CLAESSON ALF (SE)
CSJERNYIK GABOR (SE)
GRAVENFORS YLVA (SE)
KERS INGER (SE)
SKOGHOLM KARIN (SE)
SOHN DANIEL (SE)
BESIDSKI YEVGENI (SE)
CLAESSON ALF (SE)
CSJERNYIK GABOR (SE)
GRAVENFORS YLVA (SE)
KERS INGER (SE)
SKOGHOLM KARIN (SE)
SOHN DANIEL (SE)
| WO1997034883A1 | 1997-09-25 | |||
| WO1999014212A1 | 1999-03-25 | |||
| WO1999014213A1 | 1999-03-25 | |||
| WO1999005134A1 | 1999-02-04 | |||
| WO2005013914A2 | 2005-02-17 |
| US20050137190A1 | 2005-06-23 | |||
| US20060025415A1 | 2006-02-02 |
| CLAIMS
1. A compounds of formula I,
X is O or CH 2 ; R 3 is hydrogen or Ci -4 alkyl;
Ri-Y is selected from Ri-Ci -4 alkyl, Ri-Ci -4 alkylN(Ci -4 alkyl)Ci -4 alkyl, Ri-Ci -4 alkylNHCi. 4 alkyl, Ri-Ci -4 alkylNH, Rj-NH, Ri-C(O), Ri-O, Ri-Ci -4 alkylO, Ri-OCi -4 alkyl, Ri-C(O)Ci- 4 alkyl0, Ri-OCi -4 alkylC(O), Ri-Ci -4 alkyl-SO 2 -O or Ri-SO 2 -O;
Ri is phenyl, tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, - N(Ci -4 alkyl) 2 , -NHCi -4 alkyl, NH 2> imidazolyl, thiazolyl or pyridinyl, which may be independently mono-, di-, or tri-substituted with Rn, Ri 2 , and/or R n , wherein Rn, Ri 2 , and Rn are independently selected from: halogen, Ci -6 alkyl, Ci -6 alkoxy, C 3- 6Cycloalkyl, C 3-6 CyClOaIkOXy, C 3-6 cycloalkylCi. ealkoxy, CN, OH, -OCF 3 , -OCHF 2 , -OCH 2 F, -O(CH 2 )i -6 CF 3 , -O(CH 2 )i -6 CHF 2 , - 0(CH 2 ) I-6 CH 2 F, -OCH(CF 3 ) 2 , -OCH(CF 2 ) 2 , -OCH(CF) 2 , -O(CH 2 )i -6 CH(CF 3 ) 2 , - O(CH 2 )i -6 CH(CF 2 ) 2 , -0(CH 2 ) I-6 CH(CF) 2 , -0(CH 2 ) I-6 CH(CHi -6 CF 3 ),, -0(CH 2 ) L 6 CH(CHi -6 CHF 2 ) 2 , -0(CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 )^CF 3 , -(CH 2 ) I-6 CHF 2 , -(CH 2 ) I-6 CH 2 F, -CH(CF 3 ) 2 , -CH(CF 2 ) 2 , -CH(CF) 2 , -(CH 2 )L
6 CH(CF 3 ) 2 , -(CH 2 )i -6 CH(CF 2 ) 2 , -(CH 2 )^CH(CF) 2 , -(CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , - (CH 2 )i -6 CH(CHi -6 CHF 2 ) 2 , -(CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , -OSO 2 CH 3 , -OSO 2 (CH 2 )L 6CH 3 , -OSO 2 CF 3 , -OSO 2 CHF 2 , -OSO 2 CH 2 F, -OSO 2 (CH 2 ) I-6 CF 3 , -OSO 2 (CH 2 )L 6CHF 2 , -OSO 2 (CH 2 ) I-6 CH 2 F, -OSO 2 CH(CF 3 ) 2 , -OSO 2 CH(CF 2 ) 2 , -OSO 2 CH(CF) 2 , - OSO 2 (CH 2 )i -6 CH(CF 3 ) 2 , -OSO 2 (CH 2 )i -6 CH(CF 2 ) 2 , -OSO 2 (CH 2 )i -6 CH(CF) 2 , -
OSO 2 (CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , -OSO 2 (CH 2 )i -6 CH(CHi -6 CHF 2 ) 2 , -OSO 2 (CH 2 ) I- 6 CH(CHi -6 CH 2 F) 2 , -SO 2 CH 3 , -SO 2 (CH 2 )i -6 CH 3 , -SO 2 CF 3 , -SO 2 CHF 2 , -SO 2 CH 2 F, - SO 2 (CH 2 ) 1-6 CF 3 , -SO 2 (CH 2 ) 1-6 CHF 2 , -SO 2 (CH 2 ) 1-6 CH 2 F, -SO 2 CH(CF 3 ) 2 , - SO 2 CH(CF 2 ) 2 , -SO 2 CH(CF) 2 , -SO 2 (CH 2 ) 1-6 CH(CF 3 ) 2 , -SO 2 (CH 2 ) 1-6 CH(CF 2 ) 2 , - SO 2 (CH 2 ) J-6 CH(CF) 2 , -SO 2 (CH 2 ) 1-6 CH(CH 1-6 CF 3 ) 2 , -SO 2 (CH 2 ) 1-6 CH(CH 1-6 CHF 2 ) 2 , -SO 2 (CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , phenyl, phenylCi -6 alkyl-, phenoxy, Ci -6 alkylphenyl 5 and Ci -6 alkoxyphenyl-;
R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl, pyrazinyl or pyridinyl, which may be independently mono-, di-, or tri-substituted with Ri 4 , Ri 5 , and/or Ri 6 ; wherein R H , R I 5 , and/or Ri 6 are independently selected from: halogen, Ci -6 alkyl, Ci -6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 cycloalkylCi.0 6 alkoxy, CN, OH, -OCF 3 , -OCHF 2 , -OCH 2 F, -O(CH 2 )i -6 CF 3 , -O(CH 2 )i -6 CHF 2 , -
0(CH 2 ) I-6 CH 2 F, -OCH(CF 3 ) 2 , -OCH(CF 2 ) 2 , -OCH(CF) 2 , -O(CH 2 )i -6 CH(CF 3 ) 2 , - O(CH 2 )i -6 CH(CF 2 ) 2 , -0(CH 2 ) I-6 CH(CF) 2 , -O(CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , -O(CH 2 )i. 6CH(CHi -6 CHF 2 ) 2 , -0(CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 )^CF 3 , -(CH 2 ) I-6 CHF 2 , -(CH 2 ) I-6 CH 2 F, -CH(CF 3 ) 2 , -CH(CF 2 ) 2 , -CH(CF) 2 , -(CH 2 )i.5 6 CH(CF 3 ) 2 , -(CH 2 )i -6 CH(CF 2 ) 2 , -(CH 2 )^CH(CF) 2 , -(CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , -
(CH 2
)i -6
CH(CHi -6
CHF 2
) 2
, -(CH 2
) I-6
CH(CHi -6
CH 2
F) 2
, -OSO 2
CH 3
, -OSO 2
(CH 2
) I- 6
CH 3
, -OSO 2
CF 3
, -OSO 2
CHF 2
, -OSO 2
CH 2
F, -OSO 2
(CH 2
) I-6
CF 3
, -OSO 2
(CH 2
) I- 6
CHF 2
, -OSO 2
(CH 2
) I-6
CH 2
F, -OSO 2
CH(CF 3
) 2
, -OSO 2
CH(CF 2
) 2
, -OSO 2
CH(CF) 2
, - OSO 2
(CH 2
)i -6
CH(CF 3
) 2
, -OSO 2
(CH 2
)i -6
CH(CF 2
) 2
, -OSO 2
(CH 2
)i -6
CH(CF) 2
, -0 OSO 2
(CH 2
)i -6
CH(CHi -6
CF 3
) 2
, -OSO 2
(CH 2
)i -6
CH(CHi -6
CHF 2
) 2
, -OSO 2
(CH 2
) I- 6
CH(CHi -6
CH 2
F) 2
, -SO 2
CH 3
, -SO 2
(CH 2
)i -6
CH 3
, -SO 2
CF 3
, -SO 2
CHF 2
, -SO 2
CH 2
F, - SO 2
(CH 2
) I-6
CF 3
, -SO 2
(CH 2
) I-6
CHF 2
, -SO 2
(CH 2
)i -6
CH 2
F, -SO 2
CH(CF 3
) 2
, - SO 2
CH(CF 2
) 2
, -SO 2
CH(CF) 2
, -SO 2
(CH 2
)i -6
CH(CF 3
) 2
, -SO 2
(CH 2
)i -6
CH(CF 2
) 2
, - SO 2
(CH 2
) I-6
CH(CF) 2
,
Ci -6 alkoxyphenyl-, piperidinyl, and C 3-6 heterocycloalkyloxy; or pharmaceutically-acceptable salts thereof.
2. The compounds according to claim 1, wherein:o X is O or CH 2 ;
R 3 is hydrogen or Ci -4 alkyl; Ri-Y is selected from Ri-C M alkyl, Ri-C M alkylN(C M alkyl)C M alkyl, R r C M alkyDSIH, Ri - NH, Ri-C(O), Ri-O, Ri-Ci -4 alkylO, Ri -C(O)C M alkyl0 and Ri-SO 2 -O; Ri is phenyl, tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, - N(Ci_4alkyl)2, -NHCi_4alkyl, NH 2 , imidazolyl, thiazolyl or pyridinyl, which may be 5 independently mono-, di-, or tri-substituted with Rn, Ri 2 , and/or R n , wherein Rn, Ri 2 , and Rn are independently selected from C 1-6 alkyl; R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl and pyridinyl, which may be independently mono-, di-, or tri-substituted with R H , R15, and/or Ri 6 ; wherein R H , R I 5 , and/or Ri 6 are independently selected from:0 Ci-ealkyl, Ci -6 alkoxy, -OCF 3 , -0(CH 2 ) I -6 CF 3 , -CF 3 , -OSO 2 CF 3 , phenyl, Ci- βalkylphenyl, piperidinyl and C 3- 6heterocycloalkyloxy; or pharmaceutically-acceptable salts thereof.
3. The compounds according to any one of claim 1 or 2, wherein R 3 is hydrogen or methyl.5
4. The compounds according to any one of claim 1 to 3, wherein Ri-methyl, Ri-ethyl, R 1 - propyl, Ri -butyl, Ri-NH, Ri-C(O), Ri-O, Ri-methyl(methylamino)methyl, Ri- methyl(ethylamino)methyl, Ri-methyl(ethylamino)ethyl, Ri-ethyl(ethylamino)methyl, Ri- ethylamino, Ri-methoxy, Ri-ethoxy, Ri-propoxy, Ri-butoxy, Ri-carbonylmethoxy, R 1 -o carbonylethoxy, Ri-carbonyl-propoxy, , Ri-methylsulfonyl, Ri-ethylsulfonyl, Ri- propylsulfonyl, Ri-butylsulfonyl, Ri-sulfonyloxy, Ri-methylsulfonyloxy or Ri- ethylsulfonyloxy.
5. The compounds according to any one of claim 1 to 4, wherein Ri is phenyl,5 tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dimethylamine, diethylamine, ethylamine, NH 2 , imidazolyl, thiazolyl or pyridinyl.
6. The compounds according to any one of claim 1 to 4, wherein R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl or pyridinyl.o
7. The compounds according to any one of claim 1 to 6, wherein R H , R15, and Ri 6 are independently selected from: methyl, i-propoxy, n-butoxy, trifiuoromethyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoromenthanesulfonic acid, tetrahdyropyranyloxy, phenyl, dimethylphenyl or piperidinyl.
8. Compounds selected from the group consisting of N-[(2R)-8-{[Benzyl(methyl)amino]methyl}-5-methyl-l,2,3,4-tetrahydronaphthalen-2-yl]-4-
(trifluoromethoxy)benzamide,
N-[(2R)-8-(3,4-Dihydroisoquinolin-2(lH)-ylmethyl)-5-methyl-l,2,3,4- tetrahydronaphthalen-2-yl]-4-(trifluoromethoxy)benzamide,
N-{(2R)-8-[(2,6-Dimethylmorpholin-4-yl)methyl]-5-methyl-l,2,3,4-tetrahydronaphthalen- 2-yl} -4-(trifiuoromethoxy)benzamide,
N-[(2R)-8-{[Benzyl(methyl)amino]methyl}-5-methyl-l,2,3,4-tetrahydronaphthalen-2-yl]-5- methyl-2-phenyl-2H-l,2,3-triazole-4-carboxamide,
N-[(2R)-8-(3,4-Dihydroisoquinolin-2(lH)-ylmethyl)-5-methyl-l,2,3,4- tetrahydronaphthalen-2-yl]-5-methyl-2-phenyl-2H-l,2,3-triazole-4-carboxamide, 4-Butoxy-N-{(3S)-5-[(l-methylpiperidin-4-yl)amino]-3,4-dihydro-2H-chromen-3- yl}benzamide,
N-{(3S)-5-[(2-Pyrrolidin-l-ylethyl)amino]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]-4- (trifluoromethoxy)benzamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]-2,4- bis(trifluoromethyl)benzamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-[(3S)-5-(pyrrolidin-l-ylmethyl)-3,4-dihydro-2H- chromen-3-yl]-2H-l,2,3-triazole-4-carboxamide, 4-{[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]carbamoyl}phenyl trifluoromethanesulfonate,
N-{(3S)-5-[(4-Methylpiperazin-l-yl)carbonyl]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-{(3S)-5-[(4-methylpiperazin-l-yl)carbonyl]-3,4- dihydro-2H-chromen-3-yl} -2H- 1 ,2,3-triazole-4-carboxamide,
N-{(3S)-5-[(4-Methylpiperazin-l-yl)methyl]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide, 2-(2,4-Dimethylphenyl)-5-methyl-N-{(3S)-5-[(4-methylpiperazin-l-yl)methyl]-3,4-dihydro-
2H-chromen-3-yl} -2H- 1 ,2,3-triazole-4-carboxamide,
N-{(3S)-5-[(4-Methylpiperazin-l-yl)methyl]-3,4-dihydro-2H-chromen-3-yl}-2,4- bis(trifluoromethyl)benzamide, N-[(3S)-5-(Piperidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]-4-
(trifluoromethoxy)benzamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-[(3S)-5-(piperidin-l-ylmethyl)-3,4-dihydro-2H- chromen-3-yl]-2H-l,2,3-triazole-4-carboxamide,
N-[(3S)-5-(Piperidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]-2,4- bis(trifluoromethyl)benzamide,
4-Piperidin-l-yl-N-[(3S)-5-(piperidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3- yljbenzamide,
4-Isopropoxy-N-[(3S)-5-(piperidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]benzamide,
N-{(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2,3,4-tetrahydronaphthalen-2- yl} -4-(trifluoromethoxy)benzamide,
4-({(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2,3,4-tetrahydronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate,
2-(2,4-Dimethylphenyl)-5-methyl-N-[(3S)-5-(piperazin-l-ylmethyl)-3,4-dihydro-2H- chromen-3-yl]-2H-l,2,3-triazole-4-carboxamide, N-{(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydronaphthalen-2-yl}-
4-(trifluoromethoxy)benzamide,
4-({(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate,
N-{(3S)-5-[(l-Methylpiperidin-4-yl)oxy]-3,4-dihydro-2H-chromen-3-yl}-4- (trifluoromethoxy)benzamide,
4-Butoxy-N-{(3S)-5-[(l-methylpiperidin-4-yl)oxy]-3,4-dihydro-2H-chromen-3- yl}benzamide,
N-{(3S)-5-[2-(Dimethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide, N-[(3S)-5-(2-Pyrrolidin-l-ylethoxy)-3,4-dihydro-2H-chromen-3-yl]-4-
(trifluoromethoxy)benzamide, N-{(3S)-5-[(l-Methylpyrrolidin-3-yl)oxy]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Diethylamino)-2-oxoethoxy]-l,2,3,4-tetrahydronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate, N-{(2R)-8-[2-(Diethylamino)-2-oxoethoxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-4-piperidin-
1-ylbenzamide,
N- {(2R)-8-[( 1 -Methylpiperidin-4-yl)oxy]- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl} -4-
(trifluoromethoxy)benzamide,
4-Butoxy-N-{(2R)-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2- yl}benzamide,
4-({(2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate,
N- {(2R)-8-[( 1 -Methylpiperidin-4-yl)oxy]- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl} -2,4- bis(trifluoromethyl)benzamide, 2-(2,4-Dimethylphenyl)-5-methyl-N-{(2R)-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4- tetrahydronaphthalen-2-yl} -2H- 1 ,2,3-triazole-4-carboxamide,
5-Methyl-N-{(2R)-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-2- phenyl-2H-l,2,3-triazole-4-carboxamide,
N- {(2R)-8-[( 1 -Methylpiperidin-4-yl)oxy]- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl} -4-piperidin- 1 - ylbenzamide,
4-Piperidin- 1 -yl-N-[(2R)-8-(2-pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yljbenzamide,
N-[(2R)-8-(2-Pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphthalen-2-yl]-2,4- bis(trifluoromethyl)benzamide, 4- { [(2R)-8-(2-Pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]carbamoyl}phenyl trifluoromethanesulfonate,
N-[(2R)-8-(2-Pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-
(trifluoromethoxy)benzamide,
5-Methyl-2-phenyl-N-[(2R)-8-(2-pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphthalen-2-yl]- 2H- 1 ,2,3-triazole-4-carboxamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-{(3S)-5-[(l-methylpiperidin-3-yl)oxy]-3,4-dihydro-
2H-chromen-3-yl}-2H-l,2,3-triazole-4-carboxamide, N-{(3S)-5-[(l-Methylpiperidin-3-yl)oxy]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide,
N-{(3S)-5-[(l-Methylpiperidin-3-yl)oxy]-3,4-dihydro-2H-chromen-3-yl}-4-piperidin-l- ylbenzamide, N-{(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-4-
(trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate,
N-{(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-5-methyl-2- phenyl-2H-l ,2,3-triazole-4-carboxamide,
N-{(2R)-8-[2-(Ethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-4-
(trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Ethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-yl}carbamoyl)phenyl trifluoromethanesulfonate, N- {(2R)-8-[2-(Ethylamino)ethoxy]- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl} -4-piperidin- 1 - ylbenzamide,
N-{(2R)-8-[2-(Ethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-5-methyl-2-phenyl-
2H- 1 ,2,3-triazole-4-carboxamide,
N-{(2R)-8-[(l-Methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2-yl}-4- (trifluoromethoxy)benzamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]-3,4-dihydroisoquinoline-
2(1 H)-carboxamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]-5-(trifluoromethyl)-3,4- dihydroisoquinoline-2( 1 H)-carboxamide, N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-yl]indoline-l-carboxamide,
5-Methyl-2-phenyl-N-[(2R)-8-(2-pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphthalen-2-yl]-
1 ,3-oxazole-4-carboxamide,
N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}-5-methyl-2-phenyl-l,3- oxazole-4-carboxamide, N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}-5-methyl-2-phenyl-2H-
1 ,2,3-triazole-4-carboxamide, N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}-2-phenyl-2H-l,2,3- triazole-4-carboxamide,
N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}-4-
(trifluoromethoxy)benzamide, 4-({(3S)-5-[2-(ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}carbamoyl)phenyl trifluoromethanesulfonate,
N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl}-4-piperidin-l- ylbenzamide,
N- {(2R)-8-[2-(Dimethylamino)-l , 1-dimethylethyl] -5 -methyl- 1 ,2,3,4-tetrahydronaphthalen- 2-yl} -4-(trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Dimethylamino)-l,l-dimethylethyl]-5-methyl-l,2,3,4-tetrahydronaphthalen-
2-yl} carbamoyl)phenyl trifluoromethanesulfonate,
N- {(2R)-8-[2-(Dimethylamino)-l , 1-dimethylethyl] -5 -methyl- 1 ,2,3,4-tetrahydronaphthalen-
2-yl} -5-methyl-2-phenyl-2H- 1 ,2,3-triazole-4-carboxamide, N-{(3S)-5-[(l-methyl-lH-imidazol-2-yl)methoxy]-3,4-dihydro-2H-chromen-3-yl}-6-(2,2,2- trifluoroethoxy)nicotinamide,
(3S)-3-({[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]carbonyl}amino)-3,4-dihydro-2H- chromen-5-yl 1 -methyl- lH-imidazole-4-sulfonate,
(3S)-3-({[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]carbonyl}amino)-3,4-dihydro-2H- chromen-5-yl 1 -methyl- lH-imidazole-4-sulfonate,
(3S)-3-({[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]carbonyl}amino)-3,4-dihydro-2H- chromen-5-yl 2,4-dimethyl- 1 ,3 -thiazole-5 -sulfonate,
(3S)-3-({[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]carbonyl}amino)-3,4-dihydro-2H- chromen-5-yl pyridine-3-sulfonate, (3S)-3-({[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]carbonyl}amino)-3,4-dihydro-2H- chromen-5-yl 2,4-dimethyl- l,3-thiazole-5-sulfonate, and
(3S)-3-({[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]carbonyl}amino)-3,4-dihydro-2H- chromen-5-yl pyridine-3 -sulfonate, and
N-[(35)-5-(2-Amino-l,l-dimethylethoxy)-3,4-dihydro-2H-chromen-3-yl]-5-methyl-2- phenyl-2H- 1 ,2,3-triazole-4-carboxamide, or pharmaceutically-acceptable salts thereof.
9. The compound λ/-{(35)-5-[2-(Dimethylamino)-l,l-dimethylethoxy]-3,4-dihydro-2H- chromen-3-yl} -S-methyl^-phenyl^H- 1 ,2,3-triazole-4-carboxamide or pharmaceutically- acceptable salts thereof.
10. The compound according to any one of claims 1 to 9 or a pharmaceutically-accep table salts thereof, for use in therapy.
11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically- acceptable salts thereof, for the manufacture of a medicament for treatment of acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.
12. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically-accep table salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
13. A method of treatment of pain disorders or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain, comprising administering to a mammal, including man in need of such treatment, a therapeutically effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically-acceptable salts thereof.
14. Compounds selected from the group consisiting of (2i?)-N-Benzyl-8-bromo-5-methyl-N-[(15)-l-phenylethyl]-l,2,3,4-tetrahydronaphthalen-2- amine
Methyl (7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene- 1 -carboxylate
(7i?)-N-Benzyl-7-{benzyl[(15)-l-phenylethyl]amino}-N,4-dimethyl-5,6,7,8- tetrahydronaphthalene- 1 -carboxamide
(7i?)-7-Amino-7V-benzyl-7V,4-dimethyl-5 ,6,7,8-tetrahydronaphthalene- 1 -carboxamide
(2i?)-8- { [Benzyl(methyl)amino]methyl} -5-methyl- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine (2i?)-N-Benzyl-8-(3,4-dihydroisoquinolin-2(lH)-ylcarbonyl)-5-methyl-N-[(15)-l- phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine
(2i?)-8-(3,4-Dihydroisoquinolin-2(lH)-ylcarbonyl)-5-methyl-l,2,3,4-tetrahydronaphthalen-
2-amine (2R)-8-(3 ,4-Dihydroisoquinolin-2( 1 H)-ylmethyl)-5 -methyl- 1 ,2,3 ,4-tetrahydronaphthalen-
2-amine
(2i?)-N-Benzyl-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-methyl-N-[(15)-l-phenylethyl]-
1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-8-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-5-methyl-l,2,3,4-tetrahydronaphthalen-2- amine
(2i?)-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-methyl-l,2,3,4-tetrahydronaphthalen-2- amine
(35)-3 -(Dibenzylamino)-3 ,4-dihydro-2H-chromen-5 -yl trifluoromethanesulfonate
(35)-λ/ 3 ,λ/ 3 -Dibenzyl-λ/ 5 -(l-methylpiperidin-4-yl)chromane-3,5-diamine (35)-N 5 -(l-Methylpiperidin-4-yl)chromane-3,5-diamine
(35)-λ/ 3 ,λ/ 3 -dibenzyl-λ/ 5 -(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
(35)-N 5 -(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
Methyl (35)-3-(dibenzylamino)chromane-5-carboxylate
(35)-7V,7V-Dibenzyl-5 -(pyrrolidin- 1 -ylcarbonyl)chroman-3 -amine (35)-5 -(Pyrrolidin- l-ylcarbonyl)chroman-3 -amine
(35)-5 -(pyrrolidin- 1 -ylmethyl)chroman-3-amine
(2i?)-N,N-Dibenzyl-8-(2 -pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-8-(2 -pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(35)-7V,7V-Dibenzyl-5 -[(4-methylpiperazin- 1 -yl)carbonyl] chroman-3 -amine (35)-5 - [(4-methylpiperazin- 1 -yl)carbonyl] chroman-3 -amine
(35)-5 - [(4-methylpiperazin- 1 -yl)methyl] chroman-3 -amine
(35)-N,N-Dibenzyl-5 -(piperidin- 1 -ylcarbonyl)chroman-3 -amine
(35)-5-(Piperidin-l-ylcarbonyl)chroman-3 -amine
(3 S)-5 -(piperidin- 1 -ylmethyl)chroman-3 -amine (2i?)-λ/-Benzyl-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-λ/-[(15)-l-phenylethyl]-
1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2,3,4-tetrahydronaphthalen-2-amine (35)-7V,7V-Dibenzyl-5 -(piperazin- 1 -ylcarbonyl)chroman-3 -amine
(35)-7V,7V-Dibenzyl-5 -(piperazin- 1 -ylmethyl)chroman-3 -amine tert-Butyl 4-{[(35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl]methyl}piperazine-l- carboxylate 5 tert-butyl 4-{[(35)-3-amino-3,4-dihydro-2H-chromen-5-yl]methyl}piperazine-l- carboxylate
(2R)-5-methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4-tetrahydronaphthalen-2-amine
(35)-7V,7V-Dibenzyl-5 - [( 1 -methylpiperidin-4-yl)oxy] chroman-3 -amine
(35)-5 - [( 1 -methylpiperidin-4-yl)oxy] chroman-3 -amine i o (35)-7V,7V-Dibenzyl-5 - [2-(dimethylamino)ethoxy]chroman-3 -amine
(35)-5 - [2-(dimethylamino)ethoxy] chroman-3 -amine
(35)-7V,7V-Dibenzyl-5 -(2-pyrrolidin- 1 -ylethoxy)chroman-3 -amine
(3S)-5-(2-pyrrolidin-l-ylethoxy)chroman-3-amine
(35)-7V,7V-Dibenzyl-5 -[( 1 -methylpyrrolidin-3 -yl)oxy] chroman-3 -amine is (35)-5-[(l-Methylpyrrolidin-3-yl)oxy]chroman-3-amine
2- { [(7i?)-7-(Dibenzylamino)-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } -N,N- diethylacetamide
2- { [(7i?)-7-amino-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } -N,N-diethylacetamide
(2i?)-N,λ/-Dibenzyl-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2-amine 20 (2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2-amine
(35)-N,N-Dibenzyl-5 - [( 1 -methylpiperidin-3 -yl)oxy] chroman-3 -amine
(35)-5 - [( 1 -Methylpiperidin-3 -yl)oxy] chroman-3 -amine
(2i?)-N,λ/-Dibenzyl-8-[2-(dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-amine
(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthalen-2-amine 25 tert-Butyl (2-{[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l- yl]oxy } ethyl)ethylcarbamate tert-Butyl (2- { [(7R)-7-amino-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } ethyl)ethylcarbamate
(2R)-N,N-Dibenzyl-8-[(l-methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2-amine
(2R)-8-[(l-Methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydronaphthalen-2-amine 30 tert-Butyl (2- {[(3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5- yl]oxy } ethyl)ethylcarbamate tert-Butyl (2-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5-yl]oxy}ethyl)ethylcarbamate 2-[(7R)-I- {Benzyl[( IS)- 1 -phenylethyl] amino} -4-methyl-5 ,6,7,8-tetrahydronaphthalen- 1 - yl] -2-methylpropanenitrile
(2i?)-8-(2-Amino-l,l-dimethylethyl)-N-benzyl-5-methyl-N-[(15)-l-phenylethyl]-l,2,3,4- tetrahydronaphthalen-2-amine (2i?)-N-Benzyl-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-methyl-N-[(15)-l- phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine
(2i?)-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-methyl-l,2,3,4-tetrahydronaphthalen-2- amine
(35)-5-(2-Ammo- 1 , 1 -dime thylethoxy)-N,N-dibenzylchroman-3 -amine tert-Butyl (2-{[(35)-3-amino-3,4-dihydro-2H-chromen-5-yl]oxy}-2- methylpropyl)carbamate tert-butyl (2-methyl-2-{[(35)-3-{[(5-methyl-2-phenyl-2H-l,2,3-triazol-4- yl)carbonyl] amino } -3 ,4-dihydro-2H-chromen-5 -yl] oxy } propyl)carbamate
(35)-7V,7V-dibenzyl-5 - [( 1 -methyl- lH-imidazol-2-yl)methoxy] chroman-3 -amine (35)-5-[(l -methyl- lH-imidazol-2-yl)methoxy]chroman-3-amine
(35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl 1 -methyl- IH- imidazole -4-sulfonate
(35)-3-amino-3,4-dihydro-2H-chromen-5-yl 1 -methyl- IH- imidazole-4-sulfonate
(35)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5-yl 2,4-dimethyl-l,3- thiazole-5 -sulfonate (35)-3-amino-3,4-dihydro-2H-chromen-5-yl 2,4-dimethyl-l,3-thiazole-5-sulfonate
(35)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5-yl pyridine-3-sulfonate
(35)-3-amino-3,4-dihydro-2H-chromen-5-yl pyridine-3 -sulfonate, and
6-(3,3,3-trifluoropropoxy)nicotinic acid
15. Use of compounds according to claim 14 as intermediates in the preparation of the compound of formula I. |
NEW COMPOUNDS 805
Field of the Invention
The present invention relates to new compounds, to pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.
Background
Voltage-gated sodium channels are critical elements in the control of electrical excitability of various cell types, including muscle and neuronal cells. In muscle and neuronal cells voltage-gated sodium channels are mainly responsible for the rising phase of the action potential. Voltage-gated sodium channels are composed of a single alpha subunit and one or two beta subunits. There are 10 known alpha subunit proteins, of which nine are functional as an ion channel. The different alpha subunit proteins are herein referenced to as Navl.x, with x being an integer between 1 and 9. This labelling is in accordance with the conventions of the International Pharmacological Association (REF). Alpha subunits are large proteins of an approximate weight of 260 kDA (~ 2000 amino acids), and are functional as voltage-gated sodium channels as monomeric structures. Four beta subunits are known at present. Beta subunits are smaller proteins of an approximate weight of 33-36 kDa. Beta subunits can modulate functional expression, as well as the characteristics of channel opening and closing (gating) of alpha subunits.
Five major lines of evidence support the notion that voltage-gated sodium channels are important therapeutic targets: a) the biophysical characteristics of voltage-gated sodium channels, b) the tissue expression pattern of voltage-gated sodium channels, c) evidence from preclinical research, d) the association between several congenital diseases and channelopathies of voltage-gated sodium channels, and
e) evidence from the usage of pharmacological agents active at voltage-gated sodium channels in the clinic.
A main biophysical characteristic of voltage-gated sodium channels is the fast opening and closing (activation and inactivation) of the channel upon an appropriate voltage stimulus. These features make voltage-gated sodium channels absolutely essential in the generation of the upstroke of the action potential in most neuronal and muscle cells, and thereby central to the functionality of such tissue. Thus, inhibitory pharmacological interference with the activity of NaVs is expected to have dampening effects on excitability of such tissue. Such agents may thus be useful in the treatment of diseases that involve hyperactivity of neuronal or muscle tissue.
As outlined above, there are nine functional alpha subunits of voltage-gated sodium channels. Each of these alpha subunits has a characteristic tissue expression pattern. Tissue-specific up- or down-regulation of the expression of several of the voltage-gated sodium channels in human diseases or preclinical disease models in animals strongly supports a central role for specific voltage-gated sodium channels in distinct diseases.
Navl.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states (Acta Neurochirurgica (2002) 144(8) 803-810). Navl.7 is also expressed in dorsal root ganglion neurons and contributes to the small tetrodoxin (TTX) sensitive component seen in these cells. Navl.7 may thus be a potential pain target in addition to its role in neuroendocrine excitability (EMBO Journal (1995) 14(6) 1084-1090).
The present invention relates to a novel group of compounds that exhibit NaV 1.7 inhibiting activity, and are therefore expected to be useful in the prophylaxis and treatment of different acute and chronic pain conditions.
WO 97/34883, WO 99/14212, WO 99/05135 and WO 99/14213 describe compounds for use in treatment of pain. The compounds described in these prior art documents bind to serotonine receptors. The compounds of the present invention have little to none activity towards the
serotonine receptor. The compounds of the present invention also are contemplated to have an improved pharmacokinetic profile compared to the compounds in the prior art, including a higher oral bioavailability, a decreased clearance and a decreased volume of distribution. Without being bound to any theory, the difference in pharmacokinetic profile is believed to be due to the fact that the right hand side of the molecule is aromatic in the compounds of the present invention while this is not the case for the known compounds.
Disclosure of the Invention According to the invention there is provided compounds of formula I,
X is O or CH 2 ;
R 3 is hydrogen or Ci -4 alkyl; Ri-Y is selected from Ri-Ci -4 alkyl, Ri-Ci -4 alkylN(Ci -4 alkyl)Ci -4 alkyl, Ri-Ci -4 alkylNHCi.
4 alkyl, Ri-Ci -4 alkylNH, Rj-NH, Ri-C(O), Ri-O, Ri-Ci -4 alkylO, Ri-OCi -4 alkyl, Ri-C(O)Ci-
4 alkyl0, Ri-OCi -4 alkylC(O), Ri-Ci -4 alkyl-SO 2 -O or Ri-SO 2 -O;
Ri is phenyl, tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, -
N(Ci -4 alkyl) 2 , -NHCi -4 alkyl, NH 2> imidazolyl, thiazolyl or pyridinyl, which may be independently mono-, di-, or tri-substituted with Rn, Ri 2 , and/or Rn, wherein Rn, Ri 2 , and Rn are independently selected from: halogen, Ci -6 alkyl, Ci -6 alkoxy, C3_6Cycloalkyl, C3-6Cycloalkoxy, C 3-6 cycloalkylCi. ealkoxy, CN, OH, -OCF 3 , -OCHF 2 , -OCH 2 F, -O(CH 2 )i -6 CF 3 , -O(CH 2 )i -6 CHF 2 , - 0(CH 2 ) I-6 CH 2 F, -OCH(CF 3 ) 2 , -OCH(CF 2 ) 2 , -OCH(CF) 2 , -O(CH 2 )i -6 CH(CF 3 ) 2 , - O(CH 2 )i -6 CH(CF 2 ) 2 , -0(CH 2 ) I-6 CH(CF) 2 , -O(CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , -0(CH 2 )i.
6 CH(CHi -6 CHF 2 ) 2 , -0(CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 )^CF 3 , -(CH 2 ) I-6 CHF 2 , -(CH 2 ) I-6 CH 2 F, -CH(CF 3 ) 2 , -CH(CF 2 ) 2 , -CH(CF) 2 , -(CH 2 )i-
6 CH(CF 3 ) 2 , -(CH 2 ) 1-6 CH(CF 2 ) 2 , -(CH 2 )^CH(CF) 2 , -(CH 2 ) 1-6 CH(CH 1-6 CF 3 ) 2 , - (CH 2 ) 1-6 CH(CH 1-6 CHF 2 ) 2 , -(CH 2 ) 1-6 CH(CH 1-6 CH 2 F) 2 , -OSO 2 CH 3 , -OSO 2 (CH 2 ) I- 6 CH 3 , -OSO 2 CF 3 , -OSO 2 CHF 2 , -OSO 2 CH 2 F, -OSO 2 (CH 2 ) 1-6 CF 3 , -OSO 2 (CH 2 ) ! . 6CHF 2 , -OSO 2 (CH 2 ) I-6 CH 2 F, -OSO 2 CH(CF 3 ) 2 , -OSO 2 CH(CF 2 ) 2 , -OSO 2 CH(CF) 2 , - OSO 2 (CH 2 ) I-6 CH(CF 3 ^, -OSO 2 (CH 2 )i -6 CH(CF 2 ) 2 , -OSO 2 (CH 2 ) 1-6 CH(CF) 2 , -
OSO 2 (CH 2 ) 1-6 CH(CH 1-6 CF 3 ) 2 , -OSO 2 (CH 2 ) 1-6 CH(CH 1-6 CHF 2 ) 2 , -OSO 2 (CH 2 ) 1- 6 CH(CH 1-6 CH 2 F) 2 , -SO 2 CH 3 , -SO 2 (CH 2 ) 1-6 CH 3 , -SO 2 CF 3 , -SO 2 CHF 2 , -SO 2 CH 2 F, - SO 2 (CH 2 ) I-6 CF 3 , -SO 2 (CH 2 ) I-6 CHF 2 , -SO 2 (CH 2 )i -6 CH 2 F, -SO 2 CH(CF 3 ) 2 , - SO 2 CH(CF 2 ) 2 , -SO 2 CH(CF) 2 , -SO 2 (CH 2 )i -6 CH(CF 3 ) 2 , -SO 2 (CH 2 )i -6 CH(CF 2 ) 2 , - SO 2 (CH 2 ) I-6 CH(CF) 2 , -SO 2 (CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , -SO 2 (CH 2 )i -6 CH(CHi -6 CHF 2 ) 2 ,
-SO 2 (CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , phenyl, phenylCi -6 alkyl-, phenoxy, Ci -6 alkylphenyl and Ci -6 alkoxyphenyl-;
R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl, pyrazinyl or pyridinyl, which may be independently mono-, di-, or tri-substituted with Ri 4 , Ri 5 , and/or Ri 6 ; wherein Ri 4 , Ri 5 , and/or Ri 6 are independently selected from: halogen, Ci -6 alkyl, Ci -6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3-6 cycloalkylCi. 6alkoxy, CN, OH, -OCF 3 , -OCHF 2 , -OCH 2 F, -O(CH 2 )i -6 CF 3 , -O(CH 2 )i -6 CHF 2 , - 0(CH 2 ) I-6 CH 2 F, -OCH(CF 3 ) 2 , -OCH(CF 2 ) 2 , -OCH(CF) 2 , -O(CH 2 )i -6 CH(CF 3 ) 2 , - O(CH 2 )i -6 CH(CF 2 ) 2 , -0(CH 2 ) I-6 CH(CF) 2 , -O(CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , -0(CH 2 ) L 6 CH(CHi -6 CHF 2 ) 2 , -0(CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , -CF 3 , -CHF 2 , -CH 2 F, -(CH 2 )^CF 3 ,
-(CH 2 ) I-6 CHF 2 , -(CH 2 ) I-6 CH 2 F, -CH(CF 3 ) 2 , -CH(CF 2 ) 2 , -CH(CF) 2 , -(CH 2 )L 6CH(CF 3 ) 2 , -(CH 2 )i -6 CH(CF 2 ) 2 , -(CH 2 )^CH(CF) 2 , -(CH 2 )i -6 CH(CHi -6 CF 3 ) 2 , - (CH 2 )i -6 CH(CHi -6 CHF 2 ) 2 , -(CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , -OSO 2 CH 3 , -OSO 2 (CH 2 )L 6CH 3 , -OSO 2 CF 3 , -OSO 2 CHF 2 , -OSO 2 CH 2 F, -OSO 2 (CH 2 ) I-6 CF 3 , -OSO 2 (CH 2 )L 6CHF 2 , -OSO 2 (CH 2 ) I-6 CH 2 F, -OSO 2 CH(CF 3 ) 2 , -OSO 2 CH(CF 2 ) 2 , -OSO 2 CH(CF) 2 , -
OSO 2
(CH 2
) I-6
CH(CF 3
^, -OSO 2
(CH 2
)i -6
CH(CF 2
) 2
, -OSO 2
(CH 2
)i -6
CH(CF) 2
, -
SO 2 (CH 2 ) I-6 CH(CF) 2 , -SO 2 (CH 2 ) I-6 CH(CHi -6 CF 3 ),, -SO 2 (CH 2 )i -6 CH(CHi -6 CHF 2 ) 2 ,
-SO 2 (CH 2 ) I-6 CH(CHi -6 CH 2 F) 2 , phenyl, phenylCi -6 alkyl-, phenoxy, d -6 alkylphenyl, C 1-6 alkoxyphenyl-, piperidinyl, and C^heterocycloalkyloxy; or pharmaceutically-acceptable salts thereof.
5 One embodiment relates to compounds of formula I wherein: X is O or CH 2 ; R 3 is hydrogen or Ci -4 alkyl;
Ri-Y is selected from Ri-Ci -4 alkyl, Ri-Ci -4 alkylN(Ci -4 alkyl)Ci -4 alkyl, Ri-Ci -4 alkylNH, Ri- NH, Ri-C(O), Ri-O, Ri-Ci -4 alkylO, Ri -C(O)C M alkyl0 and Ri-SO 2 -O;o Ri is phenyl, tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, - N(Ci -4 alkyl) 2 , -NHCi -4 alkyl, NH 2 , imidazolyl, thiazolyl or pyridinyl, which may be independently mono-, di-, or tri-substituted with Rn, Ri 2 , and/or Rn, wherein Rn, Ri 2 , and Rn are independently selected from Ci -6 alkyl; R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl and pyridinyl, whichs may be independently mono-, di-, or tri-substituted with Ri 4 , Ri 5 , and/or Ri 6 ; wherein Ri 4 , Ri 5 , and/or Ri 6 are independently selected from: Ci -6 alkyl, Ci -6 alkoxy, -OCF 3 , -0(CH 2 ) I-6 CF 3 , -CF 3 , -OSO 2 CF 3 , phenyl, Ci- 6 alkylphenyl, piperidinyl and C^heterocycloalkyloxy; or pharmaceutically-acceptable salts thereof.o
In a further embodiment relates to compounds of formula I, wherein X is O. In one embodiment relates to compounds of formula I, wherein X is CH 2 .
Another embodiment relates to compounds of formula I, wherein R 3 is hydrogen.5 One embodiment relates to compounds of formula I, wherein R 3 is methyl. A further embodiment relates to compounds of formula I, wherein R 3 is ethyl.
In one embodiment relates to compounds of formula I, wherein Ri-Y is selected from Ri- methyl, Ri-ethyl, Ri-propyl, Ri-butyl, Ri-NH Ri-C(O), R r O, Ri-o methyl(methylamino)methyl, Ri-methyl(ethylamino)methyl, Ri-methyl(ethylamino)ethyl, Ri-ethyl(ethylamino)methyl, Ri-ethylamino, Ri-methoxy, Ri-ethoxy, Ri-propoxy, Ri- butoxy, Ri-carbonylmethoxy, Ri-carbonylethoxy, Ri-carbonyl-propoxy, , Ri-
methylsulfonyl, Ri-ethylsulfonyl, Ri-propylsulfonyl, Ri-butylsulfonyl, Ri-sulfonyloxy, Ri- methylsulfonyloxy or Ri-ethylsulfonyloxy.
One embodiment relates to compounds of formula I, wherein Ri-Y is selected from 5 R 1 -methyl, Ri-CH 2 C(CH 3 ) 2 , Ri-NH Ri-C(O), Ri-O, Ri-methyl(methylamino)methyl, R 1 - ethylamino, Ri-methoxy, Ri-ethoxy, Ri- Ri-CH 2 C(CHs) 2 O, Ri-carbonylmethoxy or Ri- sulfonyloxy.
Another embodiment relates to compounds of formula I, wherein Ri is phenyl,o tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dimethylamine, diethylamine, ethylamine, NH 2 , imidazolyl, thiazolyl or pyridinyl. Yet another embodiment relates to compounds of formula I, wherein Ri is phenyl, tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dimethylamine, diethylamine, ethylamine, NH 2 , imidazolyl, thiazolyl or pyridinyl, whichs may be independently mono- or di-substituted with methyl.
In another embodiment of the invention there is provided compounds of formula I wherein Ri is phenyl, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or pyridinyl. o In a further embodiment of the invention there is provided compounds of formula I wherein Ri is mono- or di-substituted with methyl.
One embodiment relates to compounds of formula I, wherein R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl or pyridinyl, which may be independently5 mono- or di-substituted with Ri 4 , Ri 5 , and/or Ri 6 ; wherein R H , R I 5 , and are independently selected from:
Ci-βalkyl, Ci -6 alkoxy, -OCF 3 , -O(CH 2 )i -6 CF 3 , -CF 3 , -OSO 2 CF 3 , phenyl, Ci- 6 alkylphenyl, piperidinyl, and C 3- 6heterocycloalkyloxy; o In a further embodiment of the invention R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl or pyridinyl, which may be independently mono- or di-substituted with Ri 4 , R 15 , and/or Ri 6 ;
wherein Ri 4 , Ri 5 , and Ri 6 are independently selected from: fluoro, iodo, chloro, bromo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, and all isomeric forms of pentyl and hexyl, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, t-butoxy, i-butoxy, fluoromethyl, difiuoromethyl, trifiuoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifiuoropropyl, fluorobutyl, difluorobutyl, trifluorobutyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, fluoropropoxy, difluoropropoxy, trifluoropropoxy, fluorobutoxy, difluorobutoxy, trifluorobutoxy, fluoropentoxy, difluoropentoxy, trifluoropentoxy, trifluoromenthanesulfonic acid, difluoromenthanesulfonic acid, fluoromenthanesulfonic acid, menthanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, phenyl, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, oxepanyloxy, dioxanyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopropyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, phenyl, methylphenyl, dimethylphenyl, piperidinyl.
In one embodiment of the invention R 2 is phenyl, triazolyl, tetrahydroisoquinolinyl, oxazolyl, indolinyl or pyridinyl, which may be independently mono- or di-substituted with Ri 4 , R 15 , and/or Ri 6 ; wherein Ri 4 , Ri 5 , and Ri 6 are independently selected from: methyl, i-propoxy, n-butoxy, trifiuoromethyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoromenthanesulfonic acid, tetrahdyropyranyloxy, phenyl, dimethylphenyl or piperidinyl.
For the avoidance of doubt the present invention relates to any one of compounds falling within the scope of formula I as defined above.
Another embodiment relates to a compound having the formula (Ia)
X is O or CH 2 ;
Y is -Oo-iW 1 -; -O 0- IW 1 C(O)W 1 - ; -O 0- I W 1 C(CHs) 2 W 1 - ; or -W 1 N(R 30 )R 3 I-, wherein R 30 = H or W 1 CH 3 and R 3 1 = W 1 ; Ri is NR20R21 or an aromatic or non-aromatic ring RA, optionally containing one, two or three heteroatoms selected from N, O and S, which ring may be fused to one or two other aromatic or non-aromatic ring(s) RB and/or RC, said ring(s) RB and/or RC optionally containing one, two or three heteroatoms selected from N, O and S, which ring(s) A, B, and/or C may be mono-, di-, or tri-substituted with with Rn, R12, and/or Ri 3; wherein Rn, Ri 2 , and/or Ri 3 is/are
C i-6 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkoxy; halogen; (CH 2 ) 0- 6CN; OH; C 1-6 alkoxy; NR 20 R 2 I ; 0 0- i(CH 2 )o -6 CF 3 ; 0 0- i(CH 2 )o -6 CHF 2 ; 0 0- i(CH 2 )o -6 CH 2 F; O 0- i(CH 2 )o -6 CH(CF 3 ) 2 ; 0 0- i(CH 2 )o -6 CH(CHF 2 ) 2 ; 0 0- i(CH 2 )o -6 CH(CH 2 F) 2 ; SO 2 (CH 2 ) 0- 6 CH 3 ; SO 3 (CH 2 ) O-6 CH 3 ; SO 3 CF 3 ; SO 2 NR 20 R 2I ; phenyl; phenyl-Ci -6 alkyl; phenoxy;
Ci -6 alkylphenyl; Ci -6 alkoxyphenyl; Ci -6 haloalkoxyphenyl; Ci -6 haloalkylphenyl; provided that if Y is -W 1 N(R 30 )R 3 I-, then Ri is not NR 20 R 2 I unless R 31 = (CH 2 ) 1-4 ; and provided that if Y is -W 1 N(R 30 )R 3 I-, and Ri is a ring RA containing one or more heteroatom(s), then Y is only attached to said ring RA through any atom of said ring RA other than such heteroatom, unless R 31 = (CH 2 ) 1-4 ;
R 2 is an aromatic or non-aromatic ring RD, optionally containing one, two or three heteroatoms selected from N, O and S, which ring may be fused to one or two other aromatic or non-aromatic ring(s) RE and/or RF, said ring(s) RE and/or RF optionally containing one, two or three heteroatoms selected from N, O and S, which ring(s) RD, RE, and/or RF may be mono-, di-, or tri-substituted with R H , R 1S , and/or
Ri 6 ; wherein Ri 4 , Ri 5 , and/or Ri 6 independently is/are
C i- 6 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkoxy; C 3-6 cycloalkyl-Ci. 6 alkoxy; halogen; (CH 2 )O -6 CN; OH; Ci -6 alkoxy; NR 20 R 2 I ; 0 0- i(CH 2 )o -6 CF 3 ; 0 0- i(CH 2 )o -6 CHF 2 ; O 0- 1 (CH 2 ) O-6 CH 2 F; Oo-i(CH 2 ) 0-6 CH(CF 3 ) 2 ; Oo-i(CH 2 ) 0-6 CH(CHF 2 ) 2 ; O 0- i(CH 2 ) 0- 6 CH(CH 2 F) 2 ; SO 2 (CH 2 )O -6 CH 3 ; SO 3 (CH 2 ) 0-6 CH 3 ; SO 3 CF 3 ; SO 2 NR 20 R 2 I; phenyl; 5 phenyl-Ci -6 alkyl; phenoxy; Ci -6 alkylphenyl; Ci -6 alkoxyphenyl; Ci -6 haloalkoxyphenyl; Ci -6 haloalkylphenyl; an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, and S, wherein the substituent(s) is(are) selected from Ci -6 alkyl, C 3-6 cycloalkyl, phenyl-Ci -6 alkyl, (CH 2 ) m OR 23 , and COR 22 ; an optionally substituted heteroaromatic ring containing I 0 one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) selected from Ci -6 alkyl, C 3-6 cycloalkyl and phenyl-Ci -6 alkyl; or COR 22 ;
R 3 Is H Or W 1 CH 3 ; wherein
W 1 is divalent hydrocarbyl group having 0-4 carbon atoms; is R 20 is H, Ci -6 alkyl, or C 3-6 cycloalkyl;
R 2 i is H, Ci -6 alkyl, or C 3-6 cycloalkyl; and
R 22 is Ci -6 alkyl, C 3-6 cycloalkyl, CF 3 , NR 20 R 21 , phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO 2 ; 2 o m is 2-6, and R 23 is H, Ci -6 alkyl, C 3-6 cycloalkyl or phenyl-Ci -6 alkyl, and pharmaceutically-acceptable salts thereof.
For the avoidance of doubt it is to be understood that where in this specification a group is 25 qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.
For the avoidance of doubt it is to be understood that in this specification 'Ci -6 ' means a 3 o carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term Ci -4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or t-butyl. It is to be understood that all isomeric forms are included in the definition of 'alkyl' such as for example Ri -propyl which can be interpreted as RiCH 2 CH 2 CH 2 or RiCH(CH 3 )CH 2 , or RiC(CH 3 ) 2 .
The term "Co" in Co -4 alkyl refers to a situation where no carbon atom is present.
The term "alkoxy", unless stated otherwise, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. The term "alkoxy" may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy or i-butoxy,. It is to be understood that all isomeric forms are included in the definition of 'alkoxy' such as for example Ri-propoxy which can be interpreted as RiCH 2
CH 2
CH 2
O or RiCH(CH 3
)CH 2
O, or
In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system. The term "Ci. 6 cycloalkyl" may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "C 3- 6CycloalkylCi-6alkoxy-" may be, but is not limited to cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylpropoxy or cyclohexylbutoxy.
In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine (fluoro), iodine (iodo), chlorine (chloro) or bromine (bromo).
In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with one or more halogen atoms as defined above. The term "Ci- 6 haloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl or fluorochloromethyl. The term "Ci -3 haloalkoxy" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
The term
In this specification, unless stated otherwise, the term "heterocycloalkyl" refers to an monocyclic, bicyclic or bridged hydrocarbon ring system, which may be aromatic, having one or more heteroatoms independently selected from O, N or S. The term "C 1- 6 heterocycloalkyl" may be, but is not limited to pyrrolidinyl, piperidinyl oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, pyranyl, oxepanyl or dioxanyl or when aromatic may be oxazolyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, benzofuryl or benzothienyl. Heteroaryl may also be quinolinyl or isoquinolinyl.
The term "heterocycloalkyloxy" refers to a heterocycloalkyl as defined avobe substituted on a oxygen molecule as for example in example 86.
The term "hydrocarbyl" refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
The term "amine" or "amino" refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical.
For the avoidance of doubt a group R H substituted with a group 0(CH 2 )I-OCF 3 includes trifluoromethoxy group as in example 2.
It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.
Another embodiment of the invention relates to compounds selected from the group consisting of
N-[(2R)-8-{[Benzyl(methyl)amino]methyl}-5-methyl-l,2,3,4- tetrahydronaphthalen-2-yl]-4- (trifluoromethoxy)benzamide,
N-[(2R)-8-(3,4-Dihydroisoquinolin-2(lH)-ylmethyl)-5-methy l-l,2,3,4- tetrahydronaphthalen-2-yl]-4-(trifluoromethoxy)benzamide,
N-{(2R)-8-[(2,6-Dimethylmorpholin-4-yl)methyl]-5-methyl-l ,2,3,4-tetrahydronaphthalen-
2-yl}-4-(trifluoromethoxy)benzamide,
N-[(2R)-8-{[Benzyl(methyl)amino]methyl}-5-methyl-l,2,3,4- tetrahydronaphthalen-2-yl]-5- methyl-2-phenyl-2H-l,2,3-triazole-4-carboxamide, N-[(2R)-8-(3,4-Dihydroisoquinolin-2(lH)-ylmethyl)-5-methyl-l ,2,3,4- tetrahydronaphthalen-2-yl]-5-methyl-2-phenyl-2H-l,2,3-triazo le-4-carboxamide,
4-Butoxy-N-{(3S)-5-[(l-methylpiperidin-4-yl)amino]-3,4-di hydro-2H-chromen-3- yl}benzamide,
N-{(3S)-5-[(2-Pyrrolidin-l-ylethyl)amino]-3,4-dihydro-2H- chromen-3-yl}-4- (trifluoromethoxy)benzamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen- 3-yl]-4-
(trifluoromethoxy)benzamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen- 3-yl]-2,4- bis(trifluoromethyl)benzamide, 2-(2,4-Dimethylphenyl)-5-methyl-N-[(3S)-5-(pyrrolidin-l-ylme thyl)-3,4-dihydro-2H- chromen-3-yl]-2H-l,2,3-triazole-4-carboxamide,
4-{[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen -3-yl]carbamoyl}phenyl trifluoromethanesulfonate,
N-{(3S)-5-[(4-Methylpiperazin-l-yl)carbonyl]-3,4-dihydro- 2H-chromen-3-yl}-4- (trifluoromethoxy)benzamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-{(3S)-5-[(4-methylpiper azin-l-yl)carbonyl]-3,4- dihydro-2H-chromen-3-yl} -2H- 1 ,2,3-triazole-4-carboxamide,
N-{(3S)-5-[(4-Methylpiperazin-l-yl)methyl]-3,4-dihydro-2H -chromen-3-yl}-4-
(trifluoromethoxy)benzamide, 2-(2,4-Dimethylphenyl)-5-methyl-N-{(3S)-5-[(4-methylpiperazi n-l-yl)methyl]-3,4-dihydro-
2H-chromen-3-yl} -2H- 1 ,2,3-triazole-4-carboxamide,
N-{(3S)-5-[(4-Methylpiperazin-l-yl)methyl]-3,4-dihydro-2H -chromen-3-yl}-2,4- bis(trifluoromethyl)benzamide,
N-[(3S)-5-(Piperidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3 -yl]-4- (trifluoromethoxy)benzamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-[(3S)-5-(piperidin-l-yl methyl)-3,4-dihydro-2H- chromen-3-yl]-2H-l,2,3-triazole-4-carboxamide,
N-[(3S)-5-(Piperidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3 -yl]-2,4- bis(trifluoromethyl)benzamide,
4-Piperidin-l-yl-N-[(3S)-5-(piperidin-l-ylmethyl)-3,4-dih ydro-2H-chromen-3- yljbenzamide, 4-Isopropoxy-N-[(3S)-5-(piperidin-l-ylmethyl)-3,4-dihydro-2H -chromen-3-yl]benzamide,
N-{(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2 ,3,4-tetrahydronaphthalen-2- yl}-4-(trifluoromethoxy)benzamide,
4-({(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l, 2,3,4-tetrahydronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate, 2-(2,4-Dimethylphenyl)-5-methyl-N-[(3S)-5-(piperazin-l-ylmet hyl)-3,4-dihydro-2H- chromen-3-yl]-2H-l,2,3-triazole-4-carboxamide,
N-{(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2,3 ,4-tetrahydronaphthalen-2-yl}-
4-(trifluoromethoxy)benzamide,
4-({(2R)-5-Methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2, 3,4-tetrahydronaphthalen-2- yl}carbamoyl)phenyl trifluoromethanesulfonate,
N-{(3S)-5-[(l-Methylpiperidin-4-yl)oxy]-3,4-dihydro-2H-ch romen-3-yl}-4-
(trifluoromethoxy)benzamide,
4-Butoxy-N-{(3S)-5-[(l-methylpiperidin-4-yl)oxy]-3,4-dihy dro-2H-chromen-3- yl}benzamide, N-{(3S)-5-[2-(Dimethylamino)ethoxy]-3,4-dihydro-2H-chromen-3 -yl}-4-
(trifluoromethoxy)benzamide,
N-[(3S)-5-(2-Pyrrolidin-l-ylethoxy)-3,4-dihydro-2H-chrome n-3-yl]-4-
(trifluoromethoxy)benzamide,
N-{(3S)-5-[(l-Methylpyrrolidin-3-yl)oxy]-3,4-dihydro-2H-c hromen-3-yl}-4- (trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Diethylamino)-2-oxoethoxy]-l,2,3,4-tetrahy dronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate,
N- {(2R)-8-[2-(Diethylamino)-2-oxoethoxy]- 1,2,3, 4-tetrahydronaphthalen-2-yl}-4-piperidin-
1-ylbenzamide, N-{(2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydrona phthalen-2-yl}-4-
(trifluoromethoxy)benzamide,
4-Butoxy-N-{(2R)-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4- tetrahydronaphthalen-2- yl}benzamide,
4-({(2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahyd ronaphthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate, N-{(2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydrona phthalen-2-yl}-2,4- bis(trifluoromethyl)benzamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-{(2R)-8-[(l-methylpiper idin-4-yl)oxy]-l,2,3,4- tetrahydronaphthalen-2-yl} -2H- 1 ,2,3-triazole-4-carboxamide,
5-Methyl-N-{(2R)-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4- tetrahydronaphthalen-2-yl}-2- phenyl-2H-l ,2,3-triazole-4-carboxamide,
N- {(2R)-8-[( 1 -Methylpiperidin-4-yl)oxy]- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl} -4-piperidin- 1 - ylbenzamide,
4-Piperidin- 1 -yl-N-[(2R)-8-(2-pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yljbenzamide, N-[(2R)-8-(2-Pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphth alen-2-yl]-2,4- bis(trifluoromethyl)benzamide,
4- { [(2R)-8-(2-Pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]carbamoyl}phenyl trifluoromethanesulfonate,
N-[(2R)-8-(2-Pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronap hthalen-2-yl]-4- (trifluoromethoxy)benzamide,
5-Methyl-2-phenyl-N-[(2R)-8-(2-pyrrolidin-l-ylethoxy)-l,2 ,3,4-tetrahydronaphthalen-2-yl]-
2H- 1 ,2,3-triazole-4-carboxamide,
2-(2,4-Dimethylphenyl)-5-methyl-N-{(3S)-5-[(l-methylpiper idin-3-yl)oxy]-3,4-dihydro-
2H-chromen-3-yl}-2H-l,2,3-triazole-4-carboxamide, N-{(3S)-5-[(l-Methylpiperidin-3-yl)oxy]-3,4-dihydro-2H-chrom en-3-yl}-4-
(trifluoromethoxy)benzamide,
N-{(3S)-5-[(l-Methylpiperidin-3-yl)oxy]-3,4-dihydro-2H-ch romen-3-yl}-4-piperidin-l- ylbenzamide,
N-{(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronap hthalen-2-yl}-4- (trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydrona phthalen-2- yl} carbamoyl)phenyl trifluoromethanesulfonate,
N-{(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronap hthalen-2-yl}-5-methyl-2- phenyl-2H-l,2,3-triazole-4-carboxamide,
N-{(2R)-8-[2-(Ethylamino)ethoxy]-l,2,3,4-tetrahydronaphth alen-2-yl}-4-
(trifluoromethoxy)benzamide, 4-({(2R)-8-[2-(Ethylamino)ethoxy]-l,2,3,4-tetrahydronaphthal en-2-yl}carbamoyl)phenyl trifluoromethanesulfonate,
N- {(2R)-8-[2-(Ethylamino)ethoxy]- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl} -4-piperidin- 1 - ylbenzamide,
N-{(2R)-8-[2-(Ethylamino)ethoxy]-l,2,3,4-tetrahydronaphth alen-2-yl}-5-methyl-2-phenyl- 2H-l,2,3-triazole-4-carboxamide,
N-{(2R)-8-[(l-Methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydr onaphthalen-2-yl}-4-
(trifluoromethoxy)benzamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen- 3-yl]-3,4-dihydroisoquinoline-
2(1 H)-carboxamide, N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen-3-y l]-5-(trifluoromethyl)-3,4- dihydroisoquinoline-2( 1 H)-carboxamide,
N-[(3S)-5-(Pyrrolidin-l-ylmethyl)-3,4-dihydro-2H-chromen- 3-yl]indoline-l-carboxamide,
5-Methyl-2-phenyl-N-[(2R)-8-(2-pyrrolidin-l-ylethoxy)-l,2 ,3,4-tetrahydronaphthalen-2-yl]-
1 ,3-oxazole-4-carboxamide, N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl }-5-methyl-2-phenyl-l,3- oxazole-4-carboxamide,
N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3 -yl}-5-methyl-2-phenyl-2H-
1 ,2,3-triazole-4-carboxamide,
N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3 -yl}-2-phenyl-2H-l,2,3- triazole-4-carboxamide,
N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3 -yl}-4-
(trifluoromethoxy)benzamide,
4-({(3S)-5-[2-(ethylamino)ethoxy]-3,4-dihydro-2H-chromen- 3-yl}carbamoyl)phenyl trifluoromethanesulfonate, N-{(3S)-5-[2-(Ethylamino)ethoxy]-3,4-dihydro-2H-chromen-3-yl }-4-piperidin-l- ylbenzamide,
N- {(2R)-8-[2-(Dimethylamino)-l , 1-dimethylethyl] -5 -methyl- 1 ,2,3,4-tetrahydronaphthalen-
2-yl}-4-(trifluoromethoxy)benzamide,
4-({(2R)-8-[2-(Dimethylamino)-l,l-dimethylethyl]-5-methyl -l,2,3,4-tetrahydronaphthalen-
2-yl} carbamoyl)phenyl trifluoromethanesulfonate, N- {(2R)-8-[2-(Dimethylamino)-l , 1-dimethylethyl] -5 -methyl- 1 ,2,3,4-tetrahydronaphthalen-
2-yl} -5-methyl-2-phenyl-2H- 1 ,2,3-triazole-4-carboxamide,
N-{(3S)-5-[(l-methyl-lH-imidazol-2-yl)methoxy]-3,4-dihydr o-2H-chromen-3-yl}-6-(2,2,2- trifluoroethoxy Nicotinamide,
(3S)-3-({[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]carbonyl }amino)-3,4-dihydro-2H- chromen-5-yl 1 -methyl- lH-imidazole-4-sulfonate,
(3S)-3-({[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]car bonyl}amino)-3,4-dihydro-2H- chromen-5-yl 1 -methyl- lH-imidazole-4-sulfonate,
(3S)-3-({[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]carbonyl }amino)-3,4-dihydro-2H- chromen-5-yl 2,4-dimethyl- 1 ,3 -thiazole-5 -sulfonate, (3 S)-3 -( { [6-(3 ,3 ,3 -trifluoropropoxy)pyridin-3 -yl]carbonyl} amino)-3 ,4-dihydro-2H- chromen-5-yl pyridine-3-sulfonate,
(3S)-3-({[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]car bonyl}amino)-3,4-dihydro-2H- chromen-5-yl 2,4-dimethyl- l,3-thiazole-5-sulfonate, and
(3S)-3-({[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]car bonyl}amino)-3,4-dihydro-2H- chromen-5-yl pyridine-3-sulfonate,
N-[(35)-5-(2-Amino-l,l-dimethylethoxy)-3,4-dihydro-2H-chr omen-3-yl]-5-methyl-2- phenyl-2H- 1 ,2,3-triazole-4-carboxamide, and
N- {(35)-5-[2-(Dimethylamino)- 1 , 1 -dimethylethoxy]-3,4-dihydro-2H-chromen-3-yl} -5- methyl-2-phenyl-2H- 1 ,2,3-triazole-4-carboxamide, or pharmaceutically-acceptable salts thereof.
For the avoidance of doubt the present invention relates to any one of the specific compounds mentioned above.
The present invention relates to the compounds of formula I or Ia as hereinbefore defined as well as to pharmaceutical acceptable salts thereof. Salts for use in pharmaceutical
compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I or Ia.
A suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid. In addition, a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Co.). The compounds of the present invention may also exists as solvents, solvated hydrates or cocrystals.
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
Compounds of the present invention have been named with the aid of computer software (ACDLabs 8.0 or 9.0/Name(IUPAC)).
Process Another object of the invention is the processes (a), (b) or (c) for the preparation of compounds of general Formula I or Ia and salts thereof.
(a) acylation of a compound of formula II, with an acylating reagent such as a compound of formula III, wherein halo is fluoro, chloro or bromo and Ri, R 2 , R 3 , X and Y are as defined in Formula I or Ia.
The reaction may be carried out using a suitable acylating reagent such as an acyl chloride, in a suitable solvent such as dichloromethane, chloroform, toluene or acetonitrile at a temperature between -20 0 C and reflux.. The reaction is advantageously effected by the presence of a base. A suitable base may be an organic amine base such as pyridine, 2,6-lutidine, collidine, triethylamine, morpholine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene or tetramethylguanidine or an alkali metal or an alkaline earth metal carbonate or hydroxide such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. The reaction may be aided by the presence of 4-dimethylaminopyridine.
(b) acylation of a compound of formula II, with a suitable carboxylic acid IV, wherein Ri, R 2 , R 3 , X and Y are as defined in Formula I or Ia.
The transformation may be performed using a suitable activating reagent such as 2-(1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate or N,N'- carbonyldiimidazole with a suitable base such as triethylamine or diisopropylethylamine. The reaction may be performed in a suitable solvent such as dimethylformamide, acetonitrile or dichloromethane at a temperature between -20 0 C and reflux.
(c) coupling of amine II with a source of a carbonyl group such as N,N'- carbonyldiimidazole VI in the presence of a suitable cyclic secondary amine such as quinoline V, wherein R 1 , R 2 , R 3 , X and Y are as defined in Formula I or Ia.
The reaction may be preformed in a suitable solvent such as dichloromethane or dimethylformaide at a temperature between -20 °C and reflux.
Protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3 rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of Formula I or Ia, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Moreover, certain compounds of Formula I or Ia may act as prodrugs of other compounds of Formula I or Ia.
All prodrugs of compounds of Formula I or Ia are included within the scope of the invention.
Intermediates
A further embodiment of the invention relates to compounds selected from the group consisting of (2i?)-N-Benzyl-8-bromo-5-methyl-N-[(15)-l-phenylethyl]-l,2,3 ,4-tetrahydronaphthalen-2- amine
Methyl (7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene- 1 -carboxylate
(7i?)-N-Benzyl-7-{benzyl[(15)-l-phenylethyl]amino}-N,4-di methyl-5,6,7,8- tetrahydronaphthalene- 1 -carboxamide
(7i?)-7-Amino-7V-benzyl-7V,4-dimethyl-5 ,6,7,8-tetrahydronaphthalene- 1 -carboxamide
(2R)-S- { [Benzyl(methyl)amino]methyl} -5-methyl- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-N-Benzyl-8-(3,4-dihydroisoquinolin-2(lH)-ylcarbonyl )-5-methyl-N-[(15)-l- phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine (2i?)-8-(3,4-Dihydroisoquinolin-2(lH)-ylcarbonyl)-5-methyl-l ,2,3,4-tetrahydronaphthalen-
2-amine
(2R)-8-(3 ,4-Dihydroisoquinolin-2( 1 H)-ylmethyl)-5 -methyl- 1 ,2,3 ,4-tetrahydronaphthalen-
2-amine
(2i?)-N-Benzyl-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-m ethyl-N-[(15)-l-phenylethyl]- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-8-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-5-methyl-l ,2,3,4-tetrahydronaphthalen-2- amine
(2i?)-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-methyl-l,2 ,3,4-tetrahydronaphthalen-2- amine
(35)-3 -(Dibenzylamino)-3 ,4-dihydro-2H-chromen-5 -yl trifluoromethanesulfonate
(35)-λ/ 3 ,λ/ 3 -Dibenzyl-λ/ 5 -(l-methylpiperidin-4-yl)chromane-3,5-diamine (35)-N 5 -(l-Methylpiperidin-4-yl)chromane-3,5-diamine
(35)-λ/ 3 ,λ/ 3 -dibenzyl-λ/ 5 -(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
(35)-N 5 -(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
Methyl (35)-3-(dibenzylamino)chromane-5-carboxylate
(35)-7V,7V-Dibenzyl-5 -(pyrrolidin- 1 -ylcarbonyl)chroman-3 -amine (35)-5-(Pyrrolidin-l-ylcarbonyl)chroman-3 -amine
(35)-5-(pyrrolidin- 1 -ylmethyl)chroman-3-amine
(2i?)-7V,7V-Dibenzyl-8-(2-pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-8-(2-pyrrolidin- 1 -ylethoxy)- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(35)-7V,7V-Dibenzyl-5 -[(4-methylpiperazin- 1 -yl)carbonyl] chroman-3 -amine (35)-5 - [(4-methylpiperazin- 1 -yl)carbonyl] chroman-3 -amine
(35)-5 - [(4-methylpiperazin- 1 -yl)methyl] chroman-3 -amine
(35)-N,N-Dibenzyl-5 -(piperidin- 1 -ylcarbonyl)chroman-3 -amine
(35)-5-(Piperidin-l-ylcarbonyl)chroman-3 -amine
(3 S)-5 -(piperidin- 1 -ylmethyl)chroman-3 -amine (2i?)-λ/-Benzyl-5-methyl-8-[(4-methylpiperazin-l-yl)carbony l]-λ/-[(15)-l-phenylethyl]-
1 ,2,3 ,4-tetrahydronaphthalen-2-amine
(2i?)-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2,3 ,4-tetrahydronaphthalen-2-amine
(35)-7V,7V-Dibenzyl-5 -(piperazin- 1 -ylcarbonyl)chroman-3 -amine
(35)-N,N-Dibenzyl-5 -(piperazin- 1 -ylmethyl)chroman-3 -amine tert-Butyl 4-{[(35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl]methy l}piperazine-l- carboxylate tert-butyl 4-{[(35)-3-amino-3,4-dihydro-2H-chromen-5-yl]methyl}piperazi ne-l- carboxylate
(2R)-5-methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4- tetrahydronaphthalen-2-amine (35)-λf,λ/-Dibenzyl-5-[(l-methylpiperidin-4-yl)oxy] chroman-3 -amine
(35)-5 - [( 1 -methylpiperidin-4-yl)oxy] chroman-3 -amine
(35)-N,N-Dibenzyl-5 - [2-(dimethylamino)ethoxy]chroman-3 -amine
(35)-5-[2-(dimethylamino)ethoxy] chroman-3 -amine
(35)-7V,7V-Dibenzyl-5 -(2-pyrrolidin- 1 -ylethoxy)chroman-3 -amine
(3S)-5-(2-pyrrolidin-l-ylethoxy)chroman-3-amine
(35)-7V,7V-Dibenzyl-5 -[( 1 -methylpyrrolidin-3 -yl)oxy] chroman-3 -amine (35)-5-[(l-Methylpyrrolidin-3-yl)oxy]chroman-3-amine
2- { [(7i?)-7-(Dibenzylamino)-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } -N,N- diethylacetamide
2- { [(7i?)-7-amino-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } -7V,7V-diethylacetamide
(2i?)-N,λ/-Dibenzyl-8-[(l-methylpiperidin-4-yl)oxy]-l,2, 3,4-tetrahydronaphthalen-2-amine (2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronapht halen-2-amine
(35)-7V,7V-Dibenzyl-5 - [( 1 -methylpiperidin-3 -yl)oxy] chroman-3 -amine
(35)-5 - [( 1 -Methylpiperidin-3 -yl)oxy] chroman-3 -amine
(2i?)-N,λ/-Dibenzyl-8-[2-(dimethylamino)ethoxy]-l,2,3,4- tetrahydronaphthalen-2-amine
(2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphth alen-2-amine tert-Butyl (2- { [(7R)-7-(dibenzylamino)-5 ,6,7,8-tetrahydronaphthalen- 1 - yl]oxy } ethyl)ethylcarbamate tert-Butyl (2- { [(7R)-7-amino-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } ethyl)ethylcarbamate
(2R)-N,N-Dibenzyl-8-[(l-methylpiperidin-3-yl)oxy]-l,2,3,4 -tetrahydronaphthalen-2-amine
(2R)-8-[(l-Methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydrona phthalen-2-amine tert-Butyl (2- {[(3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5- yl]oxy } ethyl)ethylcarbamate tert-Butyl (2-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5-yl]oxy}ethyl)ethy lcarbamate
2-[(7R)-I- {Benzyl[( IS)- 1 -phenylethyl] amino} -4-methyl-5 ,6,7,8-tetrahydronaphthalen- 1 - yl] -2-methylpropanenitrile (2i?)-8-(2-Amino-l,l-dimethylethyl)-N-benzyl-5-methyl-N-[(15 )-l-phenylethyl]-l,2,3,4- tetrahydronaphthalen-2-amine
(2i?)-N-Benzyl-8-[2-(dimethylamino)-l,l-dimethylethyl]-5- methyl-N-[(15)-l- phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine
(2i?)-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-methyl-l, 2,3,4-tetrahydronaphthalen-2- amine
(35)-5-(2-Amino- 1 , 1 -dime thylethoxy)-7V,7V-dibenzylchroman-3 -amine
tert-Butyl (2-{[(35)-3-amino-3,4-dihydro-2H-chromen-5-yl]oxy}-2- methylpropyl)carbamate tert-butyl (2-methyl-2-{[(35)-3-{[(5-methyl-2-phenyl-2H-l,2,3-triazol-4 - yl)carbonyl] amino } -3 ,4-dihydro-2H-chromen-5 -yl] oxy } propyl)carbamate (35)-7V,7V-dibenzyl-5 - [( 1 -methyl- lH-imidazol-2-yl)methoxy] chroman-3 -amine (35)-5 -[( 1 -methyl- IH- imidazol-2 -yl)methoxy] chroman-3 -amine
(35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl 1 -methyl- IH- imidazole -4-sulfonate (35)-3-amino-3,4-dihydro-2H-chromen-5-yl 1 -methyl- IH- imidazole-4-sulfonate (35)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5 -yl 2,4-dimethyl-l,3- thiazole-5 -sulfonate
(35)-3-amino-3,4-dihydro-2H-chromen-5-yl 2,4-dimethyl-l,3-thiazole-5-sulfonate (35)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5 -yl pyridine-3-sulfonate (35)-3-amino-3,4-dihydro-2H-chromen-5-yl pyridine-3 -sulfonate, and 6-(3,3,3-trifluoropropoxy)nicotinic acid
Another embodiment relates to the use of these compounds as intermediates in the preparation of compounds of the invention.
Medical use The compounds of the invention exhibit voltage-gated sodium channel inhibiting activity, especially Navl .7 blocking activity, for example as demonstrated in the test described below.
The present invention relates to the compounds of formula I or Ia, which inhibit any sodium channel.
Modulation of voltage-gated sodium channels by pharmacological or genetical tools points to a central role for distinct voltage-gated sodium channels in several disease models.
A mouse line has been generated which through advanced molecular biology technologies eliminates the functional expression of Navl.7 in DRG neurons that express Navl.8
(Proceedings of the National Academy of Sciences USA (2004) 101(34) 12706-12711).
This mouse line shows greatly reduced pain responses in several pain behaviour models. Likewise, Herpes-vector mediated knockdown of Navl .7 in primary afferents of wildtype mice results in a decrease in inflammatory hyperalgesia (Human Gene Therapy (2005)
16(2) 271-277).
Antagonists of NaV channels have been shown to be useful for treating a variety of conditions, including acute and chronic nociceptive, visceral, inflammatory, central and peripheral neuropathic pain. More specifically, modulators of NaV activity are currently used or being tested in the clinic as anaesthetics, including local anaesthetics(Pain (2000) 87(1) 7-17), neuropathic pain reliefers (European Journal of Pain (2002) 6(Supplement 1) 61-68), acute pain reliefers (The Cochrane Database of Systematic Reviews (2005) 3), chronic pain reliefers (Pharmacotherapy (2001) 21(9) 1070-1081), inflammatory pain reliefers (Proceedings of the National Academy of Sciences USA (1999) 96(14) 7645- 7649), headache reliefers (Headache (2001) 41(Supplement 1) S25-S32). The compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of a condition which is effected or facilitated by inhibition of voltage-gated sodium channels, in particular pain, such as acute and chronic pain disorders including but not limited to widespread pain, localized pain, nociceptive pain, inflammatory pain, central pain, central and peripheral neuropathic pain, central and peripheral neurogenic pain, central and peripheral neuralgia, low back pain, postoperative pain, visceral pain, pelvic pain, allodynia, anesthesia dolorosa, causalgia, dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, hyperpathia, ischemic pain, sciatic pain, pain associated with cystitis, including but not limited to interstitial cystitis, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with osteoarthritis, pain associated with rheumatoid arthritis and pain associated with cancer.
Other indications that may be treated with the compounds of the inventions are, but not limited to, migraine, pruritus, fibromyalgia, tinnitus and epilepsy.
The compounds of the present invention may be administered alone or in combination with other compounds, especially therapeutically active compounds.
The compounds of the present invention may for example be combined with one or more of the following therapeutically active compounds: proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, tentorpazole, pantoprazole, esomeprazole, revaprazan or sorprazan.
Thus one embodiment of the invention relates to a combination wherein a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable
ester, solvates, hydrated solvates, hydrates or cocrystals thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) or (Ia) is administered concurrently, simultaneously, sequentially or separately with another pharmaceutically active compound or compounds selected from the following: (i) antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fiuvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, pro trip ty line, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(ii) atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof.
(iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (v) anticonvulsants including for example carbamazepine, valproate, lamotrogine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vi) Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (ix) stroke therapies including for example abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(x) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xi) neuropathic pain therapies including for example gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof, (xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xiii) GABAb modulators such as baclofen, and equivalents and pharmaceutically active salts and metabolite(s) thereof.
(xiv) Glutamate receptor antagonists and equivalents and pharmaceutically active salts and metabolite(s) thereof. (xv) insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos,secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xvi) mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within therapeutically active dosage ranges and/or the dosage described in the publication reference.
One embodiment of the invention relates to compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, for use in therapy.
Another embodiment relates to the use of compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, in the manufacture of a medicament for treatment of pain.
A further embodiment relates to the use of compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, in the manufacture of a medicament for treatment of acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.
One embodiment relates to a method of treatment of pain, or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, or a pharmaceutical composition comprising said compounds.
An agent for the treatment of pain, or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain, which comprises as active ingredient a compounds of formula I or Ia as defined above , or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, or a pharmaceutical composition comprising said compounds.
Pharmaceutical compositions
The compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
One embodiment relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I or Ia as defined above, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
Another embodiment relates to said pharmaceutical composition according, for use in the treatment of pain or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.
Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 25.0 mg/kg body weight at oral administration and about 0.005 to 10.0 mg/kg body weight at parenteral administration. Example of ranges of daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration.
Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, be longer acting than, produce fewer side effects than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
The invention is illustrated by way of the following examples.
Examples General Methods
Starting materials used were available from commercial sources, or prepared according to literature procedures.
Microwave irradiation was performed in a Creator , Initiator or Smith Synthesizer Single -mode microwave cavity producing continuous irradiation at 2450 MHz. Mass spectra were recorded on one of the following instruments: a Perkin-Elmer SciX API 150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform II single quadrupole; or a Micromass Platform LCZ single quadrupole mass spectrometer (the latter three instruments were equipped with a pneumatically assisted electrospray interface (LC- MS)). Prep-HPLC: Preparative chromatography was run on Waters auto purification HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 μm. Gradient with acetonitrile/0.1 M ammonium acetate in 5 % acetonitrile in MiIIiQ Water, typically run from 20% to 60% acetonitrile, in 13 min. Flow rate: 20 mL/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV- vis. -detector equipped with a Waters Symmetry ® column (C 18, 5 μm, 100 mm x 19 mm). Gradient with acetonitrile/0.1 % trifiuoroacetic acid in MiIIiQ Water, typically run from 35% to 60% acetonitrile in 20 min. Flow rate: 10 mL/min. Alternatively, another column was used; Atlantis C18 19 x 100 mm, 5 μm column. Gradient with acetonitrile/0.1 M ammonium acetate in 5% acetonitrile in MiIIiQ Water, run from 0% to 35-50% acetonitrile, in 15 min. Flow rate: 15 mL/min.
NMR spectra were recorded on a Varian Unity+ 400 NMR Spectrometer, operating at 400 MHz for proton and 100 MHz for carbon- 13, and equipped with a 5 mm BBO probe with
Z-gradients; or on a Bruker av400 NMR spectrometer operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 3 mm flow injection SEI 1 HZD- 13 C probehead with Z-gradients, using a BEST 215 liquid handler for sample injection; or on a Bruker DPX400 NMR spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 4-nucleus probe with Z-gradients. The following reference signals were used: TMS δ 0.00, or the residual solvent signal of DMSO-J 6 δ 2.49, CD 3 OD δ 3.31 or CDCl 3 δ 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively. Column chromatography was performed using Merck Silica gel 60 (0.040-0.063 mm), or employing a Combi Flash ® Companion ™ system using RediSep ™ normal-phase flash columns.
Compounds have been named using ACD/Name, version 9.0, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004.
Rotamers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
Reactants
Following reactants, either new (see synthetic procedures described below), commercially available or described in the literature, were used for the preparation of the target compounds (table 1):
Amines: Amine 1: (2R)-8-{[benzyl(methyl)amino]methyl}-5-methyl-l,2,3,4-tetrah ydronaphthalen-
2-amine
Amine 2: (2R)-8-(3,4-dihydroisoquinolin-2(lH)-ylmethyl)-5-methyl-l,2, 3,4- tetrahydronaphthalen-2-amine
Amine 3: (2R)-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-methyl-l,2,3,4 - tetrahydronaphthalen-2-amine
Amine 5: (3S)-N5-(l-methylpiperidin-4-yl)chromane-3,5-diamine
Amine 7: ((3S)-N5-(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
Amine 8: (3S)-5-(pyrrolidin-l-ylmethyl)chroman-3-amine
Amine 9: (2R)-8-(2-pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphthale n-2-amine
Amine 11: (3S)-5-[(4-methylpiperazin-l-yl)carbonyl]chroman-3-amine
Amine 12: (3S)-5-[(4-methylpiperazin-l-yl)methyl]chroman-3-amine Amine 13: (3S)-5-(piperidin-l-ylmethyl)chroman-3-amine
Amine 14: (2R)-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l, 2,3,4- tetrahydronaphthalen-2-amine
Amine 15: tert-butyl 4-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5-yl]methyl}piperazi ne-
1-carboxylate Amine 16: (2R)-5-methyl-8-[(4-methylpiperazin-l-yl)methyl]-l,2,3,4- tetrahydronaphthalen-2-amine
Amine 19: (3S)-5-[(l-methylpiperidin-4-yl)oxy]chroman-3-amine
Amine 20: (3S)-5-[2-(dimethylamino)ethoxy]chroman-3-amine
Amine 21: (3S)-5-(2-pyrrolidin-l-ylethoxy)chroman-3-amine Amine 22: (3S)-5-[(l-methylpyrrolidin-3-yl)oxy]chroman-3-amine
Amine 23 : 2- { [(7R)-7-amino-5 ,6,7,8-tetrahydronaphthalen- 1 -yl]oxy } -N ,N- diethylacetamide
Amine 24: (2R)-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronapht halen-2-amine
Amine 25: (3S)-5-[(l-methylpiperidin-3-yl)oxy]chroman-3-amine Amine 26: (2R)-8-[2-(dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthale n-2-amine
Amine 27: tert-butyl (2-{[(7R)-7-amino-5,6,7,8-tetrahydronaphthalen-l- yl]oxy } ethyl)ethylcarbamate
Amine 28: (2R)-8-[(l-methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydronapht halen-2-amine
Amine 29: tert-butyl (2-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5- yl]oxy}ethyl)ethylcarbamate
Amine 33: (2R)-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-methyl-l,2,3, 4- tetrahydronaphthalen-2-amine
Amine 34 : (35)-5 - [( 1 -methyl- 1 H-imidazol-2-yl)methoxy] chroman-3 -amine
Amine 35: (35)-3-amino-3,4-dihydro-2H-chromen-5-yl 1 -methyl- IH- imidazole-4- sulfonate
Amine 36: (35)-3-amino-3,4-dihydro-2H-chromen-5-yl 2,4-dimethyl-l,3-thiazole-5- sulfonate
Amine 37: (35)-3-amino-3,4-dihydro-2H-chromen-5-yl pyridine-3 -sulfonate
Carboxylic acids:
Acid 1: 5-methyl-2-phenyl-2H-l,2,3-triazole-4-carboxylic acid
Acid 2: 4-butoxybenzoic acid Acid 3: 4- {[(trifluoromethyl)sulfonyl]oxy} benzoic acid
Acid 4: 2-(2,4-dimethylphenyl)-5-methyl-2H-l,2,3-triazole-4-carboxyl ic acid
Acid 5: 2,4-bis(trifluoromethyl)benzoic acid
Acid 7: 4-isopropoxybenzoic acid
Acid 8: 4-piperidin-l-yl-benzoic acid Acid 9: 5-methyl-2-phenyl-l,3-oxazole-4-carboxylic acid
Acid 10: 2-phenyl-2H-l,2,3-triazole-4-carboxylic acid
Acid 11 : 6-(2,2,2-trifluoroethoxy)nicotinic acid
Acid 12: 6-(3,3,3-trifluoropropoxy)nicotinic acid
Acid 13: 6-(tetrahydro-2H-pyran-4-yloxy)nicotinic acid Acy I chlorides:
Acyl chloride 1 : 4-(trifluoromethoxy)benzoyl chloride
Acyl chloride 3: 2,4-bis(trifiuoromethyl)benzoyl chloride
Secondary amines:
Sec amine 1: 5-Trifluoromethyl-l,2,3,4-tetrahydroisoquinoline Sec amine 2: Indoline
Sec amine 3: 1,2,3,4-tetrahydroisoquinoline
General methods of synthesis. Method A: The acid chloride (1.2 mole equivalent) was added to a solution of the amine (1 mole equivalent) and triethylamine (1.2 mole equivalent) in dry dichloromethane. The reaction mixture was stirred at ambient temperature for 5-30 min and concentrated in vacuo. The crude product was purified by preparative HPLC. Method B: 7V,7V'-Carbonyldiimidazole (1.2 mole equivalent) was added to a solution of the carboxylic acid (1.2 mole equivalent) in anhydrous dimethylformamide followed by addition of a solution of the amine (1 mole equivalent) in anhydrous dimethylformamide. The reaction
mixture was heated at 80 0 C for 2-12 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by preparative HPLC. Method C: Triethylamine (3 mole equivalent) and 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafiuorophosphate (1.5 mole equivalent) were added to a solution of the carboxylic acid (1 mole equivalent) in anhydrous acetonitrile and he reaction mixture was stirred for 10 min. A solution of the amine (1 mole equivalent) in anhydrous acetonitrile was added and the reaction mixture was stirred at ambient temperature for 1 h. The volatiles were removed in vacuo and the crude residue was purified by preparative HPLC. Method D:
The secondary amine (as the hydrochloride, 1 mole equivalent) was added to a solution of 7V,7V'-carbonyldiimidazole in anhydrous dichloromethane and the mixture was stirred at ambient temperature for 40 min. The amine (1 mole equivalent) and triethylamine (1 mole equivalent) were added and the reaction mixture was stirred at ambient temperature overnight. The volatiles were removed in vacuo and the crude product was purified by preparative HPLC. Method E: Hydrochloric acid (3 M, 1-5 mL) was added to a solution of the Boc-protected final product in ethyl acetate (1-5 mL) and the reaction mixture was heated at 40 0 C for 1 h. The mixture was neutralised with sodium hydroxide (5 M) to pH ~9 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo and the crude product was purified by preparative HPLC. Method F:
Triethylamine (3 mole equivalent) and 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafiuorophosphate (1.5 mole equivalent) were added to a solution of the carboxylic acid (1 mole equivalent) in anhydrous acetonitrile and he reaction mixture was stirred for 10 min. A solution of the amine (1 mole equivalent) in anhydrous acetonitrile was added and the reaction mixture was stirred at ambient temperature for 1 h. The volatiles were removed in vacuo, dichloromethane (2 mL) and trifiuoroacetic acid (0.5
mL) were added and the resulting mixture was stirred at ambient temperature. The volatiles were removed in vacuo and the residue was purified by preparative HPLC.
Table 1. The following compounds were prepared according to Methods A-F, using the reactants mentioned above: amines and counterparts which are either carboxylic acids or acyl chlorides or secondary amines.
Example 91
N-[(3S)-5-(2- Amino-l,l-dimethylethoxy)-3,4-dihydro-2H-chromen-3-yl]-5-met hyl-2- phenyl-2H- 1 ,2,3-triazole-4-carboxamide A solution of tert-butyl (2-methyl-2-{[(35)-3-{[(5-methyl-2-phenyl-2H-l,2,3-triazol-4 - yl)carbonyl]amino}-3,4-dihydro-2H-chromen-5-yl]oxy}propyl)ca rbamate (126 mg, 0.24 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at ambient temperature for 2 h. The volatiles were removed in vacuo. The residue was partitioned between sodium hydroxide (1 M) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. A part of the product (22 mg) was purified by column chromatography using first chloroform and then a mixture of chloroform, methanol and aqueous ammonia (95:5:0.5) as the eluent to give 17 mg of the title compound: MS (ESI) m/z 422 [M+η] + ; 1 R NMR (DMSO-J 6 ) δ 8.47 (d, 1 H), 8.05 (d, 2 H), 7.59 (t, 2 H),
7.46 (t, 1 H), 7.02 (t, 1 H), 6.66 (d, 1 H), 6.50 (d, 1 H), 4.32 (m, 1 H), 4.19 (m, 1 H), 3.86 (m, 1 H), 2.98 (m, 1 H), 2.80 (m, 1 H), 2.72 (s, 2 H), 2.55 (s, 3 H), 1.66 (br s, 2 H), 1.29 (s, 6 H).
Example 92
λ L {(3S)-5-[2-(Dimethylamino)-l,l-dimethylethoxy]-3,4-dihydro-2 H-chromen-3-yl}-5- methyl-2-phenyl-2H- 1 ,2,3-triazole-4-carboxamide
Sodium cyanoborohydride (10 mg, 0.157 mmol) and acetic acid (1 drop) were added to a solution of N-[(3S)-5-(2-amino-l,l -dimethyl ethoxy)-3,4-dihydro-2η-chromen-3-yl]-5- methyl-2-phenyl-2H-l,2,3-triazole-4-carboxamide (22 mg, 0.052 mmol) and formaldehyde (0.040 mL, 0.53 mmol) in methanol (1.7 mL) and the reaction mixture was stirred at ambient temperature overnight. The volatiles were removed and the residue was partitioned between sodium hydroxide (1 M) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography, using chloroform and then a mixture of chloroform, methanol and aqueous ammonia (95:5:0.5) as the eluent to give 16 mg (68% yield) of the title compound: MS (ESI) m/z 450 [M+H] + ; 1 H NMR (DMSO-J 6 ) δ 8.46 (d, 1 H), 8.04 (d, 2 H), 7.59 (t, 2 H), 7.46 (t, 1 H), 7.01 (t, 1 H), 6.70 (d, 1 H), 6.50 (d, 1 H), 4.31 (m, 1 H), 4.18 (m, 1 H), 3.86 (m, 1 H), 2.97 (m, 1 H), 2.79 (m, 1 H), 2.54 (s, 3 H), 2.50 (m, obscured by solvent signal, 2 H), 2.27 (s, 6 H), 1.32 (s, 6 H).
Synthesis of intermediates
Intermediate example 1-1
(2R)-N-Benzyl-8-bromo-5-methyl-N-[(lS)-l-phenylethyl]-l,2 ,3,4- tetrahydronaphthalen-2-amine
Benzyl bromide (2.052 g, 12 mmol), potassium iodide (100 mg, 0.6 mmol), and potassium carbonate (3.45 g, 25 mmol) were added to a solution of (2i?)-8-bromo-5-methyl-N-[(15)- l-phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine (3.8 g, 10 mmol, described inJ Med. Chem. 1993, 36, 2066) in acetonitrile (50 mL) and the reaction mixture was heated at reflux overnight. The mixture was cooled down to room temperature, dilute with ethyl acetate, and extracted with saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate and concentrated. Purification by column chromatography,
using heptane/ethyl acetate (80:20) as the eluent, gave 3.78 g (87% yield)of the title compound: 1 U NMR (DMSO-J 6 ) δ 7.47 (d, 2 H), 7.38 - 7.43 (m, 2 H), 7.30 - 7.37 (m, 4 H), 7.29 (d, 1 H), 7.18 - 7.26 (m, 2 H), 6.89 (d, 1 H), 3.93 - 3.96 (m, 1 H), 3.69 (d, 1 H), 2.96 - 3.06 (m, 1 H), 2.80 - 2.89 (m, 1 H), 2.60 - 2.72 (m, 1 H), 2.26 - 2.38 (m, 1 H), 2.07 (s, 3 H), 1.52 - 1.61 (m, 1 H), 1.39 - 1.51 (m, 1 H), 1.31 (d, 3 H). MS (ESI) m/z 436 [M+H] + .
Intermediate example 1-2
Methyl (7R)-7-{benzyl[(lS)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene-1-carboxylate
(2i?)-N-Benzyl-8-bromo-5-methyl-N-[(15)-l-phenylethyl]-l,2,3 ,4-tetrahydronaphthalen-2- amine (3.78 g, 8.7 mmol) dissolved in a mixture of dimethylformamide (8 mL) and methanol (2 mL) containing palladium acetate (97 mg, 0.435 mmol), propane- 1,3- diylbis(diphenylphosphine) (144 mg, 0.348 mmol) and triethylamine (2.66 mL, 19.14 mmol) was treated with carbon monoxide at 70 0 C for 22 h. The mixture was cooled down to ambient temperature, diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water and brine. The organic phase was dried over magnesium sulfate and concentrated. Purification by column chromatography, using heptane/ethyl acetate (95:5) as the eluent, gave 2.66 g, (74% yield) of the title compound: 1 H NMR (DMSO-J 6 ) δ 7.50 (d, 1 H), 7.45 (d, 2 H), 7.40 (d, 1 H), 7.29 - 7.36 (m, 5 H), 7.18 - 7.26 (m, 2 H), 7.02 - 7.07 (m, 1 H), 3.86 - 3.99 (m, 2 H), 3.77 (s, 3 H), 3.65 - 3.73 (m, 1 H), 3.11 - 3.20 (m, 1 H), 2.87 - 3.06 (m, 2 H), 2.59 - 2.73 (m, 1 H), 2.26 - 2.41 (m, 1 H), 2.15 (s, 3 H), 1.57 - 1.67 (m, 1 H), 1.42 - 1.57 (m, 1 H), 1.26 - 1.33 (m, 3 H); MS (ESI) m/z 414 [M+H] + .
Intermediate example 1-3
(7R)-N-Benzyl-7-{benzyl[(lS)-l-phenylethyl]amino}-N,4-dim ethyl-5,6,7,8- tetrahydronaphthalene-1-carboxamide
To a solution of methyl (7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene-1-carboxylate (826 mg, 2 mmol) in toluene (4 mL) trimethylaluminium (2 M solution in toluene, 4 mL, 8 mmol,) was added under an atmosphere of argon. The mixture was stirred at ambient temperature for 2 min and TV- methyl- 1-phenylmethanamine (773 mg, 1.6 mmol) was added. The reaction mixture was
heated at 60 0 C overnight, cooled to 5-20 0 C and water (50 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phase were dried over magnesium sulfate and concentrated. Purification by column chromatography, using heptane/ethyl acetate (80:20) as the eluent, gave 255 mg, (34% yield) of the title 5 compound: 1 R NMR (CDCl 3 ) δ 7.29 - 7.56 (m, 11 H), 7.14 - 7.26 (m, 3 H), 6.89 - 7.05 (m, 2 H), 4.24 - 4.36 (m, 1 H), 3.93 - 4.07 (m, 2 H), 3.70 - 3.87 (m, 2 H), 3.01 - 3.10 (m, 1 H), 2.94 - 2.99 (m, 1 H), 2.57 - 2.82 (m, 4 H), 2.31 - 2.52 (m, 1 H), 2.11 - 2.18 (m, 3 H), 1.65 - 1.80 (m, 1 H), 1.35 - 1.43 (m, 2 H), 1.28 - 1.32 (m, 2 H); MS (ESI) m/z 503 [M+H] + . o Intermediate example 1-4
(T/fJ-T-Amino-N-benzyl-N^-dimethyl-SjojTjS-tetrahydronaph thalene-l-carboxamide
A mixture of (7i?)-7V-benzyl-7- {benzyl[( 1 S)- 1 -phenylethyl] amino} -7V,4-dimethyl-5 ,6,7,8- tetrahydronaphthalene-1-carboxamide (577 mg, 1.15 mmol), palladium on charcoal (10%, 50 mg) and ammonium formate (362 mg, 5.75 mmol) in ethanol (10 mL) was irradiated ins a microwave under an atmosphere of argon at 110 0 C for 5 min. The mixture was cooled down to ambient temperature, filtered through Celite, and concentrated in vacuo. The residue was purified by column chromatography, using chloroform and a mixture of chloroform, methanol and aqueous ammonia (90:9:1) as the eluent, to give 245 mg (69% yield) of the title compound: 1 R NMR (CDCl 3 ) δ 7.37 - 7.40 (m, 2 H), 7.28 - 7.36 (m, 2 H),0 7.10 - 7.16 (m, 1 H), 7.01 - 7.06 (m, 1 H), 6.94 - 7.01 (m, 1 H), 4.67 - 4.88 (m, 1 H), 3.11 - 3.33 (m, 2 H), 2.99 - 3.08 (m, 2 H), 2.77 - 2.90 (m, 2 H), 2.71 (s, 3 H), 2.59 - 2.71 (m, 1 H), 2.30 - 2.47 (m, 1 H), 2.18 - 2.25 (m, 3 H), 2.07 - 2.15 (m, 2 H); MS (ESI) m/z 309 [M+H] + . 5 Intermediate example 1-5
Amine 1: (2/?)-8-{[Benzyl(methyl)amino]methyl}-5-methyl-l,2,3,4- tetrahydronaphthalen-2-amine
(7i?)-7-Amino-λ/-benzyl-N,4-dimethyl-5,6,7,8-tetrahydronaph thalene-l-carboxamide (245 mg, 0.8 mmol) was dissolved in tetrahydrofuran (6 mL), treated with borane ino tetrahydrofuran (1 M , 4 mL, 4 mmol) under an atmosphere of argon and stirred for 2.5 h. Water (10 mL) was added dropwise, followed by addition of hydrochloric acid (2 M, 2 mL) and the mixture was stirred overnight at 50 0 C. A saturated solution of sodium
bicarbonate was added and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give 242 mg (94% yield) of the title compound: 1 U NMR (CDCl 3 ) δ 7.28 - 7.36 (m, 4 H), 7.21 - 7.26 (m, 1 H), 7.08 - 7.13 (m, 1 H), 6.95 - 6.99 (m, 1 H), 3.51 (s, 2 H), 3.44 (s, 2 H), 3.06 - 3.18 5 (m, 2 H), 2.77 - 2.88 (m, 1 H), 2.59 - 2.73 (m, 1 H), 2.43 - 2.53 (m, 1 H), 2.21 (s, 3 H),
2.15 (s, 3 H), 2.01 - 2.09 (m, 1 H), 1.67 - 1.80 (m, 2 H), 1.52 - 1.65 (m, 1 H); MS (ESI) m/z 295 [M+H] + .
Intermediate example 1-6o (2R)-N-Benzyl-8-(3,4-dihydroisoquinolin-2(lH)-ylcarbonyl)-5- methyl-N-[(lS)-l- phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine
The title compound was prepared as described for Intermediate example 1-3 in 59% yield, starting from methyl (7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene-1-carboxylate and 1,2,3,4-tetrahydroisoquinoline: 1 H NMR (CDCl 3 )s δ 7.27 - 7.50 (m, 6 H), 7.11 - 7.25 (m, 5 H), 6.75 - 7.11 (m, 5 H), 4.88 - 5.23 (m, 1 H), 4.34 (d, 2 H), 3.96 - 4.18 (m, 1 H), 3.70 - 3.91 (m, 2 H), 3.38 - 3.68 (m, 2 H), 3.12 - 3.35 (m, 1 H), 3.02 (br s, 2 H), 2.73 (br s, 2 H), 2.28 - 2.54 (m, 2 H), 2.17 (s, 3 H), 1.51 - 1.59 (m, 3 H), 0.94 - 1.06 (m, 1 H); MS (ESI) m/z 515 [M+H] + . 0 Intermediate example 1-7
(2R)-8-(3,4-Dihydroisoquinolin-2(lH)-ylcarbonyl)-5-methyl -l,2,3,4- tetrahydronaphthalen-2-amine
The title compound was synthesized as described for Intermediate example 1-4 in 60% yield, starting from (2i?)-N-benzyl-8-(3,4-dihydroisoquinolin-2(lH)-ylcarbonyl)-5 -methyl-5 N-[(15)-l-phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine: 1 R NMR (CDCl 3 ) δ 7.17 - 7.25 (m, 2 η), 7.09 - 7.16 (m, 1 η), 7.02 - 7.07 (m, 1 η), 6.86 - 6.98 (m, 2 η), 5.04 - 5.14 (m, 1 η), 4.75 - 4.84 (m, 1 η), 4.30 - 4.49 (m, 1 η), 3.82 - 4.11 (m, 1 η), 3.40 - 3.61 (m, 1 η), 3.22 (d, 1 η), 2.96 - 3.03 (m, 1 η), 2.80 - 2.91 (m, 2 η), 2.74 - 2.80 (m, 1 η), 2.61 - 2.74 (m, 2 η), 2.25 (s, 3 η), 2.00 - 2.13 (m, 1 η); MS (ESI) m/z 321 [M+η] + .o
Intermediate example 1-8
Amine 2: (2R)-8-(3,4-Dihydroisoquinolin-2(lH)-ylmethyl)-5-methyl-l,2, 3,4- tetrahydronaphthalen-2-amine
The title compound was synthesized as described for Intermediate example 1-5 in 89% yield, starting from (2i?)-8-(3,4-dihydroisoquinolin-2(lH)-ylcarbonyl)-5-methyl-l ,2,3,4- tetrahydronaphthalen-2-amine: 1 R NMR (CDCl 3 ) δ 7.07 - 7.18 (m, 4 η), 6.96 - 7.04 (m, 2 η), 3.63 (br s, 2 η), 3.56 - 3.61 (m, 2 η), 3.19 - 3.28 (m, 1 η), 3.08 - 3.18 (m, 1 η), 2.84 - 2.92 (m, 2 η), 2.69 - 2.76 (m, 2 η), 2.61 - 2.68 (m, 1 η), 2.49 - 2.60 (m, 1 η), 2.24 (s, 3 η), 1.99 - 2.05 (m, 1 η), 1.84 - 1.94 (m, 1 η), 1.66 - 1.81 (m, 2 η), 1.52 - 1.66 (m, 1 η); MS (ESI) m/z 307 [M+η] + .
Intermediate example 1-9
(2R)-N-Benzyl-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-methy l-N-[(lS)-l- phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine The title compound was synthesized as described for Intermediate example 1-3 in 22% yield, starting from methyl (7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene-1-carboxylate and 2,6-dimethylmorpholine: 1 H NMR (CDCl 3 ) δ 7.36 - 7.49 (m, 4 H), 7.28 - 7.35 (m, 4 H), 7.19 - 7.25 (m, 2 H), 6.94 - 6.99 (m, 1 H), 6.80 - 6.91 (m, 1 H), 4.55 - 4.74 (m, 1 H), 3.97 - 4.08 (m, 1 H), 3.87 - 3.96 (m, 1 H), 3.73 - 3.86 (m, 1 H), 2.99 - 3.13 (m, 2 H), 2.68 - 2.82 (m, 2 H), 2.57 - 2.67 (m, 1 H), 2.32 - 2.49 (m, 2 H), 2.16 (s, 3 H), 1.70 - 1.87 (m, 1 H), 1.55 - 1.58 (m, 3 H), 1.36 - 1.40 (m, 2 H), 1.34 - 1.36 (m, 1 H), 1.29 - 1.34 (m, 1 H), 1.23 (d, 2 H), 1.06 - 1.11 (m, 2 H), 0.92 - 1.02 (m, 2 H); MS (ESI) m/z 497 [M+H] + .
Intermediate example I- 10
(2R)-8-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-5-methyl-l, 2,3,4- tetrahydronaphthalen-2-amine
The title compound was synthesized as described for Intermediate example 1-4 in 60% yield, starting from (2i?)-N-benzyl-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-meth yl-N- [(15)-l-phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine: 1 H NMR (DMSO-J 6 ) δ 6.98 - 7.03 (m, 1 H), 6.79 - 6.91 (m, 1 H), 4.33 - 4.47 (m, 1 H), 3.43 - 3.60 (m, 2 H), 3.33 (s, 3 H), 3.03 - 3.18 (m, 1 H), 2.84 - 2.99 (m, 1 H), 2.53 - 2.81 (m, 3 H), 2.35 - 2.47 (m, 1 H),
2.18 (s, 3 H), 1.92 (br s, 2 H), 1.34 - 1.55 (m, 1 H), 1.12 - 1.17 (m, 3 H), 0.91 - 0.98 (m, 3 H); MS (ESI) m/z 303 [M+H] + .
Intermediate example I- 11
5 Amine 3: (2R)-8-[(2,6-dimethylmorpholin-4-yl)methyl]-5-methyl-l,2,3,4 - tetrahydronaphthalen-2-amine
The title compound was synthesized as described for Intermediate example 1-5 in 88% yield, starting from (2i?)-8-[(2,6-dimethylmorpholin-4-yl)carbonyl]-5-methyl-l,2, 3,4- tetrahydronaphthalen-2-amine: 1 R NMR (CDCl 3 ) δ 6.95 - 7.03 (m, 2 H), 3.55 - 3.71 (m, 2o H), 3.34 - 3.39 (m, 2 H), 3.23 - 3.51 (m, 2 H), 3.12 - 3.23 (m, 1 H), 2.78 - 2.89 (m, 1 H), 2.64 - 2.73 (m, 2 H), 2.50 - 2.59 (m, 1 H), 2.20 - 2.26 (m, 3 H), 2.02 - 2.13 (m, 1 H), 1.85 - 1.96 (m, 2 H), 1.68 - 1.77 (m, 2 H), 1.54 - 1.67 (m, 1 H), 1.09 - 1.18 (m, 6 H); MS (ESI) m/z 289 [M+H] + . s Intermediate example 1-12
(3S)-3-(Dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate
Triethylamine (8.8 mL, 63.2 mmol) was added to a cooled (-40 0 C) solution of (35)-3- (dibenzylamino)chroman-5-ol (15.6 g, 45.2 mmol, described in WO9914212A1) in anhydrous dichloromethane (250 mL) under an atmosphere of nitrogen. A solution of0 trifluoromethanesulfonic anhydride (9.4 mL, 56.5 mmol) in anhydrous dichloromethane (70 mL) was added dropwise to the reaction mixture over 25 min. The cooling was removed, the reaction mixture was stirred until it reached room temperature, cooled again to 0 0 C and saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over5 magnesium sulfate and concentrated in vacuo. Purification by column chromatography, using a gradient of heptane/ethyl acetate as the eluent, gave 20.0 g (93% yield) of the title compound: 1 U NMR (CDCl 3 ) δ 7.36 - 7.44 (m, 4 η), 7.33 (t, 4 η), 7.21 - 7.27 (m, 2 η), 7.13 (t, 1 η), 6.82 (t, 2 η), 4.29 - 4.37 (m, 1 η), 4.02 (t, 1 η), 3.77 (s, 4 η), 3.20 - 3.31 (m, 1 η), 3.00 - 3.10 (m, 1 η), 2.86 - 2.97 (m, 1 η); MS (ESI) m/z 478 [M+η] + .o
Intermediate example 1-15 (3S)-λ /3 r /V 3 -Dibenzyl-λ /5 -(l-methylpiperidin-4-yl)chromane-3,5-diamine
A mixture of (35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (500 mg, 1.05 mmol), palladium acetate (24 mg, 0.11 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (50 mg, 0.09 mmol), cesium carbonate (512 mg, 1.57 mmol) and 4-amino-l-methylpiperidine (0.13 mL, 1.05 mmol) was heated at 130 0 C for 18 h. The mixture was diluted with dichloromethane, filtered through a pad of celite concentrated in vacuo. Purification by column chromatography, using a gradient of methanol in dichloromethane as the eluent, gave 263 mg (57% yield) of the title compound: MS (ESI) m/z 442 [M+H] + .
Intermediate example 1-16
Amine 5: (35)-iV 5 -(l-Methylpiperidin-4-yl)chromane-3,5-diamine
Palladium on charcoal (10%, 212 mg) and ammonium formate (1.100 g, 17.4 mmol) were added to a solution of (35)-λ/ 3 ,λ/ 3 -Dibenzyl-λ/ 5 -(l-methylpiperidin-4-yl)chromane-3,5- diamine (770 mg, 1.74 mmol) in anhydrous methanol. The mixture was heated at reflux under nitrogen for 20 h. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous ammonia and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to yield (35)-λ/ 5 -(l-methylpiperidin-4-yl)chromane-3, 5 -diamine, 326 mg (72%) 1 R NMR (DMSO-J 6 ) δ 6.83 (t, 1 H), 6.13 (d, 1 H), 6.03 (d, 1 H), 4.27 (d, 1 H), 3.90 - 3.99 (m, 1 H), 3.42 - 3.49 (m, 1 H), 3.11 - 3.23 (m, 1 H), 3.00 - 3.11 (m, 1 H), 2.71 (d, 2 H), 2.61 (dd, 1 H), 2.15 (s, 3 H), 1.93 - 2.08 (m, 2 H), 1.81 - 1.91 (m, 2 H), 1.40 - 1.55 (m, 2 H); MS (ESI) m/z 262 [M+H] + .
Intermediate example 1-21 (3S)-λ /3 r /V 3 -dibenzyl-λ /5 -(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
The title compound was synthesized as described for Intermediate example 1-15 in 61% yield, starting from (35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate and l-(2-aminoethyl)pyrrolidine: MS (ESI) m/z 442 [M+H] + .
Intermediate example 1-22
Amine 7: (3S)-iV 5 -(2-pyrrolidin-l-ylethyl)chromane-3,5-diamine
The title compound was synthesized as described for Intermediate example 1-16 in quantitative yield, starting from (35)-λ/ 3 ,λ/ 3 -dibenzyl-λ/ 5 -(2-pyrrolidin-l-ylethyl)chromane- 3,5-diamine: 1 R NMR (CDCl 3 ) δ 6.96 - 7.08 (m, 1 H), 6.30 (d, 1 H), 6.23 (d, 1 H), 4.04 - 4.14 (m, 1 H), 3.75 (dd, 1 H), 3.33 - 3.45 (m, 1 H), 3.22 (t, 2 H), 2.75 - 2.85 (m, 2 H), 2.70 - 2.78 (m, 1 H), 2.52 - 2.62 (m, 4 H), 2.20 (dd, 1 H), 1.77 - 1.83 (m, 4 H); MS (ESI) m/z 262 [M+H] + .
Intermediate example 1-23
Methyl (3S)-3-(dibenzylamino)chromane-5-carboxylate (35)-3-(Dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (4.0 g, 8.4 mmol) was dissolved in a mixture of dimethylformamide and methanol (6:2, 12 mL) and the flask was subjected to vacuum followed by carbon monoxide twice. Palladium(II) acetate (94 mg, 0.42 mmol), l,3-bis(diphenylphosphino)propane (121 mg, 0.29 mmol) and triethylamine (2.6 mL, 18.5 mmol) were added to the reaction mixture, which was again subjected to vacuum followed by carbon monoxide. The reaction mixture was heated at 70 0 C for 6.5 h, cooled to room temperature, filtered through a pad of celite, rinsed with methanol and concentrated in vacuo. Purification by column chromatography, using a gradient of heptane/ethyl acetate as the eluent, gave 2.66 g (82% yield) of the title compound: 1 R NMR (DMSO-J 6 ) δ 7.35 - 7.43 (m, 5 H), 7.32 (t, 4 H), 7.14 - 7.27 (m, 3 H), 6.98 (dd, 1 H), 4.33 (dd, 1 H), 4.06 (t, 1 H), 3.83 (s, 3 H), 3.68 - 3.80 (m, 4 H), 3.19 (d, 2 H), 2.97 - 3.07 (m, 1 H); MS (ESI) m/z 388 [M+H] + .
Intermediate example 1-24 (3S)-N,λ L Dibenzyl-5-(pyrrolidin-l-ylcarbonyl)chroman-3-amine Trimethylaluminium (2 M in toluene, 2.48 mL, 4.96 mmol) was added to a solution of methyl (35)-3-(dibenzylamino)chromane-5-carboxylate (480 mg, 1.24 mmol) in anhydrous toluene and the reaction mixture was stirred at ambient temperature for 5 min. Pyrrolidine (0.31 mL, 3.72 mmol) was added and the mixture was heated at 80 0 C overnight. The mixture was cooled and quenched with water. The formed precipitate was filtered off and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated in vacuo to give 428 mg (81% yield) of the title compound: MS (ESI) m/z All [M+H] + .
Intermediate example 1-25 (3S)-5-(Pyrrolidin-l-ylcarbonyl)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 73% yield, starting from (35)-N,λ/-dibenzyl-5-(pyrrolidin-l-ylcarbonyl)chroman-3-ami ne: MS (ESI) m/z 247 [M+H] + .
Intermediate example 1-26
Amine 8: (3S)-5-(pyrrolidin-l-ylmethyl)chroman-3-amine Borane in tetrahydrofuran (1 M, 4 mL, 4.0 mmol) was added slowly to a solution of (3S)- 5-(pyrrolidin-l-ylcarbonyl)chroman-3-amine (199 mg, 0.81 mmol) in anhydrous tetrahydrofuran and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with water, acidified using hydrochloric acid (3 M) and the mixture was stirred overnight. The mixture was neutralised with sodium hydroxide (5 M) to pH ~9. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The organic phase was concentrated in vacuo to give 179 mg (95% yield) of the title compound: 1 R NMR (DMSO-J 6 ) δ 7.01 (t, 1 H), 6.83 (d, 1 H), 6.66 (d, 1 H), 4.00 - 4.09 (m, 1 H), 3.42 - 3.56 (m, 3 H), 3.05 - 3.13 (m, 1 H), 2.95 - 3.05 (m, 1 H), 2.40 - 2.47 (m, 4 H), 2.35 - 2.42 (m, 1 H), 1.65 - 1.73 (m, 4 H); MS (ESI) m/z 233 [M+H] + .
Intermediate example 1-27 (2/f)-N r /V-Dibenzyl-8-(2-pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydrona phthalen-2-amine
The title compound was synthesized as described below for Intermediate example 1-47 in 72% yield, starting from (7i?)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l-ol hydrobromide, described in WO9734883A1) and 2-pyrrolidin-l-ylethanol: MS (ES) m/z 441 [M+l] + .
Intermediate example 1-28
Amine 9: (2/?)-8-(2-pyrrolidin-l-ylethoxy)-l,2,3,4-tetrahydronaphthal en-2-amine The title compound was synthesized as described below for Intermediate example 1-16, in quantitative yield, starting from (2i?)-N r /V-dibenzyl-8-(2-pyrrolidin-l-ylethoxy)-l,2,3,4- tetrahydronaphthalen-2-amine: 1 R NMR (CD 3 OD) δ 7.03 (t, 1 H), 6.59 - 6.73 (m, 2 H),
4.00 - 4.18 (m, 2 H), 3.05 - 3.18 (m, 1 H), 2.95 - 3.05 (m, 1 H), 2.91 (t, 2 H), 2.77 - 2.84 (m, 2 H), 2.62 - 2.75 (m, 4 H), 2.19 - 2.31 (m, 1 H), 1.92 - 2.02 (m, 1 H), 1.73 - 1.88 (m, 4 H), 1.43 - 1.58 (m, 1 H); MS (ES) m/z 261 [M+l] + .
Intermediate example 1-30
(3S)-N,λ L Dibenzyl-5-[(4-methylpiperazin-l-yl)carbonyl]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-24 in 92% yield, starting from methyl (35)-3-(dibenzylamino)chromane-5-carboxylate and 1- methylpiperazine: MS (ESI) m/z 456 [M+H] + .
Intermediate example 1-31
Amine 11 : (35)-5- [(4-methylpiperazin-l-yl)carbonyl] chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 70% yield, starting from (35)-N,7V-dibenzyl-5-[(4-methylpiperazin-l-yl)carbonyl]chrom an-3- amine: 1 H NMR (DMSO-J 6 ) δ 7.11 (t, 1 H), 6.77 (d, 1 H), 6.68 (d, 1 H), 4.04 - 4.13 (m, 1 H), 3.50 - 3.69 (m, 4 H), 3.02 - 3.19 (m, 3 H), 2.75 - 2.87 (m, 0.5 H), 2.58 - 2.69 (m, 0.5 H), 2.30 - 2.45 (m, 2 H), 2.22 (br s, 2 H), 2.19 (s, 3 H); MS (ESI) m/z 276 [M+H] + .
Intermediate example 1-32 Amine 12: (3S)-5-[(4-methylpiperazin-l-yl)methyl]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-26 in 86% yield, starting from (35)-5-[(4-methylpiperazin-l-yl)carbonyl]chroman-3-amine: 1 H NMR (CDCl 3 ) δ 7.06 (t, 1 H), 6.85 (d, 1 H), 6.78 (dd, 1 H), 4.11 - 4.18 (m, 1 H), 3.75 - 3.82 (m, 1 H), 3.41 (s, 2 H), 3.28 - 3.41 (m, 1 H), 3.14 (dd, 1 H), 2.58 - 2.67 (m, 1 H), 2.35 - 2.57 (m, 6 H), 2.31 (s, 3 H), 1.65 - 1.75 (m, 2 H); MS (ESI) m/z 262 [M+H] + .
Intermediate example 1-33 (35)-N,iV-Dibenzyl-5-(piperidin-l-ylcarbonyl)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-24 in 90% yield, starting from methyl (35)-3-(dibenzylamino)chromane-5-carboxylate and piperidine: MS (ESI) m/z 441 [M+H] + .
Intermediate example 1-34 (3S)-5-(Piperidin-l-ylcarbonyl)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 89% yield, starting from (35)-N,λ/-dibenzyl-5-(piperidin-l-ylcarbonyl)chroman-3-amin e: MS (ESI) m/z 261 [M+H] + .
Intermediate example 1-35
Amine 13: (3S)-5-(piperidin-l-ylmethyl)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-26 in 90% yield, starting from (35)-5-(piperidin-l-ylcarbonyl)chroman-3-amine: 1 H NMR (CDCl 3 ) δ 7.06 (t, 1 H), 6.87 (d, 1 H), 6.77 (d, 1 H), 4.07 - 4.17 (m, 1 H), 3.79 (dd, 1 H), 3.31 - 3.44 (m, 3 H), 3.15 (dd, 1 H), 2.63 (dd, 1 H), 2.38 (br s, 3 H), 1.60 - 1.76 (m, 3 H), 1.50 - 1.59 (m, 2 H), 1.38 - 1.48 (m, 2 H); MS (ESI) m/z 247 [M+H] + .
Intermediate example 1-36
(2R)-λ L Benzyl-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-λ L [(lS)-l-phenylethyl]- l,2,3,4-tetrahydronaphthalen-2-amine
The title compound was synthesized as described for Intermediate example 1-24 in 48% yield, starting from methyl (7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7,8- tetrahydronaphthalene-1-carboxylate and 1-methylpiperazine : MS (ESI) m/z 482 [M+H] + .
Intermediate example 1-37
Amine 14: (2/?)-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2,3,4- tetrahydronaphthalen-2-amine The title compound was synthesized as described for Intermediate example 1-16 in 62% yield, starting from (2i?)-N-benzyl-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl] -λ/-[(15)- l-phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine: MS (ESI) m/z 288 [M+H] + .
Intermediate example 1-38 (3S)-N,λ L Dibenzyl-5-(piperazin-l-ylcarbonyl)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-24 in 83% yield, starting from methyl (35)-3-(dibenzylamino)chromane-5-carboxylate and piperazine: MS (ESI) m/z 442 [M+H] + .
Intermediate example 1-39
(3S)-N,λ L Dibenzyl-5-(piperazin-l-ylmethyl)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-26 in 88% yield, starting from (35)-N,λ/-dibenzyl-5-(piperazin-l-ylcarbonyl)chroman-3-amin e: MS (ESI) m/z 428 [M+H] + .
Intermediate example 1-40 tert-Butyl 4-{[(3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5- yl]methyl}piperazine-l-carboxylate
(35)-N,λ/-Dibenzyl-5-(piperazin-l-ylmethyl)chroman-3 -amine (408 mg, 0.95 mmol) was treated with di-tert-butyl dicarbonate (208 mg, 0.95 mmol) and triethylamine (0.13 mL, 0.95 mmol) in dichloromethane and the mixture was stirred overnight. The volatiles were removed in vacuo, methanol was added, the solution was filtered and concentrated in vacuo. Purification by column chromatography, using a gradient of heptane in ethyl acetate as the eluent, gave 160 mg (32% yield) of the title compound: MS (ESI) m/z 528 [M+η] + .
Intermediate example 1-41
Amine 15: tert-bntyl 4-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5- yl]methyl}piperazine-l-carboxylate
The title compound was synthesized as described for Intermediate example 1-16 in 77% yield, starting from tert-butyl 4-{[(35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5- yl]methyl}piperazine-l-carboxylate: 1 R NMR (CDCl 3 ) δ 6.89 - 7.13 (m, 1 η), 6.63 - 6.89 (m, 2 η), 4.06 - 4.21 (m, 1 η), 3.73 - 3.84 (m, 1 η), 3.32 - 3.49 (m, 5 η), 3.15 (dd, 0.5 η), 2.89 - 3.01 (m, 0.5 η), 2.75 - 2.90 (m, 1 η), 2.55 - 2.66 (m, 0.5 η), 2.39 - 2.49 (m, 0.5 η), 2.29 - 2.38 (m, 2 η), 1.59 - 1.82 (m, 3 η), 1.40 - 1.52 (m, 9 η); MS (ESI) m/z 348 [M+η] + .
Intermediate example 1-42
Amine 16 : (2R)-5-methyl-8- [(4-methylpiper azin- l-yl)methyl] - 1 ,2,3,4- tetrahydronaphthalen-2-amine
The title compound was synthesized as described for Intermediate example 1-26 in 87% yield, starting from (2R)-5-methyl-8-[(4-methylpiperazin-l-yl)carbonyl]-l,2,3,4- tetrahydronaphthalen-2-amine: MS (ESI) m/z 274 [M+H] + .
Intermediate example 1-47 (3S)-N,λ L Dibenzyl-5-[(l-methylpiperidin-4-yl)oxy]chroman-3-amine l-Methylpiperidin-4-ol (103 mg, 0.90 mmol), triphenylphosphine (199 mg, 0.76 mmol) and diisopropyl azodicarboxylate (0.15 mL, 0.76 mmol) were added to a solution of (3S)- 3-(dibenzylamino)chroman-5-ol (239 mg, 0.69 mmol, described in WO9914212A1) in tetrahydrofuran (10 mL) and the mixture was stirred overnight. Additional amounts of 1- methylpiperidin-4-ol (51 mg, 0.45 mmol), triphenylphosphine (100 mg, 0.38 mmol) and diisopropyl azodicarboxylate (0.075 mL, 0.38 mmol) were added, stirred for another 6 h and concentrated in vacuo. The residue was purified twice by column chromatography, using a gradient of ethyl acetate in heptane followed by a gradient of methanol in dichloromethane as the eluents, to give 167 mg (55% yield) of the title compound: MS (ES) m/z 443 [M+ 1] + .
Intermediate example 1-48
Amine 19: (3S)-5-[(l-methylpiperidin-4-yl)oxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 85% yield, starting from (35)-N,λ/-dibenzyl-5-[(l-methylpiperidin-4-yl)oxy]chroman-3 -amine (167 mg, 0.38 mmol): 1 U NMR (CDCl 3 ) δ 7.00 (t, 1 H), 6.37 - 6.46 (m, 2 H), 4.28 - 4.39 (m, 1 H), 4.04 - 4.10 (m, 1 H), 3.69 - 3.76 (m, 1 H), 3.26 - 3.34 (m, 1 H), 2.92 - 3.02 (m, 1 H), 2.54 - 2.67 (m, 2 H), 2.36 - 2.44 (m, 1 H), 2.29 - 2.36 (m, 2 H), 2.28 (s, 3 H), 1.91 - 2.02 (m, 2 H), 1.78 - 1.90 (m, 2 H); MS (ES) m/z 263 [M+l] + .
Intermediate example 1-49 (3S)-λyV-Dibenzyl-5- [2-(dimethylamino)ethoxy] chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-47 in 37% yield, starting from (35)-3-(dibenzylamino)chroman-5-ol (described in WO9914212A1)
and 2-(dimethylamino)ethanol, but using a large excess (6 equivalents) of each 2- (dimethylamino)ethanol, triphenylphosphine and diisopropyl azodicarboxylate: MS (ES) m/z 417 [M+ 1] + .
Intermediate example 1-50
Amine 20: (3S)-5-[2-(dimethylamino)ethoxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 95% yield, starting from (35)-N,λ/-dibenzyl-5-[2-(dimethylamino)ethoxy]chroman-3-ami ne: 1 H NMR (CD 3 OD) δ 7.02 (t, 1 H), 6.40 - 6.51 (m, 2 H), 4.06 - 4.13 (m, 3 H), 3.67 - 3.74 (m, 1 H), 3.15 - 3.26 (m, 1 H), 2.94 - 3.04 (m, 1 H), 2.77 - 2.83 (m, 2 H), 2.38 - 2.45 (m, 1 H), 2.37 (s, 6 H); MS (ES) m/z 237 [M+l] + .
Intermediate example 1-51 (3S)-N,λ L Dibenzyl-5-(2-pyrrolidin-l-ylethoxy)chroman-3-amine The title compound was synthesized as described for Intermediate example 1-47 in 37% yield, starting from (35)-3-(dibenzylamino)chroman-5-ol (described in WO9914212A1) and 2-pyrrolidin-l-ylethanol but using a large excess (6 equivalents) of each 2-pyrrolidin- 1-ylethanol, triphenylphosphine and diisopropyl azodicarboxylate: MS (ES) m/z 443 [M+l] + .
Intermediate example 1-52
Amine 21: (3S)-5-(2-pyrrolidin-l-ylethoxy)chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 99% yield, starting from (35)-N,λ/-dibenzyl-5-(2-pyrrolidin-l-ylethoxy)chroman-3-ami ne: 1 H NMR (CDCl 3 ) δ 6.98 - 7.05 (m, 1 H), 6.39 - 6.51 (m, 2 H), 4.05 - 4.16 (m, 3 H), 3.66 - 3.75 (m, 1 H), 3.16 - 3.25 (m, 1 H), 2.91 - 3.04 (m, 3 H), 2.66 - 2.76 (m, 4 H), 2.36 - 2.46 (m, 1 H), 1.79 - 1.88 (m, 4 H); MS (ES) m/z 263 [M+l] + .
Intermediate example 1-53 (3S)-N,λ L Dibenzyl-5-[(l-methylpyrrolidin-3-yl)oxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-47 in 51% yield, starting from (35)-3-(dibenzylamino)chroman-5-ol (described in WO9914212A1)
and l-methylpyrrolidin-3-ol but using a large excess (6 equivalents) of each 2-pyrrolidin- 1-ylethanol, triphenylphosphine and diisopropyl azodicarboxylate: MS (ES) m/z 429 [M+l] + .
Intermediate example 1-54
Amine 22: (35)-5-[(l-Methylpyrrolidin-3-yl)oxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 68% yield, starting from (35)-N,λ/-dibenzyl-5-[(l-methylpyrrolidin-3-yl)oxy]chroman- 3-amine: MS (ES) m/z 249 [M+ 1] + .
Intermediate example 1-55
2-{[(7R)-7-(Dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l -yl]oxy}-N,iV- diethylacetamide
The title compound was synthesized as described for Intermediate example 1-47 in 73% yield, starting from (7i?)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l-ol hydrobromide (described in WO9734883A1) and 7V,7V-diethyl-2-hydroxyacetamide: MS (ES) m/z 457 [M+l] + .
Intermediate example 1-56 Amine 23: 2-{[(7R)-7-amino-5,6,7,8-tetrahydronaphthalen-l-yl]oxy}-λyV - diethylacetamide
The title compound was synthesized as described for Intermediate example 1-16 in quantitative yield, starting from 2-{[(7i?)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen- l-yl]oxy}-N,N-diethylacetamide: 1 U NMR (DMSO-J 6 ) δ 6.99 (t, 1 H), 6.59 - 6.69 (m, 2 H), 4.73 (s, 2 H), 3.20 - 3.39 (m, 4 H), 2.89 - 2.99 (m, 2 H), 2.68 - 2.84 (m, 2 H), 2.08 -
2.20 (m, 1 H), 1.78 - 1.89 (m, 1 H), 1.31 - 1.45 (m, 1 H), 1.15 - 1.21 (m, 6 H); MS (ES) m/z 277 [M+l] + .
Intermediate example 1-57 (2/f)-N r /V-Dibenzyl-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahyd ronaphthalen-2- amine
The title compound was synthesized as described for Intermediate example 1-47 in 61% yield, starting from (7i?)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l-ol hydrobromide (described in WO9734883A1) and l-methylpiperidin-4-ol: MS (ES) m/z 441 [M+l] + .
Intermediate example 1-58
Amine 24: (2R)-8-[(l-Methylpiperidin-4-yl)oxy]-l,2,3,4-tetrahydronapht halen-2- amine
The title compound was synthesized as described for Intermediate example 1-16 in 86% yield, starting from (2i?)-7V r /V-dibenzyl-8-[(l-methylpiperidin-4-yl)oxy]-l,2,3,4- tetrahydronaphthalen-2-amine (0.81 g, 1.8 mmol): 1 H NMR (DMSO-J 6 ) δ 6.99 (t, 1 H), 6.73 (d, 1 H), 6.62 (d, 1 H), 4.28 - 4.39 (m, 1 H), 2.85 - 2.98 (m, 2 H), 2.67 - 2.81 (m, 2 H), 2.52 - 2.61 (m, 2 H), 2.04 - 2.26 (m, 6 H), 1.56 - 1.95 (m, 7 H), 1.29 - 1.43 (m, 1 H); MS (ES) m/z 261 [M+ 1] + .
Intermediate example 1-59 (3S)-N,λ L Dibenzyl-5-[(l-methylpiperidin-3-yl)oxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-47 in 48% yield, starting from (35)-3-(dibenzylamino)chroman-5-ol (described in WO9914212A1) and l-methylpiperidin-3-ol but using a large excess (6 equivalents) of each 1- methylpiperidin-3-ol, triphenylphosphine and diisopropyl azodicarboxylate: MS (ES) m/z 443 [M+l] + .
Intermediate example 1-60 Amine 25: (3S)-5-[(l-Methylpiperidin-3-yl)oxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in quantitative yield, starting form (35)-N,7V-dibenzyl-5-[(l-methylpiperidin-3- yl)oxy]chroman-3-amine: MS (ES) m/z 263 [M+l] + .
Intermediate example 1-61
(2R)-N^V-Dibenzyl-8-[2-(dimethylamino)ethoxy]-l,2,3,4-tet rahydronaphthalen-2- amine
The title compound was synthesized as described for Intermediate example 1-47, starting from (7i?)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l-ol hydrobromide (described in WO9734883A1) and 2-(dimethylamino)ethanol: MS (ES) m/z 415 [M+l] + .
Intermediate example 1-62
Amine 26: (2R)-8-[2-(Dimethylamino)ethoxy]-l,2,3,4-tetrahydronaphthale n-2-amine
The title compound was synthesized as described for Intermediate example 1-16, starting from (2i?)-N,N-diberizyl-8-[2-(dimethylamino)ethoxy]-l,2,3,4-tetr ahydronaphthalen-2- amine: 1 H NMR (CD 3 OD) δ 7.03 (t, 1 H), 6.63 - 6.71 (m, 2 H), 4.00 - 4.12 (m, 2 H), 3.06 ■ 3.16 (m, 1 H), 2.96 - 3.06 (m, 1 H), 2.74 - 2.87 (m, 4 H), 2.36 (s, 6 H), 2.21 - 2.31 (m, 1 H), 1.91 - 2.02 (m, 1 H), 1.42 - 1.63 (m, 1 H); MS (ES) m/z 235 [M+l] + .
Intermediate example 1-63 tert-Butyl (2-{[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l- yl]oxy}ethyl)ethylcarbamate
The title compound was synthesized as described for Intermediate example 1-47 in 72% yield, starting from (7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l-ol hydrobromide (described in WO9734883A1) and tert-butyl ethyl(2- hydroxyethyl)carbamate: MS (ES) m/z 515 [M+ 1] + .
Intermediate example 1-64
Amine 27: tert-Buty\ (2-{[(7R)-7-amino-5,6,7,8-tetrahydronaphthalen-l- yl] oxy} ethyl)ethylcarbamate
The title compound was synthesized as described for Intermediate example 1-16 in 72% yield, starting from tert-butyl (2-{[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen- l-yl]oxy}ethyl)ethylcarbamate: 1 U NMR (DMSO-J 6 ) δ 7.01 (t, 1 H), 6.72 (d, 1 H), 6.65 (d, 1 H), 4.19 - 4.27 (m, 1 H), 3.94 - 4.09 (m, 1 H), 3.47 - 3.56 (m, 2 H), 3.28 (q, 2 H), 2.62 - 3.00 (m, 5 H), 2.05 - 2.17 (m, 1 H), 1.31 - 1.45 (m, 10 H), 1.06 (t, 3 H); MS (ES) m/z 335 [M+l] + .
Intermediate example 1-65
(2R)-N,N-Dibenzyl-8-[(l-methylpiperidin-3-yl)oxy]-l,2,3,4 -tetrahydronaphthalen-2- amine
The title compound was synthesized as described for Intermediate example 1-47 in 11% yield, starting form (7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-l-ol hydrobromide (described in WO9734883A1) and l-methylpiperidin-3-ol: MS (ES) m/z 441 [M+l] + .
Intermediate example 1-66
Amine 28: (2R)-8-[(l-Methylpiperidin-3-yl)oxy]-l,2,3,4-tetrahydronapht halen-2- amine
The title compound was synthesized as described for Intermediate example 1-16 in 92% yield, starting from (2R)-N,N-dibenzyl-8-[(l-methylpiperidin-3-yl)oxy]-l,2,3,4- tetrahydronaphthalen-2-amine: MS (ES) m/z 261 [M+l] + .
Intermediate example 1-67 ter^Butyl (2-{[(3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5- yl] oxy} ethyl)ethylcarbamate
The title compound was synthesized as described for Intermediate example 1-47 in 76% yield, starting from (3S)-3-(dibenzylamino)chroman-5-ol (described in WO9914212A1) and tert-butyl ethyl(2-hydroxyethyl)carbamate: MS (ES) m/z 517 [M+ 1] + .
Intermediate example 1-68
Amine 29: tert-Butyl (2-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5- yl] oxy} ethyl)ethylcarbamate The title compound was synthesized as described for Intermediate example 1-16 in 98% yield, starting from tert-butyl (2-{[(3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5- yl]oxy}ethyl)ethylcarbamate: 1 U NMR (DMSO-J 6 ) δ 6.99 (t, 1 H), 6.49 (d, 1 H), 6.38 (d, 1 H), 3.95 - 4.09 (m, 3 H), 3.46 - 3.57 (m, 3 H), 3.27 (q, 2 H), 2.98 - 3.09 (m, 1 H), 2.75 - 2.86 (m, 1 H), 2.12 - 2.23 (m, 1 H), 1.31 - 1.47 (m, 9 H), 1.00 - 1.11 (m, 3 H); MS (ES) m/z 337 [M+l] + .
Intermediate example 1-74
2-[(7R)-7-{Benzyl[(lS)-l-phenylethyl]amino}-4-methyl-5,6, 7,8-tetrahydronaphthalen- l-yl]-2-methylpropanenitrile
Sodium bis(trimethylsilyl) amide (1 M in tetrahydrofuran, 2.6 mL, 2.6 mmol,) was added to a solution of isobutyronitrile (0.21 mL, 2.3 mmol) in toluene (3 mL) under an atmosphere of argon. The mixture was stirred for 10 min at room temperature and added to a stirred suspension of (2i?)-λ/-benzyl-8-bromo-5-methyl-λ/-[(15)-l-phenylethyl]-l ,2,3,4- tetrahydronaphthalen-2-amine (868 mg, 2 mmol), palladium acetate (5 mg, 0.02 mmol), and 2,2'-bis(diphenylphosphino)-l,r-binaphthalene (13 mg, 0.02 mmol) in toluene (2 mL) under an atmosphere of argon. The mixture was heated at 100 0 C overnight and cooled to ambient temperature. Ethyl acetate was added and the organic phase was washed with an aqueous sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate and concentrated. Purification by column chromatography, using, heptane in ethyl acetate (95:5) as the eluent, gave 456 mg, (54% yield) of the title compound: 1 U NMR (CDCl 3 ) δ 7.45 - 7.51 (m, 3 H), 7.44 (s, 1 H), 7.28 - 7.34 (m, 4 H), 7.18 - 7.24 (m, 2 H), 7.04 - 7.08 (m, 1 H), 6.96 - 7.00 (m, 1 H), 4.07 - 4.11 (m, 1 H), 3.98 (d, 1 H), 3.85 (d, 1 H), 3.42 - 3.49 (m, 1 H), 3.06 - 3.15 (m, 1 H), 2.89 - 2.99 (m, 1 H), 2.69 - 2.77 (m, 1 H), 2.48 - 2.60 (m, 1 H), 2.16 (s, 3 H), 1.76 (d, 6 H), 1.66 - 1.73 (m, 1 H), 1.48 (d, 3 H); MS (ESI) m/z 423 [M+H] + .
Intermediate example 1-75
(2R)-8-(2-Amino-l,l-dimethylethyl)-N-benzyl-5-methyl-N-[( lS)-l-phenylethyl]- l,2,3,4-tetrahydronaphthalen-2-amine
A solution of 2-[(7i?)-7-{benzyl[(15)-l-phenylethyl]amino}-4-methyl-5,6,7, 8- tetrahydronaphthalen-l-yl]-2-methylpropanenitrile (1.97 g, 4.7 mmol) in tetrahydrofuran (25 mL) was added to a suspension of lithium aluminium hydride (193 mg, 5.1 mmol) in tetrahydrofuran (25 mL) under an atmosphere of argon. The mixture was heated at reflux for 1 h, while vigorously stirred. The mixture was cooled down to ambient temperature, and cautiously quenched with water (0.160 mL). A solution of sodium hydroxide (15%, 0.160 mL) and water (0.48 mL) was added and the resulting mixture was stirred overnight. The formed precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo, and purified by column chromatography, starting with a gradient of ethyl acetate in heptane and followed by a gradient of chloroform and
chloroform/methanol/ammonia 7 M in methanol (90:9:1) as the eluents, to give 1.5 g (75% yield) of the title compound: 1 U NMR (CDCl 3 ) δ 7.49 (d, 2 H), 7.39 - 7.43 (m, 2 H), 7.28 - 7.37 (m, 4 H), 7.19 - 7.26 (m, 2 H), 7.07 (d, 1 H), 6.92 (d, 1 H), 4.05 (q, 1 H), 3.92 - 3.99 (m, 1 H), 3.78 - 3.85 (m, 1 H), 3.22 - 3.29 (m, 1 H), 3.01 - 3.09 (m, 1 H), 2.90 - 3.01 (m, 2 5 H), 2.63 - 2.74 (m, 2 H), 2.50 - 2.60 (m, 1 H), 2.14 (s, 3 H), 1.56 - 1.74 (m, 2 H), 1.41 (d, 3 H), 1.37 (d, 6 H); MS (ESI) m/z All [M+H] + .
Intermediate example 1-76
(2R)-N-Benzyl-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-m ethyl-N-[(lS)-l-o phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine
Formaldehyde (1 mL, 12 mmol, 37% aqueous solution), and acetic acid (100 μL) were added sequentially to a solution of (2i?)-8-(2-amino-l,l-dimethylethyl)-λ/-benzyl-5- methyl-λ/-[(15)-l-phenylethyl]-l,2,3,4-tetrahydronaphthalen -2-amine (500 mg, 1.2 mmol) in methanol (6 mL). The mixture was stirred for 20 min at ambient temperature, sodiums cyanoborohydride (226 mg, 3.6 mmol) was added in portions and the stirring was continued for 1 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by column chromatography, using a gradient of methanol in chloroform as the eluent, to give0 304 mg (56% yield) of the title compound: 1 H NMR (CDCl 3 ) δ 7.51 (d, 2 H), 7.39 - 7.44 (m, 2 H), 7.28 - 7.37 (m, 4 H), 7.19 - 7.26 (m, 2 H), 7.13 (d, 1 H), 6.91 (d, 1 H), 4.02 - 4.09 (m, 1 H), 3.95 - 4.02 (m, 1 H), 3.79 - 3.85 (m, 1 H), 3.31 - 3.42 (m, 1 H), 2.98 - 3.09 (m, 1 H), 2.52 - 2.74 (m, 4 H), 2.08 - 2.18 (m, 9 H), 1.58 - 1.72 (m, 3 H), 1.37 - 1.47 (m, 9 H); MS (ESI) m/z 455 [M+H] + .5
Intermediate example 1-77
Amine 33: (2/f)-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-methyl-l,2,3 ,4- tetrahydronaphthalen-2-amine
A mixture of (2i?)-N-benzyl-8-[2-(dimethylamino)-l,l-dimethylethyl]-5-met hyl-N-[(15)-l-o phenylethyl]-l,2,3,4-tetrahydronaphthalen-2-amine (304 mg, 0.67 mmol), palladium on charcoal (100 mg, 10%) and ammonium formate (630 mg, 10 mmol) in ethanol (20 mL) was heated at 85 0 C for 1 h. The mixture was cooled down to ambient temperature, filtered
through celite and concentrated. Purification by column chromatography, using a gradient of methanol in chloroform as the eluent afforded 137 mg (78% yield) of the title compound: 1 U NMR (CDCl 3 ) δ 7.19 (d, 1 H), 6.97 (d, 1 H), 3.27 - 3.34 (m, 1 H), 3.09 - 3.18 (m, 1 H), 2.77 - 2.87 (m, 1 H), 2.65 - 2.76 (m, 2 H), 2.61 - 2.65 (m, 2 H), 2.20 (s, 3 H), 2.10 (s, 6 H), 2.01 - 2.09 (m, 1 H), 1.75 (br s, 2 H), 1.53 - 1.64 (m, 1 H), 1.45 (d, 6 H); MS (ESI) m/z 261 [M+H] + .
Intermediate example 1-78 (3S)-5-(2-Amino-l,l-dimethylethoxy)-N,λ L dibenzylchroman-3-amine Lithium aluminium hydride (82 mg, 2.16 mmol) was added to a solution of 2-{[(35)-3- (dibenzylamino)-3,4-dihydro-2H-chromen-5-yl]oxy}-2-methylpro panamide (464 mg, 1.08 mmol, described in WO 9914212) in tetrahydrofuran (5 mL). The reaction mixture was stirred at ambient temperature overnight under an atmosphere of nitrogen. Several drops of sodium hydroxide (2 M) were added, and the resulting suspension was stirred for 45 min. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography, using a gradient of methanol in chloroform as an eluent, to give 155 mg (34% yield) of the title compound: MS (ESI) m/z 417 [M+H] + .
Intermediate example 1-79 tert-Bntyl (2-{[(3S)-3-amino-3,4-dihydro-2H-chromen-5-yl]oxy}-2- methylpropyl)carbamate
Di-tert-butyl dicarbonate (89 mg, 0.41 mmol) was added to a solution of (35)-5-(2-amino- l,l-dimethylethoxy)-7V,7V-dibenzylchroman-3 -amine (155 mg, 0.37 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at ambient temperature overnight under an atmosphere of nitrogen. The volatiles were removed in vacuo. The residue was dissolved in methanol (8 mL), and ammonium formate (466 mg, 7.4 mmol) and palladium on charcoal (10%, 90 mg) were added. The mixture was heated at 45 0 C under an atmosphere of nitrogen for 5 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated to give 122 mg (98% yield) of the title compound: MS (ESI) m/z 337 [M+η] + .
Intermediate example 1-80 tert-buty\ (2-methyl-2- { [(35)-3- { [(5-methyl-2-phenyl-2H- 1 ,2,3-triazol-4- yl)carbonyl]amino}-3,4-dihydro-2H-chromen-5-yl]oxy}propyl)ca rbamate 2-(lη-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (124 mg, 0.33 mmol) was added to a solution of tert-butyl (2-{[(35)-3-amino-3,4-dihydro-2H-chromen-5- yl]oxy}-2-methylpropyl)carbamate (110 mg, 0.33 mmol), 5-methyl-2-phenyl-2H-l,2,3- triazole-4-carboxylic acid (66 mg, 0.33 mmol) and triethylamine (0.14 ml, 0.98 mmol) in acetonitrile (3.5 mL). The reaction mixture was stirred at ambient temperature for 2.5 h and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane yielding 135 mg (79 %) of the titel compound: MS (ESI) m/z 522 [M+H] + .
Intermediate example 1-81
Acid 3: 4-{[(Trifluoromethyl)sulfonyl]oxy}benzoic acid
A suspension of 4-(trifluoromethanesulfonyloxy)benzaldehyde (5.2 g, 20.5 mmol, described in JACS, 1987, 109, 5478) and potassium dichromate (2.5 g) in sulfuric acid (30%, 47 mL) was heated at 65 0 C for 1 h. The mixture was allowed to cool to ambient temperature and then poured on ice. The formed precipitate was filtered off and washed with several portions of water. The crude product was recrystallized from water/ethanol (1:1) affording 2.63 g (47% yield) of the title compound: mp 178-180 0 C; 1 U NMR (DMSO-J 6 ) δ 8.11 (d, 2 H), 7.64 (d, 2 H).
Intermediate example 1-82
(3S)-N,λ L dibenzyl-5-[(l-methyl-lH-imidazol-2-yl)methoxy]chroman-3-ami ne
Diisopropyl azodicarboxylate (0.28 mL, 1.47 mmol) was added dropwise to a solution of (35)-3-(dibenzylamino)chroman-5-ol (423 mg, 1.22 mmol, described in WO9914212A1), (1 -methyl- lη-imidazol-2-yl)methanol (165 mg, 1.47 mmol) and triphenylphosphine (386 mg, 1.47 mmol) in tetrahydrofuran (5 mL) at 50 0 C under an athmosphere of nitrogen. The reaction mixture was stirred at 50 0 C over night. The reaction mixture was partioned between IM sodium hydroxide and ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane yielding 340 mg of the title compound with a impurity of triphenylphosphine; MS (APPI) m/z 440 [M+H + ].
Intermediate example 1-83
Amine 34: (35)-5-[(l-methyl-lH-imidazol-2-yl)methoxy]chroman-3-amine
The title compound was synthesized as described for Intermediate example 1-16 in 9 % yield, starting from (35)-N,N-diberizyl-5-[(l-methyl-lH-imidazol-2-yl)methoxy]chr oman- 3-amine using 59 w% of 10 % palladium on charcoal; 1 H NMR (400 MHz, DMSO-J 6 ) δ ppm 7.18 (s, 1 H), 7.02 (t, 1 H), 6.86 (s, 1 H), 6.72 (d, 1 H), 6.40 (d, 1 H), 5.09 (s, 2 H), 4.02 (d, 1 H), 3.68 (s, 3 H), 3.50 (t, 1 H), 2.99 - 3.09 (m, 1 H), 2.79 (dd, 1 H), 2.18 (dd, 1 H); MS (APPI) m/z 260 [M+H + ]
Intermediate example 1-84 (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl l-methyl-lH-imidazole-4- sulfonate
To a solution of (35)-3-(dibenzylamino)chroman-5-ol (300 mg, 0.87 mmol, described in WO9914212A1) in acetonitrile (10 mL) was triethylamine (0.363 mL, 2.61 mmol) and 1- methyl-lη-imidazole-4-sulfonyl chloride (173 mg, 0.96 mmol) added and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was concentrated in vacuo and purified by column chromatography using a gradient of ethyl acetate in heptane to yield 375 mg (88 %); 1 H NMR (400 MHz, DMSO-J 6 ) δ ppm 8.06 (d, 1 H), 7.93 (d, 1 H), 7.30 - 7.42 (m, 8 H), 7.18 - 7.27 (m, 2 H), 7.06 (t, 1 H), 6.69 (dd, 1 H), 6.62 (dd, 1 H), 4.17 - 4.31 (m, 1 H), 3.97 (t, 1 H), 3.61 - 3.73 (m, 7 H), 2.84 - 2.99 (m, 2 H), 2.63 - 2.75 (m, 1 H); MS (ESI) m/z 490 [M+H + ].
Intermediate example 1-85
Amine 35: (3S)-3-amino-3,4-dihydro-2H-chromen-5-yl l-methyl-lH-imidazole-4- sulfonate The title compound was synthesized as described for Intermediate example 1-16 in 50 % yield, starting from (35)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl 1-methyl-lH- imidazole-4-sulfonate using 20 equiv of ammonium formate; MS (ESI) m/z 310 [M+η + ].
Intermediate example 1-86 tert-butyl [(3S)-5-hydroxy-3,4-dihydro-2H-chromen-3-yl]carbamate
To a solution of (35)-3-(dibenzylamino)chroman-5-ol (1.0 g, 2.89 mmol, described in WO9914212A1) in methanol (40 mL) were added ammonium formate (3.65 g, 57.9 mmol) and 10 % palladium on charcoal (200 mg). The reaction mixture was heated to reflux for 2 h. The reaction mixture was filtered through celite and volatiles were removed by evaporation in vacuo. The crude was dissovled in tetrahydrofuran (20 mL) and water (20 mL) and added di-tert-butyl dicarbonate (0.694 g, 3.18 mmol) and 10 % sodium hydroxide (5 mL). The reaction mixture was stirred at ambient temperature for 7 h. The reaction mixture was partly concentrated in vacuo and added IM hydrochloric acid until a neutral pη was reached. The reaction mixture was extracted with ethyl acetate (3 x 20 mL) dried over sodium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of methanol in dichloromethane to yield 0.482 g (63 %) of the title compound; 1 R NMR (400 MHz, DMSO-J 6 ) δ ppm 9.43 (s, 1 H), 6.96 (d, 1 H), 6.86 (t, 1 H), 6.36 (dd, 1 H), 6.23 (dd, 1 H), 3.98 - 4.09 (m, 1 H), 3.66 - 3.83 (m, 1 H), 3.59 (t, 1 H), 2.78 (dd, 1 H), 2.40 (dd, 1 H), 1.40 (s, 9 H); MS (ESI) m/z 266 [M+H + ], m/z 264 [M-H + ].
Intermediate example 1-87
(3iS)-3-[(tør^butoxycarbonyl)amino]-3,4-dihydro-2H-chrom en-5-yl 2,4-dimethyl-l,3- thiazole-5-sulfonate
The title compound was synthesized as described for Intermediate example 1-84 in 66 % yield, starting from tert-butyl [(35)-5-hydroxy-3,4-dihydro-2H-chromen-3-yl]carbamate and 2,4-dimethyl-l,3-thiazole-5-sulfonyl chloride; MS (ESI) m/z 441 [M+η + ], m/z 439 [M-H + ].
Intermediate example 1-88
Amine 36: (3S)-3-amino-3,4-dihydro-2H-chromen-5-yl 2,4-dimethyl-l,3-thiazole-5- sulfonate
To a solution of (35)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5 -yl 2,4- dimethyl-l,3-thiazole-5-sulfonate (263 mg, 0.42 mmol) in dichloromethane (10 mL) was
trifluoroacetic acid (1 mL) added and the reaction mixture was stirred at ambient temperature for 3.5 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (20 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo to yield the title compound (quantitative); 1 H NMR (400 MHz, DMSO-J 6 ) δ ppm 7.13 (t, 1 H), 6.80 (dd, 1 H), 6.53 (dd, 1 H), 4.04 - 4.10 (m, 1 H), 3.60 - 3.66 (m, 1 H), 3.03 - 3.13 (m, 1 H), 2.76 - 2.85 (m, 1 H), 2.72 (s, 3 H), 2.43 (s, 3 H), 2.22 - 2.32 (m, 1 H); MS (ESI) m/z 341 [M+H + ].
Intermediate example 1-89
(3S)-3-[(fert-butoxycarbonyl)amino]-3,4-dihydro-2H-chrome n-5-yl pyridine-3- sulfonate
The title compound was synthesized as described for Intermediate example 1-84 in 64 % yield, starting from tert-\mϊy\ [(35)-5-hydroxy-3,4-dihydro-2H-chromen-3-yl]carbamate and pyridine-3-sulfonyl chloride hydrochloride; 1 H NMR (400 MHz, DMSO-J 6 ) δ ppm
9.07 (dd, 1 H), 9.01 (dd, 1 H), 8.35 - 8.40 (m, 1 H), 7.76 (dd, 1 H), 7.13 (t, 1 H), 6.96 -
7.08 (m, 1 H), 6.81 (d, 1 H), 6.54 (dd, 1 H), 4.05 - 4.13 (m, 1 H), 3.63 - 3.78 (m, 2 H), 2.78 (dd, 1 H), 2.51 - 2.58 (m, 1 H), 1.40 (s, 9 H); MS (ESI) m/z 407 [M+H + ], m/z 405 [M-H + ].
Intermediate example 1-90
Amine 37: (3S)-3-amino-3,4-dihydro-2H-chromen-5-yl pyridine-3-sulfonate
The title compound was synthesized as described for Intermediate example 1-88 in 93 % yield, starting from (35)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5 -yl pyridine-3-sulfonate; 1 U NMR (400 MHz, DMSO-J 6 ) δ ppm 8.97 - 9.07 (m, 2 H), 8.34 - 8.40 (m, 1 H), 7.73 - 7.79 (m, 1 H), 7.10 (t, 1 H), 6.76 (dd, 1 H), 6.50 (dd, 1 H), 3.99 - 4.08 (m, 1 H), 3.56 (dd, 1 H), 2.96 - 3.06 (m, 1 H), 2.71 - 2.81 (m, 1 H), 2.21 (dd, 1 H), 1.66 (br. s., 2 H); MS (ESI) m/z 407 [M+H + ], m/z 405 [M-H + ].
Intermediate example 1-91 Acid 12: 6-(3,3,3-trifluoropropoxy)nicotinic acid
To a solution of potassium tert-butoxide (0.864g, 7.7 mmol) in tetrahydrofuran (10 mL) 3,3,3-trifluoropropan-l-ol (0.878g, 7.7 mmol) was added at 0 0 C. After 5 min 6-
chloronicotinate (1.3 g, 7.0 mmol) was added to the stirred solution. The mixture was allowed to reach ambient temperature and stirred for additional 2 h. Brine was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue as a yellow oil (1.26g, 4.8 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and water (1 mL) and treated with lithium hydroxide (0.126g, 3.0 mmol). The mixture was stirred at ambient temperature for 16h then the tetrahydrofuran was removed in vacuo. The residue was diluted by water (5 mL) and the pH was adjusted to 2 by 4M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried in vacuo affording the title product as a white solid (0.913g, 81 %). 1 H NMR (400 MHz, DMSO- J 6 ) δ ppm 8.72 (d, 1 H), 8.16 (dd, 1 H), 6.91 (d, 1 H), 4.56 (t, 2 H), 2.81 (dd, 2 H); MS (ESI) m/z 236 [M+H + ].
Biological tests Expression of voltage-gated sodium channel in cell lines:
Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art. The so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.
Li + influx assay
The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells. A suitable Na- free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO4 0.81, CaC12 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 minutes. Then, the Na free buffer is removed and cells are incubated with a buffer rich in LiCl for 60 minutes at 37 0 C. The LiCl buffer is also
enriched in potassium ions, causing a depolarizing stimulus to the cells. Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO4 0.81, CaC12 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. To enhance signal-to-noise ratio, an effective concentration (for example 100 μM) of the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener, may be added to the medium to enhance signal detection. Furthermore, and also to enhance signal-to-noise ratio, an effective concentration (for example 10 μg/ml) of suitable scorpion venom may also be added to the medium to delay channel inactivation. In order to find a modulator of the voltage-gated sodium channel of interest, the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.
The described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format. The described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.
If needed the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-transfection or through establishment of a stable co-transfected cell line. The successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp. A cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.
Whole-cell voltage clamp electrophysiology assay
Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically affect such channels.
Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform. The cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch-clamp platforms. Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms. A suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest. A suitable stimulus protocol may consist of eight voltage pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV, but may also have other suitable parameters.
Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature (26). In this assay, cells that express the human voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.
Example
Title compounds of the above Examples were tested in the Whole-cell voltage clamp electrophysiology assay described above and were found to exhibit IC 50 values oas sown in the table below.