CH 2
)
0
-
1 NHIRa or CH 2 N(phenyl)SO 2
CH
3 , where said aryl, heteroaryl, and Het are optionally substituted by 1, 2 or 3 groups selected from CiAalkyl, 30 oxo or halogen, which Ci 4 alkyl being optionally substituted by hydroxy or 1 to 3 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5-or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted by Ci 4 alkoxy, and which heterocycle may optionally be fused to pyridyl or triazolyl, optionally substituted by trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5-membered monocyclic or a 35 8- or 9-membered bicyclic ring system, optionally containing 1 or 2 N atoms, further optionally containing 2 or 3 double bonds and also optionally substituted by CiAalkyl, oxo, phenyl, or SO 2 CiAalkyl, and Ra is as hereinbefore defined.
WO 2007/003965 PCT/GB2006/050184 4 Preferably, R7 and R 8 , together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, piperazinyl or morpholinyl ring, which ring is optionally substituted by one or two groups selected from oxo, methyl, phenyl, CH 2 -0-phenyl, NH 2 , H \ 0 -N1 N,-N-C0 O H II Y N-C-N I H
SO
2
CH
3 5 N N H 0 N F N- N tBu
CF
3 / N N N / N N N \N /N -N -N -NN | -N N N NNN N< N 10 N O
-
N-N N,'N N N
H
3
CO
WO 2007/003965 PCT/GB2006/050184 5 0 0 N N N O or and which ring is optionally fused to 3-trifluoromethylpyridyl or 1,2,4-triazolyl, and which ring is further optionally spiro-fused to 0 NH N! NN N 0 N 5 , ,SO 2
CH
3 or where * indicates the spiro-centre. In one embodiment of the present invention, there is provided the compound of formula (Ia): R1 -S(O)"-X -Z-N - (Ia) 10 or a pharmaceutically acceptable salt thereof, wherein ring A, n, X, Y, R', R 3 , R 4 , R7 and R' are as defined in relation to formula (I). Preferably, ring A is phenyl or pyridyl. Preferably, n is 1 or 2. More preferably, n is 2. Preferably, X is a bond or -CH 2 -. More preferably, X is a bond. 15 Preferably, Y is a bond or -CH 2 -. More preferably, Y is a bond. Preferably, R 1 is hydrogen, CI 6 alkyl, hydroxy, CI 6 alkoxy, halogen, CN, C0 2 (C1.4alkyl) or
C(CH
3
)
2 0H, optionally substituted by 1 to 5 halogen atoms. More preferably, R 1 is hydrogen, CI 4 alkyl, C1.4alkoxy, halogen, CN, CO 2
CH
3 or C(CH 3
)
2 0H, optionally substituted by 1 to 3 halogen atoms. Most preferably, R 1 is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, CN, CO 2
CH
3 or 20 C(CH 3
)
2 0H. Preferably, R 3 is hydrogen, C 1
.
6 alkyl, hydroxy, C 1
.
6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. More preferably, R 3 is hydrogen, C 1
.
4 alkyl, C1.4alkoxy, halogen or CN, optionally substituted by 1 to 3 halogen atoms. Most preferably, R 3 is hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN.
WO 2007/003965 PCT/GB2006/050184 6 Preferably, R 4 is hydrogen or halogen. More preferably, R 4 is hydrogen, fluorine or chlorine. Preferably, R7 is hydrogen, benzyl or piperidinyl, optionally substituted by methoxy or pyrazolyl, which pyrazolyl is optionally substituted by 1 or 2 methyl or ethyl groups. More preferably, R7 is hydrogen, 4-methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl. 5 Preferably, R 8 is hydrogen. In an alternative preference, R7 and R 8 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycle, optionally containing one further heteroatom selected from N and 0, which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from C1.4alkyl, oxo, 10 CH 2 -0-phenyl, phenyl, heteroaryl, CH 2 heteroaryl, Het, NH 2 , (CH 2
)
0
-
1 NHIRa or CH 2 N(phenyl)SO 2
CH
3 , where said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups selected from CI 4 alkyl, oxo, halogen, which CI 4 alkyl being optionally substituted by hydroxy or 1 to 3 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted by CI 4 alkoxy, 15 and which heterocycle may optionally be fused to pyridyl or triazolyl, optionally substituted by trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5- membered monocyclic or a 8- or 9 membered bicyclic ring system, optionally containing 1 or 2 N atoms, further optionally containing 2 or 3 double bonds and also optionally substituted by CI 4 alkyl, oxo, phenyl or SO 2
CI
4 alkyl; 20 and where Ra is as defined in relation to formula (I). More preferably, R7 and R 8 , together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperazinyl or morpholinyl ring, or an oxo-substituted piperazinyl ring further substituted on the nitrogen atom by thiazolyl, 1-ethyl-3-methyl-1,2-pyrazol-5-yl, fluorophenyl or pyridyl, or a piperidinyl or dihydropyridinyl ring optionally substituted with one or two groups selected 25 from methyl, phenyl, CH 2 -0-phenyl, NH 2 , H 0 -N N1,N H N -_ N H SO 2
CH
3 H N tBu
CF
3 N N NN / N N / N N WO 2007/003965 PCT/GB2006/050184 7
-
-N -NN |-N \ N N N OH -NN N 1 0 1-N NN N H3C ,No NN N / \N 0 !- N0 0 N N N
H
3 CO or 5 and further optionally fused to 3-trifluoromethylpyridyl or 1,2,4-triazolyl, and further optionally spiro-fused to 0 10 formula (Iaa): R NR9
-
( aa) r "N \ / \ /OC 3 o R3 or a pharmaceutically acceptable salt thereof, wherein R and R3 are as defined in relation to formula (I), WO 2007/003965 PCT/GB2006/050184 8 and R 9 is (CH 2 )o- 3 NRaR, where Ra and Rb are as defined in relation to formula (I), or (CH 2 )o- 3 heteroaryl or (CH 2 )o- 3 Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from CI 6 alkyl, hydroxy, oxo, CI 6 alkoxy or halogen, which CI 6 alkyl being optionally substituted by hydroxy or 1 to 5 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5 5 or 6-membered ring which optionally contains 1 or 2 heteroatoms selected from N and 0, and which ring is optionally substituted by Ci 4 alkyl, hydroxy or CiAalkoxy. Preferably, R 1 is hydrogen, CI 6 alkyl, hydroxy, CI 6 alkoxy, halogen, CN, C0 2 (Ci-alkyl) or
C(CH
3
)
2 0H, optionally substituted by 1 to 5 halogen atoms. More preferably, R 1 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy, chlorine, CN, CO 2
CH
3 or C(CH 3
)
2 0H. 10 Preferably, R 3 is hydrogen, C 1
.
6 alkyl, hydroxy, C 1
.
6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. More preferably, R3 is methyl, trifluoromethyl, trifluoromethoxy, CN, fluorine, chlorine or bromine. Preferably, R 9 is (CH 2
)
0
-
1 NRaRb, where Ra and Rb are as hereinbefore defined, or heteroaryl or Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected 15 from Ci 4 alkyl or oxo, which CiAalkyl being optionally substituted by hydroxy or 1 to 3 fluorine atoms, and where said heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted by methoxy. Examples of suitable R 9 groups include: tBu
SO
2
CH
3 / Bu - I N i H 11 1 N -N-C-O ' N IN
CF
3 20 N N -N N -N N \ N NN 20H 01 N /-- N -N I -N N N
H
3
CO
WO 2007/003965 PCT/GB2006/050184 9 0 0 N N N 0 '-band " . In another preferred embodiment of the present invention, there is provided the compound of formula (Iab): N 0
F
3 C N R9 (Iab) 5 R3 or a pharmaceutically acceptable salt thereof, wherein R 3 is as defined in relation to formula (I) and R 9 is as defined in relation to formula (Iaa). Preferably, R 3 is hydrogen, CI 6 alkyl, hydroxy, CI 6 alkoxy or halogen. More preferably, R 3 is hydrogen or halogen. Most preferably, R 3 is fluorine, chlorine or bromine. 10 Preferably, R 9 is heteroaryl, optionally substituted by 1 or 2 groups independently selected from Cl-alkyl, and where said heteroaryl is optionally fused to a 5- or 6-membered ring which optionally contains a nitrogen atom. Examples of suitable R 9 groups include: / NNI/ N / NN i and 15 The independent syntheses of any optical isomers or their chromatographic separations may be achieved as known in the art. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. The present invention includes within its scope solvates of the compounds of formula (I), for 20 example hydrates, and salts thereof. The present invention also includes within its scope any enantiomers, diasteromers, geometric isomers and tautomers of the compounds of formula (I). It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the invention.
WO 2007/003965 PCT/GB2006/050184 10 As used herein, the term "C1- 6 alkyl" means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t butyl, n- and isopropyl, ethyl and methyl. "CI-4alkyl" shall be understood in an analogous manner, as shall "C1- 6 alkoxy" and "C i 4 alkoxy". 5 The term "C 2
-
6 alkenyl" means linear or branched chain alkenyl groups having from 2 to 6 carbon atoms and includes all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3 butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl). The term "C 2
-
6 alkynyl" means linear or branched chain alkynyl groups having from 2 to 6 carbon atoms and includes all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3 10 butynyl, 1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). The term "C 3
-
8 cycloalkyl" means a cyclic alkane ring having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "aryl" refers to phenyl and naphthyl. 15 The term "heteroaryl" as used herein is intended to include the following groups: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and pyrrolidinyl. The term "Het" means a heteroaliphatic ring of 3 to 7 ring atoms, which ring contains 1, 2 or 3 heteroatoms selected from N, 0 or S or a group S(O), S(0) 2 , NH or NC-alkyl. Examples of Het include 20 aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, pyran, dioxanyl, morpholine, oxathiolanyl, dithianyl, oxathianyl, thiomorpholinyl, trioxanyl, trithianyl. The terms "thiophenyl" and "thienyl" have the same meaning herein and are used interchangeably. Similarly, the following pair of terms has the same meaning: "pyridinyl" and "pyridyl". 25 Exemplary compounds of the present invention include those listed in the Examples section hereinbelow and their pharmaceutically acceptable salts. These compounds and those defined by the immediately preceding definitions are useful in therapy, particularly as NK-3 antagonists. The terms "administration of' and or "administering a" compound should be understood to 30 mean providing a compound of the invention to the individual in need of treatment. The term "subject," (alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The compounds of the present invention may be administered in the form of pharmaceutically 35 acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, WO 2007/003965 PCT/GB2006/050184 11 methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, 5 subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those 10 formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N' dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or 15 inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form. Also, in the case of an alcohol group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. 20 The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each 25 route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with 30 the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used 35 herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
WO 2007/003965 PCT/GB2006/050184 12 The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical 5 compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, 10 lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate 15 or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for 20 example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring 25 phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol 30 anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The 35 oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a WO 2007/003965 PCT/GB2006/050184 13 palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, 5 suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, 10 for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. 15 Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those 20 suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending 25 medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature 30 and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) 35 The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
WO 2007/003965 PCT/GB2006/050184 14 In the treatment or prevention of conditions which require NK-3 receptor modulation an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may 5 be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active 10 ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, 15 body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Thus there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof 20 for use in a method of treatment of the human or animal body by therapy. Likewise there is provided the use of a compound of formula (I) for the manufacture of a medicament for treating a neurokinin-3 mediated disease. There is also disclosed a method of treatment of a subject suffering from a neurokinin-3 mediated disease, which comprises administering to that patient a therapeutically effective amount of a 25 compound of formula (I) or a pharmaceutically acceptable salt thereof. Examples of diseases mediated by neurokinin-3 include CNS disorders such as depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal 30 affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (including generalised anxiety disorder (GAD), social anxiety disorder (SAD), agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); phobias (including agoraphobia and social phobia); 35 psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, acute psychosis, alcohol psychosis, autism, delirium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and WO 2007/003965 PCT/GB2006/050184 15 delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); post-traumatic stress disorder; attention deficit hyperactive disorder (ADHD); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (memory disorders, amnesia, amnesic disorders and age-associated memory 5 impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states)); convulsive disorders such as epilepsy (which includes simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, 10 tonic seizures, tonic clonic seizures and atonic seizures); psychosexual dysfunction (including inhibited sexual desire (low libido), inhibited sexual arousal or excitement, orgasm dysfunction, inhibited female orgasm and inhibited male orgasm, hypoactive sexual desire disorder (HSDD), female sexual desire disorder (FSDD), and sexual dysfunction side-effects induced by treatment with antidepressants of the SSRI-class); sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep 15 apnea and narcolepsy); disorders of eating behaviours (including anorexia nervosa and bulimia nervosa); neurodegenerative diseases (such as Alzheimer's disease, ALS, motor neuron disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of 20 posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities (such as abuse of cocaine, ethanol, nicotine, 25 benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative, hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof); pain (which includes neuropathic pain (including diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; pain associated with fibromyalgia or cancer; AIDS-related and HIV-related neuropathy; chemotherapy 30 induced neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia; sympathetically maintained pain and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis; reflex sympathetic dystrophy such as shoulder/hand syndrome), acute pain (e.g. musculoskeletal pain, post operative pain and surgical pain), inflammatory pain and chronic pain, pain associated with normally non-painful sensations such as 35 "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased, sensitivity, to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the WO 2007/003965 PCT/GB2006/050184 16 stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia), pain associated with migraine, and non-cardiac chest pain); certain CNS-mediated disorders such as emesis, irritable bowel syndrome, and non-ulcer dyspepsia; COPD, asthma, cough, gastro-oesophageal reflex induced cough, and exacerbated asthma; urinary incontinence; hypertension; and conditions associated 5 with platelet hyperaggregability such as tissue ulceration, nephrotic syndrome, diabetes, migraine, coronary artery disease, pre-eclampsia and stroke. Preferably, the compounds of the invention are useful for the treatment of depression; anxiety disorders; phobias; psychosis and psychotic disorders; post traumatic stress disorder; attention deficit hyperactive disorder (ADHD); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities; and irritable bowel 10 syndrome. More preferably, the compounds of the invention are useful for the treatment of depression; anxiety disorders; phobias; and psychosis and psychotic disorders (especially schizophrenia, schizo affective disorder, and schizophreniform diseases. Most preferably, the compounds of the invention are useful for the treatment of schizophrenia. The compounds for use in the present invention are generally active in the following tests. They 15 normally have an IC 5 o of less than 1gM and preferably less than 100nM. Details of the NK-3 receptor and its heterologous expression can be found in Huang et al., BBRC, 1992, 184: 966-972 and Sadowski et al., Neuropeptides, 1993, 24: 317-319. A membrane preparation is prepared as follows. A 10-layer cell factory is seeded with CHO cells stably expressing NK-3 receptors. The CHO cells are prepared in a triple T175 flask in 11 growth 20 medium which contains Iscore's modified Dulbecco's medium containing 10ml/l 200mM L-Glutamine, l0ml/l penicillin-streptomycin, one vial of hypoxanthine-thymidine 500x/1, lmg/ml geneticin and 10% fetal bovine serum (inactivated). The cells are grown for 3 days in an incubator. The medium is washed off and the factory is rinsed twice with 400ml PBS (Ca, Mg-free). 400ml enzyme free dissoc. solution (EFDS) is added and the factory is maintained for 10 min at room temperature. The cells are dislodged 25 and the suspension poured into 500ml centrifuge bottles. The process is repeated with 200ml EFDS and the mixtures pooled giving 6 bottles in all, which are spun in a centrifuge for 10 min at 2200 rpm. The supernatants are aspirated and the residual cell pellets are frozen at -80* for 30 min to improve cell lysis and then resuspended in 40ml Tris with inhibitors per cell factory. The cells are homogenized in 40ml aliquots with 8 strokes of a glass-teflon grinder at setting 40. The homogenate is 30 transferred to 50ml centrifuge tubes and placed on a rocker for 15 min at r.t. The homogenate is rehomogenised and held on ice if necessary before being centrifuged again as above. The supernatant is transferred to Sorvall tubes for an SS-34 roter and held on ice. 40ml cold Tris with inhibitors is used to resuspend and combine the pellets which are again spun as above. The supernatants are again transferred to Sorvall tubes which, with those above, are spun 35 at 18000 rpm for 20 min. The supernatants are discarded and the pellets resuspended in a Storage Buffer consisting of 2.50ml IM Tris pH7.4, 50gl 1000x protease inhibitors (4mg/ml leupeptin (Sigmo), 40mg/ml Bacitracin WO 2007/003965 PCT/GB2006/050184 17 (Sigma) and 10mM phosphoranidon (Peninsula) all dissolved in water) plus 0.5ml 0.5M MnCl 2 made up to 50ml with H2Odd. A 10ml syringe is used with 20-, 23- and 25-gauge needles sequentially. A Bradford protein assay in conducted on 2-1 Ogl aliquots with BSA as standard before 500 1000lg aliquots are snap-frozen in liquid nitrogen for storage at -80*C. 5 The membrane binding assay is carried out as follows. The amount of membranes needed to specifically bind < 10% of 125 I-NeurokinB is predetermined. The frozen stocks are then diluted to allow addition in 50gl. The test compounds are dissolved in DMSO. An automated apparatus (Tecan) is programmed to add 5gl of compound or DMSO, approximately 100,000 cpm of isotope in 20gl buffer which is 10 prepared from 50gMTris, pH7.5, 150gM NaCl, bovine serum albumin to 0.02%, and protease inhibitors as in the storage buffer, made up as 0.5M stock, and 175gl assay buffer (as the storage buffer but containing 5gM MnCl 2 and without NaCl) into deep well Marsh boxes (Marsh Biomedical Products) in a 96-well format. Excess unlabelled competing peptide is added by hand for non-specific binding as indicated below. The binding reaction is initiated by adding 50gl of cell membranes. The tubes are 15 incubated with shaking for lh at r.t. and filtered on a Tomtec 96 well cell harvester using Mach III filtermats (Tomtec) or using either a Packard 96-well harvester or Tomtec 9600 using Unifilter GF/C (Packard), presoaked in 0.25% polyethyleneimine and washed five times with IX wash buffer (0.1M.Tris, pH7.4 and IM NaCl, 1X = 100ml of lOX stock per litre of cold distilled water). If using Unifilter plates, 60gl Microscint 20 (Packard) is added to each well and the plate is then heat-sealed before counting in a 20 Packard Topcount. Alternatively the filters from the filtermat are placed in 75xlOOmm plastic tubes and counted on a Cobra gamma counter. For the assay, typically 1 Ogg of membrane is used at 25,000 cpm which is filtered over a Unifilter GF/C presoaked in 0.5% BSA. Compounds of the present invention may be prepared by methods disclosed in the documents 25 hereinbefore referred to and by methods known in the art of organic synthesis and the Schemes set forth below. According to a general process (A), compounds of formula (I) where Z is a bond may be prepared by the reaction of a compound of formula (II) with a compound of formula (III):
R
5
R
6 S(O)n-X 0 HN/ Y R3j R4 (II) (III) 30 WO 2007/003965 PCT/GB2006/050184 18 where A, B, n, X, Y, R', R2, R3, BW, R, R, R and R are as defined in relation to formula (I). The reaction is conveniently preformed in the presence of a hydride source, such as a sodium triacetoxyborohydride, and a mild acid, such as acetic acid, in a suitable solvent, such as 1,2 dichloroethane. 5 Where they are not commercially available, the starting materials of formulae (II) and (III) may be prepared by methods illustrated in the following Schemes, by methods analogous to those described in the accompanying Descriptions and Examples, or by standard methods well known from the art. For example, compounds of formula (II) can be made from known compounds using procedures analogous to those found in published International applications WO 2002/081435, WO 2004/031137 and WO 10 2004/031139 (all Merck Sharp & Dohme Limited). It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. For instance, a compound of formula (I) where BW is bromine may be transformed into a 15 compound of formula (I) where BW is hydrogen by hydrogenation using, for example, a palladium on carbon catalyst and hydrogen gas, in a suitable solvent, such as ethyl acetate. In addition, a compound of formula (I) where R is methoxybenzyl may be transformed into a compound of formula (I) where R is hydrogen by treatment with ceric ammonium nitrate in a suitable solvent system such as acetonitrile/water. The resultant compound of formula (I) may be transformed 20 into a different compound of formula (I) by reaction with, for example, a substituted piperidinone in the presence of a hydride source such as sodium triacetoxyborohydride, and acid, such as acetic acid, in a suitable solvent, such as 1,2-dichloroethane. Also, a compound of formula (Iaa) where R9 is a BOC-protected amine, may be transformed to a compound of formula (Iaa) where R9 is an amine by treatment with acid, such as hydrochloric acid, in a 25 suitable solvent, such as 1,4-dioxane. The resultant compound of formula (Iaa) may be transformed into a compound of formula (Iaa) whereR9 is a urea derivative by reaction with an alkyl isocyanate in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane. General synthetic schemes: 30 Scheme 1 WO 2007/003965 PCT/GB2006/050184 19
R
1
R
1 0 RR RR3
R
1 - (D- 0 i SH + Br B B
R
3
R
4
R
3
R
4 R 0 R O R O iv O v, vi R2 R2 0' R2
NR
7
R
8 B B B
R
3
R
4
R
3
R
4
R
3
R
4 Cis & Trans Reagents: i) Et 3 N, CH 2 Cl 2 ; ii) mCPBA, CH 2 Cl 2 ; iii) 2,2-bis(2-iodoethyl)-1,3-dioxolane, NaH, DMF; iv) pTsOH, AcOH, H20, 50 'C; v) R 7 RNH, NaBH(OAc) 3 , AcOH, 1,2-dichloroethane; vi) separate isomers 5 Scheme 2 MeO 2 C- -S HOS B B Reagents: i) MeMgBr, THF, -78 C. Scheme 3 R1 R3 0-Br + B R2 R2 R4 SH 10 R3 R4 Reagents: i) NaH, DMF Scheme 4 R1 R1 0 SHR R2 S O R R3 iii
R
4 Br R1 0 R1 O R2D O i R2 15 R3 ) R4
R
3 Re WO 2007/003965 PCT/GB2006/050184 20 Reagents: i) 1,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate, CsF, DMF, 60 'C; ii) mCPBA, CH 2 Cl 2 ; iii) nBuLi, THF; iv) pTsOH, AcOH, H20, 50 C. Scheme 5 5
R
5 R 1 R5 R 6 R5 R 6 H O -XX /O || S X O R 0 2 SH R3 RR R3 R R3' R 0 R 5
R
6 0 Y Reagents: i) BF 3 .OEt 2 , CH 2 C1 2 ; ii) pTsOH, AcOll, 1120, 50 'C; iii) NaIO 4 , MeOHl, 1120. Scheme 6 10
R
5
R
6
R
5
R
6 R1 H- MeO 2 SOX R 5
R
6 ii R 2 S-X / R3 R4 R3 R4-SH R3 R Ri " Iii, iv
R
5
R
6 ai- 0 Reagents: i) MeSO 2 Cl, Et 3 N, CH 2 Cl 2 ; ii), Et 3 N, DMF, 80 C; iii) mCPBA, CH 2 Cl 2 ; iv) pTsOH, AcOH, H20, 50 C. Scheme 7 09 0 0 ii iii
H
2 N-(C) O 1,- 0 HN HN- HN N Ca HN
-
OH 15 ring C = aryl, heteroaryl WO 2007/003965 PCT/GB2006/050184 21 Reagents: i) haloacetyl chloride, ii) ethanolamine, iii) di-tert-butyl azodicarboxylate, nBu 3 P, EtOAc. The following abbreviations are used in the Schemes, Descriptions and Examples: DMF: NN dimethylformamide; DMSO: dimethylsulfoxide; Et 2 O: diethyl ether; EtOAc: ethyl acetate; h: hour(s); 5 MeCN: acetonitrile; MeOH: methanol; min: minute(s); RT: room temperature; TF: tetrahydrofuran The following Descriptions and Examples illustrate the present invention. Description 1: 1-Chloro-4-[(4-fluorobenzyl)thio]benzene Triethylamine (6.3 mL, 45.1 mmol) was added dropwise to a stirred solution of 4-chlorothiophenol (5 g, 10 34.7 mmol) and 4-fluorobenzyl bromide (6.9 g, 36.4 mmol) in CH 2 Cl 2 (60 mL) over 5 min. The mixture was stirred for 1h at ambient temperature then partitioned between CH 2
C
2 and water. The organic extracts were washed with brine, dried (Na 2
SO
4 ) and concentrated in vacuo to give the title compound (8.78 g, 100%). 'H NMR (500MHz, CDCl 3 ): 6 7.23-7.19 (6H, m), 6.96 (2H, t, J8.6), 4.04 (2H, s). 15 Description 2: 2-[4-(4-Chlorobenzylsulfanyl)phenyljpropan-2-ol A solution of 4-(4-chlorobenzylsulfanyl)benzoic acid methyl ester (prepared according to the method of Description 1) (3 g, 10.2 mmol) in THF (50 mL) was cooled to -78 'C. Methyl magnesium bromide (3M in Et 2 O, 10 mL, 30 mmol) was added dropwise. The mixture was stirred at this temperature for 30 min, 20 then warmed to RT. Water and EtOAc were added and the phases separated. The organic layer was washed with brine, dried over Na 2
SO
4 , filtered and evaporated in vacuo. The title compound (2.71 g, 90%) was obtained after column chromatography on silica gel (Gradient: EtOAc in hexanes 10% to 30%). 'H NMR (360MHz, CDCl 3 ): 6 7.37 (d, J8.4, 2H); 7.24 (m, 6H); 4.05 (s, 2H); 1.55 (s, 6H). 25 Description 3: 5-{[(4-Chlorophenyl)methyljthio}-2-(trifluoromethyl) pyridine NaH (60% dispersion in mineral oil, 1.2 g, 30 mmol) was added to a stirred, cooled (0 *C) solution of 4 chlorobenzenemethanethiol (4.22 g, 26.5 mmol) in DMF (50 mL). The mixture was stirred at 0 *C for 10 min, then 5-bromo-2-(trifluoromethyl)pyridine (5 g, 22.1 mmol) was added. The mixture was stirred 30 at RT for 4 h, then water was added. The mixture was extracted with EtOAc and the combined organic fractions were washed with water and brine, dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure to give the title compound (6.74 g, 100%). m/z (ES*) 304 (M+1). The following compounds were prepared according to the method of Description 3. 35 WO 2007/003965 PCT/GB2006/050184 22 Description Compound
F
3 C S Br
F
3 C - S F Description 6: 1-Chloro-4-[(4-fluorobenzyl)sulfonyllbenzene 3-Chloroperbenzoic acid (15.1 g, 87.5 mmol) was added in portions to a stirred, cooled (0 *C) solution of 1-chloro-4-[(4-fluorobenzyl)thio]benzene (Description 1; 8.78 g, 34.7 mmol) in CH 2 Cl 2 (80 mL). The 5 mixture was warmed to RT and stirred overnight. The mixture was cooled in ice and Ca(OH) 2 (9.7 g, 131 mmol) was added. The mixture was stirred for 20 min, filtered through HyfloTM and the solvent was evaporated under reduced pressure to give the title compound (9.34 g, 95%). 'H NMR (500MHz, CDCl 3 ): 6 7.55 (d, J8.6, 2H); 7.43 (d, J8.6, 2H); 7.08 (dd, J5.4, 8.7, 2H); 7.00-6.94 (m, 2H); 4.27 (s, 2H). 10 Description 7: 8-[(4-Chlorophenyl)sulfonyl]-8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane NaH (60% in mineral oil, 1.53 g, 39 mmol) was added to a solution of 1-chloro-4-[(4 fluorobenzyl)sulfonyl]benzene (Description 6; 4.67 g, 16.3 mmol) in DMF (120 mL) and the mixture was stirred at RT for 10 min. 2,2-Bis(2-iodoethyl)-1,3-dioxolane (6.85 g, 17.9 mmol) was added and the 15 mixture was stirred at RT overnight. The mixture was cooled in ice and water was added. Aqueous NaHCO 3 (saturated) was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15 - 20% EtOAc/hexane to give the title compound (4.00 g, 59%). 20 'H NMR (500MHz, CDCl 3 ): 6 7.33 (d, J8.5, 2H); 7.23 (m, 4H); 7.00 (t, J8.6, 2H); 3.95 (t, J6.0, 2H); 3.88 (t, J5.9, 2H); 2.59-2.53 (m, 2H); 2.48 (d, J 12.9, 2H); 1.75 (d, J 13.1, 2H); 1.44-1.38 (m, 2H). Description 8: 4-[(4-Chlorophenyl)sulfonyl]-4-(4-fluorophenyl)cyclohexanone p-Toluenesulfonic acid monohydrate (3.03 g, 15.9 mmol) was added to a stirred, heated (50 "C) solution 25 of 8-[(4-chlorophenyl)sulfonyl]-8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (Description 7; 4.00 g, 9.73 mmol) in acetic acid (90 mL) and water (10 mL) and the mixture was stirred at 50 "C overnight. The mixture was cooled, diluted with EtOAc and neutralised with K 2 C0 3 . The mixture was extracted with WO 2007/003965 PCT/GB2006/050184 23 EtOAc. The combined organic fractions were washed with brine, dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure to give the title compound (3.3 g, 90%). 'H NMR (500MHz, CDCl 3 ): 6 7.37-7.30 (m, 4H); 7.25 (m, 2H); 7.10-7.04 (m, 2H); 2.80 (m, 2H); 2.72 2.66 (m, 2H); 2.50 (m, 2H); 2.22-2.15 (m, 2H). 5 The following compounds were prepared according to the methods of Descriptions 1-8. R O 0 R' Description R R' 9 H 4-Br 10 3-Cl 4-Br 11 3-CF 3 4-Br 12 4-Cl 3-F 13 4-Cl 4-F 14 4-Cl 4-Br 15 4-Cl 4-CN 16 4-Cl 4-Me 17 4-Cl 4-CF 3 18 4-Cl 4-(OCF 3 ) 19 4-Cl 2,5-F 2 20 4-Cl 3,4-C 2 21 4-Cl 2-F, 4-Br 22 4-CN 4-Br 23 4-Me 4-Br 24 4-CF 3 3-Br 25 4-CF 3 4-F 26 4-CF 3 4-Cl 27 4-CF 3 4-Br 28 4-CF 3 3,4-C 2 WO 2007/003965 PCT/GB2006/050184 24 29 4-CF 3 3-F, 4-Cl 30 4-(OCF 3 ) 4-Br 31 4-C(Me) 2 0H 4-Cl 32 4-CO 2 Me 4-Cl The following compounds were prepared according to the methods of Descriptions 1-8. N 0
F
3 C /
-
_0 R'< Description R' 33 4-F 34 4-Cl 35 4-Br 5 Description 36: 8-[4-(Trifluoromethyl)phenylthio]-1,4-dioxa-spiro[4.5]decane Cesium fluoride (10.2 g, 67.7 mmol) was heated to 180 *C under vacuum for 2 h, cooled to RT, placed under a N 2 atmosphere and 4-(trifluoromethyl)benzenethiol (5.2 g, 29.2 mmol), 1,4-dioxa-spiro[4.5]dec 8-yl methanesulfonate (J. Med. Chem. 1992, 35, 2243.) (5.3 g, 22.5 mmol) and DMF (44 mL) were 10 added. The mixture was heated to 60 *C for 3 h, cooled and water and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried (Na 2
SO
4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (100:0 increasing to 90:10) to give the title compound (3.51 g, 50%). 'H NMR (500MHz, CDCl 3 ): 6 7.52 (d, J8.1, 2H); 7.42 (d, J8.1, 2H); 3.93 (s, 4H); 3.31 (m, 1H); 2.02 (m, 15 2H); 1.85 (m, 2H); 1.75 (m, 2H); 1.62 (m, 2H). Description 37: 8-[4-(Trifluoromethyl)benzenesufonyl]-1,4-dioxa-spiro[4.5]decane Prepared from 8-[4-(trifluoromethyl)phenylthio]-1,4-dioxa-spiro[4.5]decane (Description 36) according to the method of Description 6. 20 'H NMR (500MHz, CDCl 3 ): 6 8.05 (d, J8.1, 2H); 7.87 (d, J8.1, 2H); 3.93 (m, 4H); 2.95 (m, 1H); 2.08 (m, 2H); 1.90-1.75 (m, 4H); 1.55 (m, 2H). Description 38: 8-(4-Bromo)phenylmethyl-8-[4-(trifluoromethyl)benzenesulfonyl]-1,4-dioxa spiro[4.5]decane WO 2007/003965 PCT/GB2006/050184 25 n-Butyllithium (1.6M in hexanes, 1.7 mL, 2.7 mmol) was added dropwise to a stirred, cooled (-78 *C) solution of 8-[4-(trifluoromethyl)benzenesulfonyl]-1,4-dioxa-spiro[4.5]decane (Description 37, 1 g, 2.86 mmol) in THF (10 mL) and the mixture was stirred at -78 *C for 20 min. A solution of 4 bromobenzyl bromide (1.43 g, 5.7 mmol) in THF (4 mL) was added dropwise and the mixture was stirred 5 at -78 *C for 2 h. Water and EtOAc were added, the mixture warmed to RT and the layers were separated. The organic layer was washed with brine, dried (Na 2
SO
4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (95:5 increasing to 85:15) to give the title compound (1.16 g, 78%). 'H NMR (500MHz, CDCl 3 ): 6 7.95 (d, J8.1, 2H); 7.80 (d, J8.1, 2H); 7.40 (d, J8.2, 2H); 7.13 (d, J8.2, 10 2H); 3.82 (s, 4H); 3.10 (s, 2H); 1.95 (m, 6H); 1.68 (m, 2H). Description 39: 4-(4-Bromo)phenylmethyl-4-[4-(trifluoromethyl)benzenesulfonylcyclohexanone Prepared from 8-(4-bromo)phenylmethyl-8-[4-(trifluoromethyl)benzenesulfonyl]-1,4-dioxa spiro[4.5]decane (Description 38) according to the method of Description 8. 15 'H NMR (500MHz, CDCl 3 ): 6 8.09 (d, J8.1, 2H); 7.90 (d, J8.1, 2H); 7.42 (d, J8.2, 2H); 6.98 (d, J8.2, 2H); 2.96 (s, 2H); 2.84 (m, 2H); 2.43 (m, 2H); 2.15-2.00 (m, 4H). Description 40: 4-(4-Bromo)phenylmethyl-4-[4-(chloro)benzenesulfonyl] cyclohexanone Prepared from 1,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate and 4-chlorobenzenethiol according to the 20 method of Descriptions 36-39. 'H NMR (500MHz, CDCl 3 ): 6 7.88 (d, J8.1, 2H); 7.60 (d, J8.1, 2H); 7.42 (d, J8.2, 2H); 6.98 (d, J8.2, 2H); 2.95 (s, 2H); 2.82 (m, 2H); 2.41 (m, 2H); 2.10 (m, 2H); 2.01 (m, 2H). Description 41: 8-Phenyl-1,4-dioxaspiro[4.5]decane-8-methyl Methanesulfonate 25 Triethylamine (0.57 g, 0.0056 mol) then methanesulfonyl chloride (0.57 g, 0.00495 mol) were added dropwise to 8-phenyl- 1,4-dioxaspiro[4.5]decane-8-methanol (Bioorganic & Medicinal Chemistry Letters 2002, 12, 1755-1758, 0.82 g, 0.0033 mol) in CH 2 C1 2 (10 mL) and the mixture was stirred at RT for 16 h. The mixture was diluted with CH 2 Cl 2 , washed with water and brine, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound. 30 'H NMR (360MHz, CDCl 3 ): 6 1.52-1.70 (4H, m), 1.88-1.97 (2H, m), 2.30-2.34 (2H, m), 2.55 (3H, s), 3.88-3.97 (4H, m), 4.10 (2H, s), 7.24 (1H, m), 7.35-7.43 (4H, m). Description 42: 8-Phenyl-8-[(phenylthio)methyl]]-1,4-dioxa-spiro[4.5]decane Thiophenol (0.22 g , 0.002 mol) followed by triethylamine (0.2 g, 0.002 mol) were added to 8-phenyl- 1,4 35 dioxaspiro[4.5]decane-8-methyl methanesulfonate (Description 41, 0.5 g, 0.00 15 mol) in DMF (8 mL) and the mixture was stirred at 80 *C for 16 h. The mixture was cooled, diluted with water and extracted with EtOAc. The combined organic fractions were washed with water, and brine, dried (MgSO 4 ) and the WO 2007/003965 PCT/GB2006/050184 26 solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound (0.21 g, 42%). 'H NMR (360MHz, CDCl 3 ): 6 1.53-1.69 (4H, m), 1.94-2.02 (2H, m), 2.35 (2H, m), 3.16 (2H, s), 3.87 3.96 (4H, m), 7.06-7.41 (10H, m). 5 Description 43: 4-Phenyl-4-[(phenylsulfonyl)methyl]]cyclohexanone To an ice-bath-cooled solution of 8-phenyl-8-[(phenylthio)methyl]]-1,4-dioxa-spiro[4.5]decane (Description 42, 0.21 g, 0.00062 mol) in CH 2 Cl 2 (8 mL) was added portionwise 3-chloroperbenzoic acid (70%, 0.36 g, 0.0015 mol). After allowing the mixture to warm to RT it was stirred for 16 h. Ca(OH) 2 10 (0.068 g, 0.00092 mol) was added and the mixture was stirred at RT for 15 min. The mixture was filtered through celite and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (5 mL) and water (0.5 mL) andp-toluenesulfonic acid monohydrate (176 mg, 0.00093 mol) was added. The mixture was heated at 50 *C for 16 h, cooled and EtOAc and water were added. The layers were separated and the organic layer was washed with water, and aqueous NaHCO 3 , dried 15 (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound (0.16 g, 80%). 'H NMR (360MHz, CDCl 3 ): 6 2.26-2.48 (6H, m), 2.83 (2H, m), 3.45 (2H, m), 7.19-7.60 (1OH, m). Description 44: 8-(4-Bromophenyl)-8-[(4-trffluoromethyl)phenylthiol]-1,4-dioxa-spiro[4.5]decane 20 Boron trifluoride diethyl etherate (1.82 g, 13 mmol) then 4-(trifluoromethyl)thiophenol (2.3 g, 13 mmol) were added dropwise to a stirred, cooled (-10 *C) solution of 8-(4-bromo-phenyl)-1,4-dioxa spiro[4.5]decan-8-ol (prepared according to Zhang, Y.; Schuster, G.B. J. Org. Chem. 1994, 59, 1855.) (2 g, 6.4 mmol) in CH 2 Cl 2 (32 mL) and the mixture was stirred at RT for 2 h. Water was added, the layers were separated and the organic layer was washed with brine, dried (Na 2
SO
4 ), filtered and the 25 solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (98:2 increasing to 90:10) to give the title compound (0.4 g, 13%). 'H NMR (400MHz, CDCl 3 ): 6 7.40 (m, 4H); 7.15 (d, J8.4, 2H); 7.05 (d, J8.4, 2H); 3.96 (m, 4H); 2.20 1.50 (m, 8H). 30 Description 45: 4-(4-Bromophenyl)-4-[(4-trffluoromethyl)benzenesulfinyl] cyclohexanone Sodium metaperiodate (131 mg, 0.7 mmol) in water (1 mL) was added to a solution of 4-(4 bromophenyl)-4-[(4-trifluoromethyl)phenylthio]cyclohexanone [prepared from 8-(4-bromophenyl)-8-[(4 trifluoromethyl)phenylthiol]-1,4-dioxa-spiro[4.5]decane (Description 44) according to the method of 35 Description 8] (0.22 g, 0.51 mmol) in methanol (2 mL) and the mixture was stirred at RT overnight. The mixture was filtered and the solvent was evaporated under reduced pressure. Water and EtOAc were added and the layers were separated. The organic fraction was washed with brine, dried (Na 2
SO
4 ) and the WO 2007/003965 PCT/GB2006/050184 27 solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with hexane/EtOAc (50:50) to give the title compound. 'H NMR (360MHz, CDCl 3 ): 6 7.52 (m, 4H); 7.02 (m, 4H); 7.05 (d, J8.4, 2H); 2.55 (m, 5H); 2.26 (m, 3H). 5 Description 46: 1-(1,1-Dimethylethyl) 4-Methyl 1,4-Piperidinedicarboxylate Trimethylsilyldiazomethane (2.OM in hexane, 147 mL, 0.29 mol) was added over 30 min. via an addition funnel to a stirred, cooled (0 C) solution of 1 -(1,1 -dimethylethyl) 1,4-piperidinedicarboxylate (45.0 g, 0.20 mol) in CH 2 Cl 2 /MeOH (3:1. 1200 mL). The solvent was evaporated under reduced pressure to give 10 the title compound (47 g) as a light yellow oil. This was used directly in the next step without further purification. 'H NMR (400MHz, CDCl 3 ) 6 1.46 (s, 9H), 1.58-1.68 (m, 2H), 1.86-1.91 (m, 2H), 2.45 (tt, 1H), 2.81-2.87 (m, 2H), 3.70 (s, 3H), 4.00-4.05 (m, 2H). 15 Description 47: 1-(1,1-Dimethylethyl) 4-Methyl 4-(Pent-4-en-1-yl)-1,4-piperidinedicarboxylate A solution of 1-(1,1-dimethylethyl) 4-methyl 1,4-piperidinedicarboxylate (Description 46, 25 g, 0.10 mol) in THF (250 mL) was added to a stirred, cooled (0 *C) solution of potassium bis(trimethylsilyl)amide (30.7 g, 0.15 mol) in THF (750 mL) and the mixture was stirred at 0 *C for 1 h. 5-Bromo-1-pentene (19.4 mL, 0.164 mol) was added and the mixture was allowed to warm to RT and stirred for 1.5 h. The 20 mixture was poured into saturated aqueous NaHCO 3 and extracted with EtOAc (3x). The combined organic fractions were washed with brine, dried (Na 2
SO
4 ), filtered, and the solvent was evaporated under reduced pressure to give the title compound (30.9 g) which was used in the next step without further purification. 'H NMR (400MHz, CDCl 3 ) 6 1.26-1.40 (m, 4H), 1.46 (s, 9H), 1.50-1.54 (m, 2H), 1.99-2.06 (m, 2H), 25 2.11-18 (m, 2H), 2.80-2.98 (m, 2H), 3.72 (s, 3H), 3.87-3.95 (m, 2H), 4.95-5.02 (m, 2H), 5.72-5.80 (m, 1H). Description 48: 1-(1,1-Dimethylethyl) 4-Methyl 4-(4-Oxobut-1-yl)-1,4-piperidinedicarboxylate A solution of 1 -(1,1 -dimethylethyl) 4-methyl 4-(pent-4-en- 1 -yl)- 1,4-piperidinedicarboxylate 30 (Description 47, 29.4 g, 0.0945 mol) in methanol (1000 mL) was cooled to -78 'C and ozone was bubbled into the solution until a blue color persisted. The excess ozone was removed with a stream of N 2 , then methyl sulfide (69 mL, 0.95 mol) was added, the cooling bath was removed, and the mixture was allowed to warm to RT over 1.5 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography, eluting with 2:1 heptane/EtOAc, to give the title compound 35 (23.0 g). 'H NMR (400MHz, CDCl 3 ) 6 1.29-1.40 (m, 2H), 1.46 (s, 9H), 1.50-1.57 (m, 4H), 2.09-2.13 (m, 2H), 2.41-2.44 (m, 2H), 2.82-2.95 (m, 2H), 3.73 (s, 3H), 3.86-3.89 (m, 2H), 9.74 (s, 1H).
WO 2007/003965 PCT/GB2006/050184 28 Description 49: 1-[(1,1-Dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-piperidinebutanoic acid Jones reagent (2.6M , 28.2 mL) was added via syringe to a solution of 1-(1,1-dimethylethyl) 4-methyl 4 (4-oxobut- 1-yl)-1,4-piperidinedicarboxylate (Description 48, 23.0 g, 0.0734 mol) in acetone (775 mL). 5 After 5 min, the solvent was evaporated under reduced pressure and the residue was taken up in water. The mixture was extracted with Et 2 O (3x) and the combined organic fractions were washed with brine, dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure to give the title compound (23.4 g) which was used in the next step without further purification. 'H NMR (400MHz, CDCl 3 ) 6 1.33-1.41 (m, 2H), 1.46 (s, 9H), 1.50-1.57 (br s, 4H), 2.09-2.19 (m, 2H), 10 2.32-2.34 (m, 2H), 2.85-2.89 (m, 2H), 3.73 (s, 3H), 3.81-3.89 (m, 2H). Description 50: Methyl 1-[(1,1-Dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4 piperidinebutanoate Trimethylsilyldiazomethane (2.OM in hexane, 53 mL, 0.11 mol) was added to a stirred, cooled (0 *C) 15 solution of 1-[(1,1-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-piperidinebutanoic acid (Description 49, 23.4 g, 0.071 mol) in CH 2 Cl 2 /MeOH (3:1, 480 mL). The mixture was stirred at RT for 15 min, then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title compound (20.1 g). 'H NMR (400MHz, CDCl 3 ) 6 1.33-1.42 (m, 2H), 1.43 (s, 9H), 1.57-1.59 (m, 4H), 2.08-2.14 (m, 2H), 20 2.26-2.31 (m, 2H), 2.84-2.94 (m, 2H), 3.68 (s, 3H), 3.73 (s, 3H), 3.83-3.90 (m, 2H). Description 51: (RS)-8-(1,1-Dimethylethyl) 2-Methyl 1-Oxo-8-azaspiro[4.5]decane-2,8 dicarboxylate Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexanes, 47 mL, 0.070 mol,) was added 25 to a stirred, cooled (-78 *C) solution of methyl 1-[(1,1-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4 piperidinebutanoate (Description 50, 20.1 g, 0.058 mol) in THF (600 mL). The mixture was stirred at -78 'C for 25 min., then additional lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexanes, 31 mL) was added and the mixture was stirred at -78 'C for 20 min. The mixture was poured into saturated aqueous ammonium chloride and extracted with Et 2 O (3x). The combined organic 30 fractions were washed with brine, dried (Na 2
SO
4 ), and the solvent was evaporated under reduced pressure to give the title compound (19.9 g) which was taken on to the next step without further purification. Description 52: 1,1-Dimethylethyl 1-Oxo-8-azaspiro[4.5]decane-8-carboxylate Pulverized lithium hydroxide (26 g, 1.10 mol) was added to a solution of (RS)-8-(1, 1 -dimethylethyl) 2 35 methyl 1-oxo-8-azaspiro[4.5]decane-2,8-dicarboxylate (Description 51, 17.2 g, 0.055 mol) in ethanol/THF/water (2:2:1, 555 mL) and the mixture was stirred at 90 'C for 60 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water was added and the mixture was WO 2007/003965 PCT/GB2006/050184 29 extracted with CH 2 Cl 2 (3x). The combined organic fractions were washed with brine, dried (Na 2
SO
4 ), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title compound (9.41 g). 'H NMR (400MHz, CDCl 3 ) 6 1.29-1.37 (m, 2H), 1.47 (s, 9H), 1.62-1.69 (m, 2H), 1.92-1.95 (m, 4H), 5 2.30-2.34 (m, 2H), 3.05-3.10 (m, 2H), 3.87-3.92 (m, 2H). Description 53: (1RS,2RS)-1,1-Dimethylethyl 2-(1-Hydroxyprop-1-yl)-1-oxo-8-azaspiro[4.5]decane 8-carboxylate 1,1-Dimethylethyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 52, 4.5 g, 17.8 mmol) was 10 dried by adding and evaporating toluene (3 x 10 mL) under reduced pressure, dissolved in THF (100 mL) and cooled to -78 'C. Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 24 mL, 36 mmol,) was added and the mixture was stirred at -78 'C for 30 min. Propionaldehyde (2.6 mL, 36 mmol) was added and the mixture was stirred at -78 'C for 5 min. The mixture was diluted with Et 2 O, poured into saturated aqueous ammonium chloride and extracted with Et 2 O (3x). The combined organic 15 fractions were washed with brine, dried (Na 2
SO
4 ), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title compound (4.75 g). 'H NMR (400MHz, CDCl 3 ) 6 0.97 (t, 3H), 1.33-1.37 (m, 2H), 1.47 (s, 9H), 1.54-1.68 (m, 5H), 1.75-1.78 (m, 1H), 2.07-2.13 (m, 2H), 2.30-2.33 (m, 1H), 2.95-3.15 (m, 2H), 3.62-3.63 (m, 1H), 3.84-3.94 (m, 20 2H). Description 54: 1,1-Dimethylethyl 2-(1-Oxoprop-1-yl)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate DMSO (2.6 mL, 37 mmol) was added slowly to a stirred, cooled (-78 *C) solution of oxalyl chloride (1.6 mL, 18.3 mmol) in CH 2 Cl 2 (150 mL) and the mixture was stirred at -78 *C for 5 min. A solution of 25 (1RS,2RS)-1,1-dimethylethyl 2-(1-hydroxyprop-1-yl)-l-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 53, 4.75 g, 15.3 mmol) in CH 2 Cl 2 (40 mL) was added via an addition funnel and the mixture was stirred at -78 'C for 45 min. Triethylamine (10.2 mL, 73.2 mmol) was added and the mixture was stirred at -78 'C for 5 min., then allowed to warm to RT for 1.5 h. The mixture was poured into water and extracted with CH 2 Cl 2 (3x). The combined organic fractions were washed with brine, dried 30 (Na 2
SO
4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 15% EtOAc in hexanes, to give the title compound (3.98 g) as a pink oil. Description 55: 1,1-Dimethylethyl 1,3-Diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4' 35 piperidine]-1'-carboxylate Trifluoroacetate and 1,1-Dimethylethyl 2,3-Diethyl-4,5 dihydrospiro[cyclopentapyrazole-6(2H),4'-piperidine]-1'-carboxylate Trifluoroacetate WO 2007/003965 PCT/GB2006/050184 30 Ethyl hydrazine oxalate (0.096 g, 0.640 mmol) was added to a solution of 1,1-dimethylethyl 2-(1 oxoprop-1-yl)-l-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 54, 0.165 g, 0.533 mmol) in ethanol (5 mL) and the mixture was stirred at 85 'C for 12 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was taken up in a minimal amount of 40:40:20 5 MeCN/water/DMSO solution and purified by Gilson reverse phase IPLC (Column: YMC-Pack Pro C18, 100 X 20 mm I.D.; Gradient Eluent: 10:90 to 90:10 v/v MeCN/water + 0.1% trifluoroacetic acid over 12.5 min; Detection: PDA, 210-400 nm; Flow rate: 20 mL/min) to give 1,1-dimethylethyl 1,3-diethyl-4,5 dihydrospiro [cyclopentapyrazole-6(H),4 '-piperidine]-l '-carboxylate trifluoroacetate (0.220 g); 1H NMR (400MHz, CDCl 3 ) 6 1.23 (t, 3H), 1.42 (t, 3H), 1.50 (s, 9H), 1.60-1.63 (m, 2H), 1.88-1.93 (m, 2H), 10 2.42-2.47 (m, 2H), 2.56-2.61 (m, 4H), 2.86-2.89 (m, 2H), 4.00 (q, 2H), 4.10-4.13 (m, 2H); m/z (ES*) 334 (M+ 1); and 1,1-dimethylethyl 2,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(2H),4'-piperidine] 1'-carboxylate trifluoroacetate (0.016 g); 1 H NMR (400MHz, CDCl 3 ) 6 1.27 (t, 3H), 1.38 (t, 3H), 1.48 (s, 9H), 1.51-1.57 (m, 2H), 1.75-1.79 (m, 2H), 2.22-2.45 (m, 2H), 2.58-2.65 (m, 4H), 3.51-3.60 (m, 2H), 3.64-3.67 (m, 2H), 4.03 (q, 2H); m/z (ES*) 334 (M+1). 15 Description 56: 1,3-Diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4'-piperidine] Dihydrochloride Acetyl chloride (1.17 mL, 16.4 mmol) was added to a stirred, cooled (0 *C) solution of 1,1-dimethylethyl 1,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4'-piperidine]-l'-carboxylate trifluoroacetate 20 (Description 55, 0.547 g, 1.64 mmol) in MeOH (16 mL). The mixture was allowed to warm to RT and stirred for 60 h. The solvent was evaporated under reduced pressure to give the title compound. 1 H NMR (400MHz, CDCl 3 ) 6 1.32 (t, 3H), 1.54 (t, 3H), 2.00 (d, 2H), 2.37-2.45 (m, 2H), 2.66-2.69 (m, 2H), 2.73-2.82 (m, 4H), 3.18-3.24 (m, 2H), 3.47-3.52 (d, 2H), 4.41 (q, 2H). 25 Description 57: 1-(1,1-Dimethylethyl) 4-piperidinedicarboxylate Anhydride with 1H-Imidazole-1 carboxylic Acid Carbonyldiimidazole (39.4 g, 243 mmol) was added in portions to a stirred solution of 1 -(1,1 dimethylethyl) 4-piperidinedicarboxylate (42.5 g, 187 mmol) in CH 2 Cl 2 (550 mL) and the mixture was stirred at 4 *C overnight. The mixture was poured into Et 2 O (2 L) and ice water (2 L), the layers were 30 separated and the organic layer was washed with cold aqueous NaHCO 3 (saturated, 500 mL) and brine (500 mL), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (52 g). Description 58: 1,1-Dimethylethyl 4-(1,3-Dioxobutyl)piperidinecarboxylate 35 Acetone (41 mL) in THF (300 mL) was added dropwise to a stirred suspension of KH (30% in mineral oil, 75 g, 561 mmol) in THF (1.4 L) at RT. The mixture was cooled to -78 *C and treated with 1-(1,1 dimethylethyl) 4-piperidinedicarboxylate anhydride with 1H-imidazole-1-carboxylic acid WO 2007/003965 PCT/GB2006/050184 31 (Description 57, 52 g) in THF (500 mL). The mixture was allowed to warm to RT and stirred overnight, then ethanol (50 mL) was added dropwise over 5 min. The mixture was poured into hydrochloric acid (IN, 2 L) and extracted with Et 2 O (2 x1 L). The combined organic fractions were washed with aqueous NaHCO 3 (saturated, 500 mL) and brine (500 mL), dried (MgSO 4 ) and the solvent was evaporated under 5 reduced pressure. Isohexane (1 L) and acetonitrile (500 mL) were added, the layers were separated and the isohexane layer was extracted with MeCN (500 mL). The MeCN layers were combined and the solvent was evaporated under reduced pressure. The residue was filtered through a silica pad, eluting with 0-20% EtOAc in hexanes, to give the title compound as a colorless solid (36 g, 72%). 'H NMR (CDCl 3 ) 6 5.50 (1H, s), 4.18-4.11 (2H, m), 2.79-2.62 (2H, m), 2.34-2.27 (1H, m), 2.07 (3H, s), 10 1.80 (2H, brd, J 14.3), 1.60-1.51 (2H, m), 1.46 (9H, s). Description 59: 1,1-Dimethylethyl 4-[1-(1,1-Dimethylethyl)-3-methyl-1H-pyrazol-5 yljpiperidinecarboxylate t-Butyl hydrazine hydrochloride (14.8 g, 118 mmol) then triethylamine (17 mL, 120 mmol) were added to 15 a solution of 1,1-dimethylethyl 4-(1,3-dioxobutyl)piperidinecarboxylate (Description 58, 8 g, 29.7 mmol) in ethanol (200 mL) and the mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure and the residue was suspended in EtOAc (1 L), washed with aqueous NaOH (IN, 500 mL), water (500 mL) and brine (500 mL), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (9.5 g). 20 'H NMR (CDCl 3 ) 6 5.87 (1H, s), 4.27-4.18 (2H, m), 3.09-2.99 (1H, m), 2.79-2.68 (2H, m), 2.20 (3H, s), 1.85 (2H, brd, J 13.3), 1.63 (9H, s), 1.61-1.52 (2H, m), 1.48 (9H, s). Description 60: 4-[1-(1,1-Dimethylethyl)-3-methyl-1H-pyrazol-5-yljpiperidine Methanolic HCl (IN, 100 mL) was added to a solution of 1,1-dimethylethyl 4-[1-(1,1-dimethylethyl)-3 25 methyl-1H-pyrazol-5-yl]piperidinecarboxylate (Description 59, 9.5 g, 29 mmol) in MeOH (100 mL) and the mixture was stirred at RT for 4 h. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc. The solid was collected, suspended in aqueous NaOH (4N, 20 mL) and extracted with CH 2 Cl 2 (2 x 100 mL). The combined organic fractions were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound (6.4 g). 30 'H NMR (CDCl 3 ) 6 5.91 (1H, s), 3.17 (2H, brd, J 13.0), 3.03 (1H, tt, J 13.0, 4.3), 2.69 (2H, dt, J 12.8, 3.5), 2.21 (3H, s), 1.86 (2H, brd, J 13.4), 1.67 (9H, s), 1.68-1.56 (2H, m). Description 61: 4-[1-(-(2,2,2-Trifluoroethyl))-3-methyl-1H-pyrazol-5-yljpiperidine Prepared from 1,1-dimethylethyl 4-(1,3-dioxobutyl)piperidinecarboxylate (Description 58) according to 35 the methods of Descriptions 59 and 60, substituting trifluoroethyl hydrazine oxalate for t-butyl hydrazine hydrochloride.
WO 2007/003965 PCT/GB2006/050184 32 'H NMR (CDC1 3 ) 6 5.91 (1H, s), 4.58 (2H, dd, J 16.4, 8.6), 3.17 (2H, brd, J 13.2), 2.70 (2H, dt, J 12.5, 2.4), 2.60 (1H, tt, J12.1,4.1), 2.23 (3H, s), 1.82 (2H, brd, J14.4), 1.58 (2H, qd, J12.5, 3.8). Description 62: 1,1-Dimethylethyl 4-[(2-Oxocyclopentyl)carbonyl]-1-piperidinecarboxylate 5 Prepared from 1 -(1,1 -dimethylethyl) 4-piperidinedicarboxylate anhydride with 1H-imidazole- 1 carboxylic acid (Description 57) according to the method of Description 58, substituting cyclopentanone for acetone. 'H NMR (CDCl 3 ) 6 13.75 (1H, brs), 4.27-4.06 (2H, m), 2.78-2.69 (2H, m), 2.57 (2H, t, J6.2), 2.42 (2H, t, J7.2), 2.37-2.30 (1H, m), 1.96-1.89 (2H, m), 1.75-1.63 (4H, m), 1.46 (9H, s). 10 Description 63: 4-(2-Ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine Prepared from 1,1-dimethylethyl 4-[(2-oxocyclopentyl)carbonyl]-1-piperidinecarboxylate (Description 62) according to the methods of Descriptions 59 and 60, substituting ethyl hydrazine oxalate for t-butyl hydrazine hydrochloride. 15 'H NMR (CDCl 3 ) 6 4.02 (2H, dd, J 14.5, 8.0), 3.18 (2H, brd, J 12.4), 2.72 (2H, dt, J 12.6, 2.5), 2.68-2.63 (5H, m), 2.40-2.33 (2H, m), 1.81 (2H, brd, J 13.6), 1.69 (2H, qd, J 12.6, 4.1), 1.42 (3H, t, J7.4). Description 64: 1,1-Dimethylethyl 4-(1,3-Dioxo-2-methylbutyl)piperidinecarboxylate NaH (60% in mineral oil, 75 mg, 1.9 mmol) was added to 1,1-dimethylethyl 4-(1,3 20 dioxobutyl)piperidinecarboxylate (Description 58, 0.5 g, 1.9 mmol) in DMF (5 mL). The mixture was stirred at RT for 1 h, then added to a solution of iodomethane (0.59 mL, 9.5 mmol) in DMF (5 mL). Water (500 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated brine (50 mL), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 15-25% 25 EtOAc in hexanes, to give the title compound (175 mg). Description 65: 4-[1,3,4-Trimethyl-1H-pyrazol-5-yljpiperidine Prepared from 1,1-dimethylethyl 4-(1,3-dioxo-2-methylbutyl)piperidinecarboxylate (Description 64) according to the methods of Descriptions 59 and 60, substituting methyl hydrazine oxalate for t-butyl 30 hydrazine hydrochloride. 'H NMR (CDCl 3 ) 6 4.07 (2H, q, J7.6), 3.19 (2H, brd, J 11.8), 2.77-2.67 (3H, m), 2.14 (3H, s), 2.02 (3H, s), 1.92 (2H, qd, J 11.8, 4.1), 1.69 (2H, brd, J 13.0), 1.36 (3H, t, J7.4). Description 66: 1-Phenylmethyl-4-(3,5-diethyl-1H-pyrazol-1-yl)piperidine 35 Triethylamine (3.54 mL, 25.5 mmol) was added to a stirred solution of 4-hydrazino-1 (phenylmethyl)piperidine dihydrochloride (3.53 g, 12.7 mmol) in ethanol (50 mL) and the mixture was stirred at RT for 5 min. 3,5-Heptanedione (3.26 g, 25.5 mmol) was added and the mixture was stirred at WO 2007/003965 PCT/GB2006/050184 33 RT for 4 days. The mixture was diluted with EtOAc, washed with aqueous NaOH (0.5M), brine, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 100% hexane to 100% Et 2 O, to give the title compound (2.7 g, 7 1%). 5 'H NMR (CD 3 0D) 6 7.35-7.20 (511, m), 5.85 (111, s), 4.02-3.94 (111, m), 3.55 (211, s), 2.99 (211, d, J9.2), 2.63-2.51 (411, m), 2.27-2.12 (411, m), 1.73 (211, t, J 11.8), 1.24-1.16 (611, m). Description 67: 4-(3,5-Diethyl-1H-pyrazol-1-yl)piperidine Ammonium formate (5.73 g, 90 mmol) and Pd on C (300 mg) were added to a stirred solution of 1 10 phenylmethyl-4-(3,5-diethyl-1H-pyrazol-1-yl)piperidine (Description 66, 2.7 g, 9 mmol) in methanol (75 mL) and the mixture was stirred under reflux for 3 h. The mixture was cooled, filtered through HyfloTM and the solvent was evaporated under reduced pressure. The residues was dissolved in MeOH and poured onto SCX cartridges (Varian Bond ElutTM; 10 mL/500 mg). The cartridges were washed with MeOH, then eluted with methanolic ammonia (2M). The solvent was evaporated under reduced pressure 15 to give the title product. (1.6 g, 85%). 'H NMR (CD 3 0D) 6 5.86 (111, s), 4.18-4.10 (111, m), 3.15 (211, dd, J2.1, 10.9), 2.75-2.53 (611, m), 2.07 1.97 (211, m), 1.79 (211, d, J 14.0), 1.25-1.17 (611, m). Description 68: 1,1-Dimethylethyl 1,2-Dihydro-1-(1-methylethyl)-2-oxospiro[3H-indole-3,4' 20 piperidine]-1'-carboxylate NaH (60% in mineral oil, 344 mg, 8.6 mmol) was added in portions to a stirred, cooled (0 *C) solution of 1,1-dimethylethyl 1,2-dihydro-2-oxospiro[3H-indole-3,4'-piperidine]-l'-carboxylate (2.0 g, 6.6 mmol) in DMF (10 mL) and the mixture was stirred at 0 *C for 10 min. 2-lodopropane (0.86 mL, 8.6 mmol) was added and the mixture was allowed to warm to RT and stirred overnight. Water (100 mL) was added and 25 the mixture was extracted with EtOAc (3 x 50 mL). The combined organic fractions were dried (MgSO 4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (70:30) to give the title compound as a solid (2.3 g). 'H NMR (CDCl 3 ) 6 7.29-7.23 (211, m), 7.06-7.02 (211, m), 4.68-4.62 (111, m), 3.88-3.76 (411, m), 1.82 30 1.74 (411, m), 1.50 (911, s), 1.47 (611, d, J7.3). Description 69: 1-(1-Methylethyl)spiro[3H-indole-3,4'-piperidin]-2(1H)-one Trifluoroacetate Trifluoroacetic acid (2 mL) was added dropwise to a solution of 1,1 -dimethylethyl 1,2-dihydro- 1 -(1 methylethyl)-2-oxospiro[3H-indole-3,4'-piperidine]-l'-carboxylate (Description 68) in CH 2 Cl 2 (20 mL) 35 and the mixture was stirred at RT for 4 h. The solvent was evaporated under reduced pressure to give the title compound as a tan solid (2.35 g).
WO 2007/003965 PCT/GB2006/050184 34 'H NMR (CDCl 3 ) 6 9.01 (1H, s), 8.54 (1H, s), 7.32-7.28 (2H, m), 7.12 (1H, t, J7.12), 7.04 (1H, d, J 7.12), 4.65-4.59 (1H, m), 4.00 (2H, q, J 11.9), 3.45 (2H, d, J 12.4), 2.39-2.31 (2H, m), 1.90 (2H, d, J 14.8), 1.49 (6H, d, J7.0). 5 Description 70: 1,1-Dimethylethyl 4-[(6-Methoxy-3-nitro-2-pyridinyl)aminolpiperidinecarboxylate 1,1-Dimethylethyl 4-amino-1-piperidinecarboxylate (10.01 g, 50 mmol) and triethylamine (34.85 mL, 25.3 g, 250 mmol) were added to a solution of 2-chloro-6-methoxy-5-nitropyridine (9.43 g, 50 mmol) in DMSO (100 mL) and the mixture was stirred at 100 *C for 12 h. The mixture was cooled and added dropwise to water (1200 mL). The mixture was stirred at RT for 12 h, then the solid was collected, 10 washed with water and dried in vacuo to give the title compound as a yellow powder (16.70 g, 95%). 'H NMR (360MHz, CDCl 3 ) 6 1.48 (9H, s), 1.52-1.62 (2H, m), 2.02-2.1 (2H, br m), 2.95-3.09 (2H, br m), 3.95 (3H, s), 4.00-4.10 (2H, br m), 4.23-4.35 (1H, m), 6.07 (1H, d, J9), 8.28 (1H, d, J9), 8.63 (1H, br d). Description 71: 1,3-Dihydro-5-methoxy-3-(4-piperidinyl)-2H-imidazo[4,5-bjpyridin-2-one 15 Dihydrochloride Platinum oxide (hydrated, 1.1 g) was added to a suspension of 1,1-dimethylethyl 4-[(6-methoxy-3-nitro 2-pyridinyl)amino]piperidinecarboxylate (Description 70, 16.75 g, 47.52 mmol) in ethanol (250 mL) and the mixture was shaken under H 2 (25 to 35 psi) for 4 h. CH 2 Cl 2 (25 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene 20 (125 mL) and treated with N-ethyldiisopropylamine (24.40 mL, 18.42 g, 142.57 mmol) then NN' carbonyldiimidazole (8.48 g, 52.28 mmol) were added. The mixture was stirred at 90 *C for 24 h, cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in CH 2 Cl 2 and washed with aqueous Na 2
CO
3 (5%) and HCl (0.01N), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanolic HCl (3M, 200 mL) and stirred at RT for 25 90 min. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc. The solid was collected and dried in vacuo to give the title compound as a purple solid (9.00 g, 59%). 'H NMR (400MHz, D 6 -DMSO) 6 1.87 (2H, br d, J 13), 2.75 (2H, qd, J 13, 4), 3.08 (2H, br q, J 11), 3.40 (2H, br d, J 13), 3.75 (3H, s), 4.45-4.55 (1H, m), 6.41 (1H, d, J8), 7.29 (1H, d, J8), 8.75 (1 H, br), 9.01 (1 H, br), 10.90 (1H, s). 30 Description 72: (3RS)-Ethyl 1-(Phenylmethyl)-3-piperidinecarboxylate Benzyl chloride (165 mL, 181 g, 1.43 mol) was added in one portion to an intensively stirred, cooled (0 *C) mixture of (3RS)-ethyl 3-piperidinecarboxylate (200 mL, 201 g, 1.29 mol) and triethylamine (200 mL, 145 g, 1.43 mol) in MeCN (400 mL) and the mixture was stirred at RT for 2.5 h. The solid was 35 collected, washed with MeCN (2 x 200 mL) and dried in vacuo. The solid was dissolved in Et 2 O (300 mL) and washed with water (2 x 300 mL). The organic layer was dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure to give the title compound as an oil (270 g, 85%).
WO 2007/003965 PCT/GB2006/050184 35 Description 73: (3RS)-1-(Phenylmethyl)-3-piperidinecarboxylic Acid Hydrazide Acetic acid (20 mL) and hydrazine hydrate (136 mL (140 g, 2.8 mol) were added to a solution of (3RS) ethyl 1-(phenylmethyl)-3-piperidinecarboxylate (Description 72, 270 g, 1.092 mol) in ethanol (310 mL) 5 and the mixture was heated under reflux for 3 days. The mixture was cooled and the solvent was partly evaporated under reduced pressure until a precipitation occurred. The solid was collected, aqueous KOH (50 g in 100 mL) was added and the mixture was extracted with CHCl 3 (2 x 300 mL). The combined organic fractions were dried (Na 2
SO
4 ) the solvent was partly evaporated under reduced pressure until a precipitation occurred. The solid was collected, the filtrate was diluted with Et 2 O (200 mL) and further 10 solid was collected. The combined solids were washed with Et 2 O and dried in vacuo to give the title compound as a solid (217 g, 92%). Description 74: (3RS)-1-(Phenylmethyl)-3-piperidinecarboxylic Acid 2 [(Methylamino)thioxomethylhydrazide 15 Methyl isothiocyanate (90 g, 1 43 mol) in toluene (50 mL) was added to a stirred solution of (3RS)-1 (phenylmethyl)-3-piperidinecarboxylic acid hydrazide (Description 73, 210 g, 0.90 mol) in toluene (500 mL) and the mixture was stirred at RT for 1 h. The solid was collected, washed with Et 2 O and dried in vacuo to give the title compound as a solid (245 g, 90%). 20 Description 75: (3RS)-1-(Phenylmethyl)-3-(4-methyl-5-thio-4H-1,2,4-triazol-3-yl)piperidine Sodium (50 g, 2.18 mol) was added in portions to stirred, cooled (0 *C) MeOH (785 mL). Once the sodium had dissolved, (3RS)-1-(phenylmethyl)-3-piperidinecarboxylic acid 2 [(methylamino)thioxomethyl]hydrazide (Description 74, 230 g, 0.76 mol) was added and the mixture was heated under reflux for 1 h. The mixture was cooled in ice and aqueous acetic acid (126 mL, 131 g, 25 2.19 mol) in water (400 mL) was added. The solid was collected, washed with Et 2 O and dried in vacuo to give the title compound as a solid (173 g, 79%). Description 76: (3RS)-1-(Phenylmethyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (3RS)-1-(Phenylmethyl)-3-(4-methyl-5-thio-4H-1,2,4-triazol-3-yl)piperidine (Description 75, 160 g, 30 0.56 mol) was dissolved by portions of 15-20 g in stirred, cooled (0 *C) concentrated nitric acid (70%, 500 mL). The mixture was stirred at 0 *C for 1 h then poured into stirred, cooled (0 *C) aqueous KOH (600 g) with continuing addition of ice. The mixture was divided into 4 portions and each portion of 500 mL was extracted with CHCl 3 (300 mL). The combined organic fractions were dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure to give the title compound. 35 Description 77: (3RS)-3-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidine Hydrochloride WO 2007/003965 PCT/GB2006/050184 36 Pd on C (5%) was added to a mixture of (3RS)-1-(phenylmethyl)-3-(4-methyl-4H-1,2,4-triazol-3 yl)piperidine (Description 76) and hydrochloric acid (conc., 50 mL) in methanol (400 mL) and the mixture was shaken under an atmosphere of H 2 (100 atm.) at 90 *C for 24 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved at reflux in iso 5 propanol (100 mL) and hydrochloric acid (conc., 50 mL) was added. The mixture was cooled and stored at 5*C for 3 days. The solid was collected, washed with Et 2 O and dried in vacuo to give the title compound as a solid (103 g, 91%). H NMR (D 6 -DMSO) 6 9.80-9.40 (3H, m), 3.90 (3H, s), 3.80-2.80 (5H, m), 2.20-1.70 (4H, m). 10 Description 78: 1-(3-Pyridinylmethyl)piperazine Trifluoroacetate Sodium triacetoxyborohydride (254 g, 1.2 mol) was added in portions to a rigorously stirred solution of 1,1-dimethylethyl piperazinecarboxylate (186 g, 1 mol), acetic acid (120 mL, 2 mol) and 3 pyridinecarboxaldehyde (107 g, 1 mol) in CH 2 Cl 2 (700 mL), keeping the mixture at slow reflux. The mixture was stirred overnight at RT, washed with aqueous acetic acid (5%, 2 x 150 mL) and dried 15 (CaCl 2 ). The solution was cooled in ice and trifluoroacetic acid (350 mL, 3.5 mol) was added with stirring. The mixture was stirred at RT until thin layer chromatography (silica gel; chloroform:ethanol:benzene; 7:2:1; ninhydrin development) indicated complete consumption of starting material. The solvent was partially evaporated under reduced pressure at 70 *C. The mixture was then allowed to crystallize (Et 2 O was added to help crystallization if needed). The solid was collected, washed 20 with Et 2 O (2 x 100 mL), Et 2 O:EtOAc (2:1, 100 mL), and again with Et 2 O (100 mL). The solid was dried in vacuo to give the title compound as a solid (390 g, 75%). 'H NMR (D 6 -DMSO) 6 8.85 (2H, br s), 8.70 (2H, m), 8.12 (1H, d), 7.69 (1H, t), 6.0 (1H, br s), 3.90 (2H, s), 3.20 (4H, m), 2.80 (4H, m). 25 Description 79: [1,2-Bis(hydroxyimino)propyljpiperazine Piperazine (84 g, 0.96 mol) in distilled water (400 mL) was added dropwise to a solution of N-hydroxy-2 (hydroxyimino)propanimidoyl chloride (33 g, 0.24 mol) in ethanol (100 mL), maintaining the reaction temperature below 30*C. The mixture was stirred at RT for 24 h, then filtered, washing with hot water (150 mL). The solvent was evaporated under reduced pressure to give a mixture of the title compound 30 and piperazine, which was used without further purification. Description 80: 1-(4-Methyl-1,2,5-oxadiazol-3-yl)piperazine Hydrochloride NaOH (20 g, 0.5 mol) was added slowly to an intensively stirred solution of [1,2 bis(hydroxyimino)propyl]piperazine (Description 79) in water (350 mL). The mixture was placed in an 35 autoclave (0.5 L) and stirred for 5 h at 190 *C. The mixture was cooled and stirred overnight. The mixture was extracted with Et 2 O (5 x 150 mL), and the combined organic fractions were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH, acidified WO 2007/003965 PCT/GB2006/050184 37 with hydrochloric acid (1 eq), and the solvent was evaporated under reduced pressure. The residue was recrystallized from isopropanol to give the title compound (5.8 g). H NMR (D 6 -DMSO) 6 9.50 (2H, br s), 3.50 (4H, t), 3.21 (4H, t), 2.38 (3H, s). 5 Description 81: 4-(Chloromethyl)-4,5-dihydro-2-methyl-4-thiazolol A mixture of thioacetamide (7.5 g, 0.1 mol), 1.3-dichloroacetone (14 g, 0.11 mol), sodium bicarbonate (9.3 g, 0.11 mol) and dichloroethane (60 mL) was stirred at RT for 48 h. The mixture was filtered, washing with dichloroethane (20 mL), to give a solution of the title compound which was used without further purification. 10 Description 82: 4-(Chloromethyl)-2-methylthiazole Hydrochloride Thionyl chloride (13.1 g, 0.11 mol) in dichloroethane (60 mL) was added to an intensively stirred solution of 4-(chloromethyl)-4,5-dihydro-2-methyl-4-thiazolol in dichloroethane (Description 81), maintaining the reaction temperature below 30 *C. The mixture was stirred at 65-70 *C for 30 min, cooled and the 15 solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc to give the title compound as a crystalline solid (17.12 g, 93%). Description 83: 1-[(2-Methyl-4-thiazolyl)methyllpiperazine 4-(Chloromethyl)-2-methylthiazole hydrochloride (Description 82, 92 g, 0.5 mol) in MeOH (400 mL) 20 was added slowly to a stirred solution of piperazine (500 g, 5.81 mol) in methanol (800 mL) and the mixture was heated under reflux for 3 h. The mixture was cooled and methanolic KOH (1 mol in 400 mL) was added. The mixture was stirred at RT overnight, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in iso-propanol, filtered and purified by flash column chromatography on silica gel, eluting with iso-propanol-triethylamine (5:1) and the residue was vacuum 25 distilled. A fraction with b.p. 123-127*C/- torr was collected to give the title compound as a light yellow dense oil which formed hygroscopic low melting (~30 *C) crystals on standing (57.1 g, 58%). 'H NMR (D 6 -DMSO) 6 7.20 (1H, s), 3.45 (2H, s), 3.15 (1H, br s), 2.60 (4H, t), 2.50 (3H, s), 2.30 (4H, m). Description 84: 1,1-Dimethylethyl 4-[2-(1-Hydroxy-1-methylethyl)-4-methyl-1H-imidazol-1-yl]-1 30 piperidinecarboxylate n-Butyllithium (1.6M in hexanes, 5.7 mL, 9.0 mmol) was added dropwise to a stirred, cooled (-78 *C) solution of 1,1 -dimethylethyl 4-(4-methyl- 1H-imidazol- 1 -yl)- 1 -piperidinecarboxylate (as prepared in W093/19059, 2 g, 7.5 mmol) in THF (50 mL) and the mixture was stirred at -78 *C for 1 h. Ethyl bromide (0.7 mL, 9.0 mmol) was added and the mixture was stirred at RT for 5 h. Acetone (1.1 mL, 35 0.88 g, 15 mmol) was added and the mixture was stirred at RT overnight. Water was added and the mixture was extracted with EtOAc. The combined organic fractions were dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on WO 2007/003965 PCT/GB2006/050184 38 silica gel, eluting with CH 2 Cl 2 /MeOH (100:0 increasing to 98:2), to give the title compound (0.9 g, 37%). m/z (ES') 324 (M+1). Description 85: 4-[2-(1-Hydroxy-1-methylethyl)-4-methyl-1H-imidazol-1-yljpiperidine 5 1,1-Dimethylethyl 4-[2-(1-hydroxy-1-methylethyl)-4-methyl-1H-imidazol-1-yl]-l-piperidinecarboxylate (Description 84, 450 mg, 1.4 mmol) was dissolved in ethanolic HCl (4M, 6 mL) and stirred at RT overnight. The solvent was evaporated under reduced pressure, aqueous NaHCO 3 (saturated) was added and the mixture was extracted with CHCl 3 / iPrOH (85:15). The combined organic fractions were dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure to give the title compound (257 mg, 10 83%). 'H NMR (500MHz, CDCl 3 ) 6 6.84, 6.53 (total 1H, each s), 5.25, 4.83 (total 1H, each s), 3.16 (2H, m), 2.69 (2H, s), 2.18 (1H, m), 2.11 (3H, s), 1.98-1.79 (3H, m), 1.60, 1.59 (total 6H, each s). Description 86: 2-Chloro-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)acetamide 15 Chloroacetyl chloride (3.1 mL, 40 mmol) was added to a stirred mixture of 1-ethyl-3-methyl-1H-pyrazol 5-amine (4.5 g, 36 mmol) and K 2 C0 3 (9.9 g, 72 mmol) in CH 2 Cl 2 (75 mL). The mixture was stirred at RT for 15 min, diluted with MeOH and filtered. The solvent was evaporated under reduced pressure to give the title compound (5.6 g, 77%). 'H NMR (CD 3 0D) 6 6.72 (1H, s), 4.33 (4H, dd, J0.0, 7.0), 2.43 (3H, s), 1.47 (3H, t, J7.3). 20 Description 87: N-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)-2-[(2-hydroxyethyl)aminoacetamide Ethanolamine (1.04 mL, 17 mmol) was added to a stirred mixture of 2-chloro-N-(1-ethyl-3-methyl-1H pyrazol-5-yl)acetamide (Description 86, 872 mg, 4.3 mmol) and Nal (50 mg) in MeCN (15 mL) and the mixture was stirred at 80 *C for 4.5 h. The mixture was cooled and CHCl 3 / isopropyl alcohol (3:1) and 25 water were added. The layers were separated and the aqueous layer was extracted with CHCl 3 / isopropyl alcohol. The combined organic fractions were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound (0.534 g, 54%). 'H NMR (CD 3 0D) 6 6.08 (1H, s), 3.99 (2H, q, J7.2), 3.67-3.63 (2H, m), 3.46 (2H, s), 2.79-2.73 (2H, m), 2.19 (3H, s), 1.33 (3H, t, J7.2). 30 Description 88: 1-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)piperazin-2-one Di-tert-butyl azodicarboxylate (0.915 g, 4 mmol) and tri-n-butyl phosphine (1 mL, 4 mmol) were added to a stirred solution of N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-2-[(2-hydroxyethyl)amino]acetamide (Description 87, 0.3 g, 1.3 mmol) in EtOAc (10 mL) and the mixture was stirred at RT for 6 h. The 35 mixture was poured onto SCX cartridges (Varian Bond ElutTM; 10 mL/500 mg). The cartridges were washed with MeOH, then eluted with methanolic ammonia (2M). The solvent was evaporated under WO 2007/003965 PCT/GB2006/050184 39 reduced pressure and the residue was purified by chromatography on silica gel, eluting with
CH
2 Cl 2 /MeOH (100:0 increasing to 90:10), to give the title compound (190 mg, 40%). 'H NMR (CDCl 3 ) 6 5.89 (1H, s), 3.92-3.86 (2H, m), 3.69 (2H, s), 3.60-3.56 (2H, m), 3.20 (2H, t, J5.5), 2.25 (3H, s), 1.43-1.39 (3H, m). 5 Description 89: 2-Bromo-N-(3-fluorophenyl)acetamide Bromoacetyl bromide (23.5 mL, 0.27 mol) was added slowly to a stirred, cooled mixture of 3 fluoroaniline (25 g, 0.225 mol) in EtOAc (250 mL) and aqueous KHCO 3 (20%, 250ml). The mixture was allowed to warm to RT and the layers were separated. The organic layer was diluted with EtOAc, washed 10 with aqueous citric acid (10%) and brine, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound (51.72 g, 92%). 'H NMR (360MHz, CD 3 0D) 6 7.54 (1H, dt, J 11, 2), 7.34-7.24 (2H, m), 6.84 (1H, t, J 7), 3.96 (2H, s). Description 90: 1-(3-Fluorophenyl)piperazinone Hydrochloride 15 Ethanolamine (4.5 mL, 75 mmol) was added to stirred 2-bromo-N-(3-fluorophenyl)acetamide (Description 89, 5.0 g, 21 mmol) in EtOAc (25 mL) and the mixture was stirred at 60 *C for 2 h. The mixture was cooled, EtOAc and water were added and the layers were separated. The organic layer was dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc (135 mL) and tributylphosphine (5.3 mL, 21 mmol) was added. The mixture was cooled to 0 *C 20 and di-tert-butylazodicarboxylate (4.8 g, 21 mmol) was added dropwise over 1 h. The mixture was stirred at 0 *C for 0.5 h, then at 40 *C for 1.5 h. The mixture was cooled and ethanolic HCl (4M, 4.7 mL) was added. The mixture was stored at 0 *C for 0.5 h., and the solid was collected, washing with cold EtOAc, and dried in vacuo to give the title compound. 'H NMR (400MHz, CD 3 0D) 6 3.68-3.71 (2H, m), 3.97-4.00 (2H, m), 4.02 (2H, s), 7.12 (1H, m), 7.18 25 7.22 (2H, m), 7.48 (1H, m). Description 91: N-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)-3-azetidinamine A mixture of 1-ethyl-3-methyl-1H-pyrazol-5-amine (1.0 g, 8.0 mmol), 1-(diphenylmethyl)-3-azetidinyl methanesulfonate (2.5 g, 8.0 mmol) and K 2 C0 3 (2.2 g, 16.0 mmol) in DMF (10 mL) was stirred at 60 *C 30 for 24 h. The mixture was cooled, poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic fractions were dried (Na 2
SO
4 ) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 mL), palladium hydroxide (200 mg) was added and the mixture was shaken under H 2 (45 psi) for 72 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica 35 gel, eluting with CH 2 Cl 2 /MeOH (90:10), to give the title compound as an oil. (168 mg, 12%). 'H NMR (CD 3 0D) 6 5.15 (1H, s), 4.17-4.15 (1H, m), 3.90-3.81 (4H, m), 3.58 (2H, m), 2.09 (1H, s), 1.28 (3H, t, J7.1).
WO 2007/003965 PCT/GB2006/050184 40 Description 92: 8-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane A mixture of 1-ethyl-3-methyl-1H-pyrazol-5-amine (1 g, 8 mmol), 2,2-bis(2-iodoethyl)-1,3-dioxolane (3 g, 8 mmol) and K 2 C0 3 were dissolved in MeCN (15 mL) and heated under reflux for 4 days. The 5 mixture was cooled and the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc (100 mL) and washed with water (50 mL). The organic fraction was dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/EtOAc (80:20), to give the title compound (470 mg). 10 Description 93: 1-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)-4-piperidinone 8-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (Description 92) in aqueous acetic acid (75%, 16 mL) was heated under reflux for 16 h. The mixture was cooled and aqueous NaHCO 3 (saturated, 300 mL) was added slowly. The mixture was extracted with EtOAc (2 x 200 mL) and the combined organic fractions were washed with brine (100 mL), dried (MgSO 4 ) and the solvent was 15 evaporated under reduced pressure. Heptane was added and evaporated under reduced pressure to give the title compound as an oil (0.3 g). 'H NMR (CDCl 3 ) 6 5.69 (1H, s), 4.05 (2H, g, J7.2), 3.19 (4H, m), 2.59 (4H, m), 2.23 (3H, s), 1.42 (3H, t, J7.3). 20 Example 1: Trans-1-[4-(4-Bromophenyl)-4-(4-chlorobenzenesufonyl)cyclohexyl]-4-(2-ethyl-5 methyl-2H-pyrazol-3-yl)piperidine Sodium triacetoxyborohydride (0.3 g, 1.4 mmol) and acetic acid (62 mg, 1 mmol) were added to a mixture of 4-(4-bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone (Description 14, 0.44 g, 1 mmol) and 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine (0.2 g, 1 mmol) in 1,2-dichloroethane 25 (8 mL) and the mixture was stirred at RT for 16 h. Water and EtOAc were added and the layers were separated. The organic layer was washed with aqueous NaHCO 3 (saturated), water, and brine, dried (MgSO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/isohexane mixtures, to give the title compound. 'H NMR (360MHz, CDCl 3 ) 6 1.185 (2H, m), 1.36 (3H, t, J7.2), 1.60 (2H, m), 1.79-1.93 (2H, m), 2.14 30 (2H, t, J 11.3), 2.19 (3H, s), 2.30 (2H, t, J 13.7), 2.35-2.50 (2H, m), 2.58 (2H, m), 2.86 (2H, m), 3.96 (2H, q,J7.2), 5.73 (1H, s), 7.09 (2H, d,J8.7), 7.22 (2H, d,J8.7), 7.34 (2H, d,J8.7), 7.43 (2H, d,J8.7). m/z (ES*) 603, 605 (M+1). The following compounds were prepared according to the method of Example 1 substituting a suitable 35 cyclohexanone for 4-(4-bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone and a suitable amine for 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine.
WO 2007/003965 PCT/GB2006/050184 41 Ex. Name ES MS 2 Cis & Trans-i -[4-(2-Fluoro-4-bromophenyl)-4-(4- 622, 624 chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 3 Trans-i '-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-1,3-diethyl- 644, 646 4,5-dihydrospiro[cyclopentapyrazole-6(iH),4'-piperidine] 4 Trans-I - {4-[4-(Trifluoromethyl)phenyl]-4-(4-chlorobenzenesulfonyl)cyclohexyl} -4- 594 2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 5 Trans-i -[4-(3,4-Dichlorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl- 594 5-methyl-2H-pyrazol-3-yl)piperidine 6 Trans-i -[4-(2,5-Difluorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl- 562 5-methyl-2H-pyrazol-3-yl)piperidine 7 Trans-i -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-[ I -(I,i - 632, 634 dimethylethyl)-3-methyl-iH-pyrazol-5-yl]piperidine 8 Trans-i -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-[i-(-(2,2,2- 658/660 trifluoroethyl))-3-methyl-iH-pyrazol-5-yl]piperidine 9 Trans-I - {4-[4-(Trifluoromethoxy)phenyl]-4-(4-chlorobenzenesulfonyl)cyclohexyl} - 610 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 10 Trans-1-[4-(4-Fluorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethy-5- 544 ethyl-2H-pyrazol-3-yl)piperidine II Trans-i -[4-(4-Methylphenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethy-5- 541, 543 methyl-2H-pyrazol-3-yl)piperidine 12 Trans-i -[4-(4-Cyanophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- 551 methyl-2H-pyrazol-3-yl)piperidine 13 Trans-1-[4-(4-Bromophenyl)-4-(benzenesulfonyl)cyclohexyl]-4-(2-ethyl-5-methyl- 570 2H-pyrazol-3-yl)piperidine 14 Trans-i -[4-(3-Fluorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethy-5- 544 methyl-2H-pyrazol-3-yl)piperidine 15 Trans-I - {4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl]-4- 638, 640 (2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 16 Trans-1-[4-(4-Bromophenyl)-4-(4-cyanobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- 595, 597 methyl-2H-pyrazol-3-yl)piperidine 17 Trans-i -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(3,5-diethyl- 618, 620 iH-pyrazol-1-yl)piperidine 18 Trans-I - {4-(4-Bromophenyl)-4-[3-(trifluoromethyl)benzenesulfonyl]cyclohexyl]-4- 638, 640 (2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 19 Trans-i -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(4H- 1,2,4- 563/565 triazol-4-yl)piperidine WO 2007/003965 PCT/GB2006/050184 42 Ex. Name ES MS 20 Trans-4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 678, 680 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 21 Trans-1-{4-(3-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl]-4- 638, 640 (2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 22 Trans-i -[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 594 2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 23 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 636, 638 (2-ethyl-5-methyl-2H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine 24 Cis-1-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- 604, 606 ethyl-2H-pyrazol-3-yl)piperidine 25 Cis-4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 678, 680 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 26 Cis- I -[4-(3,4-Dichlorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- 594 methyl-2H-pyrazol-3-yl)piperidine 27 Cis & Trans-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 638, 640 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 28 Cis & Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 636, 638 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine 29 Cis & Trans-i -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 604, 606 ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 30 Cis- I -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 594, 596 thiazolyl)piperazinone 31 Trans-i -[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 594, 596 thiazolyl)piperazinone 32 Trans-i -[4-(4-Bromophenyl)-4-(4-methylbenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- 584, 586 methyl-2H-pyrazol-3-yl)piperidine 33 Trans-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethoxy)benzenesulfonyl)cyclohexyl]-4- 654, 656 2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 34 Trans-i -[4-(4-Bromophenyl)-4-(3-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- 604, 606 methyl-2H-pyrazol-3-yl)piperidine 35 Trans-4-[1-{4-(4-Chlorophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 634 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 36 (R)-Cis-1-[4-(3,4-Dichlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 628 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 37 Trans-i -[4-(3,4-Dichlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 628 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine WO 2007/003965 PCT/GB2006/050184 43 Ex. Name ES MS 38 Trans-i '-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 711, 713 1,2-dihydro-1 -(methylsulfonyl)spiro[3H-indole-3,4'-piperidine] 39 Trans-i '-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 1- 689, 691 (1-methylethyl)spiro[3H-indole-3,4'-piperidin]-2(1H)-one 40 Trans-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 612, 614 3-methyl- 1,2,4-oxadiazol-5-yl)piperidine 41 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 597, 599 (4H-1,2,4-triazol-4-yl)piperidine 42 (RS)-Cis-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 597, 599 3-(1H-1,2,4-triazol- 1 -yl)piperidine 43 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 597, 599 (1H-tetrazol- 1 -yl)piperidine 44 Trans-8-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 1- 676, 678 phenyl-1,3,8-triazaspiro[4.5]decan-4-one 45 Trans-3-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 693, 695 piperidin-4-yl]-1,3-dihydro-5-methoxy-2H-imidazo[4,5-b]pyridin-2-one 46 Trans-N-[ 1- {4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 713, 715 piperidin-4-yl}methyl-N-phenylmethanesulfonamide 47 Trans-N-[4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 677, 679 cyclohexyl}-4-phenylpiperidin-4-yl}-methyl]acetamide 48 (RS)-Trans-4-[4-(4-Bromophenyl)-4-(4- 638, 640 trifluoromethyl)benzenesulfonyl)cyclohexyl]-2-(phenoxymethyl)morpholine 49 Trans-i -[1- {4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 677, 679 piperidin-4-yl]-1,4-dihydro-2H-3, I-benzoxazin-2-one 50 Trans-6-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 569, 571 5,6,7,8-tetrahydro-[ 1,2,4]triazolo[ 1,5-a]pyrazine 51 (RS)-Trans- 1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 611, 613 yclohexyl]-3-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine 52 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 622, 624 (3-pyridinylmethyl)piperazine 53 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 613, 615 (4-methyl-1,2,5-oxadiazol-3-yl)piperazine 54 S)-Trans- 1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 635, 637 _-(phenylmethyl)-3-pyrrolidinemethanamine 55 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 642, 644 [(2-methyl-4-thiazolyl)methyl]piperazine WO 2007/003965 PCT/GB2006/050184 44 Ex. Name ES MS 56 Cis- 1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4-[(2- 642, 644 methyl-4-thiazolyl)methyl]piperazine 57 S)-Cis-1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-N- 635, 637 (phenylmethyl)-3-pyrrolidinemethanamine 58 Cis-N-[4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 677, 679 cyclohexyl}-4-phenylpiperidin-4-yl}-methyl]acetamide 59 Cis-3-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 693, 695 piperidin-4-yl]-1,3-dihydro-5-methoxy-2H-imidazo[4,5-b]pyridin-2-one 60 Trans-1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-3- 569, 571 (1H-1,2,4-triazol-3-yl)azetidine 61 Cis-8-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 676, 678 phenyl-1,3,8-triazaspiro[4.5]decan-4-one 62 Cis- 1'-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 1,2- 711, 713 dihydro-l-(methylsulfonyl)spiro[3H-indole-3,4'-piperidine] 63 Trans-3-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 676, 678 piperidin-4-yl]-3,4-dihydro-2(1H)-quinazolinone 64 (RS)-Trans-1-[4-(4-Bromophenyl)-4-(4- 597, 599 (trifluoromethyl)benzenesulfonyl)cyclohexyl]-3-(1H-1,2,4-triazol-1-yl)piperidine 65 Cis-4-[1-{4-(3,4-Dichlorophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 668 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 66 Trans-4-[1-{4-(3,4-Dichlorophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 668 cyclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 67 Cis- 1'-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 1,3- 678/680 diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4'-piperidine] 68 Trans-1 '-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 678/680 1,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4'-piperidine] 69 N-[Trans-4-(4-Bromophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl]-4- 582, 584 (methoxy)benzenemethanamine 70 Trans-1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 692, 694 [1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl]piperidine 71 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 668, 670 [2-(1-hydroxy-1-methylethyl)-4-methyl-1H-imidazol-1-yl]piperidine 72 Cis-4-[1-{4-(4-Fluororophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl} 618 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 3 Trans-4-[1-{4-(4-Fluororophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 618 cyclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine WO 2007/003965 PCT/GB2006/050184 45 Ex. Name ES MS 74 Trans-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-2,6- 560, 562 dimethylmorpholine 75 Cis-1 -[4-(4-Fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4-(2- 578 ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 76 Trans-i -[4-(4-Fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 578 2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 77 Trans-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 653, 655 (1-ethyl-3-methyl-1H-pyrazol-5-yl)piperazin-2-one 78 Cis-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1-(1- 653, 655 thyl-3-methyl-1H-pyrazol-5-yl)piperazin-2-one 79 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 652, 654 [1,3,4-Trimethyl-1H-pyrazol-5-yl]piperidine 80 Cis-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-2,6- 560, 562 dimethylmorpholine 81 Cis-1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 652, 654 [1,3,4-trimethyl-1H-pyrazol-5-yl]piperidine 82 Trans-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 639, 641 (3-fluorophenyl)piperazinone 83 Cis- 1 -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-N-(1 - 625, 627 ethyl-3-methyl-1H-pyrazol-5-yl)-3-azetidinamine 84 Trans-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-N- 625, 627 1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-azetidinamine 85 Trans-i -[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 666, 668 [1-(1, 1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]piperidine 86 Cis-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1-(3- 639, 641 fuorophenyl)piperazinone 87 Cis-4-{1-[4-(4-Bromophenyl)-4-(4-cyanobenzenesulfonyl)cyclohexyl]piperidin-4- 635, 637 yl}-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 88 Trans-4-{1-[4-(4-Bromophenyl)-4-(4-cyanobenzenesulfonyl)cyclohexyl]piperidin-4- 635, 637 yl}-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 89 Trans-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 664, 666 2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine 90 Trans-i -[4-(4-Chloro-3-fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 612 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 91 Cis- 1 -[4-(4-Chloro-3-fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 612 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine WO 2007/003965 PCT/GB2006/050184 46 Ex. Name ES MS 92 Cis-4-[1-{4-(4-Chloro-3-fluorophenyl)-4-[4-(trifluoromethyl)benzenesulfony] 652, 654 cyclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 93 Trans-4-[1-{4-(4-Chloro-3-fluorophenyl)-4-[4-(trifluoromethyl)benzenesulfony] 652, 654 cyclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 94 Cis-6-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 603 5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,6-naphthyridine 95 Trans-6-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 603 5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,6-naphthyridine 96 Trans-4-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 578 (2-pyridinyl)piperazinone 97 Cis-4-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1-(2- 578 pyridinyl)piperazinone 98 Trans-I - {4-(4-Chlorophenyl)-4-[4-(1 -hydroxy- 1 -methylethyl)benzenesulfonyl] 584 yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 99 Trans-Methyl 4-({1-(4-Chlorophenyl)-4-[4-(2-ethyl-5-methyl-2H-pyrazol-3- 584 yl)piperidinyl]cyclohexyl} sulfonyl)benzoate 100 1,1-Dimethylethyl [1-(Trans-4-(4-chlorophenyl)-4-{[4- 601 (trifluoromethyl)phenyl]sulfonyl}cyclohexyl)-4-piperidinyl]carbamate 101 Trans-I - {4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} - 639, 641 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 102 Cis-1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl}-4- 639, 641 2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 103 Trans-4-[1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl] 679,681 cyclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 104 Cis-4-[1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} 679, 681 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 105 Cis-4-[1-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} 635 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 106 Trans-4-[1-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl] 635 cyclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 107 Cis-1-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl}-4- 595 2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 108 Trans-I - {4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} - 595 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 109 Cis- 1- {4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} -4- 665, 667 (2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine WO 2007/003965 PCT/GB2006/050184 47 Ex. Name ES MS 110 Trans-I - {4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} - 665, 667 4-(2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine 111 Trans-4-[1-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} 619 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 112 Cis-4-[1-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} 619 piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine 113 Trans-I - {4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} -4- 579 (2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 114 Trans-1-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl}-4- 605 2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine 115 Cis- 1- {4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]cyclohexyl} -4- 605 (2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine 116 Cis- 1 -[4-(4-Bromophenylmethyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 618, 620 ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 117 Trans-1-[4-(4-Bromophenylmethyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 618, 620 ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 118 Cis- 1- {4-(4-Bromophenylmethyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 652, 654 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 119 Trans-I - {4-(4-Bromophenylmethyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 652, 654 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine 120 Cis & Trans-i -[4-Phenyl-4-(phenylsulfonylmethyl)cyclohexyl]-4-(2-ethyl-5-methyl- 506 2H-pyrazol-3-yl)piperidine 121 (RS)-Trans-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfinyl) 622, 624 cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine Example 122: Trans-1-{4-Phenylmethyl-4-[4-(trifluoromethyl)benzenesulfonyl] cyclohexylj-4-(2 ethyl-5-methyl-2H-pyrazol-3-yl)piperidine Pd on C (30 mg) was added to a solution of trans-1-{4-(4-bromophenylmethyl)-4-[4 5 (trifluoromethyl)benzenesulfonyl]cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine (Example 119, 57 mg, 87 gmol) in EtOAc (5 mL) and the mixture was vigorously stirred under a H2 atmosphere overnight. The mixture was filtered through HyfloTM and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with EtOAc/MeOH/NH 3 (Aq.) (98:2:0.2) to give the title compound (10 mg, 20%). 10 'H NMR (500MHz, CD 3 0D): 6 7.99 (d, J8.1, 2H); 7.89 (d, J8.1, 2H); 7.36 (d, J8.2, 211); 7.24 (m, 3H); 5.83 (s, 111); 4.02 (q, J7.2, 2H); 3.26 (s, 2H); 3.01 (d, J11.3, 2H); 2.63 (m, 111); 2.35 (m, 3H); 2.16 (s, 3H); 2.10 (d, J 13.1, 2H); 1.90 (m, 6H); 1.63 (m, 4H); 1.33 (t, J7.2, 3H).
WO 2007/003965 PCT/GB2006/050184 48 Example 123: Trans-4-(4-Bromophenyl)-4-{1[4-(trifluoromethyl)phenylsulfonyl}cyclohexanamine Ceric ammonium nitrate (232 mg, 0.423 mmol) was added to a stirred suspension of N-[trans-4-(4 bromophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl]-4-(methoxy)benzenemethanamine 5 (Example 69, 99 mg, 0.17 mmol) in MeCN (1.0 ml) and water (0.35 ml) at RT. The mixture was stirred overnight and a further portion of ceric ammonium nitrate (29 mg, 0.053 mmol) was added. After stirring at RT for a further 1 h, the mixture was diluted with EtOAc and water. The aqueous layer was separated and re-extracted with EtOAc. The combined organic layers were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography, 10 eluting with 10% MeOH in CH 2 Cl 2 , to give the title compound (48 mg, 62%). 'H NMR (400MHz, CDCl 3 6 1.02 (2H, q, J 12.4), 1.88 (2H, d, J 12.3), 2.32 (2H, m), 2.53 (2H, d, J 13), 2.84 (1H, m), 7.09 (2H, d, J8.2), 7.43 (4H, d, J8.1), 7.63 (2H, d, J8.0). The following compound was prepared according to the method of Example 1 substituting trans-4-(4 15 bromophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexanamine (Example 123) for 4-(4 bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone and 1-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4 piperidinone (Description 93) for 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine. Ex. Name ES MS (M+1) 124 Trans-N-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 653, 655 cyclohexyl]-1-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine-4-amine Example 125: 1-(Trans-4-(4-Chlorophenyl)-4-{1[4 20 (trifluoromethyl)phenylsulfonyl}cyclohexyl)piperidin-4-amine Hydrochloride Hydrogen chloride in dioxane (4N, 10 mL) was added to a stirred solution of 1,1 -dimethylethyl [1 -(trans 4-(4-chlorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl} cyclohexyl)-4-piperidinyl]carbamate (Example 100, 2.045 g, 3.4 mmol) in CH 2 Cl 2 (10 mL) and the mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure to give the title compound (1.73 g, 95%). 25 'H NMR (360MHz, CD 3 0D): 6 7.78 (t, 2H), 7.55 (d, 2H), 7.35 (q, 4H), 3.53 (d, 3H), 3.06 (t, 2H), 2.85 (d, 2H), 2.38 (t, 3H), 2.21 (d, 4H), 1.93 (d, 2H), 1.41 (d, 2H). Example 126: N-(1,1-Dimethylethyl)-N'-[1-(Trans-4-(4-chlorophenyl)-4-{[4 (trffluoromethyl)phenylsulfonyl}cyclohexyl)piperidin-4-yljurea 30 t-Butyl isocyanate (0.0255 mL, 0.224 mmol) was added to a stirred solution of 1-(trans-4-(4 chlorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl) piperidin-4-amine hydrochloride (Example 125, 0.1 g, 0.186 mmol) and triethylamine (0.077 mL, 0.558 mmol) in CH 2 Cl 2 (5 mL) and the mixture was stirred at RT for 2 h. Water was added and the mixture was extracted with CH 2 Cl 2 . The combined organic fractions were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure.
WO 2007/003965 PCT/GB2006/050184 49 The residue was purified by preparative thin layer chromatography on silica gel, eluting with 5% MeOH in CH 2 Cl 2 , to give the title compound (40 mg, 36%). 'H NMR (500MHz, CD 3 0D): 6 7.77 (d, 2H), 7.53 (d, 2H), 7.31 (q, 4H), 3.37 (t, 1H), 2.77 (d, 2H), 2.71 (d, 2H), 2.52 (s, 1H), 2.25 (q, 4H), 1.99 (d, 2H), 1.79 (d, 2H), 1.29 (t, 2H), 1.26 (s, 9H), 1.21-1.13 (m, 5 2H).

Claims (26)

1. A compound of formula (I): R 5 R 6 7// A S(O)n-X Z-N (I) R ~ YR B 5 R3 R4 wherein: rings A and B are independently aryl or heteroaryl; n is 0, 1 or 2; X and Y are independently selected from a bond, -CH 2 -, -C(CiAalkyl) 2 - and -N(Ci 4 alkyl)-; 10 Z is a bond, -CH 2 - or -C(CiAalkyl) 2 -; R 1 is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 - 8 cycloalkyl, hydroxy, CI 6 alkoxy, halogen, CN, C0 2 (CI 6 alkyl) or C(CH 3 ) 2 0H, optionally substituted by 1 to 8 halogen atoms; R 2 is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 2 -6alkynyl, C 3 - 8 cycloalkyl or halogen; R 3 is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 - 8 cycloalkyl, hydroxy, CI 6 alkoxy, halogen 15 or CN, optionally substituted by 1 to 8 halogen atoms; R 4 is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 2 -6alkynyl, C 3 - 8 cycloalkyl or halogen; R5 and R6 are independently selected from hydrogen, C1_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 8 cycloalkyl, hydroxy, CI 6 alkoxy or halogen; R is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 - 8 cycloalkyl, (CH 2 )o- 2 aryl, (CH 2 ) 0 20 2 heteroaryl or Het, optionally substituted by 1 to 8 halogen atoms, CiAalkyl, hydroxy, CiAalkoxy or heteroaryl, which heteroaryl is optionally substituted by 1 to 3 groups selected from CiAalkyl; R 8 is hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl or C 3 - 8 cycloalkyl; or R7 and R 8 , together with the nitrogen atom to which they are attached, form a 4- to 7 membered heterocycle, optionally containing 1, 2 or 3 further heteroatoms selected from N, 0 and S, 25 which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from C1_ 6 alkyl, C 2 6 alkenyl, C 2 - 6 alkynyl or C 3 - 8 cycloalkyl, hydroxy, oxo, (CH 2 )o- 3 C 1 . 6 alkoxy, (CH 2 )o-30aryl, (CH 2 )o- 3 aryl, (CH 2 )o- 3 heteroaryl, (CH 2 )o- 3 Het, or (CH 2 ) 0 - 3 NRaRb, wherein said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from C 1 . 6 alkyl, hydroxy, oxo, C 1 . 6 alkoxy or 30 halogen, which C 1 . 6 alkyl being optionally substituted by hydroxy or 1 to 5 halogen atoms, and where said aryl, heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains 1, WO 2007/003965 PCT/GB2006/050184 51 2 or 3 heteroatoms selected from N, 0 or S and which ring is optionally substituted by C14alkyl, hydroxy, oxo, C1.4alkoxy or halogen, and which heterocycle may optionally be fused to heteroaryl, which heteroaryl is optionally substituted by CI 6 alkyl or trifluoromethyl, 5 and which heterocycle may optionally be spiro-fused to a 5- or 10-membered mono- or bi-cyclic ring system optionally containing 1, 2 or 3 heteroatoms selected from N, 0 and S, and further optionally containing 1, 2 or 3 double bonds and also optionally substituted by 1 to 3 groups independently selected from CI 6 alkyl, hydroxy, oxo, phenyl and SO 2 CI 6 alkyl; Ra is hydrogen, CI 6 alkyl, C(O)CI 6 alkyl, C(O)OCI 6 alkyl, C(O)NH(CI 6 alkyl), (CH 2 )o- 3 aryl, 10 (CH 2 )o- 3 heteroaryl or SO 2 CI 6 alkyl, optionally substituted by C1 6 alkyl; Rb is hydrogen, CI 6 alkyl or aryl; and pharmaceutically acceptable salts thereof.
2. A compound as claimed in Claim 1 wherein ring A is phenyl, pyridyl or pyrimidyl. 15
3. A compound as claimed in Claim 1 or Claim 2 wherein ring B is aryl or pyridyl.
4. A compound as claimed in any one of Claims 1 to 3 wherein n is 1 or 2. 20
5. A compound as claimed in any one of Claims 1 to 4 wherein X is a bond, -CH 2 - or -C(C 1 . 4 alkyl) 2 -.
6. A compound as claimed in any one of Claims 1 to 5 wherein Y is a bond, -CH 2 - or -C(C 1 . 4 alkyl) 2 -. 25
7. A compound as claimed in any one of Claims 1 to 6 wherein Z is a bond or -CH-.
8. A compound as claimed in any one of Claims 1 to 7 wherein R 1 is hydrogen, C 1 . 6 alkyl, hydroxy, C 1 . 6 alkoxy, halogen, CN, C0 2 (C 1 . 4 alkyl) or C(CH 3 ) 2 0H, optionally substituted by 1 to 5 halogen atoms. 30
9. A compound as claimed in any one of Claims 1 to 8 wherein R 2 is hydrogen or C 1 6 alkyl.
10. A compound as claimed in any one of Claims 1 to 9 wherein R 3 is hydrogen, C 1 . 6 alkyl, hydroxy, C 1 . 6 alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. 35
11. A compound as claimed in any one of Claims 1 to 10 wherein R 4 is hydrogen or halogen. WO 2007/003965 PCT/GB2006/050184 52
12. A compound as claimed in any one of Claims 1 to 11 wherein R5 is hydrogen, C1 6 alkyl, hydroxy, CI 6 alkoxy, or halogen.
13. A compound as claimed in any one of Claims 1 to 12 wherein R6 is hydrogen or C1 6 alkyl. 5
14. A compound as claimed in any one of Claims 1 to 13 wherein R is hydrogen, CI 6 alkyl, (CH 2 ) 0 2 aryl, or Het, optionally substituted by Ci 4 alkyl, CiAalkoxy or heteroaryl, which heteroaryl is optionally substituted by 1 or 2 methyl or ethyl groups. 10
15. A compound as claimed in any one of Claims I to 14 wherein R 8 is hydrogen or C1 6 alkyl.
16. A compound as claimed in any one of Claims 1 to 13 wherein R7 and R 8 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycle, optionally containing 1 or 2 further heteroatoms selected from N and 0, 15 which heterocycle may optionally contain one double bond, and which heterocycle may optionally be substituted by one or two groups selected from CiAalkyl, oxo, CH 2 -0-phenyl, phenyl, heteroaryl, CH 2 heteroaryl, Het, NH 2 , (CH 2 ) 0 - 1 NHIRa or CH 2 N(phenyl)SO 2 CH 3 , where said aryl, heteroaryl, and Het are optionally substituted by 1, 2 or 3 groups selected from CiAalkyl, oxo or halogen, which Ci 4 alkyl being optionally substituted by hydroxy or 1 to 3 halogen atoms, and 20 where said heteroaryl and Het are also optionally fused to a 5-or 6-membered ring which optionally contains a nitrogen atom and which ring is optionally substituted by Ci 4 alkoxy, and which heterocycle may optionally be fused to pyridyl or triazolyl, optionally substituted by trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5-membered monocyclic or a 8- or 9-membered bicyclic ring system, optionally containing 1 or 2 N atoms, further optionally 25 containing 2 or 3 double bonds and also optionally substituted by CiAalkyl, oxo, phenyl, or SO 2 CiAalkyl, and Ra is as defined in Claim 1.
17. A compound as claimed in Claim 1 of formula (Ia): R A S(O)"-X Z-N Sk8 (Ia) 30 R3 R4 or a pharmaceutically acceptable salt thereof, wherein ring A, n, X, Y, R 1 , R 3 , R 4 , R7 and R 8 are as defined in Claim 1. WO 2007/003965 PCT/GB2006/050184 53
18. A compound as claimed in Claim 17 of formula (Iaa): RS N R9 0 - (Iaa) R3 5 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are as defined in Claim 1, and R 9 is (CH 2 ) 0 - 3 NRaRb, where Ra and Rb are as defined in Claim 1, or (CH 2 )o- 3 heteroaryl or (CH 2 )o- 3 Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from C 1 . 6 alkyl, hydroxy, oxo, C 1 . 6 alkoxy or halogen, which C 1 . 6 alkyl being optionally substituted by hydroxy 10 or 1 to 5 halogen atoms, and where said heteroaryl and Het are also optionally fused to a 5- or 6 membered ring which optionally contains 1 or 2 heteroatoms selected from N and 0, and which ring is optionally substituted by C 1 . 4 alkyl, hydroxy or C1.4alkoxy.
19. A compound as claimed in Claim 17 of formula (Iab): 15 N 0 F 3 C N R9 (Iab) R3 or a pharmaceutically acceptable salt thereof, wherein R 3 is as defined in Claim 1 and R 9 is as defined in Claim 18.
20 20. A compound as claimed in Claim 1 which is selected from Examples 1 to 126 or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 25
22. A compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof for use in therapy. WO 2007/003965 PCT/GB2006/050184 54
23. Use of a compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a NK-3 receptor mediated disease. 5
24. A method of treatment of a subject suffering from a NK-3 receptor mediated disease, which comprises administering to that patient a therapeutically effective amount of a compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof.
25. The use of Claim 23 or the method of Claim 24 wherein the NK-3 receptor mediated disease is 10 selected from: depression; anxiety disorders; phobias; psychosis and psychotic disorders; post-traumatic stress disorder; attention deficit hyperactive disorder (ADHD); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities; and irritable bowel syndrome.
26. A method of preparing a compound of Claim 1 where Z is a bond by the reaction of a 15 compound of formula (II) with a compound of formula (III): R 5 R 6 S(O)n-X 0 HN/ Y R3j R4 (II) (III) where A, B, n, X, Y, R 1 , R 2 , R 3 , R 4 , Ri, Ri, Ri and R 8 are as defined in Claim 1.
AU2006264652A 2005-07-06 2006-07-04 Substituted cyclohexyl derivatives as NK-3 receptor antagonists Abandoned AU2006264652A1 (en)

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US8394858B2 (en) 2009-12-03 2013-03-12 Novartis Ag Cyclohexane derivatives and uses thereof
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