MX2008005322A - Pharmaceutical use of substituted amides - Google Patents
Pharmaceutical use of substituted amidesInfo
- Publication number
- MX2008005322A MX2008005322A MXMX/A/2008/005322A MX2008005322A MX2008005322A MX 2008005322 A MX2008005322 A MX 2008005322A MX 2008005322 A MX2008005322 A MX 2008005322A MX 2008005322 A MX2008005322 A MX 2008005322A
- Authority
- MX
- Mexico
- Prior art keywords
- carbonyl
- benzyl
- aza
- bicyclo
- methyl
- Prior art date
Links
- 150000001408 amides Chemical class 0.000 title abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 239
- 201000010099 disease Diseases 0.000 claims abstract description 88
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 230000003247 decreasing Effects 0.000 claims abstract description 30
- 230000000051 modifying Effects 0.000 claims abstract description 28
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 26
- 239000003862 glucocorticoid Substances 0.000 claims abstract description 25
- 230000000694 effects Effects 0.000 claims abstract description 22
- 230000003834 intracellular Effects 0.000 claims abstract description 18
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 15
- -1 hetcycloalkyl Chemical group 0.000 claims description 618
- 125000000217 alkyl group Chemical group 0.000 claims description 505
- 125000001072 heteroaryl group Chemical group 0.000 claims description 255
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 228
- 125000003545 alkoxy group Chemical group 0.000 claims description 222
- 125000003118 aryl group Chemical group 0.000 claims description 205
- 229910052757 nitrogen Inorganic materials 0.000 claims description 183
- 239000000203 mixture Substances 0.000 claims description 151
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 141
- 125000004043 oxo group Chemical group O=* 0.000 claims description 121
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 116
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 106
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 95
- 125000005843 halogen group Chemical group 0.000 claims description 92
- 229910052760 oxygen Inorganic materials 0.000 claims description 88
- 239000001301 oxygen Chemical group 0.000 claims description 81
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 77
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 71
- 125000005842 heteroatoms Chemical group 0.000 claims description 68
- 239000002253 acid Substances 0.000 claims description 63
- 125000005418 aryl aryl group Chemical group 0.000 claims description 61
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 55
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 53
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 49
- 125000002619 bicyclic group Chemical group 0.000 claims description 47
- 125000002950 monocyclic group Chemical group 0.000 claims description 44
- 239000011780 sodium chloride Substances 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 41
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 claims description 39
- 239000004202 carbamide Substances 0.000 claims description 32
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 31
- 125000003342 alkenyl group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 230000003287 optical Effects 0.000 claims description 27
- 125000004104 aryloxy group Chemical group 0.000 claims description 26
- JFUAWXPBHXKZGA-IBGZPJMESA-N 4-fluoro-2-[(4R)-5,5,5-trifluoro-4-hydroxy-2-methyl-4-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-yl]phenol Chemical compound C([C@@](O)(CC=1NC2=CN=CC=C2C=1)C(F)(F)F)C(C)(C)C1=CC(F)=CC=C1O JFUAWXPBHXKZGA-IBGZPJMESA-N 0.000 claims description 24
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 24
- 239000008103 glucose Substances 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 24
- 208000008589 Obesity Diseases 0.000 claims description 23
- 235000020824 obesity Nutrition 0.000 claims description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 206010020772 Hypertension Diseases 0.000 claims description 16
- 206010061227 Lipid metabolism disease Diseases 0.000 claims description 16
- 150000002829 nitrogen Chemical group 0.000 claims description 16
- 206010058108 Dyslipidaemia Diseases 0.000 claims description 15
- 206010022489 Insulin resistance Diseases 0.000 claims description 15
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
- 206010053643 Neurodegenerative disease Diseases 0.000 claims description 13
- 206010037175 Psychiatric disease Diseases 0.000 claims description 13
- 235000020828 fasting Nutrition 0.000 claims description 13
- 208000002249 Diabetes Complications Diseases 0.000 claims description 12
- 206010012655 Diabetic complications Diseases 0.000 claims description 12
- 230000002685 pulmonary Effects 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 150000004702 methyl esters Chemical class 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 8
- 125000004951 trihalomethoxy group Chemical group 0.000 claims description 8
- WFCLWJHOKCQYOQ-UHFFFAOYSA-N 1-acetylpiperidine-4-carboxylic acid Chemical compound CC(=O)N1CCC(C(O)=O)CC1 WFCLWJHOKCQYOQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims description 6
- VFRZDAXDCOOZHS-UHFFFAOYSA-N C1=CC(C[N-]C)=CC=C1C(=O)N1C(CC(C)(C)C2)CC2(C)C1 Chemical compound C1=CC(C[N-]C)=CC=C1C(=O)N1C(CC(C)(C)C2)CC2(C)C1 VFRZDAXDCOOZHS-UHFFFAOYSA-N 0.000 claims description 5
- 238000007911 parenteral administration Methods 0.000 claims description 5
- 239000000546 pharmaceutic aid Substances 0.000 claims description 5
- YKDQXOIMEHOEPR-UHFFFAOYSA-N 1,1,1-trifluoro-N-methyl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]methanesulfonamide Chemical compound C1=CC(CN(C)S(=O)(=O)C(F)(F)F)=CC=C1C(=O)N1C(CC(C)(C)C2)CC2(C)C1 YKDQXOIMEHOEPR-UHFFFAOYSA-N 0.000 claims description 4
- PYHAMICSQUNALN-UHFFFAOYSA-N 1,1,1-trifluoro-N-propan-2-yl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]methanesulfonamide Chemical compound C1=CC(CN(C(C)C)S(=O)(=O)C(F)(F)F)=CC=C1C(=O)N1C(CC(C)(C)C2)CC2(C)C1 PYHAMICSQUNALN-UHFFFAOYSA-N 0.000 claims description 4
- AGLPIWZPGAHPRR-UHFFFAOYSA-N 1,1,3-trimethyl-3-[[4-(3,3,5-trimethylbicyclo[3.2.1]octane-7-carbonyl)phenyl]methylsulfonyl]urea Chemical compound C1=CC(CS(=O)(=O)N(C)C(=O)N(C)C)=CC=C1C(=O)C1C(CC(C)(C)C2)CC2(C)C1 AGLPIWZPGAHPRR-UHFFFAOYSA-N 0.000 claims description 4
- PPBNZMOTWZUZSR-UHFFFAOYSA-N 1-methyl-3-(2,2,4,4-tetrafluoro-1,3-benzodioxin-6-yl)-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound O1C(F)(F)OC(F)(F)C2=CC(NC(=O)N(CC=3C=CC(=CC=3)C(=O)N3C4CC(CC(C)(C)C4)(C)C3)C)=CC=C21 PPBNZMOTWZUZSR-UHFFFAOYSA-N 0.000 claims description 4
- VEGWOLUQSKYGRW-UHFFFAOYSA-N 1-methyl-3-(oxan-4-yl)-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1CCOCC1 VEGWOLUQSKYGRW-UHFFFAOYSA-N 0.000 claims description 4
- JWWSGOZNENOQAY-UHFFFAOYSA-N 1-methyl-3-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1=NN=C(C(F)(F)F)S1 JWWSGOZNENOQAY-UHFFFAOYSA-N 0.000 claims description 4
- NUORRIAVDREEGD-UHFFFAOYSA-N 3-(1,1-dioxothiolan-3-yl)-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1CCS(=O)(=O)C1 NUORRIAVDREEGD-UHFFFAOYSA-N 0.000 claims description 4
- ICSQCBDQMMDGFF-UHFFFAOYSA-N 3-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C1OC2=CC=CC=C2OC1CNC(=O)N(C)CC1=CC=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=C1 ICSQCBDQMMDGFF-UHFFFAOYSA-N 0.000 claims description 4
- KEOCVIHBRMRXGI-UHFFFAOYSA-N 3-(3-ethylsulfanylphenyl)-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound CCSC1=CC=CC(NC(=O)N(C)CC=2C=CC(=CC=2)C(=O)N2C3CC(CC(C)(C)C3)(C)C2)=C1 KEOCVIHBRMRXGI-UHFFFAOYSA-N 0.000 claims description 4
- ANPHSPCZNRQFOD-UHFFFAOYSA-N 3-[(3-methoxyphenyl)methyl]-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound COC1=CC=CC(CNC(=O)N(C)CC=2C=CC(=CC=2)C(=O)N2C3CC(CC(C)(C)C3)(C)C2)=C1 ANPHSPCZNRQFOD-UHFFFAOYSA-N 0.000 claims description 4
- GTKSUQAXJMGFHW-UHFFFAOYSA-N 6-azabicyclo[3.2.1]octan-6-yl-[4-[(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl]phenyl]methanone Chemical compound C1C(CCC2)CC2N1C(=O)C(C=C1)=CC=C1CN1CCNS1(=O)=O GTKSUQAXJMGFHW-UHFFFAOYSA-N 0.000 claims description 4
- SGWRTECNYOCNRM-UHFFFAOYSA-N N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]benzamide Chemical compound C1C(C)(C)CC(C)(C2)CC1N2C(=O)C(C=C1)=CC=C1CNC(=O)C1=CC=CC=C1 SGWRTECNYOCNRM-UHFFFAOYSA-N 0.000 claims description 4
- NBOVQLYCFKHNKA-UHFFFAOYSA-N N-[methyl-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]carbamoyl]benzamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC(=O)C1=CC=CC=C1 NBOVQLYCFKHNKA-UHFFFAOYSA-N 0.000 claims description 4
- OVTLFMCUZBWBQV-UHFFFAOYSA-N N-cyclopropyl-1,1,1-trifluoro-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]methanesulfonamide Chemical compound C1C(C)(C)CC(C)(C2)CC1N2C(=O)C(C=C1)=CC=C1CN(S(=O)(=O)C(F)(F)F)C1CC1 OVTLFMCUZBWBQV-UHFFFAOYSA-N 0.000 claims description 4
- ODJCYZDFLRBWAP-UHFFFAOYSA-N N-ethyl-1,1,1-trifluoro-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]methanesulfonamide Chemical compound C1=CC(CN(CC)S(=O)(=O)C(F)(F)F)=CC=C1C(=O)N1C(CC(C)(C)C2)CC2(C)C1 ODJCYZDFLRBWAP-UHFFFAOYSA-N 0.000 claims description 4
- QTCWKLLBDQUVCP-UHFFFAOYSA-N N-methyl-4-(2,2,2-trifluoroacetyl)-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]benzamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)C1=CC=C(C(=O)C(F)(F)F)C=C1 QTCWKLLBDQUVCP-UHFFFAOYSA-N 0.000 claims description 4
- BGWCKXCDVZWQKZ-UHFFFAOYSA-N N-methyl-4-methylsulfonyl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]benzamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)C1=CC=C(S(C)(=O)=O)C=C1 BGWCKXCDVZWQKZ-UHFFFAOYSA-N 0.000 claims description 4
- DTPCQXQFPGRYKK-UHFFFAOYSA-N N-methyl-6-morpholin-4-yl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]pyridine-3-carboxamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)C(C=N1)=CC=C1N1CCOCC1 DTPCQXQFPGRYKK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-N piperidine-1-carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims description 4
- QDBIBQDKTSZUHD-UHFFFAOYSA-N 1-(4-acetylphenyl)-1,3-dimethyl-3-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)N(C)C1=CC=C(C(C)=O)C=C1 QDBIBQDKTSZUHD-UHFFFAOYSA-N 0.000 claims description 3
- UJZZMQSLQUTGHF-UHFFFAOYSA-N 1-methyl-3-(4-phenylmethoxyphenyl)-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC(C=C1)=CC=C1OCC1=CC=CC=C1 UJZZMQSLQUTGHF-UHFFFAOYSA-N 0.000 claims description 3
- FRAKHUZTNLUGPB-UHFFFAOYSA-N 3,3,5-trimethyl-7-azabicyclo[3.2.1]octane Chemical compound C1C2NCC1(C)CC(C)(C)C2 FRAKHUZTNLUGPB-UHFFFAOYSA-N 0.000 claims description 3
- LPWIMZFJCZRXMO-UHFFFAOYSA-N 3-acetyl-N-methyl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]benzamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)C1=CC=CC(C(C)=O)=C1 LPWIMZFJCZRXMO-UHFFFAOYSA-N 0.000 claims description 3
- IQRQNDPPYQGSHP-UHFFFAOYSA-N 3-cyano-N-methyl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]benzamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)C1=CC=CC(C#N)=C1 IQRQNDPPYQGSHP-UHFFFAOYSA-N 0.000 claims description 3
- ULWKUZYCQMRWET-UHFFFAOYSA-N N-methyl-3-(trifluoromethoxy)-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]benzamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)C1=CC=CC(OC(F)(F)F)=C1 ULWKUZYCQMRWET-UHFFFAOYSA-N 0.000 claims description 3
- OFQGWEUOQHIUJO-UHFFFAOYSA-N N-methyl-N-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]morpholine-4-carboxamide Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)N1CCOCC1 OFQGWEUOQHIUJO-UHFFFAOYSA-N 0.000 claims description 3
- KRTYCGAKOZTRQE-UHFFFAOYSA-N [4-[(5-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl]phenyl]-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octan-7-yl)methanone Chemical compound C1C(C)(C)CC(C)(C2)CC1N2C(=O)C(C=C1)=CC=C1CN(S1(=O)=O)CCN1CC1=CC=CC=C1 KRTYCGAKOZTRQE-UHFFFAOYSA-N 0.000 claims description 3
- LLANIPZMPRAEJJ-UHFFFAOYSA-N 1-[[4-(3-azabicyclo[3.2.2]nonane-3-carbonyl)phenyl]methyl]-3-(4-fluorophenyl)imidazolidin-2-one Chemical compound C1=CC(F)=CC=C1N1C(=O)N(CC=2C=CC(=CC=2)C(=O)N2CC3CCC(CC3)C2)CC1 LLANIPZMPRAEJJ-UHFFFAOYSA-N 0.000 claims description 2
- QETDMEAISLFTCT-UHFFFAOYSA-N 1-[[4-(3-hydroxy-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl]methyl]-1,3-dimethyl-3-(1,3-thiazol-2-yl)urea Chemical compound C=1C=C(C(=O)N2C3CCC2CC(O)C3)C=CC=1CN(C)C(=O)N(C)C1=NC=CS1 QETDMEAISLFTCT-UHFFFAOYSA-N 0.000 claims description 2
- TYEMDHROSLZRIO-UHFFFAOYSA-N 1-[[4-(3-hydroxy-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl]methyl]-3-(4-hydroxycyclohexyl)-1,3-dimethylurea Chemical compound C=1C=C(C(=O)N2C3CCC2CC(O)C3)C=CC=1CN(C)C(=O)N(C)C1CCC(O)CC1 TYEMDHROSLZRIO-UHFFFAOYSA-N 0.000 claims description 2
- NYSAOBYFQCUEAB-UHFFFAOYSA-N 1-methyl-3-(4-methylphenyl)sulfonyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NS(=O)(=O)C1=CC=C(C)C=C1 NYSAOBYFQCUEAB-UHFFFAOYSA-N 0.000 claims description 2
- CEEPBTQQEOZFJP-UHFFFAOYSA-N 1-methyl-3-[4-(trifluoromethoxy)phenyl]-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1=CC=C(OC(F)(F)F)C=C1 CEEPBTQQEOZFJP-UHFFFAOYSA-N 0.000 claims description 2
- JYKLWTAJDINPDZ-UHFFFAOYSA-N 1-methyl-3-[4-(trifluoromethylsulfanyl)phenyl]-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1=CC=C(SC(F)(F)F)C=C1 JYKLWTAJDINPDZ-UHFFFAOYSA-N 0.000 claims description 2
- CKGZJCCYBBNXJO-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl-[4-[(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl]phenyl]methanone Chemical compound C1CCC2CCCCC2N1C(=O)C(C=C1)=CC=C1CN1CCNS1(=O)=O CKGZJCCYBBNXJO-UHFFFAOYSA-N 0.000 claims description 2
- DAUIQNNTKDDSOM-UHFFFAOYSA-N 3-(3-acetylphenyl)-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1=CC=CC(C(C)=O)=C1 DAUIQNNTKDDSOM-UHFFFAOYSA-N 0.000 claims description 2
- HMZVIRWCNYBKRA-UHFFFAOYSA-N 3-(3-cyanophenyl)-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1=CC=CC(C#N)=C1 HMZVIRWCNYBKRA-UHFFFAOYSA-N 0.000 claims description 2
- ZTRPVVIFDQYFGS-UHFFFAOYSA-N 3-(4-acetylphenyl)-1-methyl-1-[[4-(3,3,5-trimethyl-7-azabicyclo[3.2.1]octane-7-carbonyl)phenyl]methyl]urea Chemical compound C=1C=C(C(=O)N2C3CC(CC(C)(C)C3)(C)C2)C=CC=1CN(C)C(=O)NC1=CC=C(C(C)=O)C=C1 ZTRPVVIFDQYFGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
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Abstract
The use of substituted amides for modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11βHSD1 and may be useful in the treatment of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.
Description
PHARMACEUTICAL USE OF SUBSTITUTE AMIDES
FIELD OF THE INVENTION The present invention relates to the use of substituted amides and pharmaceutical compositions comprising the same for treating diseases wherein it is desirable to modulate the activity of dehydrogenase 11β-hydroxysteroid type 1 (11βHSD1). The present invention also relates to novel substituted amides, to their use in therapy, to pharmaceutical compositions comprising the same, to the use of said compounds in the manufacture of medicaments and to the therapeutic methods comprising the administration of the compounds. The present compounds modulate the activity of dehydrogenase 11β-hydroxysteroid type 1 (11βHSD1) and are therefore useful in the treatment of diseases in which such modulation is beneficial, such as the metabolic syndrome.
BACKGROUND OF THE INVENTION Metabolic syndrome is a global health problem. In the United States, the prevalence in the adult population is currently estimated to be approximately 25% and continues to increase both in the United States and throughout the world. The metabolic syndrome is characterized by a combination of insulin resistance, dyslipidemia, obesity and hypertension that leads to morbidity and increased mortality from cardiovascular diseases. People with metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is increasing in the same way.
In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and about 70% of people with type 2 diabetes additionally have hypertension once, again leading to increased mortality of cardiovascular diseases.
In clinical preparation it has been widely known that glucocorticoids are capable of inducing all the cardinal features of the metabolic syndrome and type 2 diabetes. Dehydrogenase 11 β-hydroxysteroid type 1 (11 βHSD1) catalyzes the local generation of active glucocorticoid in various tissues and organs predominantly including the liver and adipose tissue, but also, for example, skeletal muscle, bones, pancreas, endothelium, ocular tissue and certain parts of the central nervous system. In addition, 11βHSD1 serves as a local regulator of glucocorticoid actions in tissues and organs where it is expressed (Tannin et al., J. Biol. Chem., 266, 16653 (1991); Bujalska et al., Endocrinology, 140; , 3188 (1999), Whorwood et al., J. Clin Endocrinol Metab., 86, 2296 (2001), Cooper et al., Bone, 27, 375 (2000), Davani et al., J. Biol. Chem. , 275, 34841 (2000), Brem et al., Hypertension, 31, 459 (1998), Rauz et al., Invest. Ophthalmol, Vis. Sci., 42, 2037 (2001), Moisan et al., Endocrinology, 127, 1450 (1990)).
The role of 11βHSD1 in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with carbenoxolone of the non-specific inhibitor ßHSD1 11 improves insulin sensitivity in volunteer support volunteers and people with type 2 diabetes. Also, 11βHSD1 in genetically deficient mice are resistant to insulin resistance induced by Obesity and stress. Additionally, genetically deficient mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL cholesterol. Conversely, mice expressing 11βHSD1 in adipocytes develop insulin resistance, hyperlipidemia and visceral obesity, a phenotype resembling the metabolic syndrome in humans (Andrews et al., J. Clin.Endocrinol.Metab., 88, 285 (2003). ), Walker et al., J. Clin Endocrinol, Metab., 80, 3155 (1995), Morton et al., J. Biol. Chem., 276, 41293 (2001), Kotelevtsev et al., Proc. Nati Acad. Sci. USA, 94, 14924 (1997), Masuzaki et al., Science, 294, 2166 (2001)).
The more mechanistic aspects of the modulation 11 ßHSD1 and therefore the modulation of the intracellular levels of the active glucocorticoid have been investigated in several rodent models and different cellular systems. 11 ßHSD1 promotes the characteristics of the metabolic syndrome by increasing the hepatic expression of the enzymes that limit the proportion in gluconeogenesis, namely carboxykinase phosphoenolpyruvate and glucose-6-phosphatase, promoting the differentiation of preadiposites in adipocytes, also facilitating obesity, directly and indirectly by stimulating hepatic VLDL secretion, decreasing liver LDL intake and increasing vessel contractility (Kotelevtsev et al. al., Proc. Nati. Acad. Sci. USA, 94. 14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001); Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195 (2002), Brindley & Salter, Prog. Lipid Res., 30, 349 (1991)).
Publications WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093, and WO
01/90094 describe various thiazole-sulfonamides as inhibitors of the dehydrogenase enzyme 11 β-hydroxysteroid type 1, and further states that said compounds may be useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive diseases, immune diseases and depression.
SUMMARY OF THE INVENTION Substituted amides that modulate 11βHSD1 activity leading to altered intracellular concentrations of active glucocorticoid have now been found. More specifically, the present compounds inhibit the activity of 11βHSD1 leading to decreased intracellular concentrations of active glucocorticoid. In addition, the present compounds can be used to treat diseases wherein the decreased level of active intracellular glucocorticoid is desirable, such as, for example, metabolic syndrome, type 2 diabetes, decreased glucose tolerance (IGT), decreased fasting glucose ( IFG), dyslipidemia, obesity, hypertension, late diabetic complications, cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis,
neurodegenerative and psychiatric diseases and adverse effects of treatment or therapy with glucocorticoid receptor agonists.
An object of the present invention is to provide compounds, pharmaceutical compositions and the use of compounds that modulate the activity of 11βHSD1.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS In the following structural formulas and throughout the specification, the following terms have the indicated meaning. The examples provided in the definitions present in this application are not inclusive unless stated otherwise. They include but are not limited to the examples mentioned.
The term "halo" includes fluorine, chlorine, bromine and iodine.
The term "trialomethyl" includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
The term "trihalomethoxy" includes trifluoromethoxy, trichloromethoxy, tribromomethoxy and triiodomethoxy.
The term "alkyl" includes straight chain saturated methylene and saturated aliphatic hydrocarbon groups C ^ Cs and C3-C8 branched saturated hydrocarbon groups having the specific number of carbon atoms. For example, this definition includes methyl (Me), ethyl (Et), propyl
(Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (i-Bu), sec-butyl (s-Bu), isopentyl, and neopentyl.
The term "alkenyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C3-C6 unsaturated aliphatic hydrocarbon groups having the specific number of carbon atoms. For example, this definition includes ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl and methylbutenyl.
The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C4-C6 branched unsaturated aliphatic hydrocarbon groups having the specific number of carbon atoms. For example, this definition includes ethenyl, propynyl, butynyl, pentynyl, hexynyl and methylbutynyl.
The term "monocyclic, bicyclic or tricyclic partially saturated or saturated ring system" represents but is not limited to aziridinyl, azepanyl, azocanyl, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, phthalimide, 1, 2,3,4-tetrahydro-quinolinyl, 1, 2,3,4-tetrahydro-isoquinolinyl, 1, 2,3,4-tetrahydro-quinoxalinyl, indolinyl, 1,6-aza-bicyclo [3.2. 1] octane, 2-aza-bicyclo [4.1.1] octane, 2-aza-bicyclo [3.2.1] octanyl, 7-aza-bicyclo [4.1.1] octanyl, 9-aza-bicyclo [3.3.2] decanyl, 4-aza-tricyclo [4.3.1.13'8] undecanyl, 9-aza-tricyclo [3.3.2.03,7] decanyl.
The term "partially saturated or saturated ring" represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, and tetrahydropyranyl.
The term "partially saturated or saturated aromatic ring" means cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, and pyrimidinyl.
The term "cycloalkyl" represents a saturated mono, bi-, tri or spirocarbocyclic group having the specific number of carbon atoms (eg, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbonyl, norcaryl, and adamantyl).
The term "cycloalkylalkyl" represents a cycloalkyl group as defined above linked through an alkyl group having the indicated number of carbon atoms or an alkyl group substituted as defined above for example, cyclopropylmethyl, cyclobutylmethyl, and adamantylmethyl).
The term "cycloalkenyl" represents a partially saturated mono-, bi-, tri- or spirocarbocyclic group having the specific number of carbon atoms (for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl).
The term "cycloalkylcarbonyl" represents a cycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group (eg, cyclopropylcarbonyl and cyclohexylcarbonyl).
The term "cycloalkylalkylcarbonyl" represents a cycloalkyl group as defined above linked through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above (eg, cyclohexylmethylcarbonyl and cycloheptylthylcarbonyl).
The term "hetcycloalkyl" represents a mono-, bi-, tri-, or spirocarbocyclic group having the specific number of atoms with 1-4 of the specific number being heteroatoms or groups selected from nitrogen, oxygen, sulfur and S (0) m (m = 0-2) (for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidine, and pyridizine).
The term "hetcycloalkylalkyl" represents a hetcycloalkyl group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, tetrahydrofuranylmethyl, tetrahydropyranylethyl, and tetrahydrothiopyranylmethyl).
The term "hetcycloalkylcarbonyl" represents a hetcycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group (eg, 1-piperidin-4-yl-carbonyl and 1- (1, 2, 3,4-tetrahydro-isoquinolin-6-yl) carbonyl).
The term "alkyloxy" represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge (e.g., methoxy, ethoxy, propyloxy, allyloxy, and cyclohexyloxy).
The term "alkyloxyalkyl" represents an alkyloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (eg, methyloxymethyl).
The term "aryl" includes a carbocyclic aromatic ring that is monocyclic, bicyclic or polycyclic such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and biphenylenyl. Aryl also includes the partially hydrogenated derivatives of the carbocyclic aromatics listed above. Examples of partially hydrogenated derivatives include 1,2,3,4-tetrahydronaphthyl and 1,4-dihydronaphthyl.
The term "hetaryl" includes pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1, 2,3-triazol-1) -yl, 1, 2,3-triazol-2-yl-1, 2,3-triazol-4-yl, 1,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, -oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5- thiophenyl), furanyl (2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl) , 4-
pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [b] furanyl (2-benzo [ b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl), 2,3-dihydro -benzo [b] furanyl (2- (2,3-dihydro-benzo [b] furanyl), 3- (2,3-dihydro-benzo [b] furanyl), 4- (2,3-dihydro-benzo [ b) furanyl), 5- (2,3-dihydro-benzo- [b] furanyl), 6- (2,3-dihydro-benzo- [b] furanyl), 7- (2,3-dihydro-benzo [ b) furanyl)), 1,4-benzodioxin (2- (1,4-benzodioxin), 3- (1,4-benzodioxin), 5- (1,4-benzodioxin), 6- (1,4-benzodioxin) ), 7- (1,4-benzodioxin), 8- (1,4-benzodioxin)), benzo [b] thiophenyl (2-benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b ] thiophenyl, 5-benzo [b] thiophenyl, 6-benzo [b] thiophenyl or, 7-benzo [b] thiophenyl), 2,3-dihydro-benzo [b] thiophenyl (2- (2,3-dihydro-benzo [b] thiophenyl), 3- (2,3-dihydro-benzo [ b] thiophenyl), 4- (2,3-dihydrobenzo [b] thiophenyl), 5- (2,3-dihydro-benzo [b] thiophenyl), 6- (2,3-dihydro-benzo [b] thiophenyl) 7- (2,3-dihydro-benzo [b] thiophenyl)), 4,5,6-J-tetrahydro-benzo [b] thiophenyl (2- (4,5,6,7-tetrahydro-benzo [b] thiophenyl) ), 3- (4,5,6,7-tetrahydro-benzo [b] thiophenyl), 4- (4,5,6,7-tetrahydro-benzo [b] thiophenyl), 5- (4,5,6 , 7-tetrahydro-benzo [b] thiophenyl), 6- (4,5,6,7-tetrahydro-benzo [b] thiophenyl), 7- (4,5,6,7-tetrahydro-benzo [b] thiophenyl) )), thieno [2,3-b] thiophenyl, 4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl (4- (4,5,6,7-tetrahydro-thieno [2, 3-c] pyridyl), 5-4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl), 6- (4,5,6,7-tetrahydro-thieno [2,3-c] ] pyridyl), 7- (4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl)), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl , 6-indolyl, 7-indolyl), isoindolyl (1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), 1,3-dihydro-isoindolyl (1- (1,3-dihydro-isoindolyl), 2- (1,3-dihydro-isoindolyl), 3- (1,3-dihydro-isoindolyl), - (1,3-dihydro-isoindolyl), 5- (1,3-dihydro-isoindolyl), 6- (1,3-dihydro-isoindolyl), 7- (1,3-dihydro-isoindolyl)), indazole ( 1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl , 8-benzimidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), benzo- [1 , 2,5] oxadiazolyl, (4-benzo [1, 2,5] oxadiazole, 5-benzo [1, 2,5] oxadiazole), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-
carbazolyl, 4-carbazolyl), piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl) or, and pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl).
The term "arylalkyl" represents an aryl group as defined above linked through an alkyl group having the indicated number of carbon atoms (eg, benzyl, phenyloethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- (1 -naphthyl) ethyl).
The term "hetarylalkyl" or "hetaralkylol" represents a hetaryl group as defined above linked through a group having the indicated number of carbon atoms (e.g., (2-furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (2-pyridyl) methyl, and 1-methyl-1- (2-pyrimidyl) ethyl).
The term "aryloxyhetaryl" represents an aryloxy group as defined above linked through a hetaryl group (e.g., 2-phenoxy-pyridyl).
The term "aryloxy" represents an aryl group as defined above linked through an oxygen bridge (e.g., phenoxy and naphthyloxy).
The term "hetaryloxy" represents a hetaryl group as defined above linked through an oxygen bridge (e.g., 2-pyridyloxy).
The term "arylalkyloxy" represents an arylalkyl group as defined above linked through an oxygen bridge (for example, phenethyloxy and naphthylmethyloxy).
The term "hetarylalkyloxy" represents a hetarylalkyl group as defined above linked through an oxygen bridge (e.g., 2-pyridylmethyloxy).
The term "alkyloxycarbonyl" represents an alkyloxy group as defined above linked through a carbonyl group (e.g., methylformate and ethylformate).
The term "aryloxycarbonyl" represents an aryloxy group as defined above linked through a carbonyl group (eg, phenylformiate and 2-thiazolylformate).
The term "arylalkyloxycarbonyl" represents an "arylalkyloxy" group as defined above linked through a carbonyl group (eg, benzylf-ormiate and phenylethylformate).
The term "alkylthio" represents an alkyl group having the indicated number of carbon atoms attached through a sulfur bridge (e.g., methyl or ethylthio).
The term "arylthio" represents an aryl group as defined above linked through a sulfur bridge (for example, benzothiol and naphthylthiol).
The term "hetarylthio" represents a hetaryl group as defined above linked through a sulfur bridge (e.g., pyridine-2-thiol and thiazole-2-thiol).
The term "arylthioalkyl" represents an arylthio group as defined above attached through an alkyl group having the indicated number of carbon atoms (for example, methylsulfanyl benzene and ethylsulfanyl naphthalene).
The term "hetarylthioalkyl" represents a hetarylthio group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, 2-methylsulfanyl-pyridine and 1-ethylsulfanyl-isoquinoline).
The term "hetaryloxyaryl" represents a hetaryloxy group as defined above linked through an aryl group as defined above (e.g., Ifenoxy-isoquinolyl and 2-phenoxypyridyl).
The term "hetaryloxyhetaryl" represents a hetaryloxy group as defined above linked through a hetaryl group as defined above (e.g., 1- (2-pyridyloxy-isoquinoline) and 2- (imidazol-2-yloxy-pyridine)) .
The term "aryloxyalkyl" represents an aryloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (e.g., phenoxymethyl and naphthyloxymethyl).
The term "aryloxyaryl" represents an aryloxy group as defined above linked through an aryl group as defined above (e.g., 1-phenoxy-naphthalene and phenyloxyphenyl).
The term "arylalkyloxyalkyl" represents an arylalkyloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, ethoxy-methyl-benzene and 2-methoxymethyl-naphthalene).
The term "hetaryloxyalkyl" represents a hetaryloxy group as defined above attached through an alkyl group having the indicated number of carbon atoms (eg, 2-pyridyloxymethyl and 2-quinolyloxyethyl).
The term "hetarylalkyloxyalkyl" represents a hetarylalkyloxy group as defined above linked through an alkyl group having the indicated number of carbon atoms (for example, 4-methoxymethyl-pyrimidine and 2-methoxymethyl-quinoline).
The term "alkylcarbonyl" means an alkyl group as defined above having the indicated number of carbon atoms bonded through a carbonyl group (eg, octylcarbonyl, pentylcarbonyl and 3-hexenylcarbonyl).
The term "arylcarbonyl" represents an aryl group as defined above linked through a carbonyl group (eg, benzoyl).
The term "hetarylcarbonyl" represents a hetaryl group as defined above bonded through a carbonyl group (eg, 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl and oxazolylcarbonyl).
The term "carbonylalkyl" represents a carbonyl group bonded through an alkyl group having the indicated number of carbon atoms (eg, acetyl).
The term "alkylcarbonylalkyl" represents an alkylcarbonyl group as defined above linked through an alkyl group having the indicated number of carbon atoms (e.g., propan-2-one and 4.4, -dimethyl-pentan-2-) ona).
The term "arylcarbonylalkyl" represents an arylcarbonyl group as defined above attached through an alkyl group having the indicated number of carbon atoms (e.g., 1-phenyl-propan-1-one and 1- (3-chloro- phenyl) -2-methyl-butan-1-one).
The term "hetarylcarbonylalkyl" represents a hetarylcarbonyl group as defined above attached through an alkyl group having the indicated number of carbon atoms (e.g., 1-pyridin-2-propan-1-one and 1- (1- H-imidazol-2-yl) -propan-1-one).
The term "alkylcarbonyl" represents an arylalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group (eg, phenylpropylcarbonyl and phenylethylcarbonyl).
The term "hetarylalkylcarbonyl" represents a hetarylalkyl group as defined above wherein the alkyl group is in turn linked through a carbonyl (e.g., imidazolylpentylcarbonyl).
The term "alkylcarbonylamino" represents an "alkylcarbonyl" group as defined above, wherein the carbonyl is in turn linked through the nitrogen atom of an amino group (eg, methylcarbonylamino, cyclopentylcarbonyl-aminomethyl, and methylcarbonylaminophenyl). The nitrogen atom itself can be substituted with an alkyl or aryl group.
The term "alkylcarbonylaminoalkyl" represents an "alkylcarbonylamino" group linked through an alkyl group having the indicated number of carbon atoms (for example, N-propyl-acetamide and N-butyl-propionamide).
The term "arylalkylcarbonylamino" represents an "arylalkylcarbonyl" group as defined above linked through an amino group (e.g., phenylacetamide and 3-phenyl-propionamide).
The term "arylalkylcarbonylaminoalkyl" represents an "arylalkylcarbonylamino" group linked through an alkyl group having the indicated number of carbon atoms (for example, N-ethyl-phenylacetamide and N-butyl-3-phenyl-propionamide).
The term "arylcarbonylamino" represents an "arylcarbonyl" group as defined above linked through an amino group (for example, benzamide and naphthalene-1-carboxylic acid amide).
The term "arylcarbonylaminoalkyl" represents an "arylcarbonylamino" group linked through an alkyl group having the indicated number of carbon atoms (for example, N-propyl-benzamide and N-butyl-naphthalene-1-carboxylic acid amide) .
The term "alkylcarboxy" represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn linked through an oxygen bridge (for example, heptylcarboxy, cyclopropylcarboxy and 3-pentenylcarboxy).
The term "arylcarboxy" represents an arylcarbonyl group as defined above wherein the carbonyl is in turn linked through an oxygen bridge (eg, benzoic acid).
The term "alkylcarboxyalkyl" represents an alkylcarboxy group as defined above wherein the oxygen is attached via an alkyl bridge (eg, heptylcarboxymethyl, propylcarboxy-butyl, and 3-pentylcarboxyethyl).
The term "arylalkylcarboxy" represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn linked through an oxygen bridge (eg, benzylcarboxy and phenylpropylcarboxy).
The term "arylalkylcarboxyalkyl" represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn linked through an alkyl group having the indicated number of carbon atoms (eg, benzylcarboxymethyl and phenylpropylcarboxypropyl).
The term "hetarylcarboxy" represents a hetarylcarbonyl group as defined above, wherein the carbonyl is in turn linked through an oxygen bridge (e.g., pyridine-2-carboxylic acid).
The term "hetarylalkylcarboxy" represents a hetarylalkylcarbonyl group as defined above, wherein the carbonyl is in turn linked through an oxygen bridge (eg, 1- (imidazol-2-yl) -acetic acid and acid. 3-pyrimidin-2-yl-propionic).
The term "alkyl S (0) m" represents an alkyl group having the number of carbon atoms indicated, wherein the alkyl group is in turn bound through a sulfur bridge, where the sulfur is replaced with oxygen atoms (m = 0-2) (for example, ethylsulfonyl and ethylsulfinyl).
The term "arylS (0) m" represents an aryl group as defined above, wherein the aryl group is in turn linked through a sulfur bridge, where the sulfur is replaced by m oxygen atoms (m = 0-2) (for example, phenylsulfinyl and naphthyl-2-sulfonyl).
The term "hetaryl (0) m" represents a hetaryl group as defined above, wherein the hetaryl group is in turn linked through a sulfur bridge where the sulfur is substituted with m carbon atoms (m = 0-2) (for example, thiazole-2-sulfinyl and pyridine-2-sulfonyl).
Certain of the previously defined terms may occur more than once in the structural formulas and in said occurrence each term will be defined independently of the other.
The term "optionally substituted" as used herein means that the groups in question are substituted or unsubstituted with one or more specified substituents.
When the groups in question are substituted with one or more than one substituent, the substituents may be the same or different.
The term "treatment" or "treating" is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder and the term includes administration of the active compound to prevent or delay the onset of symptoms or complications, alleviate (both permanently and temporarily) the symptoms or complications and / or eliminate the disease, condition or disorder. In addition, "treatment" or "treating" includes the prevention and / or prophylaxis of the disease, condition or disorder.
The term "pharmaceutically acceptable" is defined as being appropriate for administration to humans without adverse events.
The term "prodrug" is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for the development of prodrugs are well known in the art.
In addition, in one embodiment, the present invention provides a novel substituted amide, a prodrug thereof or a salt thereof with a pharmaceutically acceptable base or acid or any optional isomer or mixture of optical isomers, including a racemic mixture of any form tautomeric, wherein the compound is of formula I:
where:
R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R 0R11NC (= Y) -, and R10R 1NS (O) n-; R2 is selected from H, C6 alkyl, and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 10-12 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from C-Cß alkyl, C3-C10 cycloalkyl, C3-C he hetcycloalkyl, C3-C6-spirocycloalkyl, 3-6-spirochetocycloalkyl. members, aryl, hetaryl, C-C6aryl alkyl, C C-C6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR 3R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, Cn-Cß alkyloxy, C-rC6alkyloxykyloxy, CrCastharyl alkyloxy, alkyl
alkyloxy alkylcarboxy C Cß, arylcarboxy, hetarylcarboxy, alkylcarboxy CtC6aryl, and alkylcarboxy hetaryl C Ce, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18; ring A is a saturated or partially saturated bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; Ring A is substituted with 0-3 groups selected from C 1 -C 8 alkyl, halo, OH, oxo, cyano, C 6 alkyloxy, C 1 -C 6 alkyloxy CrC ^ or C 1 -C 6 alkylcarbonyl, wherein each alkyl group is substituted with 0-3 R18; R5 is selected from H, C | -C6 alkyl, C3-C6 cycloalkyl, halo, OH, and cyano; R6 and R7 are independently selected from H, C? -C6 alkyl, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a partially saturated or saturated monocyclic ring of 3-8 members consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 selected from nitrogen , oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, alkyl
C? -C6, oxo, and C6alkyloxy; R 8 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, aryl, hetaryl, C 1 -C 6 alkyl aryl, C 6 alkyl heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered cycloalkyl, C 6 alkyl aryloxy,
C6-C6hetarylloxy alkyl, C6-6alkyloxy C6-6alkyloxy alkyloxy, and alkyl CTCaalkyloxy C Cehetaryl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R19; R 9 is selected from C 8 alkyl, C 2 -C 8 alkenyl, aryl, hetaryl, C 6 aryl alkyl, C 1 -C 6 heteroaryl, C 3 -C 10 cycloalkyl > 3-10 membered cycloalkyl, C 1 -C 6 alkyloxy alkyl, and Ci-C 1 alkyloxy alkyl
aryl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R20; R 10 and R 11 are independently selected from H, C 8 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, C 1 -C 6 alkyl aryl, and CrC 6 heteroaryl alkyl, wherein each alkyl / alkyl, cycloalkyl group , hetcycloalkyl, aryl, and hetaryl are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 alkyl groups selected
aryl, hetaryl, C6 alkyl aryl, alkyl hetaryl, hydroxy, oxo, COOH, C-C6 alkyloxy, C6-C6 alkyloxy, C6-C6 alkyloxy hetaryl, C6-C6 alkyloxy C6-C6 alkyloxy, C 1 -C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, C 1 -C 6 alkylcarbonyl aryl, C 1 -C 6 alkylcarbonyl hetaryl, C 1 -C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, C 1 -C 6 alkylcarboxyl aryl, and C 8 alkylcarboxyl hetaryl; R 12 is selected from OH, Ci-Cβ alkyl, C 3 -C 10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, C 1 -C 8 alkyloxy, aryl, C 1 -C 6 alkyl aryl, hetaryl, C 1 -C 6 -heteroyl alkyl, aryloxy, hetaryloxy, and NR 3R14; R13 and R14 are independently selected from H, alkyl
C3-C10 cycloalkyl, aryl, hetaryl, alkyl CrC ^ aplo, and C-i-C-hetaryl alkyl, wherein each alkyl / alkyl, cycloalkyl, aryl, and hetaryl group are independently substituted with 0-3 R22; alternatively, R13 and R4, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of
of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, aryl, hetaryl, C 1 -C 6 alkyl, C 1 -C 6 alkyl, hetaryl, OH, oxo, C 1 β alkyloxy, C 1 -C aryl alkyloxy, C 1 -C 6 alkaryloxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 alkylcarbonyl. -C6, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl C? -C6 aryl, alkylcarbonyl CrCßhetaryl, alkylcarboxy CtC6, arylcarboxy, hetarylcarboxy, alkylcarboxy C Caryl, and alkylcarboxy CrChehetyl; R15 is selected from H, C | -C6 alkyl, and C3-C6 cycloalkyl; R16 and R17 are independently selected from H, alkyl
C3-C10 cycloalkyl, halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, alkyl dC-β, aryl , and hetaryl, wherein the alkyl and cycloalkyl groups are independently substituted with 0-3 R22; R18 is selected from halo, OH, oxo, COOH, cyanoxy d-Cβ alkyloxy, C3-C10 cycloalkyloxy, aryloxy, hetaryloxy, hetarylthio, and C-t-C-galalkyl alkyloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, CrC8 alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalo-methylenedioxo, C3-C6 spirocycloalkyl, alkyloxy d -Ce, aryl, hetaryl, alkyl
Ci-Caryl, alkyl d-C6hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12,
-N (R15) C (= Y) NR13R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, d-C6 alkyl, CrC6 alkyloxy, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, d-C8 alkyl, and CrC6aryl alkyl; m is selected from 0, 1 and 2; n is selected from 1 and 2; And it is selected from O and S; or a salt thereof with a pharmaceutically acceptable base or acid, or any isomer or optical mixture of optical isomers including a racemic mixture or any tautomeric form.
In another embodiment, the present invention provides novel substituted amides of the formula I, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O) 2-; R2 is alkyl dC; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, where this ring is substituted with 0-2 group selected from d-C8 alkyl, aryl, hetaril, alkyl d-C6aryl, alkyl d-C6hetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, C6-alkyloxy, d-C6alkyloxy, alkyloxy-d-C-hetaryl, d-C6alkyloxy-d-C6alkyl, alkylcarboxy d-C6, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C6aryl, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18; ring A is a bicyclic or tricyclic saturated or partially saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 atoms. carbon and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from C1-C alkyl, halo, OH, oxo, cyano, d-C4 alkyloxy, dC alkyl alkyloxy dC or dC4 alkylcarbonyl, wherein each alkyl / alkyl group is substituted with 0-1 R18; R5 is H; R6 and R7 are independently selected from H and C? -C alkyl; and, n is 2.
In another embodiment, the present invention provides the novel substituted amides of the formula I, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O )2-; R2 is C4 alkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated ring of 5-6 members consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2
additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 1-2 groups selected from alkyl d-C8, aryl, hetaryl, alkyl d-C6 aryl, alkyl d-C6hetaryl, -C ( = 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, d-C6 alkyloxy, dyalkyloxy d-C6aryl, dyalkyloxy d-C6hetaryl, alkyl d-C6alkyloxy-C6, alkylcarboxy d-C6, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C6aryl, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18; Ring A is a bicyclic or tricyclic saturated or partially saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, OH, oxo, cyano, d-C4 alkyloxy, CC alkyloxy d-C4 alkyl or dC4 alkylcarbonyl, wherein each alkyl / alkyl group is replaced with 0-1 R18; R5 is H; R6 and R7 are independently selected from H and dC4 alkyl; and, n is 2.
In another embodiment, the present invention provides the novel substituted amides of the formula I, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R 1NS ( O) 2-; R2 is selected from H, C4 alkyl, and C3-C6 cycloalkyl; Ring A is a bicyclic or tricyclic saturated or partially saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, OH, oxo, cyano, C4 alkyloxy, dC4 alkyloxy alkyloxy or C? -C alkylcarbonyl, wherein each alkyl / alkyl group is replaced with 0-1 R18; R5 is H; R6 and R7 are independently selected from H and alkyl dC; Y,
n is 2
In another embodiment, the present invention provides the novel substituted amides of the formula I, wherein: R is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O )2-; R2 is C4 alkyl.
In another embodiment, the present invention provides the novel substituted amides of Formula I, and the use of compounds of Formula I, wherein: R 8 is selected from d-C 6 alkyl, C 2 -C 6 alkenyl, aryl, hetaryl, alkyl d-C4aryl, alkyl d-C4-hetaryl, C3-C6 cycloalkyl, 3-6-membered hetcycloalkyl, d-C4-alkyloxy alkyl, and d-C4-haloalkyloxy alkyl, wherein each of the alkyl / alkyl, alkenyl groups, aryl, hetaryl, cycloalkyl, and hetcycloalkyl are independently substituted with 0-2 R19; R9 is selected from d-C6 alkyl, C2-C6 alkenyl, aryl, hetaryl, CtC4alkyl alkyl, d-C4 alkyl hetaryl, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, and C1-C4alkyloxy alkyl, wherein each one of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-2 R20; R10 and R11 are independently selected from H, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, and hetaryl, wherein each of the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from C -? - C8 alkyl, aryl, hetaryl, hydroxy, oxo, COOH, d-C6alkyloxy, C6alkyloxy alkyloxy, C 1 -C 6 -heteroyl alkyloxy, and d-C 6 alkylcarbonyl;
R12 is selected from OH, d-C4 alkyl, C3-C6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, d-C alkyloxy, aryl, d-C4 alkyl aryl, hetaryl, d-C hetaryl alkyl, aryloxy, and hetaryloxy; 19 20 21 R, R and R are independently selected from H, halo, OH, oxo, cyano, d-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, alkyloxyC? -C4, aryl, hetaryl, alkyl d-C4aryl, alkyl CtC4hetaryl, -C (= 0) R12, -S (0) nR12, and -S (0) nNR13R14; and, n is 2.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of the formula la:
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of the formula Ib:
Ib In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of the formula le:
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of the formula Id:
Id In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of the formula le:
In another embodiment, the present invention provides the novel substituted amide of Formula I, wherein:
R1 and R2, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic or bicyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, C3-C-cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6-membered spiro-ethycycloalkyl , aril,
hetaryl, alkyl d-C6aryl, alkyl d-C6hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, d-C6-alkyloxy, d-C6-alkyloxy aryl, d-C6healkyloxyloxy, C6-alkyloxy-d-C6alkyloxy, alkylcarboxy-d6-C6, arylcarboxy, hetarylcarboxy, C1-Carylcarboxylcarboxy, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18.
In another embodiment, the present invention provides the novel substituted amide of the formula I, wherein R 1 and R 2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 5-12 members, consisting of nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 1-3 groups selected from d-C8 alkyl, C3-cycloalkyl C10, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiro-ethycycloalkyl, aryl, hetaryl, d-C6aryl alkyl, d6-C6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R5) C (= Y) NR13R14, -C (= NR6) NR17, OH, oxo, d-C6alkyloxy, alkyloxy C C6aryl, d-C6hearyl alkyloxy, C6alkyl, d-C6alkyloxy, C6alkylcarboxy, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C6aryl, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted do with 0-3 R18.
In another embodiment, the present invention provides the novel substituted amide of the formula I, wherein R 1 and R 2, together with the nitrogen to which they are attached, form a 5-membered saturated ring consisting of the nitrogen shown, 2-3 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from alkyl d-C8, aryl, hetaryl, alkyl d-C6aryl, alkyl d -C6hetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, C6 alkyloxy, alkyloxy d-C6ar C 1 -C 6 -alkaryloxy, d-C6alkyloxy d-C6alkyl, alkylcarboxy d-C6, arylcarboxy, hetarylcarboxy, alkylcarboxy d-Cearyl, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18 .
In another embodiment, the present invention provides the novel substituted amide of the formula I, wherein R 1 and R 2, together with the nitrogen to which they are attached, form a 5-membered saturated ring consisting of the nitrogen shown, 2-3 carbon atoms, and 1-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from d-C8 alkyl, aryl, hetaryl, alkyl d-C6aryl, alkyl d-C6hetar I, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, d-C6alkyloxy, alkyloxyCtC6arol , alkyloxy d-C6hetaryl, alkyl dC6alkyloxy d-C6, alkylcarboxyC? -C6, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C6aryl, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0 -3 R18.
In another embodiment, the present invention provides the novel substituted amide of the formula I, wherein R1 and R2, together with the nitrogen to which they are attached, form a saturated 5-membered ring consisting of the nitrogen shown 2-3 carbon atoms, and 1-2 additional heteroatoms selected from nitrogen and S (0) m, wherein this ring is substituted with 0-2 groups selected from d-C8 alkyl, aryl, hetaryl, alkyl d-C6aryl, alkyl d-Ceheta lo, r -C (= 0) R12, -S (0) nR12, OH, oxo, d-C6alkyloxy, dyalkyloxy d, C6aryl alkyloxy, C6hetaryl alkyloxy, and d6alkyloxy dC6alkyloxy alkyl, wherein each alkyl and aryl group hetaryl is substituted with 0-3 R18.
In another embodiment, the present invention provides the novel substituted amide of the formula I, wherein R and R2, together with the nitrogen to which they are attached are:
N G.? N N G? , N / SII-om wherein this ring is substituted with 0-2 groups selected from d-C8 alkyl, aryl, hetaryl, d-C6aryl alkyl, d-C6hetaryl alkyl, -C (= 0) R12, -S (0 ) nR 12, OH, oxo, C 6 alkyloxy, dyalkoxy d-C 6 aryl, alkyloxy d-C 6 hetaryl, and alkyl dC 6 alkyloxy d C 6, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R 18.
In another embodiment, the present invention provides the novel substituted amide of Formula I, wherein Ring A is selected from:
Ring A is replaced with 0-2 R25; and, R25 is selected from C8 alkyl, halo, hydroxy, oxo, cyano, C (= 0) R12, and dyalkoxy d-C6, wherein R12 is as defined above.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is selected from:
Ring A is replaced with 0-2 R25; and R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of Formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of Formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R? 25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and C6-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and C6alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is
Ring A is replaced with 0-2 R25; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel substituted amide or prodrug thereof of formula I, wherein Ring A is azepane.
In another embodiment, the present invention provides the novel compound of formula I, wherein the substituted amide or a prodrug thereof is selected from the group: N-Methyl-N- [4- (1, 3,3-trimethyl- 6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl) -benzyl] -isobutyramide cyclopentanecarboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide acid cyclohexanecarboxylic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide piperidine-1-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide 1-Acetyl-piperidine-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-car bonil) -
benzyl-amide cyclopentanecarboxylic acid ethyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide rnorpholine-4-carboxylic acid methyl- [4 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 2,2-N-Trimethyl-N- [4- (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -propionamide tetrahydro-furan-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide N-Methyl-4-trifluoromethoxy-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane- 6-carbonyl) -benzyl] -benzamide thiophene-2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide furan-2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3-Chloro-4- (propane) acid -2-sulfonyl) -thiophene-2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 6-Chloro- N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - nicotinamide 5-Methyl-isoxazole-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide 3,3, N -Trimethyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -butyramide 3-Cyano-N-methyl-N- [4 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide
N-Methyl-2-phenoxy-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide N-methyl-methyl ester -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -malonamic acid 3-Methyl-but-2-enoic methyl- [4 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-2-phenyl-N- [4- (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide 1-Trifluoromethyl-cyclobutanecarboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [ 3.2.1] octane-6-carbonyl) -benzyl] -amide
3,5-Dimethoxy-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide
4-Methanesulfonyl-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-3-trifluoromethoxy -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 2,2-Difluoro-1,3-benzodioxole-4 acid -carboxylic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-6-morpholin-4-yl-N - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -nicotinamide
N-Methyl-4- (2,2,2-trifluoro-acetyl) -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ] -benzamide N- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-N- [4- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isophathalamic acid 2,3-Dihydro-benzofuran-7-carboxylic acid methyl- [4- (1, 3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -am ida 3-Acetyl-N-methyl-N- [4- (1, 3,3-trimethyl-6- aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide
1, 1, 3-Trimethyl-3- [4- (1, 3,3-trimethyl-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfonylurea N-Methyl-N- [4- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 2,2,2-Trifluoro-ethanesulfonic acid methyl- [4- (1, 3,3- trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide N-Methylphenyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide
Trifluoro-N-isopropyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide N-Cyclopropyl-trifluoro-N- [ 4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide N-Ethyl-trifluoro-N- [4- (1, 3,3- trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide
Trifluoro-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 3-Benzoyl-1-methyl-1 - [4- (1, 3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea
3-Cyclohexyl-1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (4-methyl- phenyl) sulfonyl-1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea1,3-Dimethyl-3-phenyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (2, 3-Dihydro-1,4-benzodioxin-2-ylmethyl) -1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) - benzyl] -urea 3- (3-methoxy-benzyl) -1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ]-urea
3- (1, 1-Dioxo-tetrahydro-thiophen-3-yl) -1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6- carbonyl) -benzyl] -urea 1-Methyl-3- (tetrahydro-pyran-4-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane- 6-carbonyl) -benzyl] -urea acid methyl ester. { 1,3-Dimethyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -acetic 1-Methyl-3- (5-trifluoromethyl-1, 3,4-thiadiazol-2-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 2-methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic acid 3- methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic acid 1-Methyl-3- (3-ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] -octane-6-carbonyl) -benzyl ] -urea 1-Methyl-3- (4-ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo-t3.2.1] -octane-6-carbonyl) -benzyl ]-urea
3- (4-Benzyloxy-phenyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea
1-Methyl-3- (4-trifluoromethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - urea 3- (4-Acetyl-phenyl) -1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3-Acetyl-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ]-urea
3- (3-Cyano-phenyl) -1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - urea
1-Methyl-3- (4-trifluoromethyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -urea
3- (4-Methoxy-benzyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - urea 1 -Methyl-3- (2,2,4,4-tetrafluoro-4H-benzo- [1, 3] dioxin-6-yl) -1 - [4- (1, 3,3-trimethyl-6- aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4-trifluoro-methoxy-phenyl) -1- [4- (1, 3,3-trimethyl- 6-aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- [4- (2,2,2-trifluoro-acetyl) -cyclohexyl] -1- [4 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1- (4-Acetyl-phenyl) -1,3-dimethyl-3- [ 4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Phenyl-3-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -urea piperidine-1-carboxylic acid methyl- [4- (octahydro-quinoline-1 -carbonyl) -benzyl] -amide piperidine-1-carboxylic acid [4- (3-aza-bicyclo- [3.2.2] nonane- 3-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid methyl- [4- (octahydro-quinolin-1 -carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (3-aza- bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide 1,3-Dimethyl-3- [4- (octahydro-quinolin-1 -carbonyl) -benzyl] -1-phenyl-urea 1 - [4- (3-Aza-bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (6-aza -bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide piperidine-1-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1 ] octane-3-carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide morpholine-4 acid -carboxylic methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] -amide 1- [4- (6-Aza-bicyclo- [3.2.1] octane-6-carbonyl) -be ncil] -1,3-dimethyl-3-phenyl-urea 1,3-Dimethyl-1-phenyl-3- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane- 3-carbonyl) -benzyl] -urea piperidine-1-carboxylic acid [4- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide morpholine-4 acid -carboxylic [4- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2 .1] octane-8-carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea 1- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8- carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) - benzyl] -methyl-amide
Morpholine-4-carboxylic acid [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide N-Adamantan-2-yl-4- (1, 3-dimethyl-3-pyridin-2-yl-ureidomethyl) -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3- pyridin-2-yl-urea 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-pyridin-2-yl -urea morpholine-4-carboxylic acid [4- (adamantan-2-ylcarbamoyl) -benzyl] -methyl-amide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-thiazol-2-yl-urea 1,3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -1-thiazol-2-yl-urea 4- [3- (1-Acetyl-piperidin-4-yl) -1, 3-dimethyl-ureidomethyl] -N-adamantan-2-yl-benzamide 1- (1-Acetyl-piperidin-4-yl) -3- [4- (3-aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-urea N-Adamantan-2 -yl-4- (1,3-dimethyl-3-pyrimidin-2-yl-ureidomethyl) -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] - 1, 3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- (1,3-dimethyl-3-thiaz ol-2-yl-ureidomethyl) -benzamide N-Adamantan-2-yl-4- (1,3-dimethyl-3-phenyl-ureidomethyl) -benzamide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- [3- (4-hydroxy-cyclohexyl) -1, 3-dimethyl-ureidomethyl] -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -3- (4-hydroxy-cyclohexyl) -1, 3 -dimethyl-urea 1- (4-hydroxy-cyclohexyl) -1, 3-dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] - urea 1-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -imidazolidin-2-one [4- (1, 1-Dioxo-isothiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone [4- (1, 1-Dioxo -1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl) -methanone [4- (5-Methyl-1, 1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl) -methanone (Octahydro-quinolin-1- IH 4 - (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (4-Aza-tricyclo [4.3.1. 13.8] -undec-4-yl) - [4- (1, 1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (Octahydro-isoquinolin-2-yl) - [ 4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (3-Aza-bicyclo [3.2.2] non-3-yl) - [4- (1, 1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (6-Aza-bicyclo [3.2.1] oct-6-yl) - [4- (1, 1-dioxo-1 , 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone [4- (5-Benzyl-1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone
or a salt thereof with a pharmaceutically acceptable acid or base or any isomer or optical mixture of optical isomers including a racemic mixture, or any tautomeric form.
In another embodiment, the present invention provides novel compounds of the formula I, wherein the substituted amide or prodrug thereof is selected from the group: [4- (1-Amino-cyclopropyl) -phenyl] - (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone piperidine-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] ] octane-6-carbonyl) -benzyl] -amide N-Methyl-N- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] -octane-6-carbonyl) - benzyl] -butyramide N-Methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3-Aza-bicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -N-methyl-benzamide 3-Cyano-N-methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3-Azabicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -3-cyano-N-methyl-benzamide 3-Fluoro-N-methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [ 4- (3-Aza-bicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -3-fluoro-N-methyl-benzamide N- [4- (Azepane-1-carbonyl) -benzyl] -3 -fluoro-N-methyl-benzamide N- [4- (Azepano-1-carbonyl) -benc il] -N-methyl-benzamide N- [4- (Azepane-1-carbonyl) -benzyl] -3-cyano-N-methyl-benzamide piperidine-1-carboxylic acid [4- (azepane-1-carbonyl) - benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (azepane-1-carbonyl) -benzyl] -methyl-amide N- [4- (Octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3-Azabicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -benzamide N- [4- (Azepane-1-carbonyl) -benzyl] -benzamide N- [4- (6 -Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -N-methyl-benzamide 4 - [(Benzoyl-methyl-amino) -methyl] -N- (3-hydroxy-adamantan-1-) il) -benzamide N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -3-cyano-N-methyl-benzamide 4 - [(3-Cyano-benzoyl- methyl-amino) -metl] -N- (3-hydroxy-adamantan-1-yl) -benzamide
N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -3-fluoro-N-methyl-benzamide 4 - [(3-Fluoro-benzoyl-methyl-amino) -methyl] -N- (3-hydroxy-adamantan-1-yl) -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -amide N- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 3-Fluoro-N-methyl-N- [4- (1, 8 , 8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -benzamide 3-Fluoro-N- [4- (3-hydroxy-8-aza-bicyclo [3.2. 1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide N-Methyl-N- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] -octane-3- carbonyl) -benzyl] -benzamide N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -benzamide N- [4- (1, 8,8-Trimethyl-3 -aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -benzamide N- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] - benzamide 1-Acetyl-piperidine-4-carboxylic acid [4- (azepane-1-carbonyl) -benzyl] -methyl-amide 4- (Benzoylamino-methyl) -N- (3-hydroxy-adamantan-1-yl) - benzamide 3-Cyano-N-methyl-N- [ 4- (1, 8,8-trimethyl-3-aza-bi-cyclo [3.2.1] octane-3-carbonyl) -benzyl] -benzamide 3-Cyano-N- [4- (3-fluoro-8- aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 3-Fluoro-N- [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8 -carbonyl) -benzyl] -N-methyl-benzamide 4- (3-Fluoro-benzoylamino-methyl) -N-methyl-N- (3-fluoro-adamantan-1-yl) -benzamide 4- (3-Cyano- benzoylamino-methyl) -N-methyl-N- (3-fluoro-adamantan-1-yl) -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3- aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl-amide N- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N- methyl-benzamide 4 - [(Benzoyl-methyl-amino) -methyl] -N- (3-fluoro-adamantan-1-yl) -benzamide 3-Cyano-N- [4- (3-hydroxy-8-aza- bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 4- (Benzoylamino-methyl) -N- (3-fluoro-adamantan-1-yl) -benzamide 1-Acetyl-piperidine acid -4-carboxylic acid [4- (3-aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide N- [4- (3-Fluoro-8-aza-bicyclo [3.2.1 ] octane-8-carbonyl) -benzyl] -ben zamide 4- (3-Cyano-benzoylamino-methyl) -N- (adamantan-2-yl) -benzamide 4- (3 ^ Fluoro-benzoylamido-methyl) -N- (adamantan-2-yl) -benzam ida N - [4- (4-Azatriciclo- [4.3.1.1 * 3,8 *] undecano-4-carbonyl) -benzyl] -3-fluoro-N-methyl-benzamide
N-. { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide N-. { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -acetamide 4-methanesulfonyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide N-Methyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide
N-Methyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -acetamide
4-Methanesulfonyl-N-methyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl-benzamide N- [4- (Azepane-1-carbonyl ) -benzyl] -N-methyl-methanesulfonamide N- [4- (3-Aza-bicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -N-methyl-methanesulfonamide N-methyl- N- [4- (1, 8,8-tri-methyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] -methane-sulfonamide
N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -N-methyl-methanesulfonamide N- [4- (3-Hydroxy-8-aza-bicyclo [ 3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-methanesulfonamide N-Methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -methanesulfonamide N- (3-Hydroxy-adamantan -1-yl) -4 - [(methanesulfonyl-methyl-amino) -methyl] -benzamide N- (3-Fluoro-adamantan-1-yl) -4 - [(methanesulfonyl-methyl-amino) -methyl] -benzamide N- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-methanesulfonamide N-Adamantan-2-yl-4 - [(methanesulfonyl-methyl) -amino) -methyl] -benzamide N- (4- { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] - cyclo-propylsulfamoyl.} - phenyl) -acetamide 4-chloro-N-. { 1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzene-sulfonamide 1-Methyl-1 H-imidazole-4-sulfonic acid. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -amide N-. { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -etanosulfonamide
1- [4- (Azepano-1-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (3-hydroxy-adamantan-1-yl-carbamoyl) - benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-hydroxy-adamantan-1-yl-carbamoyl) -benzyl] -methyl-amide
4- (1,3-Dimethyl-3-phenyl-ureidomethyl) -N- (3-hydroxy-adamantan-1-yl) -benzamide piperidine-1-carboxylic acid [4- (3-fluoro-adamantan-1-yl) -carbamoyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-fluoro-adamantan-1-yl-carbamoyl) -benzyl] -methyl-amide 4- (1,3-Dimethyl-3-) phenyl-ureidomethyl) -N- (3-fluoro-adamantan-1-yl) -benzamide N-Adamantan-2-yl-4- (1,3-dimethyl-3-pyridin-2-yl-ureidomethyl) -benzamide 1 , 3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -1-pyridin-2-yl-urea 1- [4- ( 3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-thiazol-2-yl-urea 1- (1-Acetyl-piperidin-4-) il) -1, 3-dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -urea 1- (1-Acetyl-piperidin-4) -yl) -3- [4- (3-hydroxy-8-aza-bicyclo [3.2.1] -octane-8-carbonyl) -benzyl] -1,3-dimethyl-urea 1,3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -1-pyrimidin-2-yl-urea morpholine-4-carboxylic acid [4- (4 -aza-tricycle [4.3.1.1 * 3,8 *] - undecane-4-carbonyl) -be ncil] -methyl-amide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -3- (4-hydroxy-cyclohexyl) -1, 3 dimethyl-urea 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -3- (4-fluoro-cyclohexyl) -1, 3-dimethyl-urea N-Adamantan- 2-yl-4- [3- (1-cyclopropyl-piperidin-4-yl) -1, 3-dimethyl-ureidomethyl] -benzamide 1- [4- (3-Methoxy-8-aza-bicyclo [3.2.1 ] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea N-Adamantan-2-yl-4- [3- (4-fluoro-phenyl) -2-oxo-imidazolidin-1 -ylmethyl] -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -3- (4-fluoro-phenyl) -imidazolidin-2-one 1- (4 -Fluoro-phenyl) -3- [4- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -imidazolidin-2-one N-Adamantan-2-yl-4 - (2-Oxo-3-phenyl-imidazolidin-1-ylmethyl) -benzamide N-Adamantan-1-yl-4- (1,1-dioxo - [1, 2,5] thiadiazolidin-2-ylmethyl) - Benzamide N-Adamantan-2-yl-4- (1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -benzamide (4-Azatricyclo [4.3.1.1 * 3,8 *] - undec 4-yl) - [4- (1, 1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] -methanone Azepan-1 -yl- [4- (1, 1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] -methanone Azepan-1-yl- [4- (5-methyl-1,1-dioxo) - [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] -methanone N-Adamantan-1-yl-4- (5-methoxymethyl-1, 1-dioxo- [1, 2,5] thiadiazolidin-2 -ylmethyl) -benzamide 4- (1,1-Dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -N- (3-hydroxy-adamantan-1-yl) -benzamide
acid methyl ester. { 5- [4- (Adamantan-1-yl-carbamoyl) -benzyl] -1,1-dioxo- [1, 2,5] thiadiazolidin-2-yl} -acetic or a salt thereof with a pharmaceutically acceptable acid or base or any optical isomer or mixture of optical isomers including a racemic mixture or any tautomeric form.
In another embodiment, the present invention provides the novel use of a substituted amide or prodrug thereof or a salt thereof with a pharmaceutically acceptable acid or base or any optical isomer or mixture of optical isomers including a racemic mixture or any tautomeric form , wherein the substituted amide or a prodrug thereof is of the formula I:
wherein: R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R10R11NC (= Y) -, and R10R1 NS (O) n-; R2 is selected from H, C6 alkyl, and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 2-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl , aryl, hetaryl, C C-C6aryl alkyl, C C-C6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, d-C6alkyloxy, C6-C6alkyloxy, C6hearyl alkyloxy, C6-C6alkyloxy-C6i alkyl, alkylcarboxy d-C6, arylcarboxy, hetarylcarboxy, C-C6aryl alkylcarboxy, and alkylcarboxy d-C6hetaryl, wherein each alkyl and aryl group / hetaryl group is substituted with 0-3 R18;
ring A is a partially saturated or saturated bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; Ring A is substituted with 0-3 groups selected from C 8 alkyl, halo, OH, oxo, cyano, d-C 6 alkyloxy, d-C 6 alkyloxy d-C 6 alkyl or dC 6 alkylcarbonyl, wherein each alkyl group is replaced with 0-3 R18; R5 is selected from H, alkyl dC6 > C3-C6 cycloalkyl, halo, OH, and cyano; R6 and R7 are independently selected from H, d-C6 alkyl, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a 3-8 membered saturated or partially saturated monocyclic ring consisting of the carbon atom shown, 2-5 additional carbon atoms, and 0-2 selected heteroatoms of nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, d-C6 alkyl, oxo, and d-C6 alkyloxy;
R8 is selected from C- | -C8 alkyl, C2-C8 alkenyl, aryl, hetaryl, d-C6aryl alkyl, d-C6hetaryl alkyl, C3-C3 cycloalkyl, 3-10 membered hetcycloalkyl, d-C-alkyloxy alkyl , alkyl d-Cehetaryloxy, aryl d-C6alkyloxy d-C6 alkyl, and d-C6alkyloxy d-Cehetaryl alkyl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0 -3 R19; R9 is selected from d-C8 alkyl, C2-C8 alkenyl, aryl, hetaryl, C?-C6aryl alkyl, C?-C6hexyl alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, CtC6aryloxy alkyl, and aryl alkyl d- C6alkyloxy C C6, wherein each alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group are independently substituted with 0-3 R20; R10 and R11 are independently selected from H, C? -C8 alkyl, C3-C? 0 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, d-C6aryl alkyl, and C? -C6 -hetaryl alkyl, wherein each group of alkyl / alkyl, cycloalkyl, hetcycloalkyl, aryl, and hetaryl is independently substituted with 0-3 R21;
alternatively, R 0 and R 11, together with the nitrogen to which they are attached, form a saturated or partially saturated 5- to 12-membered monocyclic, bicyclic or tricyclic ring consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0- 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, aryl, hetaryl, alkyl d-Cearyl, C alqu-C6hetaryl alkyl, hydroxy , oxo, COOH, d-C6alkyloxy, d-C6aryl alkyloxy, alkyloxy d-Cehetaryl, d-C6alkyloxy d-C6 alkyl, d6C6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, dicarbarylcarbonyl, C6-C6-alkylcarbonyl, alkylcarboxy d-C6, arylocarboxy, hetarylcarboxy, alkylcarboxy d-C6aryl, and alkylcarboxy d-C6 hetaryl; R 12 is selected from OH, d-C 8 alkyl, C 3 -C 10 cycloalkyl 3-10 membered cycloalkyl, trihalomethyl, CrC 8 alkyloxy, aryl, d-C-β-alkyl, hetaryl, d-C 6 -hetaryl alkyl, aryloxy, hetaryloxy, and NR 13 R 14; R13 and R14 are independently selected from H, C?-C8 alkyl, C3-C10 cycloalkyl, aryl, hetaryl, d-Ceaplo alkyl, and d-C6hetaryl alkyl, wherein each alkyl / alkyl, cycloalkyl, aryl, and hetaryl group they are independently replaced with 0-3 R22; alternatively, R13 and R14, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from C?-C8 alkyl, aryl, hetaryl, C alqu-C6aryl alkyl, alkyl d-C6hetaryl, OH , oxo, d-C6 alkyloxy d-C6aryl alkyloxy, d-C6hearyl alkyloxy, d-C6alkyloxy d-C6 alkyl, d-C6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, dicarbarylcarbonyl, alkylcarbonyl d-Cehetaryl, C6 alkylcarboxy, arylcarboxy, hetarilcarboxi, alkylcarboxy C? -C6aryl, and alkylcarboxy d-C6hetarl; R15 is selected from H, d-C6 alkyl, and C3-C6 cycloalkyl; R16 and R17 are independently selected from H, d-C8 alkyl, C3-C10 cycloalkyl, halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N ( R13) S (0) nR12, d-C8 alkyl, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are optionally substituted with 0-3 R22;
R 18 is selected from halo, OH, oxo, COOH, cyano C 6 alkyloxy, C 3 -C 10 cycloalkyloxy, aryloxy, hetaryloxy, hetarylthio and d-C 6 alkyloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, d-C8 alkyl, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalomethylenedioxo, C3-C6-spirocycloalkyl, alkyloxy d-C6 > aryl, hetaryl, alkyl d-C6aryl, alkyl d-C6hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12,
-N (R15) C (= Y) NR13R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, d-C6 alkyl, C6 alkyloxy, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, d-C8 alkyl, and d-C6aryl alkyl; m is selected from 0, 1, and 2; n is selected from 1 and 2; And it is selected from O and S; or a salt thereof with a pharmaceutically acceptable base or acid or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric form.
In another embodiment, the present invention provides the novel use of the compounds of the formula I, wherein: R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R10R1 NC (= Y) - , and R10R1 NS (O) n-; R2 is selected from H, d-C6 alkyl, and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 2-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl, d-C6aryl alkylene, C6 hetaryl alkylene, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R3) S (0) nR12, -N (R15) C (= Y) NR13R14 , -C (= NR16) NR17, OH, oxo, d-C6-alkyloxy, C-C6-alkyloxy, alkyloxy
d-C6hetaryl, alkyl d-C6 alkyloxy d-C6, alkylcarboxyC C6, arylcarboxy, hetarylcarboxy, alkylcarboxyC? -C6aryl, and alkylcarboxy d-C6hetaryl, wherein each aryl / hetaryl group is substituted with 0-3 R18; ring A is a 5-12 member partially saturated or saturated bicyclic or tricyclic ring consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from CrC8 alkyl, halo, OH, oxo, cyano, d-C6 alkyloxy, C6 alkyloxyC6 alkyloxy or C-? -C6 alkylcarbonyl, wherein each alkyl / alkylene group is replaced with 0-3 R18; R5 is selected from H, d-C6 alkyl, C3-C6 cycloalkyl, halo, OH, and cyano; R8 and R7 are independently selected from H, d-C6 alkyl, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a 3-8 membered saturated or partially saturated monocyclic ring consisting of the carbon atom shown, 2-5 additional carbon atoms, and 0-2 selected heteroatoms of nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, d-C6 alkyl, oxo, and d-Cβ alkyloxy; R8 is selected from d-C8 alkyl, C2-C8 alkenyl, aryl, hetaryl, alkylene d-daplo, d-C6healkylene alkylene, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, d-C6-aryloxy alkylene, C-alkylene. -C6heteroyloxy, C6-C6alkyloxy-C6alkylaryl, and d-C6alkyloxy-C6-C6 hetaryl alkylene, wherein each alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group are independently substituted with 0-3 R19; R9 is selected from d-C8 alkyl, C2-C8 alkenyl, aryl, hetaryl, d6-C6 alkylene, d6-C6 alkylene, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, d-daryloxy alkylene, and d6-C6 alkylene. alkyloxy d-C6 aryl, wherein each alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is substituted with 0-3 R; R 10 and R 11 are independently selected from H, C 8 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, d-C 6 arylene alkylene, and d-C 6 heteroaryl alkylene, wherein
each alkyl / alkylene, cycloalkyl, hetcycloalkyl, aryl, and hetaryl group is independently substituted with 0-3 R21; alternatively, R 0 and R 11, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0- 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from C?-C8 alkyl, aryl, hetaryl, d-C6aryl alkylene, C-alkylene, hydroxy, oxo, COOH, d-C6alkyloxy, C- [alpha] -C6alkyloxy alkyloxy, d-C6hearyl alkyloxy, d-C6alkylamino d-C6alkyloxy, d-C6alkyloxycarbonyl, arylcarbonyl, hetarylcarbonyl, dicarbarylcarbonyl d-C6arol, alkylcarbonyl d-C6hetaryl , C C6 alkylcarboxy, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C6aryl, and alkylcarboxy C Cehetaryl; R12 is selected from OH, d-C8 alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, C?-C8 alkyloxy, aryl, C-rC6aryl alkylene, hetaryl, C-helenyl alkylene, aryloxy, hetaryloxy, and NR13R14; R13 and R14 are independently selected from H, CrC8 alkyl, C3-C10 cycloalkyl, aryl, hetaryl, CrC6aryl alkylene, and CrC6hetaryl alkylene, wherein each alkyl / alkylene, cycloalkyl, aryl, and hetaryl group is independently substituted with 0-3 R22;
alternatively, R13 and R14, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, aryl, hetaryl, alkylene CrC6aryl, alkylene CrC6hetaryl, OH, oxo, dyalkoxy d-C6, CrC6aryl alkyloxy, CrC6heteroyl alkyloxy, dCalkyl alkyloxy CrC6, dC6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl CrC6aryl, alkylcarbonyl CrC6hetaryl, alkylcarboxy d-Cß, arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy CrC6hetaryl; R15 is selected from H, CrC6 alkyl, and C3-C6 cycloalkyl;
R16 and R17 are independently selected from H, d-C8 alkyl, C3-C10 cycloalkyl, halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N ( R13) S (0) nR12, C C8alkyl, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are independently substituted with 0-3 R22;
R 8 is selected from halo, OH, oxo, and cyano; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, alkyl
CrC8, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalo-methylenedioxo, C3-C6-spirocycloalkyl, d-Cß alkyloxy, aryl, hetaryl, CrC6aryl alkylene, d-C6hetaryl alkylene, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, d-C6 alkyl, CrC6 alkyloxy, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, d-C8 alkyl, and CrC6aryl alkylene; m is selected from 0, 1, and 2; n is selected from 1 and 2; And it is selected from O and S;
In another embodiment, the present invention provides the novel use of the compounds of the formula I, wherein:
R1 is selected from R8 (C = 0) -, R9S (0) 2-, R 0R11NC (= O) -, and R10R11NS (O) 2-; R2 is d-C4 alkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from alkyl d-C8, aryl, hetaryl, alkyl CrC6aryl, alkyl d-Cehetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, CrC6alkyloxy, CrC6aryl alkyloxy, CrC6heteroyl alkyloxy, CrC6alkyloxy CrC6 alkyl, alkylcarboxy d-C6,
arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy CrC6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R 8; ring A is a bicyclic or tricyclic partially saturated or saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, OH, oxo, cyano, dyalkyloxy, C4 alkyloxy alkyloxy d-C4 or alkylcarbonyl d-C4, wherein each alkyl / alkyl group is substituted with 0-1 R18; R5 is H; R6 and R7 are independently selected from H and dC4 alkyl; and, n is 2.
In another embodiment, the present invention provides novel use of the compounds of Formula I, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R1 NC (= O) -, and R10R11NS (O) 2-; R2 is alkyl dC; alternatively, R and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from d-C8 alkyl, aryl, hetaryl, alkylene CrC6aryl, alkylene CrC6hetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, CrC6alkyloxy, CrC6aryl alkyloxy, CrC6heteroyl alkyloxy, CrC6alkyloxy d-C6 alkyl, CrC6 alkylcarboxy, arylcarboxy, hetarylcarboxy, alkylcarboxy d-C-phenyl, and alkylcarboxy CrC6hetaryl, wherein each aryl / hetaryl group is substituted with 0-3 R18; ring A is a bicyclic or tricyclic partially saturated or saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m;
ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, OH, oxo, cyano, d-C4 alkyloxy, d-C4 alkyloxy alkoxy dC or dC4 alkylcarbonyl, wherein each alkyl / alkylene group is replaced with group 0-1 R18; R5 is H; R6 and R7 are independently selected from H and alkyl dC; and, n is 2.
In another embodiment, the present invention provides the novel use of the compounds of the formula I, wherein: R8 is selected from CrC6 alkyl, C2-C6 alkenyl, aryl, hetaryl, d-C4-alkyl, d-C4-hetaryl alkyl, C3-cycloalkyl -C6 > 3-6 membered cycloalkyl, d-C4-aryloxy alkyl, and d-C4hetarylloxy alkyl, wherein each alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is independently substituted with 0-2 R19; R9 is selected from d-C6 alkyl, C2-C6 alkenyl, aryl, hetaryl, alkyl dC aryl, dC hetaryl alkyl, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, and d-C4alkyloxy alkyl, wherein each alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is independently substituted with 0-2 R20; R10 and R11 are independently selected from H, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, and hetaryl, wherein each cycloalkyl, hetcycloalkyl, aryl, and hetaryl group are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a monocyclic, saturated or partially saturated ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected of nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from CrC8 alkyl, aryl, hetaryl, hydroxy, oxo, COOH, d-C6 alkyloxy, CrC6aryl alkyloxy, alkyloxy d-C-hesteryl , and d-C6 alkylcarbonyl;
R12 is selected from OH, d-C4 alkyl, C3-C6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, C1-C4 alkyloxy, aryl, alkyl d-daryl, hetaryl, alkyl d-C4-hetaryl, aryloxy, and hetaryloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, d-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, d-C4 alkyloxy, aryl , hetaryl, alkyl d-C4 aryl, alkyl d-C4hetaryl, -C (= 0) R12, -S (0) nR1, and -S (0) nNR13R14; and, n is 2.
In another embodiment, the present invention provides the novel use of the compounds of Formula I, wherein: R8 is selected from d-C6 alkyl, C2-C6 alkenyl, aryl, hetaryl, d-dicaryl alkylene, d-C4 alkylene hetaryl , C3-C6 cycloalkyl, 3-6 membered cycloalkyl, d-C4alkyloxy alkylene, and dicarboxylic alkylene, wherein each alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is independently substituted with 0-2 R19; R9 is selected from CrC6 alkyl > C2-C6 alkenyl, aryl, hetaryl, d-alkynyl alkylene, d-C4hearyl alkylene, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, and d-C4alkyloxy alkylene, wherein each alkyl / alkylene, alkenyl, aryl group, hetaryl, cycloalkyl, and hetcycloalkyl are independently substituted with 0-2 R20; R 0 and R 11 are independently selected from H, C 3 -C 6 cycloalkyl > hetcycloalkyl
3-6 members, aryl, and hetaryl, wherein each cycloalkyl, hetcycloalkyl, aryl, and hetaryl group is independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a monocyclic, saturated or partially saturated ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected of nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from d-C8 alkyl, aryl, hetaryl, hydroxy, oxo, COOH, d-C6 alkyloxy, CrC6aryl alkyloxy, alkyloxy
CrC6hetaryl, and d-C6 alkylcarbonyl;
R 12 is selected from OH, C 4 alkyl, C 3 -C 6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, d-C alkyloxy, aryl, d-daryl alkylene, hetaryl, Crd-hetaryl alkylene, aryloxy, and hetaryloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, CrC6 alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, dC alkyloxy, aryl, hetaryl, alkylene d-C4aryl, d-C4 -hetaryl alkylene, -C (= 0) R12, -S (0) nR12, and -S (0) nNR13R14; and, n is 2.
In another embodiment, the present invention provides the novel use of compounds wherein the substituted amide or prodrug thereof is of the formula la:
In another embodiment, the present invention provides the novel use of compounds wherein the substituted amide or prodrug thereof is of the formula Ib:
Ib
In another embodiment, the present invention provides the novel use of compounds wherein the substituted amide or prodrug thereof is of the formula le:
In another embodiment, the present invention provides the novel use of compounds wherein the substituted amide or prodrug thereof is of the formula Id:
Id In another embodiment, the present invention provides the novel use of compounds wherein the substituted amide or prodrug thereof is of the formula le:
you
In another embodiment, the present invention provides the novel use of compounds of formula I, wherein: R and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 5-12 members which consists of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen and S (0) m,
wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, C3-C-cycloalkyl, C3-C10 heterocycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spirohetcycloalkyl, aryl, hetaryl, alkyl d-C-aryl, alkyl d-C6hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, - C (= NR16) NR17, OH, oxo, d-C6alkyloxy, CrCharyl alkyloxy, CrCysharyl alkyloxy, d-Cysalkyloxy CrCßalkyl, alkylcarboxyCrC6, arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy d-C6 hetaryl, wherein each alkyl group and aryl / hetaryl is substituted with 0-3 R 8.
In another embodiment, the present invention provides the novel use of the compounds of the formula I, wherein:
R1 and R2, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic or bicyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl, CrC6aryl alkylene, alkylene d-Cehetaryl, - C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R5) C (= Y) NR13R14, -C (= NR16 ) NR17, OH, oxo, C6 alkyloxy, C6 alkyloxy aryl, CrC6heteroyl alkyloxy, CrC6alkyloxy CrC6 alkylcarboxy CrC6 alkyl, arylcarboxi, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy CrC6hetaryl, wherein each aryl / hetaryl group is substituted with 0-3 R18.
In another embodiment, the present invention provides novel use of the compound of Formula I, wherein: Ring A is selected from:
Ring A is replaced with 0-2 R? 25; and R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, C (= 0) R12, and C6 alkyloxy, wherein R512 is as defined above.
In another embodiment, the present invention provides novel use of the compounds of Formula I, wherein: Ring A is selected from:
. Ring A is replaced with 0-2 R; and R, 25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel use of compounds of Formula I, wherein:
Ring A is replaced with 0-2 R 25.; and R, 25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and d-C6 alkyloxy.
In another embodiment, the present invention provides the novel use of compounds of Formula I, wherein the substituted amide or prodrug thereof is selected from the group: N-Methyl-N- [4- (1, 3,3-trimethyl) -6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isobutyramide
cyclopentane carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide Ccyanohexane carboxylic acid methyl- [4- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide Piperidine-1-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl ) -benzyl] -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide 1-Acetyl-piperidine-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide cyclopentane-carboxylic acid ethyl- [ 4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide morpholine-4-carboxylic acid methyl- [4- (1, 3,3- trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 2,2-N-Trimethyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -propionamide tetrahydric acid ro-furan-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide N-Methyl-4-trifluoromethoxy-N - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide thiophene-2-carboxylic acid methyl- [4- (1, 3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide Furan-2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3-Chloro-4- (propane-2-sulfonyl) -thiophene-2-carboxylic acid methyl- [4- (1, 3,3-trimethyl- 6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 6-chloro-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2 .1] octane-6-carbonyl) -benzyl] -nicotinamide 5-Methyl-isoxazole-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane- 6-carbonyl) -benzyl-amide
3,3, N-Trimethyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -butyramide 3-Cyano-N-methyl -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-2-phenoxy-N- [4- ( 1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide methyl ester of N-Methyl-N- [4- (1, 3,3-trimethyl- 6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -malonic acid 3-Methyl-but-2-enoic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-2-phenyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane- 6-carbonyl) -benzyl] -acetamide 1-Trifluoromethyl-cyclobutane carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - Amide 3,5-Dimethoxy-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 4-methanesulfonyl- N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-3-trifluoromethoxy-N- [ 4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 2,2-Difluoro-1,3-benzodioxole-4-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-6-morpholin-4-yl-N- [4- (1, 3,3-trim ethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -nicotinamide N-Methyl-4- (2,2,2-trifluoro-acetyl) -N- [4- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide acid N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - isophthalic acid 2,3-Dihydro-benzofuran-7-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3- Acetyl-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 1, 1, 3-Trimethyl-3 - [4- (1, 3,3-trimethyl-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfonylurea N-Methyl-N- [4- (1, 3,3-trimethyl-6- aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 2,2,2-Trifluoro-ethanesulfonic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2 .1] octane-6-carbonyl) -
benzyl-amide N-Methylphenyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide
Trifluoro-N-isopropyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide N-Cyclopropyl-trifluoro-N- [ 4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide N-Ethyl-trifluoro-N- [4- (1, 3,3- trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide
Trifluoro-N-methyl-N- [4- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 3-Benzoyl-1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3-Cyclohexyl-1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (4-methi-phenyl) sulfonyl-1-methyl-1 - [4- (1, 3, 3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1,3-Dimethyl-3-phenyl-1- [4- (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (2,3-Dihydro-1,4-benzodioxin-2-ylmethyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3-methoxy-benzyl) -1-methyl-1 - [ 4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea
3- (1, 1-Dioxo-tetrahydro-thiophen-3-yl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6- carbonyl) -benzyl] -urea 1-Methyl-3- (tetrahydro-pyran-4-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane- 6-carbonyl) -benzyl] -urea acid methyl ester. { 1,3-Dimethyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -acetic 1-Methyl-3- (5-trifluoromethyl-1, 3,4-thiadiazol-2-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 2-methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic
3- methyl acid ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureidoj-benzoic 1-Methyl-3- (3- ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] -octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4 -ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-brciclo- [3.2.1] -octano-6-carbonyl) -benzyl] -urea 3- (4-Benzyloxy- phenyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4 -trifluoro-methylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (4-Acetyl- phenyl) -1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3-Acetyl) phenyl) -1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3- Cyano-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl- 3- (4-trifluoromethyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (4-Methoxy-benzyl) -1-methyl-1- [4- (1, 3.3- tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (2,2,4,4-tetrafluoro-4H-benzo- [1, 3 ] dioxin-6-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4-trifluoro-methoxy-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -urea 1-Methyl- 3- [4- (2,2,2-trifluoro-acetyl) -cyclohexyl] -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1- (4-Acetyl-phenyl) -1,3-dimethyl-3- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6 -carbonyl) -benzyl] -urea 1-Phenyl-3-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -urea piperidine-1-carboxylic acid methyl- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -amide piperidine-1-carboxylic acid [4- (3-aza-bicyclo- [3.2.2] nonane- 3-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid methyl- [4- (octahydro-quinoline-1-carbonyl) -benzyl-amide, morpholine-4-carboxylic acid [4- (3-aza-bicyclo] - [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide 1,3-Dimethyl-3- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -1-phenyl-urea 1- [4- (3-Aza-bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (6-aza- bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide
piperidine-1-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] -amide 1- [4- (6-Aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -1,3-dimethyl- 3-Phenyl-urea 1,3-Dimethyl-1-phenyl-3- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -urea piperidine-1-carboxylic acid [4- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3 -hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8- carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea 1- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1 , 3-di-methyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide acidmorpholine-4-carboxylic acid [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide N-Adamantan-2-yl-4- (1, 3 -dimethyl-3-pyridin-2-yl-ureidomethyl) -benzamide 1 - [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl-1,3-dimethyl-3-pyridine- 2-yl-urea 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-pyridin-2-yl-urea morpholine-4-carboxylic acid [4- (adamantan-2-ylcarbamoyl) -benzyl] -methyl-amide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1 , 3-dimethyl-3-thiazol-2-yl-urea 1,3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] - 1-thiazol-2-yl-urea 4- [3- (1-Acetyl-piperidin-4-yl) -1,3-dimethyl-ureidomethyl] -N-adamantan-2-yl-benzamide 1- (1 -Acetyl-piperidin-4-yl) -3- [4- (3-aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-urea N-Adamantan-2-yl -4- (1,3-dimethyl-3-pyrimidin-2-yl-urethydomethyl) -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) - benzyl] -1,3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- (1,3-dimethyl-3-thiazole-2 -yl-ureidomethyl) -benzamide N-Adamantan-2-yl-4- (1,3-dimethyl-3-phenyl-ureidomethyl) -benzamide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2. 1] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- [3- (4-hydroxy-cyclohexyl) -1, 3-dimethyl-ureidomethyl] -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -3- (4-hydroxy-cyclohexyl) -1, 3-dimethyl- urea
1- (4-Hydroxy-cyclohexyl) -1,3-dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -urea 1-Methyl -3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -imidazolidin-2-one [4- (1,1-Dioxo- isothiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone [4- (1,1-Dioxo-1, 2 , 5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl) -methanone [4- (5-Methyl-1,1-dioxo- 1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl) -methanone (Octahydro-quinolin-1-yl) - [ 4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (4-Aza-tricyclo [4.3.1.13,8] -undec-4-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (Octahydro-isoquinolin-2-yl) - [4- (1,1-dioxo-1, 2,5- thiadiazolidin-2-ylmethyl) -phenyl] -methanone (3-Aza-bicyclo [3.2.2] non-3-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) ) -phenyl] -methanone (6-Aza-bicyclo [3.2.1] oct-6-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - methanone [4- (5-Ben cil-1, 1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone or a salt thereof with a pharmaceutically acceptable base or acid or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric form.
In another embodiment, the present invention is provided for the novel preparation of a pharmaceutical composition for the treatment of conditions, diseases or disorders wherein a modulation or an inhibition of 11βHSD1 activity is beneficial.
In another embodiment, the present invention provides the novel preparation of a pharmaceutical composition, wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.
In another embodiment, the present invention provides the novel preparation of a pharmaceutical composition, wherein: the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased tolerance to glucose (IGT), decreased fasting glucose (IFG), the progress of
IGT to type 2 diabetes, the progress of the metabolic syndrome to type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric diseases and the adverse effects of treatment or glucocorticoid receptor agonist therapy.
In another embodiment, the present invention provides the novel preparation of a pharmaceutical composition, wherein: the pharmaceutical composition is appropriate for a route of administration selected from oral, nasal, buccal, transdermal, pulmonary and parenteral.
In another embodiment, the present invention provides a novel method for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition for the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an amount of effective of a compound of the present invention.
In another embodiment, the present invention provides a novel method wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.
In another embodiment, the present invention provides a novel method wherein the conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), glucose. fasting decreased (IFG), progression of IGT to type 2 diabetes, progress of metabolic syndrome to type 2 diabetes "late diabetic complications, neurodegenerative and psychiatric disorders and adverse effects of treatment or therapy with glucocorticoid receptor agonist.
In another embodiment, the present invention provides a novel method wherein administration is via a selected route of oral, nasal, buccal, transdermal, pulmonary and parenteral.
In another embodiment, the present invention provides a novel compound, which is a useful agent for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.
In another embodiment, the present invention provides a novel method wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.
In another embodiment, the present invention provides a novel method wherein conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), glucose in decreased fasting (IFG), progress of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, psychiatric and neurodegenerative disorders and adverse effects of treatment or glucocorticoid receptor agonist therapy.
In another embodiment, the present invention provides a pharmaceutical composition of a novel method that is understood as an active ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
In another embodiment, the present invention provides a novel pharmaceutical composition that is suitable for oral, nasal, transdermal, pulmonary or parenteral oral administration.
The compounds of the present invention have asymmetric centers and can occur as racemates, racemic mixtures and as individual enantiomers or distereoisomers with
all isomeric forms being included in the present invention as well as mixtures thereof.
The present invention also encompasses the pharmaceutically acceptable salts of the present compounds. Said salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable basic addition salts, pharmaceutically acceptable metal salts, alkylated ammonium salts and ammonium. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of the appropriate inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric and nitric acids. Representative examples of the appropriate organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, masonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, salicylic, bismethylene, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic, sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthates, glycerophosphates and ketoglutarates. Additional examples of the pharmaceutically acceptable organic and inorganic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference. Examples of the metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc and calcium salts. Examples of the amines and the organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N, N'-dibenzylethylene diamine, N -benzylphenylethylamine, N-methyl-D-glucamine and guanidine. Examples of the cationic amino acids include lysine, arginine and histidine.
In addition, some of the compounds of the present invention can form solvates in water or common organic solvents. Said solvates are within the scope of the invention.
The pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium tert-butoxide, calcium hydroxide and magnesium hydroxide in solvents such as ether, THF, methanol, tert-butanol, dioxane and isopropanol, ethanol. Organic bases such as lysine, arginine, diethanolamine, choline, guandin and its derivatives, etc. they can also be used. Alternatively, the acid addition salts if applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid , salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmic acid, succinic acid, benzoic acid, benzenesulfonic acid and tartaric acid in solvents such as ethyl acetate, ether, alcohols, acetone, THF and dioxane. The solvent mixture can also be used.
The stereoisomers of the compounds forming part of this invention can be prepared by using reagents in their simple enantiomeric form in the process where possible or by conducting the reaction in the presence of reagents or catalysts in their simple enantiomer form or by resolving the mixture. of stereoisomers by conventional methods. Some preferred methods include the use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid and lactic acid, where applicable or chiral bases such as brucine, (R) - or (S) - phenylethylamine, cinchona alkaloids and their derivatives. The commonly used methods are compiled by Jaques ef al. in "Enantiomers, Racemates and
Resolution "(Wiley Interscience, 1981) More specifically, the compound of the present invention can be converted to a 1: 1 mixture of diastereomeric amides by treating them with chiral amine, amino acids, aminoalcohols derived from amino acids, the conventional reaction conditions can be used for convert the acid to an amide, the diastereomers can be separated by fractional crystallization or chromatography and the
Stereoisomers of the compound of the formula I can be prepared by hydrolyzing the pure diastereomeric amide.
Various polymorphs of the compounds forming part of this invention can be prepared by crystallizing said compounds under different conditions. For example, using different commonly used solvents or their mixtures for recrystallization, crystallizations at different temperatures; several modes of cooling, ranging from cooling very fast to very slow during crystallizations. The polymorphs can also be obtained by heating or fusing the compound followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, ir spectroscopy, differential analysis calorimetry, powder X-ray diffraction or said other techniques.
The invention also encompasses the prodrugs of the present compounds, which undergo administration. of chemical conversion through metabolic processes before becoming active pharmacological substances. In general, said prodrugs will be functional derivatives of the present compounds, which are rapidly convertible in vivo to the required compound of the present invention. Conventional procedures for the selection and preparation derived from appropriate prodrugs are described, for example in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
It is a well-known problem in drug discovery that compounds, such as enzyme inhibitors, can be very potent and selective in biochemical tests, even if inactive in vivo. This lack of so-called bioavailability can be absorbed into a number of different factors such as lack of or poor absorption in the intestine, first pass metabolism in the liver and / or poor intake in the cells. Although the factors that determine bioavailability are not fully understood, there are many examples in the scientific literature - well known to those skilled in the art - of how the
compounds, which are potent and selective in biochemical tests but show slow activity or no activity in vivo, in drugs that are biologically active.
Within the scope of the invention to modify the compounds of the present invention, the "parent compound" is mentioned by linking the chemical groups that will improve the bioavailability of said compounds in such a way that ingestion in the cells or mammals is facilitated.
Examples of such modifications, which are not intended in any way to limit the scope of the invention, include changing one or more carboxyl groups to esters (eg, methyl esters, ethyl esters, tert-bulks, acetoxymethyl esters, pivaloyloxymethyl esters). or other acyloxymethyl esters). The compounds of the invention, the original compounds, such modified by linking the chemical groups are called "modified compounds"
The invention also comprises the active metabolites of the present compounds.
The compounds according to the invention alter and more specifically reduce the level of active intracellular glucocorticoids and are therefore useful for the treatment of conditions, diseases and disorders in which said modulation or reduction is beneficial.
Accordingly, the present compounds may be applicable for the treatment of metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), decreased fasting glucose (IFG), Autoimmune Diabetes. Late in Adults (LADA, for its acronym in English); type 1 diabetes, late diabetic complications including cardiovascular diseases, cardiovascular disorders, disorders in lipid metabolism, neurodegenerative and psychiatric disorders, intraocular pressure dysregulation including glaucoma, immune disorders, inappropriate immune responses,
musculoskeletal disorders, gastrointestinal disorders, polycystic ovary syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of glucocorticoids Exogenous or endogenous and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoids, Cushing's disease, Cushing's syndrome, adverse effects of treatment with glucocorticoid receptor agonists of autoimmune diseases, adverse effects of agonist treatment of the glucocorticoid receptor for inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of diseases with an inflammatory component, adverse effects of the glucocorticoid receptor agonist treatment as a part of the cancer chemotherapy, adverse effects of glucocorticoid agonist treatment for surgery / post-surgery or other trauma, adverse effects of glucocorticoid receptor agonist therapy in the context of tissue or organ transplantation or adverse effects of treatment with the glucocorticoid receptor agonist glucocorticoid receptor in other diseases, disorders or conditions wherein the glucocorticoid receptor agonists provide clinically beneficial effects.
More specifically, the present compounds may be applicable for the treatment of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsulinemia, inappropriately low insulin secretion, decreased tolerance to glucose (IGT), decreased fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA; pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, decreased HDL cholesterol, decreased LDL / HDI ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake , hypertension, late complications of diabetes, micro / macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, disease
coronary artery, cardiac hypertrophy, myocardial ischemia, coronary insufficiency, congestive coronary failure, stroke, myocardial infarction, arrhythmia, decreased blood flow, erectile dysfunction (female or male), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurodegenerative and psychiatric disorders, Alzheimer's disease, neuronal death, decreased cognitive function, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsy, addiction to chemicals, eye pressure disorders, glaucoma, polycystic ovary syndrome (PCOS), inappropriate immune responses, inappropriate polarization T helper-1 / T helper 2, bacterial infections, mycobacterial infections, fungal infections, viral infections, parasite infestations, sub-optimal responses to immunizations, immune dysfunction, baldness partial or complete or ot ras diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels and any combination thereof, adverse effects of treatment with the glucocorticoid receptor agonist of allergic inflammatory diseases such as asthma and atopic dermatitis, adverse effects of the treatment with the glucocorticoid receptor agonist of irritable bowel disease such as Crohn's disease and ulcerative colitis; Adverse effects of treatment with the glucocorticoid receptor agonist of the immune system, connective tissue and joints, for example, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schonlein purpura, Wegener's granulomatosis, temporal arthritis, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis-polymyositis, pemphigus vulgaris, adverse effects of treatment with glucocorticoid receptor agonist of endocrinological diseases such as hyperthyroidism, hypoaldosteronism, hypopituitarism, adverse effects of treatment with glucocorticoid receptor agonist of hematological diseases, such as hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria , Adverse effects of treatment with cancer glucocorticoid receptor agonist such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumors, acute lymphoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea a, adverse effects treatment with the glucocorticoid receptor agonist of muscle diseases in the neuro-muscular junction,
for example, myasthenia gravis and hereditary myopathies (for example, Duchenne muscular dystrophy), adverse effects of treatment with the glucocorticoid receptor agonist in the context of surgery and transplantation, for example trauma, post-surgical stress, surgical stress, kidney transplantation, transplantation of the liver, lung transplantation, transplantation of the pancreatic islet, stem cell transplantation, bone marrow transplantation, heart transplant, adrenal gland transplant, tracheal transplant, intestine transplant, corneal transplant, skin graft, keratoplasty, lens implantation and other procedures where suppression with glucocorticoid receptor agonists is beneficial; adverse effects of treatment with glucocorticoid receptor agonist of brain abscess, nausea / vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, acular aneurysms or adverse effects of treatment with glucocorticoid receptor agonist in other diseases , disorders and conditions wherein the glucocorticoid receptor agonists provide clinically beneficial effects.
Accordingly, in a further aspect the invention relates to a compound according to the invention for use as a pharmaceutical composition.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one component according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
The pharmaceutical composition preferably in a unit dosage form, comprising from about 0.05 mg / day to about 2000 mg / day, preferably from about 0.1 mg / day to about 1000 mg / day and more preferably from about 0.5 mg / day to about 500 mg / day of a compound according to the invention.
In other embodiments, the patient is treated with a compound according to the invention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months. .
In yet another embodiment, the pharmaceutical composition is for oral, nasal, buccal, transdermal, pulmonary or parenteral administration.
Therefore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment of disorders and diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.
The invention also relates to a method for the treatment of disorders and diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound in accordance with the invention.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment of any disease and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
Furthermore, in a preferred embodiment of the invention, the present compounds are used for the preparation of a medicament for the treatment of conditions and disorders wherein a decreased level of active intracellular glucocorticoid is desired, such as the conditions and diseases mentioned above.
In still a preferred embodiment of the invention, the present compounds are used for the preparation of a medicament for the treatment of the metabolic syndrome, insulin resistance, dyslipidemia, obesity hypertension, type 2 diabetes, impaired glucose tolerance (IGT). , fasting decreased glucose (IFG), progression of IGT to type 2 diabetes, progression of the metabolic syndrome in type 2 diabetes, late diabetic complications (for example, cardiovascular diseases, arteriosclerosis and atherosclerosis), neurodegenerative and psychiatric disorders and adverse effects of treatment or therapy with the glucocorticoid receptor agonist.
In another embodiment of the present invention, the route of administration can be any route that effectively transports a compound according to the invention to the desired or appropriate site or action, such as oral, nasal, buccal, transdermal, pulmonary or parenteral.
In yet a further aspect of the invention the present compounds are administered in combination with one or more additional active substances in any appropriate ratio. Said additional active substances can, for example, be selected from antiobesity agents, antidiabetics, agents that modify lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and / or prevention of complications that result from or are associated with diabetes and agents for the treatment and / or prevention of complications and disorders that result from or are associated with obesity.
In addition, in a further aspect of the invention, the present compounds can be administered in combination with one or more anti-obesity agents or appetite regulating agents.
Said agents can be selected from the group consisting of CART agonists (cocaine-regulated amphetamine transcription), NPY antagonists (Y neuropeptides),
MC4 agonists (melanocortin 4), orexin antagonists, TNF agonists (tumor necrosis factor), CRF agonists (corticotropin release factor), CRF BP antagonists (corticotropin releasing factor binding protein), urocortin agonists, β3 antagonists , MSH agonists (hormone that stimulates the melanocyte), MCH antagonists (hormone that concentrate the melanocytes), CCK agonists (cholecystokinin), serotonin intake inhibitors, serotonin and norepinephrine re-ingestion inhibitors, mixed serotonin and noraadrenergics, 5HT agonists (serotonin), bombesin agonists, galanin antagonists, growth hormone, compounds that release growth hormone, agonists TRH (hormone that releases thyrotropin), modulators UCP 2 or 3 (decoupling protein 2 or 3), leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators (p-proliferator-activated receptor) eroxisome), RXR modulators (retinoid X receptor), TR ß agonists, AGRP inhibitors (Agouti release protein), histamine H3 antagonists, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention, the anti-obesity agent is leptin, dexamfetamine or amphetamine, fenfluramine or dexfenfluramine, sibutramine, orlistat, mazindol or phentermine.
Suitable anti-diabetic agents include insulin, insulin analogs and derivatives such as those described in EP 792 290 (Novo Nordisk A / S), for example, NeB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A / S), for example, AspB28 human insulin, US 5,504,188 (Eli Lilly), for example, Lys828 Pro829 human insulin, EP 368 187 (Aventis), for example Lantus, which are all incorporated herein as reference, GLP-1 (glucagon as peptide-1) and GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, which is incorporated herein by reference as well as orally active hypoglycemic agents.
Orally active hypoglycemic agents preferably comprise sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those described in WO 99/01423 of Novo Nordisk A / S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, channel openers. calcium such as those described in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of the liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose intake, compounds that modify the metabolism of lipids such as antihyperlipidemic agents and antilipidemic agents such as PPARa modulators, PPARd modulators, cholesterol absorption inhibitors, HSL (lipase sensitive hormone) inhibitors and HMG CoA inhibitors (statins), nicotinic acid, fibrates , anion exchangers, compounds that decrease food intake, bile acid resins, RXR agonists and agents that act on the ATP-dependent potassium channel of ß-cells.
In one embodiment, the present compounds are administered in combination with insulin or an analog or derivative of insulin, such as Nc829-tetradecanoyl des (B30) human insulin,
Asp human insulin, Lys Pro human insulin, Lantus®, or a mixed preparation comprising one or more of these.
In an additional embodiment, the present compounds are administered in combination with a sulfonylurea, for example, tolbutamide, glibenclamide, glipizide or glycazide.
In another embodiment, the present compounds are administered in combination with a biguanide, for example metformin.
In yet another embodiment, the present compounds are administered in combination with a meglitinide for example, repaglinide or senaglinide.
In yet another embodiment, the present compounds are administered in combination with a thiazolidinedione, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds described in WO 97/41097 such as 5 - [[4- [3-Methyl-4-oxo] -3,4-dihydro-2-quinazolinyl] methoxy] phenyl-methyl] thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
In yet another embodiment, the present compounds may be administered in combination with the insulin sensitizers described in WO 99/19313 such as (-) 3- [4- [2-phenoxazin-10-yl] ethoxy] phenyl] -2 acid. -ethoxypropanoic acid or a pharmaceutically acceptable salt thereof, preferably the arginine salt.
In a further embodiment, the present compounds are administered together with an α-glucosidase inhibitor, for example, miglitol or acarbose.
In another embodiment, the present compounds are administered in combination in combination with an agent acting on the ATP-dependent potassium channel of the β-cells for example, tolbutamide, glibenclamide, glipizide, glycazide or repaglinide.
Therefore, the present compounds can be administered in combination with nateglinide.
In yet another embodiment, the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin , fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrotyrosine.
In one embodiment, the present compounds are administered in combination with more than one of the aforementioned compounds, for example, in combination with a
sulfonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
In addition, the present compounds are administered in combination with one or more anti-hypertensive agents. Examples of anti-hypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, ß2 receptor blockers eg S-atenolol, OPC-1085, ACE inhibitors (angiotensin-converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, triolapril, fosinopril, ramipril, cilazapril, delapril , imidapril, moexipril, espirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine , nimodipine, diltiazem, amlodipine, nitrendipine, verapamil, lacidoipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, bamidipine, efonodipine , iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine, pranidipine, fumidipine, blockers such as doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, diuretics such as thiazides / sulfonamides (eg, bendro-flumetazide), chlorothalidone, hydrochlorothiazide, and clopamide), loop diuretics (eg, bumetanide, furosemide, and torasemide) and potassium-sparing diuretics (eg, amiloride, spironolactone), ET-A endothelin antagonists such as ABT-546, ambrisetan, atrasentan, SB-234551, CI-1034, S-0139 and YM-598, endothelin antagonists for example, bosentan and J-104133, renin inhibitors such as alisquiren, vasopressin V1 antagonists for example, OPC-21268, vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260, B-type natriuretic peptide agonists eg, Nesiritide, angiotensin II antagonists such as irbesartan, ciesartancilexetil, losartan, valsartan, telmisartan, eprosartan, ciesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and agonists YM-358, 5-HT2 for example, phenoldopam and quetanserin, adenosine A1 antagonists such as naftopidil, N-0861 and FK-352, thromboxane A2 antagonists such as KT2-962, end inhibitors opeptidase for example, ecadotril, agonists
nitric oxide oxide such as LP-805, dopamine D1 antagonists for example, MYD-37, dopamine D2 agonists such as nolomirola, n-3 fatty acids for example, omacor, prostacyclin agonists such as treprostinil, beraprost, PGE1 agonists for example, ecraprost , Na + / K + ATPase modulators eg PST-2238, potassium channel activators for example, KR-30450, vaccines such as PMD-3117, Indapamides, CGRP-unigen, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxonidine, CoAprovel, MondoBiotech-811.
Additional reference may be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
Therefore, the present compounds can be administered in combination with one or more glucocorticoid receptor agonists. Examples of such glucocorticoid receptor agonists are betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and the like), mometasone, triamcinolonacetonide, triamcinolonhexacetonide GW-685698, NXC-1015, NXC- 1020, NXC-1021, NS-126, P-4112, P-4114, RU-24858 and T-25 series.
It should be understood that any combination of the compounds according to the invention with one or more above-mentioned compounds and optionally one or more additional pharmacologically active substances are considered within the scope of the present invention.
PHARMACEUTICAL COMPOSITIONS The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in multiple or simple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients.
in accordance with the conventional techniques described in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions can be formulated specifically for the administration of any appropriate route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will depend on the general conditions and age of the subject to be treated, the nature of the condition to be treated and the active ingredient selected.
Pharmaceutical compositions for oral administration include solid dosage forms such as soft or hard capsules, capsules, tablets, troches, lozenges, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release in accordance with methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution in sterile injectable solutions or dispersions before use. Slow-release injectable formulations (depot) are also contemplated as being within the scope of the present invention.
Other appropriate forms of administration include suppositories, syrups, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc.
A typical oral dose is in the range of from about 0.001 to about 100 mg / kg body weight per day, preferably from about 0.01 to about 50 mg / kg body weight per day, and more preferred from about 0.05 to about 10 mg / kg in body weight per day administered in one or more doses such as 1 to 3 doses. The exact dose will depend on the frequency and mode of administration, sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant disease to be treated and other factors evident to those experts in the technique.
The formulations may be present concomitantly in unit dosage forms by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 2000 mg, for example, from about 0.1 to about 1000 mg, from about 0.5 mg to about 500 mg., From about 1 mg to about 200 mg, for example, about 100 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and the like, typical doses are in the order of about half the dose used for oral administration.
The compounds of this invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free basic salt and a basic addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds for use in accordance with the present invention which are generally prepared by reacting the free base with an appropriate organic and inorganic acid or by reacting the acid with an organic or inorganic appropriate. When a compound to be used in accordance with the present invention, contains a free base said
salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a compound to be used in accordance with the present invention contains a free acid said salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent or a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with an appropriate cation such as sodium or ammonium ion. Other salts that are not pharmaceutically acceptable may be useful in the preparation of compounds for use in accordance with the present invention and these form a further aspect of the present invention.
For parenteral administration, solutions of the compounds present in sterile solution, aqueous propylene glycol or peanut or safflower oil can be used. Said aqueous solutions should be properly stabilized if necessary and the liquid diluent first becomes isotonic with sufficient saline or glucose. Saline solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed is readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of the suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylase, magnesium stearate talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides of the fatty acid, fatty acid esters pentaerythritol, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any prolonged release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or mixed with a wax. The formulations can also
include wetting agents, emulsifiers and suspending agents, preservatives, sweetening agents or flavoring agents.
Pharmaceutical compositions formed by the combination of the compounds of the invention and pharmaceutically acceptable carriers are then ray administered in a variety of dosage forms appropriate for the described routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the pharmacy art.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient and which may include an appropriate excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid or as a liquid emulsion of oil in water or water in oil.
The compositions intended for oral use can be prepared according to any known method, and said compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide flavorful and pharmaceutically elegant preparations. The tablets may contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, disintegrating and granulating agents, for example corn starch or alginic acid, binding agents, for example starch. , gelatin or acacia and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be covered or may not be covered by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a delay time material such as monostearate of
glyceryl or glyceryl distearate can be used. They may also be covered by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference to form osmotic therapeutic tablets for controlled release.
Formulations for oral use can also be prepared as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsule wherein the ingredient active is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.
The aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum, the dispersing or wetting agents can be a naturally occurring phosphatide such as lecithin or condensation products of an alkyl oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecathyl-eneoxyketanol or condensation products of ethylene oxide with derived partial esters of the fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, safflower oil or coconut oil or in a mineral oil such as a liquid paraffin. Oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
Powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a wetting or dispersing agent, the suspending agent and one or more preservatives. Wetting or dispersing agents and suspending agents are exemplified by those previously mentioned. Additional excipients, for example, coloring agents, flavors and sweeteners may also be present.
Pharmaceutical compositions comprising a compound for use in accordance with the present invention may also be in the form of water-in-oil emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil or a mineral oil, for example a liquid paraffin or a mixture thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soy, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain a demulcent, preservative or coloring and flavoring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated in accordance with known methods using appropriate wetting or dispersing agents and
the suspension agents described above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are water, Ringer's solution and suspension solution or isotonic solvent. For this purpose, any soft fixed oil can be used using mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will further melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gelatins, suspensions solutions, etc. are contemplated. containing the compounds of the present invention. For the purpose of this application, topical applications will include mouth rinses and liquids for gargling.
Compounds for use in accordance with the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
In addition, some of the compounds for use in accordance with the present invention can form solvates with water or common organic solvents. Said solvates are also contemplated within the scope of the present invention.
In addition, in a further embodiment, there is provided a pharmaceutical composition comprising a compound for use in accordance with the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable carriers, excipients or diluents.
If a solid carrier is used for oral administration, the preparation may be packaged in a hard gelatin capsule in powder or granule form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as a non-aqueous or aqueous liquid solution or suspension.
A typical tablet that can be prepared by conventional tabletting techniques can contain: Center: Active compound (as free compound or salt thereof) 5.0 mg Lactosum PH. Eur. 67.8 mg Cellulosz, microcrist. (Avicel) 31.4 mg Amberlite®! RP88 * 1.0 mg Magnesii stearas PH. Enough quantity
Coating: Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T ** approx. 0.9 mg
Potassium polyacrylline NF, disintegrating tablet, Rohm and Haas. ** Monoglyceride used as a plasticizer for film coating.
The compounds of the invention can be administered to a patient who is a mammal, especially a human in need thereof. Said mammals also include animals, both domestic animals, for example house pets and non-domestic animals, such as wildlife.
Any characteristic or combination of features described in this document is considered essential for this invention.
The present invention also relates to the subsequent methods for the preparation of the compounds of the invention.
The present invention is further illustrated in the following representative examples which are, however, not intended to limit the scope of the invention in any way.
EXAMPLES, COMPOUNDS OF GENERAL FORMULA (I) The following examples and the general procedures refer to intermediate compounds and final products for the general formula (I) identified in the specification and in the synthesis schemes. The preparation of the compounds of the general formula (I) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described for each compound included within the disclosed scope of the invention. The compound for which this occurs will be readily recognized by those skilled in the art. In these cases, the reactions can be successfully performed by modifications known to those skilled in the art, which is, by appropriate protection of interference groups, by switching to other conventional reagents or by routine modification of the reaction conditions. Alternatively, other reactions described herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all the preparative methods, all the initial materials are known or can be easily prepared from initial materials
known. The structures of the compounds are confirmed by elemental analysis or nuclear magnetic resonance (NMR), where the peaks assigned to the characteristic protons in the title compounds are presented where appropriate. 1 H NMR (dH) exchanges are provided in parts per million (ppm) in downfield of tetramethylsilane as an internal reference standard. M.p .: is the melting point (for its acronym in English) and is provided in in ° C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43; 2923 (1978) in Merck silica gel 60 (Art. 9385). HPLC analyzes were performed using 5 μm C18 4 x 250 mm column eluted with several mixtures of water and acetonitrile, flow = 1 ml / min, as described in the experimental section.
Microwave oven synthesis: The reaction was heated by microwave oven irradiation in sealed microwave glasses in an Emrys Optimizer Simple Emrys Optimizer EXP from PersonalChemistry®.
Preparative HPLC: Column: 1.9 x 15 cm Waters XTerra RP-18. Stabilizer: linear gradient 5 - 95% in 15 min, MeCN, 0.1% TFA, flow rate of 15 ml / min. The pooled fractions were evaporated to dryness under vacuum or evaporated in vacuo until the MeCN was removed and subsequently frozen and freeze-dried.
The abbreviations as used in the examples have the following meaning: TLC: Thin layer chromatography CDCI3: Chloroform Deuterio CD3OD: Methanol Tetradeuterio DCM: Dichloromethane DMF: N, N-dimethylformamide DMSO- Dimethylsulfoxide Hexadeuterio > • DMSO: Dimethylsulfoxide DIPEA: Diisopropylethylamine EDAC: 1 1 - ((33-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EtOAc: Ethyl acetate THF: Tetrahydrofuran HOBT: 1 -Hydroxy-benzotriazole MeCN: Acetonitrile NMP: N-Methylpyrrolidinone TFA: Acid Trifluoroacetic min: minutes hrs: hours
General Method A: (II)
A (II)
By allowing a benzyl amine (I) wherein R2, R5, R6, R7 and A are defined as above for coupling with an acid (II) wherein R8 is defined as above under standard amide forming conditions using a coupling reagent (III) ) (for example
HOBT, EDAC and DIPEA in dry THF) yielding amide (IV) wherein R2, R5, R6, R7, R8 and A are defined as above; or by allowing a benzyl amine (I) wherein R2, R5, R6, R7 and A are defined as above to be reacted with an acid derivative (II) wherein X is halo, R8 (C = 0) 0-, alkyloxy d -C6o alkyloxy d-C6 aryl and R8 is defined as above under basic conditions (for example triethylamine, K2C03, NaH and the like) in a solvent (for example THF, DCM, DMF, NMP and the like) producing amide (III); wherein R2, R5, R6, R7, R8 and A are defined as above.
General method B: (II)
By allowing a benzyl amine (I) wherein R2, R5, R6, R7 and A are defined as above to be reacted with a sulfonyl halide (II) wherein X is halo and R9 is defined as above under basic conditions (for example triethylamine , K2C03, NaH and the like) in a solvent (for example THF, DCM, DMF, NMP and the like) producing sulfone amide (III); wherein R2, R5, R6, R7, R9 and A are defined as above.
General method C:
By allowing a benzyl amine (I) wherein R2, R5, R6, R7 and A are defined as above to be reacted with an isocyanate (II) wherein R10 is defined as above in a solvent (for example THF, DCM, DMF, NMP and the like) producing urea (III); wherein R2, R5, R6, R7, R10 and A are defined as above. The tri-substituted urea (III) can also be reacted with an alkyl halide or mesylate (IV); wherein X is halide or OS02Me and R11 is defined above to react under basic condition (for example triethylamine, K2C03, NaH and the like) in a solvent (for example THF, DCM, DMF, NMP and the like) producing tetrahedral urea. replaced (V); wherein R2, R5, R6, R7, R10, R11 and A are defined as above.
General method D:
By allowing a benzyl amine (I) wherein R2, R5, R6, R7 and A are defined as above to be reacted with an isothiocyanate (II) wherein R10 is defined as above in a solvent (for example THF, DCM, DMF, NMP and the like) producing thiourea (III); wherein R2, R5, R6, R7, R10 and A are defined as above. The tri-substituted thiourea (III) can also be reacted with an alkyl halide or mesylate (IV); wherein X is halide or OS02Me and R is defined above to react under basic condition (for example triethylamine, K2C03, NaH and the like) in a solvent (for example THF, DCM, DMF,
NMP and the like) producing tetra-substituted thiourea (V); wherein R2, R5, R6, R7, R10, R11 and A are defined as above.
General method E: (II)
(IV)
(SAW)
By allowing a benzyl amine (I); wherein R5, R6, R7 and A are defined as above to be reacted with a protected ethyl amine (II); wherein X is halo, alkyl d-C6OS (0) 2-, aryl-OS (0) 2- or alkyl CrC6OS (0) 2 aryl- and R26 is C8 alkyl, C3-C10 cycloalkyl, het-cycloalkyl C3- C 0, C 3 -C 6 -spirocycloalkyl, 3-6-membered spiroethycycloalkyl, aryl, hetaryl, d-C 6 -aryl alkyl, CrC 6 -hetaryl alkyl, -C (= 0) R 12, -S (0) nR 12, -S (0) nNR 13 R 14 and CrC6 alkyloxy CrC6 alkyl to react under basic condition (for example triethylamine, K2C03, NaH and
the like) in a solvent (for example THF, DCM, DMF, NMP and the like) producing ethylene diamine (III); wherein R5, R6, R7 and A are defined as above and R26 is d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 het-cycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl, alkyl CrC6aryl, CrC6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14 and CrC6alkyloxy d-C6 alkyl. The deprotection of ethylene diamine (III); wherein R5, R6, R7 and A are defined as above and R26 is CrC8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6spirocycloalkyl, 3-6 spirohetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, -C ( = 0) R12, -S (0) nR12, -S (0) nNR13R14 and C6 alkyloxy alkyloxy CrC6, in a mixture of for example TFA / DCM followed by the reaction with phosgene under basic conditions (for example triethylamine, DIPEA, DBU and the like) in a solvent (for example THF, DCM, toluene and the like) produces 2-oxo-imidazolidine (IV); wherein R5, R6, R7 and A are defined as above and R26 is d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 het-cycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl, alkyl CrC6aryl, d-C6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14 and CrC6alkyloxy CrC6 alkyl; or by allowing a benzyl sulfonate (V); wherein R5, R6, R7, A are defined as above and R27 is d-C6 alkyl and aryl, to be reacted with a protected ethylene-di-amine (II); wherein R26 is d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 het-cycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiro-ethycycloalkyl, aryl, hetaryl, dC ^ aryl alkyl, CrC6heteroylcarbon, -C (= 0 ) R12, -S (0) nR12, -S (0) nNR13R14 and dC6 alkylCi 6 alkyloxy to react under basic condition (for example triethylamine, K2C03, NaH and the like) in a solvent (for example THF, DCM, DMF, NMP and the like) producing ethylene di-amine (III); wherein R5, R6, R7 and A are defined as above and R26 is d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 het-cycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl, alkyl CrC6aryl, d-C6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14 and CrC6alkyloxy d-C6 alkyl. The deprotection of ethylene diamine (III); wherein R5, R6, R7 and A are defined as above and R26 is CrC8 alkyl, C3-C10 cycloalkyl, C3-C10 het-cycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spirohetcycloalkyl, aryl, hetaryl, CrC6aryl alkyl, alkyl d-C-hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14 and alkyl d-C6 alkyloxy CrC6 in a mixture of for example
TFA / DCM followed by the reaction of phosgene under basic conditions (for example triethylamine, DIPEA, DBU ad the like) in a solvent (for example THF, DCM, toluene and the like) produces 2-oxo-imidazolidine (IV); wherein R5, R6, R7 and A are defined as above and R26 is d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 het-cycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl, alkyl dC ^ aryl, CrC6hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14 and C6-C6alkyloxy alkyl.
R26 is CrC8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spirohetcycloalkyl, aryl, hetaryl, CrCearyl alkyl, d-Cehetaryl alkyl, -C (= 0) R12, -S ( 0) nR12, -S (0) nNR13R14 and d-C6 alkyl alkyloxy d-C6 wherein R12, R13, and R14 are defined above and each alkyl, aryl / hetaryl group is substituted with 0-3 R18 which is defined above .
General method F:
By allowing a benzyl amine (I); wherein R5, R6, R7 and A are defined as above to be reacted with a sulfonyl halide (II); wherein m is 1, 2 or 3 and R26 is further defined under basic conditions (for example triethylamine, K2C03, NaH and the like) in a solvent (for example THF, DCM, DMF, NMP and the like) producing cyclic sulfone amide (III); wherein m is 1, 2 or 3 and R5, R6, R7 and A are defined as above and R26 is defined later.
26 R is CrC6 alkyl, aryl, hetaryl, C? -C6alkyl, CrC6hetaryl, C (= 0) R, -S (0) nR12, -S (0) nNR13R14, alkyloxy d-C6, alkyloxy CrCearyl, alkyloxy d-Cehetaryl, alkyl
CrC6alkyloxy CrC6; wherein R12, R13 and R14 are defined above and each alkyl, aryl / hetaryl group is substituted with 0-3 R which is defined above.
General method G: (II)
I)
By dissolving sulphonamide (I); wherein R5, R6, R7 and A are defined as above 26 to be reacted with a hydroxyl ethyl halide (II); wherein R is as defined below under conditions of Mitsunobu (for example PPh3 and DIAD) in a solvent (for example THF and the like) producing substituted sulfamide (III); wherein R5, R6, R7 and A are defined as above and R26 is as defined below. The substituted sulfamide (III); wherein R5, R6, R7 and A are defined as above and R26 is as defined below and cyclized under basic conditions (for example K2C03 in DMSO) yielding [1, 2,5] thiadiazolidine 1,1-substituted-dioxide (IV ); wherein R5, R6, R7 and A are defined as above and R26 is as defined below. The introduction of the additional substituents can be carried out when [1, 2,5] thiadiazolidine 1,1-dioxide (IV) is allowed; wherein R5, R6, R7 and A are defined as above and R, 26 is as defined below to undergo deprotection (by
example TFA / DCM) producing [1, 2,5] thiadiazolidine 1,1-substituted-dioxide (V); wherein R5, R6, R7 and A are defined as above and R26 is as defined below, which may be alkylated with (VI); wherein R27 is as defined below under basic conditions (for example NaH in DMSO or DMF) or via a Mitsunobu reaction (for example PPh3 and DIAD) in a solvent (for example THF and the like) with alcohol (Vil); wherein R27 is as defined below yielding 1, 2,5] thiadiazolidine 1,1-substituted-dioxide (VIII); wherein R5, R6, R7 and A is defined as above and R26 and R27 are defined later.
R26 is CrC6 alkyl, aryl, hetaryl, CrC6aryl alkyl, d-C6 alkyl hetaryl and CrC6alkyloxy CrC6 alkyl; wherein each alkyl, aryl / hetaryl group is substituted with 0-3 R18 which was defined above.
R27 is d-C6 alkyl, aryl, hetaryl, CrCearyl alkyl, d-Cehetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, CrC6alkyloxy d-C6 alkyl; wherein R12, R13 and R14 are defined above and each alkyl, aryl / hetaryl group is substituted with 0-3 R18 which is defined above.
SPECIFIC EXAMPLES Example 1-1 (General procedure (A)) N-Methyl-N-f4- (1,3,3-trimethyl-6-aza-biciclof3.2.noctane-6-carbonyl) -benzyl-acetamide
Step A: [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamic acid tert-butyl ester
To a solution of 4- (feri-butoxycarbonylamino-methyl) -benzoic acid (15.0 g, 59.69 mmol) in THF (200 mL) was added with stirring HOBt (8.87 g, 65.66 mmol) followed by EDAC (12.59 g, 65.66 mmol) ) and the mixture was stirred for 30 min. at room temperature. To the resulting mixture was added 1,3-trimethyl-6-aza-bicyclo [3.2.1] octane, hydrochloride (12.46 g, 65.66 mmol) and DIPEA (21.84 mL, 125.36 mmol). The reaction mixture was stirred for 16 hrs. at room temperature. The solvent was evaporated and water (100 mL) was added to the residue. The mixture was extracted with EtOAc (3x50 mL) and the combined organic phases were washed with saturated aqueous ammonium chloride (3x50 mL). The organic phase was dried (MgSO) and the evaporated solvent yielded crude amide which was dissolved in EtOAc (50 mL) and filtered through a pad of silica gel using EtOAc as eluent. The combined fractions evaporated, which produced 23 g (99%) of [4 (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] t-butyl ester. -carbámico 1 H NMR (400 MHz, CDCl 3) d 0.94 (d, 3 H), 1.02 (d, 3 H), 1.12 (d, 3 H), 1.17-1.59 (m, 14.5 H), 1.75 (m, 1 H), 2.23 ( m, 0.5H), 3.23 (q, 0.5H), 3.26 (d, 0.5H), 3.58 (d, 0.5H), 3.96 (m, 0.5 H), 4.33 (bs, 2H), 4.60 (m, 0.5 H), 5.02 (bs, 0.5 H), 7.29 (m, 2H), 7.40 (t, 2H). HPLC-MS (Method Z1): m / z = 387 (M + 1); tr = x.xx min (yy% ELS).
Stage B: Methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamic acid fert-butyl ester
To a solution of the above carbamate (560 mg, 1.45 mmol) in THF (30 mL) was added sodium hydride (151 mg, 3.77 mmol, 60% in oil) with stirring and the mixture was stirred for 1 h. at room temperature. To the resulting mixture was added methyl iodide (514 mg, 3.62 mmol) dissolved in THF (1 mL). The reaction mixture was stirred for 16 h. at room temperature. The solvent was evaporated and water (30 mL) was added to the residue. The mixture was extracted with EtOAc (3x25 mL) and the combined organic phases were washed with water (3x25 mL), brine (25 mL),
dried (MgSO.sub.4) and the evaporated solvent yielded 560 mg (97%) of methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-hydroxy) -ethyl-ethyl ester. carbonyl) -benzyl] -carbamic acid as a solid. , 1 H NMR (400 MHz, DMSO- / 6) d 0.89 (d, 3 H), 0.96 (d, 3 H), 1.05 (d, 3 H), 1.15-1.50 (m, 13.5 H), 1.74 (m, 1 H ), 2.04 (m, 0.5H), 2.78 (s, 3H), 3.11 (m, 1 H), 3.28 (d, 0.5H), 3.42 (d, 0.5H), 3.92 (m, 0.5 H), 4.39 (m, 2.5H), 7.26 (m, 2H), 7.38 (d, 1 H), 7.44 (d, 1 H). HPLC-MS (Method Z1): m / z = 401 (M + 1); tr = x.xx min (yy% ELS).
Step C: (4-Methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone
To a solution of the above amide (560 mg, 1.4 mmol) in DCM (9 mL) was added with stirring TFA (3 mL) and the mixture was stirred for 16 h. at room temperature. The solvent was evaporated and water (10 mL) was added to the residue and the pH was adjusted to 11. The mixture was extracted with DCM (3x15 mL) and the organic phases were washed with brine (15 mL), dried (MgSO). ) and the solvent was evaporated yielding 410 mg (97%) of (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone as an oil. 1 H NMR (400 MHz, MeOD) d 0.95 (d, 3 H), 1.02 (d, 3 H), 1.12 (d, 3 H), 1.2-1.68 (m, 5 H), 1.84 (m, 1 H), 2.16 (m , 0.5H), 2.72 (s, 3H), 3.19 (m, 1 H), 3.59 (d, 0.5H), 4.01 (t, 0.5H), 4.20 (s, 2H), 4.52 (t,
0. 5 H), 7.50-7.58 (m, 4H). HPLC-MS (Method Z1): m / z = 301 (M + 1); tr = 1.44 min (100% ELS).
Step D: To a solution of the above benzyl amine (155 mg, 0.516 mmol) in DCM (3 mL) was added with agitation TEA (107 μL, 0.774 mmol) followed by acetyl chloride (41 μL, 0.568 mmol) and the mixture was stirred for 16 h. at room temperature. The mixture was washed with water (3x1 mL),
dried (MgSO) and the solvent was evaporated. The residue was purified using preparative HPLC (Method
Z4): Isolated amount = 47 mg; tr = 10.48 min (27%) of the title compound as an oil. 1 H NMR (400 MHz, MeOD) d 0.95 (d, 3 H), 1.02 (d, 3 H), 1.12 (d, 3 H), 1.2-1.67 (m, 5 H), 1.82 (m,
1 H), 2.17 (m, 3.5H), 2.93 + 3.02 (2 x s, 3H, rotamers), 3.19 (m, 1 H), 3.57 (d, 0.5H), 4.03 (m, 0.5H),
4. 50 (m, 0.5 H), 4.62-4.68 (m, 2H), 7.3-7.52 (m, 4H). HPLC-MS (Method Z1): m / z = 343 (M + 1); tr = 1.78 min (100% ELS).
Example 1-2 (General procedure (A)) N-Methyl-N-4 - (1,3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl) -benzyl-isobutyramide
The title compound is prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-) il) -methanone and isobutyryl chloride. HPLC-MS (Method Z1): m / z = 371 (M + 1); tr = 1.89 min (100% ELS).
Example 1-3 (General procedure (A)) Cyclopentanecarboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1-octane-6-carbonyl) -benzin-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and cyclopentanecarbonyl chloride. HPLC-MS (Method Z1): m / z = 397 (M + 1); tr = 2.08 min (100% TIC).
Example 1-4 (General procedure (A)) Cyclohexanecarboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.noctane-6-carbon-p-benzin-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and cyclohexanecarbonyl chloride. HPLC-MS (Method Z1): m / z = 411 (M + 1); tr = 2.16 min (100% ELS).
Example 1-5 (General procedure (A)) Piperidine-1-carboxylic acid methyl-f4- (1,3,3-trimethyl-6-aza-bicycloic -3.2.1-octane-6-carbonyl) -benzyl-
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and piperidine-1 -carbonyl chloride. HPLC-MS (Method Z1): m / z = 412 (M + 1); tr = 2.09 min.
Example 1-6 (General Procedure (A)) 1,3-Dimethyl-3-phenyl-1-f4- (1,3,3-trimethyl-6-aza-bicyclo | -3.2.1-octane-6-carbonyl) -benzyl- urea
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and N-methyl-N-phenylcarbamoyl chloride. HPLC-MS (Method Z1): m / z = 435 (M + 1); tr = 2.19 min.
Example 1-7 (General procedure (A)) N-Methyl-N-4 - (1,3,3-trimethyl-6-aza-bicyclo [3.2.1-octane-6-carbonyl) -benzyl-benzamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and benzoyl chloride. HPLC-MS (Method Z1): m / z = 405 (M + 1); tr = 1.98 min.
Example 1-8 (General procedure (A)) 1-Acetyl-piperidine-4-carboxylic acid methyl-4 - (1,3,3-trimethyl-6-aza-bicycloic-3,2-octane-6-carbonyl-benzyl) amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 1-acetyl-piperidine-4-carbonyl chloride. HPLC-MS (Method Z1): m / z = 454 (M + 1); tr = 1.61 min.
Example 1-9 (General procedure (A)) 1-Acetyl-piperidine-3-carboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-bicycloic -3.2-octane-6-carbonyl) -bencill-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 1-acetyl-piperidine-3-carbonyl chloride. HPLC-MS (Method Z1): m / z = 454 (M + 1); tr = 1.65 min.
Example 1-10 (General procedure (A)) Cyclopentanecarboxylic acid ethyl-4- (1, 3,3-trimethyl-6-aza-bicycloic -3.2.1-octane-6-carbonyl) -benzyl-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-ethylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and cyclopentanecarbonyl chloride. HPLC-MS (Method Z1): m / z = 411 (M + 1); tr = 2.17 min.
Example 1-11 (General procedure (A)) Morpholine-4-carboxylic acid methyl-4 - (1, 3,3-trimethyl-6-aza-bicyclo3.2.noctane-6-carbonyl) -benzyl-
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and morpholine-4-carbonyl chloride. HPLC-MS (Method Z1): m / z = 414 (M + 1); tr = 1.74 min.
Example 1-12 (General procedure (A)) 2,2-N-Trimethyl-N-f4- (1,3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzine-propionamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-feriyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 2,2-dimethyl-propionyl chloride. HPLC-MS (Method Z1): m / z = 385 (M + 1); tr = 2.04 min.
Example 1-13 (General procedure (A)) Tetrahydrofuran-3-carboxylic acid methyl-r4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl-benzyl-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and tetrahydro-furan-3-carbonyl chloride. HPLC-MS (Method Z1): m / z = 399 (M + 1); tr = 1.68 min.
Example 1-14 (General Procedure (A)) N-Methyl-4-trifluoromethoxy-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.noctane-6-carbonyl) -benzyl- benzamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 4-trifluoromethoxy-benzoyl chloride. HPLC-MS (Method Z1): m / z = 489 (M + 1); tr = 2.24 min.
Example 1-15 (General procedure (A)) Thiophene-2-carboxylic acid methyl-r4- (1,3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzyl-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and thiophene-2-carbonyl chloride. HPLC-MS (Method Z1): m / z = 41 1 (M + 1); tr = 1.97 min.
Example 1-16 (General procedure (A)) Furan-2-carboxylic acid methyl-f4- (1.3.3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzyl-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and furan-2-carbonyl chloride. HPLC-MS (Method Z1): m / z = 395 (M + 1); tr = 1.96 min.
Example 1-17 (General procedure (A)) 3-Chloro-4- (propane-2-sulfonyl) -thiophene-2-carboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-bicyclo3. 2.noctane-6-carbonyl) -benzyl-amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3-chloro-4- (propane-2-sulfonyl) -thiophene-2-carbonyl chloride. HPLC-MS (Method Z1): m / z = 551 (M + 1); tr = 2.0 min.
EXAMPLE 1-18 (General procedure (A)) 6-Chloro-N-methyl-N-f4- (1,3,3-trimethyl-6-aza-bicycloic -3.2.1-octane-6-carbonyl) -benzyl- nicotinamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 6-chloro-nicotinoyl chloride. HPLC-MS (Method Z1): m / z = 440 (M + 1); tr = 1.90 min.
Example 1-19 (General Procedure (A)) 5-Methyl-isoxazole-3-carboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-bicichlor3.2.noctane-6-carbonyl) -benzill -amide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 5-methyl-isoxazole-3-carbonyl chloride. HPLC-MS (Method Z1): m / z = 410 (M + 1); tr = 1.91 min.
Example 1-20 (General Procedure (A)) 3.3.N-Trimethyl-N-f4- (1, 3,3-trimethyl-6-aza-bicycloic -3.2.1-octane-6-carbonyl-benzy-butyramide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3,3-dimethyl-butyryl chloride. HPLC-MS (Method Z1): m / z = 399 (M + 1); tr = 2.12 min.
Example 1-21 (General procedure (A)) 3-Cyano-N-methyl-N-f4- (1, 3,3-trimethyl-6-aza-bicichlor3.2.1loctane-6-carbonyl) -benzyl-benzamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3-cyano-benzoyl chloride. HPLC-MS (Method Z1): m / z = 430 (M + 1); tr = 1.92 min.
Example 1-22 (General procedure (A)) N-Methyl-2-phenoxy-N-f4- (1,3,3-trimethyl-6-aza-bicyclo3.2.noctane-6-carbonyl) -benzopylacetamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and phenoxy-acetyl chloride. HPLC-MS (Method Z1): m / z = 435 (M + 1); tr = 2.02 min.
Example 1-23 (General procedure (A)) N-Methyl-N-4- (1,3,3-trimethyl-6-aza-bicyclof3.2.noctane-6-carbonyl) -benzyl-malonamic acid methyl ester
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and methyl ester of chlorocarbonyl acetic acid. HPLC-MS (Method Z1): m / z = 401 (M + 1); tr = 1.69 min.
Example 1-24 (General procedure (A)) 3-Methyl-but-2-enoic acid methyl-r4- (1,3,3-trimethyl-6-aza-bicycloic -3.2.1-octane-6-carbonyl) -benzyl-
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3-methyl-but-2-enoyl chloride. HPLC-MS (Method Z1): m / z = 383 (M + 1); tr = 1.92 min.
Example 1-25 (General Procedure (A)) N-Methyl-2-phenyl-N-f4- (1,3,3-trimethyl-6-aza-bicyclof3.2.1-octane-6-carbonyl) -benzyl-acetamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and phenyl-acetyl chloride. HPLC-MS (Method Z1): m / z = 419 (M + 1); tr = 2.03 min.
Example 1-26 (General procedure (A)) 1-Trifluoromethyl-cyclobutanecarboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-bicycloic3.2.1 loctane-6-carboniD-benzyl-amide
To a solution of 1-trifluoromethyl-cyclobutanecarboxylic acid (33.6 mg, 0.2 mmol) in THF (5 mL) was added with stirring HOBt (27 mg, 0.2 mmol) followed by EDAC (38 mg, 0.2 mmol) and the mixture was stirred for 30 min. at room temperature. To the resulting mixture was added (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (50 mg, 0.17 mmol, Example 1) and DIPEA (35 μL, 0.2 mmol). The reaction mixture was stirred for 16 h. at room temperature. The solvent was evaporated and the residue was purified using preparative HPLC (Method Z4): Isolated amount = 40 mg (53%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.94 (d, 3 H), 1.04 (d, 3 H), 1.13 (d, 3 H), 1.17-1.60 (m, 4.5 H), 1.75-1.90 (m, 2 H), 2.10 (m, 1 H), 2.24 (m, 0.5H), 2.55 (m, 2H), 2.73 (m, 2H), 2.83 + 2.86 (2 xs, 3H, rotamers), 3.15 (d, 0.5H), 3.26 (t, 1 H), 3.60 (d, 0.5H), 3.98 (bs, 0.5 H), 4.46 (bs, 0.5H), 4.63 (m, 2H), 7.29 (m, 2H), 7.40 (t, 2H) ). HPLC-MS (Method Z1): m / z = 451 (M + 1); tr = 2.18 min.
Example 1-27 (General Procedure (A)) 3.5-Dimethoxy-N-methyl-N-f4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl) -benzin-benzamide
The title compound was prepared by a similar procedure as described in Example 1, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3,5-dimethoxy-benzoyl chloride. HPLC-MS (Method Z1): m / z = 465 (M + 1); tr = 2.05 min.
Example 1-28 (General procedure (A)) 4-Methanesulfonyl-N-methyl-N-4 (1, 3,3-trimethyl-6-aza-bicyclof3.2.1-octane-6-carbonyl) -benzyl-
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 4-methanesulfonyl-benzoic acid. HPLC-MS (Method Z1): m / z = 483 (M + 1); tr = 1.78 min.
Example 1-29 (General Procedure (A)) N-Methyl-3-trifluoromethoxy-N-f4- (1, 3,3-trimethyl-6-aza-bicycloic -3.2.11-octane-6-carbonyl) -bencip-benzamide
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3-trifluoromethoxy-benzoic acid. HPLC-MS (Method Z1): m / z = 489 (M + 1); tr = 2.23 min.
EXAMPLE 1-30 (General Procedure (A)) 2,2-Difluoro-1,3-benzodioxole-4-carboxylic acid methyl-4 - (1, 3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl) -bencill-amide
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 2,2-difluoro-benzo [1,3] dioxol-4-carboxylic acid. HPLC-MS (Method Z1): m / z = 485 (M + 1); tr = 2.21 min.
Example 1-31 (General procedure (A)) N-Met l-6-morpholin-4-yl-N-r4- (1,3,3-trimethyl-6-aza-bicyclof3.2.1-octane-6-carbonyl) - benzyl-nicotinamide
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -methanone and 6-morpholin-4-yl-nicotinic acid. HPLC-MS (Method Z1): m / z = 491 (M + 1); tr = 1.52 min.
Example 1-32 (General Procedure (A)) N-Methyl-4- (2,2,2-trifluoro-acetyl) -N-r4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6 -carbonyl) -benzyl-1-benzamide
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 4- (2,2,2-trifluoro-acetyl) -benzoic acid. HPLC-MS (Method Z1): m / z = 519 (M + 18); tr = 1.84.min.
Example 1-33 (General Procedure (A)) 3-Acetyl-N-methyl-N-4 (1, 3,3-trimethyl-6-aza-bicyclof3.2.noctane-6-carbonyl) -benzyl-benzamide
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -methanone and 3-acetyl-benzoic acid. HPLC-MS (Method Z1): m / z = 447 (M + 1); tr = 1.90 min.
Example 1-34 (General procedure (A)) N-Methyl-N-f4- (1, 3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzyl-isofalmic acid
To a solution of isophthalic acid monomethyl ester (72 mg, 0.4 mmol) in THF (10 mL) was added HOBt (54 mg, 0.4 mmol) followed by stirring with EDAC (77 mg, 0.4 mmol) and the mixture was stirred by 30 min. at room temperature. To the resulting mixture was added (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (100 mg, 0.33 mmol, Example 1 ) and DIPEA (70 μL, 0.4 mmol). The reaction mixture was stirred for 16 h. at room temperature. The solvent was evaporated and the residue was purified using preparative HPLC (Method Z4): Isolated amount = 100 mg (65%) of N-methyl-N- [4- (1, 3,3-trimethyl-6-methyl) methyl ester -aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isophthalamic as an oil.
To the solution of ester (100 mg) in EtOH (5 mL) was added water (2 mL) and 1 N NaOH (0.5 mL). The mixture was stirred at room temperature for 6 h and the volatiles were evaporated. The residue was dissolved in water (5 mL) and washed with Et20 (2 x 10 mL) and the pH adjusted to 1 by 1 N HCl. The aqueous phase was extracted with EtOAc (3x10 mL), the combined organic phases were dried (MgSO4) and evaporated, which yielded 73 mg (49%) of the title compound as a solid. 1 H NMR (400 MHz, CDCl 3) d 0.95 (d, 3 H), 1.05 (s, 3 H), 1.14 (d, 3 H), 1.33-1.49 (m, 3.5 H), 1.58 (m, 1 H), 1.79 ( m, 1 H), 2.27 (m, 0.5H), 2.88 + 3.08 (2 xs, 3H, rotamers), 3.28 (m, 1.5H), 3.63 (d, 0.5H), 4.02 (m, 0.5 H), 4.53-4.79 (m, 2.5H), 7.21-7.70 (m, 6H), 8.15 (m, 2H).
HPLC-MS (Method Z1): m / z = 449 (M + 1); tr = 1.76 min.
Example 1-35 (General procedure (A)) 2,3-Dihydro-benzofuran-7-carboxylic acid methyl-f4- (1, 3,3-trimethyl-6-aza-biciclof3.2.noctane-6-carboniD-benzyl- amide
The title compound was prepared by a similar procedure as described in Example 23, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 2,3-dihydro-benzofuran-7-carboxylic acid. HPLC-MS (Method Z1): m / z = 447 (M + 1); tr = 2.02 min.
Example 1-36 (General Procedure (A)) N- [4- (1, 3,3-Trimethyl-6-aza-biciclof3.2.noctane-6-carbonyl) -benzyl-benzamide
To a solution of [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamic acid ester (11 g), 28.5 mmol, Example 1) in DCM (40 mL) was added with stirring TFA (20 mL) and the mixture was stirred for 16 h. at room temperature. The solvent was evaporated and to the residue water (50 mL) was added and the pH adjusted to 11. The mixture was extracted with DCM (3x20 mL) and the organic phases were washed with brine (20 mL), dried (MgSO4) and the solvents were evaporated yielding 7.7 g (94%) of (4-aminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone as a oil.
1 H NMR (400 MHz, CDCl 3) d 0.97 (d, 3 H), 1.02 (d, 3 H), 1.12 (d, 3 H), 1.15-1.44 (m, 4.5 H), 1.56 (t, 1 H), 1.75 ( m, 1 H), 2.23 (m, 0.5H), 3.01 (bs, 2H, NH2), 3.15 (d, 0.5H), 3.57 (d, 0.5H), 3.89 (d, 2H), 3.97 (t, 0.5H), 4.58 (t, 0.5 H), 7.38 (m, 4H). HPLC-MS (Method Z1): m / z = 287 (M + 1); tr = 1.2 min (100% ELS).
To a solution of the above benzyl amine (100 mg, 0.35 mmol) in DCM (5 mL) was added with stirring TEA (150 μL, 1.05 mmol) followed by benzoyl chloride (60 μL, 0.52 mmol) and the mixture was stirred for 16 h. at room temperature. The mixture was washed with water (3x1 mL), dried (MgSO4) and the solvent was evaporated. The residue was purified using preparative HPLC (Method Z4): Isolated amount = 95 mg (70%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.92 (d, 3 H), 0.95 (d, 3 H), 1.01 (d, 3 H), 1.13-1.58 (m, 4.5 H), 1.74 (m, 1 H), 2.21 ( m, 0.5H), 3.12 (d, 0.5H), 3.22 (t, 1 H), 3.56 (d, 0.5H), 3.94 (t, 0.5H), 4.58 (m, 2.5 H), 7.22-7.32 ( m, 4H), 7.40 (t, 2H), 7.49 (m, 2H), 7.87 (d, 2H). HPLC-MS (Method Z1): m / z = 391 (M + 1); tr = 1.91 min (100% ELS).
Example 1-37 (General Procedure (A)) [4- (1-Amino-cyclopropyl) -phenyl- (1, 3,3-trimethyl-6-aza-biciclof3.2.noct-6-yl) -methanone To one solution NaH (1.95 g, 0.049 mol, 60% in oil, washed with dry THF) in dry DMF (50 mL) was added dropwise a solution of [4- (1, 3,3-Trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -acetonitrile (7.0 g, 0.024 mol) in dry DMF (180 ml) at 0 ° C. To the resulting mixture was added dropwise a solution of 1, 2-dibromoethane (8.14 mL, 0.094 mol) in dry DMF (25 mL) and the mixture was stirred for 16 hrs at room temperature at which time it was made as a quince by the addition of crushed ice. The aqueous phase was extracted with AcOEt (3x250 mL) and the organic phases were washed with water (2x100 mL), brine (1x100 mL), dried (MgSO4) and filtered by evaporation of the volatiles. This produced 5.28 g (69%) of crude 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropanecarbonitrile as an oil. HPLC-MS (Method Z1): m / z = 323 (M + 1); tr = 2.02 min (100% ELS).
In previous nitrile (5.25 g, 16.28 mmol) was added to the mixture of. Concentrated HCl (120 mL) and AcOH (30 mL) and stirred at 80 ° C for 18 hrs. The reaction mixture was diluted with ice water (300 mL) and the pH was adjusted to 3 by the addition of 4 N NaOH. The oily precipitate was extracted with diethyl ether (3x200 mL) and the combined organic phases were washed with water (2x100 mL), brine (1x80 mL), dried (MgSO4), filtered and the volatiles were evaporated in vacuo yielding 4.7 g. (85%) of 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropane-carboxylic acid acid as a solid. HPLC-MS (Method Z1): m / z = 342 (M + 1); tr = 1.83 min (100% ELS).
To a solution of the above carboxylic acid (3.00 g, 8.79 mmol) in DCM (600 mL) was added H2SO4 (7.2 mL) followed by NaN3 (1.38 g, 21.23 mmol). The mixture was stirred at 45 ° C for 16 hrs and cooled to room temperature and quenched by the addition of ice water (300 mL). The pH was adjusted to 11 by the addition of 4N NaOH and the mixture was extracted with DCM (2x150 mL). The volatiles were evaporated and the residue was subjected to preparative HPLC purification yielding 2.7 g (98%) of [4- (1-amino-cyclopropyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo). [3.2.1] oct-6-yl) -methanone as an oil. HPLC-MS (Method Z1): m / z = 313 (M + 1); tr = 1.30 min (100% ELS). H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 0.99-1.03 (m, 5 H), 1.13 (m, 5 H), 1.17-1.5 (m, 3.5 H), 1.58 (d, 1 H), 1.75 (m, 1 H), 2.17 (bs, 2H, NH2), 2.24 (dd, 0.5H), 3.17 (d, 0.5H), 3.28 (t, 1 H), 3.58 (d, 0.5H), 3.99 (t, 0.5H), 4.60 (m, 0.5 H), 7.29-7.33 (m, 2H), 7.37-7.42 (m, 2H).
To a solution of [4- (1-amino-cyclopropyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (150 mg, 0.48) mmol) in DCM (4 mL) was added with stirring TEA (100 μL, 0.72 mmol) followed by benzoyl chloride (61 μL, 0.53 mmol) and the mixture was stirred for 16 h. at room temperature. The mixture was washed with water (3x1 mL), dried (MgSO4) and the residue was evaporated. The residue was purified using preparative HPLC (Method Z4): Isolated amount = 116 mg (58%) of the title compound as an oil.
1 H NMR (400 MHz, CDCl 3) d 0.92 (d, 3 H), 1.00 (s, 3 H), 1 .1 1 (s, 3 H), 1.13-1.44 (m, 5.5 H), 1.57 (m, 1 H), 1.71 (m, 2H), 2.20 (m, 0.5H), 3.11 (d, 0.5H), 3.25 (m, 1 H), 3.55 (d, 1 H), 3.96 (m, 0.5H), 4.58 (m, 0.5 H), 7.09 (t, 2H), 7.28 (dd, 2H), 7.44 (t, 2H), 7.51 (t, 1 H), 7.63 (d, 1 H), 7.90) d, 2H ). HPLC-MS (Method Z1): m / z = 417 (M + 1); tr = 2.0 min (100% ELS).
The following compounds were made as indicated in Method A above. Ex Structure MW Name lUPAC LC / MS -38 411, 59 Piperidine-3-412 carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-azabicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide J-39 370.54 N-Methyl-N- [4- (1, 3,3-tri- 371 methyl-6-aza-bicyclo [3.2.1] - octane-6-carbonyl) - benzyl] -butyramide -40 390.53 N-Methyl-N- [4- (octahydro-391 quinoline-1-carbonyl) -benzyl-benzamide
M1 376.50 N- [4- (3-Aza-bicyclo [3.2.2] - 377 nonane-3-carbonyl) -benzyl] -N-methyl-benzamide
-42 415.54 3-Cyano-N-methyl-N- [4-416 (octahydro-quinoline-1-carbonyl) -benzyl] -benzamide
Example 2-1 (General procedure (B1)) 1.1-Dimethyl-3-methyl-3- [4- (1, 3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzyl-sulfonamide
To a solution of (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (100 mg, 0.33 mmol, Example 1) in DCM (25 mL) was added with stirring TEA (140 μL, 1 mmol) followed by dimethisulfamoyl chloride (54 μL, 0.5 mmol) and the mixture was stirred for 1 h. at room temperature. The mixture was evaporated and the residue was purified using preparative HPLC (Method Z4): Isolated amount = 28 mg (21%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.94 (d, 3 H), 1.03 (d, 3 H), 1.13 (d, 3 H), 1.17-1.61 (m, 4.5 H), 1.77 (m, 1 H), 2.24 ( m, 0.5H), 2.70 (s, 3H), 2.86 (s, 6H), 3.16 (d, 0.5H), 3.26 (m, 1 H), 3.60 (d, 0.5H), 3.97 (t, 0.5 H) ), 4.34 (d, 2H), 4.61 (m, 0.5H), 7.38 (m, 2H), 7.44 (t, 2H). HPLC-MS (Method Z1): m / z = 408 (M + 1); tr = 1.98 min (100% ELS).
Example 2-2 (General procedure (B1)) N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.11octane-6-carbonyl) -benzyl-methanesulfonamide
The title compound was prepared by a procedure as described in Example 33, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6) -yl) -metanone and methanesulfonyl chloride. HPLC-MS (Method Z1): m / z = 379 (M + 1); tr = 1.8 min (100% ELS).
Example 2-3 (General procedure (B1)) 2.2.2-Trifluoro-ethanesulfonic acid methyl- [4- (1,3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonip-benzyl-amide
The title compound was prepared by a procedure as described in Example 33, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6) -yl) -metanone and 2,2,2-trifluoro-ethanesulfonyl chloride. HPLC-MS (Method Z1): m / z = 447 (M + 1); tr = 2.09 min.
Example 2-4 (General procedure (B1)) N-Methylphenyl-N-f4- (1, 3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzyl-methanesulfonamide
The title compound was prepared by a procedure as described in Example 33, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6) -yl) -metanone and benzylsulfonyl chloride. HPLC-MS (Method Z1): m / z = 455 (M + 1); tr = 2.17 min.
The following compounds were made as indicated in the general procedure (B2) above.
Example 2-5 (General procedure (B2)) Trifluoro-N-isopropyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl) -benzyl-methanesulfonamide
Stage A: 4- (Tetrahydro-pyran-2-yloxymethyl) -benzoic acid
To a solution cooled with ice water of 4-hydroxymethyl-benzoic acid methyl ester
(6.0 g, 36.11 mmol) and 3,4-dihydro-2H-pyran (16.47 mL, 180.53 mmol) in DCM (125 mL) was added p-toluenesulfonic acid monohydrate (69 mg, 0.36 mmol). The mixture was stirred for 4 h. at room temperature. The solvent was evaporated to yield (~ 9 g) crude 4- (tetrahydro-pyran-2-yloxymethyl) -benzoic acid methyl ester (LC / MS: 272 [M + 23]) as an oil.
To a solution of the ester (~ 9 g) in EtOH (50 mL) was added 1 N NaOH (55 mL) and the mixture was stirred for 16 h. at room temperature. The volatiles were evaporated and the aqueous phase was washed with
Et20 (50 mL). The pH of the aqueous phase was adjusted to 3 by the addition of 1 N HCl. The precipitate was extracted with Et20 (2 x 50 mL), dried (Na2SO4) and evaporated to yield 6 g (71%) of 4- (tetrahydro-pyran-2-yloxymethyl) -benzoic acid as a solid. 1 H NMR (400 MHz, CDCl 3) d 1.55-1.92 (m, 6H), 3.55 (m, 1 H), 3.91 (t, 1 H), 4.59 (d, 1 H), 4.74 (t, 1 H), 4.87 (d, 1 H), 7.48 (d, 2H), 8.09 (d, 2H). HPLC-MS (Method Z1): m / z = 259 (M + 23); tr = 1.42 min.
Step B: (4-Hydroxymethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone
To a solution of the above benzoic acid (6.0 g, 25.40 mmol) in dry THF (100 mL) was added with stirring HOBt (3.8 g, 27.93 mmol) followed by EDAC (5.36 g, 27.93 mmol) and the mixture was stirred for 30 minutes. min. at room temperature. To the resulting mixture was added 1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane, hydrochloride (5.3 g, 27.93 mmol) and DIPEA (9.29 mL, 53.33 mmol). The reaction mixture was stirred for 16 h. at room temperature. The solvent was evaporated and water (100 mL) was added to the residue. The mixture was extracted with Et20 (3x35 mL) and the combined organic phases were dried (MgSO4) and the solvent was evaporated yielding the crude amide which was dissolved in MeOH (100 mL). To this mixture was added p-toluenesulfonic acid (1). g) and the mixture was stirred for 2 h at room temperature. The solvent was evaporated and the residue was purified using silica gel column chromatography (Flash 40) using first as a mixture of EtOAc-Heptane (1: 2) (500 mL) followed by EtOAc-Heptane 2: 1 as eluents. The pure fractions were collected, evaporated to a volume of 1/10 and the precipitate was filtered and washed with an Et20 (20 mL) which produced after drying 5.2 g (71%) of (4-hydroxymethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone as a solid. TLC (EtOAc-Heptane) 2: 1 Rf: 0.2.
H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.02 (d, 3 H), 1.12 (s, 3 H), 1.14-1.60 (m, 5 H), 1.75 (m, 1 H), 2.23 (m , 0.5H), 2.54 (bs, 1 H), 3.19 (q, 0.5H), 3.26 (d, 0.5H), 3.59 (d, 0.5H), 3.96 (t, 0.5 H), 4.60 (m, 0.5 H), 4.69 (d, 2H), 7.34-7.40 (m, 4H). HPLC-MS (Method Z1): m / z = 288 (M + 1); tr = 1.81 min.
Step C: [4- (l-Propylamino-methyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone
To a solution cooled with ice water of the above benzyl alcohol (500 mg, 1.74 mmol), TEA (0.5 mL, 3.48 mmol) in DCM (40 mL) was added with stirring methanesulfonyl chloride (203 μL, 2.61 mmol) and the mixture it was stirred for 1 h at room temperature. The mixture was washed with water (20 mL), dried (MgSO) and the solvent was evaporated. To the residue dissolved in DCM (20 mL) was added isopropyl amine (800 mL) and the mixture was stirred for 1 h at room temperature followed by evaporation of the solvent. The residue was purified using silica gel column chromatography (Flash 40) and AcOEt as eluent. The pure fractions were collected and evaporated yielding 300 mg (53%) of [4- (isopropylamino-methyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6- il) -metanone as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.92 (d, 3 H), 1.02 (d, 3 H), 1.12 (m, 9 H), 1.18-1.45 (m, 4 H), 1.56 (m, 1 H), 1.75 (m , 1 H), 1.94 (bs, 1 H), 2.24 (dd, 0.5H), 2.87 (m, 1 H), 3.20 (q, 0.5H), 3.27 (dd, 0.5H), 3.57 (d, 0.5 H), 3.82 (d, 2H), 3.97 (d, 0.5H), 4.60 (m, 0.5H), 7.38 (m, 4H). HPLC-MS (Method Z1): m / z = 329 (M + 1); tr = 1.28 min (100% ELS).
Step D: To a solution of the above isopropyl amine (100 mg, 0.304 mmol) in DCM (15 mL) cooled to -50 ° C (dry ice / acetone) was added with stirring TEA (130 μL, 0.913 mmol) followed by trifluoromethanesulfonic anhydride (100 μL, 0.61 mmol) and the mixture was stirred for 30 min. at -50 ° C.
Water (0.2 mL) was added to the mixture, the solvent evaporated and the residue was purified using
Preparative HPLC (Method Z4): Isolated amount = 65 mg (46%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.03 (d, 3 H), 1.13 (bs, 9 H), 1.16-1.61 (m, 4.5 H), 1.77 (m,
1 H), 2.24 (dd, 0.5H), 3.18 (q, 1 H), 3.28 (d, 0.5H), 3.60 (d, 0.5H), 3.94 (t, 0.5 H), 4.25 (m, 1 H ), 4.31- 4.85 (bs, 2H), 4.62 (m, 0.5H), 7.45 (m, 4H).
HPLC-MS (Method Z1): m / z = 461 (M + 1); tr = 2.50 min (100% ELS).
Example 2-6 (General procedure (B2)) N-Cyclopropyl-trifluoro-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl) -benzin-methanesulfonamide
The title compound was prepared by a procedure as described in Example 46, starting from (4-cyclopropylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6) -yl) -metanone and trifluoro-methanesulfonic anhydride. HPLC-MS (Method Z1): m / z = 459 (M + 1); tr = 2.45 min.
Example 2-7 (General procedure (B2)) N-Ethyl-trifluoro-N-r4- (1.3.3-trimethyl-6-aza-bicyclo3.2.1-octane-6-carbonyl) -benzyl-methanesulfonamide
The title compound was prepared by a procedure as described in Example 46, starting from (4-ethylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6) -yl) -metanone and trifluoro-methanesulfonic anhydride. HPLC-MS (Method Z1): m / z = 447 (M + 1); tr = 2.43 min (100% ELS).
EXAMPLE 2-8 (General procedure (B2)) Trifluoro-N-methyl-N-4 - (1,3,3-trimethyl-6-aza-bicyclo3.2.noctane-6-carbonyl) -benzyl-methanesulfonamide
The title compound was prepared by a procedure as described in Example 46, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6) -yl) -metanone and trifluoro-methanesulfonic anhydride. HPLC-MS (Method Z1): m / z = 433 (M + 1); tr = 2.35 min.
The following compounds were made as indicated in General Methods B1 and B2 above.
Example 3-1 (General procedure (C)) 3-Benzoyl-1-methyl-1-r4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1 loctane-6-carbonyl) -benzyl-urea
To a solution of (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (70 mg, 0.23 mmol, Example 1) in DCM (20 mL) was added benzoyl isocyanate (51 mg, 0.35 mmol) and the mixture was stirred for 16 h. at room temperature. The mixture was evaporated and the residue was purified on silica gel column chromatography (Flash 40) using first a mixture of AcOEt-Heptane (1: 1) as eluent followed by pure AcOEt. The pure fractions were collected and evaporated which yielded 45 mg (43%) of the title compound. 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.03 (s, 3 H), 1.13 (s, 3 H), 1.16-1.60 (m, 4.5 H), 1.76 (m, 1 H), 2.23 ( m, 0.5H), 2.99 (bs, 3H), 3.16 (d, 0.5H), 3.26 (m, 1 H), 3.58 (d, 0.5H), 3.96 (m, 0.5 H), 4.61 (m, 0.5 H), 4.64 (s, 2H), 7.42 (m, 6H), 7.55 (t, 1 H), 7.89 (m, 2H), 8.66 (bs, 1 H).
HPLC-MS (Method Z1): m / z = 448 (M + 1); tr = 1.85 min (100% ELS).
Example 3-2 (General procedure (C)) 3-Cyclohexyl-1-methyl-1-f4- (1, 3,3-trimethyl-6-aza-biciclof3.2.1loctane-6-carbonyl) -benzyl-urea
The title compound was prepared by a similar procedure as described in Example 37, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -methanone and isocyanato-cyclohexane. HPLC-MS (Method Z1): m / z = 426 (M + 1); tr = 2.06 min.
Example 3-3 (General procedure (C))
3- (4-Methyl-benzenesulfonyl) -1-methyl-1 - [4- (1,3,3-trimethyl-6-aza-bicyclof3.2.1-octane-6-carbonyl-benzyl-urea)
The title compound was prepared by a similar procedure as described in Example 37, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -methanone and 4-methyl-benzenesulfonyl isocyanate. HPLC-MS (Method Z1): m / z = 499 (M + 1); tr = 2.02 min.
Example 3-4 (General procedure (C)) 3- (2,3-Dihydro-1,4-benzodioxin-2-ylmethyl) -1-methyl-1 - [4- (1,3,3-trimethyl-6-aza-bicyclo [3.2.noctane-6-carbonyl) -bencill-urea
Step A: 1-Methyl-3-. { methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamoyl} -3H-imidazol-1-ium, iodide
To a solution of (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (1.1 g, 3.66 mmol, Example 1) in DCM (40 mL) was added CDI (0.9 g, 5.49 mmol) and the mixture was stirred for 16 h. at room temperature. The mixture was washed with water (25 mL), dried (Na2SO4) and evaporated. To the residue dissolved in MeCN (40 mL) was added methyl iodide (2.5 mL,
36. 61 mmol) and the resulting mixture was stirred for 16 h. at room temperature. The solvent was evaporated yielding 2 g (-100%) of 1-methyl-3-. { methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamoyl} -3H-imidazol-1-ium, iodide.
Step B: To a solution of 2,3-dihydro-benzo [1,4] dioxin-2-yl-methylamine (22 mg, 0.134 mmol) in a mixture of DCM (2 mL) and TEA (16 μL, 0.134 mmol ) a solution of the above imidazolium salt (60 mg, 0.112 mmol) in DCM (2 mL) was added. The mixture was stirred for 16 h. at room temperature and the solvent was evaporated. The residue was purified using preparative HPLC (Method Z4): Isolated amount = 50 mg (91%) of the title compound as a solid. H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.02 (s, 3 H), 1.12 (s, 3 H), 1.16-1.60 (m, 4.5 H), 1.76 (m, 1 H), 2.23 ( m, 0.5H), 2.88 (s, 3H), 2.97 (bs, 1 H), 3.14 (d, 0.5H), 3.25 (t, 1 H), 3.53 (m, 0.5H), 3.59 (d, 0.5 H), 3.68 (m, 0.5H), 3.97 (m, 2H), 4.30 (d, 2H), 4.53 (d, 2H), 4.60 (m, 0.5H), 4.96 (t, 0.5H), 6.85 ( m, 4H), 7.27 (m, 2H), 7.41 (t, 2H).
HPLC-MS (Method Z1): m / z = 493 (M + 1); tr = 2.10 min (100% ELS).
Example 3-5 (General procedure (C)) 3- (3-Methoxy-benzyl) -1-methyl-1-r4- (1.3.3-trimethyl-6-aza-bicyclof3.2.noctane-6-carbonyl) -bencip-urea
The title compound was prepared by a similar procedure as described in Example 40, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 3-methoxy-benzylamine. HPLC-MS (Method Z1): m / z = 465 (M + 1); tr = 2.02 min (100% ELS).
Example 3-6 (General procedure (C)) 3- (1,1-Dioxo-tetrahydro-thiophen-3-yl) -1-methyl-1-f4- (1, 3,3-trimethyl-6-aza- biciclof3.2.1loctane-6-carbonyl) - benzyl-urea
The title compound was prepared by a similar procedure as described in Example 40, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 1,1-dioxo-tetrahydro-thiophen-3-ylamine. HPLC-MS (Method Z1): m / z = 463 (M + 1); tr = 1.63 min (100% ELS).
Example 3-7 (General procedure (C)) 1-Methyl-3- (tetrahydro-pyran-4-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1 octane-6-carbonyl) -benzin-urea
The title compound was prepared by a similar procedure as described in Example 40, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and tetrahydro-pyran-4-yl-ami? A. HPLC-MS (Method Z1): m / z = 429 (M + 1); tr = 1.69 min (100% ELS).
Example 3-8 (General procedure (C)) Methyl ester of (1,3-Dimethyl-3-r4- (1, 3,3-trimethyl-6-aza-bicichlor3.2.noctane-6-carbonylbenzyl) methyl ester -ureidol-acetic
The title compound was prepared by a similar procedure as described in Example 40, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -methanone and methylamino-acetic acid methyl ester HPLC-MS (Method Z1): m / z = 431 (M + 1); tr = 1.85 min (100% ELS).
Example 3-9 (General procedure (C)) 1-Methyl-3- (5-trifluoromethyl-1, 3,4-thiadiazol-2-yl) -1-r4- (1,3,3-trimethyl-6-aza- biciclor3.2.1loctano-6-carboniD-bencill-urea
The title compound was prepared by a similar procedure as described in Example 40, starting from (4-methylaminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone and 5-trifluoromethyl- [1, 3,4] thiadiazol-2-ylamine. HPLC-MS (Method Z1): m / z = 497 (M + 1); tr = 2.19 min (100% ELS).
The following compounds were made as indicated in General Method C above.
Example 4-1 (General procedure (E))
1-Methyl-3-r4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.11octane-6-carbonyl) -benzyl-imidazolidin-2-one)
Step A: (2-Hydroxy-ethyl) - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ester te / t-butyl ester carbamic
To a solution of tert-butyl ester of acid [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamic acid (1.7 g, 4.4 mmol, Example 1) in DMF (50 mL) was added with hydride hydride. sodium (211 mg, 8.8 mmol, 60% in mineral oil) and the mixture was stirred for 15 min. at room temperature. To the resulting mixture was added (2-bromo-ethoxymethyl) -benzene (1.1 mL, 5.28 mmol). The reaction mixture was stirred for 16 h. at room temperature and warmed by the addition of saturated aqueous ammonium chloride (50 mL) followed by water (50 mL). The mixture was extracted with Et20 (2x100 mL) and the combined organic phases were washed with saturated aqueous ammonium chloride (2x100 mL), dried (Na2SO4) and the solvent was evaporated. The residue was purified using silica gel column chromatography (Flash 40) yielding 1.4 g of (2-benzyloxy-ethyl) - [4- (1, 3,3-trimethyl-6-aza-) butyl butyl ester. bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamic acid as an oil. HPLC-MS (Method Z1): m / z = 521 (M + 1); tr = 2.67 min.
To the above benzyl ether (1.4 g, 2.69 mmol) dissolved in EtOH (50 mL) was added 10% Pd / C (750 mg, 50% water) and the resulting mixture was hydrogenated at 1 atm. up to 1 eq. of H2 was used. The mixture was filtered and the solvent was evaporated yielding 0.9 g (47%) of ferric acid-2-butyl ester.
hydroxy-ethyl) - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -carbamic acid as a solid. 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.03 (d, 3 H), 1 .13 (d, 3 H), 1.17-1.79 (m, 15 H), 2.23 (m,
0. 5H), 3.15 (m, 0.5H), 3.26 (m, 0.5H), 3.41 (bs, 3H), 3.59 (d, 0.5H), 3.71 (m, 2H), 3.97 (t, 0.5H),
4. 50 (m, 2H), 4.61 (m, 0.5H), 7.27 (m, 2H), 7.42 (t, 2H). HPLC-MS (Method Z1): m / z = 431 (M + 1); tr = 1.99 min.
Stage B:. { 4 - [(2-Methylamino-ethylamino) -methyl] -phenyl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -metanone
To a solution cooled in ice water of the above fe / 1-butyl ester (300 mg, 0.696 mmol), TEA (0.3 mL, 2.3 mmol) in DCM (40 mL) was added with stirring methanesulfonyl chloride (135 μL, 1.72 mmol ) and the mixture was stirred for 1 h at room temperature. Methylamine (5 mL, 33% in EtOH) was added and the mixture was stirred for 16 h at room temperature. The solvent was evaporated and water (50 m) and AcOEt (50 mL) were added to the residue. The organic phase was separated and evaporated and to the residue was added DCM (20 mL) followed by TFA (10 mL). The resulting mixture was stirred for 4 h at room temperature and the solvent was evaporated. The residue was purified using preparative HPLC HPLC (Method Z4): Isolated amount = 175 mg (44%) of. { 4 - [(2-methylamino-ethylamino) -methyl] -phenyl} - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.02 (d, 3 H), 1.12 (d, 3 H), 1.15-1.46 (m, 3 H), 1.56 (m, 1 H), 1.75 (m , 1 H), 2.16 (d, 0.5H), 2.25 (m, 0.5H), 2.42 (s, 3H), 2.74 (m, 4H), 3.15-3.29 (m, 1.5H), 3.60 (d, 0.5 H), 3.82 (d, 2H), 3.98 (m, 0.5 H), 4.60 (m, 0.5H), 7.38 (m, 4H). HPLC-MS (Method Z1): m / z = 344 (M + 1); tr = 1.09 min.
Step C: To a solution of the above amide (50 mg, 0.146 mmol) in DCM (10 mL) was added phosgene (0.1 mL, 0.29 mmol, 30% in toluene) and the mixture was stirred for 30 min. at room temperature. The solvent was evaporated and the residue was purified using preparative HPLC (Method Z4): Isolated amount = 11 mg (21%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.02 (d, 3 H), 1.13 (d, 3 H), 1.15-1.60 (m, 4.5 H), 1.75 (m, 1.5 H), 2.23 ( m, 0.5H), 2.84 (s, 3H), 3.16 (m, 2H), 3.28 (m, 3H), 3.58 (d, 0.5H), 3.97 (t, 0.5 H), 4.39 (d, 2H), 4.60 (m, 0.5H), 7.29 (dd, 2H), 7.40 (t, 2H). HPLC-MS (Method Z1): m / z = 370 (M + 1); tr = 1.71 min.
The following compound is made as indicated in General Method E above.
Example 5-1 (General procedure (F)) f4- (1,1-Dioxo-isothiazolidin-2-ylmethyl) -phenyl-1- (1,3,3-trimethyl-6-aza-bicyclo3.2.noct-6-yl) -metanone
To a mixture of (4-aminomethyl-phenyl) - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (100 mg, 0.349 mmol), TEA (100 μL, 0.698 mmol) and DCM (20 mL) was added 3-chloro-propane-1-sulfonyl chloride (51 μL, 0.419 mmol) and the mixture was stirred for 2 h at room temperature. The solvent was evaporated and the residue was dissolved in dry THF (20 mL). Sodium hydride (25 mg, 1.05 mmol, 60% in mineral oil) was added and the mixture was stirred for 90 min. at reflux temperature. The cold mixture was warmed with water (100 μL) and evaporated. The residue was purified using preparative HPLC (Method Z4): Isolated amount = 39 mg (29%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.03 (d, 3 H), 1.13 (d, 3 H), 1.17-1.60 (m, 4.5 H), 1.71-1.79 (m, 2 H), 2.23 (m, 0.5H), 2.32 (m, 2H), 3.09-3.29 (m, 4.5H), 3.60 (d, 0.5H), 3.97 (t, 0.5H), 4.20 (d, 2H), 4.61 (m , 0.5H), 7.38-7.45 (m, 4H). HPLC-MS (Method Z1): m / z = 391 (M + 1); tr = 1.8 min.
Example 6-1 (General procedure (G)) r4-p, 1-Dioxo-2H-1, 2,5-thiadiazolidin-2-ylmethyl) -phenylH1, 3,3-trimethyl-6-aza-bicyclo [3.2. 11oct-6-yl) -metanone
Step A: 1- / ert-Butyloxycarbonyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfamide
To a solution cooled with chilled water of chlorosulfonyl isocyanate (360 μL, 4.19 mmol) in DCM (20 mL) was added te / t-butanol (400 μL, 4.19 mmol) and the mixture was stirred for 30 min. at room temperature. The resulting mixture was added to a solution of (4-aminomethyl-phenyl) - (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone (1.2 g, 4.19 mmol ), TEA (1.7 mL, 12.57 mmol) in DCM (25 mL) at 0 ° C. The mixture was stirred for 2 h allowing it to reach room temperature before it was quenched with water (25 mL), dried (Na2S04) and evaporated which yielded 1.8 g (92%) of 1- / ert-butyloxycarbonyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfamide as an oil 1 H NMR (400 MHz, CDCl 3) d 0.93 (d, 3 H), 1.03 (s, 3 H), 1.12 (s, 3 H), 1.15-1.59 (m, 13.5 H), 1.76 ( m, 1 H), 2.23 (m, 0.5H), 3.13-3.28 (m, 1.5H), 3.58 (d, 0.5H), 3.96 (m, 0.5 H), 4.11 (s, 2H), 4.59 (m , 0.5H), 5.75 (bs, 1 H), 7.39 (m, 4H), 9.0 (bs, 1 H). HPLC-MS (Method Z1): m / z = 466 (M + 1); tr = 1.98 min.
Stage B: 1, 1-Dioxo-5- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -1,2-butyl ester. 2,5-thiadiazolidine-2-carboxylic acid
To a mixture of 1-fe? F-butyloxycarbonyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfamide (0.8 g , 1.72 mmol), 2-chloro-ethanol (130 μL, 1.89 mmol), triphenylphosphine (0.7 g, 2.58 mmol) in THF (50 mL) was added DIAD (0.5 mL, 2.58 mmol) and the mixture was stirred for 1 h . The solvent was evaporated and the residue was purified using silica gel column chromatography
(Flash 40) and a mixture of AcOEt-Heptane (1: 1) as eluent produced 1-fery-butyloxycarbonyl-1- (2-hydroxyethyl) -3- [4- (1, 3,3-trimethyl-6- crude aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfamide which was used in the next step is further purification.
HPLC-MS (Method Z1): m / z = 528 (M + 1).
To a solution of 1-te f-butyloxycarbonyl-1- (2-hydroxyethyl) -3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) ) -benzyl] -sulfamide in DMSO (15 mL) was added K2C03 (0.36 g, 2.58 mmol) and the mixture was stirred for 2 at room temperature. Water (25 mL) was added and the resulting mixture was extracted with AcOEt (2x25 mL). The combined organic phases were evaporated and the residue was purified using silica gel column chromatography (Flash 40) and first a mixture of AcOEt-Heptane (1: 1) followed by a mixture of AcOEt-Heptane (4: 1) as eluents yielded 250 mg (30%) of 1,1-dioxo-5- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl ferf-butyl ester. ) -benzyl] -1, 2,5-thiadiazolidine-2-carboxylic acid as an oil. HPLC-MS (Method Z1): m / z = 492 (M + 1); tr = 2.24 min (100% ELS).
Step C: [4- (1, 1-Dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct -6-il) -metanone
To a solution of 1, 1-dioxo-5- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] tert-butyl ester. 1, 2,5-thiadiazolidine-2-carboxylic acid (0.25 g, 0.51 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixture was stirred for 16 at room temperature. The mixture was evaporated and the residue was purified using preparative HPLC (Method Z4): Isolated amount = 190 mg (95%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.94 (d, 3 H), 1.04 (s, 3 H), 1.13 (s, 3 H), 1.18-1.60 (m, 4.5 H), 1.77 (m, 1 H), 2.23 ( m, 0.5H), 3.15-3.30 (m, 3.5H), 3.44 (t, 2H), 3.60 (d, 0.5H), 3.97 (t, 0.5 H), 4.18 (m, 2H), 4.61 (m, 0.5H), 5.01 (bs, 1 H), 7.43 (m, 4H). HPLC-MS (Method Z1): m / z = 392 (M + 1); tr = 1.73 min (100% ELS).
Example 6-2 (General procedure (G)) r 4 - (5-Methyl-1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenylH 1, 3,3-trimethyl-6-aza -bicyclo [3.2.1loct-6-yl] -metanone
To a mixture of [4- (1, 1-dioxo-2 / - / - 1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [ 3.2.1] oct-6-yl) -methanone (60 mg, 0.15 mmol), K2C03 (30 mg, 0.31 mmol) in DMSO (4 mL) was added iodomethane (13 μL, 0.31 mmol). The mixture was stirred for 1 h at room temperature and evaporated. The residue was purified using preparative HPLC (Method Z4): Isolated amount = 45 mg (73%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3) d 0.94 (d, 3 H), 1.04 (s, 3 H), 1.13 (s, 3 H), 1.18-1.61 (m, 4.5 H), 1.77 (m, 1 H), 2.23 ( m, 0.5H), 2.79 (s, 3H), 3.15-3.20 (m, 2H), 3.23-3.30 (m, 3.5H), 3.61 (d, 0.5H), 3.98 (t, 0.5 H), 4.24 ( d, 2H), 4.61 (m, 0.5H), 7.42 (m, 4H). HPLC-MS (Method Z1): m / z = 406 (M + 1); tr = 1.86 min (100% ELS).
The following compounds were made as indicated in the General Method G above.
PHARMACOLOGICAL METHODS
Enzyme test 11 ßHSD1
Materials Beds for the scintillation proximity test coated with 3H-cortisone and Ig anti-rabbit (SPA) were purchased from Amersham Pharmacia Biotech, ß-NADPH was from Sigma and the rabbit anti-cortisol antibodies were Fitzgerald. A yeast extract transformed with h-11 ßHSD1 (Hult ef al., FEBS Lett., 44., 25 (1998)) was used as the enzyme source. The test compounds were dissolved in DMSO (10 mM). All dilutions were performed in a stabilizer containing 50 mM TRIS-HCI (Sigma Chemical Co), 4 mM EDTA (Sigma Chemical
Co), 0.1% BSA (Sigma Chemical Co), 0.01% Tween-20 (Sigma Chemical Co) and 0.005% bacitracin (Novo Nordisk A / S), pH = 7.4. The 96-well Optiplate 96 plates were supplied by Packard. The amount of 3H-cortisol bound to the SPA beds was measured in TopCount NXT, Packard.
Methods H-11 ßHSD1, 120 nM 3H-cortisone, 4 mM ß-NADPH, antibody (1: 200), serial dilutions of the test compound and SPA particles (2 mg / well) were added to the wells. The reaction was inhibited by mixing the different components and allowed to proceed under stirring for 60 min at 30 ° C. The reaction was stopped by the addition of 10 times the excess of the stop stabilizer containing 500 μM of carbenoxolone and 1 μM of cortisone. The data was analyzed using the GraphPad Prism program.
Table 1 Inhibition of 11 ßHSD1 by the compounds of the invention
While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions may be made therein without departing from the scope and spirit of the present invention. Also, the specific pharmacological responses observed may vary in accordance with and depending on the particular active compound selected or if pharmaceutical carriers are present, as well as the type of formulation and the mode of administration employed and said expected variations or differences in the results are contemplated of
conformity with the objects and practices of the present invention. Accordingly, the invention is not limited as by the subsequent claims.
The features described in the preceding description and / or the claims can both separately and in any combination thereof be material for carrying out the invention in various forms thereof.
Preferred features of the invention: 1. A novel substituted amide or prodrug thereof or a salt thereof with a pharmaceutically acceptable base or acid or any optional isomer or mixture of optical isomers, including a racemic mixture of any tautomeric form, wherein the compound is of formula I:
I wherein: R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R10R11NC (= Y) -, and R10R11NS (O) n-; R2 is selected from H, CrC6 alkyl and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 10-12 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from C?-C8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6-spirochetocycloalkyl members, aryl, hetaryl, alkyl aryl
C6-hetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, C-C-alkyloxy, C-C6-alkyl-oxy-aryl, C-C6-alkyloxy-C6-alkyl, C-C6-alkyloxy-C-rCj alkyl,
C 1 -C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, C 1 -C 6 aryl alkylcarboxy, and C C 6 alkylcarboxy hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R 18; ring A is a saturated or partially saturated bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from C 8 alkyl, halo, OH, oxo, cyano, alkyloxy
C6-C6alkyloxyalkyl-C6alkyl or C-C6alkylcarbonyl, wherein each alkyl group is substituted with 0-3R; R5 is selected from H, C-C-alkyl, C3-C6-cycloalkyl, halo, OH, and cyano; R6 and R7 are independently selected from H, C, C, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a partially saturated or saturated monocyclic ring of 3-8 members consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 selected from nitrogen , oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, alkyl
C Cß, oxo, and C 1 -C 6 alkyloxy; R8 is selected from CrC8 alkyl, C2-C8 alkenyl, aryl, hetaryl, alkyl
aryl, C -Cß alkyl hetaryl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, C6 alkyl aryloxy, C?-C6heteroyloxy alkyl, C alqu-C - alkyl, C6 alkyloxy C C alkyloxy, and C C-Cqualkyloxy C-Cehetaryl alkyl, wherein each one of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R 9; R9 is selected from C-C8 alkyl, C2-C8 alkenyl, aryl, hetaryl, alkyl OpCβ aryl, alkyl C- | -C6 hetaryl, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, CrC6-alkyloxy alkyl, and alkyl Ci-Cβ C6 alkyloxy aryl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R20; R10 and R11 are independently selected from H, C8 alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, C -C aryl alkyl, and C6hetarylCalkyl,
wherein each alkyl / alkyl, cycloalkyl, hetcycloalkyl, aryl, and hetaryl group are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from alkyl Ci-Ca, aryl, hetaryl, alkyl CrC6 aryl, alkyl C6 hetaryl, hydroxy, oxo, COOH, C 1-6 alkyloxy, C 1-6 alkyloxy aryl, C 1-6 alkyloxy hetaryl, C 1-6 alkyloxy C 1-6 alkyloxy, C 1-6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, C 1-6 alkylcarbonyl aryl, alkylcarbonyl CrCß hetaryl, alkylcarboxy C Ce, arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6 aryl, and C-C6 alkylcarboxy hetaryl; R 12 is selected from OH, C 8 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered cycloalkyl, trihalomethyl, CrC 8 alkyloxy, aryl, CrC 6 alkyl aryl, hetaryl, CrC 6 heteroaryl, aryloxy, hetaryloxy, and NR 13 R 14; R13 and R14 are independently selected from H, CrC8 alkyl, cycloalkyl
C3-C 0, aryl, hetaryl, alkyl CrC6aryl, and alkyl CrC6hetaryl, wherein each alkyl / alkyl, cycloalkyl, aryl, and hetaryl group are independently substituted with 0-3 R22; alternatively, R13 and R14, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, aryl, hetaryl, CrC6aryl alkyl, CrC6 alkyl, hetaryl, OH, oxo, CrC6 alkyloxy, alkyloxy
CrC6 aryl, CrC6hexaryl alkyloxy, CrC6alkyloxyC6Calkyl, CrC6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, C6C aryl alkylcarbonyl, CrC6hetarylcarbonyl, CrC6 alkylcarboxy, arylcarboxy, hetarylcarboxy, CrC6arylcarboxy, and C-C6hearylcarboxyl; R15 is selected from H, CrC6 alkyl, and C3-C6 cycloalkyl; R16 and R17 are independently selected from H, C-C8 alkyl, C3-C10 cycloalkyl, halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, alkyl dC-β, aryl, and
hetaryl, wherein the alkyl and cycloalkyl groups are independently substituted with 0-3
R22; R18 is selected from halo, OH, oxo, COOH, cyanoxy d-Cβ alkyloxy, C3-C10 cycloalkyloxy, aryloxy, hetaryloxy, hetarylthio, and d-C-p-alkyloxy; R 9, R 20 and R 21 are independently selected from H, halo, OH, oxo, cyano, alkyl
CrC8, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalo-methylenedioxo, C3-C6-spirocycloalkyl, d-C-alkyloxy, aryl, hetaryl, CrCearyl alkyl, d-C-hesteryl alkyl, -C (= 0 ) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR 3R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, CrC6 alkyl > alkyloxy CrC6, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, CrC8 alkyl, and CrC6aryl alkyl; m is selected from 0, 1 and 2; n is selected from 1 and 2; And it is selected from O and S; or a salt thereof with a pharmaceutically acceptable base or acid, or any isomer or optical mixture of optical isomers including a racemic mixture or any tautomeric form.
2. A compound of clause 1, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O) 2-; R2 is CrC4 alkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 group selected from CrC8 alkyl, aryl, hetaryl, alkyl CrC6aryl, alkyl CrC6hetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, alkyloxy d-Cß. CrC6aryl alkyloxy, CrC6heteroyl alkyloxy, C6alkyloxy alkyloxy CrC6, alkylcarboxy CrC6, arylcarboxy,
hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy CrC6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R; ring A is a bicyclic or tricyclic saturated or partially saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from CrC 4 alkyl, halo, OH, oxo, cyano, CrC alkyloxy, CrC 4 alkyl, CrC 4 alkyloxy or C 1 alkylcarbonyl, wherein each alkyl / alkyl group is substituted with 0-1 R; R5 is H; R6 and R7 are independently selected from H and CrC4 alkyl; and, n is 23. A compound of Clause 1, wherein: R8 is selected from CrC6 alkyl, C-C6 alkenyl, aryl, hetaryl, alkyl dC aryl, alkyl CrC hetaryl, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, CrC4-alkyloxy alkyl , and CrC4heteroyloxy alkyl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-2 R19; R9 is selected from d-Cß alkyl, C2-C6 alkenyl, aryl, hetaryl, alkyl Crdaryl, alkyl
Heteroyl CrC4, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, and CrC aryloxy alkyl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-2 R; R10 and R11 are independently selected from H, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, and hetaryl, wherein each of the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are independently substituted with 0-3 R21; alternatively, R 0 and R 11, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected of nitrogen, oxygen, and S (0) m, where this ring is substituted with 0-2 groups selected from
C8 alkyl, aryl, hetaryl, hydroxy, oxo, COOH, CrC6 alkyloxy, CrC6aryl alkyloxy, CrC6heteroyl alkyloxy, and CrC6 alkylcarbonyl; R 12 is selected from OH, CrC alkyl, C 3 -C 6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, CrC 4 alkyloxy, aryl, C 4 alkyl aryl, hetaryl, CrC 4 heteroaryl, aryloxy, and hetaryloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, CrC6 alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, C4 alkyloxy, aryl, hetaryl, alkyl Crdaryl, alkyl d-dhetaryl, -C (= 0) R12, -S (0) nR12, and -S (0) nNR13R14; and, n is 2.
4. A compound of clause 1, where the compound is of the formula:
. A compound of clause 1, wherein the compound is of the formula Ib:
6. A compound of clause 1, where the compound is of the formula le:
you
7. A compound of clause 1, where the compound is of the formula Id:
Id
8. A compound of clause 1 wherein: R1 and R2, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic or bicyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, spiro-ethycycloalkyl of 3-6 members, aryl, hetaryl, alkyl CrC6aryl, alkyl CrChehetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, - N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, CrC6alkyloxy, arylCrC6alkylaxy, CrC6heteroyl alkyloxy, CrC6alkyloxy CrC6alkyloxy, alkylcarboxy CrC6, arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy CrC6hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18.
9. A compound of clause 1, where: Ring A is selected from
. Ring A is replaced with 0-2 R; and, R25 'is selected from CrC8 alkyl, halo, hydroxy, oxo, cyano, C (= 0) R12, and CrC6 alkyloxy, wherein R12 is as defined above.
. A compound of clause 1 where: Ring A is selected from:
Ring A is replaced with 0-2 R25; and R25 is selected from CrC8 alkyl, halo, hydroxy, oxo, cyano, and CrC6 alkyloxy.
11. A compound of clause 1 where: Ring A is
. , Ring A is replaced with 0-2 R; and, R, 25 is selected from CrC8 alkyl, halo, hydroxy, oxo, cyano, and CrC6 alkyloxy.
12. A compound of clause 1, wherein the compound is selected from the group: N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isobutyramide cyclopentanecarboxylic acid methyl- [4 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide cyclohexanecarboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza -bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -
1-carboxylic acid methyl ester piperidine-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-N- [4 - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide 1-Acetyl-piperidine-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6 -aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide 'cyclopentanecarboxylic acid ethyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6- carbonyl) -benzyl] -amide morpholine-4-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 2, 2-N-Trimethyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -propionamide tetrahydro-furan-3-carboxylic acid methyl - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide N-Methyl-4-trifluoromethoxy-N- [4- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide acid or thiophene-2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide furan-2-carboxylic acid methyl - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3-Chloro-4- (propane-2-sulfonyl) -thiophene -2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 6-Chloro-N-methyl-N- [ 4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -nicotinamide 5-Methyl-isoxazole-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3,3, N-Trimethyl-N- [4- (1, 3,3-trimethyl-6 -aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -butyramide 3-Cyano-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2. 1] octane-6-carbonyl) -benzyl] -benzamide
N-Methyl-2-phenoxy-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide
N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carboyl) -benzyl] -malonamic acid methyl ester 3-Methyl- but-2-enoic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-2-phenyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide 1-Trifluoromethyl-cyclobutanecarboxylic acid methyl- [4- (1, 3,3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3,5-dimethoxy-N-methyl-N- [4- (1,3,3-trimethyl-6- aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide
4-Methanesulfonyl-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-3-trifluoromethoxy -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 2,2-Difluoro-1,3-benzodioxole-4 acid -carboxylic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-6-morpholin-4-yl-N - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -nicotinamide
N-Methyl-4- (2,2,2-trifluoro-acetyl) -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ] -benzamide N- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-N- [4- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isophathalamic acid 2,3-Dihydro-benzofuran-7-carboxylic acid methyl- [4- (1, 3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3-Acetyl-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza -bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide
1, 1, 3-Trimethyl-3- [4- (1, 3,3-trimethyl-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfonylurea N-Methyl-N- [4- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 2,2,2-Trifluoro-ethanesulfonic acid methyl- [4- (1, 3,3- trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide N-Methylphenyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide
Trifluoro-N-isopropyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -
methanesulfonamide N-Cyclopropyl-trifluoro-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide N-Ethyl-trifluoro-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide Trifluoro-N-methyl-N- [4- (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 3-Benzoyl-1-methyl-1- [4- (1, 3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3-Cyclohexyl-1-methyl-1 - [4- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane] -6-carbonyl) -benzyl] -urea 3- (4-methyl-phenyl) sulfonyl-1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1 ] octane-6-carbonyl) -benzyl] -urea 1,3-Dimethyl-3-phenyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6 carbonyl) -benzyl] -urea 3- (2,3-Dihydro-1,4-benzodioxin-2-ylmethyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3-methoxy-benzyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [ 3.2.1] octane-6-carbonyl) -benzyl] -urea
3- (1, 1-Dioxo-tetrahydro-thiophen-3-yl) -1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6- carbonyl) -benzyl] -urea 1-Methyl-3- (tetrahydro-pyran-4-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane- 6-carbonyl) -benzyl] -urea acid methyl ester. { 1,3-Dimethyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -acetic 1-Methyl-3- (5-trifluoromethyl-1, 3,4-thiadiazol-2-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 2-methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic acid 3- methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic acid 1-Methyl-3- (3-ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] -octane-6-carbonyl) -benzyl ]-urea
1-Methyl-3- (4-ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza'-bicyclo- [3.2.1] -octane-6-carbonyl) -benzyl] -urea
3- (4-Benzyloxy-phenyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea
1-Methyl-3- (4-trifluoromethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - urea 3- (4-Acetyl-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3-Acetyl-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ] -urea 3- (3-Cyano-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) - benzyl] -urea 1-Methyl-3- (4-trifluoromethyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl ) -benzyl] -urea 3- (4-methoxy-benzyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-) carbonyl) -benzyl] -urea 1-Methyl-3- (2,2,4,4-tetrafluoro-4H-benzo- [1,3] dioxin-6-yl) -1- [4- (1, 3, 3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4-trifluoromethoxy-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- [4- (2,2,2-trifluoro-acetyl) -cyclohexyl ] -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -be ncil] -urea 1- (4-Acetyl-phenyl) -1,3-dimethyl-3- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-) carbonyl) -benzyl] -urea 1-Phenyl-3-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -urea piperidine-1-carboxylic acid methyl- [4- (octahydro-quinoline-1 -carbonyl) -benzyl] -amide piperidine-1-carboxylic acid [4- (3-aza-bicyclo- [3.2.2] nonane- 3-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid methyl- [4- (octahydro-quinolin-1 -carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (3-aza- bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide 1,3-Dimethyl-3- [4- (octahydro-quinolin-1 -carbonyl) -benzyl] -1-phenyl-urea 1 - [4- (3-Aza-bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (6-aza -bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide piperidine-1-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1 ] octane-3-carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide morpholine-4 acid -carboxylic methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] -amide
1- [4- (6-Aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea 1,3-Dimethyl-1-phenyl-3- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -urea piperidine-1-carboxylic acid [4- (3-hydroxy-8-aza -bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea 1- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea piperidine-1-carboxylic acid [ 4- (3-f luoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide N-Adamantan-2-yl-4- (1,3-dimethyl-3-pyridin-2-yl-ureidomethyl) -benzamide 1 - [ 4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-pyridin-2-yl-urea 1- [4- (3-Hydroxy-8- aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] - 1,3-dimethyl-3-pyridin-2-yl-urea morpholine-4-carboxylic acid [4- (adamantan-2-ylcarbamoyl) -benzyl] -methyl-amide 1- [4- (3-Aza-bicyclo [ 3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-thiazol-2-yl-urea 1,3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -1-thiazol-2-yl-urea 4- [3- (1-Acetyl-piperidin-4-yl) -1, 3-dimethyl-ureidomethyl] - N-adamantan-2-yl-benzamide 1- (1-Acetyl-piperidin-4-yl) -3- [4- (3-aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1 , 3-dimethyl-urea N-Adamantan-2-yl-4- (1,3-dimethyl-3-pyrimidin-2-yl-ureidomethyl) -benzamide 1- [4- (3-Aza-bicyclo [3.2.2 ] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- (1,3-dimethyl-3-thiazol-2-yl -ureidomethyl) -benzamide N-Adamantan-2-yl-4- (1,3-dimethyl-3-phenyl-ureidomethyl) -benzamide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1 ] octane-8-carbonyl) -benzyl] -1, 3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- [3- (4-hydroxy-cyclohexyl) -1, 3-dimethyl-ureidomethyl] -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -3- (4-hydroxy-cyclohexyl) -1,3-dimethyl-urea 1- (4-hydroxy-cyclohexyl) -1, 3-dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -urea 1-Methyl-3- [4- (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -imidazolidin-2-one [4- (1,1-Dioxo-isothiazolidin-2-ylmethyl) -phenyl] - (1) , 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone [4- (1,1-Dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl) -metanone
[4- (5-Methyl-1, 1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl] ) -metanone (Octahydro-quinolin-1-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (4-Aza-tricyclo [4.3.1.13] , 8] -undec-4-yl) - [4- (1, 1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (Octahydro-isoquinolin-2-yl) - [4 - (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (3-Aza-bicyclo [3.2.2] non-3-yl) - [4- (1, 1 -dixo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (6-Aza-bicyclo [3.2.1] oct-6-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone [4- (5-Benzyl-1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone or a salt thereof with a pharmaceutically acceptable acid or base or any isomer or optical mixture of optical isomers including a racemic mixture, or any tautomeric form.
13. The compound according to any of clauses 1-12, which is a useful agent for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.
14. The compound according to clause 13, wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.
. The compound according to clause 13, wherein the conditions, disorders and diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased glucose in fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and adverse effects of treatment or glucocorticoid receptor agonist therapy.
16. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of clauses 1-2 together with one or more pharmaceutically acceptable carriers or excipients.
17. The pharmaceutical composition according to clause 16 which is suitable for oral, nasal, buccal, transdermal, pulmonary or parenteral administration.
18. The use of a substituted amide, a prodrug thereof or a salt thereof with a pharmaceutically acceptable base or acid or any isomer or mixture of optical isomers, including a racemic mixture or any tautomeric form, wherein the substituted amide or a Prodrug of the same is of the formula I:
wherein: R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R10R11NC (= Y) -, and R10R11NS (O) n-; R2 is selected from H, CrC6 alkyl, and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 2-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiro-ethycycloalkyl, aryl , hetaryl, alkyl CrC6aryl, alkyl CrC6hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR 3R14, -N (R13) S (0) nR12, -N (R15) C ( = Y) NR13R14, -C (= NR16) NR17, OH, oxo, CrC6 alkyloxy, CrC6aryl alkyloxy, CrCehetaryl alkyloxy, CrCßalkyloxy CrCei alkyl,
alkylcarboxy CrC6, arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy CrChehetaryl, wherein each alkyl and aryl group / hetaryl group is substituted with 0-3 R18; ring A is a partially saturated or saturated bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from CrC8 alkyl, halo, OH, oxo, cyano, CrC6 alkyloxy, CrC6 alkylCyclo6 alkyloxy or CrC6 alkylcarbonyl, wherein each 18 alkyl group is substituted with 0-3 R; R5 is selected from H, CrC6 alkyl, C3-C6 cycloalkyl, halo, OH, and cyano; R6 and R7 are independently selected from H, CrC6 alkyl, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a saturated or partially saturated 3- to 8-membered monocyclic ring consisting of the carbon atom shown, 2-5 additional carbon atoms, and 0-2 heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, CrC6 alkyl, oxo, and CrC6 alkyloxy; R8 is selected from CrC8 alkyl, C2-C8 alkenyl, aryl, hetaryl, CrCearyl alkyl, alkyl
CrC6hetaryl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, CrC6-aryloxy alkyl, alkyl
CrCßhetaryloxy, CrC6alkyloxy CrC6 alkyl aryl, and CrC6alkyloxy CrC6hetaryl alkyl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R19; R9 is selected from CrC8 alkyl, C2-C8 alkenyl, aryl, hetaryl, CrC6aryl alkyl, CrC6heteroyl alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, CrC6aryloxy alkyl, and aryl CrCßalkyloxy d-Cβ alkyl, wherein each alkyl group / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl are independently substituted with 0-3 R20; R10 and R1 are independently selected from H, CrC8 alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, CrC6aryl alkyl, and CrC6heteroyl alkyl, wherein
each alkyl / alkyl, cycloalkyl, hetcycloalkyl, aryl, and hetaryl group is independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, aryl, hetaryl, CrC6aryl alkyl, CrC6heteroyl, hydroxy, oxo, COOH, CrC6alkyloxy, CrC6aryl alkyloxy, CrC6hearyl alkyloxy, CrC6alkyloxy CrC6alkyl, dicarboxylalkylcarbonyl, arylcarbonyl, hetarylcarbonyl, CrC6arylcarbonyl, CrC6hexylcarbonyl, CrC6 alkylcarboxy, arylocarboxy, hetarylcarboxy, CrC6arylcarboxy, and CrC6 alkylcarboxy hetaryl; R12 is selected from OH, CrC8 alkyl, C3-C10 cycloalkyl 3-10 membered cycloalkyl, trihalomethyl, CrC8 alkyloxy, aryl, CrC6aryl alkyl, hetaryl, CrC6hetaryl alkyl, aryloxy, hetaryloxy, and NR13R14; R13 and R14 are independently selected from H, C8 alkyl, C3-C10 cycloalkyl, aryl, hetaryl, CrC6aryl alkyl, and CrC6hetaryl alkyl, wherein each alkyl / alkyl, cycloalkyl, aryl, and hetaryl group are independently substituted with 0- 3 R22; alternatively, R 3 and R 4, together with the nitrogen to which they are bound, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, aryl, hetaryl, alkyl d-Cßaplo, alkyl CrC6hetaryl, OH, oxo, alkyloxy d- Cß, C 1 -C 6 alkyloxy, C 1-6 alkyloxyaryl, C 1-6 alkyloxy CrC 6, C 1-6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl CrC 6aryl, alkylcarbonyl CrC 6hetaryl, alkylcarboxy CrC 6, arylcarboxy, hetarylcarboxy, alkylcarboxy d-Caryl, and alkylcarboxy CrC 6hetaryl; R 5 is selected from H, CrC 6 alkyl, and C 3 -C 6 cycloalkyl;
R 6 and R 7 are independently selected from H, CrC8 alkyl, C3-C10 cycloalkyl, halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N ( R13) S (0) nR12, C? -C? Alkyl, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are optionally substituted with 0-3 R22; R 8 is selected from halo, OH, oxo, COOH, cyanoxyCiCi 6 > C3-C10alkyloxycycloalkyl aryloxy, hetaryloxy, hetarylthio and CrC6aryl alkyloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, alkyl
C C8, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalomethylenedioxo, C3-C6-spirocycloalkyl, CrC6-alkyloxy, aryl, hetaryl, alkyl d-Cearyl, alkyl CrChehetaryl, -C (= 0) R12 , -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15) C (= Y) NR13R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, CrC6 alkyl, C6 alkyloxy, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, CrC8 alkyl, and CrC6aryl alkyl; m is selected from 0, 1, and 2; n is selected from 1 and 2; And it is selected from O and S; or a salt thereof with a pharmaceutically acceptable base or acid or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric form.
19. Use according to clause 18, wherein: R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R10R11NC (= Y) -, and R10R11NS (O) n-; R2 is selected from H, CrC6 alkyl, and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 2-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from CrC8 alkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl,
alkylene CrCearyl, hetaryl alkylene dd, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R 5) C (= Y ) NR 3 R 14, -C (= NR 6) NR 17, OH, oxo, C 1 -C 7 alkyloxy, C 6 aryloxy alkyloxy, C 1 6 heteroaryl alkyloxy, CrC 6 alkyloxy CrC 6 alkyloxy, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkylcarboxy d-daplo, and alkylcarboxy Crdhetaryl, wherein each aryl / hetaryl group is substituted with 0-3 R18; ring A is a 5-12 member partially saturated or saturated bicyclic or tricyclic ring consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from alkyl d-C8, halo, OH, oxo, cyano, alkyloxy dd, alkylene dd alkyloxy dd or alkylcarbonyl dd, wherein each alkyl / alkylene group is substituted with 0-3 R18; R5 is selected from H, alkyl d-d, C3-C6 cycloalkyl, halo, OH, and cyano; R6 and R7 are independently selected from H, alkyl d-d, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a saturated or partially saturated 3- to 8-membered monocyclic ring consisting of the carbon atom shown, 2-5 additional carbon atoms, and 0-2 heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, alkyl dd, oxo, and alkyloxy dd; R8 is selected from dd alkyl, C2-C8 alkenyl, aryl, hetaryl, CrCearyl alkylene, CrCehetaryl alkylene, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, d-daryloxy alkylene, d-dhetaryloxy alkylene, d-alkynyl d-alkyloxy dd aryl , and C-C6alkyloxy dd hetaryl alkylene, wherein each alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group are independently substituted with 0-3 R19; R9 is selected from dd alkyl, C2-C8 alkenyl, aryl, hetaryl, alkylene d-daryl, alkylene CrC6hetaryl, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, d-C6alkyloxy alkylene, and dyalkyloxy dd aryl alkylene , wherein each alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is substituted with 0-3 R;
R10 and R11 are independently selected from H, d-C8 alkyl, C3-doCycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, d-C6aryl alkylene, and CrC6hetaryl alkylene, wherein each alkyl / alkylene group, cycloalkyl, hetcycloalkyl, aryl, and hetaryl is independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, aryl, hetaryl, alkylene d-daryl, alkylene Crdhetaryl, hydroxy, oxo, COOH alkyloxy d, alkyloxy d-daryl, alkyloxy d-dhetaryl, alkylene dd alkyloxy dd, alkylcarbonyl dd, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl d-daplo, alkylcarbonyl CrChehetyl, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkylcarboxy CrC6aryl, and alkylcarboxy d-dhetaryl; R 2 is selected from OH, d-d alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, d-alkyloxy, aryl, alkylene d-daryl, hetaryl, alkylene CrCheheryl, aryloxy, hetaryloxy, and NR13R14; R13 and R4 are independently selected from H, dd alkyl, C3-C10 cycloalkyl, aryl, hetaryl, alkylene d-daryl, and alkylene CrChehetaryl, wherein each alkyl / alkylene, cycloalkyl, aryl, and hetaryl group is independently substituted with 0-3 R22; alternatively, R13 and R14, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, aryl, hetaryl, alkylene d-daplo, alkylene d-dhetaryl, OH, oxo, alkyloxy dd, alkyloxy d-daplo, alkyloxy d-dhetaryl, alkylene dd alkyloxy dd, d-C6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl d-daplo, alkylcarbonyl d-dhetaryl, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkylcarboxi Crdaryl, and alkylcarboxy d- dhetaril; R15 is selected from H, alkyl d-d, and C3-C6 cycloalkyl;
R16 and R17 are independently selected from H, dd alkyl, C3-C10 cycloalkyl, halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, d-C8alkyl, aryl, and hetaryl, wherein the alkyl and cycloalkyl groups are independently substituted with 0-3 R22;
R18 is selected from halo, OH, oxo, and cyano; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, d-C8 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalo-methylenedioxo, C3-C6 spirocycloalkyl , alkyloxy dd, aryl, hetaryl, alkylene d-daplo, alkylene CrC6hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, - N (R15) C (= Y) NR13R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, d-d alkyl, d-alkyloxy, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, alkyl d-d, and CrC6aryl alkylene; m is selected from 0, 1, and 2; n is selected from 1 and 2; And it is selected from O and S;
. Use according to clause 18, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O) 2-; R2 is alkyl d-d; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from d-C8 alkyl, aryl, hetaryl, alkyl d-daplo, alkyl CrChehetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, d-C6 alkyloxy, alkyloxy d-daryl, alkyloxy Crdhetaryl, alkyl d-dalkyloxy dd, alkylcarboxy dd, arylcarboxi, hetarylcarboxy, alkylcarboxi d-daplo, and alkylcarboxy CrCehetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18;
ring A is a bicyclic or tricyclic partially saturated or saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, OH, oxo, cyano, alkyloxy dd, alkyl C 1-4 alkyloxy or alkylcarbonyl dd, wherein each alkyl / alkyl group is substituted with 0-1 R18; R5 is H; R6 and R7 are independently selected from H and dC4 alkyl; and, n is 2.
21. The use according to clause 19, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O) 2-; R2 is alkyl d-d; alternatively, R and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from alkyl d-C8, aryl, hetaryl, alkylene d-daryl, alkylene d-dhetaryl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, alkyloxy dd, alkyloxy d-daryl, alkyloxy CrChehetaryl, alkyl d-dalkyloxy dd, alkylcarboxy C C6, arylcarboxy, hetarylcarboxy, alkylcarboxy d-daryl, and alkylcarboxy d-dhetaryl, wherein each aryl / hetaryl group is substituted with 0-3 R; ring A is a bicyclic or tricyclic partially saturated or saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from d-C4 alkyl, halo, OH, oxo, cyano, alkyloxy dd, alkylene dC alkyloxy d-C4 or alkylcarbonyl C C4, wherein each alkyl / alkylene group is substituted with group 0-1 R18; R5 is H;
R and R are independently selected from H and d-C4 alkyl; and, n is 2.
22. Use according to clause 18, wherein: R8 is selected from dd alkyl, C2-C6 alkenyl, aryl, hetaryl, d-daryl alkyl, d-dhetaryl alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, d-daryloxy alkyl, and d-dhetaryloxy alkyl, wherein each alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is independently substituted with 0-2 R19; R9 is selected from alkyl dd, C2-C6 alkenyl, aryl, hetaryl, alkyl d-daryl, alkyl Crdhetap'lo, cycloalkyl C3-C6, hetcycloalkyl of 3-6 members, and alkyl d-daryloxy, wherein each alkyl group / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl are independently substituted with 0-2 R; R10 and R11 are independently selected from H, C3-C6 cycloalkyl, hetcycloalkyl
3-6 members, aryl, and hetaryl, wherein each cycloalkyl, hetcycloalkyl, aryl, and hetaryl group are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a monocyclic, saturated or partially saturated ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected of nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from alkyl d-C8, aryl, hetaryl, hydroxy, oxo, COOH, alkyloxy dd, alkyloxy d-daryl, alkyloxy d -dhetaryl, and alkylcarbonyl dd; R12 is selected from OH, d-C4 alkyl, C3-C6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, d-C4 alkyloxy, aryl, alkyl d-daryl, hetaryl, hetaryl alkyl, aryloxy, and hetaryloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, dd alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, d-C4 alkyloxy, aryl, hetaryl , alkyl d-C4 aryl, alkyl dC hetaryl, -C (= 0) R12,
-S (0) nR12, and -S (0) pNR13R14; Y,
n is 2
23. Use according to clause 19, wherein: R8 is selected from dd alkyl, C2-C6 alkenyl, aryl, hetaryl, alkylene dC aryl, alkylene d hetaryl, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, alkylene dC aryloxy, and alkylene d-dhetaryloxy, wherein each alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl group is independently substituted with 0-2 R19; R 9 is selected from dd alkyl, C 2 -C 6 alkenyl, aryl, hetaryl, d -aryl alkylene, d-dhetaryl alkylene, C 3 -C 6 cycloalkyl, 3-6 membered cycloalkyl, and d-C 4 aryloxy alkylene, wherein each group of alkyl / alkylene, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl are independently substituted with 0-2 R; R 0 and R 11 are independently selected from H, C 3 -C 6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, and hetaryl, wherein each cycloalkyl, hetcycloalkyl, aryl, and hetaryl group is independently substituted with 0-3 R 21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a monocyclic, saturated or partially saturated ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected of nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from C 8 alkyl, aryl, hetaryl, hydroxy, oxo, COOH, alkyloxy d, alkyloxy d-daryl, alkyloxy CrCheheryl, and alkylcarbonyl dd; R12 is selected from OH, d-alkyl, C3-C6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, d-alkyloxy, aryl, d-daryl alkylene, hetaryl, d-dhetaryl alkylene, aryloxy, and hetaryloxy; R19, R20 and R2 are independently selected from H, halo, OH, oxo, cyano, dd alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, d-C4 alkyloxy, aryl, hetaryl , alkylene d-daryl, alkylene d-dhetaryl, -C (= 0) R12, -S (0) nR12, and -S (0) nNR13R14; and, n is 2.
24. The use according to clause 18, wherein the substituted amide or prodrug thereof is of the formula:
. Use according to clause 18, wherein the substituted amide or prodrug thereof is of the formula Ib:
Ib 26. The use according to clause 18, wherein the substituted amide or prodrug thereof is of the formula le:
27. The use according to clause 18, wherein the substituted amide or prodrug thereof is of the formula Id:
28. The use according to clause 18, wherein the substituted amide or prodrug thereof is of the formula le:
29. Use according to clause 18, wherein: R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated 5- to 12-membered monocyclic or bicyclic ring consisting of the nitrogen shown, 4-10 carbon atoms and 0-2 additional heteroatoms selected from nitrogen, oxygen and S (0) m, wherein this ring is substituted with 0-3 groups selected from alkyl dd, cycloalkyl d-C10, heterocycloalkyl C3-C10 , C3-C6-Spirocycloalkyl, 3-6-membered Spiro-Ethylcycloalkyl, Aryl, Hetaryl, C6-Alkylaryl, Crystalline alkyl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N ( R13) S (0) nR12, -N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, alkyloxy dd, alkyloxy d-daryl, alkyloxy d-dhetaryl, alkyl dd alkyloxy dd, alkylcarboxid-d, arylcarboxy, hetarylcarboxy, alkylcarboxy d-daryl, and alkylcarboxy d hetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18.
. Use according to clause 19, wherein: R1 and R2, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic or bicyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms carbon and 0-2 additional heteroatoms selected from nitrogen, oxygen and S (0) m, wherein this ring is substituted with 0-3 groups selected from dd alkyl, C3-C6 spirocycloalkyl, 3-6 membered spiroethycycloalkyl, aryl, hetaryl , alkylene d-daryl, d-C6hetaryl alkylene, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R3) S (0) nR12, -N (R15) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, alkyloxy dd, alkyloxy dd aryl, alkyloxy d-dhetaryl, alkyl
d-dalkyloxid-d alkylcarboxy d-d, arylcarboxy, hetarylcarboxy, alkylcarboxy d-daplo, and alkylcarboxy d-dhetaryl, wherein each aryl / hetaryl group is substituted with 0-3 R18.
31. Use in accordance with any of clauses 18-30, where: Ring A is selected from:
Ring A is replaced with 0-2 R 25.; and R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, C (= 0) R12, and alkyloxy d-d, wherein R12 is as defined above.
32. Use in accordance with any of clauses 18-30, where: Ring A is selected from:
Ring A is replaced with 0-2 R 325; and R25 is selected from alkyl d-d, halo, hydroxy, oxo, cyano, and alkyloxy d-d-
33. Use in accordance with any of clauses 18-30, where: Ring A is selected from:
Ring A is replaced with 0-2 R25; R is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and alkyloxy d-d-
34. Use according to clause 18 or 19, wherein the substituted amide or a prodrug thereof is selected from the group of clause 12.
. The use according to any of clauses 18-34, for the preparation of a pharmaceutical composition for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.
36. Use according to clause 35, wherein the conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.
37. Use according to clause 35, wherein the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased glucose in fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of the glucocorticoid receptor agonist.
38. The use according to any of clauses 18-37, wherein the pharmaceutical composition is appropriate for a route of administration selected from oral, nasal, buccal, transdermal, pulmonary and parenteral.
39. A method for the treatment of conditions, disorders or diseases, wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound in accordance with any of clauses 1-12.
40. The method according to clause 39, wherein conditions, disorders and diseases are influenced by intracellular glucocorticoid levels.
41. The method of conformance to clause 39, wherein conditions, disorders or diseases are selected from the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), decreased glucose in fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of the glucocorticoid receptor agonist.
42. The method according to any one of clauses 40-41, wherein the administration is via a selected route of oral, nasal, buccal, transdermal, pulmonary and parenteral.
Claims (26)
1. A compound of the formula I: I wherein: R1 is selected from H, R8 (C = 0) -, R9S (0) n-, R10R11NC (= Y) -, and R10R11NS (O) n-; R2 is selected from H, alkyl d-d and C3-C6 cycloalkyl; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring of 3-12 members consisting of the nitrogen shown, 10-12 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, C3-C10 cycloalkyl, C3-C10 hetcycloalkyl, C3-C6 spirocycloalkyl, 3-6 membered spiro-ethycycloalkyl , aryl, hetaryl, alkyl dd aryl, alkyl dd hetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, -N (R15 ) C (= Y) NR13R14, -C (= NR16) NR17, OH, oxo, alkyloxy dd, alkyloxy dd aryl, alkyloxy dd hetaryl, alkyl dd alkyloxy dd, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkyl carboxy dd aryl, and alkylcarboxy CrChehetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18; ring A is a saturated or partially saturated bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from alkyl d-d, halo, OH, oxo, cyano, dyalkyloxy d, d-dalkyloxy d-d alkylcarbonyl d-d, wherein each alkyl group is substituted with 0-3 R18; R5 is selected from H, alkyl d-d, C3-C6 cycloalkyl, halo, OH, and cyano; R6 and R7 are independently selected from H, alkyl d-d, F, trihalomethyl, and trihalomethoxy; alternatively, R6 and R7, together with the carbon atom to which they are attached, form a partially saturated or saturated monocyclic ring of 3-8 members consisting of the carbon atom shown, 2-5 additional carbon atoms and 0-2 selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from halo, trihalomethyl, OH, alkyl dd, oxo, and alkyloxy dd; R8 is selected from dd alkyl, C2-C8 alkenyl, aryl, hetaryl, alkyl dd aryl, alkyl dd hetaryl, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, alkyl dd aryloxy, d-dhetaryloxy alkyl, dyalkyloxy alkyl d- daryl, and alkyl d-dalkyloxy d-dhetaryl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R19; R9 is selected from dd alkyl, C2-C8 alkenyl, aryl, hetaryl, alkyl dd aryl, alkyl dd hetaryl, C3-C10 cycloalkyl, 3-10 membered cycloalkyl, alkyl d-daryloxy, and alkyl dd alkyloxy dd aryl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-3 R; R10 and R11 are independently selected from H, d-C8 alkyl, d-C10 cycloalkyl, 3-10 membered hetcycloalkyl, aryl, hetaryl, alkyl dd aryl, and alkyl d-dhetaryl, wherein each alkyl / alkyl, cycloalkyl group , hetcycloalkyl, aryl, and hetaryl are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen atom shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from d-C8 alkyl, aryl, hetaryl, alkyl dd aryl, alkyl dd hetaryl, hydroxy, oxo, COOH , alkyloxy d, alkyloxy dd aryl, alkyloxy dd hetaryl, alkyl dd alkyloxy d-C6, alkylcarbonyl dd, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl dd aryl, alkylcarbonyl dd hetaryl, alkylcarboxy d-d, arylcarboxy, hetarylcarboxy, alkylcarboxy d-d aryl, and alkylcarboxy d-d hetaryl; R 12 is selected from OH, d-d alkyl, C 3 -C 0 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, CrC 8 alkyloxy, aryl, alkyl d-d aryl, hetaryl, alkyl d-dhetaryl, aryloxy, hetaryloxy, and NR 13 R 14; R13 and R14 are independently selected from H, d-C8 alkyl, C3-C10 cycloalkyl, aryl, hetaryl, alkyl d-daryl, and alkyl CrC6hetaryl, wherein each alkyl / alkyl, cycloalkyl, aryl, and hetaryl group are independently substituted with 0-3 R22; alternatively, R13 and R14, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic, bicyclic or tricyclic ring of 5-12 members consisting of the nitrogen shown, 4-10 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-3 groups selected from alkyl dd, aryl, hetaryl, alkyl d-daryl, alkyl dd hetaryl, OH, oxo, alkyloxy dd, alkyloxy d) aryl, alkyloxy d-dhetaryl, alkyl dd alkyloxy dd, alkylcarbonyl dd, arylcarbonyl, hetarylcarbonyl, alkylcarbonyl dd aplo, alkylcarbonyl d-dhetaryl, alkylcarboxy dd, arylcarboxy, hetarylcarboxy, alkylcarboxy d-daryl, and alkylcarboxy d-C6hetaryl; R15 is selected from H, alkyl d-d, and C3-C6 cycloalkyl; R16 and R17 are independently selected from H, alkyl d-d, C3-C10 cycloalkyl > halo, OH, cyano, -C (= 0) R12, -S (0) nR12, -S (0) nNR13R14, -N (R13) S (0) nR12, alkyl d-C8, aryl, and hetaryl, in wherein the alkyl and cycloalkyl groups are independently substituted with 0-3 R22; R18 is selected from halo, OH, oxo, COOH, cyanoxy d-d alkyloxy, C3-C10 cycloalkyloxy, aryloxy, hetaryloxy, hetarylthio and CrCearyl alkyloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, dd alkyl, C3-C10 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, methylenedioxo, dihalo-methylenedioxo, spirocycloalkyl-d, alkyloxy dd , aryl, hetaryl, alkyl d-daryl, alkyl CrCehetaryl, -C (= 0) R12, -S (0) nR12, -S (0) nNR 3R14, -N (R 3) S (0) nR12, -N (R15) C (= Y) NR13R14, and -C (= NR16) NR17; R22 is selected from H, OH, oxo, halo, cyano, nitro, d-d alkyl, d-alkyloxy, NR23R24, methylenedioxo, dihalomethylenedioxo, trihalomethyl, and trihalomethyloxy; R23 and R24 are independently selected from H, alkyl d-d, and alkyl d-daryl; m is selected from 0, 1 and 2; n is selected from 1 and 2; And it is selected from O and S; or a salt thereof with a pharmaceutically acceptable base or acid, or any isomer or optical mixture of optical isomers including a racemic mixture or any tautomeric form.
2. A compound according to claim 1, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R10R11NS (O) 2-; R2 is alkyl d-d; alternatively, R1 and R2, together with the nitrogen to which they are attached, form a 5-6 membered saturated ring consisting of the nitrogen shown, 2-4 carbon atoms, and 0-2 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 group selected from d-C8 alkyl, aryl, hetaryl, CrCearyl alkyl, d-dhetaryl alkyl, -C (= 0) R12, -S (0) nR12, -S (= 0) nNR13R14, -N (R13) S (0) nR12, OH, oxo, alkyloxy dd, alkyloxy CrCearyl, alkyloxy d-dhetaryl, alkyl C d alkyloxy dd, alkylcarboxy dd, arylcarboxi, hetarylcarboxy, alkylcarboxy d- daryl, and alkylcarboxy d-dhetaryl, wherein each alkyl and aryl / hetaryl group is substituted with 0-3 R18; ring A is a bicyclic or tricyclic saturated or partially saturated ring of 8-11 members consisting of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m; ring A is substituted with 0-3 groups selected from alkyl d-d, halo, OH, oxo, cyano, alkyloxy d-d, alkyl d-d alkyloxy d-d or alkylcarbonyl d-d, wherein each alkyl / alkyl group is substituted with 0-1 R 8; R5 is H;
R6 and R7 are independently selected from H and C C alkyl; and, n is 23. A compound according to claim 1, wherein: R1 is selected from R8 (C = 0) -, R9S (0) 2-, R10R11NC (= O) -, and R 0R11NS (O) 2-; R2 is selected from H, d-C4 alkyl and C3-C6 cycloalkyl; ring A is a partially saturated or saturated bicyclic or tricyclic ring of 8-11 members of the nitrogen shown, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen and S (0) m; Ring A is substituted with 0-3 alkyl, halo, OH, oxo, cyano, alkyloxy dd, alkyloxy d-C4 alkyl d-C4 or alkylcarbonyl dd groups, wherein each alkyl / alkyl group is substituted with 0- 1 R18; R5 is H; R6 and R7 are independently selected from H and alkyl d-dalkyl; and n is 2.
4. A compound according to claim 1, wherein: R8 is selected from dd alkyl, C2-C6 alkenyl, aryl, hetaryl, alkyl d-C4aryl, alkyl d-dhetaryl, C3-C6 cycloalkyl, 3-6 membered cycloalkyl, alkyl d-daryloxy, and d-dhetaryloxy alkyl, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-2 R19; R9 is selected from alkyl dd, C2-C6 alkenyl, aryl, hetaryl, alkyl dC aryl, alkyl dd hetaryl, cycloalkyl C3-C6, hetcycloalkyl of 3-6 members, and alkyl d-daryloxy, wherein each of the alkyl / alkyl, alkenyl, aryl, hetaryl, cycloalkyl, and hetcycloalkyl groups are independently substituted with 0-2 R20; R10 and R11 are independently selected from H, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, aryl, and hetaryl, wherein each of the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are independently substituted with 0-3 R21; alternatively, R10 and R11, together with the nitrogen to which they are attached, form a partially saturated or saturated monocyclic ring of 5-6 members consisting of the nitrogen atom shown, 4-5 carbon atoms, and 0-1 additional heteroatoms selected from nitrogen, oxygen, and S (0) m, wherein this ring is substituted with 0-2 groups selected from alkyl dd, aryl, hetaryl, hydroxy, oxo, COOH, alkyloxy dd, alkyloxy d-daryl, alkyloxy d-dhetaryl, and alkylcarbonyl d-C6; R12 is selected from OH, C4 alkyl, C3-C6 cycloalkyl, 3-10 membered hetcycloalkyl, trihalomethyl, d-C alkyloxy, aryl, d-C4 alkyl aryl, hetaryl, d-dhetaryl alkyl, aryloxy, and hetaryloxy; R19, R20 and R21 are independently selected from H, halo, OH, oxo, cyano, dd alkyl, C3-C6 cycloalkyl, 3-6 membered hetcycloalkyl, trihalomethyl, trihalomethyloxy, dihalo-methylenedioxo, alkyloxy dd, aryl, hetaryl, alkyl d-daryl, alkyl d-dhetaryl, -C (= 0) R12, -S (0) nR12, and -S (0) nNR13R14; and, n is 2.
5. A compound according to claim 1, wherein the compound is of the formula la:
6. A compound according to claim 1, wherein the compound is of the formula Ib: Ib
7. A compound according to claim 1, wherein the compound is of the formula le:
8. A compound according to claim 1, wherein the compound is of the formula Id: Id
9. A compound according to claim 1, wherein the compound is of the formula le: you
10. A compound according to claim 1, wherein: Ring A is selected from Ring A is replaced with 0-2 R > 25; and, R25 is selected from alkyl d-d, halo, hydroxy, oxo, cyano, C (= 0) R12, and alkyloxy d-d, wherein R12 is as defined above.
11. A compound according to claim 1, wherein: Ring A is Ring A is replaced with 0-2 R 325.; and, R25 is selected from d-C8 alkyl, halo, hydroxy, oxo, cyano, and alkyloxy d-d.
12. A compound according to claim 1, wherein the compound is selected from the group: N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-) carbonyl) -benzyl] -acetamide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isobutyramide cyclopentanecarboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide cyclohexanecarboxylic acid methyl- [4- (1, 3,3-trimethyl-6 -aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide piperidine-1-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- (1,3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 1-Acetyl-piperidine-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6 -aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide cyclopentanecarboxylic acid ethyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl ) -benzyl] -amide morpholine-4-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 2.2 -N-Trimethyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -propionamide tetrahydro-furan-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide N-Methyl-4-trifluoromethoxy-N- [4- (1, 3, 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide thiophene acid 2-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide furan-2-carboxylic acid methyl- [4- ( 1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3-Chloro-4- (propane-2-sulfonyl) -thiophene-2-carboxylic acid methyl - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 6-Chloro-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -nicotinamide 5-Methyl-isoxazole-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl -6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl-amide 3,3, N-Trimethyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2 .1] octane-6-carbonyl) -benzyl] -butyramide 3-Cyano-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6 carbonyl) -benzyl] -benzamide N-Methyl-2-phenoxy-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide N-Methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -malonamic acid methyl ester 3-Methyl-but- 2-enoic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-2-phenyl-N- [4 - (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -acetamide 1-Trifluoromethyl-cyclobutanecarboxylic acid methyl- [4- (1, 3,3-trimethyl -6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3,5-dimethoxy-N-methyl-N- [4- (1,3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 4-Methanesulfonyl-N-methyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-Methyl-3-trifluoromethoxy -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 2,2-Difluoro-1,3-benzodioxole-4 acid -carboxylic methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methyl-6-morpholin-4-yl-N - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -nicotinamide N-Methyl-4- (2,2,2-trifluoro-acetyl) -N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ] -benzamide N- [4- (1, 3, 3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide N-methyl-N- [4- ( 1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -isophathalamic acid 2,3-Dihydro-benzofuran-7-carboxylic acid methyl- [4- (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide 3-Acetyl-N-methyl-N- [4- (1, 3,3-trimethyl-6- aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -benzamide 1, 1, 3-Trimethyl-3- [4- (1,3,3-trimethyl-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -sulfonylurea N-Methyl-N- [4- (1 , 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 2,2,2-Trifluoro-ethanesulfonic acid methyl- [4- (1, 3,3- trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N-Methylphenyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1 ] octane-6-carbonyl) -benzyl] -methanesulfonamide Trifluoro-N-isopropyl-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - methanesulfonamide N-Cyclopropyl-trifluoro-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide N-Ethyl-trifluoro-N- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide Trifluoro-N-methyl-N- [4- (1, 3.3 -trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -methanesulfonamide 3-Benzoyl-1-methyl-1- [4- (1, 3,3-trimethyl-6-aza- bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3-Cyclohexyl-1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane] -6-carbonyl) -benzyl] -urea 3- (4-methyl-phenyl) sulfonyl-1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1 ] octane-6-carbonyl) -benzyl] -urea 1,3-Dimethyl-3-phenyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1-octane-6-carbonyl] -benzyl] -urea 3- (2,3-Dihydro-1,4-benzodioxin-2-ylmethyl) -1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2 .1] octane-6-carbonyl) -benzyl] -urea 3- (3-methoxy-benzyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2. 1] octane-6-carbonyl) -benzyl] -urea 3- (1, 1-Dioxo-tetrahydro-thiophen-3-yl) -1-methyl-1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6- carbonyl) -benzyl] -urea 1-Methyl-3- (tetrahydro-pyran-4-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane- 6-carbonyl) -benzyl] -urea acid methyl ester. { 1,3-Dimethyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -acetic 1-Methyl-3- (5-trifluoromethyl-1, 3,4-thiadiazol-2-yl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 2-methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic acid 3- methyl ester. { 3-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -ureido} -benzoic acid 1-Methyl-3- (3-ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] -octane-6-carbonyl) -benzyl ]-urea 1-Methyl-3- (4-ethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] -octane-6-carbonyl) -benzyl] - urea 3- (4-Benzyloxy-phenyl) -1-methyl-1 - [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4-trifluoromethylsulfanyl-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] - urea 3- (4-Acetyl-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 3- (3-Acetyl-phenyl) -1-methyl-1 - [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl ] -urea 3- (3-Cyano-phenyl) -1-methyl-1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) - benzyl] -urea 1-Methyl-3- (4-trifluoromethyl-phenyl) -1- [4- (1,3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl] ) -benzyl] -urea 3- (4-methoxy-benzyl) -1-methyl-1 - [4- (1,3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-) carbonyl) -benzyl] -urea 1 -Methyl-3- (2,2,4,4-tetrafluoro-4H-benzo- [1, 3] dioxin-6-yl) -1 - [4- (1, 3, 3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- (4-trifluoromethoxy-phenyl) -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -urea 1-Methyl-3- [4- (2,2,2-trifluoro-acetyl) -cyclohexyl ] -1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl] ) -benzyl] -urea 1- (4-Acetyl-phenyl) -1, 3-dimethyl-3- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -urea 1-Phenyl-3-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -urea piperid i na-1-carboxylic acid methyl- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -amide piperidine-1-carboxylic acid [4- (3-aza-bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid methyl- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (3- aza-bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide 1,3-Dimethyl-3- [4- (octahydro-quinolin-1-carbonyl) -benzyl] -1-phenyl- urea 1- [4- (3-Aza-bicyclo- [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (6 -aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide piperidine-1-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2 .1] octane-3-carbonyl) -benzyl] -amide morpholine-4-carboxylic acid [4- (6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -methyl-amide morpholine acid 4-carboxylic acid methyl- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] -amide 1- [4- (6-Aza-bicyclo- [3.2.1] octane-6-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea 1,3-Dimethyl-1-phenyl-3- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -urea piperidine-1-carboxylic acid [4- (3-hydroxy-8-aza -bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea 1- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-di-methyl-3-phenyl-urea piperidine-1-carboxylic acid [ 4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-fluoro-8-aza-bicyclo [ 3.2.1] octane-8-carbonyl) -benzyl] -methyl-amide N-Adamantan-2-yl-4- (1,3-dimethyl-3-pyridin-2-yl-ureidomethyl) -benzamide 1 - [4 - (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-pyridin-2-yl-urea 1- [4- (3-Hydroxy-8-aza -bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1 , 3-dimethyl-3-pyridin-2-yl-urea morpholine-4-carboxylic acid [4- (adamantan-2-ylcarbamoyl) -benzyl] -methyl-amide 1- [4- (3-Aza-bicyclo [3.2 .2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-thiazol-2-yl-urea 1,3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [ 2.2.1] heptane-5-carbonyl) -benzyl] -1-thiazol-2-yl-urea 4- [3- (1-Acetyl-piperidin-4-yl) -1, 3-dimethyl-ureidomethyl] -N -adamantan-2-yl-benzamide 1- (1-Acetyl-piperidin-4-yl) -3- [4- (3-aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1, 3-dimethyl-urea N-Adamantan-2-yl-4- (1,3-dimethyl-3-pyrimidin-2-yl-ureidomethyl) -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -1,3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- (1,3-dimethyl-3-thiazole-2-yl- ureidomethyl) -benzamide N-Adamantan-2-yl-4- (1,3-dimethyl-3-phenyl-ureidomethyl) -benzamide 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane -8-carbonyl) -benzyl] -1,3-dimethyl-3-pyrimidin-2-yl-urea N-Adamantan-2-yl-4- [3- (4-hydroxy-cyclohexyl) -1,3-dimethyl -ureidomethyl] -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl ] -3- (4-hydroxy-cyclohexyl) -1,3-dimethyl-urea 1- (4-hydroxy-cyclohexyl) -1,3-dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -urea 1-Methyl-3- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -imidazolidin-2-one [4- (1,1-dioxo-isothiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct- 6-yl) -metanone [4- (1, 1-Dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6) -il) -metanone [4- (5-Methyl-1, 1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3,3-trimethyl-bicyclo [3.2.1] oct-6-yl] ) -metanone (Octahydro-quinolin-1-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (4-Aza-tricyclo [4.3.1.13] , 8] -undec-4-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (Octahydro-isoquinolin-2-yl) - [4 - (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (3-Aza-bicyclo [3.2.2] non-3-yl) - [4- (1, 1 -dixo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone (6-Aza-bicyclo [3.2.1] oct-6-yl) - [4- (1,1-dioxo-1, 2,5-thiadiazolidin-2-ylmethyl) -phenyl] -methanone [4- (5-Benzyl-1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] - (1, 3 , 3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone or a salt thereof with a pharmaceutically acceptable acid or base or any isomer or optical mixture of optical isomers including a racemic mixture, or any tautomeric form.
13. A compound according to claim 1, wherein the compound is selected from the group [4- (1-Amino-cyclopropyl) -phenyl] - (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -methanone piperidine-3-carboxylic acid methyl- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -benzyl] -amide N -Methyl-N- [4- (1, 3,3-tri-methyl-6-aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -butyramide N-Methyl-N- [4- (Octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3-Aza-bicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -N-methyl-benzamide 3-Cyano- N-methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3-Azabicyclo [3.2.2] -nonano-3-carbonyl] -benzyl] - 3-cyano-N-methyl-benzamide 3-Fluoro-N-methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3-Aza-bicyclo [ 3.2.2] -nonano-3-carbonyl) -benzyl] -3-fluoro-N-methyl-benzamide N- [4- (Azepano-1 -carbonyl) -benzyl] -3-fluoro-N-methyl-benzamide N - [4- (Azepano-1-carbonyl) -benzyl] -N-methyl-benzamide N- [4- (Azepane-1-carbonyl) -benzyl] -3-cyano-N-me til-benzamide piperidine-1-carboxylic acid [4- (azepane-1-carbonyl) -benzyl] -methyl-amide Morpholine-4-carboxylic acid [4- (azepane-1-carbonyl) -benzyl] -methyl-amide N- [4- (Octahydro-quinoline-1-carbonyl) -benzyl] -benzamide N- [4- (3- Azabicyclo [3.2.2] -nonano-3-carbonyl) -benzyl] -benzamide N- [4- (Azepano-1-carbonyl) -benzyl] -benzamide N- [4- (6-Aza-bicyclo [3.2.1 ] -octane-6-carbonyl) -benzyl] -N-methyl-benzamide 4 - [(Benzoyl-methyl-amino) -methyl] -N- (3-hydroxy-adamantan-1-yl) -benzamide N- [4 - (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -3-cyano-N-methyl-benzamide 4 - [(3-cyano-benzoyl-methyl-amino) -methyl] - N- (3-hydroxy-adamantan-1-yl) -benzamide N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -3-fluoro-N-methyl- benzamide 4 - [(3-Fluoro-benzoyl-methyl-amino) -methyl] -N- (3-hydroxy-adamantan-1-yl) -benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [4- ( Octahydro-quinoline-1-carbonyl) -benzyl] -amide N- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 3- Fluoro-N-methyl-N- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -benzamide 3-Fluoro-N- [4- (3-hydro xi-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide N-Methyl-N- [4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] -benzamide N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -benzamide N- [4- (1, 8,8-Trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl] -benzamide N- [4- (3-Hydroxy-8-aza-bicyclo [ 3.2.1] octane-8-carbonyl) -benzyl] -benzamide 1-Acetyl-piperidine-4-carboxylic acid [4- (azepane-1-carbonyl) -benzyl] -methyl-amide 4- (Benzoylamino-methyl) - N- (3-hydroxy-adamantan-1-yl) -benzamide 3-Cyano-N-methyl-N- [4- (1,8,8-trimethyl-3-aza-bi-cyclo [3.2.1] octane-3-carbonyl) -benzyl] -benzamide 3-Cyano-N- [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 3-Fluoro-N- [4- (3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 4- (3-Fluoro-benzoylamino-methyl) -N-methyl-N- (3-fluoro-adamantan-1-yl) -benzamide 4- (3-cyano-benzoylamino-methyl) -N-methyl-N- (3-fluoro-adamantan-1-yl) - benzamide 1-Acetyl-piperidine-4-carboxylic acid methyl- [ 4- (1, 8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl) -benzyl-amide N- [4- (3-Fluoro-8-aza-bicyclo [3.2.1 ] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 4 - [(Benzoyl-methyl-amino) -methyl] -N- (3-fluoro-adamantan-1-yl) -benzamide 3-Cyano-N- [4- (3-hydroxy-8-aza-bicyclo [3.2 .1] octane-8-carbonyl) -benzyl] -N-methyl-benzamide 4- (Benzoylamino-methyl) -N- (3-fluoro-adamantan-1-yl) -benzamide acid 1-Acetyl-piperidine-4- carboxylic [4- (3-aza-bicyclo [3.2.2] nonane-3-carbonyl) -benzyl] -methyl-amide N- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane- 8-carbonyl) -benzyl] -benzamide 4- (3-Cyano-benzoylamino-methyl) -N- (adamantan-2-yl) -benzamide 4- (3-Fluoro-benzoylamino-methyl) -N- (adamantan-2) -yl) -benzamide N- [4- (4-Azatricyclo- [4.3.1.1 * 3,8 *] undecane-4-carbonyl) -benzyl] -3-fluoro-N-methyl-benzamide N-. { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide N-. { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -acetamide 4-methanesulfonyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide N-Methyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide N-Methyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -acetamide 4-methanesulfonyl-N-methyl-N-. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzamide N- [4- (Azepano-1-carbonyl) -benzyl] -N-methyl-methanesulfonamide N- [4- (3-Aza-bicyclo [3.2.2] -nonano-3-carbonyl) -benzyl ] -N-methyl-methanesulfonamide N-Methyl-N- [4- (1, 8,8-tri-methyl-3-aza-bicyclo [3.2.1] -octane-3-carbonyl) -benzyl] - methane-sulfonamide N- [4- (6-Aza-bicyclo [3.2.1] -octane-6-carbonyl) -benzyl] -N-methyl-methanesulfonamide N- [4- (3-Hydroxy-8-aza -bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-methanesulfonamide N-Methyl-N- [4- (octahydro-quinoline-1-carbonyl) -benzyl] -methanesulfon-amide N- ( 3-Hydroxy-adamantan-1-yl) -4 - [(methanesulfonyl-methyl-amino) -methyl] -benzamide N- (3-Fluoro-adamantan-1-yl) -4 - [(methanesulfonyl-methyl-amino) -methyl] -benzamide N- [4- (3-Fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -N-methyl-methanesulfonamide N-Adamantan-2-yl-4- [(methanesulfonyl-methyl-amino) -methyl] -benzamide N- (4-. {1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl] ) -phenyl] -cyclopropylsulfamoyl.} - phenyl) -acetamide 4-Chlorine-N-. { 1- [4- (1, 3,3-tri-methyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -benzene-sulfonamide 1-Methyl-1 H-imidazole-4-sulfonic acid. { 1- [4- (1, 3,3-trimethyl-6-aza-bicyclo- [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -amide, N-. { 1- [4- (1, 3,3-Trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl) -phenyl] -cyclopropyl} -etanosulfonamide 1- [4- (Azepane-1-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea piperidine-1-carboxylic acid [4- (3-hydroxy-adamantan-1-yl-carbamoyl ) -benzyl] -methyl-amide morpholine-4-carboxylic acid [4- (3-hydroxy-adamantan-1-yl-carbamoyl) -benzyl] -methyl-amide 4- (1,3-Dimethyl-3-phenyl-) ureidomethyl) -N- (3-hydroxy-adamantan-1-yl) -benzamide piperidine-1-carboxylic acid [4- (3-fluoro-adamantan-1-yl-carbamoyl) -benzyl] -methyl-amide morpholine- 4-carboxylic acid [4- (3-fluoro-adamantan-1-yl-carbamoyl) -benzyl] -methyl-amide 4- (1,3-dimethyl-3-phenyl-ureidomethyl) -N- (3-fluoro-adamantan) -1-yl) -benzamide N-Adamantan-2-yl-4- (1,3-dimethyl-3-pyridin-2-yl-ureidomethyl) -benzamide 1,3-Dimethyl-3- [4- (2- oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -1-pyridin-2-yl-urea 1- [4- (3-Hydroxy-8-aza-bicyclo [3.2.1 ] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-thiazol-2-yl-urea 1- (1-Acetyl-piperidin-4-yl) -1,3-dimethyl-3- [4 - (2-oxa-5-aza-bicyclo [2.2.1] heptane-5-carbonyl) -benzyl] -urea 1- (1-Acetyl-piperidin-4-yl) -3- [4- (3-hydroxy-8-aza-bicyclo [3.2.1] -octane-8-carbonyl) -benzyl] -1,3-dimethyl -urea 1, 3-Dimethyl-3- [4- (2-oxa-5-aza-bicyclo [2.2.1 -heptane-5-carbonyl] -benzyl] -1-pyrimidin-2-yl-urea morpholine-4-acid carboxylic [4- (4-aza-tricyclo [4.3.1.1 * 3,8 *] - undecane-4-carbonyl) -benzyl] -methyl-amide 1- [4- (3-Hydroxy-8-aza-bicyclo [ 3.2.1] octane-8-carbonyl) -benzyl] -3- (4-hydroxy-cyclohexyl) -1, 3-dimethyl-urea 1- [4- (3-Aza-bicyclo [3.2.2] nonane-3 -carbonyl) -benzyl] -3- (4-fluoro-cyclohexyl) -1, 3-dimethyl-urea N-Adamantan-2-yl-4- [3- (1-cyclopropyl-piperidin-4-yl) -1 , 3-dimethyl-ureidomethyl] -benzamide 1- [4- (3-Methoxy-8-aza-bicyclo [3.2.1] octane-8-carbonyl) -benzyl] -1,3-dimethyl-3-phenyl-urea N-Adamantan-2-yl-4- [3- (4-fluoro-phenyl) -2-oxo-imidazolidin-1-ylmethyl] -benzamide 1- [4- (3-Aza-bicyclo [3.2.2] nonane -3-carbonyl) -benzyl] -3- (4-fluoro-phenyl) -imidazolidin-2-one 1- (4-Fluoro-phenyl) -3- [4- (3-hydroxy-8-aza-bicyclo [ 3.2.1] octane-8-carbonyl) -benzyl] -imidazolidin-2-one N-Adamantan-2-yl-4- (2-oxo-3-phenyl-imidazolidin-1-ylmethyl) -benzamide N-Adamantan-1-yl-4- (1,1-dioxo- [1, 2, 5 ] thiadiazolidin-2-ylmethyl) -benzamide N-Adamantan-2-yl-4- (1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -benzamide (4-Azatricyclo [4.3.1.1 * 3,8 *] - undec-4-yl) - [4- (1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] -methanone Azepan-1-yl- [4- (1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -phenyl] -methanone Azepan-1-yl- [4- (5-methyl-1,1-dioxo- [1, 2, 5] thiadiazolidin-2-ylmethyl) -phenyl] -methanone N-Adamantan-1-yl-4- (5-methoxymethyl-1,1-dioxo- [1, 2,5] thiadiazolidin-2-ylmethyl) -benzamide 4 - (1,1-Dioxo- [1,2,5] thiadiazolidin-2-ylmethyl) -N- (3-hydroxy-adamantan-1-yl) -benzamide acid methyl ester. { 5- [4- (Adamantan-1-yl-carbamoyl) -benzyl] -1,1-dioxo- [1, 2,5] thiadiazolidin-2-yl} -acetic or a salt thereof with a pharmaceutically acceptable acid or base or any optical isomer or mixture of optical isomers including a racemic mixture or any tautomeric form.
14. The compound according to any of claims 1-13, which is a useful agent for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.
15. The compound according to claim 14, wherein the conditions, disorders and diseases are influenced by the intracellular glucocorticoid levels.
16. The compound according to claim 14, wherein the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased glucose in fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of the glucocorticoid receptor agonist.
17. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any of claims 1-13 together with one or more pharmaceutically acceptable carriers or excipients.
18. The pharmaceutical composition according to claim 17, which is suitable for oral, nasal, buccal, transdermal, pulmonary or parenteral administration.
19. The use of a compound according to any of claims 1-13, for the preparation of a pharmaceutical composition for the treatment of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11βHSD1 is beneficial.
20. The use according to claim 19, wherein the conditions, disease disorders are influenced by intracellular glucocorticoid levels.
21. The use according to claim 19, wherein the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased glucose in fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of the glucocorticoid receptor agonist.
22. The use according to any of claims 19-21, wherein the pharmaceutical composition is appropriate for a route of administration selected from oral, nasal, buccal, transdermal, pulmonary and parenteral.
23. A method for the treatment of conditions, disorders or diseases wherein a modulation or inhibition of the activity of 11βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to any of claims 1-13.
24. The method according to claim 23, wherein the conditions, disorders and diseases are influenced by the intracellular glucocorticoid levels.
25. The method according to claim 23, wherein the conditions, disorders or diseases are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, decreased glucose tolerance (IGT), decreased glucose in fasting (IFG), progression of IGT to type 2 diabetes, progress of the metabolic syndrome in type 2 diabetes, late diabetic complications, neurodegenerative and psychiatric disorders and the adverse effects of treatment or therapy of the glucocorticoid receptor agonist.
26. The method according to any of claims 23-25, wherein the administration is via a selected route of oral, nasal, buccal, transdermal, pulmonary and parenteral.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05110228.3 | 2005-11-01 | ||
EP06116808.4 | 2006-07-07 |
Publications (1)
Publication Number | Publication Date |
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MX2008005322A true MX2008005322A (en) | 2008-09-26 |
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