BRICKMANN KAY (SE)
HOLMEN ANDERS (SE)
HOVLAND RAGNAR (SE)
JOHANNESSON PETRA (SE)
MAANSSON AASA (SE)
PLOWRIGHT ALLEYN THOMAS (GB)
SCHNECKE VOLKER (SE)
SOERME PERNILLA (SE)
STAAHLBERG PERNILLA (SE)
WELLNER ERIC (SE)
BLOMBERG DAVID (SE)
BRICKMANN KAY (SE)
HOLMEN ANDERS (SE)
HOVLAND RAGNAR (SE)
JOHANNESSON PETRA (SE)
MAANSSON AASA (SE)
PLOWRIGHT ALLEYN THOMAS (GB)
SCHNECKE VOLKER (SE)
SOERME PERNILLA (SE)
STAAHLBERG PERNILLA (SE)
WELLNER ERIC (SE)
WO2002006245A1 | 2002-01-24 | |||
WO2001002379A1 | 2001-01-11 | |||
WO1997020823A2 | 1997-06-12 |
CLAIMS
1. A compound of formula (I)
R2 and R3 independently represent hydrogen, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl (which alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more halo, OH, cyano, -C(O)NR 8a R 8b , -C(O)OR 9 , aryl, heteroaryl, heterocyclyl); R4 represents hydrogen or Ci-Cβ alkyl which alkyl group is optionally substituted by one or more halo, OH, -C(O) NR R , C1-C4 alkoxy optionally substituted by one or more halo;
R5 represents hydrogen or Q-Cg alkyl which alkyl group is optionally substituted by one or more halo, OH, -C(O) NR R , C1-C4 alkoxy optionally substituted by one or more halo;
E represents Ci-alkylene;
n is an integer of O or 1 ;
L represents C(O) or SO2;
Z represents aryl, heteroaryl, heterocyclyl, which groups are optionally substituted by one or more groups independently selected from any of A), B) and C) as defined;
A) halo, -NR 12 C(O)R 13 , -NR 14 C(O)N(R 15a )(R 15b ), -N(R 15 ^)(R 15b )
B) Ci-Cg alkyl, Ci-Cg alkoxy, (which alkyl and alkoxy groups are optionally substituted by halo, OH, -N(R )(R ), heterocyclyl, heteroaryl (which heterocyclyl, heteroaryl groups are optionally substituted by OH, oxo, Q-Cβ alkyl, C(O)R ));
C) C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, -(0)o or iaryl, -(0)o or 1- heteroaryl, which cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl groups (group C) are optionally substituted by one or more groups independently selected from any of a), b) and c) as defined:
a) halo, -OH, oxo, cyano, -C(O)N(R 18 ^(R 1 % -N(R 19 ^(R 1 % ), -SR 2 °, -OR 20a ,
-N(R 21 )C(O)R 22 , -SO 2 (R 23 ), -N(R 24 )(CHR 25 ) m N(R 26a )(R 26b ) or C(O)R 38 ;
b) Ci-Cβ alkyl, Ci-Cβ alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl (which alkyl, alkoxy, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more halo, -OH, cyano, N(R 27a )(R 27b ), -N(R 28 )SO ( i_ 2) (R 29 ), -N(R 3 °)C(O)R 31 , -N(R 32 )C(O)N(R 33a )(R 33b ), -N(R 3 V(O)OR 35 , -S0 ( i_ 2) (R 36 ), -C(O)OR 37 , -C(O)R 38 , -C(O)N(R 39a )(R 39b ), heterocyclyl (optionally substituted by C x -C 4 alkyl,
C1-C4 alkoxy, oxo, hydroxy, carboxy, amino, Ci-Cόalkylamino, di(Ci-C6alkyl)amino in which the alkyl groups may be the same or different,));
c) aryl, heteroaryl, heterocyclyl (which aryl, heteroaryl, heterocyclyl are optionally
4ω 41 a 41 h 49a 49h 43 substituted by -OH, -C(O)R , -C(O)N(R )(R ), oxo, -N(R 1(R ), -0(R ), Ci- Cg alkyl, Ci-Cg alkoxy (which alkyl and alkoxy groups are optionally substituted by halo, -OH));
R represents Q-C 6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl (which groups are optionally substituted by one or more of -OH, halo, cyano,
44 45a 45b 44 40
Ci-C 6 alkyl, Q-C 6 alkoxy, oxo, -NR C(O)N(R )(R ), -NR C(O)(R ), heterocyclyl or heteroaryl (which heterocyclyl or heteroaryl groups are optionally substituted by Q-C4 alkyl, oxo));
7a 7b 8a 8b 10a 10b 11a lib 15a 15b 16a 16b 18a 18b 19a Jv , Jv , Jv , Jv , Jv , Jv , Jv , Jv , jv , jv , jv , jv , jv , jv , jv ,
19b 26a 26b 27a 27b 33a 33b 39a 39b 41a 41b 42a 42b 45a 45b
JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV ,
R , R independently represent hydrogen, heterocyclyl or a Ci-C 6 alkyl optionally substituted by OH, halo, C1-C4 alkoxy, cyano, amino, Ci-Cόalkylamino, di(Ci-
C6alkyl)amino in which the alkyl groups may be the same or different, heterocyclyl or heteroaryl (which heterocyclyl and heteroaryl groups are optionally substituted by OH, halo, C1-C4 alkyl, Q-C4 alkoxy),
9 13 17 20 21 22 24 25 31 34 35 37 38 40 R , R , R , R , R , R , R , R , R , R R , R , R , R independently represent hydrogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy (which alkyl and alkyloxy are optionally substituted by halo, OH, cyano, C(O)NH 2 );
12 14 28 30 32 34 44 R ,R ,R ,R ,R ,R ,R represents hydrogen, Ci-C 6 alkyl (which alkyl is optionally substituted by halo, OH, cyano, C(O)NH 2 );
R 20a represents phenyl(CH2)o-4-0- in which the phenyl is optionally substituted by halo, Ci-C 6 alkyl or Ci-C 6 alkoxy (which alkyl and alkoxy are optionally substituted by halo); R 23 , R 29 , R 36 represent -N(R 46a )(R 46b ), Ci-C 6 alkyl, Ci-C 6 alkoxy (which alkyl and alkoxy are optionally substituted by halo, OH, cyano, C(O)NH^);
43 R represents heteroaryl, heterocyclyl; m is an integer of O, 1, 2, 3, 4, 5 or 6;
with the proviso that the compound is not:
a) 1. tert-Butyl [(4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate;
2. tert-Butyl [(/rafts-4-{[(2-naphthylsulfonyl)amino]methyl} cyclohexyl)methyl] carbamate;
3. tert-Butyl( {trans-4-[( { [2-trifluoromethyl)phenyl]sulfonyl} amino)methyl] cyclohexyl)methyl)carbamate; or
b)
1. tert-Butyl [(/rafts-4-{[(l-naphthylsulfonyl)amino]methyl} cyclohexyl)methyl] carbamate 2. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-4- fiuorobenzamide
3. 2-Fluoro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
4. 2-Fluoro-iV- { [4-( { [(2-methoxypropyl)carbamoyl]amino } methyl) cyclohexyl]methyl}benzamide
5. 3,4-Dimethoxy-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzenesulfonamide
6. 3-Methyl-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino)methyl] cyclohexyl}methyl)benzamide; 7. 6-Chloro-λf-{[4-({[(4-fluorobenzyl)carbamoyl] amino} methyl) cyclohexyl] methyl } nicotinamide ;
8. 6-Chloro-λf-{[4-({[(2-methoxyethyl)carbamoyl] amino} me thyl)cyclohexyl] methyl } nicotinamide ;
9. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzamide; 10. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino]methyl}cyclohexyl)methyl] benzamide;
11. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzenesulfonamide;
12. N- [(4- { [(Benzylcarbamoyl)amino]methyl} cyclohexyl)methyl] -4- methylbenzenesulfonamide;
13. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-4- methylbenzenesulfonamide;
14. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzenesulfonamide; 15. 4-Methyl-iV- { [4-( { [(4-methylbenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzenesulfonamide:
16. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-3,4- dimethoxybenzenesulfonamide;
17. 3,4-Dimethoxy-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzenesulfonamide;
18. 4-Methyl-iV- { [4-( { [(4-methylbenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
19. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-4- fluorobenzamide 20. 4-Chloro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzamide
21. 2-Fluoro-iV-( {4-[( { [2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl] cyclohexyl}methyl)benzamide
22. 4-Nitro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino)methyl] cyclohexyl}methyl)benzamide
23. N-{[4-({[(4-Fluorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-3- methylbenzamide
24. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzamide
25. 2,3-Dichloro-N-({4-[({[2- (trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}methyl)benzamide 26. 4-Chloro-.V-{[4-({[(3- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide
27. 6-Chloro-.V-{[4-({[(2- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} nicotinamide
28. 2,3-Dichloro-N-{[4- ({[(cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzamide
29. 6-Chloro-.V-[(4- {[(propylcarbamoyl)amino]methyl}cyclohexyl)methyl]nicotinamide
30. 6-Chloro-.V-[(4- {[(isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]nicotinamide 31. 2-Fluoro-N-{[4-({[(4- fluorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide
32. 3-Cyano-N-({4-[({[2- (trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}methyl)benzamide
33. 4-Fluoro-N-{[4-({[(4- fluorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide;
34. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-2- fluorobenzamide;
35. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzamide; 36. 2,3-Dichloro-N-{[4-({[(4- methylbenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzamide;
37. N-({4-[({[2- (Trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}methyl)nicotinamide;
38. N-{[4-({[(2-Methoxyethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-3- methylbenzamide;
39. 3-Methyl-N-{[4-({[(2- phenylethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzamide;
40. 2,3-Dichloro-N-{[4-({[(2- methoxyethyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide;
41. 4-Fluoro-λ4(4-
{ [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide; 42. ^-{^-({[(S-Methoxypropy^carbamoy^aminolmethy^cyclohexy^methyl}^- methylbenzamide;
43. 6-Chloro-iV-( {4-[( {[2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl] cyclohexyl}methyl)nicotinamide;
44. 3 -Cyano-N- { [4-( { [(cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
45. 3 -Methyl-iV- [(4- { [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl] benzamide;
46. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide; 47. 3-Cyano-N-{[4-({[(2- methoxyethyl)carbamoyl] amino } me thyl)cyclohexyl]methyl} benzamide;
48. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-4- fluorobenzamide;
49. 4-Fluoro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzamide;
50. 4-Methoxy-λf-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)methyl] benzamide;
51. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methoxybenzamide; 52. 2,3-Dichloro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl] benzamide;
53. 2-Fluoro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl] benzamide;
54. 6-Chloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cyclohexyl] methyl}nicotinamide;
55. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4-chlorobenzamide
56. 2,3-Dichloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzamide
57. 4-Fluoro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino)methyl] cyclohexyl}methyl)benzamide 58. 6-Chloro-N-{[4-({[(cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexyl] methyl}nicotinamide
59. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -4- methoxybenzamide
60. 3-Cyano-iV-[(4- {[(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide 61. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-3- methylbenzamide
62. 2,3 -Dichloro-iV- { [4-( { [(3 -chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
63. tert-BvXyl ({4-[({[3'-({ [2-(4-hydroxyphenyl)ethyl]amino } methyl)biphenyl-3 - yljcarbonyl} amino)methyl]cyclohexyl}methyl)carbamate;
64. te/t-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl] carbamate;
65. 3-Chloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl] methyl} -4-fluorobenzenesulfonamide 66. 2,3-Dichloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl] methyl}benzamide
67. 2,3-Dichloro-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)methyl] benzamide
68. 4-Chloro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
69. 3-Chloro-4-fluoro-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl) cyclohexyl]methyl}benzenesulfonamide;
70. N-[(?rfl«5 f -4-{[(Benzylcarbamoyl)(isopropyl)amino]methyl}cyclohexyl) methyljbenzenesulfonamide 71. te/t-Butyl [(4-{[(l-Naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]carbamate
72. tert-BvXy\ [(?rα«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl) methyl] carbamate
73. tert-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl) methyl] carbamate
74. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -3 - fluorobenzamide 75. 2-Fluoro-iV-{[4-({ [(3 -methoxypropyl)carbamoyl] amino} methyl) cyclohexyl] methyl}benzamide
76. 2-Fluoro-N-[[4-[[[[(2-methoxyethyl)amino]carbonyl]amino]methyl] cyclohexyl]methyl] benzamide
77. 3 ,4-Dimethoxy-iV- { [4-( { [(4-methylbenzyl)carbamoyl]amino } methyl) cyclohexyl]methyl}benzenesulfonamide
78. 3 -Methyl-iV-( {4- [( { [2-(trifluoromethyl)benzyl] carbamoyl} amino) methyl]cyclohexyl}methyl)benzamide
79. 6-Chloro-iV- {[4-({[(4-fluorobenzyl)carbamoyl] amino} methyl) cyclohexyl]methyl}nicotinamide 80. 6-Chloro-iV- {[4-({[(2-methoxyethyl)carbamoyl] amino} methyl) cyclohexyl]methyl}nicotinamide
81. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl]methyl}benzamide
82. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino] methyl} cyclohexyl) methyljbenzamide
83. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl]methyl}benzenesulfonamide
84. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzenesulfonamide 85. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-4- methylbenzenesulfonamide
86. 4-Methyl-iV-{[4-({[(2- phenylethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzenesulfonamide
87. 4-Methyl-.V-{[4-({[(4- methylbenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzenesulfonamide
88. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-3,4- dimethoxybenzenesulfonamide
89. 3, 4-Dimethoxy-iV-{[4-({ [(2 -phenylethyl)carbamoyl] amino} methyl) cyclo- hexyl]methyl}benzenesulfonamide.
2. A compound according to claim 1 wherein L represents C(O).
3. A compound according to claim 1 wherein n is 1.
4. A compound according to any of claims 1 to 3 wherein Z represents
D represents N or C, optionally substituted by hydrogen, halo, Q-C4 alkyl, aryl, NR 47 C(O)R 48 ;
R x and R z independently represent hydrogen, halo, -OH, -OR , -SR , -N(R )(R ), aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, heteroaryl,
(which aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups are optionally substituted by one or more groups of the following halo, OH, oxo, -C(O)N(R )(R ), - OR 53 , -SR 54 , -C(O)OR 55 , cyano, -N(R 56 )C(O)OR 5? , - N(R 56 )C(O)N(R 52a )(R 52b ), . N(R 56 )S(O) 2 R 60 , -S(O) 2 N(R 52a )(R 52 \ -N(R 56 )(CHR 58 ) m N(R 52a )(R 52b ), -N(R 52a )(R 52b ), -C(O)R 59 , -N(R 5 V(O)R 59 , -N(R 56 )(CHR 58 ) m OR 55 ,
-N(R 56 )(CHR 58 ) m C(O)N(R 52a )(R 52b ), -N(R 56 )(CHR 58 ) m C(O)O(R 5? ), -S(O) ( i_ 2) R 60 , heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more of the following -OH, oxo, -C(O)R 61 , -C(O)N(R 62a )(R 62b ), C1-C4 alkyl
(which alkyl is optionally substituted by OH)), Ci-Cβ alkyl, Ci-Cβ alkoxy (which alkyl and alkoxy groups are optionally substituted by one or more of the following -OH, halo, - N(R 63a )(R 63b ), -C(O)OR 64 , N(R 6 V(O)OR 64 , -N(R 65 )C(O)R 66 , -
N(R 65 )C(O)N(R 63a )(R 63b ), -N(R 65 )S(O) ( i_2)(R 66 ), -C(O)N(R 63a )(R 63b ), heterocyclyl, heteroaryl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more Ci-C 4 alkyl, oxo, -C(O)R 67 ));
Ry represents hydrogen, halo, Q-Cg alkyl, Q-Cg alkoxy;
Ry and R z may together with the carbon atoms to which they are attached represent a benzene ring;
wherein
51a 51b 52a 52b .,62a 62b .,63a 63b . R , R , R , R , R , R , R , R independently represent hydrogen, Ci-Cg alkyl (optionally substituted by one or more OH, halo, heteroaryl (which heteroaryl optionally is substituted by one or more C1-C4 alkyl or C1-C4 alkoxy));
R , R , R , R , R , R , R independently represent Ci -Cβ alkyl, optionally substituted by one or more OH, halo, heteroaryl, heterocyclyl, which groups optionally are substituted by one or more Ci-Cg alkyl, OH;
R , R , R , R , R , R , R , R independently represent hydrogen, Ci -Cβ alkyl, optionally substituted by one or more OH, halo, heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups optionally are substituted by one or more Q-Cβ alkyl, OH;
R , R , R independently represent hydrogen, Ci -Cβ alkyl (optionally substituted by one or more OH, halo); 49 53 R , R independently represent C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heteroaryl, heterocyclyc, Ci-Cg alkyl (which alkyl is optionally substituted by one or more OH, halo, N(R )(R ), heteroaryl, heterocyclyl (which heteroaryl and heterocyclyl groups optionally are substituted by one or more OH, oxo, Ci-Cg alkyl, Ci-Cg alkoxy, - C(O)R 66 ));
m is an integer of O, 1, 2, 3, 4, 5, 6.
5. A compound according to any of claims 1 to 4 wherein R z represents hydrogen, halo, Q-Cg alkyl, Ci-Cg alkoxy, aryl or heteroaryl (which aryl and heteroaryl groups are optionally substituted by one or more of -OH, halo, cyano, amino, Ci-Cg alkyl, Ci-Cg alkoxy, oxo, -NR 56 C(O)R 59 ).
6. A compound according to any of claims 1 to 5 wherein Ri represents -OR .
7. A compound according to any of claims 1 to 6 wherein Z represents
D represents N or C, optionally substituted by hydrogen, halo, Q-C4 alkyl, aryl;
R X represents hydrogen, halo, -OR 68 , -SR 69 , -N(R 7 °)C(O)R 71 , -N(R 72a )(R ?2b ) aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, heteroaryl, (which aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl groups are optionally substituted by one or more groups selected from halo, OH, oxo, -C(O)N(R )(R ),
OR 74 , -SR 75 , -C(O)OR 76 , cyano, -N(R 7? )C(O)OR 78 , - N(R 77 )C(O)N(R 73a )(R ?3b ), -N(R 77 )S(O) (1-2) R 78 , -N(R 77 )(CHR 79 ) m N(R 73a )(R 73b ), -N(R 73a )(R 73b ), -C(O)R 80 , - N(R 77 )C(O)R 80 , -N(R 7? )(CHR 79 ) m OR 79 , -N(R 7? )(CHR 79 ) m OH,
-N(R 77 )(CHR 79 ) m C(O)N(R 73a )(R 73b ), -N(R 77 )(CHR 79 ) m C(O)O(R 76 ), -N(R 77 )C(O)R 8 °,
-S(O) ( i_ 2) R 78 , -S(O) (i-2)N(R 73a )(R 73b ), heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more of the following OH, oxo, C(O)R 81 , C(O)N(R 82a )(R 82b ), -N(R 82a )(R 82b ), C1-C4 alkyl, C1-C4 alkoxy (which alkyl or alkoxy is optionally substituted by one or more OH, -N(R 82a )(R 82b ))),
C1-C6 alkyl, Q-Cβ alkoxy (which alkyl and alkoxy groups are optionally substituted by one or more of the following -OH, halo, -C(O)OR 83 , -N(R 84a )(R 84b ), -N(R 85 )C(O)OR 83 , -N(R 8 V(O)R 86 , -N(R 85 )C(O)N(R 84a )(R 84b ), -N(R 85 )S(O)(i-2)R 87 , - C(O)N(R )(R ), heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more Q-C4 alkyl, oxo, -C(O)R )),
.,72a 72b .,73a 73b 82a 82b .,84a 84b .
R , R , R , R , R , R , R , R independently represent hydrogen, Ci-Cg alkyl (optionally substituted by one or more OH, halo, heteroaryl (which heteroaryl optionally is substituted by one or more Q-C4 alkyl));
R , R , R , R , R , R independently represent C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heteroaryl, heterocyclyl, Ci-Cβ alkyl (which groups are optionally substituted by one or more OH, halo, -N(R )(R ),heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups optionally are substituted by one or more OH, oxo, Q-Cg
89 alkyl, Ci-C 6 alkoxy, C(O)R ));
R , R , R , R , R , R , R , R , R , R , R independently represent hydrogen,
Ci-C 6 alkyl, optionally substituted by one or more OH, halo, heteroaryl, heterocyclyl
89 (which groups optionally are substituted by one or more OH, Ci-C 6 alkyl, C(O)R );
R , R , R independently represent hydrogen, Ci-C 6 alkyl (optionally substituted by one or more OH, halo);
m is an integer of O, 1, 2, 3, 4, 5 or 6.
8. A compound according to any of claims 4 or 7 wherein D represent N.
9. A compound according to claim 1 as represented by formula II
or a pharmaceutically acceptable salt thereof in which Ri, R 2 , R 3 and R 4 are as defined in claim 1 and Rx represents a group a), b) or c): a)
10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R x represents group a) in which Li represents a Ci alkylene chain, and both R 90 and R 91 represent H, or wherein R x represents group b) , in which R 9 2 represents a group -L 2 -L 3 -NR 93 R 94 in which L 2 is O or N, L 3 is a C2-C3 alkylene chain, and R 93 and R 94 both represent H, or wherein or R 9 2 represents piperidino, morpholino or piperazino each of which is optionally substituted by one or more of the following: hydroxy, a Ci alkyl, Ci alkoxy or a Ci alkanoyl, or wherein R x represents group c) in which L 4 is a C2-C3 alkylene chain, which chain is optionally substituted by hydroxy provided that no carbon atom in the chain is attached to two hetero atom (that is O or N) and R 95 and R 96 independently C1-C2 alkyl optionally substituted by hydroxy, or
R 95 and R 96 together with the nitrogen atom to which they are attached represent azetidino which is optionally substituted by a hydroxy.
11. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ri represents -OR ,
R2 and R3 independently represent hydrogen or Q-Cβ alkyl,
R4 represents hydrogen or Q-Cg alkyl,
R5 represents hydrogen or Q-Cg alkyl, and
R represents C3-C5 alkyl. 12. A compound selected from one or more of the following compounds:
1. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)me thy 1] carbamate
2. tert-Butyl ({?rα«5 f -4-[({[2-(2-methyl-6-oxo-l,6-dihydropyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate 3. tert-Butyl {[?rα«5 f -4-({[(2-pyrazin-2-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
4. tert-Butyl ({traws-4-[({[2-(4-ethoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
5. tert-Butyl ({?rα«5 f -4-[({[2-(6-carbamoylpyridin-3-yl)quinolin-4- yljcarbonyl} amino)-methyl]cyclohexyl}methyl)carbamate
6. tert-Butyl {[?rα«5 f -4-({[(2-phenylquinolin-4-yl)carbonyl]amino}methyl)- cyclohexyl] -methyl} carbamate
7. tert-Butyl { [trans-4-( { [(2-pyridin-4-ylquinolin-4-yl)carbonyl] amino } methyl)- cyclohexyl]methyl} carbamate 8. tert-Butyl ({?rα«5 f -4-[({[2-(3-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
9. tert-Butyl ({?rα«5 f -4-[({[2-(4-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
10. tert-Butyl {[?ra«5 f -4-({[(2-{6-[3-(dimethylamino)propoxy]pyridin-3- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
11. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(dimethylamino)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
12. tert-Butyl [(trans-4- {[({2-[4-(trifluoromethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
13. tert-Butyl ({traws-4-[({[2-(5-acetyl-2-thienyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 14. tert-Butyl ({tra«5 ι -4-[({[2-(4-fluorophenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
15. tert-Butyl ({trfl«5 f -4-[({[2-(3,5-dimethylisoxazol-4-yl)quinolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate
16. tert-Butyl {[trfl«5 f -4-({[(2-pyridin-3-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
17. Ethyl ({tra«s-4-[({[2-(4-fluorophenyl)quinolin-4- yl]carbonyl}amino)methyl]cyclo-hexyl}methyl)carbamate
18. Ethyl [(trfl«5 f -4-{[({2-[4-(dimethylcarbamoyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate 19. Ethyl ({trafts-4-[({[2-(3-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
20. tert-Butyl ({tra«s-4-[({[2-(4-methylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
21. tert-Butyl ({traws-4-[({[2-(4-chlorophenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
22. tert-Butyl ({trfl«5 f -4-[({[2-(3-methoxyphenyl)quinolin-4-yl]carbonyl}amino)- methyl]cyclohexyl}methyl)carbamate
23. tert-Butyl ( {trans-4-[( { [2-(2-methoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 24. tert-Butyl [(tra«5'-4-{[({2-[4-(methylthio)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
25. tert-Butyl ( {trans-4-[( {[2-(2,4-dimethyl- 1 ,3-thiazol-5-yl)quinolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate
26. Ethyl {[trfl«5 f -4-({[(2-pyrazin-2-ylquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
27. Ethyl ({trα«5 f -4-[({[2-(3-methoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
28. Ethyl ({trans-4-[( { [2-(4-methylphenyl)quinolin-4- yl]carbonyl}amino)methyl]cyclo-hexyl}methyl)carbamate
29. Ethyl [(?ra«5-4-{[({2-[4-(methylthio)phenyl]quinolin-4- yl} carbonyl)amino]methyl} -cyclohexyl)methyl] carbamate 30. Ethyl ({?rfl«5 f -4-[({[2-(4-ethoxyphenyl)quinolin-4-yl]carbonyl}amino)methyl]- cyclohexyl}methyl)carbamate
31. Ethyl ( {trans-4-[( { [2-(2-methoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
32. Ethyl ({zrø«s-4-[({[2-(4-chlorophenyl)quinolin-4- yljcarbonyl} amino)methyl]cyclo-hexyl}methyl)carbamate
33. tert-Butyl {[?rfl«5 f -4-({[(2-pyrimidin-5-ylquinolin-4- yl)carbonyl]amino}methyl)-cyclohexyl]methyl} carbamate
34. tert-Butyl ({?rα«5 f -4-[({[2-(4-cyanophenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 35. tert-Butyl {[?rα«5 f -4-({[(2-chloroquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
36. tert-Butyl ( {trans-4-[( {2-[4-(aminomethyl)phenyl]-6-methoxyisonicotinoyl} - amino)methyl]cyclohexyl}methyl)carbamate
37. tert-Butyl ({?ra«5'-4-[({2-[4-(aminomethyl)phenyl]-5- chloroisonicotinoyl}amino)-methyl]cyclohexyl}methyl)carbamate
38. tert-Butyl ({?ra«5'-4-[({2-[4-(aminomethyl)phenyl]-6- methylisonicotinoyl}amino)-methyl]cyclohexyl}methyl)carbamate
39. tert-Butyl [(trans-4- {[({2-[3-(aminomethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate 40. [3-(4-{[(?rα«5 f -4-{[(?ert-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl} quinolin-2-yl)phenyl] acetic acid
41. tert-Butyl [(trans-4- { [(2- phenylisonicotinoyl)amino]methyl}cyclohexyl)methyl]-carbamate
42. tert-Butyl {[trans-4-({[2-(4- methoxypheny^isonicotinoy^aminolmethy^cyclo-hexy^methyl} carbamate
43. tert-Butyl [(tra«^-4-{[(2-methyl-6- phenylisonicotinoyl)amino]methyl}cyclohexyl)-methyl]carbamate
44. tert-Butyl {[/r<røs-4-({[(5-phenylpyridin-3- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
45. tert-Butyl {[/r<røs-4-({[2-(l-benzothiophen-2- yl)isonicotinoyl]amino}methyl)cyclo-hexyl]methyl} carbamate 46. tert-Butyl {[/r<røs-4-({[(6'-ethoxy-2,3'-bipyridin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
47. tert-Butyl {[trans -4-({[2-(2, 4- dimethoxypheny^isonicotinoy^aminolmethy^cyclo-hexy^methyl} carbamate
48. tert-Butyl {[?ra«5-4-({[(2',6'-dimethoxy-2,3'-bipyridin-4- yl)carbonyl]amino}methyl)-cyclohexyl]methyl} carbamate
49. tert-Butyl {[tra«5 ι -4-({[(6'-methoxy-2,3'-bipyridin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
50. tert-Butyl {[trans -4-({[2-(4- carbamoylphenyl)isonicotinoyl]amino}methyl)cyclohexyl] methyl} carbamate 51. tert-Butyl {[tr<ms-4-({[2-(3- chlorophenyl)isonicotinoyl] amino } methyl)cyclohexyl] -methyl} carbamate
52. tert-Butyl ({tr<ms-4-[({2-[4- (aminomethyl)phenyl]isonicotinoyl}amino)methyl]cyclo-hexyl}methyl)carbamate
53. tert-Butyl {[trans -4-({[2-(3, 4- difluorophenyl)isonicotinoyl]amino}methyl)cyclohexyl]-methyl} carbamate
54. Ethyl [(trans -4- {[(2- naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]carbamate
55. 2,2-Dimethylpropyl {[?ra«5'-4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)-cyclohexyl]methyl} carbamate 56. Cyclopentyl {[zrøfts-4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
57. Isopropyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
58. Propyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
59. 2-Methoxyethyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}- methyl)cyclohexyl]methyl} carbamate
60. Ethyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)cyclo- hexyl]methyl} carbamate
61. Ethyl ( {trans-4-[( { [2-(4-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 62. Ethyl {[£rafts-4-({[(2-phenylquinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} -carbamate
63. tert-Butyl [(tr<røs-4-{[(biphenyl-3- ylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
64. tert-Butyl {[trans -4-( {[(3,4- dibromophenyl)sulfonyl]amino}methyl)cyclohexyl]-methyl} carbamate
65. tert-Butyl {[trans-4-({[(3,4- dichloropheny^sulfonyljaminolmethy^cyclohexy^methyl} -carbamate
66. tert-Butyl [(trans-4-{[(qainolin-8- ylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate 67. tert-Butyl [(trans-4-{[(bvphQnyl-4- ylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
68. tert-Butyl {[tr<ms-4-({[(4- isopropylphenyl)sulfonyl] amino } methyl)cyclohexyl] -methyl} carbamate
69. tert-Butyl [(traws-4-{[(2,3-dihydro-l,4-berizodioxin-6- ylsulfonyl)amino]methyl} cyclo-hexyl)methyl] carbamate
70. tert-Butyl ({tra«s-4-[({[5-(2-methyl-l,3-thiazol-4-yl)-2- thienyl]sulfonyl}amino)-methyl]cyclohexyl}methyl)carbamate
71. tert-Butyl {[?rara-4-({[(5-acetamido-l- naphthyl)sulfonyl]amino}methyl)cyclohexyl]-methyl} carbamate 72. tert-Butyl {[?ra«5 f -4-({[(5-isoxazol-5-yl-2- thienyl)sulfonyl] amino } me thy l)cyclo-hexyl]methyl} carbamate
73. tert-Butyl {[tra«^-4-({[(4- acetamidopheny^sulfonyljaminolmethy^cyclohexy^-methyl} carbamate
74. tert-Butyl [(?rα«5 f -4-{[(3-thienylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate
75. tert-Butyl ({tra«s-4-[({[3-(5-methyl-l,2,4-oxadiazol-3- y l)pheny 1] sulfony 1 } amino)-methy 1] cy clohexy 1 } methy l)carb amate
76. tert-Butyl [(?rfl«5 f -4-{[(isoquinolin-5-ylsulfonyl)amino]methyl}cyclohexyl)- methyl] carbamate
77. tert-Butyl {[tra«^-4-({[(4-acetamido-2-methyl-l,3-thiazol-5- yl)sulfonyl] amino} -methyl)cyclohexyl]methyl} carbamate 78. tert-Butyl [(tra«s-4-{[(l,3-benzothiazol-6- ylsulfonyl)amino]methyl}cyclohexyl)-methyl]carbamate
79. tert-Butyl [(tra«s-4-{[ethyl(2- naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
80. tert-Butyl [(tra«s-4-{[(2-naphthylsulfonyl)(2- phenylethyl)amino]methyl} cyclohexy l)-me thy 1] carbamate
81. Ethyl N-[(trans-4- {[(tert-butoxycarbonyl)ammo]methyl}cyclohexyl)methyl]- jV-(2-naphthylsulfbnyl)glycinate
82. tert-Butyl [(trans-4- { [(2-naphthylsulfonyl)(tetrahydro-2H-pyran-4- ylmethyl)amino]-methyl}cyclohexyl)methyl]carbamate 83. tert-Butyl [(trans-4-{ [(cyanomethyl)(2- naphthylsulfonyl)amino]methyl}cyclohexyl)-methyl]carbamate
84. tert-Butyl [(tra«^-4-{[allyl(2- naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
85. tert-Butyl [(tra«s-4-{[butyl(2- naphthylsulfonyl)amino]methyl} cyclohexyl)methyl]-carbamate
86. tert-Butyl [(tra«*-4-{[(2-naphthylsulfonyl)(2,2,2- trifluoroethyl)amino]methyl}cyclo-hexyl)methyl]carbamate
87. tert-Butyl [(trα«5 f -4-{[(2-naphthylsulfonyl)(propyl)amino]methyl}cyclohexyl)- methyl] carbamate 88. tert-Butyl [(trα«5 f -4-{[methyl(2-naphthylsulfonyl)amino]methyl}cyclohexyl)- methyl] carbamate
89. tert-Butyl ({tra«5-4-[(methyl{[5-(2-methyl-l,3-thiazol-4-yl)-2- thienyljsulfonyll-amino^ethyljcyclohexyllmethy^carbamate
90. tert-Butyl ({tra«5-4-[(ethyl{[5-(2-methyl-l,3-thiazol-4-yl)-2- thienyljsulfonyl} amino)-methyl]cyclohexyl}methyl)carbamate
91. tert-Butyl { [trans-4-( {methyl[(2-phenylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
92. tert-Butyl [(trans-4- {[({2-[4-(aminomethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate acetate
93. A-(A- {[(trans-A-{[(tert-
Butoxycarbonyl)amino]methyl} cyclohexy^methyljcarbamoyl} -quinolin-2-yl)benzoic acid 94. tert-Butyl ({?ra«5 f -4-[({[2-(l-oxidopyridin-4-yl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
95. tert-Butyl {[/r<røs-4-({[(2-phenylquinolin-4- yl)sulfonyl] amino} me thy l)cyclohexyl] -methyl} carbamate
96. tert-Butyl ({?rα«5 f -4-[(l-naphthoylamino)methyl]cyclohexyl}methyl)carbamate 97. N-[(?rfl«5 f -4-{[(?er?-Butylcarbamoyl)amino]methyl}cyclohexyl)methyl]-2- pyridin-4-ylquinoline-4-carboxamide
98. tert-Butyl ({trans -A-[({[2-(3- {[(methylsulfonyl)amino]methyl}phenyl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate 99. te/t-Butyl {[?rα«5 f -4-({[(2-{3-[(carbamoylamino)methyl]phenyl}quinolin-4-yl)- carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
100. te/t-Butyl [(?rα«5 f -4-{[({2-[3-(acetamidomethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
101. Methyl [3-(A-{[(trans-A-{[(tert- butoxycarbonyl)amino]methyl} cyclohexyl)methyl]-carbamoyl} quinolin-2- yl)benzyl] carbamate
102. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-aminoethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
103. tert-Butyl [(?rα«5 f -4-{[({2-[4-(acetamidomethyl)phenyl]quinolin-4- yl} carbonyl)-amino]methyl} cyclohexyl)methyl] carbamate
104. Methyl [4-(4-{[(/'ra«5-4-{[(/ 1 ert- butoxycarbonyl)amino]methyl}cyclohexyl)methyl]-carbamoyl}quinolin-2- y l)benzyl] carbamate
105. tert-Butyl { [trans-A-( { [(2- {4-[(carbamoylamino)methyl]phenyl} quinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
106. tert-Butyl ({trans-4-[({[2-(4- {[(methylsulfonyl)amino]methyl}phenyl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
107. [4-(4- { [(trans-4- { [(?ert-Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]- carbamoyl} quinolin-2-yl)phenyl] acetic acid
108. 3-(4- { [(trans-4- { [(fert-Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]- carbamoyl} quinolin-2-yl)benzoic acid
109. Tetrahydro-2H-pyran-4-yl [(trans-4- { [( {2-[6-(4-methylpiperazin- 1 -yl)pyridin- 3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate 110. l-Methylpiperidin-4-yl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
111. Oxetan-2-ylmethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
112. (15)-2-Methoxy-l-methylethyl [(?ra«*-4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl} carbonyl)amino]methyl} eye lohexyl)methyl] carbamate
113. (ltf)-2-Methoxy-l-methylethyl [(?ra«5-4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
114. Tetrahydrofuran-3-yl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate 115. 2-(2-Oxopyrrolidin-l-yl)ethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
116. (35)-Tetrahydrofuran-3-yl [(trans-4- {[( {2-[6-(4-methylpiperazin- 1 -yl)pyridin- 3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
117. 2,2-Difluoroethyl [(?ra«5-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
118. 2-Fluoroethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
119. Ethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate 120. 2-Methoxyethyl [(?ra«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
121. 1 -Cyanoethyl [(trans-4- { [( {2- [6-(4-methylpiperazin- 1 -yl)pyridin-3 - yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
122. 2-Acetamidoethyl [(/rafts-4-{[({2-[6-(4-methylpiperazm-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate 123. (3-Methyloxetan-3-yl)methyl [(£rafts-4-{[({2-[6-(4-methylpiperazm-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
124. (3R)-5-Oxopyrrolidin-3-yl [(/rafts-4-{[({2-[6-(4-methylpiperazm-l-yl)pyridm- 3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
125. β^-S-Oxopyrrolidin-S-yl [(?ra«5'-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin- 3-yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate
126. Tetrahydrofuran-3-ylmethyl [(/rafts-4-{[({2-[6-(4-methylpiperazm-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
127. Tetrahydrofuran-2-ylmethyl [(trans-4- { [( {2-[6-(4-methylpiperazin- 1 - yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate 128. (5-Methylisoxazol-3-yl)methyl [(/røfts-4-{[({2-[6-(4-metriylpiperazm-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
129. 2-(lH-Pyrazol-l-yl)ethyl [(?ra«5-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
130. 1 ,3-Thiazol-2-ylmethyl [(trans-4- {[( {2-[6-(4-methylpiperazin- 1 -yl)pyridin-3- yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
131. Pyrazin-2-ylmethyl [(trans-4- {[( {2-[6-(4-methylpiperazin- 1 -yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
132. 2-Cyanoethyl [(?ra«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate 133. (lS)-2-ηydroxy-l-methylethyl [(?ra«5 f -4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
134. tert-Butyl {[?rfl«5 f -4-({[(2-{4-[(methylamino)sulfonyl]-phenyl}quinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} -carbamate
135. tert-Butyl [(?rα«5 f -4-{[({2-[4-(aminosulfonyl)phenyl]-quinolin-4- yl} carbonyl)amino]-methyl} -cyclohexyl)methyl] -carbamate
136. Tetrahydro-2H-pyran-4-yl {[?rα«5 f -4-({[(2-{4-[(methylamino)sulfonyl]phenyl}- quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
137. (S^-Tetrahydrofuran-S-yl {[?rα«5 f -4-({[(2-{4-[(methylamino)sulfonyl]phenyl}- quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} -carbamate
138. Tetrahydro-2H-pyran-4-yl [(trans-4- { [( {2-[4-(aminosulfonyl)phenyl]-quinolin- 4-yl} carbonyl)amino]-methyl} cyclohexyl)-methyl]carbamate 139. β^-Tetrahydrofuran-S-yl [(?rfl«5 f -4-{[({2-[4-(aminosulfonyl)phenyl]-quinolin-
4-yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate
140. Tetrahydro-2H-pyran-4-yl {[trans-4-({[(2-{4-
[(dimethylamino)sulfonyl]phenyl} -quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl] - methyl} carbamate 141. (3S)-Tetrahydrofuran-3-yl {[trans-4-({[(2-{4-
[(dimethylamino)sulfonyl]phenyl} -quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl] - methyl} carbamate
142. tert-Butyl [(trans-4- {[({2-[6-(4-acetylpiperazin-l -yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate 143. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
144. tert-Butyl ({?rfl«5 f -4-[({[2-(6-pyrrolidin-l-ylpyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
145. tert-Butyl ({?rfl«5 f -4-[({[2-(6-morpholin-4-ylpyridin-3-yl)quinolin-4- yljcarbonyl} amino)methyl]cyclohexyl}methyl)carbamate
146. tert-Butyl ({?rα«5 f -4-[({[2-(6-{[2-(dimethylamino)ethyl]amino}pyridin-3- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
147. tert-Butyl {[?ra«5-4-({[(2-{6-[(3R)-3-hydroxypyrrolidin-l-yl]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate 148. tert-Butyl ({?ra«5 f -4-[({[2-(6-{[(l l S r )-2-hydroxy-l-methylethyl]amino}pyridin-
3-yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
149. ?er?-Butyl ({?ra«5'-4-[({[2-(6-{[(lR)-2-hydroxy-l-methylethyl]amino}pyridin- 3-yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
150. tert-Butyl {[?rα«5 f -4-({[(2-{6-[(3-hydroxypropyl)amino]pyridin-3-yl}quinolin- 4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
151. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-hydroxypiperidin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
152. tert-Butyl {[/rø«s-4-({[(2-{6-[bis(2-hydroxyethyl)ammo]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
153. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-carbamoylpiperidin-l-yl)pyridin-3-yl]quinolin- 4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate 154. tert-Butyl ({?rfl«5 f -4-[({[2-(6-piperazin-l-ylpyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
155. tert-Butyl ( {trans-4-[( {[2-(6- {[2-(2-hy droxyethoxy)ethyl] amino } pyridin-3 - yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
156. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[(2-methoxyethyl)amino]pyridin-3-yl}quinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
157. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(3-hydroxypiperidin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
158. 3-{[5-(4-{[(/'rarø-4-{[(/ 1 er?- Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]-carbamoyl}quinolin-2-yl)pyridin-2- yl] amino }-2-methylpropanoic acid
159. tert-Butyl ( {trans-4-[( { [2-(6- { [(5 -methylpyrazin-2-yl)methyl] amino } pyridin-3 - yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
160. tert-Butyl {[?ra«5-4-({[(2-{6-[(3 l S r )-3-(dimethylamino)pyrrolidin-l-yl]pyridin- S-yllquinolin^-y^carbonylJaminolmethy^cyclohexy^methyl} carbamate 161. tert-Butyl {[?rα«5 f -4-({[(2-{6-[4-(hydroxymethyl)piperidin-l-yl]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
162. tert-Butyl {[/røfts-4-({[(2-{6-[(2,3-dihydroxypropyl)amino]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
163. tert-Butyl { [trans-4-( { [(2- {6-[(2 l S r )-2-carbamoylpyrrolidin- 1 -yl]pyridin-3- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
164. tert-Butyl ({?rara-4-[({[2-(6-{[2-hydroxy-l- (hydroxymethyl)ethyl] amino } pyridin-3 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
165. tert-Butyl [(?rα«5 f -4-{[({2-[6-(3-oxopiperazin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
166. tert-Butyl ({tra«s-4-[({[2-(6-{[(l-methyl-lH-pyrazol-4- yl)methyl]amino}pyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
167. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[(3-amino-3-oxopropyl)amino]pyridin-3- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
168. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(3-hydroxyazetidin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
169. ?er?-Butyl ({?ra«5 f -4-[({[2-(6-{[(l l S r )-l-carbamoylpropyl]ammo}pyridin-3- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate 170. tert-Butyl ({tra«s-4-[({[2-(6-{[(5-methyl-l,2,4-oxadiazol-3- yl)methyl]amino}pyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
171. tert-Butyl {[?rα«5 f -4-({[(2-{6-[2-(hydroxymethyl)morpholin-4-yl]pyridin-3- y 1} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate 172. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-oxoimidazolidin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
173. tert-Butyl [(trans-4- { [( {2- [6-(tetrahydrofuran-3 -ylmethoxy)pyridin-3 - yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
174. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(2-hydroxyethoxy)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
175. tert-Butyl [(trans-4- { [( {2- [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3 - yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
176. tert-Butyl [(?ra«5 f -4-{[({2-[6-(2-hydroxy-l-methylpropoxy)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate 177. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[(2-oxopyrrolidin-l-yl)methoxy]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
178. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(2-amino-2-oxoethoxy)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
179. tert-Butyl {[?rα«5 f -4-({[(2-{6-[2-(4-methylpiperazin-l-yl)ethoxy]pyridin-3- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
180. tert-Butyl [(?rα«5 f -4-{[({2-[3-(4-methylpiperazin-l-yl)propoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
181. tert-Butyl [(?rfl«5 f -4-{[({2-[3-(dimethylamino)propoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
182. tert-Butyl [(trans-4- { [( {2-[2-(4-methylpiperazin- 1 -yl)ethoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate 183. tert-Butyl [(?rfl«5 f -4-{[({2-[3-(4-acetylpiperazin-l-yl)propoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
184. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[2-(dimethylamino)ethoxy]pyridin-3-yl}quinolin- 4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
185. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-hydroxyethyl)piperazin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
186. tert-Butyl {[tra«5 ι -4-({[(2-{4-[2-(dimethylamino)ethyl]-piperazin-l- yl} quinolin-4-yl)carbonyl] amino} -methyl)cyclohexyl]methyl} carbamate
187. tert-Butyl ({?rα«5 f -4-[({[2-(4-hydroxypiperidin-l-yl)quinolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate 188. tert-Butyl [(?rfl«5 f -4-{[({2-[4-(hydroxymethyl)-piperidin-l-yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate
189. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-hydroxyethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate
190. tert-Butyl {[?rα«5 f -4-({[(2-piperazin-l-ylquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
191. tert-Butyl [(trans-4- { [( {2-[4-(acetamidomethyl)piperidin- 1 -yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
192. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-acetamidoethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate 193. tert-Butyl {[?rfl«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]piperidin-l-yl}quinolin-
4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
194. tert-Butyl [(?ra«5-4-{[({2-[4-(2-aminoethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
195. Tetrahydro-2H-pyran-4-yl {[trans-4-({[(2-{6-[2- (dimethylamino)ethoxy]pyridin-3-yl} quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
196. (3S)-Tetrahydrofuran-3-yl {[trans-4-({[(2-{6-[2- (dimethylamino)ethoxy]pyridin-3-yl}quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
197. Tetrahydro-2H-pyran-4-yl { [trans-4-( { [(2- {6- [(2-hydroxyethyl)amino]pyridm- 3-yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
198. Tetrahydro-2H-pyran-4-yl ({*rαw,s-4-[({[2-(6-{[2- (dimethylamino)ethy 1] amino } -pyridin-3 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
199. (3S)-Tetrahydrofuran-3-yl ({trans-4-[({[2-(6-{[2- (dimethylamino)ethy 1] amino} -pyridin-3 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
200. β^-Tetrahydrofuran-S-yl {[?rα«5 f -4-({[(2-{6-[(2-hydroxyethyl)amino]pyridin- S-yllquinolin^-y^carbonylJaminolmethy^cyclohexy^methyl} carbamate
201. (3S)-Tetrahydrofuran-3-yl {[trans-4-({[(2-{6-[(3R)-3-hydroxypyτrolidin-l- yl]pyridin-3-yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
202. Tetrahydro-2H-pyran-4-yl {[?ra«5-4-({[(2-{6-[(3R)-3-hydroxypyrrolidin-l- yl]pyridin-3-yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamat
203. tert-Butyl { [trans-4-( { [(2- {4- [2-(dimethylamino)ethoxy]phenyl} quinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate 204. tert-Butyl ({?rfl«5 f -4-[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl}carbonyl)amino]cyclohexyl}methyl)carbamate,
205. tert-Butyl {[?rα«5 f -4-({[(2-{4-[3-(dimethylamino)-2-hydroxypropyl]piperidin- 1 -yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate;
206. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-hydroxy-3-pyrrolidin-l-ylpropyl)-piperidin-l- yl]quinolin-4-yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate;
207. tert-Butyl [(?rα«5 f -4-{[({2-[4-(2-hydroxy-3-morpholin-4-ylpropyl)piperidin-l- yl]quinolin-4-yl}-carbonyl)amino]methyl}cyclohexyl)methyl]-carbamate;
208. (R) or ( S) tert-Butyl [(?rarø-4-{[({2-[4-(2-hydroxy-3-morpholin-4- ylpropyl)piperidin- 1 -yl]quinolin-4-yl} -carbonyl)amino]methyl} cyclohexyl)methyl]- carbamate;
209. (S) or (R) tert-Butyl [(?ra«*-4-{[({2-[4-(2-hydroxy-3-pyrrolidin-l-ylpropyl)- piperidin- 1 -yl]quinolin-4-yl} carbonyl)amino] -methyl} cyclohexyl)methyl] carbamate;
210. tert-Butyl { [trans-4-( { [(2- {4-[2-(dimethylamino)-2-oxoethoxy]piperidin- 1 - yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
211. tert-Butyl {[?rfl«5 f -4-({[(2-{4-[2-(dimethylamino)ethoxy]piperidin-l- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate; 212. 2,2-Dimethylpropyl {[?rα«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]piperidin-l- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
213. tert-Butyl [(trans-4- { [( {2-[4-(morpholin-4-ylmethyl)piperidin- 1 -yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]-carbamate;
214. tert-Butyl [(?rfl«5 f -4-{[({2-[4-(4-methylpiperazin-l-yl)piperidin-l-yl]quinolin- 4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] -carbamate;
215. tert-Butyl ( {trans-4-[( { [2-(pyridin-3-yloxy)quinolin-4-yl]carbonyl} amino)- methyl]cyclohexyl}methyl)carbamate;
216. tert-Butyl [(?rα«5 f -4-{[({2-[(l-methylpiperidin-4-yl)methoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]-carbamate; 217. tert-Butyl ({?rα«5 f -4-[({[2-(3-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-l- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate;
218. tert-Butyl ( {trans-4-[( { [2-(4-aminophenyl)quinolin-4-yl]carbonyl} amino)- methyl]cyclohexyl}methyl)carbamate;
219. tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]-3-oxopiperazin-l- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate;
220. tert-Butyl [(?rα«5 f -4-{[({2-[4-(hydroxyacetyl)piperazin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
221. tert-Butyl { [trans-4-( { [(2- {4-[(4-fluorobenzyl)oxy]piperidin- 1 -yl} quinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate; 222. tert-Butyl {[zrøfts-4-({[(2-amino-l-benzothioprien-3- yl)carbony 1] amino } methyl)-cyclohexyl]methyl} carbamate;
223. tert-Butyl [(trans-4- {[( {2-[(ethylcarbamoyl)amino]- 1 -benzothiophen-3- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
224. Tetrahydro-2H-pyran-4-yl {[trans-4-({[(2-{4-[2- (dimethylamino)ethyl]piperidin- 1 -yl} quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate;
225. tert-Butyl ( {trans-4-[( { [2-( 1 '-methyl-4,4'-bipiperidin- 1 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate;
226. tert-Butyl ( {trans-4-[( {[2-(4- {2-[(2-methoxyethyl)amino]ethyl}piperidin- 1 - yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate; 227. tert-Butyl ({tra«s-4-[({[2-(4-{2-[(2-methoxyethyl)(methyl)- amino]ethyl}piperidin-l-yl)quinolin-4-yl]carbonyl}amino)-methyl]cyclohexyl}- methyl)carbamate;
228. tert-Butyl {[tra«s-4-({[(2-{4-[2-(tetrahydro-2H-pyran-4- ylamino)ethyl]piperidin- 1 -yl} quinolin-4-yl)carbonyl]amino} -methyl)cyclohexyl]- methyl} carbamate;
229. tert-Butyl {[trans-4-({[(2-{4-[2-(3-methoxyazetidin-l-yl)ethyl]piperidin-l- yl} quinolin-4-yl)carbonyl] amino} -methyl)cyclohexyl]-methyl} carbamate;
230. tert-Butyl {[?ra«5-4-({[(2-{4-[2-(3-hydroxypyrrolidin-l-yl)ethyl]piperidin-l- yl} quinolin-4-yl)carbonyl] amino} -methyl)cyclohexyl]-methyl} carbamate; 231. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-pyrrolidin-l-ylethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate;
232. tert-Butyl ({tra«^-4-[({[2-(4-{2-[(2-hydroxyethyl)(methyl)- amino]ethyl}piperidin-l-yl)quinolin-4-yl]carbonyl}amino)-methyl]cyclohexyl}- methyl)carbamate; 233. tert-Butyl {[tra«5-4-({[(2-{4-[2-(3-hydroxyazetidin-l-yl)ethyl]piperidin-l- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
234. tert-Butyl [(tra«5'-4-{[({2-[4-(2-azetidin-l-ylethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
235. l-{2-[l-(4-{[(trarø-4-{[(tert- Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]-carbamoyl} quinolin-2-yl)piperidin-4- yl]ethyl} azetidine-3-carboxylic acid;
236. tert-Butyl {[trans-4-( {[(2- {4-[2-(3-aminoazetidin- 1 -yl)ethyl]piperidin- 1 - y 1} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
237. tert-Butyl {[trα«5 f -4-({[(2-{4-[3-(dimethylamino)-2-fluoropropyl]piperidin-l- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate;
238. tert-Butyl { [trans-4-( { [(2- {3 - [2-(dimethylamino)ethoxy]azetidin- 1 - yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
239. tert-Butyl [(trans-4- {[({2-[3-(aminomethyl)phenyl]-6-(lH-pyrazol-4- yl)pyridin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate;
240. tert-Butyl [(trans-4- {[({6-[3-(aminomethyl)phenyl]-2,3'-bipyridin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate; 241. tert-Butyl [(?rfl«5 f -4-{[({6'-amino-6-[3-(aminomethyl)phenyl]-2,3'-bipyridin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
242. tert-Butyl {[?ra«5-4-({[(2-{l-[2-(dimethylamino)ethyl]-lH-pyrazol-4- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
243. tert-Butyl [(?ra«5-4-{[({2-[l-(2-hydroxyethyl)-lH-pyrazol-4-yl]quinolm-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
244. tert-Butyl ( {trans-4-[( {[2-(4- {2-[(2-fluoroethylamino]ethyl}piperidin- 1 - yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate;
245. ^r?-Butyl ({?ra«5-4-[({[2-(4-(2-((2-fluoroethyl)(methyl)amino)ethyl}piperidin- l-yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof.
13. A compound according to any of the preceding claims, including compounds of proviso b), for use in therapy.
14. A method of treating obesity or being overweight, eating disorders, dyslipidemia, atherosclerosis, heart failure, stroke, type 2 diabetes mellitus and prevention of type 2 diabetes comprising administering a pharmacologically effective amount of a compound of formula (I) or formula (II) as defined in any of claims 1 to 10, including proviso b) to a patient in need thereof.
15. A process for preparing a compound of formula (I) or formula (II) as described herein. |
NEW ACETYL COENZYME A CARBOXYLASE (ACC) INHIBITORS AND USES IN TREATMENTS OF OBESITY AND DIABETES MELLITUS - 087
Field of the invention The present invention relates to Acetyl Coenzyme A Carboxylase (ACC) inhibitors, to processes for preparing such compounds, to pharmaceutical compositions containing them, to the use of such inhibitors and to methods for their therapeutic use, particularly in the treatments of obesity and diabetes mellitus.
Background of the invention
Obesity and diabetes are reaching epidemic proportions in the USA, EU, Japan and developing countries. This epidemic is largely attributed to proliferation of key risk factors, which include a sedentary lifestyle, increased food intake and the demographic shift to a more aged population. In mammals, ACC exists in two tissue specific isozymes, a liver, adipose and pancreas specific isozyme, ACCl, and a muscle specific isozyme, ACC2. The isozymes ACCl and ACC2 have pivotal functions in fatty acid metabolism. They catalyse the production of malonyl-CoA from acetyl-CoA which is a component involved in fat oxidation. By inhibition of the ACC, the fat oxidation would be increased, which generates an improved insulin sensitivity in the body. Since the incidence of type 2 diabetes has increased dramatically during the past decade, there is a need for an effective ACC inhibitor to prevent or treat obesity and diabetes and quench their life threatening sequalae atherosclerosis, heart failure and stroke. The compounds of the invention are ACC2 inhibitors. Also, some of the compounds have ACCl inhibitory activity as well.
Compounds known as ACC inhibitors have been described, for example in J. Med. Chem. 2007, 50, 1078-1082, Yu Gui Gu et al, WO2007/011809, WO2003/072197 and WO2007/013691.
There are compounds related to formula (I) described in the literature by
WO 97/20823 and Bioorganic & Medicinal Chemistry Letters 12 (2002) 1767-1769 ( tert-
butyl [(4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]car bamate and tert- butyl [(?rfl«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]carb amate and fer?-butyl({?ra«5 f -4-[({[2-trifluoromethyl)phenyl]sulfonyl}amino)methyl]cycloh exyl) methyl) carbamate.) These compounds are disclosed as intermediates in a process for producing NPY Y5 receptor agonists. No pharmaceutical use of the prepared compounds is contemplated. The compounds disclosed in this document are disclaimed by proviso a).
Further, EP 1295 867 Al describes a compound related to formula (I), which is an intermediate in the synthesis of the final compounds having obesity activity. This compound is disclaimed as no. 63 in proviso b) below.
Further, following compounds are known in Chemical Abstracts but no references are given (disclaimed by proviso b)):
1. te/t-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)- methyl] carbamate
2. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -A- fiuorobenzamide
3. 2-Fluoro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl)cyclohexyl]- methyl}benzamide
4. 2-Fluoro-N-{[4-({[(2-methoxypropyl)carbamoyl]amino}methyl)cy clohexyl]- methyl}benzamide
5. 3,4-Dimethoxy-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methy l)cyclohexyl]- methyl}benzenesulfonamide 6. 3-methyl--V-({4-[({[2-
(trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl }methyl)benzamide;
7. 6-Chloro-iV- {[4-({ [(4-fluorobenzyl)carbamoyl] amino }methyl)cyclohexyl]- methy 1 } nicotinamide ;
8. 6-Chloro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}nicotinamide;
9. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl]- methyl}benzamide;
10. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino]methyl}cyclohexyl)me thyl]- benzamide;
11. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}me thyl)cyclo- exyl]methyl}benzenesulfonamide; 12. N- [(4- { [(Benzylcarbamoyl)amino]methyl} cyclohexyl)methyl] -4- methylbenzenesulfonamide;
13. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- methylbenzenesulfonamide;
14. 4-Methyl-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cycl ohexyl]methyl}- benzenesulfonamide;
15. 4-Methyl-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzenesulfonamide:
16. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3,4- dimethoxybenzenesulfonamide; 17. 3,4-Dimethoxy-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl )cyclohexyl]- methyl}benzenesulfonamide;
18. 4-Methyl-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzamide
19. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- fluorobenzamide
20. 4-Chloro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzamide
21. 2-Fluoro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl]cyclo- hexyl}methyl)benzamide 22. 4-Nitro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino) methyl]cyclo- hexyl}methyl)benzamide
23. N-{[4-({[(4-Fluorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide
24. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzamide
25. 2,3-Dichloro-iV-( {4-[( {[2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl]- cyclohexyl}methyl)benzamide
26. 4-Chloro-N-{[4-({[(3-chlorobenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzamide
27. 6-Chloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}nicotinamide 28. 2,3-Dichloro-N-{[4-({[(cyclopropylmethyl)carbamoyl]amino}met hyl)cyclo- hexyl]methyl}benzamide
29. 6-Chloro-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)me thyl]- nicotinamide
30. 6-Chloro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohexyl) methyl]- nicotinamide
31. 2-Fluoro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzamide
32. 3-Cyano-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino) methyl]cyclo- hexyl}methyl)benzamide 33. 4-Fluoro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzamide;
34. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexy l]methyl}-2- fluorobenzamide;
35. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4 - methylbenzamide;
36. 2,3-Dichloro-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl )cyclohexyl]- methyl}benzamide;
37. N-({4-[({[2-(Trifluoromethyl)benzyl]carbamoyl}amino)methyl]c yclohexyl}- methyl)nicotinamide; 38. N-{[4-({[(2-Methoxyethyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide;
39. 3 -Methyl-N- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] - methyl}benzamide;
40. 2,3-Dichloro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl )cyclohexyl]- methyl}benzamide;
41. 4-Fluoro-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)me thyl]- benzamide;
42. ^-{^-({[(S-Methoxypropy^carbamoy^aminolmethy^cyclohexy^methy l}^- methylbenzamide;
43. 6-Chloro-iV-( {4-[( {[2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl]cyclo- hexyl}methyl)nicotinamide; 44. 3 -Cyano-iV- { [4-( { [(cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl] - methyl}benzamide;
45. 3 -Methyl-iV- [(4- { [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl] - benzamide;
46. 4-Methyl-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cycl ohexyl]methyl}- benzamide;
47. 3-Cyano-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cycl ohexyl]- methyl}benzamide;
48. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexy l]methyl}-4- fluorobenzamide; 49. 4-Fluoro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzamide;
50. 4-Methoxy-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)m ethyl]- benzamide;
51. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4 - methoxybenzamide;
52. 2,3-Dichloro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohe xyl)methyl]- benzamide;
53. 2-Fluoro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohexyl) methyl]- benzamide; 54. 6-Chloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cycl ohexyl]methyl}- nicotinamide;
55. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4-c hlorobenzamide
56. 2,3 -Dichloro-iV- { [4-( { [(2-chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl] - methyl}benzamide 57. 4-Fluoro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl]cyclo- hexyl}methyl)benzamide
58. 6-Chloro-N-{[4-({[(cyclopropylmethyl)carbamoyl]amino}methyl) cyclohexyl]- methyl}nicotinamide
59. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -4- methoxybenzamide 60. 3-Cyano-λf-[(4- {[(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide
61. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide
62. 2,3 -Dichloro-iV- { [4-( { [(3 -chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl] - methyl}benzamide; 63. tert-Butyl ({4-[({[3'-({[2-(4-hydroxyphenyl)ethyl]amino}methyl)biphenyl -3- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate;
64. tert-Butyl [(trans -4- {[(I - naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]carbamate;
65. 3-Chloro-N-{[4-({[(2- chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}-4-flu orobenzenesulfonamide
66. 2,3-Dichloro-N-{[4-({[(2- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide
67. 2,3-Dichloro-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexy l)methyl]- benzamide 68. 4-Chloro-N-{[4-({[(3-methoxypropyl)carbamoyl]amino}methyl)cy clohexyl]- methyl}benzamide
69. 3-Chloro-4-fluoro-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}m ethyl)cyclo- hexyl]methyl}benzenesulfonamide;
70. N-[(?rfl«5 f -4-{[(Benzylcarbamoyl)(isopropyl)amino]methyl}cyclohexyl) methyljbenzenesulfonamide
71. tert-Butyl [(4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]car bamate
72. tert-Butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate
73. tert-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate
74. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -3 - fluorobenzamide
75. 2-Fluoro-N-{[4-({[(3-methoxypropyl)carbamoyl]amino}methyl)cy clohexyl]- methyl}benzamide
76. 2-Fluoro-N-[[4-[[[[(2-methoxyethyl)amino]carbonyl]amino]meth yl]cyclo- hexyl]methyl]benzamide, 77. 3,4-Dimethoxy-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methy l)cyclo- hexyl]methyl}benzenesulfonamide
78. 3 -Methyl-iV-( {4- [( { [2-(trifluoromethyl)benzyl] carbamoyl} amino)methy 1] cyclo- hexyl}methyl)benzamide
79. 6-Chloro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}nicotinamide
80. 6-Chloro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}nicotinamide
81. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl]- methyl}benzamide 82. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino]methyl}cyclohexyl)- methyljbenzamide
83. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}me thyl)cyclo- hexyl]methyl}benzenesulfonamide
84. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzenesulfonamide
85. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- methylbenzenesulfonamide
86. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] - methyl}benzenesulfonamide 87. 4-Methyl-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl)cyc lohexyl]- methyl}benzenesulfonamide
88. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3,4- dimethoxybenzenesulfonamide
89. 3,4-Dimethoxy-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl )cyclo- hexyl]methyl}benzenesulfonamide or salts thereof; or enantiomers thereof.
Description of the invention
The present invention provides a compound of formula (I)
R2 and R3 independently represent hydrogen, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl (which alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more halo, OH, cyano, -C(O)NR 8a R 8b , -C(O)OR 9 , aryl, heteroaryl, heterocyclyl);
R4 represents hydrogen or Q-Cβ alkyl, which alkyl group is optionally substituted by one or more halo, OH, -C(O) NR R , C1-C4 alkoxy, optionally substituted by one or more halo;
R5 represents hydrogen or Q-Cg alkyl, which alkyl group is optionally substituted by one or more halo, OH, -C(O) NR R , C1-C4 alkoxy, optionally substituted by one or more halo;
E represents Ci-alkylene;
n is an integer of O or 1 ;
L represents C(O) or SO2;
Z represents aryl, heteroaryl, heterocyclyl, which groups are optionally substituted by one or more groups independently selected from any of A), B) and C) as defined;
A) halo, -NR 12 C(O)R 13 , -NR 14 C(O)N(R 15a )(R 15b ), -N(R 15 ^)(R 15b )
B) Ci-Cβ alkyl, Q-Cβ alkoxy, (which alkyl and alkoxy groups are optionally substituted by halo, OH, -N(R )(R ), heterocyclyl, heteroaryl (which heterocyclyl, heteroaryl groups are optionally substituted by OH, oxo, Q-Cβ alkyl, C(O)R ));
C) C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, -(0)o or iaryl, -(0)o or 1- heteroaryl, which cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl groups (group C) are optionally substituted by one or more groups independently selected from any of a), b) and c) as defined:
a) halo, -OH, oxo, cyano, -C(O)N(R 18a )(R 18b ), -N(R 19 ^)(R 1 % ), -SR 2 °, -OR 20a , -N(R 21 )C(O)R 22 , -SO 2 (R 23 ), -N(R 24 )(CHR 25 ) m N(R 26a )(R 26b ) or C(O)R 38 ;
b) Ci-Cg alkyl, Ci-Cg alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl (which alkyl, alkoxy, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more halo, -OH, cyano, N(R 27a )(R 27b ), -N(R 28 )SO ( i_ 2) (R 29 ), -N(R 3 °)C(O)R 31 , -N(R 32 )C(O)N(R 33a )(R 33b ), -N(R 3 V(O)OR 35 , -S0 ( i_ 2) (R 36 ), -C(O)OR 37 , -C(O)R 38 , -C(O)N(R 39a )(R 39b ), heterocyclyl (optionally substituted by C x -C 4 alkyl,
C1-C4 alkoxy, oxo, hydroxy, carboxy, amino, Ci-C ό alkylamino, di(Ci-C 6 alkyl)amino in which the alkyl groups may be the same or different,));
c) aryl, heteroaryl, heterocyclyl (which aryl, heteroaryl, heterocyclyl are optionally
4ω 41 a 41 h 49a 49h 43 substituted by -OH, -C(O)R , -C(O)N(R )(R ), oxo, -N(R 1(R ), -0(R ), Ci-
Cg alkyl, Ci-Cg alkoxy (which alkyl and alkoxy groups are optionally substituted by halo, -OH));
R represents Q-C 6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl (which groups are optionally substituted by one or more of -OH, halo, cyano,
44 45a 45b 44 40
Ci-C 6 alkyl, Q-C 6 alkoxy, oxo, -NR C(O)N(R )(R ), -NR C(O)(R ), heterocyclyl or heteroaryl (which heterocyclyl or heteroaryl groups are optionally substituted by Q-C4 alkyl, oxo));
7a 7b 8a 8b 10a 10b 11a lib 15a 15b 16a 16b 18a 18b 19a Jv , Jv , Jv , Jv , Jv , Jv , Jv , Jv , jv , jv , jv , jv , jv , jv , jv ,
19b 26a 26b 27a 27b 33a 33b 39a 39b 41a 41b 42a 42b 45a 45b
JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV , JV ,
R , R independently represent hydrogen, heterocyclyl or a Ci-C 6 alkyl optionally substituted by OH, halo, C1-C4 alkoxy, cyano, amino, Ci-Cόalkylamino, di(Ci-
C6alkyl)amino in which the alkyl groups may be the same or different, heterocyclyl or heteroaryl (which heterocyclyl and heteroaryl groups are optionally substituted by OH, halo, C1-C4 alkyl, Q-C4 alkoxy),
9 13 17 20 21 22 24 25 31 34 35 37 38 40 R , R , R , R , R , R , R , R , R , R R , R , R , R independently represent hydrogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy (which alkyl and alkyloxy are optionally substituted by halo, OH, cyano, C(O)NH 2 );
12 14 28 30 32 34 44 R ,R ,R ,R ,R ,R ,R represents hydrogen, Ci-C 6 alkyl (which alkyl is optionally substituted by halo, OH, cyano, C(O)NH 2 );
R 20a represents phenyl(CH2)o-4-0- in which the phenyl is optionally substituted by halo, Ci-C 6 alkyl or Ci-C 6 alkoxy (which alkyl and alkoxy are optionally substituted by halo);
R 23 , R 29 , R 36 represent -N(R 46a )(R 46b ), Ci-C 6 alkyl, Ci-C 6 alkoxy (which alkyl and alkoxy are optionally substituted by halo, OH, cyano, C(O)NH^);
43 R represents heteroaryl, heterocyclyl; m is an integer of O, 1, 2, 3, 4, 5 or 6;
with the proviso that the compound is not:
a) 1. tert-Butyl [(4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate;
2. tert-Butyl [(/rafts-4-{[(2-naphthylsulfonyl)amino]methyl} cyclohexyl)methyl] carbamate;
3. tert-Butyl( {trans-4-[( { [2-trifluoromethyl)phenyl]sulfonyl} amino)methyl] cyclohexyl)methyl)carbamate; or
b)
1. tert-Butyl [(/rafts-4-{[(l-naphthylsulfonyl)amino]methyl} cyclohexyl)methyl] carbamate 2. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexy l]methyl}-4- fiuorobenzamide
3. 2-Fluoro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
4. 2-Fluoro-iV- { [4-( { [(2-methoxypropyl)carbamoyl]amino } methyl) cyclohexyl]methyl}benzamide
5. 3,4-Dimethoxy-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methy l)cyclohexyl] methyl}benzenesulfonamide
6. 3-Methyl-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl] cyclohexyl}methyl)benzamide; 7. 6-Chloro-λf-{[4-({[(4-fluorobenzyl)carbamoyl] amino} methyl) cyclohexyl] methyl } nicotinamide ;
8. 6-Chloro-λf-{[4-({[(2-methoxyethyl)carbamoyl] amino} me thyl)cyclohexyl] methyl } nicotinamide ;
9. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl] methyl}benzamide; 10. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino]methyl}cyclohexyl)me thyl] benzamide;
11. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}me thyl)cyclohexyl] methyl}benzenesulfonamide;
12. N- [(4- { [(Benzylcarbamoyl)amino]methyl} cyclohexyl)methyl] -4- methylbenzenesulfonamide;
13. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- methylbenzenesulfonamide;
14. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzenesulfonamide; 15. 4-Methyl-iV- { [4-( { [(4-methylbenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzenesulfonamide:
16. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3,4- dimethoxybenzenesulfonamide;
17. 3,4-Dimethoxy-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl )cyclohexyl] methyl}benzenesulfonamide;
18. 4-Methyl-iV- { [4-( { [(4-methylbenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
19. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- fluorobenzamide 20. 4-Chloro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyc lohexyl] methyl}benzamide
21. 2-Fluoro-iV-( {4-[( { [2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl] cyclohexyl}methyl)benzamide
22. 4-Nitro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino) methyl] cyclohexyl}methyl)benzamide
23. N-{[4-({[(4-Fluorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide
24. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzamide
25. 2,3-Dichloro-N-({4-[({[2- (trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}me thyl)benzamide 26. 4-Chloro-.V-{[4-({[(3- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide
27. 6-Chloro-.V-{[4-({[(2- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} nicotinamide
28. 2,3-Dichloro-N-{[4- ({[(cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexyl]meth yl}benzamide
29. 6-Chloro-.V-[(4- {[(propylcarbamoyl)amino]methyl}cyclohexyl)methyl]nicotinami de
30. 6-Chloro-.V-[(4- {[(isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]nicotina mide 31. 2-Fluoro-N-{[4-({[(4- fluorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide
32. 3-Cyano-N-({4-[({[2- (trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}me thyl)benzamide
33. 4-Fluoro-N-{[4-({[(4- fluorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide;
34. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexy l]methyl}-2- fluorobenzamide;
35. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4 - methylbenzamide; 36. 2,3-Dichloro-N-{[4-({[(4- methylbenzyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzam ide;
37. N-({4-[({[2- (Trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}me thyl)nicotinamide;
38. N-{[4-({[(2-Methoxyethyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide;
39. 3-Methyl-N-{[4-({[(2- phenylethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzami de;
40. 2,3-Dichloro-N-{[4-({[(2- methoxyethyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide;
41. 4-Fluoro-λ4(4-
{ [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide; 42. ^-{^-({[(S-Methoxypropy^carbamoy^aminolmethy^cyclohexy^methy l}^- methylbenzamide;
43. 6-Chloro-iV-( {4-[( {[2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl] cyclohexyl}methyl)nicotinamide;
44. 3 -Cyano-N- { [4-( { [(cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
45. 3 -Methyl-iV- [(4- { [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl] benzamide;
46. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide; 47. 3-Cyano-N-{[4-({[(2- methoxyethyl)carbamoyl] amino } me thyl)cyclohexyl]methyl} benzamide;
48. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexy l]methyl}-4- fluorobenzamide;
49. 4-Fluoro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cyc lohexyl] methyl}benzamide;
50. 4-Methoxy-λf-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl )methyl] benzamide;
51. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4 - methoxybenzamide; 52. 2,3-Dichloro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohe xyl)methyl] benzamide;
53. 2-Fluoro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohexyl) methyl] benzamide;
54. 6-Chloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cycl ohexyl] methyl}nicotinamide;
55. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4-c hlorobenzamide
56. 2,3-Dichloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl )cyclohexyl] methyl}benzamide
57. 4-Fluoro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl] cyclohexyl}methyl)benzamide 58. 6-Chloro-N-{[4-({[(cyclopropylmethyl)carbamoyl]amino}methyl) cyclohexyl] methyl}nicotinamide
59. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -4- methoxybenzamide
60. 3-Cyano-iV-[(4- {[(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide 61. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide
62. 2,3 -Dichloro-iV- { [4-( { [(3 -chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
63. tert-BvXyl ({4-[({[3'-({ [2-(4-hydroxyphenyl)ethyl]amino } methyl)biphenyl-3 - yljcarbonyl} amino)methyl]cyclohexyl}methyl)carbamate;
64. te/t-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl] carbamate;
65. 3-Chloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl)cyc lohexyl] methyl} -4-fluorobenzenesulfonamide 66. 2,3-Dichloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl )cyclohexyl] methyl}benzamide
67. 2,3-Dichloro-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexy l)methyl] benzamide
68. 4-Chloro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
69. 3-Chloro-4-fluoro-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}m ethyl) cyclohexyl]methyl}benzenesulfonamide;
70. N-[(?rfl«5 f -4-{[(Benzylcarbamoyl)(isopropyl)amino]methyl}cyclohexyl) methyljbenzenesulfonamide 71. te/t-Butyl [(4-{[(l-Naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]car bamate
72. tert-BvXy\ [(?rα«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl) methyl] carbamate
73. tert-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl) methyl] carbamate
74. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -3 - fluorobenzamide 75. 2-Fluoro-iV-{[4-({ [(3 -methoxypropyl)carbamoyl] amino} methyl) cyclohexyl] methyl}benzamide
76. 2-Fluoro-N-[[4-[[[[(2-methoxyethyl)amino]carbonyl]amino]meth yl] cyclohexyl]methyl] benzamide
77. 3 ,4-Dimethoxy-iV- { [4-( { [(4-methylbenzyl)carbamoyl]amino } methyl) cyclohexyl]methyl}benzenesulfonamide
78. 3 -Methyl-iV-( {4- [( { [2-(trifluoromethyl)benzyl] carbamoyl} amino) methyl]cyclohexyl}methyl)benzamide
79. 6-Chloro-iV- {[4-({[(4-fluorobenzyl)carbamoyl] amino} methyl) cyclohexyl]methyl}nicotinamide 80. 6-Chloro-iV- {[4-({[(2-methoxyethyl)carbamoyl] amino} methyl) cyclohexyl]methyl}nicotinamide
81. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl]methyl}benzamide
82. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino] methyl} cyclohexyl) methyljbenzamide
83. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}me thyl) cyclohexyl]methyl}benzenesulfonamide
84. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzenesulfonamide 85. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- methylbenzenesulfonamide
86. 4-Methyl-iV-{[4-({[(2- phenylethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzene sulfonamide
87. 4-Methyl-.V-{[4-({[(4- methylbenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzenesulfonamide
88. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3,4- dimethoxybenzenesulfonamide
89. 3, 4-Dimethoxy-iV-{[4-({ [(2 -phenylethyl)carbamoyl] amino} methyl) cyclo- hexyl]methyl}benzenesulfonamide.
In another aspect the present invention provides a compound of formula (I)
Ri represents -OR or -NR R ;
R2 and R3 independently represent hydrogen, Q-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
Ci-Cβ alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl (which alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more halo, OH, cyano, -C(O)NR 8a R 8b , -C(O)OR 9 , aryl, heteroaryl, heterocyclyl);
R4 represents hydrogen or Ci-Cg alkyl, which alkyl group is optionally substituted by one or more halo, OH, -C(O) NR R , Q-C4 alkoxy, optionally substituted by one or more halo;
R5 represents hydrogen or Q-Cβ alkyl, which alkyl group is optionally substituted by one or more halo, OH, -C(O) NR R , C1-C4 alkoxy, optionally substituted by one or more halo;
E represents Ci-alkylene;
n is an integer of 0 or 1 ;
L represents C(O) or SO2;
Z represents aryl, heteroaryl, heterocyclyl, which groups are optionally substituted by one or more groups independently selected from any of A), B) and C) as defined;
A) halo, -NR 12 C(O)R 13 , -NR 14 C(O)N(R 15a )(R 15b ), -N(R 15 ^)(R 15b )
B) Ci-Cβ alkyl, Ci-Cβ alkoxy, (which alkyl and alkoxy groups are optionally substituted by halo, OH, -N(R )(R ), heterocyclyl, heteroaryl (which heterocyclyl, heteroaryl groups are optionally substituted by OH, oxo, Ci-Cβ alkyl, C(O)R ));
C) C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, which cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl groups (group C) are optionally substituted by one or more groups independently selected from any of a), b) and c) as defined:
a) halo, -OH, oxo, cyano, -C(O)N(R 18a )(R 18b ), -N(R 19 ^)(R 1 % ), -SR 2 °, -N(R 21 )C(O)R 22 , -SO 2 (R 23 ), -N(R 24 )(CHR 25 ) m N(R 26a )(R 26b );
b) Ci-Cg alkyl, Ci-Cg alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl (which alkyl, alkoxy, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more halo, -OH, cyano, N(R 27a )(R 27b ), -N(R 28 )SO ( i_ 2) (R 29 ), -N(R 3 °)C(O)R 31 , -N(R 32 )C(O)N(R 33a )(R 33b ), -N(R 3 V(O)OR 35 , -S0 ( i_ 2) (R 36 ), -C(O)OR 37 , -C(O)R 38 , -C(O)N(R 39a )(R 39b ), heterocyclyl (optionally substituted by C x -C 4 alkyl,
oxo));
c) aryl, heteroaryl, heterocyclyl (which aryl, heteroaryl, heterocyclyl are optionally
40 41 a 41 h 49a 49b 43 substituted by -OH, -C(O)R , -C(O)N(R )(R ), oxo, -N(R 1(R ), -0(R ), C x -
5 Cg alkyl, Ci-Cg alkoxy (which alkyl and alkoxy groups are optionally substituted by halo, -OH));
R represents Q-C 6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl (which groups are optionally substituted by one or more of -OH, halo, cyano,
44 45a 45b 44 40 io Ci-C 6 alkyl, Ci-C 6 alkoxy, oxo, -NR C(O)N(R )(R ), -NR C(O)(R ), heterocyclyl or heteroaryl (which heterocyclyl or heteroaryl groups are optionally substituted by Q-C4 alkyl, oxo));
7a 7b 8a 8b 10a 10b 11a lib 15a 15b 16a 16b 18a 18b 19a JV , JV , JV , JV , JV ,Jv ,Jv ,Jv ,Jv ,JV ,JV ,JV ,JV ,JV ,JV ,
, 1<5 R JV 19b , RJV 26a , RJV 26b , RJV 27a , RJV 27b , RJV 33a , RJV 33b , RJV 39a , RJV 3% , RJV 41a , RJV 41b , RJV 42a , RJV 42b , RJV 45a , RJV 45b ,
R , R independently represent hydrogen, Ci-C 6 alkyl, optionally substituted by OH, halo, cyano, heterocyclyl or heteroaryl (which heterocyclyl and heteroaryl groups are optionally substituted by OH, halo, C1-C4 alkyl, C1-C4 alkoxy),
9 π 17 20 21 22 24 25 31 34 35 37 38 40 20 R^, R , R ', R , R , R , R , R , R , R , R , R J ', R , R independently represent hydrogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy (which alkyl and alkyloxy are optionally substituted by halo, OH, cyano, C(O)NH 2 );
12 14 28 30 32 34 44 R , R , R , R , R , R , R represents hydrogen, Ci-C 6 alkyl (which alkyl is
25 optionally substituted by halo, OH, cyano, C(O)NH 2 );
R 23 , R 29 , R 36 represent -N(R 46a )(R 46b ), Ci-C 6 alkyl, Ci-C 6 alkoxy (which alkyl and alkyloxy are optionally substituted by halo, OH, cyano, C(O)NH^);
43 R represents heteroaryl, heterocyclyl; m is an integer of 0, 1, 2, 3, 4, 5 or 6;
with the proviso that the compound is not: a)
1. tert-Butyl [(4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate; 2. tert-Butyl [(/rafts-4-{[(2-naphthylsulfonyl)amino]methyl} cyclohexyl)methyl] carbamate;
3. tert-Butyl( {trans-4-[( { [2-trifluoromethyl)phenyl]sulfonyl} amino)methyl] cyclohexyl)methyl)carbamate; or
b)
1. tert-Butyl [(/rafts-4-{[(l-naphthylsulfonyl)amino]methyl} cyclohexyl)methyl] carbamate
2. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -A- fluorobenzamide 3. 2-Fluoro-λf-{[4-({[(3-methoxypropyl)carbamoyl]amino} methyl)cyclohexyl] methyl}benzamide
4. 2-Fluoro-iV- { [4-( { [(2-methoxypropyl)carbamoyl]amino } methyl) cyclohexyl]methyl}benzamide
5. 3,4-Dimethoxy-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methy l)cyclohexyl] methyl}benzenesulfonamide
6. 3-Methyl-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl] cyclohexyl}methyl)benzamide;
7. 6-Chloro-N-{[4-({[(4-fluorobenzyl)carbamoyl] amino} methyl) cyclohexyl] methyl } nicotinamide ; 8. 6-Chloro-λf-{[4-({[(2-methoxyethyl)carbamoyl] amino} me thyl)cyclohexyl] methyl } nicotinamide ;
9. 2,3-Dichloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl) cyclohexyl] methyl}benzamide;
10. 4-Methyl-N-[(4-{[(methylcarbamoyl)amino]methyl}cyclohexyl)me thyl] benzamide; 11. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}me thyl)cyclohexyl] methyl}benzenesulfonamide;
12. N- [(4- { [(Benzylcarbamoyl)amino]methyl} cyclohexyl)methyl] -4- methylbenzenesulfonamide;
13. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- methylbenzenesulfonamide;
14. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzenesulfonamide;
15. 4-Methyl-iV- { [4-( { [(4-methylbenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzenesulfonamide: 16. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3,4- dimethoxybenzenesulfonamide;
17. 3,4-Dimethoxy-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl )cyclohexyl] methyl}benzenesulfonamide;
18. 4-Methyl-iV- { [4-( { [(4-methylbenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
19. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- fluorobenzamide
20. 4-Chloro-N-{[4-({[(4-fluorobenzyl)carbamoyl]amino}methyl)cyc lohexyl] methyl}benzamide 21. 2-Fluoro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl] cyclohexyl}methyl)benzamide
22. 4-Nitro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino) methyl] cyclohexyl}methyl)benzamide
23. N-{[4-({[(4-Fluorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide
24. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzamide
25. 2,3-Dichloro-N-({4-[({[2- (trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl}me thyl)benzamide
26. 4-Chloro-.V-{[4-({[(3- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide 27. 6-Chloro-.V-{[4-({[(2- chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} nicotinamide
28. 2,3-Dichloro-N-{[4-
( { [(cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide
29. 6-Chloro-.V-[(4- { [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]nicotinamide
30. 6-Chloro-.V-[(4- {[(isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]nicotina mide
31. 2-Fluoro-N-{[4-({[(4- fluorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide 32. 3-Cyano-N-({4-[({[2-
(trifluoromethyl)benzyl]carbamoyl}amino)methyl]cyclohexyl }methyl)benzamide
33. 4-Fluoro-N-{[4-({[(4- fluorobenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide;
34. N-{[4-({[(Cyclopropylmethyl)carbamoyl]amino}methyl)cyclohexy l]methyl}-2- fluorobenzamide;
35. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4 - methylbenzamide;
36. 2,3-Dichloro-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}methyl )cyclohexyl]- methyl}benzamide; 37. N-({4-[({[2-(Trifluoromethyl)benzyl]carbamoyl}amino)methyl]- cyclohexyl}methyl)nicotinamide;
38. N-{[4-({[(2-Methoxyethyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide;
39. 3 -Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] - methyl}benzamide;
40. 2,3-Dichloro-N-{[4-({[(2- methoxyethyl)carbamoyl] amino } me thyl)cyclohexyl]methyl} benzamide;
41. 4-Fluoro-λ4(4-
{ [(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide;
42. ^-{^-({[(S-Methoxypropy^carbamoy^aminolmethy^cyclohexy^methy l}^- methylbenzamide; 43. 6-Chloro-iV-( {4-[( {[2-(trifluoromethyl)benzyl]carbamoyl} amino)methyl] cyclohexyl}methyl)nicotinamide;
44. 3 -Cyano-iV- { [4-( { [(cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
45. 3-Methyl-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)me thyl] benzamide;
46. 4-Methyl-iV- { [4-( { [(2-phenylethyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
47. 3-Cyano-N-{[4-({[(2- methoxyethyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzamide; 48. N-{[4-({ [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -4- fluorobenzamide;
49. 4-Fluoro-N-{[4-({[(2-methoxyethyl)carbamoyl]amino}methyl)cyc lohexyl] methyl}benzamide;
50. 4-Methoxy-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexyl)m ethyl] benzamide;
51. N-[(4-{[(Isobutylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4 - methoxybenzamide;
52. 2,3-Dichloro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohe xyl)methyl] benzamide; 53. 2-Fluoro-N-[(4-{[(isobutylcarbamoyl)amino]methyl}cyclohexyl) methyl] benzamide;
54. 6-Chloro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}methyl)cycl ohexyl] methyl } nicotinamide ;
55. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4-c hlorobenzamide 56. 2,3-Dichloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl )cyclohexyl] methyl}benzamide
57. 4-Fluoro-N-({4-[({[2-(trifluoromethyl)benzyl]carbamoyl}amino )methyl] cyclohexyl}methyl)benzamide
58. 6-Chloro-N-{[4-({[(cyclopropylmethyl)carbamoyl]amino}methyl) cyclohexyl] methyl}nicotinamide 59. N-{[4-({ [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -A- methoxybenzamide
60. 3-Cyano-λf-[(4- {[(propylcarbamoyl)amino]methyl} cyclohexyl)methyl]benzamide
61. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3- methylbenzamide 62. 2,3 -Dichloro-iV- { [4-( { [(3 -chlorobenzyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide;
63. tert-Butyl ( {4- [( { [3 '-( { [2-(4-hydroxyphenyl)ethyl]amino } methyl)biphenyl-3 - yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate;
64. te/t-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl] carbamate;
65. 3-Chloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl)cyc lohexyl] methyl} -4-fluorobenzenesulfonamide
66. 2,3-Dichloro-N-{[4-({[(2-chlorobenzyl)carbamoyl]amino}methyl )cyclohexyl] methyl}benzamide 67. 2,3-Dichloro-N-[(4-{[(propylcarbamoyl)amino]methyl}cyclohexy l)methyl] benzamide
68. 4-Chloro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl)cyclohexyl] methyl}benzamide
69. 3-Chloro-4-fluoro-N-{[4-({[(4-methylbenzyl)carbamoyl]amino}m ethyl) cyclohexyl]methyl}benzenesulfonamide;
70. N-[(?rfl«5 f -4-{[(Benzylcarbamoyl)(isopropyl)amino]methyl}cyclohexyl) methyljbenzenesulfonamide
71. tert-BvXy\ [(4- { [( 1 -Naphthylsulfonyl)amino]methyl} cyclohexyl)methyl]carbamate
72. tert-BvXy\ [(?rα«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl) methyl] carbamate
73. te/t-Butyl [(?rα«5 f -4-{[(l-naphthylsulfonyl)amino]methyl}cyclohexyl) methyl] carbamate
74. N- { [4-( { [(Cyclopropylmethy^carbamoyl] amino } methyl)cyclohexyl]methyl} -3 - fluorobenzamide
75. 2-Fluoro-iV- { [4-( { [(3 -methoxypropyl)carbamoyl] amino } methyl) cyclohexyl] methyl}benzamide
5 76. 2-Fluoro-N-[[4-[[[[(2-methoxyethyl)amino]carbonyl]amino]meth yl] cyclohexyl]methyl] benzamide
77. 3 ,4-Dimethoxy-iV- { [4-( { [(4-methylbenzyl)carbamoyl]amino } methyl) cyclohexyl]methyl}benzenesulfonamide
78. 3 -Methyl-iV-( {4- [( { [2-(trifluoromethyl)benzyl] carbamoyl} amino) i o methyl] cyclohexyl } methy l)benzamide
79. 6-Chloro-iV- {[4-({[(4-fluorobenzyl)carbamoyl] amino} methyl) cyclohexyl]methyl}nicotinamide
80. 6-Chloro-iV- {[4-({[(2-methoxyethyl)carbamoyl] amino} methyl) cyclohexyl]methyl}nicotinamide is 81. 2,3-Dichloro-λf-{[4-({[(2-phenylethyl)carbamoyl]amino}methy l) cyclohexyl]methyl}benzamide
82. 4-Methyl-λf-[(4-{[(methylcarbamoyl)amino] methyl} cyclohexyl) methyljbenzamide
83. 3-Chloro-4-fluoro-N-{[4-({[(2-phenylethyl)carbamoyl]amino}me thyl) 20 cyclohexyl]methyl}benzenesulfonamide
84. N-[(4-{[(Benzylcarbamoyl)amino]methyl}cyclohexyl)methyl]-4- methylbenzenesulfonamide
85. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-4- methylbenzenesulfonamide
25 86. 4-Methyl-N-{[4-({[(2- phenylethyl)carbamoyl]amino}methyl)cyclohexyl]methyl}benzene sulfonamide
87. 4-Methyl-N-{[4-({[(4- methylbenzyl)carbamoyl] amino } methyl)cyclohexyl]methyl} benzenesulfonamide
88. N-{[4-({[(2-Chlorobenzyl)carbamoyl]amino}methyl)cyclohexyl]m ethyl}-3,4- 30 dimethoxybenzenesulfonamide
89. 3, 4-Dimethoxy-iV-{[4-({ [(2 -phenylethyl)carbamoyl] amino} methyl) cyclo- hexyl]methyl}benzenesulfonamide;
or an enantiomer thereof.
In one embodiment L represents C(O).
In one embodiment of the invention n is 1.
In one embodiment Z represents
NR 47 C(O)R 48 ;
R x and R z independently represent hydrogen, halo, -OH, -OR , -SR , -N(R )(R ), aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, heteroaryl, (which aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups are optionally substituted by one or more groups of the following halo, OH, oxo, -C(O)N(R )(R ), - OR 53 , -SR 54 , -C(O)OR 55 , cyano, -N(R 56 )C(O)OR 5? , - N(R 56 )C(O)N(R 52a )(R 52b ), - N(R 56 )S(O) 2 R 60 , -S(O) 2 N(R 52a )(R 52b ), -N(R 56 )(CHR 58 ) m N(R 52a )(R 52 \ -N(R 52a )(R 52 \ -C(O)R 59 , -N(R 5 V(O)R 59 , -N(R 56 )(CHR 58 ) m OR 55 , -N(R 56 )(CHR 58 ) m C(O)N(R 52a )(R 52b ), -N(R 56 )(CHR 58 ) m C(O)O(R 57 ), -S(O) ( i. 2) R 6 °, heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more of the following -OH, oxo, -C(O)R 61 , -C(O)N(R 62a )(R 62 \ C1-C4 alkyl
(which alkyl is optionally substituted by OH)), Ci-Cβ alkyl, Ci-Cβ alkoxy (which alkyl and alkoxy groups are optionally substituted by one or more of the following -OH, halo, -
N(R 63a )(R 63 \ -C(O)OR 64 , N(R 6 V(O)OR 64 , -N(R 65 )C(O)R 66 , -
N(R 65 )C(O)N(R 63a )(R 63b ), -N(R 65 )S(O) ( i. 2) (R 66 ), -C(O)N(R 63a )(R 63b ), heterocyclyl, heteroaryl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more Ci-C 4 alkyl, oxo, -C(O)R 67 ));
Ry represents hydrogen, halo, Q-Cβ alkyl, Q-Cβ alkoxy;
Ry and R z may together with the carbon atoms to which they are attached represent a benzene ring;
wherein
51a 51b 52a 52b .,62a 62b .,63a 63b . R , R , R , R , R , R , R , R independently represent hydrogen, Ci-Cg alkyl (optionally substituted by one or more OH, halo, heteroaryl (which heteroaryl optionally is substituted by one or more Q-C4 alkyl or Q-C4 alkoxy));
R , R , R , R , R , R , R independently represent Ci -Cβ alkyl, optionally substituted by one or more OH, halo, heteroaryl, heterocyclyl, which groups optionally are substituted by one or more Ci-Cβ alkyl, OH;
R , R , R , R , R , R , R , R independently represent hydrogen, Ci -Cβ alkyl, optionally substituted by one or more OH, halo, heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups optionally are substituted by one or more Ci-Cg alkyl, OH;
R , R , R independently represent hydrogen, Ci -Cβ alkyl (optionally substituted by one or more OH, halo);
49 53 R , R independently represent C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heteroaryl, heterocyclyc, Ci-Cg alkyl (which alkyl is optionally substituted by one or more OH, halo, N(R )(R ), heteroaryl, heterocyclyl (which heteroaryl and heterocyclyl groups optionally are substituted by one or more OH, oxo, Ci-Cg alkyl, Ci-Cg alkoxy, - C(O)R 66 ));
m is an integer of O, 1, 2, 3, 4, 5, 6.
In one embodiment of the invention R z represents hydrogen, halo, Ci-Cg alkyl, Ci-Cg alkoxy, aryl or heteroaryl (which aryl and heteroaryl groups are optionally substituted by one or more of -OH, halo, cyano, amino, Ci-Cg alkyl, Ci-Cg alkoxy, oxo, -
NR 56 C(O)R 59 ).
In one embodiment of the invention Ri represents -OR .
In one embodiment of the invention Z represents
D represents N or C, optionally substituted by hydrogen, halo, C1-C4 alkyl, aryl;
R X represents hydrogen, halo, -OR 68 , -SR 69 , -N(R 7 °)C(O)R 71 , -N(R ?2a )(R ?2b ) aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, heteroaryl,
(which aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl groups are optionally substituted by one or more groups selected from halo, OH, oxo, -C(O)N(R )(R ),
OR 74 , -SR 75 , -C(O)OR 76 , cyano, -N(R 7? )C(O)OR 78 , - N(R 77 )C(O)N(R 73a )(R ?3b ), -N(R 77 )S(O) (1-2) R 78 , -N(R 77 )(CHR 79 ) m N(R 73a )(R 73b ), -N(R 73a )(R 73b ), -C(O)R 80 , - N(R 77 )C(O)R 80 , -N(R 7? )(CHR 79 ) m OR 79 , -N(R 7? )(CHR 79 ) m OH,
-N(R 77 )(CHR 79 ) m C(O)N(R 73a )(R 73b ), -N(R 77 )(CHR 79 ) m C(O)O(R 76 ), -N(R 77 )C(O)R 8 °,
-S(O) ( i_ 2) R 78 , -S(O) (i-2)N(R 73a )(R 73b ), heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more of the following OH, oxo, C(O)R 81 , C(O)N(R 82a )(R 82b ), -N(R 82a )(R 82b ), C1-C4 alkyl, C1-C4 alkoxy (which alkyl or alkoxy is optionally substituted by one or more OH, -N(R 82a )(R 82b ))),
C1-C6 alkyl, Q-Cβ alkoxy (which alkyl and alkoxy groups are optionally substituted by one or more of the following -OH, halo, -C(O)OR 83 , -N(R 84a )(R 84b ), -N(R 85 )C(O)OR 83 , -N(R 8 V(O)R 86 , -N(R 85 )C(O)N(R 84a )(R 84b ), -N(R 85 )S(O)(i-2)R 87 , - C(O)N(R )(R ), heteroaryl, heterocyclyl (which heteroaryl, heterocyclyl groups are optionally substituted by one or more Q-C4 alkyl, oxo, -C(O)R )),
.,72a 72b .,73a 73b 82a 82b .,84a 84b .
R , R , R , R , R , R , R , R independently represent hydrogen, Ci-Cg alkyl (optionally substituted by one or more OH, halo, heteroaryl (which heteroaryl optionally is substituted by one or more Q-C4 alkyl));
R , R , R , R , R , R independently represent C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heteroaryl, heterocyclyl, Ci-Cβ alkyl (which groups are optionally substituted by one or more OH, halo, -N(R )(R ),heteroaryl, heterocyclyl (which
heteroaryl, heterocyclyl groups optionally are substituted by one or more OH, oxo, Q-Cg
89 alkyl, Ci-C 6 alkoxy, C(O)R ));
R , R , R , R , R , R , R , R , R , R , R independently represent hydrogen,
Ci-C 6 alkyl, optionally substituted by one or more OH, halo, heteroaryl, heterocyclyl
89 (which groups optionally are substituted by one or more OH, Ci-C 6 alkyl, C(O)R );
R , R , R independently represent hydrogen, Ci-C 6 alkyl (optionally substituted by one or more OH, halo);
m is an integer of O, 1, 2, 3, 4, 5 or 6.
In one embodiment of the invention D represent N.
In one embodiment of the invention the compound is according to formula (I) wherein R x is selected from optionally substituted phenyl, thiazole, thienyl, pyridine, pyrazine, pyrimidine, piperidine, piperazine or imidazolidine.
A particular embodiment of the invention is provided by a compound of formula II
or a pharmaceutically acceptable salt thereof in which Ri, R 2 , R 3 and R 4 are as previously defined and Rx represents a group a), b) or c): a)
in which Li represents a bond or a C1-C4 alkylene chain and R 90 and R 91 independently represent H or C1-C6 alkyl optionally substituted by hydroxy or C1-C4 alkoxy
b)
In a particular group of compounds of formula II, R x represents group a) as above. In a second group of compounds of formula II, R x represents group b) as above. In a third group of compounds of formula II, R x represents group c) as above.
In a further group of compounds of formula II, R x represents group a) above, wherein Li represents a bond or a C1-C2 alkylene chain, or Li represents a Ci alkylene chain, and R 90 and R 91 independently represent H, C1-C3 alkyl or Ci alkyl optionally substituted by hydroxy or Ci alkoxy, or both R 90 and R 91 represent H.
In a even further group of compounds of formula II, R x represents group b) above, wherein R 9 2 represents a group -L 2 -L 3 -NR 93 R 94 in which L 2 is O or N, L 3 is a C2-C4 alkylene chain, or L 3 is a C2-C3 alkylene chain, and R 93 and R 94 independently represent H or C1-C3 alkyl optionally substituted by hydroxy or Ci alkoxy or both R 93 and R 94 represent H, or wherein or R 9 2 represents piperidino, morpholino or piperazino each of which is optionally substituted by one or more of the following: hydroxy, a Ci alkyl, Ci alkoxy or a Ci alkanoyl.
In a still further group of compounds of formula II, R x represents group c) as above, wherein L 4 is a C1-C3 alkylene chain or a C2-C3 alkylene chain, which chain is optionally substituted by hydroxy provided that no carbon atom in the chain is attached to two hetero atom (that is O or N) and R 95 and R 96 independently represent H or C1-C2 alkyl optionally substituted by hydroxy or Ci alkoxy, or R 95 and R 96 independently C1-C2 alkyl optionally substituted by hydroxy, or R 95 and R 96 together with the nitrogen atom to which they are attached represent azetidino or pyrrolidino each of which is optionally substituted by one or more of the following: hydroxy, a Ci alkyl or Ci alkoxy, or R 95 and R 96 together with the nitrogen atom to which they are attached represent azetidino which is optionally substituted by a hydroxy.
In a further embodiment of the invention a compound of formula II, or a pharmaceutically acceptable salt thereof , is provided, wherein R x represents group a) in which Li represents a Ci alkylene chain, and both R 90 and R 91 represent H, or wherein R x represents group b) , in which R 9 2 represents a group -L 2 -L 3 -NR 93 R 94 in which L 2 is O or N, L 3 is a C2-C3 alkylene chain, and R 93 and R 94 both represent H, or wherein or R 9 2 represents piperidino, morpholino or piperazino each of which is optionally substituted by one or more of the following: hydroxy, a Ci alkyl, Ci alkoxy or a Ci alkanoyl, or wherein R x represents group c) in which L 4 is a C2-C3 alkylene
chain, which chain is optionally substituted by hydroxy provided that no carbon atom in the chain is attached to two hetero atom (that is O or N) and R 95 and R 96 independently C1-C2 alkyl optionally substituted by hydroxy, or R 95 and R 96 together with the nitrogen atom to which they are attached represent azetidino which is optionally substituted by a hydroxy.
Further embodiments relate to a compound of formula (I) or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, in which
Ri represents -OR , R2 and R3 independently represent hydrogen, Q-Cg alkyl, Q-C4 alkyl, Q-C3 alkyl, Q- C2 alkyl, C2 alkyl or Ci alkyl, or both R2 and R3 represent hydrogen,
R4 represents hydrogen, Q-Cg alkyl, Q-C4 alkyl, Q-C3 alkyl, Q-C2 alkyl, C2 alkyl or Ci alkyl, or R4 represents hydrogen,
R5 represents hydrogen or Q-Cg alkyl, Q-C4 alkyl, Q-C3 alkyl, Q-C2 alkyl, C2 alkyl or Ci alkyl, or R5 represents hydrogen, and
R represents C3-C5 alkyl, C3-C4 alkyl C4-C5 alkyl or C4 alkyl, e.g. a /-butyl.
Still further embodiments relate to a compound of formula (I) or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, in which Ri represents -OR ,
R2 and R3 independently represent hydrogen or Ci -Cg alkyl, R4 represents hydrogen or Ci-Cg alkyl,
R5 represents hydrogen or Ci-Cg alkyl, and
R represents C3-C5 alkyl.
In one embodiment there is provided a compound according to formula (I) or formula (II), including compounds of proviso b), for use in therapy.
In one embodiment a method for treating obesity or being overweight, eating disorders, dyslipidemia, atherosclerosis, heart failure, stroke, type 2 diabetes mellitus and prevention of type 2 diabetes is provided, comprising administering a pharmacologically effective amount of a compound of formula (I) or formula (II) as defined herein, including proviso b) to a patient in need thereof.
In one embodiment a process for preparing the compound of the invention as described herein.
The following definitions shall apply throughout the specification and the appended claims.
Unless otherwise specified, alkyl groups and alkoxy groups as defined herein may be linear-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain.
Alkylene groups as defined herein are divalent and may be linear-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain.
The term "aryl", when used herein, includes Cg-C χo ar yl groups such as phenyl, naphthyl, and the like. Unless otherwise specified, aryl and aryloxy groups may be substituted by one or more substituents including -OH, halo, cyano, nitro, Ci-Cβ alkyl, Ci-Cβ alkoxy, sulfamoyl, methylsulfonyl, aryl, amino and methylsulfinyl. When substituted, aryl and aryloxy groups are preferably substituted by between one and three substitutents.
The term "halo", when used herein, includes fiuoro, chloro, bromo and iodo.
The term "cycloalkyl" denotes a saturated monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated bicyclic ring system composed of 8, 9 or 10 carbon atoms. The cycloalkyl may be attached to an alkyl group in a spirocyclic manner.
The term "cycloalkenyl" denotes unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms. The cycloalkenyl may be attached to an alkyl group in a spirocyclic manner.
The term "heterocyclyl" denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulfoxide (S(O)) and sulfone (SO 2 ). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "heterocyclyl" include, but are not limited to aziridinyl, azetidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,4- dioxanyl, 1,3-dioxolanyl, 1 ,2-oxathiolanyl, morpholinyl, pyrazolidinyl, 1,4-dithianyl, 1,4- oxathianyl, thiomorpholinyl, indolinyl, l,3-dihydro-2-benzofuranyl, 2,3-dihydro-l- benzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, chromanyl, isochromanyl, benzomorpholinyl, benzoxazinonyl, oxopyrrolidinyl, dioxothiolanyl and pyrrolidinonyl.
The term "heteroaryl" denotes an aromatic 5 or 6 membered monocyclic ring or an aromatic 9 or 10 membered bicyclic ring in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulfoxide (S(O)) and sulfone (SO 2 ). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "heteroaryl" include, but are not limited to, furanyl, pyrrolyl, pyrazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyridinyl, 1-oxido-pyridinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, thienyl, 1,2,4-triazolyl, furazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,2,3-thiadiazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzo[c]thienyl, benzimidazolyl, purinyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, isoquionolinyl, aza-indolyl, pyrazinopyridinyl, pyrazolopyridinyl, pyrrolopyrazinyl, benzotriazolyl, imidazo[l,2-α]pyridinyl, phthalazinyl and tetrazolyl.
Substituents on heterocyclyl and heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocyclyl and heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocyclyl and heteroaryl groups may also be in the N- or S-oxidised form.
Unless otherwise specified, the cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl may be substituted by one or more substituents including -OH, oxo, halo, cyano, amino, Q-Cβ alkyl, Ci-Cβ alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, amido, sulfamoyl, methylsulfonyl, methylsulfinyl, phenyl and Ci-Cβ alkanoyl.
The term "alkenyl" refers to a monovalent straight or branched chain alkyl group having at least one carbon-carbon double bond. The double bond of an alkenyl can be unconjugated or conjugated to another unsaturated group. Unless otherwise specified, alkenyl groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain.
The term "alkynyl" refers to a monovalent straight or branched chain alkyl group having at least one carbon-carbon triple bond. The triple bond of an alkynyl can be unconjugated or conjugated to another unsaturated group. Unless otherwise specified, alkynyl groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain.
Unless otherwise stated or indicated the term "alkoxy" denotes a group O-alkyl wherein
alkyl is as defined above.
"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of formula (I) or formula (II) is, for example, an acid-addition salt of a compound of formula (I) or formula (II) which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a base- addition salt of a compound of formula (I) or formula (II) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or £rø-(2-hydroxyethyl)amine.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such stereoisomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or chiral HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions that will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention. All tautomers, where possible, are included within the scope of the invention. The present invention also encompasses compounds containing one or more isotopes for example 14 C, 11 C or 19 F and their use as isotopically labelled compounds for pharmacological and metabolic studies. The present invention also encompasses prodrugs of a compound of formula (I) or formula (II) that is compounds which are converted into a compound of formula (I) or formula (II) in vivo.
The invention relates to any and all tautomeric forms of the compounds of the formula (I) or formula (II) that possess ACC inhibitory activity.
It is also to be understood that certain compounds of the formula (I) or formula (II) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms, which possess ACC inhibitory activity.
Compounds of the present invention have been named with the aid of computer software (ACD Name (Product Version 9.04)).
The values of variable groups may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter, for compounds of formula (I) or formula (II).
Illustrative values and examples of any substituent, R group or any part of such groups include, but are not limited to:
C1-C4 alkyl: C3-C4 alkyl, C4 alkyl, C3 alkyl, Q-C 3 alkyl, Q-C 2 alkyl, C2 alkyl , Ci alkyl, methyl, ethyl, « -propyl, isopropyl, 2 -methyl- 1 -propyl, 2- methyl-2 -propyl, butyl, ώobutyl and £-butyl (i.e. tert-butyl); Ci-C 6 alkyl: C 4 -C 6 alkyl, C 3 -C 6 alkyl, C 6 alkyl, C 5 alkyl, C 4 -C 5 alkyl, Ci-C 5 alkyl, Ci-C 4 alkyl, C 3 -C 5 alkyl, C 3 -C 4 alkyl, C 4 alkyl, C 3 alkyl, Q- C 3 alkyl, Ci-C 2 alkyl, C 2 alkyl, Ci alkyl, methyl, ethyl, « -propyl, wo-propyl, 2 -methyl- 1 -propyl, 2- methyl-2 -propyl, 2 -methyl- 1 -butyl, 3-methyl-l -butyl, 2-methyl-3- butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl,
butyl, wø-butyl, /-butyl (i.e. tert-butyϊ), pentyl, wø-pentyl, neo-pentyl and hexyl;
Ci-Cg alkyl: Q-C 6 alkyl (as above), C1-C4 alkyl (as above), methyl, ethyl, n- propyl, isø-propyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l - butyl, 3-methyl-l -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2- methyl-1 -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isø-butyl, t-butyl (i.e. tert-butyl), pentyl, zso-pentyl, weø-pentyl, hexyl, heptyl and octyl;
Q-C 6 alkoxy: C 4 -C 6 alkoxy, C 3 -C 6 alkoxy, C 6 alkoxy, C5 alkoxy, C4-C5 alkoxy,
C1-C5 alkoxy, C1-C4 alkoxy, C3-C5 alkoxy, C3-C4 alkoxy, C4 alkoxy, C3 alkoxy, C1-C3 alkoxy, C1-C2 alkoxy, C2 alkoxy, Ci alkoxy, methoxy, ethoxy, « -propyloxy, wo-propyloxy, 2-methyl-l - propyloxy, 2-methyl-2-propyloxy, 2-methyl-l -butyloxy, 3 -methyl- 1- butyloxy, 2-methyl-3 -butyloxy, 2,2-dimethyl-l -propyloxy, 2-methyl- 1-pentyloxy, 3 -methyl- 1-pentyloxy, 4-methyl-l -pentyloxy, 2-methyl- 2-pentyloxy, 3-methyl-2-pentyloxy, 4-methyl-2 -pentyloxy, 2,2- dimethyl- 1 -butyloxy, 3 ,3 -dimethyl- 1 -butyloxy, 2-ethyl- 1 -butyloxy, butyloxy, wo-butyloxy, ^-butyloxy, pentyloxy, wo-pentyloxy, neo- pentyloxy, and hexyloxy;
C2-C6 alkenyl: C4-C6 alkenyl, C3-C6 alkenyl, Cβ alkenyl, C5 alkenyl, C4-C5 alkenyl, C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C3-C5 alkenyl, C 3 -C 4 alkenyl, C 4 alkenyl, C3 alkenyl, C 2 -C 3 alkenyl, C 2 alkenyl, vinyl, allyl, butenyl, pentenyl, hexenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl;
C 2 -C 6 alkynyl: C 4 -C 6 alkynyl, C 3 -C 6 alkynyl, C 6 alkynyl, C 5 alkynyl, C 4 -C 5 alkynyl, C 2 -C 5 alkynyl, C 2 -C 4 alkynyl, C 3 -C 5 alkynyl, C 3 -C 4 alkynyl, C 4
alkynyl, C3 alkynyl, C2-C3 alkynyl, C2 alkynyl, acetylene, propynyl, 1-butynyl, 2-butynyl, 2-pentynyl, 1-pentynyl; C 3 -C 8 cycloalkyl: C3-C7 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C 4 -C 8 cycloalkyl, Cs-C 8 cycloalkyl, Cg-C 8 cycloalkyl, C 7 -C 8 cycloalkyl, C4-C7 cycloalkyl, C5-C7 cycloalkyl, Cβ-C-j cycloalkyl, C4-C6 cycloalkyl, C4-C5 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctanyl; C3-C 8 cycloalkenyl: C3-C7 cycloalkenyl, C3-C5 cycloalkenyl, C3-C4 cycloalkenyl, C4-C 8 cycloalkenyl, Cs-C 8 cycloalkenyl, Cg-C 8 cycloalkenyl, C7-C 8 cycloalkenyl, C4-C7 cycloalkenyl, C5-C7 cycloalkenyl, C6-C7 cycloalkenyl, C4-C6 cycloalkenyl, C4-C5 cycloalkenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctadienyl, decaline, hydrindane, indane, indene, and bicyclo[4.2.0]octa-l,3,5-triene. Specific compounds of the invention include one or more of the following:
1. tert-Butyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
2. tert-Butyl ({?rα«5 f -4-[({[2-(2-methyl-6-oxo-l,6-dihydropyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate 3. tert-Butyl {[?rα«5 f -4-({[(2-pyrazin-2-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
4. tert-Butyl ({zrø«s-4-[({[2-(4-ethoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
5. tert-Butyl ({?rα«5 f -4-[({[2-(6-carbamoylpyridin-3-yl)quinolin-4- yljcarbonyl} amino)-methyl]cyclohexyl}methyl)carbamate
6. tert-Butyl { [trans-4-( { [(2-phenylquinolin-4-yl)carbonyl] amino } methyl)- cyclohexyl] -methyl} carbamate
7. tert-Butyl {[?rα«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)- cyclohexyl]methyl} carbamate
8. tert-Butyl ({£rafts-4-[({[2-(3-carbamoylphenyl)qumolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
9. tert-Butyl ({£rafts-4-[({[2-(4-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 10. tert-Butyl {[£rafts-4-({[(2-{6-[3-(dimethylammo)propoxy]pyridm-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
11. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(dimethylamino)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
12. tert-Butyl [(?ra«5'-4-{[({2-[4-(trifluoromethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
13. tert-Butyl ({trøws-4-[({[2-(5-acetyl-2-thienyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
14. tert-Butyl ({trøws-4-[({[2-(4-fluorophenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 15. tert-Butyl ({?rα«5 f -4-[({[2-(3,5-dimethylisoxazol-4-yl)quinolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate
16. tert-Butyl {[?rα«5 f -4-({[(2-pyridm-3-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
17. Ethyl ({?ra«5'-4-[({[2-(4-fluorophenyl)quinolin-4- yljcarbonyl} amino)methyl]cyclo-hexyl}methyl)carbamate
18. Ethyl [(?rα«5 f -4-{[({2-[4-(dimethylcarbamoyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
19. Ethyl ({£rafts-4-[({[2-(3-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 20. ?er?-Butyl ({?ra«5 f -4-[({[2-(4-methylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
21. tert-Butyl ({?ra«5'-4-[({[2-(4-chlorophenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
22. tert-Butyl ({?rfl«5 f -4-[({[2-(3-methoxyphenyl)quinolin-4-yl]carbonyl}amino)- methyljcyclohexyllmethy^carbamate
23. tert-Butyl ( {trans-4-[( { [2-(2-methoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
24. tert-Butyl [(trans-4- {[({2-[4-(methylthio)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
25. tert-Butyl ( {trans-4-[( {[2-(2,4-dimethyl- 1 ,3-thiazol-5-yl)quinolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate 26. Ethyl {[?rfl«5 f -4-({[(2-pyrazin-2-ylquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
27. Ethyl ({£rafts-4-[({[2-(3-methoxyphenyl)qumolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
28. Ethyl ( {trans-4-[( { [2-(4-methylphenyl)quinolin-4- yljcarbonyl} amino)methyl]cyclo-hexyl}methyl)carbamate
29. Ethyl [(?ra«5-4-{[({2-[4-(methylthio)phenyl]quinolin-4- yl} carbonyl)amino]methyl} -cyclohexyl)methyl] carbamate
30. Ethyl ({?rfl«5 f -4-[({[2-(4-ethoxyphenyl)quinolin-4-yl]carbonyl}amino)methyl ]- cyclohexyl}methyl)carbamate 31. Ethyl ({trans-4-[({ [2-(2 -methoxyphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
32. Ethyl ({zrø«s-4-[({[2-(4-chlorophenyl)quinolin-4- yl]carbonyl}amino)methyl]cyclo-hexyl}methyl)carbamate
33. tert-Butyl {[?rfl«5 f -4-({[(2-pyrimidin-5-ylquinolin-4- yl)carbonyl]amino}methyl)-cyclohexyl]methyl} carbamate
34. tert-Butyl ({?rα«5 f -4-[({[2-(4-cyanophenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
35. tert-Butyl {[?ra«5 f -4-({[(2-chloroquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate 36. tert-Butyl ({?rα«5 f -4-[({2-[4-(aminomethyl)phenyl]-6-methoxyisonicotinoyl}- amino)methyl]cyclohexyl}methyl)carbamate
37. tert-Butyl ({zrørø-4-[({2-[4-(aminomethyl)phenyl]-5- chloroisonicotinoyl}amino)-methyl]cyclohexyl}methyl)carbamat e
38. tert-Butyl ({?ra«5'-4-[({2-[4-(aminomethyl)phenyl]-6- methylisonicotinoyl}amino)-methyl]cyclohexyl}methyl)carbamat e
39. tert-Butyl [(trans-4- {[({2-[3-(aminomethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
40. [3-(4-{[(?rα«5 f -4-{[(?ert-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl} quinolin-2-yl)phenyl] acetic acid
41. tert-Butyl [(trans-4- { [(2- phenylisonicotinoyl)amino]methyl}cyclohexyl)methyl]-carbamat e 42. tert-Butyl {[tr<ms-4-({[2-(4- methoxyphenyl)isonicotinoyl]amino}methyl)cyclo-hexyl]methyl} carbamate
43. tert-Butyl [(tra«s-4-{[(2-methyl-6- phenylisonicotinoyl)amino]methyl}cyclohexyl)-methyl]carbamat e
44. tert-Butyl {[traft,s-4-({[(5-phenylpyridm-3- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
45. tert-Butyl {[tr<røs-4-({[2-(l-benzothiophen-2- yl)isonicotinoyl]amino}methyl)cyclo-hexyl]methyl} carbamate
46. tert-Butyl {[traws-4-({[(6'-ethoxy-2,3'-bipyridin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate 47. tert-Butyl {[trans -4-({[2-(2, 4- dimethoxypheny^isonicotinoy^aminojmethy^cyclo-hexy^methyl} carbamate
48. tert-Butyl {[?ra«5-4-({[(2',6'-dimethoxy-2,3'-bipyridin-4- yl)carbonyl]amino}methyl)-cyclohexyl]methyl} carbamate
49. tert-Butyl {[tra/«-4-({[(6'-methoxy-2,3'-bipyridin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
50. tert-Butyl {[trans -4-({[2-(4- carbamoylphenyl)isonicotinoyl]amino}methyl)cyclohexyl] methyl} carbamate
51. tert-Butyl {[tra«^-4-({[2-(3- chlorophenyl)isonicotinoyl] amino } methyl)cyclohexyl] -methyl} carbamate 52. ?er?-Butyl ({?rara-4-[({2-[4-
(aminomethyl)phenyl]isonicotinoyl}amino)methyl]cyclo-hexy l}methyl)carbamate
53. tert-Butyl {[frαws-4-({[2-(3,4- difluorophenyl)isonicotinoyl]amino}methyl)cyclohexyl]-methyl } carbamate
54. Ethyl [(trans-4- {[(2- naphthylsulfonyl)amino]methyl} cyclohexy^methyljcarbamate
55. 2,2-Dimethylpropyl {[?ra«5'-4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)-cyclohexyl]methyl} carbamate
56. Cyclopentyl {[/røfts-4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
57. Isopropyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate 58. Propyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]-methyl} carbamate
59. 2-Methoxyethyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}- methyl)cyclohexyl]methyl} carbamate
60. Ethyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)cyc lo- hexyl]methyl} carbamate
61. Ethyl ( {trans-4-[( { [2-(4-carbamoylphenyl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate
62. Ethyl {[?rα«5 f -4-({[(2-phenylquinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} -carbamate 63. tert-Butyl [(trans-4-{[(bvphQny{-3- ylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
64. tert-Butyl {[trans -4-( {[(3,4- dibromophenyl)sulfonyl] amino } methyl)cyclohexyl] -methyl} carbamate
65. tert-Butyl {[tr<ms-4-({[(3,4- dichloropheny^sulfonyljaminolmethy^cyclohexyljmethyl} -carbamate
66. tert-Butyl [(zra/«-4-{[(quinolin-8- ylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
67. tert-Butyl [(trans-4-{[(bvphQnyl-4- ylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate 68. tert-Butyl {[trans -4-({[(4- isopropylphenyl)sulfonyl] amino } methyl)cyclohexyl] -methyl} carbamate
69. tert-Butyl [(?ra«5-4-{[(2,3-dihydro-l,4-benzodioxin-6- ylsulfonyl)amino]methyl}cyclo-hexyl)methyl]carbamate
70. tert-Butyl ({tra«^-4-[({[5-(2-methyl-l,3-thiazol-4-yl)-2- thienyljsulfonyl} amino)-methyl]cyclohexyl}methyl)carbamate
71. tert-Butyl {[?rara-4-({[(5-acetamido-l- naphthyl)sulfonyl]amino}methyl)cyclohexyl]-methyl} carbamate
72. tert-Butyl {[trans -4-({[(5-isoxazol-5-yl-2- thienyl)sulfonyl] amino } me thy l)cyclo-hexyl]methyl} carbamate
73. tert-Butyl {[trans-4-({[(4- acetamidopheny^sulfonyljaminolmethy^cyclohexy^-methyl} carbamate 74. tert-Butyl [(?rα«5 f -4-{[(3-thienylsulfonyl)ammo]methyl}cyclohexyl)methyl]- carbamate
75. tert-Butyl ({tra«s-4-[({[3-(5-methyl-l,2,4-oxadiazol-3- y l)pheny 1] sulfony 1 } amino)-methy 1] cy clohexy 1 } methy l)carb amate
76. tert-Butyl [(?rfl«5 f -4-{[(isoquinolin-5-ylsulfonyl)amino]methyl}cyclohexyl)- methyl] carbamate
77. tert-Butyl {[tra«^-4-({[(4-acetamido-2-methyl-l,3-thiazol-5- yl)sulfonyl] amino} -methyl)cyclohexyl]methyl} carbamate
78. tert-Butyl [(tra«s-4-{[(l,3-benzothiazol-6- ylsulfonyl)amino]methyl}cyclohexyl)-methyl]carbamate 79. tert-Butyl [(tra«s-4-{[ethyl(2- naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
80. tert-Butyl [(tr<røs-4-{[(2-naphthylsulfonyl)(2- phenylethyl)amino]methyl}cyclohexyl)-methyl]carbamate
81. Ethyl N-[(trans-4- {[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- N-(2-naphthylsulfonyl)glycinate
82. tert-Butyl [(trans-4- { [(2-naphthylsulfonyl)(tetrahydro-2H-pyran-4- ylmethyl)amino]-methyl}cyclohexyl)methyl]carbamate
83. tert-Butyl [(tra«5-4-{[(cyanomethyl)(2- naphthylsulfonyl)amino]methyl}cyclohexyl)-methyl]carbamate 84. tert-Butyl [(tr<ms-4-{ [allyl(2- naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
85. tert-Butyl [(tra«^-4-{[butyl(2- naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]-carbamate
86. tert-Butyl [(tra«*-4-{[(2-naphthylsulfonyl)(2,2,2- trifluoroethyl)amino]methyl} cyclo-hexyl)methyl] carbamate
87. tert-Butyl [(trα«5 f -4-{[(2-naphthylsulfonyl)(propyl)amino]methyl}cyclohexyl)- methyl] carbamate
88. tert-Butyl [(trafts-4-{[methyl(2-naphthylsulfonyl)amino]methyl}cyclohex yl)- methyl] carbamate
89. tert-Butyl ({tra«^-4-[(methyl{[5-(2-methyl-l,3-thiazol-4-yl)-2- thienyljsulfonyll-amino^ethyljcyclohexyllmethy^carbamate 90. tert-Butyl ({tra«^-4-[(ethyl{[5-(2-methyl-l,3-thiazol-4-yl)-2- thienyl]sulfonyl}amino)-methyl]cyclohexyl}methyl)carbamate
91. tert-Butyl { [trans-4-( {methyl[(2-phenylquinolin-4- yl)carbonyl]amino}methyl)cyclo-hexyl]methyl} carbamate
92. tert-Butyl [(trans-4- {[({2-[4-(aminomethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} eye Io hexyl)methyl] carbamate acetate
93. 4-(4-{[(trarø-4-{[(tert-
Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]carbamoyl} -quinolin-2-yl)benzoic acid
94. tert-Butyl ({trafts-4-[({[2-(l-oxidopyridin-4-yl)quinolin-4- yl]carbonyl}amino)methyl]-cyclohexyl}methyl)carbamate 95. tert-Butyl {[tr<røs-4-({[(2-phenylquinolin-4- yl)sulfonyl] amino} me thy l)cyclohexyl] -methyl} carbamate
96. tert-Butyl ({trα«5 f -4-[(l-naphthoylamino)methyl]cyclohexyl}methyl)carbamate
97. N-[(trfl«5'-4-{[(tert-Butylcarbamoyl)amino]methyl}cyclohexy l)methyl]-2- pyridin-4-ylquinoline-4-carboxamide 98. tert-Butyl ({trarø-4-[({[2-(3-
{[(methylsulfonyl)amino]methyl}phenyl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
99. tert-Butyl {[trα«5 f -4-({[(2-{3-[(carbamoylamino)methyl]phenyl}quinolin-4-yl)- carbonyl]amino}methyl)cyclohexyl]methyl} carbamate 100. tert-Butyl [(trα«5 f -4-{[({2-[3-(acetamidomethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate 101. Methyl [3-(4-{[(trarø-4-{[(tert- butoxycarbonyl)amino]methyl}cyclohexyl)methyl]-carbamoyl}qui nolin-2- y l)benzyl] carbamate 102. tert-Butyl [(tra«5'-4-{[({2-[4-(2-aminoethyl)phenyl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate
103. tert-Butyl [(?rα«5 f -4-{[({2-[4-(acetamidomethyl)phenyl]quinolin-4- yl} carbonyl)-amino]methyl} cyclohexyl)methyl] carbamate
104. Methyl [4-(4- {[(trans-4- {[(tert- butoxycarbonyl)amino]methyl}cyclohexyl)methyl]-carbamoyl}qui nolin-2- yl)benzyl] carbamate
105. tert-Butyl { [trans-4-( { [(2- {4-[(carbamoylamino)methyl]phenyl} quinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
106. tert-Butyl ({trans-4-[({[2-(4- {[(methylsulfonyl)amino]methyl}phenyl)quinolin-4- yljcarbonyl} amino)methyl]cyclohexyl}methyl)carbamate
107. [4-(4- { [(trans-4- { [(?ert-Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]- carbamoyl} quinolin-2-yl)phenyl] acetic acid
108. 3-(4- { [(trans-4- { [(?ert-Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]- carbamoyl} quinolin-2-yl)benzoic acid 109. Tetrahydro-2H-pyran-4-yl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-
3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methy l]carbamate
110. l-Methylpiperidin-4-yl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
111. Oxetan-2-ylmethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
112. (1 S^-Methoxy- 1-methylethyl [(?ra«*-4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate
113. (lR)-2-Methoxy- 1-methylethyl [(?ra«*-4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate 114. Tetrahydrofuran-3-yl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
115. 2-(2-Oxopyrrolidin-l-yl)ethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate
116. β^-Tetrahydrofuran-S-yl [(trans-4- {[( {2-[6-(4-methylpiperazin- 1 -yl)pyridin- 3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]c arbamate
117. 2,2-Difluoroethyl [(?ra«5-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
118. 2-Fluoroethyl [(?rfl«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
119. Ethyl [(?rfl«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate 120. 2-Methoxyethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
121. 1 -Cyanoethyl [(trans-4- { [( {2- [6-(4-methylpiperazin- 1 -yl)pyridin-3 - yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
122. 2-Acetamidoethyl [(?rfl«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
123. (3 -Methyloxetan-3 -yl)methyl [(trans-4- { [( {2-[6-(4-methylpiperazin- 1 - yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate
124. (3R)-5-Oxopyrrolidin-3-yl [(?rfl«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin- 3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]c arbamate 125. β^-S-Oxopyrrolidin-S-yl [(?ra«5'-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-
3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methy l]carbamate
126. Tetrahydrofuran-3-ylmethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate
127. Tetrahydrofuran-2-ylmethyl [(trans-4- { [( {2-[6-(4-methylpiperazin- 1 - yl)pyridin-3-yl]quinolin-4-yl} carbonyl)amino]methyl} eye lohexyl)methyl] carbamate
128. (5-Methylisoxazol-3-yl)methyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate
129. 2-(lH-Pyrazol-l-yl)ethyl [(?ra«5-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate 130. l,3-Thiazol-2-ylmethyl [(?rfl«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
131. Pyrazin-2-ylmethyl [(trans-4- {[( {2-[6-(4-methylpiperazin- 1 -yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
132. 2-Cyanoethyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
133. (1 S)-2-ηydroxy- 1 -methylethyl [(trans-4- { [( {2- [6-(4-methylpiperazin- 1 - yl)pyridin-3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohex yl)methyl]carbamate
134. tert-Butyl {[?rfl«5 f -4-({[(2-{4-[(methylamino)sulfonyl]-phenyl}quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} -carbamate
135. tert-Butyl [(/rafts-4-{[({2-[4-(ammosulfonyl)phenyl]-quinolin-4- yl} carbonyl)amino]-methyl} -cyclohexyl)methyl] -carbamate 136. Tetrahydro-2H-pyran-4-yl {[?rα«5 f -4-({[(2-{4-[(methylamino)sulfonyl]phenyl}- quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
137. β^-Tetrahydrofuran-S-yl {[?rα«5 f -4-({[(2-{4-[(methylamino)sulfonyl]phenyl}- quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} -carbamate
138. Tetrahydro-2H-pyran-4-yl [(trans-4- { [( {2-[4-(aminosulfonyl)phenyl]-quinolin- 4-yl} carbonyl)amino]-methyl} cyclohexyl)-methyl]carbamate
139. β^-Tetrahydrofuran-S-yl [(?rfl«5 f -4-{[({2-[4-(aminosulfonyl)phenyl]-quinolin- 4-yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate
140. Tetrahydro-2H-pyran-4-yl {[trans-4-({[(2-{4- [(dimethylamino)sulfonyl]phenyl} -quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl] - methyl} carbamate
141. β^-Tetrahydrofuran-S-yl {[trans-4-({[(2-{4-
[(dimethylamino)sulfonyl]phenyl} -quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl] - methyl} carbamate
142. tert-Butyl [(trans-4- {[({2-[6-(4-acetylpiperazin-l -yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
143. tert-Butyl { [trans-4-( { [(2- {6-[(2-hydroxyethyl)amino]pyridin-3-yl} quinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
144. tert-Butyl ({?rfl«5 f -4-[({[2-(6-pyrrolidin-l-ylpyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate 145. tert-Butyl ({?rfl«5 f -4-[({[2-(6-morpholin-4-ylpyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
146. tert-Butyl ({?rα«5 f -4-[({[2-(6-{[2-(dimethylamino)ethyl]amino}pyridin-3- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate
147. tert-Butyl {[?ra«*-4-({[(2-{6-[(3R)-3-hydroxypyrrolidin-l-yl]pyridin-3 - yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
148. tert-Butyl ( {trans-4- [( { [2-(6- { [( 15 r )-2-hydroxy- 1 -methylethyl] amino } pyridin- 3-yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)c arbamate
149. tert-Butyl ({trans-4-[({[2-(6-{[(lR)-2-hydroxy-l-mQthylQthyl]ammo}τpyr idm- 3-yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)c arbamate
150. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[(3-hydroxypropyl)amino]pyridin-3-yl}quinolin- 4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate 151. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-hydroxypiperidin-l-yl)pyridin-3-yl]quinolin-4 - yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
152. tert-Butyl {[/rø«s-4-({[(2-{6-[bis(2-hydroxyethyl)ammo]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
153. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-carbamoylpiperidin-l-yl)pyridin-3-yl]quinolin - 4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
154. tert-Butyl ({?rfl«5 f -4-[({[2-(6-piperazin-l-ylpyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
155. tert-Butyl ( {trans-4-[( {[2-(6- {[2-(2-hy droxyethoxy)ethyl] amino }pyridin-3- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate 156. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[(2-methoxyethyl)amino]pyridin-3-yl}quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
157. tert-Butyl [(?ra«5 f -4-{[({2-[6-(3-hydroxypiperidin-l-yl)pyridin-3-yl]quinolin-4 - yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
158. 3-{[5-(4-{[(trans-4-{[(tert- Butoxycarbonyl)amino]methyl} cyclohexyl)methyl]-carbamoyl} quinolin-2-yl)pyridin-2- yl] amino }-2-methylpropanoic acid
159. tert-Butyl ( {trans-4-[( { [2-(6- { [(5 -methylpyrazin-2-yl)methyl] amino } pyridin-3 - yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate
160. tert-Butyl {[?ra«5 f -4-({[(2-{6-[(3 l S r )-3-(dimethylamino)pyrrolidin-l-yl]pyridin- S-yllquinolin^-y^carbonylJaminolmethy^cyclohexy^methyl} carbamate
161. tert-Butyl { [trans-4-( { [(2- {6-[4-(hydroxymethyl)piperidin- 1 -yl]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
162. tert-Butyl {[?rα«5 f -4-({[(2-{6-[(2,3-dihydroxypropyl)amino]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate 163. tert-Butyl {[?ra«5 f -4-({[(2-{6-[(2 l S r )-2-carbamoylpyrrolidin-l-yl]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
164. tert-Butyl ({trarø-4-[({[2-(6-{[2-hydroxy-l- (hydroxymethyl)ethyl] amino } pyridin-3 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
165. tert-Butyl [(?rα«5 f -4-{[({2-[6-(3-oxopiperazin-l-yl)pyridm-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
166. tert-Butyl ({tra«s-4-[({[2-(6-{[(l-methyl-lH-pyrazol-4- yl)methyl]amino}pyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
167. tert-Butyl {[trafts-4-({[(2-{6-[(3-amino-3-oxopropyl)amino]pyridin-3- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
168. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(3-hydroxyazetidin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
169. tert-Butyl ({?rfl«5 f -4-[({[2-(6-{[(l l S r )-l-carbamoylpropyl]amino}pyridin-3- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate 170. tert-Butyl ({tra«s-4-[({[2-(6-{[(5-methyl-l,2,4-oxadiazol-3- yl)methyl]amino}pyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
171. tert-Butyl {[?rα«5 f -4-({[(2-{6-[2-(hydroxymethyl)morpholin-4-yl]pyridin-3- y 1} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate 172. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(4-oxoimidazolidin-l-yl)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
173. tert-Butyl [(trans-4- { [( {2- [6-(tetrahydrofuran-3 -ylmethoxy)pyridin-3 - yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
174. tert-Butyl [(?rα«5 f -4-{[({2-[6-(2-hydroxyethoxy)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
175. tert-Butyl [(trans-4- { [( {2- [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3 - yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
176. tert-Butyl [(?rα«5 f -4-{[({2-[6-(2-hydroxy-l-methylpropoxy)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate 177. tert-Butyl {[?rα«5 f -4-({[(2-{6-[(2-oxopyrrolidin-l-yl)methoxy]pyridin-3- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate
178. tert-Butyl [(?rfl«5 f -4-{[({2-[6-(2-amino-2-oxoethoxy)pyridin-3-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
179. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[2-(4-methylpiperazin-l-yl)ethoxy]pyridin-3- y 1} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate 180. tert-Butyl [(?rα«5 f -4-{[({2-[3-(4-methylpiperazin-l-yl)propoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
181. tert-Butyl [(?rfl«5 f -4-{[({2-[3-(dimethylamino)propoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
182. tert-Butyl [(trans-4- { [( {2-[2-(4-methylpiperazin- 1 -yl)ethoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
183. tert-Butyl [(?rfl«5 f -4-{[({2-[3-(4-acetylpiperazin-l-yl)propoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
184. tert-Butyl {[?rfl«5 f -4-({[(2-{6-[2-(dimethylamino)ethoxy]pyridin-3-yl}quinolin- 4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate 185. tert-Butyl [(?rfl«5 f -4-{[({2-[4-(2-hydroxyethyl)piperazin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
186. tert-Butyl {[?ra«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]-piperazin-l- yl} quinolin-4-yl)carbonyl] amino} -methyl)cyclohexyl]methyl} carbamate
187. tert-Butyl ({?rα«5 f -4-[({[2-(4-hydroxypiperidin-l-yl)quinolin-4- yljcarbonyl} amino)-methyl]cyclohexyl}methyl)carbamate
188. tert-Butyl [(trans-4- { [( {2-[4-(hydroxymethyl)-piperidin- 1 -yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate
189. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-hydroxyethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate 190. tert-Butyl {[£rafts-4-({[(2-piperazin-l-ylquinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
191. tert-Butyl [(trans-4- { [( {2-[4-(acetamidomethyl)piperidin- 1 -yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
192. tert-Butyl [(?rα«5 f -4-{[({2-[4-(2-acetamidoethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
193. tert-Butyl { [trans-4-( {[(2- {4- [2-(dimethylamino)ethyl]piperidin- 1 -yl} quinolin- 4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
194. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-aminoethyl)piperidin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
195. Tetrahydro-2H-pyran-4-yl {[trans-4-({[(2-{6-[2- (dimethylamino)ethoxy]pyridin-3-yl}quinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
196. (3S)-Tetrahydrofuran-3-yl {[trans-4-({[(2-{6-[2- (dimethylamino)ethoxy]pyridin-3-yl}quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
197. Tetrahydro-2H-pyran-4-yl { [trans-4-( { [(2- {6- [(2-hydroxyethyl)amino]pyridin- 3-yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
198. Tetrahydro-2H-pyran-4-yl ( {trans -4-[({[2-(6- {[2- (dimethylamino)ethy 1] amino } -pyridin-3 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
199. (3S)-Tetrahydrofuran-3-yl ({trans-4-[({[2-(6-{[2- (dimethylamino)ethy 1] amino } -pyridin-3 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
200. P^-Tetrahydrofuran-S-yl {[?ra«5-4-({[(2-{6-[(2-hydroxyethyl)amino]pyridin- S-yllquinolin^-y^carbonylJaminolmethy^cyclohexy^methyl} carbamate
201. (S^-Tetrahydrofuran-S-yl {[?rarø-4-({[(2-{6-[(3tf)-3-hydroxypyrrolidin-l- yl]pyridin-3-yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate
202. Tetrahydro-2H-pyran-4-yl {[?ra«5-4-({[(2-{6-[(3R)-3-hydroxypyrrolidin-l- yl]pyridin-3-yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohex yl]methyl}carbamat
203. tert-Butyl { [trans-4-( { [(2- {4- [2-(dimethylamino)ethoxy]phenyl} quinolin-4- y l)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate 204. tert-Butyl ({?rfl«5 f -4-[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl}carbonyl)amino]cyclohexyl}methyl)carbamate,
205. tert-Butyl {[?rα«5 f -4-({[(2-{4-[3-(dimethylamino)-2-hydroxypropyl]piperidin- 1 -yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate;
206. tert-Butyl [(?rα«5 f -4-{[({2-[4-(2-hydroxy-3-pyrrolidin-l-ylpropyl)-piperidin-l- yl]quinolin-4-yl} carbonyl)amino]-methyl} cyclohexyl)methyl] carbamate;
207. (R) or ( S) tert-Butyl [(trø«s-4-{[({2-[4-(2-hydroxy-3-morpholin-4- ylpropyl)piperidin- 1 -yl]quinolin-4-yl} -carbonyl)amino]methyl} cyclohexyl)methyl]- carbamate;
208. (S) or (R) tert-Butyl [(?ra«*-4-{[({2-[4-(2-hydroxy-3-pyrrolidin-l-ylpropyl)- piperidin- 1 -yl]quinolin-4-yl} carbonyl)amino] -methyl} cyclohexyl)methyl] carbamate;
209. tert-Butyl [(?ra«5 f -4-{[({2-[4-(2-hydroxy-3-pyrrolidin-l-ylpropyl)-piperidin-l- yl]quinolin-4-yl}carbonyl)amino]-methyl}cyclohexyl)methyl]ca rbamate;
210. tert-Butyl { [trans-4-( { [(2- {4-[2-(dimethylamino)-2-oxoethoxy]piperidin- 1 - yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate; 211. tert-Butyl {[?rfl«5 f -4-({[(2-{4-[2-(dimethylamino)ethoxy]piperidin-l- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
212. 2,2-Dimethylpropyl { [trans-4-( { [(2- {4- [2-(dimethylamino)ethyl]piperidin- 1 - yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
213. tert-Butyl [(trans-4- { [( {2-[4-(morpholin-4-ylmethyl)piperidin- 1 -yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]-carbamate;
214. tert-Butyl [(?rfl«5 f -4-{[({2-[4-(4-methylpiperazin-l-yl)piperidin-l-yl]quinolin- 4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] -carbamate;
215. tert-Butyl ( {trans-4-[( { [2-(pyridin-3-yloxy)quinolin-4-yl]carbonyl} amino)- methyl]cyclohexyl}methyl)carbamate; 216. tert-Butyl [(?rα«5 f -4-{[({2-[(l-methylpiperidin-4-yl)methoxy]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]-carbamate;
217. tert-Butyl ( {trans-4- [( { [2-(3 - { [2-(dimethylamino)ethyl] carbamoyl} azetidin- 1 - yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate;
218. tert-Butyl ( {trans-4-[( { [2-(4-aminophenyl)quinolin-4-yl]carbonyl} amino)- methyl]cyclohexyl}methyl)carbamate;
219. tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]-3-oxopiperazin-l- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
220. tert-Butyl [(?rα«5 f -4-{[({2-[4-(hydroxyacetyl)piperazin-l-yl]quinolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate; 221. tert-Butyl {[?rα«s-4-({[(2-{4-[(4-fluorobenzyl)oxy]piperidin-l-yl}qui nolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate;
222. tert-Butyl {[trafts-4-({[(2-amino-l-benzothioprien-3- yl)carbony 1] amino } methyl)-cyclohexyl]methyl} carbamate;
223. tert-Butyl [(?rα«5 f -4-{[({2-[(ethylcarbamoyl)amino]-l-benzothiophen-3- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate; 224. Tetrahydro-2H-pyran-4-yl {[trans -4-({[(2-{4-[2-
(dimethylamino)ethyl]piperidin- 1 -yl} quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate;
225. tert-Butyl ( {trans-4-[( { [2-( 1 '-methyl-4,4'-bipiperidin- 1 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate; 226. tert-Butyl ({?rα«5 f -4-[({[2-(4-{2-[(2-methoxyethyl)amino]ethyl}piperidin-l- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate; 227. ^r?-Butyl ({?ra«5-4-[({[2-(4-{2-[(2-methoxyethyl)(methyl)- amino]ethyl}piperidin-l-yl)quinolin-4-yl]carbonyl}amino)-met hyl]cyclohexyl}- methyl)carbamate; 228. tert-Butyl {[zrørø-4-({[(2-{4-[2-(tetrahydro-2η-pyran-4- ylamino)ethyl]piperidin- 1 -yl} quinolin-4-yl)carbonyl]amino} -methyl)cyclohexyl]- methyl} carbamate;
229. tert-Butyl {[trans-4-({[(2-{4-[2-(3-methoxyazetidin-l-yl)ethyl]piperidi n-l- yl} quinolin-4-yl)carbonyl] amino} -methyl)cyclohexyl]-methyl} carbamate; 230. tert-Butyl {[?rfl«5 f -4-({[(2-{4-[2-(3-hydroxypyrrolidin-l-yl)ethyl]piperidin-l- yl} quinolin-4-yl)carbonyl] amino} -methyl)cyclohexyl]-methyl} carbamate;
231. tert-Butyl [(trans-4- { [( {2- [4-(2-pyrrolidin- 1 -ylethyl)piperidin- 1 -yl]quinolin-4- yl} carbonyl)amino]-methyl} cyclohexyl)-methyl] carbamate;
232. tert-Butyl ({tra«^-4-[({[2-(4-{2-[(2-hydroxyethyl)(methyl)- amino]ethyl}piperidin-l-yl)quinolin-4-yl]carbonyl}amino)-met hyl]cyclohexyl}- methyl)carbamate;
233. tert-Butyl {[trans-4-( {[(2- {4-[2-(3-hydroxyazetidin- 1 -yl)ethyl]piperidin- 1 - yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
234. tert-Butyl [(tra«5-4-{[({2-[4-(2-azetidin-l-ylethyl)piperidin-l-yl]qui nolin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
235. l-{2-[l-(4-{[(trans-4-{[(tert-
Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]-carbamoyl} quinolin-2-yl)piperidin-4- yl]ethyl} azetidine-3-carboxylic acid;
236. tert-Butyl {[trans-4-( {[(2- {4-[2-(3-aminoazetidin- 1 -yl)ethyl]piperidin- 1 - yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate;
237. tert-Butyl {[?rα«5 f -4-({[(2-{4-[3-(dimethylamino)-2-fluoropropyl]piperidm-l- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
238. tert-Butyl { [trans-4-( { [(2- {3 - [2-(dimethylamino)ethoxy]azetidin- 1 - yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate; 239. tert-Butyl [(?ra«5-4-{[({2-[3-(aminomethyl)phenyl]-6-(lH-pyrazol-4- yl)pyridin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carb amate;
240. tert-Butyl [(trans-4- {[({6-[3-(aminomethyl)phenyl]-2,3'-bipyridin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
241. tert-Butyl [(?ra«5 f -4-{[({6'-amino-6-[3-(aminomethyl)phenyl]-2,3'-bipyridin-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate;
242. tert-Butyl {[?ra«5-4-({[(2-{l-[2-(dimethylamino)ethyl]-lH-pyrazol-4- yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl]methyl} carbamate;
243. ^r?-Butyl [(?ra«5-4-{[({2-[l-(2-hydroxyethyl)-lH-pyrazol-4-yl]quinoli n-4- yl} carbonyl)amino]methyl} cyclohexyl)methyl]carbamate; 244. tert-Butyl ({?ra«5'-4-[({[2-(4-{2-[(2-fluoroethylamino]ethyl}piperidin -l- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate;
245. ?er?-Butyl ({?ra«5'-4-[({[2-(4-(2-((2-fluoroethyl)(methyl)amino)ethyl} piperidin- l-yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)c arbamate; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof.
Preparation
A compound of formula (I) or formula (II) and its salts may be prepared by any process known to be applicable to the preparation of chemically related compounds. Such processes, when used to prepare a compound of the formula (I) or formula (II), or a pharmaceutically-acceptable salt thereof, are provided as a further feature of the invention.
(I)
In a further aspect the present invention also provides that the compounds of the formula (I) or formula (II) and salts thereof, can be prepared by a process a) to f) as follows (wherein all variables are as hereinbefore defined for a compound of formula (I) or formula (II) unless otherwise stated).
a) Compounds of formula (2) can be coupled to compounds of formula (3) in a solvent such as DCM to form compounds of formula (I) or formula (II). For example, if L = C(O) and Y = OH, then using a solvent such as DCM and a coupling reagent such as TBTU in the presence of a base such as TEA or NMM or by using EDC, HOBT and NMM in a mixture of 2-methyltetrahydrofuran and water. If L = SO 2 and Y = Cl, then using a solvent such as DCM in the presence of a base such as TEA.
(2) (3) (4) b) Alternatively, compounds of formula (2) can be coupled to thiols of formula (4) according to the procedure described in Wright, S., Hallstrom, K. N., J. Org. Chem., 2006, 71, p. 1080-1084 to form compounds of formula (I) where L = SO 2 .
c) Compounds of formula (I) can also be prepared by reacting compounds of formula (5), where X is a suitable group such as a trifluoromethylsulfonyl group or a halo, such as chloro or bromo, with compounds of formula (6) where Zi and Z 2 are both H or Zi and Z 2 together represent -C(CHs) 2 C(CHs) 2 -, in the presence of a transition metal catalyst, preferably palladium. These reactions take place in solvents such as dioxane or ACN and
water and in the presence of a base such as K 2 CO 3 or NaHCO 3 . Compounds of formula (5) where X is a suitable group such as a halo, such as chloro or fluoro can also be treated with compounds of formula (7) or (8) or nitrogen containing heterocycles, such as piperidine or piperazine, with or without a base such as KOH in a solvent such as THF and
ACN or pyridine to give additional compounds of formula (I),
d) Compounds of formula (I) can also be formed by reacting an amine of formula (9) with a reagent of formula (10) and LG = a suitable leaving group such as chloro or 4- nitrophenoxy, in a solvent such as DCM or THF using a base such as TEA. Similarly, compounds of formula (I) can be formed by reacting an amine of formula (9) with an isocyanate of formula (11) in a solvent such as DCM or ACN using a base such as TEA, or with a carbamoyl chloride of formula (12) in a solvent such as DCM or ACN using a base such as TEA.
(9) ( 10) ( 1 1 ) 12) e) Furthermore, additional compounds of formula (I) can be prepared by treating compounds of formula (I) where R3 = H with compounds of formula (13) where R3 is as defined herein and LG is a suitable leaving group known to someone skilled in the art, for example iodide. This reaction can take place in a solvent such as THF and/or DMF using a base such as K 2 CO 3 and/or sodium hydride.
LG (13) f) Additional compounds of formula (I) can also be prepared by treating compounds of formula (I), such as compounds of formula (14) where X is a suitable leaving group such as a halo, such as chloro or fluoro, with compounds of formula (7) or (8) or nitrogen containing heterocycles, such as piperidine or piperazine, with or without a base such as
KOH in a solvent such as THF and ACN or pyridine.
Compounds of formula (I) to (14) may be made by application of standard synthetic methods known to someone skilled in the art. The processes a)-f) can be used in different orders to form the compounds (I). Some of the described processes may involve the use of protecting groups as known to someone skilled in the art, for example, a Boc group may be used to protect an amino group. The protecting groups can then be removed according to the art, for example, using trifluoroacetic acid to remove a Boc group to give compounds of formula (I). Once a protecting group has been removed the released functional group may be manipulated further using standard synthetic methods known to someone skilled in the art. For example, an amino group may be transformed into an acetamide by treatment with an alkylating agent such as acetic anhydride.
The starting materials for the described processes a)-f) can be prepared as follows:
Compounds of formula (I) and also compounds of formula (5) and (14) can be formed by reacting a compound of formula (2) with a carboxylic acid of formula (3), using a coupling agent such as TBTU in the presence of a base such as DIPEA in a solvent such as DMF or
DCM, to form the amide bond. Alternatively, EDC, HOBT and NMM in a mixture of 2- methyltetrahydrofuran and water can be used in place of TBTU and DIPEA in DMF or DCM.
Scheme 1
Alternatively, for compounds of formula (I), (5) and (14) where L = SO 2 then compounds of formula (2) can be treated with a sulfonyl chloride of formula (3), in the presence of a base such as TEA in a solvent such as DCM, to form the sulfonamide bond as shown in Scheme 2.
(2) (3)
Scheme 2
Compounds of formula (2) can be synthesised by the method described in Scheme 3. Amines of formula (15) can be treated with different acylating agents, such as compounds of formula (10) and (11) to form the Boc-protected compounds (16). For example, the amine (15) can be treated with chloroformates (10) or 4-nitrophenylcarbonates (10) in the presence of a base such as TEA to form carbamates or the amine (15) can be treated with isocyanates (11) using TEA as a base to form ureas. The Boc protecting group in compounds of formula (16) can then be removed using an acid, for example IN HCl in EtOAc or TFA, to form amines of formula (2).
(2)
Scheme 3
Compounds of formula (3) are either commercially available or can be synthesised. For example, carboxylic acids of formula (3) can be synthesised by a coupling reaction such as a palladium coupling or a nucleophilic aromatic substitution reaction. For example, the 2- chloro compound of general formula (3) shown in Scheme 4 can be treated with the boronic ester (6) and a palladium catalyst like [l,3-bis(2,6-diisopropylphenyl)imidazol-2- ylidene](3-chloropyridyl)-palladium(II) dichloride (PEPPSI) in the presence of an aqueous alkalimetal carbonate like K 2 CO 3 using an organic solvent like dioxane to give further compounds of formula (3).
Scheme 4
Alternatively, the 2-chloro containing starting material (3) shown in Scheme 4 can be treated with an amine (7) with pyridine as solvent or with an alcohol (8) using a base such as KOH in a solvent mixture of THF and ACN to give further compounds of formula (3). It is also understandable to someone skilled in the art that the metal mediated coupling reaction can be followed by the nucleophilic substitution reaction in the same molecule. An example of this is shown in Scheme 5.
HlSL _ : Pyidine
(7)
Scheme 5
Further compounds of formula (3) may be synthesised as shown in Scheme 6. 2,3- Dihydro-indole-2,3-dione (isatin) (17) was treated with a methyl ketone (18) in the presence of KOH using EtOH as solvent to provide the quinoline compounds of formula (3).
(17) (18) (3)
Scheme 6
Thiol compounds of formula (4) required as starting material in process b) can be synthesised by refluxing an appropriate chloro-substituted derivative (19), where Z is a heteroaryl or an appropriately substituted aryl compound that will be known to someone skilled in the art, with sodium ethanethiolate (20) in a solvent such as DMF as shown in Scheme 7. For example 4-chloro-2-phenyl-quinoline (21) can be refiuxed with sodium ethanethiolate (20) in a solvent such as DMF to give the quinoline compound of formula (4) as shown in Scheme 7.
Cl — z HS-Z
DMF
(19) (20) reflux 1 .5h (4)
Scheme 7
All processes discussed herein can be used in different orders to form the required intermediates, such as compounds of formula (5) and (14). This is known to someone skilled in the art. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, techniques which are described or illustrated in the references given above, or techniques which are analogous to the above described procedure or the procedures described in the examples.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley and Sons, 1991, or PJ. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994).
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
It will be appreciated by those skilled in the art that certain compounds of formula I may be transformed into other compounds of formula I by functional group modifications known to those skilled in the art. For example a hydroxy group may be converted into a leaving group for example a mesylate and then displaced with an amine or an aliphatic carbon atom bearing a hydroxy group may be oxidised to an aldehyde and then reacted with an amine using reductive amination. Certain intermediates are believed to be novel and form a further part of the present invention.
Pharmaceutical preparations
The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-5 mg/kg body weight. Oral formulations are preferred, particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg.
According to a further aspect of the invention there is also provided a pharmaceutical formulation comprising a compound of formula (I), or pharmaceutically acceptable salt
thereof, including the compound of the proviso, in a mixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
Pharmacological properties The compounds of formula (I) or formula (II) are useful for the treatment of obesity or being overweight,
(e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating), dyslipidaemia and the treatment of type 2 diabetes mellitus.
The present compounds of formula (I) or formula (II) are useful for the prophylaxis and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as the metabolic syndrome). These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoprotein (VLDL) triglyceride rich particles, high Apo B levels, low high density lipoprotein (HDL) levels associated with low apoAI particle levels and high Apo B levels in the presence of small, dense, low density lipoproteins (LDL) particles, phenotype B.
The compounds of the present invention are expected to be useful in treating patients with combined or mixed hyperlipidemias or various degrees of hypertriglyceridemias and postprandial dyslipidemia with or without other manifestations of the metabolic syndrome.
Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as antiinflammatory properties. The cardiovascular disease conditions include macro- angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency of the lower
extremities. Because of their insulin sensitizing effect the compounds of formula (I) or formula (II) are also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome and diabetes of pregnancy. Therefore the development of long- term complications associated with chronic hyperglycaemia in diabetes mellitus, such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs, is expected to be delayed.
The compounds of formula (I) or formula (II) may also be useful in the treatment of metabolic syndrome and Prader-Willi syndrome.
In another aspect the present invention provides a compound of formula (I) or formula (II) as previously defined for use as a medicament.
In a further aspect the present invention provides the use of a compound of formula (I) or formula (II) in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) and for the treatment or prophylaxis of dyslipidaemia and for the treatment or prophylaxis of type 2 diabetes mellitus.
In a still further aspect the present invention provides a method of treating obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) dyslipidaemia and type 2 diabetes mellitus comprising administering a pharmacologically effective amount of a compound of formula (I) or formula (II), including the compound of the proviso b), to a patient in need thereof.
Combination Therapy The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat
absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or gastrointestinal motility.
The compounds of the invention may further be combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias and diabetes. For example, a compound of the present invention may be used in combination with another therapeutic agent that lowers blood pressure or that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.
The compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors).
In another aspect of the invention, the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
In addition the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin.
In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.
The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha/beta adrenergic blocker, an adrenergic
stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a CBl receptor antagonist /inverse agonist; a melanin concentrating hormone (MCH) modulator; a melanocortin-4 receptor agonist; an NPY receptor modulator; an orexin receptor modulator; a diacylglycerol acyltransferase-l inhibitor; a diacylglycerol acyltrαnsferasQ-l inhibitor; a phosphoinositide-dependent protein kinase (PDK) modulator; or modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β, PP ARa, β, γ and RORalpha; a monoamine /ra/ismission-modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent (TCA), a noradrenergic and specific serotonergic antidepressant
(NaSSA); an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/leptin receptor modulator; a ghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; an SGLT-2 inhibitor; a GLK activator; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment.
Therefore in an additional feature of the invention, there is provided a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt
thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
Therefore in an additional feature of the invention, there is provided a method for the treatment of diabetes mellitus and obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, including the compounds of the provisos b) and c), in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, including the compounds of the proviso b), and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, including the compounds of the proviso b), and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the present invention there is provided a kit comprising:
a) a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, including the compounds of the proviso b), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to another feature of the invention there is provided the use of a compound of the formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, including the compounds of the proviso b), and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of obesity and its associated complications in a warm-blooded animal, such as man.
According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, including the compounds of the proviso b), optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment.
Furthermore, a compound of the invention may also be combined with other therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis).
It will be understood that there are medically accepted definitions of obesity and being overweight. A patient may be identified by, for example, measuring body mass index
(BMI), which is calculated by dividing weight in kilograms by height in metres squared, and comparing the result with the definitions.
Pharmacological activity / Biological tests ASSAY Y
Human recombinant Acetyl-CoA Carboxylase 1 and Acetyl-CoA Carboxylase 2 (ACCl and ACC2) were assayed by determining the amount of inorganic phosphate (P 1 ) generated. Preincubation of 6 μL enzyme together with 0.3 μL compound for 15 min was done before the reaction was initiated by the addition of 4 μL substrate. The reaction was carried out in 384-well plates at room temperature containing the following constituents; 1 mM ATP, 0.4 mM Acetyl-CoA, 20 mM Citrate, 50 mM Hepes (pH 7.5), 12.5 mM NaHCO 3 , 20 mM MgAc 2 x 4 H 2 O, 1.5 mM MgSO 4 x 7 H 2 O, 1 mM TCEP, 0.025% BSA, compound at different concentrations, ACCl (diluted 1:50) or ACC2 (diluted 1:15). After 3 hr the reaction was stopped by addition of 60 μL of water followed by 30 μL Malachite Green solution. The Malachite Green solution was prepared by mixing 16.4 mL ammonium molybdate solution (7.5%), 1.64 mL Tween (11%) with 82 mL Malachite Green/H 2 SO 4 -solution (0.7g Malachite Green to 1000 mL of 10% (v/v) H 2 SO 4 ). Plates were left for 10 min at room temperature before reading the absorbance at 670 nm.
All compounds were tested in triplicate at 10 different concentrations. Control compound (0, 50 and 100% effect) was included on each plate. The inhibitory effect of a compound was calculated by %inhibition = 100 * [(X-max)/(min-max)], where X is the readout value in the compound well. Min is the average signal for 100% inhibition and Max is the average signal for 0% inhibition in the control wells. An IC50 value was derived by non- linear regression curve fitting using the following equation: y = A+((B-A)/l+((C/x) λ D))) where A is the non-specific binding, B is the total binding, C is the IC50 and D is the slope. Saturation binding Kd and Bmax were derived using the equation y = ((Blmax*x)/(Kd+x)).
ASSAY X
Human recombinant Acetyl-CoA Carboxylase 1 and Acetyl-CoA Carboxylase 2 (ACCl and ACC2) were assayed by determining the amount of inorganic phosphate (P 1 ) generated. Pre-incubation of 15 μL enzyme together with 0.75 μL DMSO +/- compound for 5 min was done before the reaction was initiated by the addition of 10 μL substrate. The reaction was carried out in 384-well plates at 37 0 C containing the following constituents (n=2); 1 mM ATP, 0.4 mM acetyl-CoA, 20 mM citrate, 50 mM Hepes (pH 7.5), 12.5 mM NaHCO 3 , 20 mM MgAc 2 x 4 H 2 O, 1.5 mM MgSO 4 x 7 H 2 O, 1 mM TCEP, 0.025% BSA, compound at different concentrations, ACCl and ACC2 diluted to generate signals resulting in assay Z'>0.5. After 1.5 h the reaction was stopped by addition of 74 μL of water followed by extensive mixing, split and transfer of 2 x 40 μL to a read-plate encompassing 30 μL distilled H 2 O per well (n=2 -> n=4). Colour reaction was initiated by addition of 30 μL malachite green reagent per well and allowed 15 min before absorbance reading of the plates at 660 nm. The malachite green reagent was prepared by mixing 16.4 mL ammonium molybdate solution (7.5%), 1.64 mL Tween (11%) with 82 mL Malachite Green/H 2 SO 4 -solution (0.7g Malachite Green to 1000 mL of 10% (v/v) H 2 SO 4 ).
All compounds were tested in triplicate at 10 different concentrations. Control compound (0, 50 and 100% effect) was included on each plate. The inhibitory effect of a compound was calculated by % inhibition = 100 * [(X-Max)/(Min-Max)], where X is the readout value in the compound well. Min is the average signal for 100% inhibition and Max is the average signal for 0% inhibition in the control wells. Curve fitting was done using the following equation: y = (A+((B-A)/(l+((x/C) λ D)))) where A and B represents the curve bottom (% inhibition) and the total amplitude (% inhibition), respectively, whereas C and D are the apparent IC50 and curve slope, respectively.
The compounds of the invention exhibit activity as ACC2 inhibitors. Further, some of the compounds do also, in addition, exhibit activity as ACCl inhibitors. Compounds of the present invention typically show an IC50 of less than 20 μM vs ACC2, preferably less than 10 μM. The following table shows the biological activities for the exemplified examples.
Examples 121-132, 150-179, 190-203 were tested using the assay conditions described in Assay X. All of the other Examples were tested using the assay conditions described in Assay Y. i) Examples 205-245 were tested using the assay conditions described in Assay X.
EXAMPLES
Abbreviations
AcOH Acetic acid
ACN Acetonitrile
DCM Dichloromethane
DIPEA iV,./V-Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DME Dimethoxyethane
DMF Dimethylformamide
DMSO Dime thy lsulfoxide
EDC 1 -Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride
EtOAc Ethyl acetate
EtOH Ethanol
HOBT 1 -Hydroxybenzotriazole
K 2 CO 3 Potassium carbonate
KOH Potassium hydroxide
MeOH Methanol
MCPBA meto-Chloroperoxybenzoic acid "
MgAc 2 Magnesium acetate
NaHCO 3 Sodium hydrogencarbonate
NH 4 Cl Ammonium chloride
NMM ./V-Methylmorpholine
NMP iV-Methyl-2-pyrrolidone
Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0)
PEPPSI l,3-bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II)dichloride
TBTU O-(benzotriazol- 1 -yl)-λf,λf,λ^,λ^-tetramethyluronium tetrafluoroborate
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran TBAF tert-Butyl ammonium fluoride aq. aqueous eq. equivalents h hour min minutes rt room temperature
HPLC Standard method A:
Column: Kromasil, C8, 10μm, 21.2 mm x 250 mm Mobile phase A: 100% ACN Mobile phase B: 5% ACN + 95% 0. IM NH 4 OAc Gradient: ca 30 -100% A over ca 30 min.
HPLC Standard method B:
Waters Fraction Lynx Purification System with Phenomenex Gemini Cl 8 5 μm 21.2 mm x 100 mm columns. The mobile phase used was varying gradients of ACN and 0.2% NH 3 buffer; flow rate 30 mL/min; MS-triggered fraction collection was used.
HPLC Standard method C:
Waters Fraction Lynx Purification System with Xbridge Prep Cl 8 5 μm OBD 19 mm x 150 mm columns. The mobile phase used was varying gradients of ACN and 0.2% NH 3 buffer; flow rate 30 mL/min; MS-triggered fraction collection was used.
HPLC Standard method D:
Column: Kromasil, C8, lOμm, 50.8 mm x 300 mm Mobile phase A: 100% ACN
Mobile phase B: 5% ACN + 95% 0.1M NH 4 OAc Gradient: ca 0 - 100% A over ca 40 min.
HPLC Standard method E:
Waters Fraction Lynx Purification System with Kromasil C8 5 μm 20 mm x 100 mm columns. The mobile phase used was varying gradients of ACN and 100 mM ammonium acetate buffer; flow rate 30 mL/min; MS-triggered fraction collection was used.
HPLC Standard method F:
Waters Fraction Lynx Purification System with Xbridge Prep Cl 8 5 μm OBD 19 mm x 150 mm columns. The mobile phase used was varying gradients of ACN and 0.1 M HCO 2 H buffer; flow rate 30 mL/min; MS-triggered fraction collection was used.
HPLC Standard method G: Column: Kromasil, C8, lOμm, 20 mm x 50 mm Mobile phase A: 100% ACN Mobile phase B: 5% ACN + 95% 0.1 M HCO 2 H Gradient: ca 20 -100% A over ca 25 min.
HPLC Standard method H: Column: Kromasil, C8, lOμm, 19 mm x 250 mm Mobile phase A: 100% ACN
Mobile phase B: 5% ACN + 95% 0.1M NH 3 Gradient: ca 30 -100% A over ca 30 min.
* Wet 1 H NMR in DMSO/DMSO-JO: The solutions are taken from a concentrated sample dissolved in (CHs) 2 SO and are diluted with (CDs) 2 SO. Since a substantial amount of (CHs) 2 SO is present in the sample, first a pre-scan is run and analysed to automatically suppress the (CH 3 ) 2 SO (2.54 ppm) and H 2 O (3.3 ppm) peaks. This means that in this so- called wet ID experiment the intensity of peaks that reside in these areas around 3.3 ppm and 2.54 ppm are reduced. Furthermore impurities are seen in the spectrum which give rise to a triplet at 1.12 ppm, a singlet at 2.96 and two multiplets between 2.76-2.70 ppm and 2.61-2.55 ppm. Most probably these impurities are dimethylsulfone and diethylsulfoxide.
Cation exchange resin CBA (carboxypropyl) commercially available from Biotage was used as its free acid.
Where a microwave is referred to it means a Biotage Initiator or Personal Chemistry
[Biotage] Emrys Optimizer. Drying organic solutions through a phase separator were performed using a IST/Biotage phase separator.
Flash column chromatography was performed using a Horizon/Biotage system with prepacked Biotage Si columns.
Where a lyophilizer is referred to it means a Flexi-Dry MP system from FTS Systems Example 1 (Method 1) tert-Butyl [(?rα«5 f -4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
2-[6-(4-Methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carbox ylic acid [Intermediate A] (50 mg, 0.14 mmol) was dissolved in DCM (3 mL) and tert-butyl {[trans-4-(ammo- methyl)cyclohexyl]methyl}carbamate (38 mg, 0.16 mmol, 1.1 eq.), TBTU (48 mg, 0.15 mmol, 1.05 eq.) and TEA (58 mg, 0.57 mmol, 4.0 eq.) were added and the reaction mixture was stirred at rt for 15 h. The reaction mixture was concentrated in vacuo to leave a residue, which was dissolved in DMSO and purified by HPLC (Standard method A) to give the title compound (47 mg, 57%): 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.10 (d, IH), 8.82 (t, IH), 8.50 (dd, IH), 8.17 - 8.07 (m, 3H), 7.82 (t, IH), 7.63 (t, IH), 7.06 (d, IH), 6.84 (d, IH), 3.69 (t, 4H), 3.28 (t, 2H), 2.84 (t, 2H), 2.48 (t, 4H), 2.29 (s, 3H), 1.90 (d, 2H), 1.78 (d, 2H), 1.59 (s, IH), 1.43 (s, 9H), 1.40 (s, IH), 1.11-0.86 (m, 4H); m/z 573.4 (M+H) + .
The following Examples 2-16 were prepared from the Intermediate listed, in place of 2- [6-
(4-methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carboxyl ic acid, and tert-butyl {[trans-4-
(aminomethyl)cyclohexyl]methyl} carbamate using essentially the same conditions as described for Example 1 (Method 1).
Example 2 tert-Butyl ({/røfts-4-[({[2-(2-methyl-6-oxo-l,6-dihydropyridm-3-yl)qum olin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 11.81 (s, IH), 8.68 (t, IH), 8.06 (d, IH), 7.99 (d, IH), 7.80 (d, IH), 7.75 (t, IH), 7.62-7.56 (m, 2H), 6.74 (t, IH), 6.30 (d, IH), 3.16 (t, 2H), 2.73
(t, 2H), 2.43 (s, 3H), 1.77 (d, 2H), 1.67 (d, 2H), 1.53-1.42 (m, IH), 1.33 (s, 9H), 1.29-1.21
(m, IH), 0.98-0.75 (m, 4H); m/z 505.2 (M+H) + .
Example 3 tert-Butyl {[?rα«5 f -4-({[(2-pyrazin-2-ylquinolin-4-yl)carbonyl]amino}methyl)cyc lo- hexyl]methyl}carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.73 (d, IH), 8.87 (t, IH), 8.82 (t, IH), 8.78 (d, IH), 8.41 (s, IH), 8.18 (d, IH), 8.13 (d, IH), 7.89-7.82 (m, IH), 7.73-7.67 (m, IH), 6.75 (t, IH),
3.20 (t, 2H), 2.74 (t, 2H), 1.79 (d, 2H), 1.69 (d, 2H), 1.57-1.44 (m, IH), 1.33 (s, 9H), 1.31- 1.22 (m, IH), 1.01-0.74 (m, 4H); m/z 476.2 (M+H) + .
Example 4 tert-Butyl ({?rα«5 f -4-[({[2-(4-ethoxyphenyl)quinolin-4-yl]carbonyl}amino)methyl ]- cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.75 (s, IH), 8.22 (d, 2H), 8.10-7.98 (m, 3H), 7.74 (t, IH), 7.56 (t, IH), 7.07 (d, 2H), 6.75 (t, IH), 4.09 (q, 2H), 3.18 (t, 2H), 2.74 (t, 2H), 1.79 (d, 2H), 1.68 (d, 2H), 1.57-1.42 (m, IH), 1.34 (t, 3H), 1.33 (s, 9H), 1.30-1.21 (m, IH), 1.01- 0.75 (m, 4H); m/z 518.0 (M+H) + . Example 5 tert-Butyl ({?rα«5 f -4-[({[2-(6-carbamoylpyridin-3-yl)quinolin-4-yl]carbonyl}ami no)- methyl]cyclohexyl}methyl)carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 9.50 (d, IH), 8.85-8.80 (m, 2H), 8.26 (s, IH), 8.22 (d, 2H), 8.17 (dd, 2H), 7.86 (td, IH), 7.75 (s, IH), 7.70 (t, IH), 6.79 (t, IH), 3.23 (t, 2H), 2.77
(t, 2H), 1.83 (d, 2H), 1.71 (d, 2H), 1.58-1.49 (m, IH), 1.36 (s, 9H), 1.34-1.26 (m, IH), 1.01-0.80 (m, 4H); m/z 518.3 (M+H) + .
Example 6 tert-Butyl {[?rα«5 f -4-({[(2-phenylquinolin-4-yl)carbonyl]amino}methyl)-cyclohex yl]- methyljcarbamate
The title compound was prepared using 2-phenyl-quinoline-4-carboxylic acid in place of 2- [6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carboxyl ic acid: 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.27 (d, 2H), 8.15-8.02 (m, 3H), 7.78 (t, IH), 7.61 (t, IH), 7.57- 7.45 (m, 3H), 6.75 (t, IH), 3.19 (t, 2H), 2.74 (t, 2H), 1.80 (d, 2H), 1.68 (d, 2H), 1.58-1.43 (m, IH), 1.33 (s, 9H), 1.31-1.23 (m, IH), 1.01-0.75 (m, 4H); m/z 474.0 (M+H) + . Example 7 tert-Butyl {[?rα«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)- cyclohexyrjmethyljcarbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.79 (t, IH), 8.75 (dd, 2H), 8.23 (dd, 2H), 8.18 (s, IH), 8.14 (dd, 2H), 7.83 (t, IH), 7.67 (t, IH), 6.75 (t, IH), 3.20 (t, 2H), 2.74 (t, 2H), 1.80 (d,
2H), 1.68 (d, 2H), 1.50 (s, IH), 1.33 (s, 9H), 1.30 (s, IH), 1.00-0.74 (m, 4H); m/z 475.1 (M+H) + .
Example 8 tert-Butyl ({?rα«5 f -4-[({[2-(3-carbamoylphenyl)quinolin-4-yl]carbonyl}amino)met hyl]- cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.80 (t, IH), 8.73 (s, IH), 8.43 (d, IH), 8.20-8.04 (m, 4H), 7.98 (d, IH), 7.79 (t, IH), 7.62 (t, 2H), 7.46 (s, IH), 6.75 (t, IH), 3.20 (t, 2H), 2.74 (t, 2H), 1.80 (d, 2H), 1.68 (d, 2H), 1.51 (s, IH), 1.33 (s, 9H), 1.30 (s, IH), 1.01-0.73 (m, 4H); m/z 517.9 (M+H) + . Example 9 tert-Butyl ({?rα«5 f -4-[({[2-(4-carbamoylphenyl)quinolin-4-yl]carbonyl}amino)met hyl]- cyclohexyl}methyl)carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.83 (t, IH), 8.40 (d, 2H), 8.18 (s, IH), 8.16 (d, 2H), 8.11 (s, IH), 8.07 (d, 2H), 7.84 (t, IH), 7.67 (t, IH), 7.48 (s, H), 6.80 (t, IH), 3.24 (t, 2H),
2.79 (t, 2H), 1.85 (d, 2H), 1.73 (d, 2H), 1.55 (s, IH), 1.38 (s, 9H), 1.34 (s, IH), 1.04-0.82 (m, 4H); m/z 517.9 (M+H) + .
Example 10 tert-Butyl {[?rα«5 f -4-({[(2-{6-[3-(dimethylamino)propoxy]pyridin-3-yl}quinolin- 4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.04 (d, IH), 8.74 (t, IH), 8.57 (dd, IH), 8.11-8.04 (m, 3H), 7.80-7.74 (m, IH), 7.62-7.56 (m, IH), 6.95 (d, IH), 6.75 (t, IH), 4.34 (t, 2H), 3.19 (t, 2H), 2.74 (t, 2H), 2.34 (t, 2H), 2.12 (s, 6H), 1.90-1.76 (m, 4H), 1.69 (d, 2H), 1.56-1.44 (m, IH), 1.33 (s, 9H), 1.31-1.23 (m, IH), 0.99-0.77 (m, 4H); m/z 576.5 (M+H) + . Example 11 tert-Butyl [(?rα«5 f -4-{[({2-[6-(dimethylamino)pyridin-3-yl]quinolin-4-yl}carbon yl)- amino]methyl}cyclohexyl)methyl]carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.00 (d, IH), 8.72 (t, IH), 8.39 (dd, IH), 8.02 (t, 2H), 7.98 (s, IH), 7.74-7.69 (m, IH), 7.55-7.49 (m, IH), 6.79-6.73 (m, 2H), 3.18 (t, 2H), 3.10
(s, 6H), 2.74 (t, 2H), 1.80 (d, 2H), 1.68 (d, 2H), 1.56-1.43 (m, IH), 1.33 (s, 9H), 1.31-1.23 (m, IH), 0.99-0.76 (m, 4H); m/z 518.4 (M+H) + . Example 12 tert-Butyl [(?rα«5 f -4-{[({2-[4-(trifluoromethyl)phenyl]quinolin-4-yl}carbonyl)a mino]- methyl }cyclohexyl)methyl]carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.80 (t, IH), 8.49 (d, 2H), 8.16 (s, IH), 8.13 (d, 2H), 7.91 (d, 2H), 7.82 (t, IH), 7.65 (t, IH), 6.75 (t, IH), 3.20 (t, 2H), 2.74 (t, 2H), 1.80 (d, 2H), 1.68 (d, 2H), 1.58-1.45 (m, IH), 1.33 (s, 9H), 1.31-1.22 (m, IH), 1.00-0.77 (m, 4H); m/z 542.2 (M+H) + . Example 13 tert-Butyl ({?rα«5 f -4-[({[2-(5-acetyl-2-thienyl)quinolin-4-yl]carbonyl}amino)me thyl]- cyclohexyl}methyl)carbamate
tert-Butyl ({?rα«5 f -4-[({[2-(4-fluorophenyl)quinolin-4-yl]carbonyl}amino)methyl ]- cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.34 (dd, 2H), 8.14-8.04 (m, 3H), 7.78 (dd, IH), 7.61 (t, IH), 7.37 (t, 2H), 6.75 (t, IH), 3.19 (t, 2H), 2.74 (t, 2H), 1.80 (d, 2H), 1.68 (d,
2H), 1.57-1.44 (m, IH), 1.33 (s, 9H), 1.30-1.25 (m, IH), 1.01-0.76 (m, 4H); m/z 493.0
(M+H) + .
Example 15 tert-Butyl ({?rα«5 f -4-[({[2-(3,5-dimethylisoxazol-4-yl)quinolin-4-yl]carbonyl}a mino)- methyl]cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.73 (t, IH), 8.04 (t, 2H), 7.79 (t, IH), 7.67-7.57 (m, 2H), 6.79-6.71 (m, IH), 3.18 (t, 2H), 2.73 (t, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 1.77 (d, 2H), 1.68 (d, 2H), 1.56-1.43 (m, IH), 1.33 (s, 9H), 1.30-1.22 (m, IH), 1.02-0.75 (m, 4H); m/z 494.0 (M+H) + . Example 16 tert-Butyl {[?rα«5 f -4-({[(2-pyridin-3-ylquinolin-4-yl)carbonyl]amino}methyl)cyc lo- hexyl]methyl}carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 9.44 (d, IH), 8.77 (t, IH), 8.68 (dd, IH), 8.62 (dt, IH), 8.16 (s, IH), 8.15-8.10 (m, 2H), 7.84-7.78 (m, IH), 7.67-7.61 (m, IH), 7.60-7.55 (m, IH), 6.75 (t, IH), 3.20 (t, 2H), 2.74 (t, 2H), 1.81 (d, 2H), 1.69 (d, 2H), 1.57-1.45 (m, IH), 1.33 (s, 9H), 1.30-1.23 (m, IH), 1.00-0.72 (m, 4H); m/z 475.3 (M+H) + .
The following Examples 17-19 were prepared from the Intermediate listed and ethyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]methyl} carbamate hydrochloride [Intermediate P] in place of tert-butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]methyl} carbamate, using essentially the same conditions as described for Example 1 (Method 1). Example 17
Ethyl ({?rα«5 f -4-[({[2-(4-fluorophenyl)quinolin-4-yl]carbonyl}amino)methyl ]cyclo- hexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.34 (dd, 2H), 8.13-8.04 (m, 3H), 7.78 (t, IH), 7.61 (t, IH), 7.37 (t, 2H), 7.03 (t, IH), 3.92 (q, 2H), 3.19 (t, 2H), 2.79 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.57-1.45 (m, IH), 1.36-1.24 (m, IH), 1.11 (t, 3H), 1.01-0.78 (m, 4H); m/z 464.9 (M+H) + .
Example 18
Ethyl [(?rα«5 f -4-{[({2-[4-(dimethylcarbamoyl)phenyl]quinolin-4-yl}carbonyl )amino]- methyl }cyclohexyl)methyl]carbamate
IH), 7.05-6.99 (m, IH), 7.65-7.48 (m, 4H), 3.92 (q, 2H), 3.20 (t, 2H), 3.01-2.91 (m, 6H),
2.79 (t, 2H), 1.84-1.65 (m, 4H), 1.56-1.45 (m, IH), 1.36-1.26 (m, IH), 1.10 (t, 3H), 1.00-
0.78 (m, 4H); m/z 517.9 (M+H) + .
Example 19 Ethyl ({?rα«5 f -4-[({[2-(3-carbamoylphenyl)quinolin-4-yl]carbonyl}amino)met hyl]- cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.81 (t, IH), 8.73 (s, IH), 8.43 (d, IH), 8.17-8.07 (m, 2H), 7.98 (d, IH), 7.79 (t, IH), 7.66-7.44 (m, 5H), 7.02 (t, IH), 3.92 (q, 2H), 3.20 (t, 2H), 2.79 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.57-1.44 (m, IH), 1.36-1.23 (m, IH), 1.10 (t, 3H), 1.00-0.71 (m, 4H); m/z 489.9 (M+H) + .
The following Examples 20-25 were prepared from the Intermediate listed in place of 2-
[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carbo xylic acid and tert-butyl {[trans-
4-(aminomethyl)cyclohexyl]methyl} carbamate, using essentially the same conditions as described for Example 1 (Method 1), and were purified by HPLC (Standard method B).
Example 20 tert-Butyl ({?rα«5 f -4-[({[2-(4-methylphenyl)quinolin-4-yl]carbonyl}amino)methyl ]- cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.76 (t, IH), 8.17 (d, 2H), 8.12-7.99 (m, 2H), 7.81-7.71 (m, 2H), 7.62-7.54 (m, 2H), 7.35 (d, IH), 6.79-6.71 (m, IH), 3.19 (t, 2H), 2.74 (t, 2H),
2.36 (s, 3H), 1.79 (d, 2H), 1.68 (d, 2H), 1.56-1.43 (m, IH), 1.33 (s, 9H), 1.31-1.21 (m, IH),
1.00-0.75 (m, 4H); m/z 488.0 (M+H) + .
Example 21 tert-Butyl ({?rα«5 f -4-[({[2-(4-chlorophenyl)quinolin-4-yl]carbonyl}amino)methyl ]cyclo- hexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.31 (d, 2H), 8.14-8.05 (m, 3H), 7.79 (t, IH), 7.65-7.56 (m, 3H), 6.75 (t, IH), 3.19 (t, 2H), 2.74 (t, 2H), 1.80 (d, 2H), 1.68 (d, 2H), 1.57-1.43 (m, IH), 1.33 (s, 9H), 1.30-1.22 (m, IH), 1.01-0.75 (m, 4H); m/z 508.0 (M+H) + .
Example 22 tert-Butyl ({/røfts-4-[({[2-(3-methoxyphenyl)qumolm-4-yl]carbonyl}amin o)- methyl]cyclohexyl}methyl)carbamate
O
(t, IH), 7.45 (t, IH), 7.07 (dd, IH), 6.75 (t, IH), 3.85 (s, 3H), 3.19 (t, 2H), 2.74 (t, 2H),
1.80 (d, 2H), 1.68 (d, 2H), 1.58-1.43 (m, IH), 1.33 (s, 9H), 1.30-1.23 (m, IH), 1.02-0.75
(m, 4H); m/z 504.6 (M+H) + .
Example 23 tert-Butyl ({?rα«5 f -4-[({[2-(2-methoxyphenyl)quinolin-4-yl]carbonyl}amino)methy l]- cyclohexyl}methyl)carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.69 (t, IH), 8.07 (t, 2H), 7.89 (s, IH), 7.80 (dd, IH), 7.78-7.75 (m, IH), 7.63-7.59 (m, IH), 7.48-7.45 (m, IH), 7.19 (d, IH), 7.12-7.09 (m, IH), 6.76 (t, IH), 3.83 (s, 3H), 3.17 (t, 2H), 2.74 (t, 2H), 1.77 (d, 2H), 1.68 (d, 2H), 1.53- 1.45 (m, IH), 1.33 (s, 9H), 1.31-1.24 (m, IH), 0.97-0.79 (m, 4H); m/z 504.7 (M+H) + .
Example 24 tert-Butyl [(?rα«5 f -4-{[({2-[4-(methylthio)phenyl]quinolin-4-yl}carbonyl)amino] - methyl}cyclohexyl)methyl]carbamate
O
2H), 8.04 (s, IH), 7.78-7.75 (m, IH), 7.60-7.57 (m, IH), 7.42-7.39 (m, 2H), 6.76 (t, IH),
3.19 (t, 2H), 2.74 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.54-1.47 (m, H), 1.34 (s, 9H), 1.31-
1.25 (m, IH), 0.97-0.79 (m, 4H); m/z 520.6 (M+H) + .
Example 25 tert-Butyl ({/rø«s-4-[({[2-(2,4-dimethyl-13-thiazol-5-yl)qumolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate
The following Examples 26-32 were prepared from ethyl {[?rα«5 f -4-(aminomethyl)cyclo- hexyl]methyl} carbamate hydrochloride [Intermediate P] and the Intermediate listed in place of 2-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carbox ylic acid, using
essentially the same conditions as described for Example 1 (Method 1), and were purified by HPLC (Standard method C). Example 26
Ethyl {[^^^^^-({[(l-pyrazin-l-ylquinolin-^y^carbony^aminojmethy^cy clohexyl]- methyljcarbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 9.75-9.75 (m, IH), 8.89 (t, IH), 8.84-8.82 (m, IH), 8.79 (d, IH), 8.42 (s, IH), 8.20 (d, IH), 8.14 (d, IH), 7.87 (t, IH), 7.71 (t, IH), 7.05 (t, IH), 3.93 (q, 2H), 3.21 (t, 2H), 2.81 (t, 2H), 1.80 (d, 2H), 1.71 (d, 2H), 1.56-1.48 (m, IH), 1.36-1.28 (m, IH), 1.12 (t, 3H), 0.99-0.81 (m, 4H); m/z 448.2 (M+H) + . Example 27
Ethyl ({?rα«5 f -4-[({[2-(3-methoxyphenyl)quinolin-4-yl]carbonyl}amino)methy l]cyclo- hexyl}methyl)carbamate
Example 28
Ethyl ({?rα«5 f -4-[({[2-(4-methylphenyl)quinolin-4-yl]carbonyl}amino)methyl ]cyclo- hexyl }methyl)car b amate
IH), 7.57 (t, IH), 7.35 (d, 2H), 7.03 (t, IH), 3.92 (q, 2H), 3.19 (t, 2H), 2.79 (t, 2H), 2.37 (s,
3H), 1.80 (d, 2H), 1.69 (d, 2H), 1.58-1.43 (m, IH), 1.38-1.24 (m, IH), 1.11 (t, 3H), 1.01-
0.76 (m, 4H); m/z 460.3 (M+H) + .
Example 29 Ethyl [(?rα«5 f -4-{[({2-[4-(methylthio)phenyl]quinolin-4-yl}carbonyl)amino] methyl}- cyclohexyl)methyl]carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.23 (d, 2H), 8.10-8.02 (m, 3H), 7.76 (t, H), 7.59 (t, IH), 7.40 (d, 2H), 7.03 (t, IH), 3.92 (q, 2H), 3.19 (t, 2H), 3.10-3.01 (m, IH), 2.79 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.57-1.45 (m, IH), 1.37-1.25 (m, IH), 1.16-1.07 (m, 5H), 1.00-0.78 (m, 4H); m/z 492.2 (M+H) + . Example 30
Ethyl ({?rα«5 f -4-[({[2-(4-ethoxyphenyl)quinolin-4-yl]carbonyl}amino)methyl ]- cyclohexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.75 (t, IH), 8.22 (d, 2H), 8.05 (dd, 2H), 8.00 (s, IH), 7.77-7.71 (m, IH), 7.56 (t, IH), 7.07 (d, 2H), 7.04-6.99 (m, IH), 4.09 (q, 2H), 3.92 (q, 2H), 3.18 (t, 2H), 2.79 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.56-1.45 (m, IH), 1.34 (t, 3H), 1.32- 1.26 (m, IH), 1.10 (t, 3H), 1.00-0.77 (m, 4H); m/z 490.2 (M+H) + . Example 31
Ethyl ({?rα«5 f -4-[({[2-(2-methoxyphenyl)quinolin-4-yl]carbonyl}amino)methy l]- cyclohexyl}methyl)carbamate
Ethyl ({?rα«5 f -4-[({[2-(4-chlorophenyl)quinolin-4-yl]carbonyl}amino)methyl ]cyclo- hexyl}methyl)carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.31 (d, 2H), 8.13-8.06 (m, 3H), 7.82-7.76 (m, IH), 7.65-7.58 (m, 3H), 7.03 (t, IH), 3.92 (q, 2H), 3.19 (t, 2H), 2.79 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.57-1.44 (m, IH), 1.36-1.25 (m, IH), 1.10 (t, 3H), 1.00-0.78 (m, 4H); m/z 480.3 (M+H) + . Example 33 tert-Butyl {[?rα«5 f -4-({[(2-pyrimidin-5-ylquinolin-4-yl)carbonyl]amino}methyl)c yclo- hexyl]methyl}carbamate
Example 1 (Method 1), but using DMF as solvent and NMM as base instead of TEA. 1 H NMR (500 MHz, DMSO-J 6 ) δ 9.66 (s, 2H), 9.34 (s, IH), 8.81 (t, IH), 8.30 (s, IH), 8.18 (t, 2H), 7.91-7.85 (m, IH), 7.75-7.69 (m, IH), 6.80 (t, IH), 3.25 (t, 2H), 2.78 (t, 2H), 1.85 (d, 2H), 1.73 (d, 2H), 1.59-1.51 (m, IH), 1.37 (s, 9H), 1.35-1.29 (m, IH), 1.04-0.82 (m, 4H); m/z 476.3 (M+H) + . Example 34 tert-Butyl ({?rα«5 f -4-[({[2-(4-cyanophenyl)quinolin-4-yl]carbonyl}amino)methyl] cyclo- hexyl }methyl)car b amate
N-M ethyl morpholine (5.9 mL, 54 mmol) and tert-butyl {[?rα«5 f -4-(aminomethyl)cyclo- hexyl]methyl} carbamate (6.7 g, 28 mmol) were added to a solution of 2-chloroquinoline-4- carboxylic acid (5.6 g, 27 mmol) in a mixture of 2-methyltetrahydrofuran (50 mL) and water (34 mL) at rt. An aqueous solution (9.1 mL) of HOBt (20% w/w) and ./V-methyl morpholine (15% w/w) was added to the stirred solution followed by the addition of EDC (6.7 g, 35 mmol). The reaction mixture was stirred vigorously at rt for 4 days. The mixture was filtered and the collected solid was washed with water containing 10% methanol to leave the title compound (6.6 g, 57%): 1 U NMR (400 MHz, DMSO-J6) δ 8.81 (t, IH), 8.07 (d, IH), 7.99 (d, IH), 7.89-7.81 (m, IH), 7.73-7.66 (m, IH), 7.59 (s, IH), 6.77 (t, IH),
3.21-3.12 (m, 2H), 2.79-2.72 (m, 2H), 1.83-1.74 (m, 2H), 1.72-1.64 (m, 2H), 1.56-1.43 (m, IH), 1.35 (s, 9H), 1.33-1.24 (m, IH), 0.90-0.75 (m, 4H); m/z 432.1 (M+H) + . Example 36 (Method 2) tert-Butyl ({/røfts-4-[({2-[4-(aminomethyl)phenyl]-6-methoxyisonicotin oyl}- amino)methyl]cyclohexyl}methyl)carbamate
The title compound was prepared using essentially the same conditions as described for Example 36 (Method 2), starting from tert-butyl [(£rafts-4-{[(2,5-dichloroisonicotinoyl)- amino]methyl}cyclohexyl)methyl]carbamate [Intermediate FF] in place of tert-butyl [(?rα«5 f -4-{[(2-chloro-6-methoxyisonicotinoyl)amino]methyl}cyclohexy l)-methyl]- carbamate: 1 U NMR (400 MHz, DMSO-J 6 ) δ 8.72 (s, IH), 8.67-8.60 (m, IH), 8.05 (d, 2H), 7.95 (s, IH), 7.45 (d, 2H), 6.81-6.74 (m, IH), 3.76 (s, 2H), 3.11 (t, 2H), 2.76 (t, 2H), 1.80 (d, 2H), 1.69 (d, 2H), 1.51-1.40 (m, IH), 1.36 (s, 9H), 1.33-1.24 (m, IH), 0.99-0.77 (m, 4H); m/z 487.1 (M+H) + . Example 38 tert-Butyl ({?rα«5 f -4-[({2-[4-(aminomethyl)phenyl]-6-methylisonicotinoyl}amino) - methyl]cyclohexyl}methyl)carbamate
The title compound was prepared using essentially the same conditions as described for Example 36 (Method 2), starting from tert-butyl [(?rα«5 f -4-{[(2-chloro-6- methylisonicotinoyl)amino]methyl}cyclohexyl)methyl]carbamate [Intermediate GG] in place of tert-butyl [(trans-4- { [(2-chloro-6-methoxyisonicotinoyl)amino]methyl} - cyclohexyl)methyl]carbamate: 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.77-8.69 (m, IH), 8.09- 8.02 (m, 3H), 7.55 (s, IH), 7.46 (d, 2H), 6.83-6.74 (m, IH), 3.78 (s, 2H), 3.14 (t, 2H), 2.76
(t, 2H), 2.59 (s, 3H), 1.77 (d, 2H), 1.70 (d, 2H), 1.56-1.44 (m, IH), 1.37 (s, 9H), 1.33-1.24 (m, IH), 0.97-0.76 (m, 4H); m/z 467.2 (M+H) + . Example 39 tert-Butyl [(?rα«5 f -4-{[({2-[3-(aminomethyl)phenyl]quinolin-4-yl}carbonyl)amino ]- methyl }cyclohexyl)methyl]carbamate
The title compound was prepared using essentially the same conditions as described for Example 36 (Method 2), starting from tert-butyl {[£rafts-4-({[(2-chloroquinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate [Example 35] in place oϊtert- butyl [(?rα«5 f -4-{[(2-chloro-6-methoxyisonicotinoyl)amino]methyl}cyclohexy l)-methyl]- carbamate. The compound was purified by flash column chromatography using EtOAc:MeOH:TEA (100:10:1) as eluent: 1 H NMR (400 MHz, MeOH-J 4 ) δ 8.21-8.11 (m, 3H), 8.08 (d, IH), 8.02 (s, IH), 7.84-7.77 (m, IH), 7.67-7.60 (m, IH), 7.57-7.48 (m, 2H), 3.96 (s, 2H), 3.35 (d, 2H), 2.90 (d, 2H), 1.94 (d, 2H), 1.83 (d, 2H), 1.71-1.58 (m, IH), 1.43 (s, 10H), 1.15-0.91 (m, 4H); m/z 503.1 (M+H) + . Example 40 (Method 3)
[3-(4-{[(?rα«5 f -4-{[(?ert-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- car b amoyl }quinolin-2-yl)phenyl] acetic acid
O
tert-Butyl {[?rfl«5 f -4-({[(2-chloroquinolin-4-yl)carbonyl]amino}methyl)cyclohexy l]- methyl} carbamate [Example 35] (200 mg, 0.46 mmol), [3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl] acetic acid (133 mg, 0.51 mmol, 1.1 eq.), Pd(PPlIs) 4 (26 mg, 0.023 mmol, 0.05 eq.), K 2 CO 3 (198 mg, 1.43 mmol, 3.1 eq.), water (2 mL), and dioxane (2 mL) were added to a vial and degassed. The reaction mixture was heated to 60 0 C for 16 h under a nitrogen atmosphere and then the reaction mixture was diluted with DCM, MeOH and a mixture of water and citric acid and the organic phase was separated and concentrated in vacuo to leave a residue. The residue was washed with MeOH to give the title compund as a white solid (188 mg, 76 %): 1 H NMR (300 MHz, DMSO-J 6 ) δ 12.38 (s, IH), 8.80 (t, IH), 8.13 (m, 5H), 7.80 (t, IH), 7.63 (t, IH), 7.51 (t, IH), 7.41 (d, IH), 6.82- 6.74 (m, IH), 3.72 (s, 2H), 3.22 (t, 2H), 2.77 (t, 2H), 1.83 (d, 2H), 1.71 (d, 2H), 1.61-1.46 (m, IH), 1.36 (s, 10H), 1.07-0.78 (m, 4H); m/z 532.3 (M+H) + . Example 41 (Method 4) tert-Butyl [(?rα«5 f -4-{[(2-phenylisonicotinoyl)amino]methyl}cyclohexyl)methyl]- carbamate
3H), 7.53-7.44 (m, 4H), 6.43-6.34 (m, IH), 4.64-4.56 (m, IH), 3.36 (t, 2H), 2.99 (t, 2H), 1.90-1.79 (m, 4H), 1.66-1.55 (m, 2H), 1.45 (s, 9H), 1.10-0.91 (m, 4H); m/z 424.2 (M+H) + Example 42 tert-Butyl {[?rα«5 f -4-({[2-(4-methoxyphenyl)isonicotinoyl]amino}methyl)cyclo- hexyl]methyl}carbamate
The title compound was prepared using essentially the same procedure as described for Example 41 (Method 4), starting from 4-methoxyphenyl boronic acid in place of phenyl boronic acid: 1 H NMR (500 MHz, CDCl 3 ) δ 8.76 (d, IH), 8.04-8.00 (m, 3H), 7.42 (dd, IH), 7.05-7.01 (m, 2H), 6.33-6.27 (m, IH), 4.63-4.57 (m, IH), 3.89 (s, 3H), 3.37 (t, 2H), 3.00 (t, 2H), 1.85 (dd, 4H), 1.64-1.55 (m, 2H), 1.46 (s, 9H), 1.11-0.93 (m, 4H). Example 43 tert-Butyl [(?rα«5 f -4-{[(2-methyl-6-phenylisonicotinoyl)amino]methyl}cyclohexyl )- methyl]carbamate
The title compound was prepared using essentially the same procedure as described for Example 41 (Method 4), starting from tert-butyl [(trans-4- {[(2-chloro-6- methylisonicotinoyl)amino]methyl}cyclohexyl)methyl]carbamate [Intermediate GG] in place of tert-butyl [(trans-4- { [(2-bromoisonicotinoyl)amino]methyl} cyclohexyl)-
methyljcarbamate. The compound was purified by flash column chromatography, using EtOAc:heptane (2:1) + 1% TEA as eluent, and then by HPLC (Standard method D). 1 H NMR (500 MHz, CDCl 3 ) δ 7.89 (d, 2H), 7.69 (s, IH), 7.37-7.30 (m, 3H), 7.23 (s, IH), 6.13 (s, IH), 4.45 (s, IH), 3.22 (t, 2H), 2.85 (t, 2H), 2.56 (s, 3H), 1.74-1.67 (m, 4H), 1.31 (s, 9H), 1.21-1.13 (m, 2H), 0.96-0.73 (m, 4H); m/z 438.2 (M+H) + . Example 44 tert-Butyl {[?rα«5 f -4-({[(5-phenylpyridin-3-yl)carbonyl]amino}methyl)cyclohexyl ]- methyljcarbamate
CDCl 3 ) δ 8.93 (d, 2H), 8.31 (s, IH), 7.62 (d, 2H), 7.52-7.44 (m, 3H), 6.53 (s, IH), 4.63 (s, IH), 3.37 (t, 2H), 2.98 (t, 2H), 1.87 (d, 2H), 1.81 (d, 2H), 1.64-1.56 (m, IH), 1.45 (s, 9H), 1.35-1.24 (m, IH), 1.06-0.89 (m, 4H); m/z 424.1 (M+H) + . The Examples 45-53 were prepared using essentially the same method as described for Example 41 (Method 4) using tert-butyl [(£rafts-4-{[(2-bromoisonicotinoyl)-amino]- methyl}cyclohexyl)methyl]carbamate [Intermediate HH] in place of tert-butyl [(trans-4- {[(2-bromoisonicotinoyl)amino]methyl}cyclohexyl)methyl]carba mate, and the appropriate boronic acid. The compounds were purified by HPLC (Standard method B). Example 45 tert-Butyl {[?rα«5 f -4-({[2-(l-benzothiophen-2-yl)isonicotinoyl]amino}methyl)cyc lo- hexyl]methyl}carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.79 (t, IH), 8.68 (d, IH), 8.39 (s, IH), 8.20 (s,
IH), 7.98-7.95 (m, IH), 7.91-7.87 (m, IH), 7.65 (d, IH), 7.40-7.35 (m, 2H), 6.75 (t, IH),
3.13 (t, 2H), 2.73 (t, 2H), 1.74 (d, 2H), 1.66 (d, 2H), 1.52-1.44 (m, IH), 1.33 (s, 9H), 1.29-
1.23 (m, IH), 0.93-0.76 (m, 4H); m/z 480.7 (M+H) + .
Example 46 tert-Butyl {[?rα«5 f -4-({[(6'-ethoxy-2,3'-bipyridin-4-yl)carbonyl]amino}methyl)c yclo- hexyl]methyl}carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.67 (d, IH), 8.65 (t, IH), 8.11 (s, IH), 7.69 (d,
IH), 7.55-7.53 (m, IH), 6.74 (t, IH), 6.67-6.65 (m, IH), 6.64-6.61 (m, IH), 3.80 (s, 3H),
3.79 (s, 3H), 3.08 (t, 2H), 2.72 (t, 2H), 1.70 (d, 2H), 1.65 (d, 2H), 1.49-1.41 (m, IH), 1.32
(s, 9H), 1.29-1.21 (m, IH), 0.90-0.74 (m, 4H); m/z 484.3 (M+H) + .
Example 48 tert-Butyl {[?rα«5 f -4-({[(2',6'-dimethoxy-2,3'-bipyridin-4-yl)carbonyl]amino}me thyl)- cyclohexyl]methyl}carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.70-8.66 (m, 2H), 8.26-8.23 (m, 2H), 7.58-
7.55 (m, IH), 6.74 (t, IH), 6.52 (d, IH), 3.96 (s, 3H), 3.90 (s, 3H), 3.09 (t, 2H), 2.72 (t,
2H), 1.71 (d, 2H), 1.65 (d, 2H), 1.50-1.41 (m, IH), 1.32 (s, 9H), 1.28-1.21 (m, IH), 0.91-
0.74 (m, 4H); m/z 485.5 (M+H) + .
Example 49 tert-Butyl {[?rα«5 f -4-({[(6'-methoxy-2,3'-bipyridin-4-yl)carbonyl]amino}methyl) cyclo- hexyl]methyl}carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.88 (d, IH), 8.75 (t, IH), 8.73 (d, IH), 8.38- 8.36 (m, IH), 8.22 (s, IH), 7.65-7.63 (m, IH), 6.94 (d, IH), 6.74 (t, IH), 3.89 (s, 3H), 3.11 (t, 2H), 2.72 (t, 2H), 1.73 (d, 2H), 1.65 (d, 2H), 1.51-1.42 (m, IH), 1.32 (s, 9H), 1.29-1.21 (m, IH), 0.92-0.74 (m, 4H); m/z 455.6 (M+H) + . Example 50 tert-Butyl {[?rα«5 f -4-({[2-(4-carbamoylphenyl)isonicotinoyl]amino}methyl)cycloh exyl]- methyljcarbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.80 (t, IH), 8.76 (d, IH), 8.28 (s, IH), 8.14 (s,
IH), 8.07 (d, IH), 7.71 (d, IH), 7.55-7.49 (m, 2H), 6.74 (t, IH), 3.12 (t, 2H), 2.72 (t, 2H),
1.73 (d, 2H), 1.65 (d, 2H), 1.51-1.43 (m, IH), 1.32 (s, 9H), 1.29-1.22 (m, IH), 0.92-0.74
(m, 4H); m/z 458.2 (M+H) + .
Example 52 tert-Butyl ({?rα«5 f -4-[({2-[4-(aminomethyl)phenyl]isonicotinoyl}amino)methyl]cy clo- hexyl }methyl)car b amate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.79 (t, IH), 8.75 (d, IH), 8.25 (s, IH), 8.07 (d, 2H),
7.68-7.64 (m, IH), 7.47 (d, 2H), 6.77 (t, IH), 3.77 (s, 2H), 3.18-3.12 (m, 2H), 2.75 (t, 2H),
2.02-1.89 (m, 2H), 1.76 (d, 2H), 1.69 (d, 2H), 1.55-1.44 (m, IH), 1.36 (s, 9H), 1.33-1.24
(m, IH), 0.97-0.75 (m, 4H); m/z 453.2 (M+H) + .
Example 53 tert-Butyl {[?rα«5 f -4-({[2-(3,4-difluorophenyl)isonicotinoyl]amino}methyl)cyclo hexyl]- methyljcarb amate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.77 (t, IH), 8.75 (d, IH), 8.27 (s, IH), 8.16-
8.11 (m, IH), 8.00-7.96 (m, IH), 7.69 (d, IH), 7.56 (q, IH), 6.74 (t, IH), 3.12 (t, 2H), 2.72
(t, 2H), 1.73 (d, 2H), 1.65 (d, 2H), 1.51-1.42 (m, IH), 1.32 (s, 9H), 1.29-1.23 (m, IH),
0.92-0.74 (m, 4H); m/z 460.5 (M+H) + .
Example 54 (Method 5)
Ethyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]carb amate
O
N- { [?rα«5 f -4-(Aminomethyl)cyclohexyl]methy 1} naphthalene-2-sulfonamide [Intermediate DD] (30 mg, 0.077 mmol) and TEA (23 mg, 0.23 mmol, 3.0 eq.) were dissolved in DCM (1 mL) and a few drops of DMSO were added. The reaction mixture was cooled to 0 0 C. A solution of ethyl chloroformate (8.4 mg, 0.077 mmol, 1.0 eq.) in DCM (1 mL) was then added dropwise and the reaction mixture was stirred at 0 0 C whilst warming to rt overnight. The reaction mixture was concentrated in vacuo to leave a residue which was purified by HPLC (Standard method A) to give the title compound (20 mg, 63%): 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, IH), 7.25 (d, 2H), 7.89 (d, IH), 7.79 (dd, IH), 7.61 (ddd, 2H), 4.64-4.57 (m, IH), 4.41 (t, IH), 4.06 (q, 2H), 2.96 (t, 2H), 2.80 (t, 2H), 1.72 (d, 4H), 1.42-1.26 (m, 2H), 1.20 (t, 3H), 0.92-0.76 (m, 4H); m/z 405.0 (M+H) + .
The following Examples 55-60 were prepared from N-{[?rfl«5 f -4-(aminomethyl)cyclo- hexyl]methyl}-2-pyridin-4-ylquinoline-4-carboxamide hydrochloride [Intermediate JJ] in place of N-{[?rfl«5 f -4-(aminomethyl)cyclohexyl]methyl}naphthalene-2-sulfonamide and the appropriate alkyl chloroformate, using essentially the same method as described for Example 54 (Method 5). Example 55
2,2-Dimethylpropyl {[?rα«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)- cyclohexyl]methyl}carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.85-8.72 (m, 3H), 8.26-8.20 (m, 2H), 8.20-8.09 (m, 2H), 7.87-7.79 (m, IH), 7.71-7.63 (m, IH), 6.99-6.91 (m, IH), 4.93-4.84 (m, IH), 3.22-
3.15 (m, 2H), 2.82-2.72 (m, 2H), 1.85-1.63 (m, 6H), 1.63-1.43 (m, 7H), 1.36-1.23 (m, 2H), 1.01-0.76 (m, 4H); m/z 487.3 (M+H) + . Example 57
Isopropyl {[?rα«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)cyc lo- hexyl]methyl}carbamate
1 H NMR (400 MHz, DMSO-J 6 ) δ 8.80 (t, IH), 8.76 (d, 2H), 8.23 (d, 2H), 8.18 (s, IH), 8.16-8.10 (m, 2H), 7.86-7.80 (m, IH), 7.71-7.65 (m, IH), 6.95 (t, IH), 4.74-4.63 (m, IH), 3.20 (t, 2H), 2.79 (t, 2H), 1.81 (d, 2H), 1.69 (d, 2H), 1.56-1.44 (m, IH), 1.37-1.24 (m, IH), 1.11 (d, 6H), 1.01-0.77 (m, 4H); m/z 461.2 (M+H) + . Example 58
Propyl {[?rα«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)cyc lohexyl]- methyljcarbamate
O
Example 59
2-Methoxy ethyl {[£rafts-4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}- methyl)cyclohexyl]methyl}carbamate
1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (dd, 2H), 8.19 (dd, 2H), 8.04 (dd, 2H), 7.90 (s, IH), 7.84-7.76 (m, IH), 7.67-7.59 (m, IH), 6.13 (t, IH), 4.66 (s, IH), 4.08 (q, 2H), 3.44 (t, 2H), 3.03 (t, 2H), 1.86 (dd, 4H), 1.69-1.54 (m, IH), 1.51-1.35 (m, IH), 1.21 (t, 3H), 1.14-0.90 (m, 4H); m/z 447.1 (M+H) + . Example 61
Ethyl ({?rα«5 f -4-[({[2-(4-carbamoylphenyl)quinolin-4-yl]carbonyl}amino)met hyl]- cyclohexyl}methyl)carbamate
The title compound was prepared from λf-{[£rafts-4-(aminomethyl)cyclohexyl]methyl}-2- (4-carbamoylphenyl)quinoline-4-carboxamide hydrochloride [Intermediate KK] in place of λf-{[/rafts-4-(aminomethyl)cyclohexyl]methyl}naphthalene-2- sulfonamide, using essentially the same method as described for Example 54 (Method 5). 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.79 (t, IH), 8.35 (d, 2H), 8.16-7.98 (m, 6H), 7.80 (dd, IH), 7.63 (dd, IH), 7.43 (s, IH), 7.03 (t, IH), 3.92 (q, 2H), 3.20 (t, 2H), 2.80 (t, 2H), 1.80 (d, 2H), 1.70 (d, 2H), 1.57-1.44 (m, IH), 1.38-1.24 (m, IH), 1.11 (t, 3H), 1.01-0.76 (m, 4H); m/z 489.9 (M+H) + . Example 62
Ethyl {[?rα«5 f -4-({[(2-phenylquinolin-4-yl)carbonyl]amino}methyl)cyclohexy l]methyl}- carbamate
The title compound was prepared from λf-{[/røfts-4-(aminomethyl)cyclohexyl]methyl}-2- phenylquinoline-4-carboxamide [Intermediate LL] in place of N-{[trans-4-(ammomQthyl)- cyclohexyl]methyl}naphthalene-2-sulfonamide, using essentially the same method as described for Example 54 (Method 5). 1 U NMR (500 MHz, CDCl 3 ) δ 8.16 (t, IH), 8.12 (d, 2H), 7.86 (s, IH), 7.74 (t, IH), 7.58-7.49 (m, 3H), 7.49-7.43 (m, IH), 6.11 (s, IH), 4.66
(s, IH), 4.07 (q, 3H), 3.41 (t, 2H), 3.02 (t, 2H), 1.88 (d, 2H), 1.81 (d, 2H), 1.64-1.58 (m, IH), 1.47-1.38 (m, IH), 1.21 (t, 3H), 1.11-0.91 (m, 4H); m/z 446.3 (M+H) + .
Example 63 (Method 6) tert-Butyl [(/rafts-4-{[(biphenyl-3-ylsulfonyl)ammo]methyl}cyclohexyl)m ethyl]- carbamate
The following Examples 64-78 were prepared by essentially the same method as described for Example 63 (Method 6), starting from tert-butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]- methyl} carbamate and the appropriate sulphonyl chloride in place of 3-biphenylsulfonyl chloride. Example 64 tert-Butyl {[?rα«5 f -4-({[(3,4-dibromophenyl)sulfonyl]amino}methyl)cyclohexyl]- methyljcarbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.05 (s, IH), 8.00 (d, IH), 7.80-7.75 (m, IH), 7.67 (d,
IH), 6.79-6.74 (m, IH), 2.73 (t, 2H), 2.60 (t, 2H), 1.70-1.61 (m, 4H), 1.37 (s, 9H), 1.30-
1.20 (m, 2H), 0.83-0.71 (m, 4H); m/z 536.9 (M-H) " .
Example 65 tert-Butyl {[?rα«5 f -4-({[(3,4-dichlorophenyl)sulfonyl]amino}methyl)cyclohexyl]m ethyl}- carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 7.96 (s, IH), 7.89 (d, IH), 7.81-7.76 (m, IH), 7.74 (d,
IH), 6.79-6.74 (m, IH), 2.73 (t, 2H), 2.60 (t, 2H), 1.70-1.60 (m, 4H), 1.37 (s, 9H), 1.30-
1.19 (m, 2H), 0.82-0.72 (m, 4H); m/z 451.0 (M+H) + .
Example 66 tert-Butyl [(?rα«5 f -4-{[(quinolin-8-ylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate
1 H NMR (500MHz, DMSO-J 6 ) δ 9.08 (m, IH), 8.56 (d, IH), 8.3 (d, 2H), 7.78-7.71 (m,
2H), 7.12 (t, IH), 6.72 (t, IH), 2.69 (t, 2H), 2.6 (t, 2H), 1.57 (t, 4H), 1.35 (s, 9H), 1.27-1.1
(m, 2H), 0.72-0.60 (m, 4H); m/z 434.1 (M+H) + .
Example 67 tert-Butyl [(/rafts-4-{[(biphenyl-4-ylsulfonyl)amino]methyl}cyclohexyl) methyl]- carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 7.87 (dd, 4H), 7.74 (d, 2H), 7.63-7.59 (m, IH), 7.52 (t, 2H), 7.44 (t, IH), 6.78-6.73 (m, IH), 2.73 (t, 2H), 2.60 (t, 2H), 1.73-1.60 (m, 4H), 1.36 (s, 9H), 1.32-1.19 (m, 2H), 0.84-0.70 (m, 4H); m/z 457.2 (M-H) " . Example 68 tert-Butyl {[?rα«5 f -4-({[(4-isopropylphenyl)sulfonyl]amino}methyl)cyclohexyl]me thyl}- carbamate
Example 69 tert-Butyl [(?rα«5 f -4-{[(2,3-dihydro-l,4-benzodioxin-6-ylsulfonyl)amino]methyl} cyclo- hexyl)methyl]carbamate
(m, IH), 4.34-4.28 (m, 4H), 2.73 (t, 2H), 2.53-2.52 (m, 2H), 1.71-1.60 (m, 4H), 1.37 (s,
9H), 1.29-1.18 (m, 2H), 0.82-0.71 (m, 4H); m/z 439.2 (M-H) " .
Example 70 tert-Butyl ({tra«5 ι -4-[({[5-(2-methyl-l,3-thiazol-4-yl)-2-thienyl]sulfonyl}amin o)- methyl]cyclohexyl}methyl)carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.03 (s, IH), 7.79 (t, IH), 7.56 (d, IH), 7.51 (d, IH), 6.75 (s, IH), 2.72 (t, 2H), 2.70-2.65 (m, 5H), 1.73-1.58 (m, 4H), 1.35 (s, 9H), 1.32-1.26 (m, IH), 1.26-1.20 (m, IH), 0.84-0.70 (m, 4H); m/z 486.0 (M+H) + .
Example 71 tert-Butyl {[^^^^-^({[(S-acetamido-l-naphthy^sulfony^aminoJmethy^cycloh exyl]- methyljcarbamate
Example 72 tert-Butyl {[?rα«5 f -4-({[(5-isoxazol-5-yl-2-thienyl)sulfonyl]amino}methyl)cyclo - hexyl]methyl}carbamate
Example 73 tert-Butyl {[?rα«5 f -4-({[(4-acetamidophenyl)sulfonyl]amino}methyl)cyclohexyl]- methyljcarbamate
1 H NMR (500 MHz, DMSO-J 6 ) 6 8.11 (dd, IH), 7.74 (dd, IH), 7.52-7.48 (m, IH), 7.31 (dd, IH), 6.76 (t, IH), 2.73 (t, 2H), 2.60 (t, 2H), 1.70-1.61 (m, 4H), 1.37 (s, 9H), 1.30-1.19 (m, 2H), 0.82-0.70 (m, 4H); m/z 387.2 (M-H) " .
Example 75 tert-Butyl ({/røfts-4-[({[3-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl]sulf onyl}amino)- methyl]cyclohexyl}methyl)carbamate
1 H NMR (500MHz, DMSO-J 6 ) δ 8.37 (t, IH), 8.22-8.17 (m, IH), 7.97-7.93 (m, IH), 7.78
(t, IH), 6.74 (t, IH), 2.72-2.67 (m, 4H), 2.63-2.55 (m, 3H), 1.70-1.57 (m, 4H), 1.34 (s, 9H),
1.29-1.15 (m, 2H), 0.80-0.68 (m, 4H); m/z 465.1 (M+H) + .
Example 76 tert-Butyl [(?rα«5 f -4-{[(isoquinolin-5-ylsulfonyl)amino]methyl}cyclohexyl)- methyl]carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 9.44 (s, IH), 8.68 (d, IH), 8.44-8.40 (m, 2H), 8.3 (dd, IH), 8.25 (m, IH), 7.81 (t, IH), 6.72 (m, IH), 2.67 (t, 2H), 2.64-2.58 (m, 2H), 1.54 (d, 4H), 1.34 (s, 9H), 1.20-1.10 (m, 2H), 0.70-0.58 (m, 4H); m/z 434.1 (M+H) + . Example 77 tert-Butyl {[?rα«5 f -4-({[(4-acetamido-2-methyl-l,3-thiazol-5-yl)sulfonyl]amino} methyl)- cyclohexyl]methyl}carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 7.78 (m, IH), 6.78 (m, IH), 2.75-2.72 (m, 2H), 2.65-
2.62 (m, 2H), 2.42 (s, 3H), 2.15 (s, 3H), 1.71-1.66 (m, 4H), 1.35 (s, 9H), 1.31-1.20 (m,
2H), 0.8-0.72 (m, 4H); m/z 461.0 (M+H) + .
Example 78 tert-Butyl [(?rα«5 f -4-{[(l,3-benzothiazol-6-ylsulfonyl)amino]methyl}cyclohexyl) - methyl]carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 9.61 (s, IH), 8.68 (d, IH), 8.27 (d, IH), 7.91 (dd, IH), 7.71-7.66 (m, IH), 6.75 (t, IH), 2.72 (t, 2H), 2.60 (d, 2H), 1.70-1.59 (m, 4H), 1.36 (s, 9H), 1.30-1.18 (m, 2H), 0.81-0.69 (m, 4H); m/z 440.0 (M+H) + . Example 79 (Method 7) tert-Butyl [(?rα«5 f -4-{[ethyl(2-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl ]- carbamate
concentrated in vacuo to leave a residue. The residue was dissolved in DMSO and purified by HPLC (Standard method E) to give the title compound (43 mg, 41%): 1 H NMR (500
MHz, DMSO-J 6 ) δ 8.48 (s, IH), 8.18 (d, IH), 8.11 (d, IH), 8.03 (d, IH), 7.89-7.77 (dd,
IH), 7.71-7.65 (m, 2H), 6.77 (t, IH), 3.19-3.15 (dd, 2H), 2.95 (d, 2H), 2.75 (t, 2H), 1.76-
1.61 (m, 4H), 1.55-1.43 (m, IH), 1.36 (s, 9H), 1.32-1.21 (m, IH), 1.00-0.94 (m, 3H), 0.89-
0.75 (m, 4H); m/z 459.2 (M-H) " .
The Examples 80-87 were prepared using essentially the same conditions as described for
Example 79 (Method 7) using the appropriate alkyl iodide in place of ethyl iodide.
Example 80 tert-Butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)(2-phenylethyl)amino]methyl}cyclohe xyl)- methyl]carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.50 (s, IH), 8.22 (d, IH), 8.13 (d, IH), 8.05 (d, IH),
7.81 (dd, IH), 7.73-7.65 (m, 2H), 7.25 (t, 2H), 7.20-7.15 (m, 3H), 6.78-6.74 (m, IH), 3.00-
2.97 (m, 2H), 2.77-2.72 (m, 4H), 2.53-2.52 (m, 2H), 1.70-1.61 (m, 4H), 1.50-1.43 (m, IH),
1.37 (s, 9H), 1.30-1.22 (m, IH), 0.85-0.73 (m, 4H); m/z 535.8 (M-H) " .
Example 81
Ethyl N-[(?rfl«5 f -4-{[(?er?-butoxycarbonyl)amino]methyl}cyclohexyl)methyl]-N- (2- naphthylsulfonyl)glycinate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.47 (s, IH), 8.18 (d, IH), 8.12 (d, IH), 8.05 (d, IH),
7.81 (dd, IH), 7.74-7.65 (m, 2H), 6.75 (t, IH), 4.07 (s, 2H), 3.93 (q, 2H), 3.05 (d, 2H), 2.73
(t, 2H), 1.75-1.59 (m, 4H), 1.48-1.39 (m, IH), 1.36 (s, 9H), 1.30-1.20 (m, IH), 1.04 (t, 3H),
0.82-0.71 (m, 4H); m/z 519.4 (M+H) + .
Example 82 tert-Butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)(tetrahydro-2H-pyran-4-ylmethyl)ami no]- methyl}cyclohexyl)methyl]carbamate
Example 83 tert-Butyl [(?rα«5 f -4-{[(cyanomethyl)(2-naphthylsulfonyl)amino]methyl}cyclohexy l)- methyl]carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.48 (s, IH), 8.18 (d, IH), 8.12 (d, IH), 8.05 (d, IH), 7.81-7.79 (dd, IH), 7.73 (m, 2H), 6.75 (t, IH), 5.59-5.50 (m, IH), 5.20-5.16 (dd, IH), 5.07- 5.05 (dd, IH), 3.79 (d, 2H), 2.96 (d, 2H), 2.73 (t, 2H), 1.70-1.60 (m, 4H), 1.55-1.45 (m, IH), 1.36 (s, 9H), 1.30-1.20 (m, IH), 0.85-0.72 (m, 4H); m/z 471.1 (M-H) " .
Example 85 tert-Butyl [(?rα«5 f -4-{[butyl(2-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl ]- carbamate
Example 86 tert-Butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)(2,2,2-trifluoroethyl)amino]methyl} cyclo- hexyl)methyl]carbamate
1 H NMR (SOO MHZ, DMSO-J 6 ) δ 8.59 (s, IH), 8.21 (d, IH), 8.15 (d, IH), 8.07 (d, IH), 7.88 (dd, IH), 7.76-7.65 (m, 2H), 6.74 (t, IH), 4.14 (q, 2H), 2.99 (d, 2H), 2.72 (t, 2H),
1.65-1.47 (m, 4H), 1.36 (s, 9H), 1.32-1.18 (m, 2H), 0.80-0.68 (m, 4H); m/z 513.1 (M-H) " .
Example 87 tert-Butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)(propyl)amino]methyl}cyclohexyl)met hyl]- carbamate
Example 88 tert-Butyl [(/rafts-4-{[methyl(2-naphthylsulfonyl)ammo]methyl}cyclohexy l)methyl]- carbamate
The title compound was prepared using essentially the same conditions as described for Example 79 (Method 7) with methyl iodide in place of ethyl iodide. The compound was purified by HPLC (Standard method A): 1 U NMR (500 MHz, DMSO-J 6 ) δ 8.43 (s, IH), 8.19 (d, IH), 8.13 (d, IH), 8.05 (d, IH), 7.76 (d, IH), 7.69 (dt, 2H), 6.77 (t, IH), 2.81-2.72 (m, 4H), 2.67 (s, 3H), 1.74-1.64 (m, 4H), 1.53-1.42 (m, IH), 1.36 (s, 9H), 1.32-1.23 (m, IH), 0.89-0.76 (m, 4H); m/z 391.1 (M - tert-butγl + H) + .
The following Examples 89-90 were prepared from tert-butyl ({?rα«5 f -4-[({[5-(2-methyl- l^-thiazol^-y^^-thienyljsulfonyllamino^ethyljcyclohexyllmeth y^carbamate (Example 70) in place of tert-butyl [(/rafts-4-{[(2-naphthylsulfonyl)amino]methyl}cyclo- hexyl)methyl] carbamate and the appropriate alkyl iodide using essentially the same conditions as described for Example 79 (Method 7).
Example 89 tert-Butyl ({tra«^-4-[(methyl{[5-(2-methyl-l,3-thiazol-4-yl)-2-thienyl ]sulfonyl}- amino)methyl]cyclohexyl}methyl)carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.09 (s, IH), 7.66 (d, IH), 7.61 (d, IH), 6.78 (t, IH), 2.80-2.74 (m, 4H), 2.70 (s, 6H), 1.75-1.67 (m, 4H), 1.55-1.48 (m, IH), 1.37 (s, 9H), 1.33- 1.26 (m, IH), 0.91-0.79 (m, 4H); m/z 498.1 (M-H) " . Example 90 tert-Butyl (|?ra«5'-4-[(ethyl{[5-(2-methyl-l,3-thiazol-4-yl)-2-thienyl ]sulfonyl}amino)- methyl]cyclohexyl}methyl)carbamate
1 H NMR (500 MHz, DMSO-J 6 ) δ 8.08 (s, IH), 7.63-7.60 (m, 2H), 6.78 (t, IH), 3.17 (q, 2H), 2.91 (d, 2H), 2.77 (t, 2H), 2.70 (s, 3H), 1.79-1.65 (m, 4H), 1.57-1.48 (m, IH), 1.37 (s, 9H), 1.34-1.25 (m, IH), 1.05 (t, 3H), 0.90-0.79 (m, 4H); m/z 512.1 (M-H) " .
Example 91 (Method 8) tert-Butyl {[?rα«5 f -4-({methyl[(2-phenylquinolin-4-yl)carbonyl]amino}methyl)cyc lo- hexyl]methyl}carbamate
Example 92 (Method 9) tert-Butyl [(?rα«5 f -4-{[({2-[4-(aminomethyl)phenyl]quinolin-4-yl}carbonyl)amino ]- methyl}cyclohexyl)methyl]carbamate acetate
The crude 2-[4-({[(9H-fluoren-9-ylmethoxy)carbonyl]-amino}methyl)pheny l]quinoline-4- carboxylic acid was reacted with tert-butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]methyl}- carbamate using essentially the same procedure as described for Example 1 (Method 1) to give the crude 9H-fluoren-9-ylmethyl [4-(4-{[(?rα«5 f -4-{[(?ert-butoxycarbonyl)amino]- methyl} cyclohexyl)methyl]carbamoyl}quinolin-2-yl)benzyl]carbamate, which was used in the next step with no further purification, m/z 725.4 (M+η) + .
The crude 9H-fluoren-9-ylmethyl [4-(4-{[(?rα«5 f -4-{[(?ert-butoxycarbonyl)amino]methyl}- cyclohexyl)methyl]carbamoyl}quinolin-2-yl)benzyl]carbamate (0.14 g, 0.19 mmol) was dissolved in DCM (4 mL) and treated with piperidine (1 mL). The reaction mixture was stirred at rt for 5 min. The reaction mixture was concentrated in vacuo to leave a residue. The residue was dissolved in DMSO and purified by ηPLC (Standard method D) to give
the title compound (35 mg, 32%). 1 R NMR (400 MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.21 (d, 2H), 8.10-8.05 (m, IH), 8.03 (s, IH), 7.77 (t, IH), 7.61-7.46 (m, 4H), 6.74 (t, IH), 3.77 (s, 2H), 3.19 (t, 2H), 2.74 (t, 2H), 1.83 (s, 2H), 1.79 (d, 2H), 1.68 (d, 2H), 1.55-1.45 (m, IH), 1.33 (s, 9H), 1.30-1.23 (m, IH), 1.00-0.76 (m, 4H); m/z 503.4 (M+H) + .
Example 93 (Method 10)
4-(4-{[(?rα«5 f -4-{[(?er?-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]car bamoyl}- quinolin-2-yl)benzoic acid
Example 94 (Method 11) tert-Butyl ({^^^^-^[({^-(l-oxidopyridin-^y^quinolin-^y^carbonyljamino^e thyl]- cyclohexyl}methyl)carbamate
The title compound was prepared from 2-phenyl-quinoline-4-thiol [Intermediate OO] (200 mg, 0.84 mmol) and tert-butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]methyl} carbamate
(0.51 g, 2.1 mmol, 2.5 eq.) using the procedure described in Wright, S. W.; Hallstrom, K. N., J. Org. Chem., 2006, 71, p. 1080-1084. The crude product was purified by HPLC (Standard method B) to give the title compound (114 mg, 27%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.62 (d, IH), 8.36 (s, IH), 8.31-8.15 (m, 4H), 7.88 (t, IH), 7.74 (t, IH), 7.61- 7.50 (m, 3H), 6.69 (t, IH), 2.76-2.69 (m, 2H), 2.65 (t, 2H), 1.57 (dd, 4H), 1.31 (s, 9H), 1.28-1.06 (m, 2H), 0.77-0.56 (m, 4H); m/z 510.8 (M+H) + . Example 96 (Method 13) tert-Butyl ({?rα«5 f -4-[(l-naphthoylamino)methyl]cyclohexyl}methyl)carbamate
Example 97 (Method 14)
N-[(?rfl«5 f -4-{[(?er?-Butylcarbamoyl)amino]methyl}cyclohexyl)methyl]-2- pyridin-4- ylquinoline-4-carboxamide
Example 98 (Method 15) tert-Butyl ({?rα«5 f -4-[({[2-(3-{[(methylsulfonyl)amino]methyl}phenyl)quinolin-4 - yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
Ό
DIPEA (42 μL, 0.24 mmol, 2.0 eq.), and methanesulfonyl chloride (14 μL, 0.18 mmol, 1.5 eq.) were added to a solution of tert-butyl [(£rafts-4-{[({2-[3-(aminomethyl)phenyl]- quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbam ate (Example 39) (60 mg, 0.12 mmol) in DCM (1 mL) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with water, DCM, and MeOH and extracted with a mixture of DCM and MeOH. The organic layer was separated and concentrated in vacuo to leave a residue which was purified by flash column chromatography, using increasingly polar mixtures of DCM and EtOAc as eluent, to give the title compound (17 mg, 24%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.10-8.01 (m, 2H), 7.98 (s, IH), 7.91 (d, IH), 7.78 (s, IH), 7.66 (t, IH), 7.48 (t, IH), 7.44-7.34 (m, 2H), 4.27 (s, 2H), 3.82 (s, 2H), 3.28-3.21 (m, 3H), 2.86- 2.80 (m, 2H), 2.78 (s, 3H), 1.78 (d, 2H), 1.70 (d, 2H), 1.57-1.45 (m, IH), 1.31 (s, 10H), 1.02-0.79 (m, 4H); m/z 581.2 (M+H) + . Example 99 (Method 16) tert-Butyl {[?rα«5 f -4-({[(2-{3-[(carbamoylamino)methyl]phenyl}quinolin-4-yl)- carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
(m, 2H), 2.81-2.73 (m, 2H), 1.83 (d, 2H), 1.71 (d, 2H), 1.59-1.48 (m, IH), 1.36 (s, 9H),
1.34-1.25 (m, IH), 1.03-0.79 (m, 4H); m/z 546.2 (M+H) + .
Example 100 (Method 17) tert-Butyl [(?rα«5 f -4-{[({2-[3-(acetamidomethyl)phenyl]quinolin-4-yl}carbonyl)a mino]- methyl}cyclohexyl)methyl]carbamate
DIPEA (42 μL, 0.24 mmol, 2.0 eq.), DMAP (1 mg, 0.008 mmol, 0.07 eq.) and acetic acid anhydride (23 μL, 0.24 mmol, 2.0 eq.) were added to a solution of tert-butyl
Example 101 (Method 18)
Methyl [3-(4-{[(?rα«5 f -4-{[(?er?-butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl}quinolin-2-yl)benzyl]carbamate
DIPEA (42 μL, 0.24 mmol, 2.0 eq.) and methyl chloroformate (23 mg, 0.24 mmol, 2.0 eq.) were added to a solution of tert-butyl [(?rfl«5 f -4-{[({2-[3-(aminomethyl)phenyl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate (Example 39) (60 mg, 0.12 mmol) in DCM (1 mL). The reaction mixture was stirred for 16 h at rt and then diluted with water and MeOH and a mixture of DCM and MeOH were added. The layers were separated and the organic phase was concentrated in vacuo to leave a residue. The residue was purified by flash column chromatography using increasingly polar mixtures of DCM and EtOAc as eluent to give the title compound (59 mg, 88% ). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 - 8.07 (m, 2H), 8.00 (s, IH), 7.95 (d, IH), 7.78 (s, IH), 7.72 (t, IH), 7.52 (t, IH), 7.43 (t, IH), 7.39 - 7.33 (m, IH), 6.54 (s, IH), 5.32 (s, IH), 4.64 (s, IH), 4.45 - 4.37 (m, 2H), 3.68 (s, 3H), 3.36 (t, 2H), 2.94 (t, 2H), 1.89 - 1.72 (m, 4H), 1.63 - 1.49 (m, IH), 1.42 (s, 10H), 1.09 - 0.83 (m, 4H); m/z 561.2 (M+H) + . Example 102 tert-Butyl [(?rα«5 f -4-{[({2-[4-(2-aminoethyl)phenyl]quinolin-4-yl}carbonyl)amin o]- methyl}cyclohexyl)methyl]carbamate
cooled to rt. Water was added and the mixture was filtered. The collected solid was purified with cation exchange resin (CBA) followed by preparative HPLC, using ACN/Water/0.2% AcOH as eluent, to give the title compund (182 mg, 76 %). 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.80 (t, IH), 8.22 (d, 2H), 8.15-8.08 (m, 2H), 8.06 (s, IH), 7.84- 7.77 (m, IH), 7.66-7.59 (m, IH), 7.40 (d, 2H), 6.79 (t, IH), 3.31 (s, 2H), 3.23 (t, 2H), 2.87- 2.69 (m, 6H), 1.83 (d, 2H), 1.72 (d, 2H), 1.61-1.48 (m, IH), 1.37 (s, 10H), 1.04-0.79 (m, 4H); m/z 530.2 (M+H) + . Example 103 tert-Butyl [(/rafts-4-{[({2-[4-(acetamidomethyl)phenyl]qumolm-4-yl}carb onyl)- amino]methyl}cyclohexyl)methyl]carbamate
DIPEA (51 mg, 0.39 mmol), DMAP (2 mg) and acetic anhydride (40 mg, 0.40 mmol) were added sequentially to a solution of tert-butyl [(?rα«5 f -4-{[({2-[4-(aminomethyl)- phenyl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate acetate (Example 92 (Method 9)) (100 mg, 0.2 mmol) in DCM (2 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to leave a residue, which was purified by preparative HPLC, using ACN/water/AcOH 0.2% as eluent, to give the title compound (51 mg, 47%). 1 H NMR (400MHz, DMSO-J 6 ) δ 8.84- 8.76 (m, IH), 8.47-8.39 (m, IH), 8.26 (d, 2H), 8.14-8.09 (m, 2H), 8.08 (s, IH), 7.84-7.78 (m, IH), 7.66-7.60 (m, IH), 7.44 (d, 2H), 6.82-6.76 (m, IH), 4.35 (d, 2H), 3.23 (t, 2H), 2.78 (t, 2H), 1.91 (s, 3H), 1.83 (d, 2H), 1.73 (d, 2H), 1.60-1.49 (m, IH), 1.37 (s, 10H), 1.04-0.80 (m, 4H); m/z 545.2 (M+H) + . Example 104 Methyl [4-(4-{[(?rα«5 f -4-{[(?er?-butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl }quinolin-2-yl)benzyl]carbamate
DIPEA (51 mg, 0.40 mmol), and methyl chloroformate (37 mg, 0.40 mmol) were added to a solution of tert-butyl [(?rfl«5 f -4-{[({2-[4-(aminomethyl)phenyl]quinolin-4- yl}carbonyl)amino]-methyl}cyclohexyl)methyl]carbamate acetate (Example 92 (Method 9)) (100 mg, 0.2 mmol) in DCM (2 mL) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was then concentrated in vacuo to leave a residue which was purified by preparative HPLC, using ACN/water/ AcOH 0.2% as eluent, to give the title compound (59 mg, 52%). 1 H NMR (400MHz, DMSO-J 6 ) δ 8.77 (t, IH), 8.21 (d, 2H), 8.11-8.05 (m, 2H), 8.03 (s, IH), 7.77 (t, IH), 7.59 (t, 2H), 7.49 (d, 2H), 6.77-6.71 (m, IH), 3.77 (s, 2H), 3.23-3.16 (m, 2H), 2.78-2.68 (m, 2H), 1.87-1.61 (m, 7H), 1.56-1.41 (m, IH), 1.32 (s, 10H), 1.01-0.74 (m, 4H); m/z 561.2 (M+H) + . Example 105 tert-Butyl {[/røfts-4-({[(2-{4-[(carbamoylammo)methyl]phenyl}qumolin-4 - yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
Potassium cyanate (48 mg, 0.60 mmol) was added to a solution of tert-butyl [(?rα«5 f -4- {[({2-[4-(aminomethyl)phenyl]quinolin-4-yl}carbonyl)amino]-m ethyl}cyclohexyl)- methyl] carbamate (Example 92 (Method 9) (0.10 g, 0.20 mmol) in a mixture of AcOH (0.1 mL) and MeOH (3 mL) and the reaction mixture was heated at 60 0 C for 15 h. The reaction mixture was cooled to rt and water was added. The mixture was filtered and the solid was dissolved in DMSO and purified by preparative HPLC, using ACN/water/ AcOH 0.2% as eluent, to give the title compound (23 mg, 21%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, 2H), 7.98 (d, 2H), 7.79 (s, IH), 7.70 (t, IH), 7.52 (t, IH), 7.36 (d, IH), 5.39-5.29
(m, IH), 4.17 (s, 2H), 3.32-3.26 (m, 2H), 2.92-2.84 (m, 2H), 1.89-1.71 (m, 4H), 1.63-1.51
(m, IH), 1.39-1.32 (m, IH), 1.38 (s, 9H), 1.07-0.84 (m, 4H); m/z 546.3 (M+H) + .
Example 106 tert-Butyl ({?rα«5 f -4-[({[2-(4-{[(methylsulfonyl)amino]methyl}phenyl)quinolin-4 - yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
Methanesulfonyl chloride (46 mg, 0.40 mmol) and DIPEA (51 mg, 0.40 mmol) were added sequentially to a solution of tert-butyl [(trans-4- {[({2- [4 (aminomethyl)-phenyl]quinolin- 4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate (Example 92 (Method 9)) (0.10 g, 0.20 mmol) in DCM (2 mL) and the reaction mixture was stirred at rt for 15h. The reaction mixture was then concentrated in vacuo to leave a residue, which was dissolved in DMSO and purified by preparative HPLC, using ACN/water/AcOH 0.2% as eluent, to give the title compound (5 mg, 4%). 1 U NMR (400 MHz, CDCl 3 ) δ 8.10 (t, 2H), 8.04 (d, 2H), 7.80 (s, IH), 7.71 (t, IH), 7.53 (t, IH), 7.45 (d, 2H), 7.13 (t, IH), 4.31 (s, 2H), 3.37-3.30 (m, 2H), 2.94 (s, 3H), 2.92-2.86 (m, 2H), 1.89-1.72 (m, 4H), 1.62-1.50 (m, IH), 1.38 (s, 9H), 1.38-1.29 (m, IH), 1.08-0.84 (m, 4H); m/z 581.2 (M+H) + . Example 107
[4-(4-{[(?rα«5 f -4-{[(?ert-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl}quinolin-2-yl)phenyl]acetic acid
vial and the vial was degassed. The reaction mixture was heated at 60 0 C for 16 h under a nitrogen atmosphere and then cooled to rt. DCM, MeOH and a mixture of water and citric acid were added and the layers were separated. The organic layer was concentrated in vacuo to leave a solid, which was washed with MeOH to give the title compund (166 mg, 89%). 1 H NMR (400MHz, DMSO-J 6 ) δ 12.40 (s, IH), 8.81 (t, IH), 8.25 (d, 2H), 8.15- 8.09 (m, 2H), 8.08 (s, IH), 7.84-7.78 (m, IH), 7.66-7.61 (m, IH), 7.46 (d, 2H), 6.79 (t, IH), 3.68 (s, 2H), 3.23 (t, 2H), 2.78 (t, 2H), 1.84 (d, 2H), 1.73 (d, 2H), 1.61-1.48 (m, IH), 1.37 (s, 10H), 1.04-0.80 (m, 4H); m/z 532.2 (M+H) + .
Example 108
3-(4-{[(?rα«5 f -4-{[(?er?-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl}quinolin-2-yl)benzoic acid
The title compound was prepared as described in Example 107 using 3-(dihydroxyboryl)benzoic acid in place of [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]acetic acid. 1 H NMR (400 MHz, DMSO-J 6 ) δ 13.19 (s, IH), 8.89-8.80 (m, 2H), 8.52 (d, IH), 8.20-8.13 (m, 3H), 8.09 (d, IH), 7.87-7.80 (m, IH), 7.73-7.64 (m, 2H), 6.83- 6.75 (m, IH), 3.24 (t, 2H), 2.78 (t, 2H), 1.89-1.67 (m, 4H), 1.60-1.48 (m, IH), 1.37 (s, 10H), 1.05-0.79 (m, 4H); m/z 518.2 (M+H) + . Example 109 (Method 19)
Tetrahydro-2H-pyran-4-yl [(/rafts-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
4-Nitrophenyl tetrahydro-2H-pyran-4-yl carbonate (Intermediate QQ) (81 mg, 0.30 mmol, 1.2 eq.) and TEA (0.32 mL, 2.3 mmol, 9.2 eq.) were added sequentially to a stirred solution of N- { [?rα«5 f -4-(aminomethyl)cyclohexyl]methyl} -2-[6-(4-methylpiperazin- 1 - yl)pyridin-3-yl]quinoline-4-carboxamide (Intermediate PP) (120 mg, 0.25 mmol) in TηF (2 mL) and the reaction mixture was stirred at rt for 12h. The reaction mixture was concentrated in vacuo to leave a residue which was dissolved in DMSO and purified by reverse phase ηPLC (Standard method A) to afford the title compound (16 mg, 11%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.88 (d, IH), 8.35 (dd, IH), 8.13-8.06 (m, 2H), 7.76 (s, IH), 7.75-7.67 (m, IH), 7.54-7.47 (m, IH), 6.75 (d, IH), 6.31-6.21 (m, IH), 4.89-4.71 (m, 2H), 3.95-3.83 (m, 2H), 3.74-3.64 (m, 4H), 3.58-3.46 (m, 2H), 3.45-3.38 (m, 2H), 3.10-2.98 (m, 2H), 2.59-2.49 (m, 4H), 2.37 (s, 3H), 1.99-1.78 (m, 6H), 1.73-1.55 (m, 3H), 1.53-1.37 (m, IH), 1.18-0.94 (m, 4H); m/z (M+H) + 601.3. Examples 110-132
The following Examples 110-132 were prepared by the general procedure of Example 109 (Method 19) by using the appropriate Intermediate RR-OOO in place of Intermediate QQ.
Example 133
(l l S r )-2-Hydroxy-l-methylethyl [(/rafts-4-{[({2-[6-(4-methylpiperazin-l-yl)pyridin-3- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate
TFA (1.3 mL) was added to a solution of (lS)-2-te/t-butoxy-l-methylethyl [(trans-4-{[({2- [6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]quinolin-4-yl} carbonyl)amino]- methyl}cyclohexyl)methyl]carbamate (Intermediate PPP) (17 mg, 27 μmol) in DCM (3 mL) and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was concentrated in vacuo to leave a residue, which was dissolved in DCM and a saturated aq. solution OfNaHCO 3 was added. The layers were separated and the organic layer was dried (phase separator) and concentrated in vacuo to leave a residue, which was purified by flash column chromatography, using a mixture of 0— »75 % EtOAc:MeOH:TEA (1:0.2:0.02) in EtOAc as eluent, to give the title compound (4.0 mg, 26%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.85 (d, IH), 8.31 (dd, IH), 8.04 (d, 2H), 7.72 (s, IH), 7.68-7.62 (m, 2H), 7.49-7.42 (m, IH), 6.71 (d, IH), 6.19 (t, IH), 4.89-4.70 (m, 2H), 3.81-3.70 (m, 4H), 3.61 (dd, IH), 3.51 (dd, IH), 3.38-3.32 (m, 2H), 3.02-2.94 (m, 2H), 2.75-2.62 (m, 4H), 2.44 (s, 3H), 1.87-1.72 (m, 4H), 1.63-1.49 (m, IH), 1.45-1.31 (m, IH), 1.16 (d, 3H), 1.07-0.84 (m, 4H); m/z (M+H) + 575.2.
Examples 134-135
The following Examples 134-135 were prepared by the general procedure of Example 1
(Method 1) using the appropriate Intermediate QQQ-RRR in place of 2-[6-(4- methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carboxylic acid and using DMF in place of
DCM.
Examples 136-141
The following Examples 136-141 were prepared by the general procedure of Example 109 (Method 19) using the appropriate Intermediate SSS-UUU in place of N- {[trans-4- (aminomethyl)cyclohexyl]methyl} -2-[6-(4-methylpiperazin- 1 -yl)pyridin-3-yl]quinoline-4- carboxamide and 4-nitrophenyl tetrahydro-2H-pyran-4-yl carbonate (Intermediate QQ) or 4-nitrophenyl β^-tetrahydrofuran-S-yl carbonate (Intermediate XX).
Example 142 (Method 20) tert-Butyl [(?rα«5 f -4-{[({2-[6-(4-acetylpiperazin-l-yl)pyridin-3-yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
1-Acetylpiperazine (0.98g, 7.6 mmol, 30 eq.) was added to a solution of te/t-butyl {{trans- 4-[({[2-(6-fluoropyridin-3-yl)quinolin-4-yl]carbonyl}amino)m ethyl]cyclohexyl}methyl)- carbamate (Intermediate VVV) (0.13 g, 0.25 mmol) in pyridine (2 mL) in a microwave vial. The reaction mixture was heated at 130 0 C in a microwave for 30 min. The reaction mixture was concentrated in vacuo to leave a residue, which was dissolved in THF and filtered through a plug of silica using THF as eluent. The filtrate was concentrated in vacuo to leave a residue, which was dissolved in DMSO and purified by preparative HPLC (Standard method C) to give the title compound (67 mg, 44%). 1 H NMR (600 MHz, DMSO/DMSO-Je*) δ 9.03 (s, IH), 8.78-8.73 (m, IH), 8.44 (d, IH), 8.06-7.98 (m, 3H), 7.77-7.71 (m, IH), 7.58-7.51 (m, IH), 6.99 (d, IH), 6.78-6.74 (m, IH), 3.70-3.63 (m, 2H), 3.61-3.57 (m, 2H), 3.56-3.52 (m, 4H), 3.21-3.16 (m, 2H), 2.77-2.72 (m, 2H), 2.03 (s, 3H), 1.83-1.77 (m, 2H), 1.71-1.66 (m, 2H), 1.54-1.47 (m, IH), 1.33 (s, 9H), 1.32-1.27 (m, IH), 0.97-0.79 (m, 4H); m/z (M+H) + 601.2.
Examples 143-172
The following Examples 143-172 were prepared by the general procedure of Example 142
(Method 20) using the appropriate amine as starting material in place of 1-acetylpiperazine.
Example 173 (Method 21) tert-Butyl [(?rα«5 f -4-{[({2-[6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]quinol in-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
Tetrahydro-3-furanmethanol (83 mg, 0.81 mmol, 5.0 eq.) and KOH (freshly ground, 64 mg, 1.14 mmol, 7.0 eq.) were added sequentially to a solution of tert-butyl({trans-4-[({[2- (6-fluoropyridin-3-yl)quinolin-4-yl]carbonyl}amino)methyl]cy clohexyl}methyl)carbamate (Intermediate VVV) (80 mg, 0.162 mmol) in a mixture of THF (1 mL) and ACN (3 mL) and the reaction mixture was heated to 65 0 C for 12h. The reaction mixture was concentrated in vacuo to leave a residue, which was taken up in DMSO and purified by reversed phase HPLC (Standard method F) to afford the title compound (12 mg, 13%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.05-9.03 (m, IH), 8.78-8.75 (m, IH), 8.59-8.57 (m, IH), 8.10-8.05 (m, 3H), 7.80-7.76 (m, IH), 7.62-7.58 (m, IH), 6.98 (d, IH), 6.78-6.75 (m, IH), 4.33- 4.21 (m, 2H), 3.79-3.73 (m, 2H), 3.66-3.62 (m, 2H), 3.55-3.52 (m, IH), 3.21-3.18 (m, 2H), 2.76-2.73 (m, 2H), 2.05-1.98 (m, 2H), 1.83-1.79 (m, 2H), 1.71-1.66 (m, 2H), 1.55-1.47 (m, IH), 1.34 (s, 9H), 1.32-1.25 (m, IH), 0.97-0.79 (m, 4H); m/z (M+H) + 575.5.
Examples 174-179 The following Examples 174-179 were prepared by the general procedure of Example 173 (Method 21) using the appropriate alcohol as starting material in place of 2- methanesulfonylethanol.
Example 180 tert-Butyl [(?rα«5 f -4-{[({2-[3-(4-methylpiperazin-l-yl)propoxy]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
4-Methyl-l-(hydroxypropyl)-piperazine (0.27 g, 1.7 mmol) and KOH (freshly ground, 0.15 g, 2.7 mmol) were added sequentially to a solution of tert-butyl {[trans-4-({[(2- chloroquinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]-methyl } carbamate (Example 35)
(0.15 g, 0.35 mmol) in a mixture of THF (1 mL) and ACN (3 mL). The reaction mixture was heated at 50 0 C for 12h and then DMSO was added and the mixture purified by HPLC (Standard method G). The fractions containing the title compound were partly concentrated in vacuo and then a saturated aq. solution OfNaHCO 3 was added. DCM was added and the layers were separated. The organic layer was dried (phase separator) and concentrated in vacuo to give the title compound (90 mg, 47%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, IH), 7.82 (d, IH), 7.63 (t, IH), 7.40 (t, IH), 6.92 (s, IH), 6.16-6.02 (m, IH), 4.65-4.56 (m, IH), 4.52 (t, 2H), 3.37 (t, 2H), 2.97 (t, 2H), 2.62-2.36 (m, 10H), 2.28 (s, 3H), 2.09-1.96 (m, 2H), 1.91-1.75 (m, 4H), 1.63-1.52 (m, IH), 1.44 (s, 9H), 1.42-1.35 (m, IH), 1.13-0.85 (m, 4H); m/z (M+H) + 554.1. Examples 181-184
The following examples were prepared by the procedure described for Example 180 using the appropriate alcohol as starting material in place of 4-methyl-l- (hydroxypropyl)piperazine.
a Prepared using 3-(4-acetylpiperazin-l-yl)propan-l-ol (Intermediate WWW) in place of 4- methyl- 1 -(hydroxypropyl)piperazine b Prepared by using te/t-butyl ({?rα«5 f -4-[({[2-(6-fluoropyridin-3-yl)quinolin-4- yl]carbonyl}amino)-methyl]cyclohexyl}methyl)carbamate (Intermediate VVV) in place of te/t-butyl {[?rα«5 f -4-({[(2-chloroquinolin-4-yl)carbonyl]amino}methyl)cyclo-hex yl]- methyl} carbamate (Example 35) c 1 H NMR (600 MHz, DMSO/DMSO-d 6 )*
Example 185 (Method 22) tert-Butyl [(/rafts-4-{[({2-[4-(2-hydroxyethyl)piperazm-l-yl]qumolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
1 -Piperazineethanol (0.43 g, 3.3 mmol, 17 eq.) was added to a solution of te/t-butyl {[?rfl«5 f -4-({[(2-chloroquinolin-4-yl)carbonyl]amino}methyl)cyclohexy l]methyl}- carbamate (Example 35) (80 mg, 0.19 mmol) in pyridine (2 mL) in a microwave vial and the reaction vessel was sealed and heated in a microwave at 135 0 C for 30 min. The reaction mixture was then concentrated in vacuo to leave a residue which was dissolved in THF and passed through a plug of silica using THF as eluent. The mixture was concentrated in vacuo to leave a residue which was dissolved in DMSO and purified by HPLC (HPLC Standard method C) to give the title compound (50 mg, 51%). 1 H NMR (600 MHz, DMSO/DMSO-d 6 )* δ 8.58 (t, IH), 7.77 (d, IH), 7.57-7.54 (m, IH), 7.52-7.48 (m, IH), 7.22-7.18 (m, IH), 7.14 (s, IH), 6.76 (t, IH), 4.43 (t, 2H), 3.68-3.63 (m, 4H), 3.52 (q, 2H), 3.12 (t, 2H), 2.74 (t, 2H), 2.43-2.39 (m, 4H), 1.80-1.63 (m, 4H), 1.51-1.42 (m, IH), 1.34 (s, 9H), 1.30-1.25 (m, IH), 0.94-0.77 (m, 4H); m/z (M+H) + 526.3. Examples 186-189
The following examples were prepared by the method described in Example 185 (Method 22) using the appropriate amine as starting material in place of 1 -piperazineethanol.
Example 190 tert-Butyl {[?rα«5 f -4-({[(2-piperazin-l-ylquinolin-4-yl)carbonyl]amino}methyl)- cyclohexyl]methyl}carbamate
Piperazine (239 mg, 2.78 mmol) was added to a solution of tert-butyl {[tr<ms-4-({[(2- chloroquinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate (Example 35) (100 mg, 0.23 mmol) in pyridine (2 mL) and the reaction mixture was heated to 130 0 C for
30 min. The reaction mixture was concentrated in vacuo to leave a residue which was purified by flash column chromatography, using a gradient of 5-70% MeOH (2% TEA) in DCM as eluent, and then preparative HPLC (Standard method H) to give the title compound (43 mg, 39 %). 1 H NMR (300 MHz, CDCl 3 ) δ 8.61-8.56 (m, IH), 7.80-7.77 (m, IH), 7.57-7.48 (m, 3H), 7.23-7.18 (m, IH), 6.79-6.74 (m, IH), 3.63-3.58 (m, 4H), 3.16-3.10 (m, 2H), 2.81-2.73 (m, 6H), 1.81-1.75 (m, 2H), 1.72-1.66 (m, 2H), 1.52-1.44 (m, IH), 1.36 (s, 9H), 1.32-1.26 (m, IH), 0.96-0.80 (m, 4H); m/z (M+H) + 482.5.
Examples 191-192 The following Examples 191-192 were prepared by the same procedure as described for Example 190 using the appropriate amine, Intermediate YYY or Intermediate ZZZ, as starting material in place of piperazine and DIPEA (37 eq.) was added to the reaction mixtures.
carbonyl)amino]methyl 3.04 (m, 2H), 2.89-2.83 (m, 4H),
} cy clohexy l)methy 1] - 2.75-2.72 (m, 2H), 1.75 (s, 3H), carbamate 1.79-1.70 (m, 4H), 1.70-1.65 (m,
2H), 1.59-1.53 (m, 2H), 1.48-1.43
(m, IH), 1.33 (s, 9H), 1 29-1.24 (m,
IH), 1.15-1.04 (m, IH), 0.94-0.77
(m, 4H)
Example 193 tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]piperidin-l-yl}quinolin- 4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
Dimethylamine (2 M in MeOH, 1.66 mL, 3.3 mmol) was added to a solution of 2-[l-(4- { [(trans-4- { [(te/t-butoxycarbonyl)amino]methyl} cyclohexyl)methyl]carbamoyl} -quinolin- 2-yl)piperidin-4-yl]ethyl methanesulfonate (Intermediate XXX Step i)) (600 mg, 0.17 mmol) in DMF (1 mL) and the reaction mixture was stirred for 20 h at rt. The reaction mixture was then purified by flash column chromatography, using a gradient of 5-70% MeOH (2% TEA) in DCM as eluent, to give the title compound (30 mg, 33%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.83-7.80 (m, IH), 7.68-7.64 (m, IH), 7.54-7.49 (m, IH), 7.24-7.14 (m, 2H), 6.96 (s, IH), 6.28-6.24 (m, IH), 4.65-4.60 (m, IH), 4.49-4.44 (m, 2H), 3.35 (t, 2H), 2.99-2.87 (m, 5H), 2.43-2.39 (m, 2H), 2.30 (s, 6H), 1.89-1.76 (m, 6H), 1.64-1.54 (m, IH), 1.49-1.40 (m, 2H), 1.43 (s, 9H), 1.31-1.19 (m, 2H), 1.09-0.89 (m, 4H); m/z (M+H) + 552.3.
Example 194 tert-Butyl [(?rα«5 f -4-{[({2-[4-(2-aminoethyl)piperidin-l-yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
Tetrahydro-2H-pyran-4-yl {[/ra«s-4-({[(2-{6-[2-(dimethylamino)ethoxy]pyridin-3- yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}car bamate
A solution of 2-dimethylaminoethanol (68 mg, 0.77 mmol) in THF (2 mL) and KOH (freshly ground, 43 mg, 0.77 mmol) were added to a solution of tetrahydro-2H-pyran-4- yl({?rα«5 f -4-[({[2-(6-fluoropyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate (Intermediate AAAA) (100 mg, 0.19 mmol) in ACN (2 mL). The reaction mixture was heated at 60 0 C for 1 h and then filtered through a plug of silica using TηF as eluent. The solvent was concentrated in vacuo and the residue was dissolved in DMSO and purified by preparative ηPLC (Standard method C) to give the title compound (7 mg, 6%). 1 H NMR (600 MHz, DMSO/DMSO-d 6 *) δ 9.05-9.04 (m, IH), 8.78-8.75 (m, IH), 8.59-8.56 (m, IH), 8.10-8.05 (m, 3H), 7.80-7.76 (m, IH), 7.62-7.58 (m, IH), 7.11-7.07 (m, IH), 6.97 (d, IH), 4.65-4.59 (m, IH), 4.41 (t, 2H), 3.78-3.74 (m, 4H), 3.21-3.18 (m, 2H), 2.83-2.79 (m, 2H), 2.64-2.61 (m, 2H), 2.20 (s, 6H), 1.84-1.77 (m, 4H), 1.72-1.67 (m, 2H), 1.55-1.48 (m, IH), 1.47-1.40 (m, 2H), 1.35-1.29 (m, IH), 0.98-0.82 (m, 4H); m/z (M+H) + 590.3.
Example 196
(3S)-TeIx ahydrofuran-3-yl {[/ra«s-4-({[(2-{6-[2-(dimethylamino)ethoxy]pyridin-3- yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}car bamate
Example 197
Tetrahydro-2H-pyran-4-yl {[/rafts-4-({[(2-{6-[(2-hydroxyethyl)amino]pyridin-3- yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}car bamate
Ethanolamine (188 mg, 3.1 mmol) was added to a solution of tetrahydro-2H-pyran-4- yl({?rfl«5 f -4-[({[2-(6-fluoropyridin-3-yl)quinolin-4-yl]-carbonyl}amino )methyl]cyclo- hexyl}methyl)carbamate (Intermediate AAAA) (80 mg, 0.15 mmol) in pyridine (2 mL) and the reaction mixture was heated to 130 0 C in a sealed microwave vial using microwave irradiation for 30 min. The reaction mixture was concentrated in vacuo to leave a residue which was dissolved in TηF and washed through a plug of silica using TηF as eluent. Concentration in vacuo left a residue which was dissolved in DMSO and purified by preparative ηPLC (Standard method C) to afford the title compound (60 mg, 69%). 1 H NMR (600 MHz, DMSO/DMSO-d 6 *) δ 8.89-8.88 (m, IH), 8.75-8.72 (m, IH), 8.29-8.26 (m, IH), 8.04-7.97 (m, 3H), 7.74-7.70 (m, IH), 7.54-7.50 (m, IH), 7.11-7.07 (m, IH), 7.03-6.99 (m, IH), 6.63 (d, IH), 4.76 (t, 2H), 4.65-4.60 (m, IH), 3.78-3.74 (m, 4H), 3.54 (q, 2H), 3.20-3.16 (m, 2H), 2.83-2.79 (m, 2H), 1.83-1.76 (m, 4H), 1.72-1.66 (m, 2H), 1.54- 1.40 (m, 3H), 1.34-1.28 (m, IH), 0.97-0.80 (m, 4H); m/z (M+H) + 562.3. Examples 198-200
The following Examples 198-200 were prepared using the procedure described for Example 197. Example 198 used Intermediate AAAA as starting material and N,N'- dimethylethylenediamine in place of ethanolamine. Examples 199-200 used Intermediate BBBB as starting material and λf,λf'-dimethylethylenediamine or ethanolamine as the required amine respectively.
Example 201
(3S)-Tetr ahydrofuran-3-yl {[?rα«5 f -4-({[(2-{6-[(3R)-3-hydroxypyrrolidin-l-yl]pyridin-
3-yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methy l}-carbamate
TFA (4 mL, 52 mmol) was added to a solution of fers-butyl {[trans-4-({[(2-{6-[(3K)-3- hydroxypyrxolidin- 1 -yl]pyridin-3-yl} quinolin-4-yl)carbonyl] amino } methyl)cyclohexyl] - methyl} carbamate (Example 147) (243 mg, 0.43 mmol) in DCM (10 mL) and the reaction mixture was stirred for 1 h at rt. The solvent was concentrated in vacuo to leave the crude amine which was used in the next step without further purification, m/z (M+H) + 460.3. A solution of 4-nitrophenyl β^-tetrahydrofuran-S-yl carbonate (Intermediate XX) (71 mg, 0.28 mmol) in THF (3 mL) and TEA (0.27 mL, 1.94 mmol) was added to a solution of the crude amine (99 mg, 0.22 mmol) in THF (2 mL) and the reaction mixture was stirred at 40
0 C for 3 h and then at rt for 16 h. The reaction mixture was concentrated in vacuo to leave a residue which was purified by flash column chromatography, using a mixture of 2-25% MeOH in DCM as eluent, to give the title compound (16 mg, 13%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.00-8.96 (m, IH), 8.76-8.70 (m, IH), 8.41-8.36 (m, IH), 8.05-7.98 (m, 3H), 7.74-7.68 (m, IH), 7.54-7.48 (m, IH), 7.19-7.13 (m, IH), 6.59-6.55 (m, IH), 5.07-5.03 (m, IH), 4.42-4.35 (m, IH), 3.76-3.47 (m, 7H), 3.20-3.15 (m, 3H), 2.82-2.77 (m, 2H), 2.09- 1.99 (m, 2H), 1.93-1.86 (m, IH), 1.84-1.77 (m, 3H), 1.72-1.66 (m, 2H), 1.54-1.47 (m, IH), 1.31 (s, 2H), 0.99-0.78 (m, 4H); m/z (M+H) + 574.3. Example 202 Tetrahydro-2H-pyran-4-yl {[/rafts-4-({[(2-{6-[(3R)-3-hydroxypyrrolidin-l-yi]pyridin- 3-yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}- carbamate
Example 202 was prepared according to the procedure described for Example 201 using 4-nitrophenyl tetrahydro-2H-pyran-4-yl carbonate (Intermediate QQ) in place of 4- nitrophenyl (35)-tetrahydrofuian-3-yl carbonate. 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.00- 8.98 (m, IH), 8.76-8.71 (m, IH), 8.41-8.37 (m, IH), 8.05-7.99 (m, 3H), 7.74-7.68 (m, IH), 7.54-7.49 (m, IH), 7.10-7.05 (m, IH), 6.57 (d, IH), 5.15-4.90 (m, IH), 4.68-4.58 (m, IH), 4.42-4.37 (m, IH), 3.79-3.73 (m, 2H), 3.57-3.48 (m, 3H), 3.42-3.33 (m, 3H), 3.21-3.16 (m, 2H), 2.48-2.45 (m, 2H), 2.07-1.96 (m, IH), 1.93-1.87 (m, IH), 1.83-1.75 (m, 4H), 1.72- 1.66 (m, 2H), 1.53-1.38 (m, 3H), 1.35-1.27 (m, IH), 0.98-0.77 (m, 4H); m/z (M+H) + 588.4.
Example 203 tert-Butyl {[/ra«s-4-({[(2-{4-[2-(dimethylammo)ethoxy]phenyl}quinolin- 4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
evaporated and the crude product was purified with HPLC chromatography, using a Kromasil C8 column, 10 μm, 250x20 ID mm, 10-90% mobilephase B over 25 min (Mobilephase A = water: ACN:formic acid 95:5:0.2, mobilephase B = ACN). The required fractions were concentrated in vacuo to give the title compound (57 mg, 68%). 1 H NMR (500 MHz, CD 3 OD) δ 8.55 (s, IH), 7.84-7.78 (m, IH), 7.67-7.61 (m, IH), 7.57-7.50 (m, IH), 7.27-7.19 (m, IH), 7.15 (s, IH), 4.61-4.51 (m, 2H), 4.09-4.01 (m, IH), 3.30-3.26 (m, 2H), 3.05-2.86 (m, 6H), 2.80 (s, 6H), 1.98-1.77 (m, 7H), 1.65-1.54 (m, IH), 1.49-1.38 (m, 2H), 1.43 (s, 9H), 1.36-1.17 (m, 3H), 1.10-0.9 (m, 4H); m/z (M+H) + 582.5. Examples 206-207
The following Examples were prepared using the method described in Example 205 using the appropriate amine as starting material in place of dimethylamine.
1 The product of Example 206 was separated by chiral chromatography, using a Chiralcel
OJ column, 5 μm, 250x20 mm, mobile phase heptane/EtOH/TEA 90/10/0.1 to give the two enantiomers, Example 208 and Example 209. Example 208 eluted first with a retention time of 12 min and Example 209 eluted second with a retention time of 16 min.
Example 208 (R) or (S) tert-Butyl [(trø«s-4-{[({2-[4-(2-hydroxy-3-morpholin-4- ylpropyl)piperidin- 1 -yl]quinolin-4-yl} -carbonyl)amino]methyl} cyclohexyl)methyl]- carbamate;
Example 209 (S) or (R) tert-Butyl [(trø«s-4-{[({2-[4-(2-hydroxy-3-pyrrolidin-l-ylpropyl)- piperidin- 1 -yl]quinolin-4-yl} carbonyl)amino]-methyl} cyclohexyl)methyl]carbamate;
Example 210 tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(dimethylamino)-2-oxoethoxy]piperidin-l-yl}qu inolin-
4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
A suspension of tert-butyl { [trans-4-( { [(2-chloroquinolin-4-yl)carbonyl]amino } - methyl)cyclohexyl]methyl} carbamate (Example 35) (75 mg, 0.17 mmol) and N,N- dimethyl-2-(piperidin-4-yloxy)acetamide trifluoroacetate (Intermediate EEEE) (155 mg, 0.52 mmol, 3 eq.) in pyridine (ImL) was heated in a microwave at 140 0 C for 80 min. The reaction mixture was concentrated in vacuo to leave a residue, which was purified by HPLC chromatography, using a Kromasil C8 column, 10μm, 250x20 ID mm, 10-90% mobilephase B over 20 min (Mobilephase A = water: ACN:formic acid 95:5:0.2, mobilephase B = ACN) to give the title compound (20 mg, 20%). 1 H NMR (500 MHz, CD 3 OD) δ 7.85-7.80 (m, IH), 7.67-7.51 (m, 2H), 7.33-7.21 (m, IH), 7.17 (s, IH), 4.29 (s, 2H), 4.23-4.16 (m, 2H), 3.75-3.67 (m, IH), 3.47-3.38 (m, 2H), 3.30-3.26 (m, 2H), 3.05 (s, 3H), 2.95 (s, 3H), 2.92-2.87 (m, 2H), 2.08-1.99 (m, 2H), 1.95-1.86 (m, 2H), 1.86-1.78 (m, 2H), 1.74-1.55 (m, 3H), 1.49-1.37 (m, IH), 1.43 (s, 9H), 1.11-0.91 (m, 4H); m/z (M+H) + 582.4. Example 211 tert-Butyl { [trans-4-( { [(2- {4-[2-(dimethylamino)ethoxy]piperidin- 1 -yl} quinolin-4- yl)carbony 1] amino } methyl)cyclohexyl]methyl} carbamate
A suspension of tert-hvXy\ { [trans-4-( { [(2-chloroquinolin-4-yl)carbonyl]amino } - methyl)cyclohexyl]methyl} carbamate (100 mg, 0.23 mmol), iV,./V-dimethyl-2-(piperidin-4- yloxy)ethanamine bis(trifluoroacetate) (Intermediate FFFF) (395 mg, 0.99 mmol, 4.3 eq.) and K 2 CO 3 (160 mg, 1.16 mmol, 5 eq.) in pyridine (2mL) was heated in a microwave at 140 0 C for 80 min. The reaction mixture was concentrated in vacuo to leave a residue, which was purified by HPLC chromatography, using a Kromasil C8 column, lOμm, 250x20 ID mm, 10-90% mobilephase B over 20 min (Mobilephase A = water: ACN:formic acid 95:5:0.2, mobilephase B = ACN) to give the title compound (30 mg, 23%). 1 H NMR (500 MHz, CD 3 OD) δ 7.84-7.79 (m, IH), 7.67-7.63 (m, IH), 7.57-7.51 (m, IH), 7.27-7.21
(m, IH), 7.16 (s, IH), 4.24-4.13 (m, 2H), 3.76-3.61 (m, 3H), 3.46-3.37 (m, 2H), 3.30-3.25
(m, 2H), 2.92-2.86 (m, 2H), 2.78-2.72 (m, 2H), 2.43 (s, 6H), 2.07-1.97 (m, 2H), 1.94-1.86
(m, 2H), 1.85-1.77 (m, 2H), 1.69-1.56 (m, 3H), 1.48-1.37 (m, IH), 1.43 (s, 9H), 1.11-0.90
(m, 4H); m/z (M+H) + 568.5.
Example 212
2,2-Dimethylpropyl {[£rafts-4-({[(2-{4-[2-(dimethylamino)ethyi]piperidin-l- yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}car bamate
2,2-Dimethylpropyl chlorocarbonate (32 μL, 0.21 mmol, 1.2 eq.) was added to a solution ofN-{[?rfl«5 f -4-(aminomethyl)cyclohexyl]methyl}-2-{4-[2-(dimethylamino)- ethyl]piperidin-l-yl}quinoline-4-carboxamide trihydrochloride (Intermediate GGGG) (100 mg, 0.18 mmol) and DIPEA (0.31 mL, 1.8 mmol, 10 eq.) in DCM (5 mL) and the reaction mixture was stirred at rt for 10 min. The reaction mixture was concentrated in vacuo to leave a residue, which was purified with HPLC chromatography, using a Kromasil C8 column, 10 μm, 250x20 ID mm, 10-90% mobilephase B over 20 min (Mobilephase A = water: ACN:formic acid 95:5:0.2, mobilephase B = ACN) to give the title compound (75 mg, 74%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.88-7.80 (m, IH), 7.71-7.64 (m, IH), 7.57-7.49 (m, IH), 7.28-7.19 (m, IH), 7.01 (s, IH), 6.20-6.12 (m, IH), 4.80-4.70 (m, IH), 4.55-4.46 (m, 2H), 3.79-3.70 (m, 2H), 3.42-3.33 (m, 2H), 3.08-2.99 (m, 2H), 2.98-2.86 (m, 2H), 2.72-2.62 (m, 2H), 2.48 (s, 6H), 1.93-1.75 (m, 6H), 1.68-1.53 (m, 4H), 1.50-1.39 (m, IH), 1.34-1.21 (m, 2H), 1.11-0.88 (m, 4H), 0.92 (s, 9H); m/z (M+H) + 566.5.
Examples 213-214
The following examples were prepared by the method described in Example 185 (Method
22) using the appropriate amine as starting material in place of 1-piperazineethanol.
Examples 215-216
Examples 215 and 216 was prepared by the method described in Example 180 using the appropriate alcohol as starting material in place of 4-methyl-l-(hydroxy-propyl)piperazine. For Example 215 cesium carbonate was used in place of KOH.
Example 217 tert-Butyl ({/røfts-4-[({[2-(3-{[2-(dimethylamino)ethyl]carbamoyl}azet idin-l- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate
Example 217 was prepared by the method described for Example 1 (Method 1) using Intermediate HHHH in place of Intermediate A and tert-butyl {[trans-4- (aminomethyl)cyclohexyl]methyl} carbamate. 1 H NMR (600 MHz, DMSO/DMSO-d 6 *) δ 8.61 (t, IH), 7.97 (t, IH), 7.79 (d, IH), 7.57 (d, IH), 7.51 (t, IH), 7.21 (t, IH), 6.75 (t, IH), 6.66 (s, IH), 4.18 (t, 2H), 4.09 (t, 2H), 3.52-3.44 (m, IH), 3.16 (q, 2H), 3.12 (t, 2H), 2.74
(t, 2H), 2.34-2.25 (m, 2H), 2.13 (s, 6H), 1.80-1.71 (m, 2H), 1.70-1.63 (m, 2H), 1.50-1.41 (m, IH), 1.34 (s, 9H), 1.31-1.23 (m, IH), 0.96-0.77 (m, 4H); m/z (M+H) + 567.6. Example 218 tert-Butyl ({/røfts-4-[({[2-(4-ammophenyl)qumolm-4-yl]carbonyl}amino)- methyl]cyclohexyl}methyl)carbamate
An aq. solution OfK 2 CO 3 (0.64 g, 4.6 mmol) was added to a suspension of tert-butyl {[?rα«5 f -4-({[(2-chloroquinolin-4-yl)carbonyl]amino}methyl)cyclohexy l]methyl}- carbamate (Example 35) (0.50 g, 1.16 mmol), (4-aminophenyl)boronic acid hydrochloride (0.24 g, 1.39 mmol) and Pd(PPh 3 ) 4 (67 mg, 0.058 mmol) in degassed dioxane (15 mL) and the reaction mixture was stirred for 16h at 60 0 C. The reaction mixture was filtered and EtOAc and water were added to the solution. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na 2 SO 4 ) and concentrated in vacuo to leave a residue, which was purified by flash column chromatography, using 40→100% EtOAc in heptane followed by 0→20% EtOH in toluene as eluent, to give the title compound (0.46 g, 81%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.73 (t, IH), 8.04-7.95 (m, 4H), 7.89 (s, IH), 7.73-7.68 (m, IH), 7.52-7.47 (m, IH), 6.78 (t, IH), 6.68 (d, 2H), 5.59 (s, 2H), 3.19 (t, 2H), 2.76 (t, 2H), 1.84-1.78 (m, 2H), 1.74- 1.67 (m, 2H), 1.57-1.46 (m, IH), 1.35 (s, 9H), 1.35-1.25 (m, IH), 1.00-0.79 (m, 4H); m/z (M+H) + 489.4. Example 219 tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(dimethylamino)ethyl]-3-oxopiperazin-l-yl}qui nolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
Example 219 was prepared by the method described in Example 185 (Method 22) using Intermediate HII as starting material in place of 1-piperazineethanol. 1 H NMR (600 MHz, DMSO/DMSO-Je* ) δ 8.60 (t, IH), 7.84-7.82 (m, IH), 7.60 (d, IH), 7.56-7.52 (m, IH), 7.26-7.22 (m, IH), 7.17 (s, IH), 6.76 (t, IH), 4.27 (s, 2H), 3.94-3.92 (m, 2H), 3.49-3.44 (m, 4H), 3.14 (t, 2H), 2.74 (t, 2H), 2.17 (s, 6H), 1.80-1.75 (m, 2H), 1.70-1.66 (m, 2H), 1.50-1.43 (m, IH), 1.34 (s, 9H), 1.31 - 1.24 (m, IH), 0.95-0.78 (m, 4H); m/z (M+H) + 567.4. Example 220 tert-Butyl [(?rα«5 f -4-{[({2-[4-(hydroxyacetyl)piperazin-l-yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
Example 220 was prepared by the method described in Example 185 (Method 22) using Intermediate JJJJ as starting material in place of 1-piperazineethanol. 1 H NMR (600 MHz, DMSO/DMSO-d 6 * ) δ 8.60 (t, IH), 7.79 (d, IH), 7.59-7.57 (m, IH), 7.54-7.51 (m, IH), 7.25-7.21 (m, IH), 7.18 (s, IH), 6.76 (t, IH), 4.62 (t, IH), 4.13 (d, 2H), 3.73-3.68 (m, 4H), 3.60-3.56 (m, 2H), 3.48-3.44 (m, 2H), 3.13 (t, 2H), 2.74 (t, 2H), 1.79-1.75 (m, 2H), 1.70-
1.65 (m, 2H), 1.51-1.43 (m, IH), 1.34 (s, 9H), 1.31-1.24 (m, IH), 0.95-0.78 (m, 4H); m/z (M+H) + 540.3. Example 221 tert-Butyl {[?rα«s-4-({[(2-{4-[(4-fluorobenzyl)oxy]piperidin-l-yl}qui nolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
Example 221 was prepared by the method described in Example 185 (Method 22) using Intermediate KKKK as starting material in place of 1-piperazineethanol. 1 H NMR (600 MHz, DMSO/DMSO-d 6 * ) δ 8.58 (t, IH), 7.76 (d, IH), 7.57-7.48 (m, 2H), 7.38-7.35 (m, 2H), 7.21-7.12 (m, 4H), 6.76 (t, IH), 4.52 (s, 2H), 4.16-4.11 (m, 2H), 3.69-3.64 (m, IH), 3.13 (t, 2H), 2.74 (t, 2H), 1.97-1.92 (m, 2H), 1.79-1.74 (m, 2H), 1.69-1.65 (m, 2H), 1.55- 1.43 (m, 3H), 1.34 (s, 9H), 1.31-1.24 (m, IH), 0.94-0.78 (m, 4H); m/z (M+H) + 605.5. Example 222 tert-Butyl {[?rα«5 f -4-({[(2-amino-l-benzothiophen-3-yl)carbonyl]amino}methyl)- cyclohexyrjmethyljcarbamate
Water (3.4 mL), NMM (0.25 mL, 2.23 mmol) and tert-butyl {[trans-4- (aminomethyl)cyclohexyl]methyl} carbamate (0.278 g, 1.15 mmol) were added to a solution of 2-amino-l-benzothiophene-3-carboxylic acid (Intermediate LLLL, 0.22 g, 1.11
mmol) in methyl-THF (5 mL). An aq. solution of HOBT-NMM (20% HOBT- 15% NMM, 0.38 mL) and EDC (0.28 g, 1.45 mmol) were added and the reaction mixture was stirred vigorously for 48 h. The reaction mixture was diluted with methyl-THF and water and the layers were separated. The aqueous layer was extracted with methyl-THF and the combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo to leave a residue. The residue was purified by flash column chromatography, using a gradient of 20— »60% EtOAc in heptane as eluent, to give the title compound (97 mg, 21%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, IH), 7.53 (d, IH), 7.32 (t, IH), 7.12 (t, IH), 6.39 (s, 2H), 6.04- 5.99 (m, IH), 4.60-4.54 (m, IH), 3.33 (t, 2H), 2.98 (t, 2H), 1.93-1.77 (m, 4H), 1.65-1.52 (m, IH), 1.47-1.36 (m, IH), 1.44 (s, 9H), 1.11-0.91 (m, 4H); m/z (M+H) + 418.2.
Example 223 tert-Butyl [(/rafts-4-{[({2-[(ethylcarbamoyl)amino]-l-benzothiophen-3- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
Ethyl isocyanate was added to a solution of tert-butyl {[trans-4-({[(2-ammo-l- benzothiophen-S-y^carbonylJaminolmethy^cyclohexylJmethyl} carbamate (Example 222, 56 mg, 0.13 mmol) in pyridine (2 mL) and the reaction mixture was stirred at 60 0 C for 16 h. The reaction mixture was concentrated in vacuo to leave a residue which was dissolved in pyridine (0.5 mL) and ethyl isocyanate was added (0.016 mL, 0.20 mmol) and the reaction mixture was stirred at 40 0 C for 48 h and then an additional portion of ethyl isocyantate was added (0.016 mL, 0.20 mmol) and the reaction mixture was heated at 80 0 C for 1.5 h in a microwave. The reaction mixture was concentrated in vacuo to leave a residue which was purified by flash column chromatography, using a gradient of 0— »5% MeOH in DCM followed by 20%— »80% tert-butyl methyl ether in toluene as eluent, to give the title compound (28 mg, 43%). 1 R NMR (400 MHz, CDCl 3 ) δ 11.46 (s, IH), 7.76
(d, IH), 7.66 (d, IH), 7.39 (t, IH), 7.24 (t, IH), 6.28 (t, IH), 4.98 (s, IH), 4.57 (s, IH),
3.41-3.32 (m, 4H), 3.01-2.94 (m, 2H), 1.94-1.78 (m, 4H), 1.67-1.55 (m, IH), 1.46-1.37 (m,
IH), 1.44 (s, 9H), 1.21 (t, 3H), 1.12-0.91 (m, 4H ); m/z (M+H) + 489.3.
Example 224
Tetrahydro-2H-pyran-4-yl {[/rafts-4-({[(2-{4-[2-(dimethylammo)ethyl]piperidin-l- yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}car bamate
Example 224 was prepared by the method described in Example 202 using
Example 225 was prepared by the method described in Example 185 (Method 22) using l-methyl-4,4'-bipiperidine as starting material in place of 1-piperazineethanol. 1 H NMR
(400 MHz, CDCl 3 ) δ 7.84 (dd, IH), 7.69 (d, IH), 7.56-7.51 (m, IH), 7.25-7.20 (m, IH), 7.04 (s, IH), 5.98 (t, IH), 4.60-4.53 (m, 3H), 3.38 (t, 2H), 2.98 (t, 2H), 2.93-2.84 (m, 4H),
2.25 (s, 3H), 1.91-1.78 (m, 8H), 1.74-1.67 (m, 2H), 1.63-1.54 (m, IH), 1.44 (s, 9H), 1.42-
1.22 (m, 6H), 1.11-0.91 (m, 5H); m/z (M+H) + 578.2.
Example 226 (Method 23) tert-Butyl ({?rα«5 f -4-[({[2-(4-{2-[(2-methoxyethyl)amino]ethyl}piperidin-l-yl)q uinolin- 4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
2-Methoxyethylamine (20 mg, 0.26 mmol, 1.5 eq.), sodium triacetoxyborohydride (66 mg, 0.31 mmol, 1.8 eq.) and one drop of AcOH were added to a solution of tert-butyl [(trans-4- { [( {2-[4-(2-oxoethyl)piperidin- 1 -yl]quinolin-4-yl} carbonyl)amino]methyl} - cyclohexyl)methyl]carbamate (Intermediate DDDDi)), 89 mg, 0.17 mmol) in EtOH (3 mL) and the reaction mixture was heated at in a microwave at 120 0 C for 10 min. The reaction mixture was concentrated in vacuo to leave a residue. DMSO (2 mL) was added to the
residue and the mixture was filtered and the filtrate was purified by HPLC (Standard Method C) to give the title compound (50 mg, 51%). 1 H NMR (600 MHz, DMSO/DMSO- J 6 * ) δ 8.57 (t, IH), 7.75 (d, IH), 7.52 (d, IH), 7.48 (dd, IH), 7.17 (dd, IH), 7.12 (s, IH), 6.76 (t, IH), 4.49 (d, 2H), 3.20 (s, 3H), 3.12 (t, 2H), 2.87 (t, 2H), 2.74 (t, 2H), 2.61 (t, 2H), 1.78-0.76 (m, 17H), 1.34 (s, 9H); m/z 582.8 (M+H) + .
Examples 227-232
The following Examples 227-232 were prepared from Intermediate DDDDi) using essentially the same conditions as described for Example 226 with the appropriate amine in place of 2-methoxyethylamine.
Example 233 tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(3-hydroxyazetidin-l-yl)ethyl]piperidin-l-yl} quinolin-
4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
Example 233 was prepared by the method described in Example 226 (Method 23) using azetidin-3-ol (Intermediate OOOO) as starting material in place of 2-methoxyethylamine.
1 H NMR (600 MHz, DMSO/DMSO-d 6 *) δ 8.57 (t, IH), 1.16-1.1 A (m, IH), 7.54-7.51 (m, IH), 7.50-7.46 (m, IH), 7.19-7.16 (m, IH), 7.11 (s, IH), 6.76 (t, IH), 4.51-4.47 (m, 2H), 4.13-4.08 (m, IH), 3.47-3.44 (m, 2H), 3.12 (t, 2H), 2.89-2.83 (m, 2H), 2.74 (t, 2H), 2.61- 2.58 (m, 2H), 2.39-2.35 (m, 2H), 1.79-1.65 (m, 6H), 1.60-1.52 (m, IH), 1.50-1.43 (m, IH), 1.34 (s, 9H), 1.30-1.24 (m, IH), 1.20-1.16 (m, 2H), 1.11-1.03 (m, 2H), 0.94-0.78 (m, 4H); m/z (M+H) + 580.2. Example 234 te/t-Butyl [(?rα«5 f -4-{[({2-[4-(2-azetidin-l-ylethyl)piperidin-l-yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
Example 234 was prepared by the method described in Example 226 (Method 23) using azetidine as starting material in place of 2-methoxyethylamine. 1 H NMR (600 MHz, DMSO/DMSO-Je* ) δ 8.56 (t, IH), 7.75 (d, IH), 7.53-7.51 (m, IH), 7.50-7.46 (m, IH), 7.19-7.16 (m, IH), 7.11 (s, IH), 6.76 (t, IH), 4.51-4.47 (m, 2H), 3.14-3.11 (m, 2H), 3.08- 3.03 (m, 2H), 2.89-2.83 (m, 2H), 2.74 (t, 2H), 2.46-2.44 (m, 2H), 2.37-2.34 (m, 2H), 1.94- 1.88 (m, 2H), 1.79-1.65 (m, 6H), 1.60-1.53 (m, IH), 1.50-1.43 (m, IH), 1.34 (s, 9H), 1.30- 1.24 (m, IH), 1.19-1.14 (m, 2H), 1.11-1.03 (m, 2H), 0.94-0.78 (m, 4H); m/z (M+H) + 564.2. Example 235 l-{2-[l-(4-{[(?rα«5 f -4-{[(?ert-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl}quinolin-2-yl)piperidin-4-yl]ethyl}azetidine-3-car boxylic acid
Example 235 was prepared by the method described in Example 226 (Method 23) using azetidine-3-carboxylic acid as starting material in place of 2-methoxyethylamine. 1 H NMR (600 MHz, DMSO/DMSO-d 6 * ) δ 8.39 (t, IH), 7.58 (d, IH), 7.36-7.34 (m, IH), 7.33-7.29 (m, IH), 7.02-6.98 (m, IH), 6.94 (s, IH), 6.58 (t, IH), 4.34-4.30 (m, 2H), 2.99-2.93 (m, 4H), 2.72-2.66 (m, 2H), 2.57 (t, 2H), 2.37-2.34 (m, 2H), 2.30-2.27 (m, 2H), 1.87 (s, IH), 1.62-1.48 (m, 6H), 1.43-1.35 (m, IH), 1.33-1.26 (m, IH), 1.17 (s, 9H), 1.13-1.07 (m, IH), 1.05-1.00 (m, 2H), 0.95-0.87 (m, 2H), 0.77-0.61 (m, 4H); m/z (M+H) + 608.2. Example 236 tert-Butyl {[?rα«5 f -4-({[(2-{4-[2-(3-aminoazetidin-l-yl)ethyl]piperidin-l-yl}qu inolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
A mixture of benzyl (l-{2-[l-(4-{[(?rα«5 f -4-{[(fert-butoxycarbonyl)amino]methyl}- cyclohexyl)methyl]carbamoyl}quinolin-2-yl)piperidin-4-yl]eth yl}azetidin-3-yl)-carbamate (Intermediate MMMM, 0.095 g, 0.13 mmol) and 5% palladium on carbon (95 mg) in MeOH (10 mL) was stirred under a hydrogen atmosphere at rt for 2h. The reaction
mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to leave a residue which was purified by preparative HPLC (Standard Method C) to give the title compound (46 mg, 60%). 1 U NMR (600 MHz, DMSO/DMSO-d 6 *) δ 8.56 (t, IH), 7.75 (d, IH), 7.54-7.51 (m, IH), 7.50-7.46 (m, IH), 7.19-7.15 (m, IH), 7.11 (s, IH), 6.76 (t, IH), 4.52-4.46 (m, 2H), 3.43-3.40 (m, 2H), 3.12 (t, 2H), 2.89-2.83 (m, 2H), 2.74 (t, 2H), 2.44-2.41 (m, 2H), 2.32 (t, 2H), 1.80-1.65 (m, 6H), 1.59-1.52 (m, IH), 1.50-1.43 (m, IH), 1.34 (s, 9H), 1.31-1.24 (m, IH), 1.19-1.14 (m, 2H), 1.11-1.03 (m, 2H), 0.94-0.78 (m, 4H); m/z (M+H) + 579.2 Example 237 tert-Butyl {[?rα«5 f -4-({[(2-{4-[3-(dimethylamino)-2-fluoropropyl]piperidin-l- yl}quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl}car bamate
(Diethylamino)sulfur trifluoride (0.039 mL, 0.30 mmol) was added slowly to a solution of tert-butyl [(trans-4- {[( {2-[4-(2-hydroxy-3-pyrrolidin- 1 -ylpropyl)piperidin- 1 -yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate (Example 206), 0.058 g, 0.10 mmol) in DCM (1 mL) at -78 0 C and the reaction mixture was allowed to reach room temperature and stirred for 16 h. EtOAc and a saturated aq. solution OfNaHCO 3 were added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo to leave a residue which was purified by HPLC (Standard Method C) to give the title compound (0.013g, 22%). 1 H NMR (600 MHz, DMSO/DMSO-d 6 * ) δ 8.57 (t, IH), 7.75 (d, IH), 7.54-7.52 (m, IH), 7.50-7.47 (m, IH), 7.19-7.16 (m, IH), 7.13 (s, IH), 6.76 (t, IH), 4.82-4.68 (m, IH), 4.54-4.47 (m, 2H), 3.13 (t, 2H), 2.93-2.85 (m, 2H), 2.74 (t, 2H), 2.16 (s, 6H), 1.86- 1.65 (m, 6H), 1.60-1.37 (m, 2H), 1.34 (s, 9H), 1.31-1.24 (m, IH), 1.21-1.07 (m, 3H), 0.94- 0.78 (m, 4H), 2.24 (s, 2H); m/z (M+H) + 584.2.
Example 238 tert-Butyl { [trans-4-( { [(2- {3- [2-(dimethylamino)ethoxy] azetidin- 1 -yl }quinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (47 mg, 0.24 mmol, 1.0 eq.), a solution of cesium carbonate (130 mg, 0.4 mmol, 1.7 eq.) in water (1 mL) and PEPPSI (8 mg, 0.012 mmol, 0.05 eq.) were added to a stirred solution of fers-butyl [(trans-4-{[({2-[3- (aminomethyl)phenyl]-6-chloropyridin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl]- carbamate (Intermediate PPPP, 115 mg, 0.24 mmol) in dioxane (3 mL) and the reaction mixture was stirred in a microwave at 140 0 C for 15 min. The reaction mixture was concentrated in vacuo and a saturated aq. solution OfNaHCO 3 was added. The mixture was extracted with EtOAc and methyl-THF. The combined organic layers were concentrated in vacuo to leave a residue which was purified by HPLC (Standard method C) to give the title compound (21 mg, 17%). 1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.76 (t, IH), 8.32 (s, IH), 8.22 (s, IH), 8.09 (d, IH), 8.04 (s, IH), 7.94 (s, IH), 7.48 (dd, IH), 7.44 (d, IH), 6.76 (t, IH), 3.92 (s, 2H), 3.15 (t, 2H), 2.72 (t, 2H), 1.76 (d, 2H), 1.67 (d, 2H), 1.50 (s, IH), 1.34 (s, 9H), 1.28 (s, IH), 0.93-0.78 (m, 4H); m/z 519.3 (M+H) + . Examples 240-241
The following Examples 240-241 were prepared using essentially the same conditions as described for Example 239 from the Intermediate PPPP and the appropriate boronic ester or acid in place of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole. Example 240 tert-Butyl [(?rα«5 f -4-{[({6-[3-(aminomethyl)phenyl]-2,3'-bipyridin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 9.41 (s, IH), 8.88 (t, IH), 8.67 (d, IH), 8.58 (d,
IH), 8.31 (s, IH), 8.28 (s, IH), 8.21 (s, IH), 8.09 (d, IH), 7.57 (dd, IH), 7.49-7.44 (m,
2H), 6.76 (t, IH), 3.85 (s, 2H), 3.18 (t, 2H), 2.74 (t, 2H), 1.77 (d, 2H), 1.68 (d, 2H), 1.53-
1.48 (m, IH), 1.34 (s, 9H), 1.30-1.27 (m, IH), 0.94-0.78 (m, 4H); m/z 530.4 (M+H) + .
Example 241 tert-Butyl [(?rα«5 f -4-{[({6'-amino-6-[3-(aminomethyl)phenyl]-2,3'-bipyridin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
1 H NMR (600 MHz, DMSO/DMSO-J 6 * ) δ 8.82-8.80 (m, 2H), 8.30 (s, IH), 8.25-8.22 (m,
2H), 8.11-8.09 (m, 2H), 7.51-7.45 (m, 2H), 6.76 (t, IH), 6.56 (d, IH), 6.34 (s, 2H), 3.96 (s,
2H), 3.16 (t, 2H), 2.74 (t, 2H), 1.76 (d, 2H), 1.68 (d, 2H), 1.54-1.47 (m, IH), 1.33 (s, 9H),
1.31-1.26 (m, IH), 0.94-0.78 (m, 4H); m/z 545.4 (M+H) + .
Example 242 tert-Butyl {[?ra«5'-4-({[(2-{l-[2-(dimethylamino)ethyl]-lH-pyrazol-4-y l}quinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate
Cesium carbonate (90 mg, 0.28 mmol) and 2-dimethylaminochloride hydrochloride (24 mg, 0.17 mmol) were added to a solution of tert-butyl{[trans-4-({[(2- {lH-τpyrazol-4- yl} quinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate (Intermediate QQQQ, 64 mg, 0.14 mmol) in EtOH (1 mL) and the reaction mixture was heated in a microwave at 140 0 C for 20 min. The reaction mixture was concentrated in vacuo to leave a residue which was purified by preparative HPLC (Standard Method G) to give the title compound (37 mg, 50%). 1 U NMR (400 MHz, DMSO-J 6 ) δ 8.73 (t, IH), 8.53 (s, IH), 8.18 (s, IH), 7.99-7.94 (m, 2H), 7.78 (s, IH), 7.72 (t, IH), 7.52 (t, IH), 6.77 (t, IH), 4.25 (t, 2H), 3.19 (t, 2H), 2.76 (t, 2H), 2.69 (t, 2H), 2.17 (s, 6H), 1.81 (d, 2H), 1.70 (d, 2H), 1.54-1.47 (m, IH), 1.35-1.25 (m, 10H), 0.98-0.79 (m, 4H); m/z 535.3 (M+H) + . Example 243 tert-Butyl [(?ra«5-4-{[({2-[l-(2-hydroxyethyl)-lH-pyrazol-4-yl]quinoli n-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
Example 243 was prepared using essentially the same conditions as described for Example 242 using 2-bromoethanol in place of 2-dimethylaminochloride hydrochloride. 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.64 (t, IH), 8.50 (s, IH), 8.20 (s, IH), 7.99-7.94 (m, 2H), 7.80 (s, IH), 7.72 (t, IH), 7.52 (t, IH), 6.77 (t, IH), 4.95 (t, IH), 4.21 (t, 2H), 3.78 (q,
2H), 3.19 (t, 2H), 2.76 (t, 2H), 1.81 (d, 2H), 1.70 (d, 2H), 1.51 (s, IH), 1.35 (s, 9H), 1.30
(m, IH), 0.99-0.79 (m, 4H); m/z 508.3 (M+H) + .
Example 244 tert-Butyl ({?rα«5 f -4-[({[2-(4-{2-[(2-fluoroethylamino]ethyl}piperidin-l-yl)qui nolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
TEA (0.318 mL, 2.28 mmol) was added in one portion to a mixture of tert-butyl [(trans-4- {[( {2-[4-(2-oxoethyl)piperidin- 1 -yl]quinolin-4-yl} carbonyl)amino]methyl} - cyclohexyl)methyl] carbamate (Intermediate DDDDi, 397 mg, 0.76 mmol) in EtOH (18 mL) and DCM (4.5 mL). 2-Fluoroethanamine hydrochloride (121 mg, 1.22 mmol) was added to the solution and the reaction mixture was stirred for 30 min and then sodium triacetoxyborohydride (322 mg, 1.52 mmol) was added in one portion. The reaction mixture was stirred at rt for 16 h and then water and a saturated aq. solution OfNaHCO 3 were added. DCM was added and the layers were separated. The second portion of DCM was added and the layers were separated. The combined organic layers were dried using a phase separator and concentrated in vacuo to leave a solid. A portion of the solid (50 mg) was dissolved in a mixture of THF/DMSO/MeOH and purified using preparative HPLC (XBridge C18 column (10 μm 250x19 ID mm), flow rate 19 mL/min) using a gradient of 40-95 % ACN in a water/ ACN/ammonia 95/5/0.2 buffer over 20 mins to give the product as a solid (27 mg obtained from 50 mg of the crude material). The remaining unpurified solid (380 mg) was used without further purification for the synthesis of Example 245. 1 H NMR (400 MHz, THF-J 8 ) δ 7.93 (d, IH), 7.68 (t, IH), 7.58 (d, IH), 7.44 (m, IH), 7.13 (m, IH), 7.11 (s, IH), 5.99 (t, IH), 4.60 (d, 2H), 4.49 (t, IH), 4.37 (t, IH), 3.58 (s, 3H), 3.25 (t,
2H), 2.89 (m, 5H), 2.80 (t, IH), 2.68 (t, 2H), 1.93-1.50 (m, 12H), 1.45-1.32 (m, 6H), 1.23
(m, 2H), 0.98 (m, 4H); m/z 570.3 (M+H) + .
Example 245 tert-Butyl ({?ra«5'-4-[({[2-(4-(2-((2-fluoroethyl)(methyl)amino)ethyl} piperidin-l- yl)quinolin-4-yl]carbonyl}amino)methyl]cyclohexyl}methyl)car bamate
O ^ O _NH
A solution of formaldehyde in water (110 μl, 1.54 mmol) was added to a solution of crude te/t-butyl ( {trans-4-[( {[2-(4- {2-[(2-fluoroethylamino]ethyl}piperidin- 1 -yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate (Example 244, 350 mg, 0.61 mmol) in THF and the mixture was stirred at rt for 30 min. Sodium cyanoborohydride (IM in THF, 1.84 mL, 1.84 mmol) was added in one portion and the mixture was stirred at rt for 16 h. Water and a saturated aq. solution OfNaHCO 3 were added and the layers were separated. DCM was added to the aq. layer, the layers were separated and the combined organic layers were dried using a phase separator and concentrated in vacuo to leave an oil. The oil was dissolved in DMSO/MeOH and purified using preparative HPLC (XBridge Cl 8 column (10 μm 250x50 ID mm), flow rate 100 mL/min) using a gradient of 35-95% ACN in water/ ACN/ammonia 95/5/0.2 buffer over 25 mins, to give the product (72 mg, 20%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, IH), 7.60 (d, IH), 7.47 (m, IH), 7.16 (m, IH), 6.85 (s, IH), 6.51 (t, IH), 4.65 (t, IH), 4.56 (t, IH), 4.44 (t, IH), 4.38 (d, 2H), 3.30 (t, 2H), 2.95 - 2.77 (m, 4H), 2.69 (t, IH), 2.63 (t, IH), 2.44 (t, 2H), 2.27 (s, 2H), 1.95 (s, IH), 1.87 - 1.68 (m, 6H), 1.57 (m, 2H), 1.41 (m, 12H), 1.20 (m, 2H), 0.95 (m, 4H); m/z 584.3 (M+H) + .
Preparation of Intermediates and Starting Materials Intermediate A 2-[6-(4-Methylpiperazin-l-yl)pyridin-3-yl]quinoline-4-carbox ylic acid
Potassium hydroxide (0.57 g, 10 mmol) was added to a mixture of 2,3-dihydro-indole-2,3- dione (isatin) (0.50 g, 3.4 mmol) and 5-acetyl-6-methyl-2(lH)-pyridinone (0.62 g, 4.1 mmol) in EtOH (4 mL) and the reaction mixture was heated at 80 0 C for 20 h. The reaction mixture was diluted with water and purified by ηPLC (standard method D) to give the title compound (0.20 g, 17%). 1 R NMR (400 MHz, DMSO-J 6 ) δ 8.60 (d, IH), 7.86 (d, IH), 7.70 (d, IH), 7.64-7.58 (m, IH), 7.50 (s, IH), 7.47-7.40 (m, IH), 6.26 (d, IH), 1.86 (s, 3H); m/z 281.1 (M+H) + . Intermediate C 2-Pyrazin-2-ylquinoline-4-carboxylic acid
The title compound (0.64 g, 38%) was prepared using 2,3-dihydroindole-2,3-dione (isatin) and 2-acetylpyrazine, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, in a manner essentially similar to that described for Intermediate B. 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.72 (d, IH), 8.81-8.75 (m, 2H), 8.73 (d, IH), 8.18 (d, IH), 7.87-7.82 (m, IH), 7.73-7.68 (m, IH), 7.33-6.97 (m, IH); m/z 252.0 (M+H) + . Intermediate D 2-(4-Ethoxyphenyl)quinoline-4-carboxylic acid
2-(6-Carbamoylpyridin-3-yl)quinoline-4-carboxylic acid
2-Chloroquinoline-4-carboxylic acid (0.15 g, 0.72 mmol), 2-cyanopyridine-5-boronic acid pinacol ester (0.20 g, 0.87 mmol) and Pd(PPlIs) 4 (42 mg, 0.036 mmol) were added to a mixture of dioxane (2 mL) and a IM aq. solution OfK 2 CO 3 (2 mL). The reaction mixture was degassed, sealed, and heated in a microwave at 140 0 C for 15 min. The reaction mixture was concentrated in vacuo to remove the dioxane and the residual water phase was lyophilized to give the title compound (0.12 g, 57%), which was used in the next step with no further purification; m/z 294.2 (M+H) + . Intermediate F 2-Pyridin-4-ylquinoline-4-carboxylic acid
The title compound (0.61 g, 36%) was prepared from 2,3-dihydroindole-2,3-dione (isatin) and 4-acetylpyridine, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, in a manner essentially similar to that described for Intermediate B. 1 H NMR (500 MHz, DMSO-J 6 ) δ 8.79 (d, 2H), 8.68 (d, IH), 8.54 (s, IH), 8.27 (dd, 2H), 8.23 (d, IH), 7.91 (t, IH), 7.77 (t, IH); m/z 251.1 (M+H) + . Intermediate G 2-(3-Carbamoylphenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and 3- carbamoyl-phenyl boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. The title compound precipitated from the reaction mixture. It was collected by filtration and used in the next step without further purification, m/z 293.6 (M+H) + . Intermediate H 2-(4-Carbamoylphenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and 4- carbamoyl-phenyl boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. The title compound precipitated from the reaction mixture. It was collected by filtration and used in the next step without further purification, m/z 293.6 (M+H) + . Intermediate I 2-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}quinoline-4-carb oxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and 6- (dimethylamino)-pyridine-3-yl boronic acid dihydrochloride, in place of 6-(4- methylpiperazin-l-yl)pyridine-5 -boronic acid pinacol ester, using essentially the same method as described for Intermediate A. The title compound precipitated from the reaction
mixture, and was collected by filtration. The dioxane filtrate was concentrated in vacuo to leave a residue which was lyophilized to leave a solid. The filtered and lyophilized solid were combined and used in the next step without further purification, m/z 294.2 (M+H) + . Intermediate K 2-[4-(Trifluoromethyl)phenyl]quinoline-4-carboxylic acid
The title compound was prepared from 2,3-dihydroindole-2,3-dione (isatin) and 4- (trifluoromethyl)-acetophenone, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, in a manner essentially similar to that described for Intermediate B. The reaction mixture was concentrated in vacuo and the residue was dissolved in water and washed with EtOAc. The layers were separated and the water phase was acidified to pη 1 with a 37% aq. solution of HCl to leave a precipitate. The precipitate was collected by filtration, washed with a IM aq. solution of HCl, and recrystallized from EtOH to give the title compound. 1 H NMR (400 MHz, DMSO-J 6 ) δ 13.94 (s, IH), 8.64 (d, IH), 8.52-8.46 (m, 2H), 8.17 (d, IH), 8.10 (d, IH), 7.90 (d, 2H), 7.88-7.82 (m, IH), 7.74-7.68 (m, IH), m/z 318.0 (M+H) + . Intermediate L 2-(5-Acetyl-2-thienyl)quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and 5- acetyl-2-thiophene boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. m/z 298.6 (M+H) + . Intermediate M 2-(4-Fluorophenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and A- fiuorobenzene boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.60 (d, IH), 8.41 (s, IH), 8.36-8.30 (m, 2H), 8.12 (d, IH), 7.84- 7.78 (m, IH), 7.69-7.63 (m, IH), 7.36 (t, 2H); m/z 268.5 (M+H) + . Intermediate N 2-(3,5-Dimethylisoxazol-4-yl)quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and 3- pyridyl boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5 -boronic acid pinacol ester, using essentially the same method as described for Intermediate A. m/z 251.2 (M+H) + .
Intermediate P
Ethyl {[^rafts^^aminomethy^cyclohexyljmethyljcarbamate hydrochloride
TEA (0.13 g, 1.2 mmol) was added to a solution of tert-butyl {[trans-4-(amino- methyl)cyclohexyl]methyl} carbamate (0.10 g, 0.41 mmol) in DCM (5 mL). The reaction mixture was cooled to 0 0 C and a solution of ethyl chloro formate (49 mg, 0.45 mmol) dissolved in DCM (1 mL) was added dropwise. The reaction mixture was stirred at 0 0 C to rt for 3h and then concentrated in vacuo to leave a residue. The residue was purified by flash column chromatography using increasingly polar mixtures of heptane and EtOAc as eluent to give the title compound (81 mg, 62%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 6.99 (t, IH), 6.72 (t, IH), 3.91 (q, 2H), 2.76 (t, 2H), 2.70 (t, 2H), 1.69-1.56 (m, IH), 1.62 (d, 4H), 1.32 (s, 9H), 1.28-1.17 (m, IH), 1.10 (t, 3H), 0.83-0.68 (m, 4H); m/z 215.21 (M - tert-butyl and ethyloxy +H) + .
ii) A 4M solution of HCl in EtOAc (1OmL) was added to a solution of tert-butyl ethyl [?rα«5 f -cyclohexane-l,4-diylbis(methylene)]biscarbamate (26 mg, 0.083 mmol) in DCM (10 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to give the crude title compound (Intermediate P) that was used in the next step with no further purification. 1 H NMR (400 MHz, DMSO-J 6 ) δ 7.80 (s, 2H), 7.03 (t, IH), 3.92 (q, 2H), 2.78 (t, 2H), 2.59 (t, 2H), 1.77-1.61 (m, 4H), 1.50-1.36 (m, IH), 1.32-1.20 (m, IH), 1.10 (t, 3H), 0.93-0.72 (m, 4H); m/z 215.2 (M+H) + .
Intermediate Q 2-[4-(Dimethylcarbamoyl)phenyl]quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and A- dimethylaminocarbonylphenyl boronic acid, in place of 6-(4-methylpiperazin-l- yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. The title compound precipitated from the reaction mixture and was collected by filtration and used in the next step with no further purification, m/z 321.2 (M+H) + . Intermediate R
2-(4-Methylphenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2,3-dihydroindole-2,3-dione (isatin) and l-/?-tolyl- ethanone, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, using essentially the same method as described for Intermediate B. The reaction mixture was concentrated in vacuo to leave a residue which was diluted with water and EtOAc was added. The layers were separated and the water phase was acidified to pη 1 with a 37% aq. solution of HCl to leave a precipitate. The precipitate was collected by filtration, washed with water, and recrystallized from EtOH to give the title compound. 1 H NMR (400 MHz, DMSO-J 6 ) δ 13.93 (bs, IH), 8.60 (d, IH), 8.39 (s, IH), 8.19-8.08 (m, 3H), 7.83-7.77 (m, IH), 7.68- 7.61 (m, IH), 7.34 (d, 2H), 2.36 (s, 3H); m/z 264.0 (M+H) + . Intermediate S 2-(4-Chlorophenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2,3-dihydroindole-2,3-dione (isatin) and l-(4- chloro-phenyl)-ethanone, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, using essentially the same reaction method as described for Intermediate B and the same isolation method as described for Intermediate R. 1 R NMR (400 MHz, DMSO-J 6 ) δ 13.97 (bs, IH), 8.61 (d, IH), 8.43 (s, IH), 8.33-8.27 (m, 2H), 8.13 (d, IH), 7.86-7.79 (m, IH), 7.71-7.65 (m, IH), 7.62-7.57 (m, 2H); m/z 284.0 (M+H) + . Intermediate T 2-(3-Methoxyphenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2,3-dihydroindole-2,3-dione (isatin) and l-(3- methoxy-phenyl)-ethanone, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, using essentially the same reaction method as described for Intermediate B and the same isolation method as described for Intermediate R. 1 H NMR (400 MHz, DMSO-J 6 ) δ 13.94 (s, IH), 8.60 (d, IH), 8.41 (s, IH), 8.13 (d, IH), 7.85-7.78 (m, 3H), 7.67 (t, IH), 7.45 (t, IH), 7.07 (dd, IH), 3.85 (s, 3H); m/z 280.0 (M+H) + . Intermediate U 2-(2-Methoxyphenyl)quinoline-4-carboxylic acid
layers were separated and the aqueous phase was acidified to pH 1 with a 37% aq. solution of HCl. The aqueous layer was lyophilized to leave a residue which was purified by HPLC (Standard Method D) to give the title compound. 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.66 (d, IH), 8.02-7.95 (m, 2H), 7.78-7.65 (m, 2H), 7.57-7.42 (m, 2H), 7.19 (d, IH), 7.13-7.07 (m, IH), 3.85 (s, 3H); m/z 280.0 (M+H) + . Intermediate V 2-[4-(Methylthio)phenyl]quinoline-4-carboxylic acid
The title compound was prepared from 2,3-dihydroindole-2,3-dione (isatin) and 4- methylthio-acetophenone, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, using essentially the same reaction method as described for Intermediate B and the same isolation method as described for Intermediate R. 1 H NMR (400 MHz, DMSO-J 6 ) δ 13.92 (bs, IH), 8.59 (d, IH), 8.40 (s, IH), 8.25-8.19 (m, 2H), 8.10 (d, IH), 7.83-7.76 (m, IH), 7.68-7.61 (m, IH), 7.42-7.37 (m, 2H), 2.52 (s, 3H); m/z 296.0 (M+H) + . Intermediate AA
2-(2,4-Dim ethyl- l,3-thiazol-5-yl)quinoline-4-carboxylic acid
The title compound was prepared from 2,3-dihydroindole-2,3-dione (isatin) and 5-acetyl- 2,4-dimethylthiazole, in place of 5-acetyl-6-methyl-2(lH)-pyridinone, using essentially the same reaction method as described for Intermediate B and the same isolation method as described for Intermediate U. 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.67 (d, IH), 7.89 (d, IH), 7.79 (s, IH), 7.71-7.65 (m, IH), 7.52-7.30 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H); m/z 285.0 (M+H) + . Intermediate BB 2-Pyrimidin-5-ylquinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and pyrimidine-5-boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. m/z 252.07 (M+H) + Intermediate CC 2-(4-Cyanophenyl)quinoline-4-carboxylic acid
The title compound was prepared from 2-chloroquinoline-4-carboxylic acid and A- cyanophenyl-boronic acid, in place of 6-(4-methylpiperazin-l-yl)pyridine-5-boronic acid pinacol ester, using essentially the same method as described for Intermediate A. m/z 275.08 (M+H) + . Intermediate DD N-{[?rfl«5 f -4-(Aminomethyl)cyclohexyl]methyl}naphthalene-2-sulfonamide
i) te/t-Butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)amino]methyl}cyclohexyl)methyl]- carbamate
The title compound was prepared from tert-butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]- methyl} carbamate (1.3 g, 5.4 mmol) and 2-naphthalenesulfonyl chloride (1.3g, 5.5 mmol) using essentially the same method as described for Example 63 (Method 6). The crude title compound (2.2 g, 86%) was used directly in the next step with no further purification. 1 H NMR (SOO MHZ, DMSO-J 6 ) δ 8.40 (s, IH), 8.15 (d, IH), 8.11 (d, IH), 8.03 (d, IH), 7.80 (dd, IH), 7.71-7.62 (m, 3H), 6.73 (t, IH), 2.70 (t, 2H), 2.61-2.55 (m, 2H), 1.69-1.57 (m, 4H), 1.34 (s, 9H), 1.30-1.16 (m, 2H), 0.79-0.67 (m, 4H). ii) TFA (15 mL) was added to a solution of fers-butyl [(?rα«5 f -4-{[(2-naphthylsulfonyl)- amino]methyl}cyclohexyl)methyl]carbamate (1.0 g, 2.3 mmol) in DCM (24 mL) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to leave the crude title compound that was used directly in the next step with no further purification. 1 U NMR (500 MHz, DMSO-J 6 ) δ 8.40 (s, IH), 8.15 (d, IH), 8.12 (d, IH), 8.03 (d, IH), 7.80 (dd, IH), 7.72-7.61 (m, 3H), 7.26-7.22 (m, IH), 7.18-7.11 (m, IH), 2.63-2.58 (m, 4H), 1.70 (d, 4H), 1.45-1.35 (m, IH), 1.34-1.25 (m, IH), 0.88-0.73 (m, 4H). Intermediate EE tert-Butyl [(?rα«5 f -4-{[(2-chloro-6-methoxyisonicotinoyl)amino]methyl}cyclohexy l)- methyl]carbamate
DIPEA (533 mg, 4.1 mmol) and a solution of tert-butyl {[trans-4-(ammomQthyl)- cyclohexyl]methyl} carbamate (500 mg, 2.1 mmol) in DMF (1 mL) were added to a solution of 2-chloro-6-methoxyisonicotinic acid (425 mg, 2.3 mmol) and TBTU (795 mg, 2.5 mmol) in DMF (4 mL) and the reaction mixture was stirred for 16 h at rt. Water was added to give a precipitate that was collected by filtration and washed with a mixture of water/MeOH (5:1) to give the title compound (800 mg, 94%). 1 R NMR (400 MHz, CDCl 3 ) δ 7.18 (d, IH), 6.93 (d, IH), 3.91 (s, 3H), 3.18 (d, 2H), 2.99 (s, 2H), 2.89 (m, 2H), 1.81- 1.67 (m, 4H), 1.54-1.43 (m, IH), 1.38 (s, 10H), 1.00-0.80 (m, 4H); m/z 410.0 (M-H) " . Intermediate FF tert-Butyl [(/rafts-4-{[(2,5-dichloroisonicotmoyl)ammo]methyl}cyclohexy l)- methyl]carbamate
DIPEA (533 mg, 4.1 mmol) and a solution of tert-butyl {[?rα«5 f -4-(aminomethyl)cyclo- hexyl]methyl} carbamate (500 mg, 2.1 mmol) in DMF (1 mL) were added to a solution of 2,5-dichloroisonicotinic acid (435 mg, 2.3 mmol) and TBTU (795 mg, 2.5 mmol) in DMF (4 mL) and the reaction mixture was stirred for 16 h at rt. Water was added to give a precipitate which was collected by filtration and washed with a mixture of water/MeOH (5:1) to give the title compound (638 mg, 74 %). 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, IH), 7.46 (s, IH), 3.24 (d, 2H), 2.95-2.86 (m, 2H), 2.71-2.64 (m, 2H), 1.85-1.69 (m, 4H), 1.57-1.44 (m, IH), 1.38 (s, 10H), 1.04-0.83 (m, 4H); m/z 414.0 (M-H) " . Intermediate GG tert-Butyl [(?rα«5 f -4-{[(2-chloro-6-methylisonicotinoyl)amino]methyl}cyclohexyl )- methyl]carbamate
DIPEA (533 mg, 4.1 mmol) and a solution of tert-butyl {[trans-4-(ammomQthyl)- cyclohexyl]methyl} carbamate (500 mg, 2.1 mmol) dissolved in DMF (1 mL) were added to a solution of 2-chloro-6-methylisonicotinic acid (389 mg, 2.3 mmol) and TBTU (795 mg, 2.5 mmol) in DMF (4 mL) and the reaction mixture was stirred for 16 h at rt. Water was added to give a precipitate which was collected by filtration and washed with a mixture of water/MeOH (5:1) to give the title compound (764 mg, 93 %). 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (s, IH), 7.38 (s, IH), 6.12 (s, IH), 4.57 (s, IH), 3.31 (t, 2H), 3.01- 2.93 (m, 2H), 2.60 (s, 3H), 1.87-1.76 (m, 4H), 1.61-1.49 (m, IH), 1.44 (s, 10H), 1.09-0.88 (m, 4H); m/z 396.1 (M+H) + . Intermediate HH tert-Butyl [(?rα«5 f -4-{[(2-bromoisonicotinoyl)amino]methyl}cyclohexyl)methyl]- carbamate
(aminomethyl)cyclohexyl]methyl}-carbamate (1.0 g, 4.1 mmol) in DMF (10 mL) and the reaction mixture was stirred at rt for 22 h. Water was added to give a precipitate which was filtered to give the title compound (1.7 g, 96%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, IH), 7.78 (s, IH), 7.55 (dd, IH), 6.21 (s, IH), 4.58 (s, IH), 3.31 (t, 2H), 2.97 (t, 2H),
1.87-1.76 (m, 4H), 1.62-1.49 (m, 2H), 1.44 (s, 9H), 1.08-0.88 (m, 4H); m/z 426.14 (M+H) + . Intermediate II tert-Butyl {[?rα«5 f -4-({[(5-bromopyridin-3-yl)carbonyl]amino}methyl)cyclohexyl] - methyl Jcarbamate
The title compound was prepared from tert-butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]- methyl} carbamate and 5-bromo-nicotinic acid, in place of 2-bromo-isonicotinic acid, using essentially the same method as described for Intermediate HH. 1 H NMR (600 MHz, DMSO-J 6 ) δ 8.91 (d, IH), 8.80 (d, IH), 8.67 (t, IH), 8.36 (t, IH), 6.74 (t, IH), 3.07 (t, 2H),
2.72 (t, 2H), 1.71 (d, 2H), 1.64 (d, 2H), 1.47-1.38 (m, IH), 1.32 (s, 9H), 1.29-1.20 (m, IH),
0.89-0.73 (m, 4H); m/z 426.14 (M-H) " .
Intermediate JJ
N-{[?rfl«5 f -4-(Aminomethyl)cyclohexyl]methyl}-2-pyridin-4-ylquinoline-4 -carboxamide hydrochloride
A solution of EtOAc (5 mL) saturated with HCl (gas) was added to a mixture of tert-butyl {[?rfl«5 f -4-({[(2-pyridin-4-ylquinolin-4-yl)carbonyl]amino}methyl)cyc lohexyl]methyl}- carbamate [Example 7] (0.15 mg, 0.32 mmol) in DCM (5 mL) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo to give the crude title compound (0.13 g, 98%), which was used directly in the next step with no further
purification. 1 R NMR (400 MHz, DMSO-J 6 ) δ 9.01 (d, 2H), 8.96 (t, IH), 8.74 (d, 2H), 8.40 (s, IH), 8.20 (t, 2H), 7.94 (s, 2H), 7.89 (t, IH), 7.75 (t, IH), 3.23 (t, 2H), 2.61 (t, 2H), 1.88-1.75 (m, 4H), 1.60-1.47 (m, 2H), 1.05-0.85 (m, 4H); m/z 375.3 (M+H) + . Intermediate KK
N-{[?rfl«5 f -4-(Aminomethyl)cyclohexyl]methyl}-2-(4-carbamoylphenyl)quin oline-4- carboxamide hydrochloride
4M HCl in dioxane (20 mL) was added to a solution of tert-butyl ({trans-4-[({[2-(4- carbamoylphenyl)quinolin-4-yl]carbonyl}amino)methyl]cyclohex yl}methyl)carbamate [Example 9] (0.45 g, 0.87 mmol) in DCM (5 mL) and the reaction mixture was stirred at rt for Ih. The reaction mixture was concentrated in vacuo to give the crude title compound (0.39 g, 99%) which was used directly in the next step with no further purification. 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.90 (t, IH), 8.36 (d, 2H), 8.18-8.11 (m, 4H), 8.05 (d, 2H), 8.01 (s, 2H), 7.83 (t, IH), 7.65 (t, IH), 7.45 (s, IH), 3.22 (t, 2H), 2.65-2.56 (m, 2H), 1.81 (t, 4H), 1.59-1.47 (m, 2H), 1.03-0.86 (m, 4H); m/z (M+H) + 417.2. Intermediate LL N-{[?rfl«5 f -4-(Aminomethyl)cyclohexyl]methyl}-2-phenylquinoline-4-carbo xamide
TFA (1.5 g, 13 mmol) was added to a solution of fers-butyl {[trans-4-({[(2- phenylquinolin-4-yl)carbonyl]amino}methyl)cyclohexyl]methyl} carbamate [Example 6] (0.20 g, 0.41 mmol) in DCM (8.0 mL) and the reaction mixture was stirred at rt for Ih. The
reaction mixture was concentrated in vacuo to leave a residue, which was dissolved in DCM and a saturated aq. solution OfNaHCO 3 was added. The layers were separated and the organic layer was dried (phase separator) and concentrated in vacuo to give the crude title compound (0.80 g, 52%) which was used directly in the next step with no further purification. 1 U NMR (400 MHz, MeOH-J 4 ) δ 8.48 (d, IH), 8.39-8.34 (m, 2H), 8.23-8.14 (m, 3H), 7.96 (t, IH), 7.80-7.69 (m, 3H), 3.41 (d, 2H), 2.81 (d, 2H), 2.03-1.85 (m, 4H), 1.78-1.61 (m, 2H), 1.22-1.03 (m, 4H); m/z 274.18 (M+H) + . Intermediate NN Methyl 4-(4-{[(?rα«5 f -4-{[(?er?-butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl }quinolin-2-yl)benzoate
2-Chloro-quinoline-4-carboxylic acid (0.23 g, 1.4 mmol) was dissolved in dioxane (5 mL) and (4-methoxycarbonylphenyl)boronic acid (0.39 g, 2.2 mmol), Pd(PPh 3 ) 4 (0.20 g, 0.17 mmol) and K 2 CO 3 (0.73 g, 5.3 mmol) were added. The reaction mixture was degassed, sealed, and heated in the microwave at 150 0 C for 30 min. The reaction mixture was filtered and concentrated in vacuo to leave a residue. The residue was purified by flash column chromatography, using a 1:2 mixture of EtO Ac/heptane with 1% acetic acid as eluent, to give the title compound (0.23 g, 53%). m/z 308.06 (M+H) + .
ii) TBTU (86 mg, 0.27 mmol) and NMM (39 mg, 0.38 mmol) were added to a solution of 2-[4-(methoxycarbonyl)phenyl]quinoline-4-carboxylic acid (29 mg, 0.10 mmol) in DMF (2 mL) and the reaction mixture was stirred at rt for 10 min. tert-Butyl {[trans-4-(ammo- methyl)cyclohexyl]methyl}carbamate (35 mg, 0.15 mmol) was then added and the reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated in vacuo to leave a residue, which was dissolved in DCM and washed with a saturated aq. solution OfNaHCO 3 and dried (phase separator). The mixture was concentrated in vacuo to leave a residue which was dissolved in DMSO and purified by HPLC (Standard method A) to give the title compound (Intermediate NN, 12 mg, 24%). m/z 530.32 (M+H) + . Intermediate OO
2-Phenylquinoline-4-thiol
4-Chloro-2-phenyl-quinoline (0.5 g, 2.1 mmol) and sodium ethanethiolate (0.88 g, 10 mmol) were dissolved in DMF (7.5 mL) and heated at 153 0 C under a nitrogen atmosphere for 1.5 h. The reaction mixture was concentrated in vacuo to half of its initial volume and then a saturated aq. solution OfNH 4 Cl was added and the pH was adjusted to 5 by the addition of a 2M aq. solution of HCl. The mixture was filtered and the solid was washed with a weakly acidic aq. solution to give the title compound (0.45 g, 91%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 12.72 (s, IH), 8.65 (dd, IH), 7.90-7.83 (m, 3H), 7.76-7.70 (m, IH), 7.61-7.57 (m, 3H), 7.54 (s, IH), 7.48-7.42 (m, IH); m/z 238.1 (M+H) + . Intermediate PP
N- { [tran s-4- (Amin omethyl)cyclohexyl]methyl }-2- [6- (4-methylp ip er azin - 1 -yl)p yr idin - 3-yl]quinoline-4-carboxamide
TFA (15 mL) was added to a solution of tert-butyl [(£ra«s-4-{[({2-[6-(4-methylpiperazin-
1 -yl)pyridin-3-yl]quinolin-4-yl} carbonyl)amino]methyl} cyclohexyl)methyl] carbamate
(Example 1) (1.5 g, 2.6 mmol) in DCM (30 mL) and the reaction mixture was stirred at rt for Ih. The reaction mixture was concentrated in vacuo to give the title compound (1.2 g,
99%), which was used with no further purification; m/z (M+H) + 473.3.
Intermediate QQ
4-Nitrophenyl tetrahydro-2H-pyran-4-yl carbonate
The Intermediates RR-OOO were prepared by the general procedure of Intermediate QQ using the appropriate alcohol in place of 4-hydroxy tetrahydropyran.
Intermediate PPP
3-yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methy l]carbamate
Intermediate PPP was synthesised according to the general method described for Example 109 (Method 19) by using (lS)-2-ter^butoxy-l-methylethyl 4-nitrophenyl carbonate (Intermediate CCC) in place of 4-nitrophenyl tetrahydro-2H-pyran-4-yl carbonate. 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, IH), 8.75-8.70 (m, IH), 8.42-8.38 (m, IH), 8.06-7.96 (m, 3H), 7.76-7.69 (m, IH), 7.56-7.49 (m, IH), 7.06-7.00 (m, IH), 6.98-6.93 (m, IH), 4.67-4.56 (m, IH), 3.63-3.54 (m, 4H), 3.26-3.24 (m, 2H), 3.21-3.15 (m, 2H), 2.82-2.74 (m, 2H), 2.65-2.61 (m, 4H), 2.39-2.35 (m, 3H), 1.84-1.76 (m, 2H), 1.73-1.66 (m, 2H), 1.55- 1.46 (m, IH), 1.36-1.26 (m, IH), 1.10-1.06 (m, 12H), 0.99-0.78 (m, 4H); m/z (M+H) + 631.3.
Intermediate 000 2-{4-[(Methylamino)sulfonyl]phenyl}quinoline-4-carboxylic acid
A solution OfK 2 CO 3 (0.37 g, 2.65 mmol) in water (2.5 mL) was added to a suspension of 2-chloroquinoline-4-carboxylic acid (0.20 g, 0.963 mmol), {4-
[(methylamino)sulfonyl]phenyl}boronic acid (0.25 g, 1.16 mmol) and PEPPSI (20 mg, 29 μmol) in dioxane (2.5 mL) and the reaction mixture was heated at 140 0 C in a microwave
for 15 min. The reaction mixture was filtered and the filtrate was partitioned between EtOAc and a 1% aq. solution of citric acid. The layers were separated and the aqueous phase was washed with EtOAc (x2) and the combined organic phases were dried (Na 2 SO 4 ) and concentrated in vacuo to leave the crude title compound (399 mg), which was used in the next step with no further purification. 1 H NMR (500 MHz, DMSO-J 6 ) δ 14.07 (s, IH), 8.68-8.66 (m, IH), 8.53-8.50 (m, 3H), 8.20 (d, IH), 7.97-7.94 (m, 2H), 7.90-7.86 (m, IH), 7.76-7.72 (m, IH), 7.58 (m, IH), 2.47 (d, 3H); m/z (M+H) + 343.0. Intermediate RRR 2-[4-(Aminosulfonyl)phenyl]-quinoline-4-carboxylic acid
The title compound was prepared by the general procedure of Intermediate QQQ using {4- [(amino)sulfonyl]-phenyl}boronic acid in place of {4-[(methylamino)sulfonyl]- phenyl}boronic acid. 1 H NMR (400 MHz, DMSO-J 6 ) δ 14.03 (s, IH), 8.63 (d, IH), 8.50- 8.43 (m, 3H), 8.16 (d, IH), 7.99-7.95 (m, 2H), 7.87-7.82 (m, IH), 7.73-7.68 (m, IH), 7.45 (s, 2H); m/z (M+H) + 328.9. Intermediate SSS-UUU
The following Intermediates SSS-UUU were prepared by the general procedure of Intermediate PP using the appropriate starting material selected from Example 134 or Example 135 in place of tertA)utyl N-[[trans-4-[[[2-[6-(4-methylpψerazmA-yl)pyτidin-3- yl]quinoline-4-carbonyl]amino]methyl]cyclohexyl]methyl]carba mate.
Intermediate VVV tert-Butyl ({/røfts-4-[({[2-(6-fluoropyridin-3-yl)quinolin-4-yl]carbon yl}amino)- methyl]cyclohexyl}methyl)carbamate
6-Fluoropyridine-3-boronic acid (1.6 g, 12 mmol), a IM aq. solution OfK 2 CO 3 (25 mL) and PEPPSI (0.18 g, 0.26 mmol) were added sequentially to a solution of 2-chloro- quinoline-4-carboxylic acid (2.0 g, 9.6 mmol) in dioxane (25 mL). The reaction mixture was degassed and then heated at 100 0 C under a nitrogen atmosphere for 2h and then cooled to rt. The dioxane was removed by concentration in vacuo and the remaining residue was diluted with MeOH and citric acid to give a mixture of pH ~ 4. The layers were separated
and the aqueous phase was extracted with EtOAc. The combined organic layers were dried followed by concentration in vacuo to give the title compound (2.8 g, 94%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.10 (s, IH), 8.87-8.78 (m, IH), 8.60 (d, IH), 8.49 (s, IH), 8.15 (d, IH), 7.84 (t, IH), 7.74-7.67 (m, IH), 7.39-7.32 (m, IH); m/z (M+H) + 269.1. ii) tert-Butyl {[?rα«5 f -4-(aminomethyl)cyclohexyl]methyl} carbamate (1.1 g, 4.5 mmol), DIPEA (1.4 mL, 8.2 mmol) and TBTU (1.4 g, 4.5 mmol) were added sequentially to a solution of 2-(6-fluoropyridin-3-yl)quinoline-4-carboxylic acid (1.0 g, 3.7 mmol) in DMF (10 mL) at 0 0 C and the reaction mixture was stirred at rt for 2 h. Water (10 mL) was added to give a precipitate and the mixture was filtered. The solid obtained was washed with a 1:1 mixture of water/MeOH to give the title compound (Intermediate VVV, 1.3 g, 70%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.12 (d, IH), 8.87-8.80 (m, IH), 8.79-8.74 (m, IH), 8.17 (s, IH), 8.14-8.09 (m, 2H), 7.84-7.78 (m, IH), 7.67-7.61 (m, IH), 7.37 (dd, IH), 6.80-6.67 (m, IH), 3.23-3.16 (m, 2H), 2.77-2.72 (m, 2H), 1.86-1.76 (m, 2H), 1.73-1.65 (m, 2H), 1.55-1.45 (m, IH), 1.34 (s, 9H), 1.33-1.28 (m, IH), 1.00-0.78 (m, 4H); m/z (M+H) + 493.1.
Intermediate WWW 3-(4-Acetylpiperazin-l-yl)propan-l-ol
3-Bromo-l-propanol (1.1 g, 7.8 mmol) and NaHCO 3 (0.66 g, 7.8 mmol) were added sequentially to a mixture of 1-acetylpiperazine (1.0 g, 7.8 mmol) in DCM (10 mL) at 4O 0 C. The reaction mixture was stirred at 4O 0 C for 4 h and then stirred at rt for 24 h. DCM, a saturated aq. solution OfNaHCO 3 and brine were added and the layers were separated. The organic layer was dried (phase separator) and concentrated in vacuo to give the title compound (0.67 g, 46%). 1 U NMR (400 MHz, CDCl 3 ) δ 3.82-3.74 (m, 2H), 3.64-3.56 (m, 2H), 3.48-3.42 (m, 2H), 2.64-2.58 (m, 2H), 2.52-2.44 (m, 4H), 2.06 (s, 3H), 1.76-1.68 (m, 2H).
Intermediate XXX tert-Butyl [(traws-4-{[({2-[4-(2-azidoethyl)piperidin-l-yl]quinolin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
DIPEA (0.3 mL, 1.73 mmol) and methanesulfonyl chloride (158 mg, 1.40 mmol) were added to a solution of tert-butyl [(£rafts-4-{[({2-[4-(2-hydroxyethyl)piperidin-l- yl]quinolin-4-yl}carbonyl)amino]methyl}cyclohexyl)methyl]car bamate (Example 189)
(363 mg, 0.69 mmol) in DCM (10 mL) at 0 0 C and the reaction mixture was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo to leave a residue which was used in the next step with no further purification, m/z (M+H) + 603.3. ii) Sodium azide (97 mg, 1.5 mmol) was added to a solution of 2-[\-(4-{[(trans-4-{[(tert- butoxycarbonyl)amino]methyl} cyclohexyl)methyl]carbamoyl} quinolin-2-yl)piperidin-4- yl]ethyl methanesulfonate (300 mg, 0.5 mmol) in DMF (3 ml) and the reaction mixture
was stirred for 20 h at rt. The reaction mixture was purified by flash column chromatography, using a gradient of 50-100% EtOAc in heptane as eluent, to give the title compound (197 mg, 72%). 1 U NMR (300 MHz, CDCl 3 ) δ 7.86-7.84 (m, IH), 7.71-7.69 (m, IH), 7.57-7.52 (m, IH), 7.26-7.22 (m, 2H), 7.05 (s, IH), 5.98-5.93 (m, IH), 4.60-4.51 (m, 2H), 3.41-3.35 (m, 4H), 3.01-2.92 (m, 4H), 1.90-1.79 (m, 6H), 1.77-1.68 (m, IH), 1.62-1.56 (m, 4H), 1.55 (s, 9H), 1.34-1.25 (m, 2H), 1.11-0.92 (m, 4H); m/z (M+H) + 550.3. Intermediate YYY 4-(Acetamidoethyl)piperidinium trifluoroacetate
Acetic anhydride (0.45 g, 4.38 mmol) was added to a solution of tert-butyl 4-(2- aminoethyl)piperidine-l-carboxylate (l.Og, 4.38 mmol) in DCM (10 mL) and the reaction mixture was stirred for 1 h at rt. A saturated aq. solution OfNaHCO 3 was added and the layers were separated. The organic layer was dried (phase separator) and concentrated in vacuo to give the title compound (1.2 g, 100%), which was used with no further purification. 1 R NMR (300 MHz, CDCl 3 ) δ 5.46-5.36 (m, IH), 4.12-3.98 (m, 2H), 3.29- 3.22 (m, 2H), 2.70-2.60 (m, 2H), 1.94 (s, 3H), 1.68-1.60 (m, 3H), 1.43 (s, 9H), 1.45-1.38 (m, 2H), 1.15-1.03 (m, 2H); m/z (M+H) + 271.3. ii) TFA (4.0 mL, 53 mmol) was added to a solution of tert-butyl 4-(2-acetamido- ethyl)piperidine-l-carboxylate (420 mg, 1.54 mmol) in DCM (10 mL) and the reaction mixture was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo to leave a residue, which was used directly in the next step with no further purification, m/z (M+H) + 171.3 (minus TFA salt).
Intermediate ZZZ 4-(Acetamidomethyl)piperidinium trifluoroacetate
Intermediate ZZZ was prepared using the same procedure described for Intermediate YYY using tert-butyl 4-(2-aminomethyl)piperidine-l-carboxylate as starting material in place of tert-butyl 4-(2-aminoethyl)piperidine- 1 -carboxylate.
Intermediate AAAA
Tetrahydro-2H-pyran-4-yl ({£rafts-4-[({[2-(6-fluoropyridin-3-yl)quinorin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
TFA (2.5 mL, 33 mmol) was added to a solution of tert-butyl({trans-4-[({[2-(6- fluoropyridin-3 -y l)quinolin-4-yl] carbonyl} amino)methyl] cyclohexyl} methyl)-carbamate (Intermediate VVV) (650 mg, 1.32 mmol) in DCM (8 mL) and the reaction mixture was
stirred at rt for Ih. The reaction mixture was concentrated in vacuo to leave the crude product that was used in the next step with no further purification, m/z (M+H) + 393.1. ii) 4-Nitrophenyl tetrahydro-2H-pyran-4-yl carbonate (Intermediate QQ) (410 mg, 1.5 mmol) and TEA (1.6 mL, 11.5 mmol) were added sequentially to a stirred solution of N- {[?rα«5 f -4-(aminomethyl)cyclohexyl]methyl}-2-(6-fluoropyridin-3-yl)q uinoline-4- carboxamide (500 mg, 1.3 mmol) in TηF (15 mL) and the reaction mixture was stirred at rt for 3 h and then at 40 0 C for 1 h. The reaction mixture was concentrated in vacuo and DCM was added to give a precipitate. The mixture was filtered to leave a solid, which was washed with DCM to give the title compound (380 mg, 57%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.51-9.43 (m, IH), 9.24-9.08 (m, 2H), 8.55-8.41 (m, 3H), 8.22-8.11 (m, IH), 8.05-7.96 (m, IH), 7.76-7.68 (m, IH), 7.48-7.41 (m, IH), 5.04-4.92 (m, IH), 4.18-4.04 (m, 2H), 3.81-3.67 (m, 2H), 3.58-3.48 (m, 2H), 3.21-3.10 (m, 2H), 2.22-1.98 (m, 5H), 1.91- 1.72 (m, 3H), 1.70-1.58 (m, IH), 1.53-1.41 (m, IH), 1.34-1.14 (m, 4H); m/z (M+H) + 521. Intermediate BBBB (35 r )-Tetrahydrofuran-3-yl ({/rafts-4-[({[2-(6-fluoropyridin-3-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
Intermediate BBBB was prepared using the same procedure as Intermediate AAAA using 4-nitrophenyl β^-tetrahydrofuran-S-yl carbonate (Intermediate XX) in place of 4- nitrophenyl tetrahydro-2H-pyran-4-yl carbonate in Step ii) to give the title compound (477 mg, 72%). 1 H NMR (400 MHz, DMSO-J 6 ) δ 9.13-9.10 (m, IH), 8.86-8.74 (m, 2H), 8.14- 8.08 (m, 3H), 7.83-7.77 (m, IH), 7.66-7.61 (m, IH), 7.39-7.34 (m, IH), 7.18-7.13 (m, IH), 5.07-5.02 (m, IH), 3.75-3.56 (m, 4H), 3.21-3.16 (m, 2H), 2.81-2.76 (m, 2H), 2.09-1.99 (m, IH), 1.83-1.76 (m, 3H), 1.70-1.65 (m, 2H), 1.54-1.45 (m, IH), 1.34-1.25 (m, IH), 0.98- 0.77 (m, 4H); m/z (M+H) + 507.1.
Intermediate CCCC tert-Butyl ({/røfts-4-[({[2-(4-hydroxyphenyl)quinolin-4-yl]carbonyl}am ino)- methyl]cyclohexyl}methyl)carbamate
IH), 1.90-1.77 (m, 6H), 1.63-1.52 (m, IH), 1.43 (s, 9H), 1.37-1.26 (m, 3H), 1.1-0.9 (m, 4H); m/z (M+H) + 523.4. ii) Sodium hydride (60% in mineral oil, 79mg, 1.98 mmol, 3 eq.) was added to a solution of trimethylsulfonium iodide (404 mg, 1.98 mmol, 3 eq.) in DMSO (5 mL) and the reaction mixture was stirred at rt for 15 min. A solution of tert-butyl [(?rα«5 f -4-{[({2-[4-(2- oxoethyl)piperidin-l-yl]quinolin-4-yl}carbonyl)amino]methyl} -cyclohexyl)- methyl] carbamate (345 mg, 0.66 mmol) in DMSO (16 mL) was added and the reaction mixture was stirred at rt for 2h. Water and a saturated aq. solution of sodium carbonate was added so the pH was 11. The mixture was extracted with DCM (2x150 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a residue. The residue was purified with HPLC chromatography, using a Kromasil C8 column, 10 μm, 250x50 ID mm, 20-90% mobilephase B over 25 min (Mobilephase A = water: ACN:formic acid 95:5:0.2, mobilephase B = ACN). The required fractions were concentrated in vacuo to leave the water phase, which was diluted with water and a saturated aq. solution of sodium carbonate was added so that the solution was pH 11. The mixture was extracted with EtOAc (2x15 OmL) and the combined organic layers was dried (Na 2 SO 4 ), filtered and concentrated in vacuo to leave the title compound (Intermediate DDDD), 0.43g, 65%). 1 R NMR (500 MHz, CDCl 3 ) δ 7.82-7.76 (m, IH), 7.66-7.60 (m, IH), 7.53-7.47 (m, IH), 7.22-7.15 (m, IH), 6.91 (s, IH), 6.42-6.36 (m, IH), 4.69-4.60 (m, IH), 4.51-4.39 (m, 2H), 3.36-3.29 (m, 2H), 2.99-2.85 (m, 5H), 2.77-2.73 (m, IH), 2.45- 2.41 (m, IH), 1.91-1.73 (m, 7H), 1.60-1.47 (m, 2H), 1.47-1.24 (m, 4H), 1.42 (s, 9H), 1.07- 0.86 (m, 4H); m/z (M+H) + 537.4. Intermediate EEEE λ^λf-Dimethyl-2-(piperidin-4-yloxy)acetamide trifluoroacetate
Sodium hydride (60% in mineral oil) (219 mg, 5.47 mmol, 1.1 eq.) was added to a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (1.0 g, 4.97 mmol), 2-chloro-iV,iV- dimethylacetamide (0.77 mL, 7.45 mmol, 1.5 eq.) and sodium iodide (149mg, 0.99 mmol, 0.2 eq.) in DMF (1OmL) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water and a IM aq. solution of citric acid was added to give a solution of pH 5. The layers were separated and the aq. phase was extracted with EtOAc (2xl50mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a residue. The residue was purified using flash column chromatography, using a mixture of EtOAc:MeOH (98:2) as eluent, to give the title compound (0.45g, 32%). 1 H NMR (500 MHz, CDCl 3 ) δ 4.08 (s, 2H), 3.71-3.61 (m, 2H), 3.51-3.45 (m, IH), 3.02- 2.95 (m, 2H), 2.94 (s, 3H), 2.85 (s, 3H), 1.81-1.73 (m, 2H), 1.50-1.40 (m, 2H), 1.35 (s, 9H). ii) TFA (2 mL, 26 mmol, 50 eq.) was added to a solution of fers-butyl 4-[2- (dimethylamino)-2-oxoethoxy]piperidine-l-carboxylate (150mg, 0.52 mmol) in DCM (2 mL) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to leave a residue. DCM (3x2 mL) was added and the solution was concentrated in vacuo each time to give the title compound (Intermediate EEEE, 155 mg, 98%), which was used in the next step without purification. Intermediate FFFF
N,N-Dimethyl-2-(piperidin-4-yloxy)ethanamine bis(trifluoroacetate)
Borane-dimethylsulfide complex (2M in THF, 0.79 mL, 1.57 mmol, 1.5 eq.) was added to a solution of tert-butyl 4-[2-(dimethylamino)-2-oxoethoxy]piperidine-l-carboxylate (Intermediate 123) (0.3g, 1.05 mmol) in THF (5 mL) and the reaction mixture was stirred at rt for 16h. The reaction mixture was concentrated in vacuo to leave a residue. Water and a saturated aq. solution of sodium carbonate was added so the pH was 11. The mixture was extracted with EtOAc (2x100 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to leave a residue, which was purified with flash column chromatography, using a mixture of heptane :EtO Ac (60:40) as eluent, to give the title compound (0.27g, 95%). 1 R NMR (500 MHz, CDCl 3 ) δ 3.83-3.78 (m, 2H), 3.70- 3.61 (m, 2H), 3.47-3.41 (m, IH), 3.14-3.06 (m, 2H), 2.96-2.90 (m, 2H), 2.61 (s, 6H), 1.82- 1.73 (m, 2H), 1.52-1.42 (m, 2H), 1.41 (s, 9H). ii) TFA (3 mL, 38.9 mmol, 39 eq.) was added to a solution of tert-butyl 4-[2- (dimethylamino)ethoxy]piperidine-l-carboxylate (0.27 g, 0.99 mmol) in DCM (3 mL) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to leave a residue. DCM (3x3 mL) was added and the mixture was concentrated in vacuo each time to give the title compound (Intermediate FFFF, 395 mg, 99%), which was used in the next step without purification. Intermediate GGGG N-{[?rfl«5 f -4-(Aminomethyl)cyclohexyl]methyl}-2-{4-[2-(dimethylamino)et hyl]- piperidin-l-yl}quinoline-4-carboxamide trihydrochloride
Hydrogen chloride (4M in 1 ,4-dioxane, 6 mL, 24 mmol) was added to a solution of tert- butyl { [trans-4-( { [(2- {4- [2-(dimethylamino)ethyl]piperidin- 1 -yl} quinolin-4- yl)carbonyl]amino}methyl)cyclohexyl]methyl}carbamate (Example 193) (0.2 g, 0.36 mmol) in a mixture of 1 ,4-dioxane and water 1 : 1 (6 mL) and the reaction mixture was stirred at rt for 15 min. The reaction mixture was concentrated in vacuo to leave a residue. 1,4-Dioxane (3x5 mL) was added and the mixture was concentrated in vacuo each time to give the title compound (0.356g, 98%) that was used with no further purification; m/z (M+H) + 452.4. Intermediate HHHH l-(4-{[(?rα«5 f -4-{[(?er?-Butoxycarbonyl)amino]methyl}cyclohexyl)methyl]- carbamoyl}quinolin-2-yl)azetidine-3-carboxylic acid
Intermediate IHI l-[2-(Dimethylamino)ethyl]piperazin-2-one
Sodium hydride (60% in mineral oil, 0.33 g, 8.12 mmol) was added to a solution oϊtert- butyl 3-oxopiperazine-l-carboxylate (0.50 g, 2.50 mmol) in DMF (8 mL) at 0 0 C and the reaction mixture was stirred at 0 0 C for 30 min. 2-(Dimethylamino)ethyl chloride hydrochloride (0.40 g, 2.75 mmol) was then added and the reaction mixture was stirred at 70 0 C for 16 h. The reaction mixture was poured into an ice-water mixture and extracted with diethylether (x4). The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo to leave a residue, which was purified by preparative HPLC (Standard Method C) to give the title compound (0.18 g, 26%). 1 H NMR (600 MHz, DMSO/DMSO-d 6 * ) δ 3.84 (s, 2H), 3.48 (s, 2H), 3.36 (t, 2H), 2.31 (t, 2H), 2.11 (s, 6H), 1.38(s, 9H); m/z (M+H) + 272.1. ii) TFA (1 mL) was added to a solution of tert-butyl 4-[2-(dimethylamino)ethyl]-3- oxopiperazine-1-carboxylate (0.176 g, 0.649 mmol) in DCM (1 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was then concentrated in vacuo to leave the crude title compound (Intermediate HII) as a TFA salt that was used with no further purification; m/z (M+H) + 172.0. Intermediate JJJJ 2-Oxo-2-piperazin-l-ylethanol
DIPEA (1.41 mL, 8.10 mmol), hydroxyacetic acid (0.23 g, 2.97 mmol) and finally TBTU
(1.04 g, 3.24 mmol) were added to a solution of tert-butyl piperazine-1-carboxylate (0.50 g, 2.70 mmol) in DCM (10 mL). The reaction mixture was stirred for 2h and then purified by flash column chromatography, using a gradient of 40— »100% EtOAc in heptane followed by 0→10% MeOH in DCM as eluent, to give the title compound (0.33 g, 50%).
1 H NMR (400 MHz, CDCl 3 ) δ 4.17 (s, 2H), 3.66-3.62 (m, 2H), 3.48-3.43 (m, 4H), 3.26-
3.22 (m, 2H), 2.80 (s, IH), 1.47 (s, 9H). ii) TFA (1 mL) was added to a solution of tert-butyl 4-(hydroxyacetyl)piperazine-l- carboxylate (0.176 g, 1.19 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo to leave the crude title compound (Intermediate JJJJ) as a TFA salt that was used with no further purification; m/z (M+H) + 144.9.
Intermediate KKKK 4-[(4-Fluorobenzyl)oxy]piperidine
An aq. solution of NaOH (50%, 7 mL), tetrabutylammonium hydrogensulphate (0.17 g, 0.50 mmol) and 4-fiuorobenzyl bromide (0.66 g, 3.48 mmol) were added to a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (0.50 g, 2.48 mmol) in toluene (15 mL). The reaction mixture was stirred vigorously for 16h and then diethylether and water were added. The layers were separated and the aqueous phase was extracted with DCM. The
combined organic layers were dried (phase separator) and concentrated in vacuo to leave a residue which was purified by flash column chromatography, using a gradient of 0— »55% EtOAc in heptane as eluent, to give the title compound (0.69 g, 90%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.28 (m, 2H), 7.05-6.99 (m, 2H), 4.51 (s, 2H), 3.81-3.73 (m, 2H), 3.58-3.51 (m, IH), 3.13-3.05 (m, 2H), 1.89-1.81 (m, 2H), 1.62-1.52 (m, 2H), 1.45 (s, 9H). ii) TFA (1.5 mL) was added to tert-butyl 4-(hydroxyacetyl)piperazine-l-carboxylate (0.69 g, 2.23 mmol) in DCM (1.5 mL) and the reaction mixture was stirred at rt for 3 h. Toluene was added and the reaction mixture was concentrated in vacuo to leave the crude title compound (Intermediate KKKK) as a TFA salt that was used with no further purification. m/z (M+H) + 209.9. Intermediate LLLL 2-Amino-l-benzothiophene-3-carboxylic acid
An aq. solution of NaOH (IM, 20 mL) was added to a solution of ethyl 2-amino-l- benzothiophene-3-carboxylate (0.66 g, 3.00 mmol) in dioxane (10 mL) and the reaction mixture was heated at 100 0 C for 2 h. The reaction mixture was concentrated in vacuo to leave an aqueous residue and then a 2M aq. solution of HCl was added such that the pH = 4 to give a precipitate. The mixture was filtered and the collected solid was washed with water to give the crude title compound (0.42 g, 72%). 1 H NMR (400 MHz, DMSO/DMSO-d 6 )* ) δ 12.25 (s, IH), 7.95 (d, IH), 7.89 (s, 2H), 7.56 (d, IH), 7.22-7.17 (m, IH), 7.04-6.99 (m, IH); m/z (M-H) " 192.2. Intermediate MMMM
Benzyl (l-{2-[l-(4-{[(?rα«5 f -4-{[(?er?-butoxycarbonyl)amino]methyl}cyclohexyl)- methyl]carbamoyl}quinolin-2-yl)piperidin-4-yl]ethyl}azetidin -3-yl)carbamate
Intermediate MMMM was prepared by the method described in Example 226 (Method 23) using benzyl azetidin-3-ylcarbamate as starting material in place of 2- methoxyethylamine. 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, IH), 7.68 (d, IH), 7.56-7.51 (m, IH), 7.39-7.29 (m, 5H), 7.25-7.20 (m, IH), 7.03 (s, IH), 5.97 (t, IH), 5.09 (s, 3H), 4.62-4.54 (m, IH), 4.54-4.47 (m, 2H), 4.39-4.30 (m, IH), 3.61 (t, 2H), 3.38 (t, 2H), 3.02- 2.89 (m, 4H), 2.86-2.79 (m, 2H), 2.47-2.44 (m, 2H), 1.90-1.74 (m, 6H), 1.64-1.53 (m, 2H), 1.47-1.37 (m, IH), 1.44 (s, 9H), 1.33-1.18 (m, 4H), 1.11-0.91 (m, 4H); m/z (M+H) + 713.2. Intermediate NNNN tert-Butyl ({?ra«s-4-[({[2-(3-hydroxyazetidin-l-yl)quinolin-4- yl]carbonyl}amino)methyl]cyclohexyl}methyl)carbamate
Intermediate NNNN was prepared by the method described in Example 185 (Method 22) using azetidin-3-ol (Intermediate OOOO) as starting material in place of 1- piperazineethanol. 1 U NMR (600 MHz, CD 3 OD) δ 7.84-7.82 (m, IH), 7.68 (d, IH), 7.57- 7.54 (m, IH), 7.27-7.23 (m, IH), 6.69 (s, IH), 4.75-4.71 (m, IH), 4.45-4.41 (m, 2H), 3.98 (dd, 2H), 3.31-3.27 (m, 2H), 2.89 (d, 2H), 1.92-1.87 (m, 2H), 1.84-1.79 (m, 2H), 1.64-1.56 (m, IH), 1.46-1.38 (m, IH), 1.43 (s, 9H), 1.09-0.93 (m, 4H); m/z (M+H) + 469.1.
Intermediate OQOO Azetidin-3-ol
A mixture of benzyl 3-hydroxyazetidine-l-carboxylate (2.05 g, 9.89 mmol) and 5% palladium on carbon (2.05 g, 0.96 mmol) in MeOH (40 mL) was stirred under a hydrogen atmosphere at rt for 3h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to leave the title compound which was used with no further purification, m/z
(M+H) + 73.9.
Intermediate PPPP tert-Butyl [(/rafts-4-{[({2-[3-(aminomethyl)phenyl]-6-chloropyridin-4- yl}carbonyl)amino]methyl}cyclohexyl)methyl]carbamate
2,6-Dichloroisonicotinic acid (3.00 g, 15.0 mmol) was dissolved in DMF and tert-butyl {[£rafts-4-(aminomethyl)cyclohexyl]methyl} carbamate (4.17 g, 17.2 mmol), TBTU (6.02 g, 18.8 mmol) and NMM (2.37 g, 2.58 mL, 23.4 mmol) were added. The reaction mixture was stirred at rt for 16 h. Water was added and the reaction mixture was filtered. The
solid that was collected was re-crystallized from a mixture of MeOH and water to give the title compound (4.29 g, 66%). 1 R NMR (400 MHz, CDCl 3 ) δ 7.56 (s, 2H), 6.29 (s, IH), 4.59 (s, IH), 3.30 (t, 2H), 2.97 (t, 2H), 1.84-1.76 (m, 4H), 1.55 (s, IH), 1.44-1.37 (m, 10H), 1.05-0.90 (m, 4H). ii) (3-Aminomethylphenyl)boronic acid hydrochloride (0.17 g, 0.91 mmol), bϊ5'(triphenylphosphine)palladium(II) chloride (30 mg, 0.04 mmol) and a solution of cesium carbonate (0.70 g, 2.16 mmol) in water (3 mL) were added to a solution of tert- butyl {[?rα«5 f -4-({[(2,6-dichloropyridin-4-yl)carbonyl]amino}methyl) cyclohexyl]methyl} carbamate (0.36 g, 0.86 mmol) in dioxane (9 mL). The reaction mixture was heated in a microwave at 130 0 C for 60 min. The reaction mixture was concentrated in vacuo and a saturated aq. solution OfNaHCO 3 was added. The layers were separated and the aq. layer was extracted with methyl-THF. The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo to leave a residue, which was purified by flash column chromatography, using a gradient of EtOAc to MeOH as eluent, to give the title compound (Intermediate PPPP, 0.12 g, 29%). 1 U NMR (400 MHz, CDCl 3 ) δ 8.01 (s, IH), 7.98 (d, IH), 7.91 (d, IH), 7.50 (s, IH), 7.48-7.41 (m, 2H), 6.27 (t, IH), 4.58 (s, IH), 3.97 (s, 2H), 3.34 (t, 2H), 2.98 (t, 2H), 1.83 (t, 4H), 1.58 (s, IH), 1.44 (s, 10H), 1.08-0.91 (m, 4H). Intermediate QOOQ tert-Butyl ({/røfts-4-[({[2-(lH-pyrazol-4-yl)qumolm-4-yl]carbonyl}amin o) methyl]cyclohexyl}methyl)carbamate
added. The reaction mixture was heated in a microwave at 140 0 C for 30 min and then a saturated aq. solution OfNaHCO 3 was added. The layers were separated and the aq. layer was extracted with EtOAc. The combined organic layers were concentrated in vacuo to give the crude title compound (286 mg, 97%), which was used with no further purification. 1 H NMR (400 MHz, DMSO-J 6 ) δ 8.73 (t, IH), 8.56 (s, IH), 8.24 (s, IH), 7.98-7.95 (m, 2H), 7.84 (s, IH), 7.72 (t, IH), 7.52 (t, IH), 6.78 (t, IH), 6.23 (s, IH), 3.19 (t, 2H), 2.76 (t, 2H), 1.81 (d, 2H), 1.69 (d, 2H), 1.51 (s, IH), 1.35 (s, 9H), 1.32 (m, IH), 0.99-0.79 (m, 4H).