MXPA01009308A - Amide derivatives - Google Patents
Amide derivativesInfo
- Publication number
- MXPA01009308A MXPA01009308A MXPA/A/2001/009308A MXPA01009308A MXPA01009308A MX PA01009308 A MXPA01009308 A MX PA01009308A MX PA01009308 A MXPA01009308 A MX PA01009308A MX PA01009308 A MXPA01009308 A MX PA01009308A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- alkylamino
- alkoxy
- amino
- alkanoylamino
- Prior art date
Links
- 150000001408 amides Chemical class 0.000 title claims abstract description 53
- -1 cyano, mercapto, nitro, amino, carboxy Chemical group 0.000 claims abstract description 1137
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 203
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 98
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 83
- 239000011780 sodium chloride Substances 0.000 claims abstract description 70
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 150000002148 esters Chemical class 0.000 claims abstract description 44
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 38
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 34
- 125000003118 aryl group Chemical group 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 102000004127 Cytokines Human genes 0.000 claims abstract description 20
- 108090000695 Cytokines Proteins 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 125000001769 aryl amino group Chemical group 0.000 claims abstract description 14
- 230000001404 mediated Effects 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract 7
- 150000001875 compounds Chemical class 0.000 claims description 140
- 125000001424 substituent group Chemical group 0.000 claims description 111
- 229910052757 nitrogen Inorganic materials 0.000 claims description 64
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 39
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- 125000001153 fluoro group Chemical group F* 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 35
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 31
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 31
- 150000002367 halogens Chemical group 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 29
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 28
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 24
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 22
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 22
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 21
- 125000005122 aminoalkylamino group Chemical group 0.000 claims description 21
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 18
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 125000001589 carboacyl group Chemical group 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
- 125000001544 thienyl group Chemical group 0.000 claims description 15
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 125000001246 bromo group Chemical group Br* 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 239000000460 chlorine Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 10
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 9
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000005239 aroylamino group Chemical group 0.000 claims description 9
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- CHXUFRRQOZZSNV-UHFFFAOYSA-N 1-methylpiperidine Chemical group [CH2]N1CCCCC1 CHXUFRRQOZZSNV-UHFFFAOYSA-N 0.000 claims description 8
- KOFZWWMCDUHEEM-UHFFFAOYSA-N 1-methylpyrrolidine Chemical group [CH2]N1CCCC1 KOFZWWMCDUHEEM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 8
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 8
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 8
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 8
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 230000001681 protective Effects 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 6
- 125000005509 dibenzothiophenyl group Chemical group 0.000 claims description 6
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 5
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 3
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000004992 haloalkylamino group Chemical group 0.000 claims description 3
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 2
- UYFHVARTBWVSCY-UHFFFAOYSA-N N-[4-chloro-3-[[6-(4-ethylpiperazin-1-yl)pyridin-3-yl]carbamoyl]phenyl]-2-morpholin-4-ylpyridine-4-carboxamide Chemical compound C1CN(CC)CCN1C(N=C1)=CC=C1NC(=O)C1=CC(NC(=O)C=2C=C(N=CC=2)N2CCOCC2)=CC=C1Cl UYFHVARTBWVSCY-UHFFFAOYSA-N 0.000 claims description 2
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 125000006319 alkynyl amino group Chemical group 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims 6
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- 125000004946 alkenylalkyl group Chemical group 0.000 claims 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- 125000004947 alkyl aryl amino group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 70
- 101710040537 TNF Proteins 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 230000002401 inhibitory effect Effects 0.000 description 28
- 238000001819 mass spectrum Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000000463 material Substances 0.000 description 21
- 241000282414 Homo sapiens Species 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 102100000918 MAPK14 Human genes 0.000 description 17
- 102100009534 TNF Human genes 0.000 description 17
- 108060001945 CRK Proteins 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 108010002352 Interleukin-1 Proteins 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000002158 endotoxin Substances 0.000 description 12
- 239000002609 media Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 210000004369 Blood Anatomy 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 102000001253 Protein Kinases Human genes 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 150000002431 hydrogen Chemical group 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 108091000081 Phosphotransferases Proteins 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 125000005842 heteroatoms Chemical group 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 239000011593 sulfur Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000001963 growth media Substances 0.000 description 7
- 239000003701 inert diluent Substances 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 101710004309 p38a Proteins 0.000 description 7
- TUBDKBIRGSSPNK-UHFFFAOYSA-N 6-(4-ethylpiperazin-1-yl)pyridin-3-amine Chemical compound C1CN(CC)CCN1C1=CC=C(N)C=N1 TUBDKBIRGSSPNK-UHFFFAOYSA-N 0.000 description 6
- 101710027753 MAP2K6 Proteins 0.000 description 6
- 102100012607 MAP2K6 Human genes 0.000 description 6
- 101710038869 MKK6 Proteins 0.000 description 6
- 210000003819 Peripheral blood mononuclear cell Anatomy 0.000 description 6
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 6
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 6
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 5
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 5
- 208000006673 Asthma Diseases 0.000 description 5
- 108090001007 Interleukin-8 Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 108010029485 Protein Isoforms Proteins 0.000 description 5
- 102000001708 Protein Isoforms Human genes 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000005342 ion exchange Methods 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrugs Drugs 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
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Abstract
This invention concerns amide derivatives of Formula (I) wherein X is CH or N;Y is CH or N;m is 0-3;R1 is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and carbamoyl;n is 0-3;R2 is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and (1-6C)alkoxycarbonyl;R3 is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy;q is 0-4;and Q is a group such as aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino, N-(1-6C)alkyl-arylamino and aryl-(1-6C)alkylamino;or pharmaceutically-acceptable salts or in-vivo-cleavable esters thereof;processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.
Description
AMID DERIVATIVES DESCRIPTION OF THE INVENTION This invention concerns certain amide derivatives that are useful as inhibitors of cytokine mediated diseases. The invention also concerns the processes for the manufacture of the amide derivatives of the invention, the pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of the inhibition of cytokine-mediated diseases. The amide derivatives described in the present invention are inhibitors of cytokine production such as Tumor Necrosis Factor (hereinafter TNF), for example TNFa, and various members of the interleukin family (hereinafter IL), for example IL -1, IL-6 and IL-8. Accordingly, the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive cytokine production occurs, for example excessive production of TNFa or IL-1. It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they can give rise to a variety of physiological effects that are believed to be important in diseases or medical conditions such as inflammation and in a regulation. For example, TNFa and IL-1 have been implicated in the cell signaling cascade which is believed to contribute to the pathology of affective states such as inflammatory and allergic diseases and cytosine-induced toxicity. It is also known that, in certain cellular systems, the production of TNFa precedes and mediates the production of other cytokines such as IL-1. Abnormal levels of cytokines have also been implicated in, for example, the production of physiologically active eicosanoids such as prostaglandins and leukotrienes, stimulation of the release of proteolytic enzymes such as collagenase, activation of the immune system, for example by stimulation of T-helper cells, activation of osteoclast activity leading to calcium reabsorption, stimulation of proteoglycan release from, for example, cartilage, stimulation of cell proliferation and for angiogenesis. It is also believed that cytokines are involved in the production and development of affective states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn's disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis, adult respiratory distress syndrome and chronic obstructive pulmonary disease), and the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, Alzheimer's disease, reperfusion injury, vascular wound that includes restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and post-menopausal osteoporosis), Paget's disease, bone metastasis, hypercalcemia, hyperparathyroidism, osteosclerosis, osteoperosis and periodontitis, and abnormal changes in bone metabolism that may accompany rheumatoid arthritis and osteoarthritis. Excessive production of cytokines has also been implicated in the mediation of some complications of bacterial, fungal and / or viral infections such as endotoxic shock syndrome, septic shock and toxic shock and in the mediation of some complications of surgery in the CNS or wound such as neurotrauma and ischemic attack. Excess cytosine production has also been implicated in the mediation or exacerbation of the development of diseases involving cartilage or muscle resorption., pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in some chronic diseases such as malignant disease and acquired immunodeficiency syndrome (AIDS), tumor invasion and tumor metastasis and multiple sclerosis. Evidence of the central role played by TNFa in the cellular signaling cascade that gives rise to rheumatoid arthritis is provided by the efficiency in clinical studies of TNFa antibodies (The Lancet, 1994, 344, 1125 and British Journal of Rheumatology, 1995 , 34, 334). Thus it is believed that cytokines such as TNFa and IL-1 are important mediators of a considerable range of diseases and medical conditions. Accordingly, it is expected that the inhibition of the production of and / or the effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions. Without wishing to imply that the compounds described in the present invention possess pharmacological activity only by virtue of an effect of an individual biological process, it is believed that the compounds inhibit the effects of cytokines by virtue of the inhibition of the enzyme p38 kinase. P38 kinase, otherwise known as the cytokine suppressor binding protein (hereinafter CSBP) and the reactivating kinase (hereinafter RK), is a member of the family of protein kinase enzymes activated by mitogen (hereinafter "MAP"). which is known to be activated by physiological stress such as that induced by ionizing radiation, cytotoxic agents, and toxins, for example endotoxins such as bacterial lipopolysaccharide and by a variety of agents such as cytokines, for example TNFa and IL-1. It is known that p38 kinase phosphorylates some intracellular proteins that are involved in the cascade of enzymatic steps leading to the biosynthesis and excretion of cytokines such as TNFa and IL-1 The known p38 kinase inhibitors have been reviewed by GJ Hanson in Expert Opinions on Therapeutic Patents, 1997, 1, 729- 733. The p38 kinase is known to exist in isoforms identified as p38a and p38β. The present invention is inhibitors of the production of cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1. According to a first aspect of the present invention, a compound of Formula I is provided
where X is CH or N; And it is CH or N; m is 0, 1, 2 or 3 R1 is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, C6-6 alkyl, C2-6 alkenyl / C2-6 alkynyl, alkoxy of C? -6, C? -6 alkylthio, C? -6 alkylsulfinyl, C? -6 alkylsulfonyl, C? -6 alkylamino, di- [C? -β] amino alkyl, C-alkoxycarbonyl? -6, N-alkylcarbamoyl of C? -6, N, N-di- [Ci-β] alkyl carbamoyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C6-6 alkanoylamino, N-alkylsulfamoyl C? -6, N, N-di- [C? _6] alkyl sulphamoyl, C? -6-alkylsulfonylamino, C? -6 N-alkyl-6-alkylsulfonylamino, C? -6 halogen-alkyl, hydroxyalkyl of C? -6, Cx-e-alkyloxy of C? -6 alkyl, cyanoalkyl of C? -6 / aminoalkyl of C? -6, alkylamino of C? -6 ~ C? -6 alkyl, di- [C] -6] amino] -alkyl-6-alkyl, C- [alpha] -6-C6-alkoxycarbonyl, C6-6 alkyl, C6-6 carbamoylalkyl, C6-6-alkylcarbamoyl -alkyl of C? -6, N, N-di- [C? _6 alkyl] carbamoyl-alkyl of C? -6, halogen-C2-alkoxy, hydroxy-C2-? Alkoxy, C? -6-alkoxy-C2-6 alkoxy, cyano-C6-alkoxy, carboxy-C06-alkoxy , Ci-e-alkoxy-Ci-β alkoxycarbamoyl-C6-6 alkoxy, C-6-N-alkylcarbamoyl-C6-alkoxy, N, N-di- [C? -6 alkyl] ] carbamoyl-C6-6 alkoxy, C2-6 amino-alkoxy / Ci-e-alkoxy of C2-6 alkoxy, di- [Ci-β alkyl] amino-C2_6 alkoxy, halogen-C2_6 alkylamino, C2-6 alkylamino C2-6 alkoxy C2-6 alkylamino C2-6 cyanoalkylamino / carboxy-alkylan C6-6 alkoxy / C6-6 alkylaminocarbonyl C? -6, C-6-carbamoyl-alkylamino, N-alkylcarbamoyl of C? -6-alkylamino of C? -6 N, N-di- [C? -6-carbayl oyl-alkylamino alkyl of Ci-e, amino -alkylamino of C2_6, alkylamino of Ci-e-alkylamino of C2_6, di- [C6-6 alkyl] amino-alkylamino of C2-6, N-alkyl of C6-6-halogeno-alkylamino of C6-6 , N-C 1 -C 6 -alkylamino-hydroxy-C 2 -C 6 -alkylamino, C 2 -6-C 6 -alkoxy-Ci-e-alkylamino of C 2-6 / N-Cyan-cyano-C6-alkylamino of? -6, N-alkyl-carboxy of Ci-e-alkylamino of C? -6, N-C? -6-alkoxycarbonyl of C? -6- C? -6 alkylamino, C? -6-C6-6 alkylaminocarbamoyl, C6-6-N-alkylcarbamoyl-C6-6alkylamino, N-? Ci-eN alkyl, N-di- [C? _6 alkyl] carbamoyl-C? -6 alkylamino, C? -6-C6-6 alkylamino-N-amino-C, N-? C 2-6 alkylamino of C2_6, N-C6-6alkyl-di- [C6-6] alkyl amino-alkylamino of C2-e, halogen-C2_6 alkanoylamino, hydroxy-C2-6 alkanoylamino , C6-6-alkanoylamino alkoxy of C2-6? C2-C cyano-alkanoylamino, C2-6 carboxy-alkanoylamino, C6-6 Ci-e-alkanoylamino alkoxycarbonyl, C2-6 carbamoyl-alkanoylamino, C6-6 alkanoylamino N-alkylcarbamoyl, N, N-di- [Ci-β] alkylcarbamoyl-C2-alkylaminoylamino, C2-6 amino-alkanoylamino of C6-6-alkanoylamino of C2-e, or di- [Ci-? -alkanoylamino of C2-6, or R1 is aryl, aryl-C6-alkyl, aryl-C6-alkoxy, aryloxy, arylamino, N-C6-arylamino, arylamino -e, C? -6-C6-arylamino-C6-alkylamino, aroylamino, arylsulfonylamino, N-arylsulphamoyl, aryl-C6-arylamino-heteroaryl, heteroaryl-alkyl of < Z? -β, heteroaryloxy, heteroaryl-C? -6alkoxy, heteroaryl-N, N-C? -6-heteroarylamino, heteroaryl-Ci-β-alkylamino, N? -6-heteroaryl-alkylamino C? -6, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-Ci-β alkynylamino, heteroaryl-C? -6alkoxy-C? _6alkyl, heteroaryl-C? -6alkylamino-C? -6alkylamino , N-C 1-6 -heteroaryl-alkylamino alkyl of Cj-6-C? -6-alkyl, heterocyclyl, heterocyclyl-C? -alkyl, heterocyclyloxy, heterocyclyl-C? -6alkoxy, heterocyclylamino, N -C6 -6-heterocyclylamino alkyl, C6-6 heterocyclyl-alkylamino, Ci-e-heterocyclyl-C-e-heterocyclylcarbonylamino N-alkyl, heterocyclylsulfonylamino, N-heterocyclylsulphamoyl, heterocyclyl-C2-6 alkanoylamino, heterocyclyl-d-6-alkoxy-C6-6alkyl, heterocyclyl-C6-6alkylamino-Ci-b-alkyl or N-C-alkyl? -6- C 1-6 heterocyclyl-alkylamino of C 1-6 alkyl or (R 1) m, is an alkylenedioxy group of C? -3, and wherein any of the substituents R 1 defined above that comprise a CH 2 group that is attached to 2 carbon atoms or to a group of CH3 that is attached "to a carbon atom can optionally carry in each of the groups CH2 or CH3 a substituent selected from hydroxy, amino, C? -6 alkoxy, alkylamino of C? -β, di- [C? _6] amino and heterocyclyl alkyl, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent R1 may optionally carry 1 or 2 substituents selected from hydroxy, halogen, C-alkyl ? -6, C? -6 alkoxy, carboxy, C? -6-alkoxycarbonyl, N-alkylcarbamoyl of C? -6, N, N-di- [C-alkyl] ß] carbamoyl, C2-e alkanoyl, amino, C? -6 alkylamino, di- [C? -6] amino alkyl, halogen-C? -6 alkyl, hydroxy-C? -6 alkyl, alkoxy of C6-6-C6-6alkyl, cyano-C6-6alkyl, amino- C- [beta] -alkyl, C6-6alkylamino- C6-6alkyl, di- [C- alkyl] -6. aminoalkyl of C? -6, aryl and aryl-C? -6 alkyl, n is 0, 1, 2 or 3; R2 is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, C6-6 alkoxycarbonyl, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-6 alkoxy, alkylamino of C? -6 or di- [C? -6 alkyl. Not me; R3 is hydrogen, halogen, C? -6 alkyl or alkoxy
Q is 0, 1, 2, 3 or 4; and Q is aryl, aryloxy, aryl-C6-6 alkoxy, arylamino, N-C6-arylamino-N-alkyl, aryl-alkylamino of CI-6A N-C6-6-aryl-alkylamino of C? -6, aroylamino, arylsulfonylamino, N-arylcarbamoyl, N-arylsulfamoyl, aryl-C2-6 alkanoylamino, C3-7 cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-Ci-β alkoxy, heteroarylamino, N-C alkyl? -6-heteroarylamino, heteroaryl-C 1-6 alkylamino, N-C 1-6 alkyl-heteroaryl-C 1-6 alkylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, N-heteroarylcarbamoyl, N-heteroarylsulfamoyl, heteroaryl-C 2-6 alkanoylamino, heterocyclyl , heterocyclyloxy, heterocyclyl-C1-6-alkoxy, heterocyclylamino, N-C6-heterocyclylamino-N-alkyl, heterocyclyl-C1-6-alkylamino, N-C6-e-heterocyclyl-C4-alkylamino, heterocyclylcarbonyl , heterocyclylsulfonylamino, N-heterocyclylcarbamoyl, N-heterocyclylsulphamoyl or heterocyclyl-alkanoylamino of Cz-ßr and Q is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 alkylthio -6, Ci-e alkylsulfinyl, C? -6 alkylsulfonyl, Ci-e alkylamino, di- [C? _6] amino alkyl, C 1-6 alkoxycarbonyl, N-alkylcarbamoyl Ci-e, N, N -di- [C 1-6 alkylcarbamoyl] carbamoyl, C 2-6 alkanoyl, C 2-6 alkanoyloxy, C 1-6 alkanoylamino, C 1-6 N-alkylsulfamoyl, N, N-di- [C 1-6 alkyl] sulfamoyl , C alca-β-alkylsulfonylamino, N-C?-6-alkylsulfonylamino of Ci-e, halogen-C 1-6 alkyl, hydroxy-Ci-e alkyl, C?-6-alkyloxy-C 1 -alkyl 6, Cyan-C6-alkyl, Ci-e-amino-alkyl, C6-C6-alkyl-C6-alkyl, di- [C6-6 alkyl. amino-Ci-βalkyl, carboxyCalkyl-6alkyl, C?-6alkyl-C de-6alkylcarbonyl, Ci-e-carbamoyl-Ci-alkyl, C-6-alkylcarbamoyl Ci-6-alkyl -e, N, N-di- [Ci-β alkyl] carbamoyl-C?-6 alkyl, halogen-C 2 -6 alkoxy, hydroxy-C 2-6 -alkoxy, d-6-alkoxy-C 2-6 alkoxy / cyano -Ci-e alkoxy, carboxy-C 1-6 alkoxy, d-β-alkoxy-C-alkoxycarbamoyl, carbamoyl-C 1-6 -alkoxy / N-alkylcarbamoyl-C 1-6 -alkoxy / N, N -di- [Ci-β] alkylcarbamoyl-C 1-6 alkoxy, C 2-6 alkoxy, C 2-6 alkylamino C 2-6 alkoxy di- [C 1-6 alkylamino-C 2 alkoxy] -6 / haloalkylamino of C2_6, hydroxy-alkylamino C2-6, alkoxy of Ci-β-alkylamino of C2-6 / cyano-alkylamino of C1-6, carboxy-alkylamino of C? -β, alkoxycarbonyl of C? 6-alkylamino of Ci-β, carbamoyl-alkylamino of C? -6, N-alkylcarbamoyl of C? _6-alkylamino of C 1-6 N, N-di- [alkyl of Ci-e] carbamoyl-alkylamino of amino-alkylamino of C2-6, C? _6-alkylamino alkylamino of C2 -6, di- [Ci-e] amino-alkylamino of C2-e, N-C6-alkyl-halo-alkylamino of C? -6, N-alkyl of C? -6-hydroxy-alkylamino of C2-6, N-C6-alkyl-6-alkoxy of Ci-e-alkylamino of C2-6 / N-C-alkyl -6-cyano-C1-6 alkylamino, N-alkyl of Ci-β -carboxy-C 1-6 alkylamino, N- C 1-6 alkyl-alkoxycarbonyl of C? -6-C? -β alkylamino, N-C? -6-carbamoyl-C 1-6 alkylamino , N-C 1-6 alkyl-N-alkylcarbamoyl of C? _6-alkylamino of C? -e, N-alkyl of Ci-e-N, N-di- [C? -6] alkyl carbamoyl-alkylamino of Ci-e, N-C6-6-amino-alkylamino of C2-6 alkyl, N-C6-6alkylamino of C6-6alkylamino of C2-6, N-alkyl of C? -6-di- [Ci-β] alkyl amino-alkylamino of C2-e, halogen-alkanoylamino of C2-6 hydroxy-alkanoylamino of C2-6, alkoxy of C6-6-alkanoylamino of Cz-ßr cyano-alkanoylamino of C2-β, carboxy-alkanoylamino of C2_6, alkoxycarbonyl of C6-6-alkanoylamino of C2-6, carbamoyl-alkanoylamino of C2-6, N-alkylcarbamoyl of C6-6-alc C2-β, N, N-di- [Ci-β-carbamoyl-C2-e-alkanoylamino, C2_e-amino-alkanoylamino, C6-6-C6-6 alkanoylamino alkylamino, di- [C] alkyl ester ? -6] amino-alkanoylamino of C2-6, aryl, aryl-C 1 -6 alkyl, aryl-C 1 -alkoxy, aryloxy, arylamino, C 1 -6-arylamino-N-alkyl, arylamino-C 1-6 alkylamino, N-C 1 -C 6 -alkyl -alkylaryl -6-, aroylamino, arylsulfonylamino, liarylsulphamoyl, aryl-C2-6alkanoylamino heteroaryl, heteroaryl-C6-6alkyl, heteroaryloxy, heteroaryl-C6-6alkoxy, heteroarylamino, N-alkyl- C? -6-heteroarylamino, heteroaryl-Ci-e-alkylamino, C? -6-heteroaryl-alkylamino of Ci-β, heteroarylcarbonylamino, heteroarylsulfonylamino, N-heteroarylsulfamoyl, heteroaryl-C2-6 alkanoylamino, heteroaryl- C6-C6-C6-alkoxy, C6-C6-C6-C6-C6-C6-alkylamino, C-C6-C6-C6-C6-C6-C6-C3-C6-C3-C3-C3-C3-C3-C3-C3-C3-C6-C3-C3-C3-C3-C3-C3-C3-C3-C3 6, heterocyclyl, heterocyclyl-C6-alkyl, heterocyclyloxy, heterocyclyl-C6-alkoxy, heterocyclylamino, N-C6-6-heterocyclylamino-alkyl, heterocyclyl-C4-alkylamino, N-alkyl C? -6-heterocyclyl-Ci-β-alkylamino, heterocyclylcarbonyl amino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-C2_6 alkanoylamino, heterocyclyl-C6-6alkyl-C6-6alkyl, heterocyclyl-C6-6alkylamino-C6-6alkyl and N-alkyl- Ci-β-heterocyclyl-C 1-6 alkylamino-C 6 alkyl, or Q is substituted with an alkylenedioxy group of
C? -3, and wherein any of the substituents on Q defined above that comprise a CH2 group that is attached to 2 carbon atoms or to a group of CH3 that is attached to a carbon atom can optionally carry in each of the CH2 or CH3 groups a substituent selected from hydroxy, amino, Ci-β alkoxy, C? _6 alkylamino, di- [Ci-? amino alkyl and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent Q can optionally carry 1 or 2 substituents selected from hydroxy, halogen, C?-6 alkyl / C ?e alkoxy, carboxy, C?-6 alkoxycarbonyl, C?-6N-alkylcarbamoyl, N, N-di- [C?-6] alkylcarbamoyl, C 2-6 alkanoyl amino, C?-6 alkylamino, di- [Ci-β] amino alkyl, halogen-Ci-β alkyl, hydroxy-alkyl Ci-e alkoxy, C? -6-C6-6alkyl, cyano-C6-6alkyl, C6-6alkylamino, C6-6alkylamino-C6-6alkylamino di- [C] -β-aminoalkylalkyl C de-β, aryl and aryl-Ci-e alkyl; or a pharmaceutically acceptable salt or an indole ester in vivo thereof. According to a second aspect of the present invention there is provided a compound of Formula I wherein each of X, Y, R1, R2, m, n, q, and Q have any of the meanings defined above and R3 is selected from from halogen and Ci-β alkyl; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. In this specification, the term "C" -6 alkyl includes straight chain and branched chain alkyl groups such as propyl, isopropyl and tert-butyl, and C3_6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. However, references to individual alkyl groups such as "propyl" are specific to the straight chain version only, references to individual branched chain alkyl groups such as "isopropyl" are specific to the branched chain version only and references to Individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention is "applied to other generic terms, for example Ci-alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, C? -6 alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di- [C? -6] amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino It should be understood that, for some of the compounds of Formula I defined above, they may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any of the optically active or racemic form possessing the property of inhibiting cytokines, in particular TNF.The synthesis of the optically active forms can be carried out by techniques standard of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a race form Likewise, the inhibitory properties against TNF can be evaluated using the standard laboratory techniques referred to below. Suitable values for the generic radicals referred to above include those indicated below. A suitable value for R 1 or Q when it is aryl for a substituent on Q when it is aryl or for the aryl group within a substituent 'R 1 or a group Q or within a substituent on Q is, for example, phenyl, indenyl, indanyl , naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl. A suitable value for R 1 or Q when it is heteroaryl, for the heteroaryl group within a substituent R 1 or a group Q, for a substituent on Q when it is heteroaryl or for the heteroaryl group within a substituent on Q is, for example, a 5 or 6 aromatic limbs monocyclic ring, a 9 or 10 membered bicyclic ring or a tricyclic ring of 13 or 14 members each with up to five heteroatoms in the ring selected from oxygen, nitrogen and sulfur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl , pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, olyl, isoolyl , azolinyl, oxalinyl, cinolinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, S, S-dioxodibenzothiophenyl, xanthenyl, dibenzo-1,4-dioxinyl, phenoxythinyl, phenoxazinyl, dibenzothiinyl, phenothiazinyl, thiantrenyl, benzofuropyridyl, pyridoindolyl, acridinyl or phenanthridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridaz inyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, olyl, isoolyl, azolinyl, oxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl, more preferably furyl, thienyl, isoxazolyl, thiazolyl , pyridyl, benzothienyl, benzofurazanyl, olyl, carbazolyl, dibenzofuranyl or dibenzothiophenyl. A suitable value for R 1 or Q when it is heterocyclyl, for a substituent on Q when it is heterocyclyl or for the heterocyclyl group within a substituent R 1 or a group Q or within a substituent on Q is, for example, a monocyclic or bicyclic ring from 3 to 10 members saturated or partially saturated non-aromatic with up to five heteroatoms selected from oxygen, nitrogen and sulfur, for example oxirane, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, pyrrolidinyl, 1,1-dioxidoisothiazolidinyl, morpholinyl, tetrahydro -1,4-thiazinyl, 1,1-dioxotetrahydro-l, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, or, for example, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, or , for example, benzo derivatives thereof such as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indolinyl, isoin dolinyl, chromanyl and isochromanyl, preferably the heterocyclyl group is pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperazin-1-yl or homopiperazin-1-yl. A suitable value for Q when it is C3_7 cycloalkyl is, for example, a non-aromatic mono or bicyclic 3- to 7-membered carbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1] heptyl, preferably cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, more preferably cyclohexyl. Suitable values for various groups R1, R2 or R3, or for various substituents on Q or on an aryl, heteroaryl or heterocyclyl group within R1 or on an aryl, heteroaryl or heterocyclyl group on a substituent on Q include: - for halogen: fluorine, chlorine, bromine and iodine; for alkyl of d-6: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl and cyclohexyl; for C2-6 alkenyl: vinyl and allyl; for C2_6 alkynyl: ethynyl and 2-propynyl; for C?-6 alkoxy: methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, butoxy, cyclobutyloxy and cyclopentyloxy; for C? -β alkylamino: methylamino, ethylamino, propylamino, cyclobutylamino and cyclohexylamino; for di- [Ci-amino alkyl: dimethylamino, diethylamino and N-ethyl-N-methylamino; for C 1 _6 alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-alkylcarbamoyl of C? -6: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for N, N-di- [C? -6] alkylcarbamoyl: N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl; for C?-β 'acetyl and propionyl alkanoyl; for halogen-Ci-e alkyl: fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2-fluoroethyl, 2-chloroethyl and 2-bromoethyl; for hydroxy-C de-β 'alkyl. hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for C 1 -C 6 alkoxy C 6 -alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for cyano-C6-6alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl; for amino-alkyl of d-6: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl; for C 1-6 alkylamino of C? -6: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; for di- [C 1-6 alkyl] amino-alkyl of C? -6 dimethylaminomethyl, diethylaminoethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl. Suitable values for R1 or Q and suitable values for a substituent on R1 or Q include: -for aryl-C6_6alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl; for aryl-C6-alkoxy: benzyloxy and 2-phenylethoxy; for aryloxy: phenoxy and 2-naphthyloxy; for arylamino: anilino; for N-alkyl of C? _6-arylamino: N-methylanilino and v N-ethylanilino; for aryl-alkylamino of Ci-e: benzylamino, 2-phenethylamino, 2-phenylpropylamino, and 3-phenylpropylamino; for C-C6-aryl-C-C6-alkylamino N-alkyl: N-benzyl-N-methylamino; for aroylamino: benzamido and 2-naphthoylamino; Arylsulfonylamino: benzensulfonylamido; for N-arylcarbamoyl: N-phenylcarbamoyl; for N-arylsulphamoyl: N-phenylsulphamoyl; for aryl-C2-6 alkanoylamino: phenylacetamido and 3-phenylpropionamido; for the heteroaryl-C6_6alkyl: heteroarylmethyl, 2-heteroarylethyl, 2-heteroarylpropyl and 3-heteroarylpropyl; for heteroaryl-alkoxy of C-heteroarylmethoxy and 2-heteroarylethoxy; for N-C 1 -6-heteroarylamino: N-methylheteroarylamino; for heteroaryl-C 1-6 alkylamino: heteroarylmethylamino, 2-heteroarylethylamino and 3-heteroarylpropylamino; for C-β-β-N-methylheteroarylmethylamino and N-methyl-2-heteroarylethylamino N-alkyl of Ci-e-heteroaryl-alkylamino; for C2-β heteroaryl-alkanoylamino: heteroarylacetamido and 3-heteroarylpropionamido; for C6-C6-heteroaryl-C-β-heteroarylmethoxymethyl, 2- heteroarylethoxymethyl and 3- heteroarylpropoxymethyl; for heteroaryl-C 1-6 alkylamino-C 6 -alkyl: heteroarylmethylaminomethyl, 2-heteroarylethylaminomethyl and 3-heteroarylpropylaminomethyl;
for N-C 1-6 alkyl-heteroaryl-alkylamino of Ci-e-C-6 alkyl: N-heteroarylmethyl-N-methylaminomethyl, N- (2-heteroarylethyl) -N-methylaminomethyl and N- (3- heteroarylpropyl) -N-methylaminomethyl; for heterocyclyl-C6_6alkyl: heterocyclylmethyl, 2-heterocyclylethyl, 2-heterocyclylpropyl and 3-heterocyclylpropyl; for heterocyclyl-C6-alkoxy: heterocyclylmethoxy and 2-heterocyclylethoxy; for N-C 1 -C 6 -heterocyclylamino N-alkyl-N-methylheterocyclylamino; for heterocyclyl-alkylamino Ci-e: heterocyclylmethylamino, 2-heterocyclylethylamino and 3-heterocyclylpropylamino; for N-C6-C6-heterocyclyl-C6-6 alkylamino: N-methylheterocyclylmethylamino and N-methyl-2-heterocyclyl-ethylamino; for heterocyclyl-alkanoylamino of Cz-β 'heterocyclylacetamido and 3-heterocyclylpropionamido; for heterocyclyl-C6-alkoxy-Ci-e alkyl: heterocyclylmethoxymethyl, 2-heterocyclycytoxymethyl and 3-heterocyclylpropoxymethyl; for C6-6-C6-6 alkyl heterocyclyl-alkylamino: heterocyclylmethylaminomethyl, 2-heterocyclylethylaminomethyl and 3-heterocyclylethylamino-methyl; for N-C 1-6 alkyl-heterocyclyl-C 1-6 alkylamino-Ci-e alkyl N-heterocyclylmethyl-N-methylaminomethyl, N- (2-heterocyclylethyl) -N-methylamine and N- (3-heterocyclylpropyl) -limethylamino ethyl; for C1-3 alkylenedioxy: methylenedioxy, ethylenedioxy and trimethylenedioxy; for alkylthio of C? -ß '. methylthio, ethylthio and propylthio; for C 1 -C 6 alkylsulfinyl: methylisulfinyl, ethylsulfinyl and propylsulfinyl; for β-alkylsulfonyl: methylsulfonyl, ethylsulfonyl and propylsulfonyl; for C2-6 alkanoyloxy: acetoxy and propionyloxy; for Ci-β alkanoylamino: formamido, acetamido and propionamido; for N-alkylsulfamoyl of C? _6: N-methylsulfamoyl and N-ethylsulphamoyl; for N, N-di- [C? _6] alkyl sulfamoyl: N, N-dimethylsulphamoyl; for C? _6 alkylsulfonylamino: methanesulfonyl, and ethanesulfonylamino; for Ci-e-alkylsulfonylamino N-alkyl of Ci-e: N-methylmetanesulfonylamino and N-methylenesulfonylamino; for carboxy-alkyl of d6: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl; for Ci-e alkyloxycarbonyl Ci-e alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-ethoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl 3-ethoxycarbonylpropyl; for carbamoyl-Ci-β alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; for N-alkylcarbamoyl of Ci-β-C-6 alkyl: N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1- (N-methylcarbamoyl) ethyl, 1- (N-ethylcarbamoyl) ethyl, 2- (N - methylcarbamoyl) ethyl, 2- (N-ethylcarbamoyl) ethyl and 3- (N-methylcarbamoyl) propyl; for N, N-di- [Ci-β-alkyl carbamoyl-Ci-β N alkyl, N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl, N, N-diethylcarbamoylmethyl, 1- (N, N -dimethylcarbamoyl) ethyl, 1- (N, N-diethylcarbamoyl) ethyl, 2- (N, N-dimethylcarbamoyl) ethyl, 2- (N, N-diethylcarbamoyl) ethyl, 3- (N, N-dimethylcarbamoyl) ) - propyl and 4- (N, N-dimethylcarbamoyl) butyl; for halo-β-alkoxy: 2-chloroethoxy, 2-bromoethoxy, 3-chloropropoxy, 1,1,2,2-tetrafluoroethoxy and 2,2,2-trifluoroethoxy; for C2-6i hydroxy-alkoxy 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxy-1-methylethoxy, 2-hydroxy-2-propoxy and 4-hydroxybutoxy; for d-β-alkoxy of Cz-β '2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 2-methoxy-1-methylethoxy and 4-ethoxybutoxy; for cyano-C6-6alkoxy: cyanomethoxy, 2-cyanoethoxy and 3-cyanopropoxy; for carboxy-alkoxy of Ci-e: carboxymethoxy, 1-carboxyethoxy, 2-carboxyethoxy, and 3-carboxypropoxy;
for Ci-β-alkoxy alkoxycarbonyl: methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, 2-ethoxycarbonylethoxy-3-ethoxycarbonylpropoxy; for carbamoyl-Ci-β alkoxy: carbamoylmethoxy 2- carbamoylethoxy; for N-alkylcarbamoyl of Ci-β-alkoxy of Ci-e: N-methylcarbamoylmethoxy, 2- (N-ethylcarbamoyl) ethoxy and 3- (N-methylcarbamoyl) propoxy; for N, N-di- [Ci-e alkyl] carbamoyl-alkoxy of Ci-e: N, N-dimethylcarbamoylmethoxy, 2- (N, N-dimethylcarbamoyl) ethoxy and 3- (N, N-diethylcarbamoyl) -propoxy); for amino-alkoxy-β: 2-aminoethoxy, 2-amino-1-methylethoxy, 3-aminopropoxy, 2-amino-2-methylpropoxy and 4-aminobutoxy; for Ci-e-alkoxy alkylamino of C2- & : 2-methylaminoethoxy, 2-methylamino-1-methylethoxy and 3-ethylaminopropoxy;
for di- [C] _6-amino-alkoxy-β: 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-dimethylamino, 2-dimethylamino-2-methylethoxy, 3-dimethylamino-4-dimethylaminobutoxy; for halogen-alkyl of C2-β: 2-fluoroethylamino, 2-chloroethylamino, 2-bromoethylamino, 3-fluoropropylamino-3-chloropropylamino; for C2-e hydroxy-alkylamino: 2-hydroxyethylamino, 3-hydroxypropylamino, 2-hydroxy-2-methylpropylamino and 4-hydroxybutylamino; for Ci-β-alkylamino alkoxy of C2-β: 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino; for cyanoalkylamino of C? -6: cyanomethylamino, 2-cyanoethylamino and 3-cyanopropylamino; for carboxy-alkylamino of Ci-β: carboxymethylamino, 1-carboxyethylamino, 2-carboxyethylamino-3-carboxypropylamino; for C6-6-alkylamino of C6-6 methoxycarbonylmethylamino, 2- (ethoxycarbonyl) ethylamino and 3- (tert-butoxycarbonyl) -propylamino for carbamoyl-alkylamino of Ci-β: carbamoylmethylamino-2-carbamoylethylamino; for N-alkylcarbamoyl of Ci-β-alkylamino of C? -6: N-methylcarbamoyl-ethylamino, N-ethylcarbamoylmethylamino and 2- (N-methylcarbamoyl) -ethylamino; for N, N-di- [C 1-6 alkylcarbamoyl-C 1-6 alkylamino: N, N-dimethylcarbamoylmethyl amino, N, N-diethylcarbamoylmethylamino and 2- (N, -dimethylcarbamoyl) ethylamino for aminoalkylamino of C2-6: 2-aminoethylamino, 3-aminopropylamino, 2-amino-2-methylpropylamino and 4-aminobutylamino; for Ci-e-alkylamino alkylamino of C2_ß: 2-methylaminoethylamino, 2-ethylaminoethylamino, 2-propylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-methylamino-2-methylpropylamino and 4-methylaminobutylamino; for di- [C? _] alkyl] amino-C 2-6 alkylamino: 2-dimethylaminoethylamino, 2- (N-ethyl-N-methylamino) ethylamino, 2-diethylaminoethylamino, 2-dipropylaminoethylamino, 3-dimethylaminopropylane, 3- diethylaminopropylamino, 2-dimethylamino-2-methylpropyl-amino and 4-dimethylaminobutyl-ano; for N-C6-6-halogenoalkylamino of C2-β: N- (2-chloroethyl) -N-methylamino, N- (2-bromoethyl) -N-methylamino and N- (2-bromoetiD-N- ethylamino, for N-alkyl of C6-6-hydroxyalkylamino of C2-6: N- (2-hydroxyethyl) -N-ethylamino, N- (3-hydroxypropyl) -N-methylamino and N-ethyl-N- ( 2- hydroxyethyl) amino; for N-C 1-6 alkyl-C 2-6 alkylamino of C 2-6: N-methyl-N- (2-methoxyethyl) -amino, N-methyl-N- (3-methoxypropyl) ) amino and N-ethyl-N- (2-methoxyethyl) amino; for N-alkyl of Ci-β-cyano-alkylamino of Ci-β: N- (cyanomethyl) -N-methylamino; for N-alkyl of C? -6-carboxyalkyl amino of C? -6: N-carboxymethyl-N-methylamino and N- (2-carboxyethyl) -N-methylamino; for N-C? -6-alkoxycarbonyl of de-alkylamino of Ci-e N-methoxycarbonylmethyl-N-methylamino, N- (2-ethoxycarbonylethyl) -N-ethylamino and N- (2-tert-butoxycarbonylethyl) -limethylamino; for N-C 1-6 alkyl-carbamoylalkylamino of C? -6: N -carbamoylmethyl-N-methylamino and N- (2-carbamoylethyl) -N-methylamino; for N-C 1-6 alkyl-N-alkylcarbamoyl-C 1-6 alkylaminocarbamoyl: N- (N-methylcarbamoylmethyl) -N-methylamino, N- (N-ethylcarbamoylmethyl) -N-methylamino and N- [ 2- (N-methylcarbamoyl) ethyl] -N-methylamino; for N-alkyl of C? -6-N / N-di- [C? -6 alkyl. Carbamoylaminoalkylamino of C? _s: N- (N, N-dimethylcarbamoylmethyl) -N-methylamino and N- [2- (N, N-dimethylcarbamoyl) ethyl] -N-methylamino; for N-alkyl-Ci-β-aminoalkylamino of d-β: N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -limethylamino and N- (4-aminobutyl) -N-methylamino; for N-alkyl of Ci-β-alkylamino of d-6- to cycloalkyl of C2- N- (2-methylaminoethyl) -N-methylamino, N- (2-methylaminoethyl) -N-methylamino, N- (3- methylaminopropyl) -limethylamino, N- (3-ethylaminopropyl) -N-ethylamino, and N- (4-methylaminobutyl) -N-methylamino; for N-alkyl of Ci-β-di- [C?-6] alkyl amino-alkylamino of C2-β N- (2-dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino and N- (4-dimethylaminobutyl) -N-methylamino; for halo-alkanoylamino of-β: 2-chloroacetamido and 3-chloropropionamido; for C2_6 hydroxy-alkanoylamino: 2-hydroxyacetamido and 3-hydroxypropion gone; for Ci-β-alkanoylamino alkoxy of C2_ß: 2-methoxyacetamido and 3-ethoxypropionamido; for C2-β cyano-alkanoylamino: 2-cyanoacetamido and 3-cyanopropionamido; for carboxy-alkanoylamino of C2-β 2-carboxyacetamido and 3-carboxypropionamido; for Ci-β-alkanoylamino alkoxylamino of C2-β: 2-methoxycarbonylacetamido, 2- (tert-butoxycarbonyl) acetamido and 3-methoxycarbonylpropionamido for carbamoyl-alkanoylamino of d-jβ: 2-carbamoylacetamido, 3- carbarmoylpropione gone and - carbamoylbutyramide;
for N-alkylcarbamoyl of Ci-β-alkanoylamino of Cz-β '. 2- (N-methylcarbamoyl) acetamido and 3- (N-ethylcarbamoyl) propioanamido for N, N-di- [Ci-β alkyl] carbamoyl-C2_6 alkanoylamino: 2- (N, N-dimethylcarbamoyl) -acetamido , 2- (N, N-diethylcarbamoyl) acetamido and 3- (N, N-dimethylcarbamoyl) -propionamido; for amino-alkanoylamino of d-β: 2-aminoacetamido, 2-aminopropionamido and 3-aminopropionamido; for C2-β-d-e-alkanoylamino alkylamino: 2-methylaminoacetamido, 2-ethylaminoacetamido, 2-methylaminopropionamido and 3-methylaminopropionamido; for di- [Ci-β alkyl] amino-C2-6 alkanoylamino: 2-dimethylaminoacetamido, 2-diethylaminoacetamido, 2-dimethylaminopropionamido and 3-dimethylaminopropionamido. When, as defined above, any of the substituents on R1 or Q comprising a CH2 group that is attached to 2 carbon atoms or a CH3 group that is attached to a carbon atom can optionally carry on each of the CH2 groups or CH3, a substituent selected from hydroxy, amino, C? -6 alkoxy, Ci-? alkylamino, di- [C? -6] amino and heterocyclyl alkyl, suitable substituents thus formed include, for example, C6-6 substituted heterocyclyl-alkoxy groups such as 2-hydroxy-3-piperidinepropoxy and 2-hydroxy-3-morpholinopropoxy, substituted C2-β-amino-alkoxy groups such as 3-amino-2-hydroxypropoxy, alkylamino groups of -substituted C 2 -β alkoxy such as 2-hydroxy-3-methylaminopropoxy, substituted C 2 -6 alkyloxy-C 1 -C 6 -alkyl groups such as 3-dimethylamino-2-hydroxypropoxy, 3- [N - (3-dimethylaminopropyl) -N-methylamino] propoxy and 3- [N- (3-dimethylaminopropyl) -N-methylamino] -2-hydroxypropoxy, groups C? _ heter heterocyclyl-alkylamino such as 2-hydroxy-3-piperidinpropylamino and 2-hydroxy-3-morpholinopropylamino, substituted C2-e amino-alkylamino groups such as 3-a ?c ?o?-2-hydroxypropylamino, alkylamino groups of substituted C 2 -6-alkylamino of C 2-6 such as 2-hydroxy-3-methylaminopropylane, substituted di- [C?-β] alkyl amino-alkylamino groups of C 2-6 such as 3-dimethylamino-2- hydroxypropylamino, 3- [N- (3-dimethylaminopropyl) -N-methylamino] propylamino and 3- [N- (3-dimethylaminopropyl) -N-methylamino] -2-hydroxypropylamino and alkylamino groups of C? -6-C-alkyl ? -6 substituted such as 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2, 2-dimethylpropylaminomethyl, 2-morpholino-ethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and 3-morpholinopropylaminomethyl. To avoid any doubt it should be understood that, when X or Y is a CH group and the ring in which the X and Y groups are embedded carries one or more substituents R1, a substituent R1 can be located in any suitable location on that ring including on the carbon atom in the X or Y position. A suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid addition salt of a compound of Formula I which is sufficiently basic, for example a salt of acid addition with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of Formula I that is sufficiently acidic, for example an alkali metal or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such such as methylamine, di-ethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Prodrug design edited by H. Bundgaard,
(Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K., idder, et al. (Academic Press, 1985); b) A textbook on drug design and development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5"Desing and Application of Prodrugs" by H., Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews,, 1-38 (1992); d) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Ka eya, et al. , Chem. Pharm. Bull., 32, 692 (1984). Examples of such prodrugs can be used to form in vivo cleavable esters of a compound of Formula I. An in vivo cleavable ester of a compound of Formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is split into the human or animal body to produce the acid of origin. Suitable pharmaceutically acceptable esters for carboxy include alkoxymethyl esters of Ci-e, for example methoxymethyl; alkanoyloxymethyl esters of C? -6, for example pivaloyloxymethyl; phthalidyl esters; cycloalkoxycarbonyloxy esters of C3-8-Ci-β alkyl, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, for example 5-methyl-l, 3-dioxolan-2-ylmethyl; and esters of C6-6 alkoxycarbonyloxyethyl, for example 1-methoxycarbonyloxyethyl; and they can be formed in any carboxy group in the compounds of this invention. Particular novel compounds of the first aspect of the invention include, for example, amide derivatives of Formula I, or pharmaceutically acceptable salts thereof, wherein: (a) R ° is hydrogen, halogen (such as fluoro, chloro or bromine) or C? -6 alkyl (such as methyl, ethyl, propyl and isopropyl), preferably R'3 is hydrogen, chlorine, methyl or ethyl, more preferably hydrogen, chlorine or methyl; and X, Y, R1, R2, Q, m, n and q have any of the meanings defined above or in this section that relate to particular novel compounds of the invention; (b) Q is phenyl or a 5- or 6-membered heteroaromatic monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen, and sulfur bearing a basic substituent selected from of the substituents for Q defined above; and X, Y, R1, R2, R, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention: (c) Q is phenyl, indenyl, indanyl or fluorenyl which carry optionally 1, 2 or 3 substituents, selected from the substituents for Q defined above; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (d) Q is phenyl or a 5- or 6-membered heteroaromatic monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen, and sulfur bearing a basic substituent selected from amino, C 1-6 alkylamino, di- [d-β] alkyl amino, Ci-β amino-alkyl, C 1 -C 6 alkylamino-C 6 alkyl, di- [Ci-β alkyl] amino-alkyl of d-β, amino-alkoxy of d-β, alkylamino of C α -6-alkoxy of d-β, di- [Ci-β alkyl] amino-alkoxy of C2_6, amino-alkylamino of C2- β, Ci-β-alkylamino of d-β, di- [C? _] amino-alkylamino alkyl of Zz-zr N-C de-β-amino-alkylamino of C 2 -β, N-alkyl of Ci-β-alkylamino of Ci-β-alkylamino of de, N-C 1 -C 6 alkyl- di- [C ?e] alkyl] amino-alkylamino of C 2 ß, amino-alkanoylamino of d-β, alkylamino of Ci- ß-alkanoylamino of C2_ß, di- [alkyl of d_6] amino-alkanoylamino of C2-6 / heteroaryl, heteroaryl-alkyl of C? _ß, heteroaryl-Ci-β alkoxy, heterocyclyl, heterocyclyl-Ci-β alkyl and heterocyclyl-Ci-β alkoxy, and wherein any heteroaryl or heterocyclyl group in a basic substituent on Q can optionally carry 1 or 2 substituents selected from halogen, C? _ Alquiloalkyl, Cz-ßamino alkanoyl, C? _6alkylamino and di- [C?-6] alkyl amino; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to the particular novel compounds of the invention; (e) Q is phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulfur optionally carrying 1, 2 or 3 substituents selected from hydroxy, halogen, trifluoromethyl, cyano, nitro, amino, carboxy, C? -6 alkyl, C? -6 alkoxy / Ci-? alkylamino, di- [Ci-? amino alkyl, alkoxycarbonyl Ci-ß, C2-6 alkanoyl / halogen-Ci-β alkyl, C6-6 alkoxy of C6-6alkyl, Ci-β-aminoalkyl, C6-6alkylamino of Ci -6alkyl -β, di- [Ci-β alkyl] amino-Ci-β alkyl, halogen-C 2-6 alkoxy, hydroxy-C 2 -6 alkoxy, C 6 -alkoxy-d-β alkoxy, cyano-alkoxy C? _6, C? -6-carboxy-alkoxy, Ci-? -alkoxy-d-6-alkoxycarbonyl, C2-? Amino-alkoxy, C? -6-alkoxy-C2_6 alkylamino, di- [d-alkyl] -β] amino-alkoxy of d-β, pyridyl, imidazolyl, pyridyl-Ci-β alkyl, and idazolyl-alkyl or of d_6, pyridyl-d-6-alkoxy, imidazolyl-Ci-β-alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, C-6-alkyl, 4-alkyl-cyperazinyl, C2-β / pyrrolidinyl-Ci-alkylcarbazinyl -β, piperidinyl-Ci-e alkyl, morpholinyl-C ?6 alkyl, piperazinyl-C? _-alkyl, 4-alkylpiperazinyl of C?-6-Ci-β alkyl, 4-alkanoylpiperazinyl of C2-β- C? -6 alkyl, pyrrolidinyloxy, piperidinyloxy, C? -6 1-alkylpiperidinyloxy, pyrrolidinyl-C2-6 alkoxy, piperidinyl-C2-6alkoxy, morpholinyl-C2-6alkoxypiperazinyl-C2-6alkoxy , C 2-6 alkoxy-4-alkylpiperazinyl and C 2 -6-alkoxy-4-alkanoylpiperazinyl d-β-alkoxy carries an alkylene dioxy substituent of d-; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (f) Q is phenyl, indenyl, indanyl, fluorenyl or a 5- or 6-membered heteroaromatic monocyclic ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulfur optionally bearing 1, 2 or 3 substituents selected from of hydroxy, halogen, trifluoromethyl, cyano, nitro, amino, carboxy, C? -6 alkoxy of C? _6 alkoxy, C? _6 alkylamino, di- [Ci-b] amino alkyl, C? _6 alkoxycarbonyl, d-β alkanoyl, Ci-β-alkanoylamino, C?-6-alkylsulfonylamino, C N-6-C alca-6-alkylsulfonylamino-C 6 alkyl, phenyl, furyl, thienyl, azetidinyl, pyrrolinyl, pyrrolidinyl, 1,1-dioxidoisothiazolidinyl , piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl-Ci-β alkyl, pipendinyl-Ci-e alkyl, morpholinyl-C?-6 alkyl and piperazinyl-C? _6 alkyl, and wherein any phenyl group , furyl, thienyl or heterocyclyl in a substituent on Q can optionally carry 1 or 2 substitutes listeners selected from halogen, Ci-β alkyl, Ci-e alkoxy and C2_6 alkanoyl; and X, Y, R "", R2, R3, m, n and q have any of the meanings defined above or in this section that relate to particular novel compounds of the invention; (g) Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl. , quinazolinyl, quinoxalinyl, or naphthyridinyl optionally carrying 1 or 2 substituents selected from those defined in paragraphs (b), (d) or (e) above; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (h) Q is phenyl, 2- or 3-furyl, 2- or 3-thienyl, 2-,
4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, or
4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-, 3-,
- or 6-benzofuranyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl, 2-, 5- or 6-benzoxazolyl, 2-, 5- or 6 -benzimidazolyl, 2-, 5- or 6-benzothiazolyl, 3-, 5- or 6-indazolyl, 5-benzofurazanyl, 2-, 3-, 6- or 7-quinolyl, 3-,
6- or 7-isoquinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, or 1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl which optionally carries 1 6 2 substituents selected from those defined in paragraphs (b), (d) or (e) above; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above in this section that relate to particular novel compounds of the invention; (i) Q is a 5- or 6-membered heteroaromatic monocyclic ring, a 9- or 10-membered bicyclic ring or a tricyclic ring of 13 or 14 members each with up to five heteroatoms in the ring selected from oxygen, nitrogen and sulfur optionally carrying 1, 2 or 3 substituents selected from hydroxy, halogen, trifluoromethyl, cyano, nitro, amino, carboxy, d-β alkyl, C?-6 alkoxy, d-3 alkylenedioxy, Ci-alkylamino e, di- [Ci-β] alkyl amino and Ci-β alkoxycarbonyl; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which refers to particular novel compounds of the invention; (j) Q is a tricyclic ring of 13 or 14 heteroaromatic members each with up to five heteroatoms in the ring selected from oxygen, nitrogen and sulfur optionally carrying 1, 2 or 3 substituents selected from hydroxy, halogen, trifluoromethyl , cyano, nitro, amino, carboxy, Ci-β alkyl, Ci-β alkoxy, C? -3 alkylenedioxy, d-6 alkylamino, di- [C ?6] amino alkyl, and C alkoxycarbonyl? _6; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (k) Q is furyl, thienyl, oxazoyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl , quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl which optionally carry 1 or 2 substituents selected from those defined in paragraph (i) above; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (1) Q is 1-, 2- or 3-carbazolyl, 1-, 2-, 3- or 4-dibenzofuranyl or 1-, 2-, 3- or 4-dibenzothiophenyl which optionally carry 1 or 2 substituents selected from of those defined in paragraph (i) above; and X, Y, R1, R2, R3, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (m) n is O; and X, Y, R1, R3, Q, m and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (n) n is 1 and R 2 is halogen or C 6 -6 alkyl; and X, Y, R1, R3, Q, m and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (o) q is 0, and X, Y, R1, R2, R3, Q, m and n have any of the meanings defined above or in this section that relate to particular novel compounds of the invention;
(p) m is 1 and R1 is amino, C? -6 alkylamino / di- [C? -6] amino alkyl, C amino-6-aminoalkyl, Ci-β-alkyl-C?-6alkylamino, di- [d-6-alkyl] amino-C de _-alkyl, C 2-6 -alkoxy, C alqu-alkylamino C6-C6-alkoxy, di- [C6-6alkyl] amino-C2-6alkoxy, amino-alkylamino of C6-6alkylamino of C2_6 alkylamino, di- [Ci-βalkyl] ] amino-alkylamino of C2_ß, N-C6-6-amino-alkylamino of C2-6, N-alkyl of Ci-β-alkylamino of C? -6-alkylamino of C2-?, N-alkyl of Ci-? ß-di- [Ci-β] alkyl amino-C2-6 alkylamino, heteroaryl, heteroaryl-C6-alkyl, heteroaryl-Ci-alkoxy, heterocyclyl, heterocyclyl-Ci-β alkyl, heterocyclyloxy or heterocyclyl-C6-alkoxy, and wherein any heteroaryl or heterocyclyl group in a substituent R1 may optionally carry 1 or 2 substituents selected from hydroxy, halogen, Ci-β alkyl, C6-alkoxy, alkanoyl of C2_ß, amino, Ci-β alkylamino and di- [C? -6] amino alkyl; and X, Y, R2, R3, Q, n and q have any of the meanings defined above or in this section that relate to particular novel compounds of the invention; (q) m is 1 and R 1 is amino, Ci-e alkylamino, di- [d-6] alkyl, amino-C de-6-alkyl, Ci-β-alkylamino-Ci-β alkyl, di- [C? _] -alkyl] amino-C de-6alkyl, d-β-alkylamino / Ci-β-alkoxy alkylamino of C 2-6, di- [C?-6alkyl] amino-alkoxy of C 2 β , amino-alkylamino of d-β, Ci-β-alkylamino of C2-6 alkylamino, di- [Ci-β] alkyl amino-alkylamino of d-β, N-C?-6-amino-alkylamino of C2_6, N-C 1-6 alkylamino of C? -6-C2-β alkylamino, N-alkyl of Ci-β-di- [C? -6] alkyl amino-alkylamino of d-β, pyridyl , imidazolyl, pyridyl-C-6 alkyl, imidazolyl-C6-6alkyl, pyridyl-C6-6alkoxy, imidazolyl-C6-6alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-alkylpiperazinyl e, homopiperazinyl, 4-alkylhomopiperazinyl of C6-6, 4-alkanoylpiperazinyl of C2-6, pyrrolidinyl-alkyl of Ci-β, piperidinyl-C6-6 alkyl, morpholinyl-C6-6 alkyl, piperazinyl-alkyl of Ci-β, 4-alkyl C? _d-C? -6-alkyl, 4-alkanoylpiperazinyl of d-β-C? -6 alkyl, pyrrolidinyloxy, piperidinyloxy, 1-alkylpiperidinyloxy of Ci-β, pyrrolidinyl-C 2-6 alkoxy, piperidinyl- C2-β alkoxy, -6-piperazinyl-6-piperazinyl-6,6-alkoxy-C 2-6 alkoxy-2-6-alkoxy or C 2-6 -alkanoylpiperazinyl-C 2-6 alkoxy; and / Y? R2, R3 / Qr n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention; (r) m is 1 and R1 is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, carboxy, Ci-e alkoxycarbonyl, Ci-β alkyl or C6-6 alkoxy, and X, Y, R2 , R3, Q, n and q have any of the meanings defined above or in this section that relate to particular novel compounds of the invention; (s) m is 2 and the first substituent R1 is selected from the substituents specified in paragraph (q) above and the second substituent R1 is selected from the substituents specified in paragraph (r) above: and X, Y, R2, R3, Q, n and q have any of the meanings defined above or in this section that relate to particular novel compounds of the invention; (t) each of X and Y is a CH group; and R1, R2, R3, Q, m, n and q have any of the meanings defined above or in this section that relate to particular novel compounds of the invention; and (u) one or both of X and Y is a group N; R1, R2, R3, Q, m, n and q have any of the meanings defined above or in this section which relate to particular novel compounds of the invention. The novel novel compounds of the second aspect of the invention include, for example, amide derivatives of Formula I, or pharmaceutically acceptable salts thereof, wherein: (a) R3 is halogen (such as fluoro, chloro or bromo) or Ci-e alkyl (such as methyl, ethyl, propyl and isopropyl), preferably R is chloro, methyl or ethyl, more preferably chloro or methyl; and X, Y, R1, R2, Q, m, n and q have any of the meanings defined above. A preferred compound of the first aspect of the invention is an amide derivative of Formula I wherein X is CH or N: Y is CH or N: R3 is hydrogen, fluoro, chloro, bromo, methyl or ethyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2- methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,
3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) N-methylamino, N- ( 3-aminopropyl) -N-methylamino, N- (2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3- ethylaminopropyl) -N-methylamino, N- (2-dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-diethylaminopropyl) -N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-metilhomopiperazinilo, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetilpiperazinilmetilo, pyrrolidinyloxy , 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, 2- (pyrrolidinyl) etho xi, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- (piperazinyl) propoxy 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ethoxy or 3- (4-acetylpiperazinyl) propoxy; n is 0 or 1; R2 is fluoro, chloro, bromo, methyl or ethyl; q is 0; and Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl. , quinoxalinyl or naphthyridinyl optionally carrying 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, ethylaminomethyl, ethylaminomethyl , dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, -ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-di-ethylaminopropoxy, 3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piper idinilo, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-metilhomopiperazinilo, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetilpiperazinilmetilo, pyrrolidinyloxy, 1-metilpirrolidiniloxi, piperidinyloxy, 1-metilpiperidiniloxi, 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- (piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-ethylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ethoxy and 3- (4-acetylpiperazinyl) propoxy; or a pharmaceutically acceptable salt thereof. A further preferred compound of the first aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3; it is hydrogen chlorine or methyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3- methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-a-inoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- (2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino), N- (2-dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-diethylaminopropyl) -N-methylamino, 2- pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l-yl, homopiperazin-1- yl, 4-acetylpiperazin-l-4-yl-methylhomopiperazin-l-, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-metilpipera zin-l-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-Acetyl-l-yl) ethoxy or 3- (4-Acetyl-l-yl) propoxy; n is 0; q is 0; and Q is phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl, 2-indolyl, 2-benzothienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4-benzofurazanyl, 2-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or 7- quinoxalinyl optionally bearing 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyrid yl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin- 1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2- piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-l-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-metilpiperazin- 1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy and 3- (4-acetylpiperazin-1-yl) propoxy; or a pharmaceutically acceptable salt thereof. A further preferred compound of the first aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is hydrogen, chlorine or methyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, di-ethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy , 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-ethylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, - ethylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, '3-diethylaminopropylamino, N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- (2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino), N- ( 2-dimethylaminoethyl) -N-ethylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3- diethylaminopropyl) -N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin -l-yl, homopiperazin-1-yl, 4-methylhomopiperazin-l-yl, 4-acetylpiperazin-l-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl , 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-1-ylpropoxy 2- (4methylpiperazin-l- il) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy or 3- (4-acetylpiperazin-1-yl) propoxy; n is 0; q is 0; and Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally carries 1 'or 2 substituents selected from the group from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, ethylaminomethyl, ethylaminomethyl, di-ethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2- Methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-di-ethylaminopropoxy , 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino , piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1 -methylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, pi peridin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin- l-Ileytoxy, 3-piperazin-1-ylpropoxy, 2- (4-methyl-piperazin-1-yl) ethoxy, 3- (4-methyl-piperazin-1-yl) -propoxy, 2- (4-acetyl-piperazin-1-yl) -ethoxy and 3- (4-acetylpiperazin-1-yl) propoxy; or a pharmaceutically acceptable salt thereof.
A further preferred compound of the first aspect of the invention is an amide derivative of Formula I wherein X is CH Y is CH or N; R3 is hydrogen, chlorine or methyl; m is 1 or 2; R1 is hydroxy, fluoro, chloro, methyl, ethyl, propyl, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2 -diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2- hydroxypropoxy, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 3-methylaminopropylamino,
2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-di ethylaminopropylamino, 4-dimethylaminobutylamino, 3-amino-2-hydroxy-propylamino, 3-dimethylamino-2-hydroxypropylamino, N- (2-dimethylaminoethyl) -N-methylamino, N- (3- dimethylaminopropyl) - N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4- (2-hydroxyethyl) piperazin-l- yl, homopiperazin-1-yl, 4-methylhomopiperazin-l-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopirrolidin- 1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,
4- (2-hydroxyethyl) iperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, l-benzyl-piperidin-4-yloxy, 2 pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-yl-propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-l-yl-propoxy, 2- ( yl 4-methylpiperazin-1-) ethoxy, 3- (4-methylpiperazin-l-yl) propoxy, 2-hydroxy-3-pyrrolidin-l-yl-propoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy , piperidin-4-ylamino, l-methylpiperidin-4-ylamino, l-benzylpiperidin-4-ylamino, 2-pyrrolidin-l-ylethylamino, 3-pyrrolidin-l-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino , 3-piperidinopropylamino, 2-piperazin-1-ylethylamino, 3-piperazin-1-yl-propylamino, 2- (4-methyl-piperazin-1-yl) -ethylamino, 3- (4-methyl-piperazin-1-y-Di-propylamino, 2- (1-) methylpyrrolidin-2-yl) ethylamino, 3- (l-methylpyrrolidin-2-yl) propylamino, 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylamine ethyl, 3-dimethylamino-2, 2-dimetilpropilaminometilo, 2- (1-methylpyrrolidin-2-ylethyl) aminomethyl, 3-pyrrolidin-l-ilpropilaminometilo, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-l-iletilaminometilo, 3 - (4-methylpiperazin-1-ylpropyl) aminomethyl, or 2-pyridylmethoxy; n is 0; q is 0; and Q is 2-pyridyl, 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, morpholino, piperidino, 4- hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. A preferred compound especially of the first aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is hydrogen, chlorine or methyl; m is 1 and R1 is selected from diethylaminomethyl, N- (3-dimethylaminopropyl) -N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- yl 4-methylhomopiperazin-l-ethylpiperazin-l-yl, homopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-l-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-l- ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimetilaminopropilaminometilo, 3-dimethylamino-2, 2- dimetilpropilaminometilo, 2- (1-methylpyrrolidin-2-ylethyl) aminomethyl, 3-pyrrolidin-l-ylpropylamino ethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, "2-piperazin-l-iletilaminometilo, 3- (4-methylpiperazin-l- ilpropyl) aminomethyl and 2-pyridylmethoxy;
n is 0; q is 0; and Q is 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. A particularly especially preferred compound of the first aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is hydrogen, chlorine or methyl; m is 1 and R1 is N- (3-dimethylaminopropyl) -N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-methylpiperazin-1-ylmethyl or pyrrolidin-3-yloxy; n is 0; q is 0; and Q is 2-morpholinopyrid-4-yl; or a pharmaceutically acceptable salt thereof. A particular preferred compound of the invention is, for example: - N- [3- (4-methylpipérazin-1-ylmethyl) phenyl] -2-methyl-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide, N- [ 6- (4-ethylpiperazin-1-yl) pyrid-3-yl] -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide, - [6- (4-methyl-piperazin-1-yl) pyrid- 3-yl] -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) enzamide or N-. { 6- [N- (3-dimethylaminopropyl) -N-methylamino] pyrid-3-yl} 2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide; or a pharmaceutically acceptable salt thereof. A preferred compound of a second aspect of the invention is an amide derivative of Formula I wherein X is CH or N; And it is CH or N; R3 is fluoro, chloro, bromo, methyl or ethyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2- methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,
3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, '3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) -N-methylamino, N - (3-aminopropyl) -N-methylamino, N- (2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- ( 3-ethylaminopropyl) -N-methylamino, N- (2-dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3- diethylaminopropyl) -N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl , piperazinylmethyl, 4-methylpiperazinylmethyl, homopiperazinylmethyl, 4-methylhomopiperazinylmethyl, 4-acetylpiperazinyl ethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, homopiperidinyloxy, 1-methylhomopiperidinyloxy, 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- (piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ) ethoxy, '3- (4-acetilpiperazinil) propoxy, 3-dimetilaminopropilaminometilo, 3-dimethylamino-2, 2-dimetilpropilaminometilo, 2- (l- etilpirrolidiniletil) aminomethyl, 3-pirrolidinilpropilaminometilo, 2-morfoliniletilaminometilo, 3 ~ morfolinilpropilaminometilo, 2- piperazinylethylaminomethyl, 3- (4-methylpiperazinylopropyl) aminomethyl, pyridylmethoxy, imidazolyl ethoxy, thiazolylmethoxy and 2-methylthiazolylmethoxy; n is 0 or 1. R2 is fluoro, chloro, bromo, methyl or ethyl; q is 0; and Q is phenyl, indenyl, indanyl, tetrahydronaphthyl, fluorophenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl. , benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl which optionally carry 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy , propoxy, isopropoxy, cyclopentyloxy, methylenedioxy, methylamino, ethylamino, diethylamino, dimethylamino, acetamido, propionamido, methanesulfonamido, N-methylmethanesulfonamido, aminomethyl, methylaminomethyl, ethylaminomethyl, diethylaminomethyl, dimethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, -ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methy laminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, phenyl, furyl, thienyl, pyridyl, pyridylmethyl, pyridylmethoxy, azetidinyl, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholino, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-metilhomopiperazinilo, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetilpiperazinilmetilo, pyrrolidinyloxy, 1-metilpirrolidiniloxi, piperidinyloxy, 1-metilpiperidiniloxi, 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) ropoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3 - (piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ethoxy and 3- (4-acetylpiperazinyl) propoxy, and wherein any phenyl group, furyl , thienyl, pyridyl or heterocyclyl in a Q substituent may carry 1 or 2 substituents selected from fluoro, chloro, methyl and methoxy or a pharmaceutically acceptable salt thereof. A preferred compound of a second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is chloro or methyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3- methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-di ethylaminopropylamino, diethylaminopropylamino 3-N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- ( 2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino, N- (2- dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-diet ilaminopropyl) -N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin -l-yl, homopiperazin-1-yl, 4-methylhomopiperazin-l-yl, 4-acetylpiperazin-l-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl , 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-l- il) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy or 3- (4-acetylpiperazin-1-yl) propoxy; n is 0; q is 0; and Q is phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl, 2-indolyl, 2 -benzothienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4-benzofurazanyl, 2-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or 7-quinoxalinyl optionally bearing 1 or 2 substituents selected from hydroxy, fluoro, chloro, 'trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, inometilo methylates, ethylaminomethyl, dimethylaminomethyl , diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy , 2-dimethyloxyethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl idyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin- 1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2- piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-l-ylpropoxy, 2- (4-methylpiperazin-l-yl) ethoxy, 3- (4-metilpiperazin- 1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy and 3- (4-acetylpiperazin-1-yl) propoxy, or a pharmaceutically acceptable salt thereof. A further preferred compound of a second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is chloro or methyl; m is 0, 1 6 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, -methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-di-ethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- (2-methylaminoethyl) -N -methylamino, N- (2-ethylaminoethyl) -N-methylano, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino, N- (2-dimethylaminoethyl) -N- methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-diethylaminopropyl) -N-methylamino, 2-p iridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1 ilo, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4- methylpiperazin-1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy or 3- (4-acetylpiperazin-1-yl) propoxy; n is 0; q is 0; and Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino , ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, -metila inoetoxi, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-etilaminopropoxi, 2-dimethylaminoethoxy, 2 -diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l-yl, homopiperazin-1-yl, 4- methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl , Piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy , 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-yl-propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy 2-piperazin-l-ylethoxy, 3-piperazin-l-yl-propoxy, 2 - (4-methylpiperazin-l-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-acetyl-l-yl) ethoxy and 3- (4-acetyl-l-yl) propoxy; or a pharmaceutically acceptable salt thereof. A further preferred compound of the second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 or 2;
R1 is hydroxy, fluoro, chloro, methyl, ethyl, propyl, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2 -diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2- hydroxypropoxy, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino, N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- yl piperazin-1-yl 4-methylhomopiperazin-l-ethylpiperazin-l-yl, 4- (2-hydroxyethyl) homopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1 -methylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4- (2-hydroxyethyl) piperazin-1-ylmethyl or pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, l-benzyl-piperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin- l-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazyl-l-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, ' 3- (4-methylpiperazin-l-yl) propoxy, 2-hydroxy-3-pyrrolidin-l-yl-propoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy, 4-ylamino piperidyl, l-methylpiperidin -4-ylamino, l-benzylpiperidine-4-ylamino, 2-pyrrolidin-l-ylethylamino, 3-pyrrolidin-l-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-1 -ethylamino, 3-piperazin-1-yl-propylamino, 2- (4-methyl-piperazin-1-yl) -ethylamino, 3- (4-methyl-piperazin-1-yl-propylamino, 2- (1-methylpyrrolidin-2-yl) -ethylamino, 3- (1-methylpyrrolidin-2-yl) propylamino, 2-dimethylaminoethylamino-methyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2, 2-dimethylp ropilaminometilo, 2- (l-methylpyrrolidin-2-ylethyl) -aminometilo, 3-pyrrolidin-l-ilpropilaminometilo, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1-iletilaminometilo, 3- (4-methylpiperazin-l-ylpropyl ) aminomethyl or 2-pyridylmethoxy; n is 0; q is 0; and Q is 2-pyridyl, 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-l-yl, 2-hydroxymethyl-pyrrolidin-l-yl, morpholino, piperidino, 4- hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl; or pharmaceutically acceptable salt thereof. An especially preferred compound of a second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 and R1 is selected from diethylaminomethyl, N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, yl 4-ethylpiperazin-l-yl 4-methylhomopiperazin-l-yl 4-methylpiperazin-I-, homopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl, 4-methylhomopiperazin-1- ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-l-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3- dimetilaminopropilaminometilo, 3-dimethylamino-2, 2-dimetilpropilaminometilo, 2- (l-methylpyrrolidin-2-ylethyl) aminomethyl, 3-pyrrolidin-l-ilpropilaminometilo, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1-iletilaminometilo, 3 - (4-methylpiperazin-1-ylpropyl) aminomethyl and 2-pyridylmethoxy; n is 0; q is 0; and Q is 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof.
A further especially preferred compound of the second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it's CH or N; R3 is chloro or methyl; m is 1 and R1 is selected from diethylaminomethyl, N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1 ilmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, N- methylpyrrolidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, homopiperidin-4-yloxy, N-methylhomopiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaninomethyl, 2- (1-methylpyrrolidin-2-ylethyl) -aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1 iletilaminomethyl, 3- (4-methylpiperazin-li) lpropyl) aminomethyl, 2-pyridylmethoxy, 4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy;
n is 0; q is 0; and Q is phenyl carrying 1 6 2 substituents selected from fluoro, chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido, N-methylmethanesulfonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin- 1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl, or Q is 1-fluorenyl or 4-dibenzofuranyl, or Q is 3-pyridyl or 4-pyridyl bearing a substituent selected from azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin -1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl; or a pharmaceutically acceptable salt thereof. A further especially preferred compound of the second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 and R1 is N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-methylhomopiperazin- l -yl, or 4-methylpiperazin-1-ylmethyl;
n is 0; q is 0; and Q is 2- (pyrrolidin-1-yl) pyrid-4-yl, 2- (3-pyrrolin-1-11) pyrid-4-yl, 2-piperidinopyrid-4-yl, 2-morpholinopyrid-4-yl , 1-fluorenyl, dibenzofuran-4-yl, 3-acetamidophenyl or 3- (2-furyl) phenyl; or a pharmaceutically acceptable salt thereof. A further especially preferred compound of the second aspect of the invention is an amide derivative of Formula I wherein X is CH; And it is CH or N, R3 is chlorine or methyl; m is 1 and R1 is N- (3-dimethylaminopropyl) -N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-methylpiperazin-1-ylmethyl; n is 0; q is 0; and Q is 2-morpholinopyrid-4-yl; or a pharmaceutically acceptable salt thereof. An amide derivative of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, can be prepared by any process known to be applicable to the preparation of chemically related compounds. Such processes, when used to prepare a novel amide derivative of Formula I, are provided as a further feature of the invention and are illustrated by the following representative variants of the process in which, unless otherwise indicated, X, And, R1, R2, R3, m, n, q and Q have any of the meanings defined above. The necessary initial materials can be obtained by standard procedures of organic chemistry. The preparation of such initial materials is described together with the following representative variants of the process and within the attached examples. Alternatively the necessary starting materials are obtainable by procedures analogous to those illustrated which are within the common experience of an organic chemist. (a) A compound of Formula 1, or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof, can be prepared by reacting an aniline of Formula II.
with a benzoic acid of Formula III, or an activated derivative thereof;
under standard amide bond forming conditions, wherein the variable groups are as defined above and wherein any functional group is protected, if necessary, and: (i) eliminates any protecting group: (ii) optionally forming a pharmaceutically salt acceptable or ester unfolds in vivo. A suitable reactive derivative of a carboxylic acid of Formula III is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example, an ester formed by the reaction of the acid with a phenol, such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example, an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide. Standard amide bond forming conditions conveniently include the presence of a suitable base such as, for example, an alkali metal or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, eg, sodium carbonate, potassium carbonate, sodium ethoxide, butoxide, potassium, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl lithium, for example, n-butyllithium, or a dialkylamino lithium, for example diisopropylamide lithium, or , for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methanol, ethanol, tetrahydrofuran, methylene chloride, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin- 2-one, dimethisulfoxide or acetone, and at a temperature in the range, for example, from 0 to 100 ° C, conveniently at or near room temperature. Typically a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent at a non-extreme temperature for example in the region of -10 to 40 ° C, typically at room temperature of about 20 ° C. The conditions that form standard amide bond typically include activating the carboxy group, for example, by treatment with a halo reagent (for example oxalyl chloride) to form an acyl halide in an organic solvent at room temperature and then reactivating the activated compound with an aniline Any functional groups are protected and deprotected as necessary Conveniently, a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region of
-10 to 40 ° C, typically ambient temperature of approximately 20 ° C. The protecting groups can in general be selected from any of the groups described in the literature or known to the skilled chemist as is appropriate for the protection of the group in question and can be introduced by conventional methods. The protecting groups can be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protective group in question, such methods being selected as to effect removal of the protecting group with minimal disturbance of the protective groups. groups on the other side in the molecule. Specific examples of protecting groups are given subsequently for reasons of convenience, in which "lower" as in, for example, lower alkyl means that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for removing protective groups are given below, these are also non-exhaustive. The use of protecting groups and deprotection methods not specifically mentioned are, of course, within the scope of the invention. A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or an ester-forming silanol (the alcohol or silanol preferably contains 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain C? -?? Alquilo grupos grupos alkyl groups (eg isopropyl, tert-butyl); lower alkyl, lower alkoxy groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower acyloxyaliphatic lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkyl lower alkoxycarbonyloxy groups (for example 1-methoxycarbonyloxy ethyl, 1-ethoxycarbonyloxyethyl); lower alkyl groups (for example benzyl, p_-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri (lower alkyl) silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); lower alkyl tri (lower alkyl) silyl groups (for example trimethylsilylethyl); and C2-6 alkenyl groups (for example allyl and vinylethyl). Particularly suitable methods for the removal of the carboxyl protecting groups include for example acid-, base-, metal- or enzymatically catalyzed hydrolysis. Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (e.g., acetyl); lower alkoxycarbonyl groups (e.g., tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example, allyloxycarbonyl); lower alkoxycarbonyl aryl groups (for example, benzoyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl); trialkylsilyl lower (for example trimethylsilyl, tert-butyldimethylsilyl) and lower alkyl, aryl groups (for example benzyl). Examples of amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p_-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p_-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); lower alkoxycarbonyl groups aryl (for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl) alkylidene (for example methylidene), benzylidino and benzylidene substituted groups. Removal of the hydroxy and amino protecting groups include, for example, acid, base, metal or enzymatically catalyzed hydrolysis for groups such as p_-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photically for groups such as o-nitrobenzyloxycarbonyl. refers to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & amp;; Sons 1992, for general guidance on reaction conditions and reagents. The reading refers to Protective Groups in Organic Synthesis, 2nd Edition, by Green et al. , Published by John Wiley & Sons for general guidance on protective groups. The benzoic acid of Formula III can be prepared by cleavage of the corresponding ester thereof which in turn can be prepared by the reaction of an aniline of formula IV
wherein R is, for example, lower alkyl or benzyl with a carboxylic acid of Formula V or an activated derivative thereof as defined above. H02C (CH2) q Q V under standard amide bond forming conditions as defined above, wherein the variable groups are as defined above and where any functional group is protected if necessary. (b) A compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, can be prepared by reacting an aniline of Formula VI
VI with a carboxylic acid of Formula V, or a reactive derivative thereof as defined above, H02C (CH2) q QV under standard amide bond forming conditions as defined above, wherein the variable groups are as defined above and wherein any functional group is protected if necessary, and: (i) eliminates any protective group; and (ii) Optionally forming a pharmaceutically acceptable salt or ester cleavable in vivo. The aniline of Formula VI can be prepared by the reduction of the corresponding nitrobenzene compound of Formula VII
where the variable groups are as defined above and where any functional group is protected if necessary. Typical reaction conditions for reduction include the use of ammonium formate or hydrogen gas in the presence of a catalyst, for example a metal catalyst such as palladium on carbon.
A metal dissolving reduction can be carried out, for example, using iron in the presence of an acid, for example an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric or acetic acid. The reaction is conveniently carried out in the presence of an organic solvent (preferably a polar protic solvent) and preferably with heating, for example about 60 ° C. Any functional group is protected and checked out as necessary. The nitrobenzene compound of Formula VII can be prepared by the reaction of the aniline of Formula II.
with a carboxylic acid of Formula VIII, or a reactive derivative thereof as defined above,
under conditions that form standard amide bond as defined above, wherein the variable groups are as defined above and where any functional group is protected if necessary. (c) a compound of Formula I wherein R 1 or a substituent on Q is Ci-β alkoxy or substituted d-β-alkoxy, Ci-β alkylthio, C?-6 alkylamino, di- [C 1 -C 6 alkyl] β] amino or substituted Ci-β alkylamino can be prepared by alkylation, conveniently in the presence of a suitable base as defined above, of an amide derivative of Formula I wherein R 1 or a substituent on Q is hydroxy, mercapto guanino as appropriate. The reaction is preferably carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxides. The reaction is conveniently carried out at a temperature in the range, for example, from 10 to 150 ° C, preferably in the range from 20 to 80 ° C. A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy in alkoxy or substituted alkoxy, or for the alkylation of mercapto and alkylthio, or for the alkylation of amino in alkylamino or substituted alkylamino, for example a alkyl or substituted alkyl halide, for example an alkyl chloride, bromide or iodide of C? -6, or an alkyl chloride, bromide or iodide of Ci-β, in the presence of a suitable base as defined above, in a suitable inert solvent or diluent as defined above and at a temperature in the range, for example, from 10 to 140 ° C, conveniently at or near room temperature. (d) A compound of formula I wherein a substituent on Q is amino, Ci-β alkylamino, di- [Ci-β] alkyl amino, substituted C?-6 alkylamino, N-C alquilo alkyl- 6-substituted C2_ß alkylamino or an N-linked heterocyclyl group can be prepared by the reaction, conveniently in the presence of a suitable base as defined above, of an amide derivative of Formula I wherein a substituent on Q is a leaving group suitable with an appropriate amine. A suitable leaving group is, for example, a halogen group such as fluoro, chloro or bromo, a C?-6 alkanesulfonyloxy group such as methanesulfonyloxy or an arylsulfonyloxy group such as 4-toluenesulfonyloxy. The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined above and at a temperature in the range, for example from 20 to 200 ° C, conveniently in the range of from 75 to 150 ° C.
(e) a compound of Formula I wherein R1 or a substituent on Q is C alca _s alkanoylamino or substituted C 2-6 alkanoylamino can be prepared by the acylation of a compound of Formula I wherein R 1 or a substituent on Q is amino . A suitable acylating agent is, for example, any agent known in the art for the acylation of amino in acylamino, for example, an acyl halide, for example an alkanoyl chloride or bromide of C? _6 conveniently in the presence of a base suitable, as defined above, an alkanoic acid anhydride or mixed anhydride, for example a C6-C6 alkanoic acid anhydride such as acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and an alkoxy carbonyl halide C? -6, for example an alkoxycarbonyl chloride of C? _6 in the presence of a suitable base as defined above. In general, the acylation is carried out in a suitable inert solvent or diluent as defined above and at a temperature, in the range, for example, from -30 to 120 ° C, conveniently at or near room temperature. (f) a compound of Formula I wherein R 1 or a substituent on Q is C alca-6-alkylsulfonylamino can be prepared by the reaction of a compound of Formula I wherein R 1 or a substituent on Q is amino with an acid Ci-β alkanesulfonic acid, or an activated derivative thereof. A suitable activated derivative of a C?-6 alkan sulfonic acid is, for example, an alkanesulphonyl halide, for example an alkanesulfonyl chloride formed by the reaction of the sulfonic acid and an inorganic acid chloride, for example thionyl chloride. The reaction is preferably carried out in the presence of a suitable base as defined above, particularly pyridine, and a suitable inert solvent or diluent as defined above, particularly methylene chloride. (g) a compound of Formula I wherein R1 or a substituent on Q is carboxy, carboxyC1-6alkyl, Ci-β-carboxy-alkoxy, C?-6-carboxy-alkylamino, N-C-alkyl ? -6, C? -6 carboxy-alkylamino or carboxy-C2-6 alkanoyla can be prepared by cleavage of a compound of Formula I wherein R1 or a substituent on Q is C? -6 alkoxycarbonyl, alkoxycarbonyl of C? -6-Ci-β alkyl, Ci-β-alkoxy-C6-6 alkoxycarbon, C? _6-alkylamino of C? _6, N-C? -6-alkoxycarbonyl of C? 6-C 1-6 alkylamino or C? -6-alkanoylamino-d-β alkoxycarbonyl as appropriate. The cleavage reaction can be conveniently carried out by any of many methods known in the art for such a transformation. The reaction can be carried out, for example, by hydrolysis under acidic or basic conditions. A suitable base is, for example, an alkali metal, alkaline earth metal or carbonate or ammonium hydroxide, for example sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or ammonium hydroxide. The reaction is preferably carried out in the presence of water and a suitable solvent or diluent such as methanol or ethanol. The reaction is conveniently carried out at a temperature in the range of 10 to 150 ° C, preferably at or near room temperature. (h) A compound of Formula I wherein R 1 is C 1-6 amino-amino, C 1-6 alkylamino-C 1-6 alkyl, di- [1-6 alkyl] amino-C 1 alkyl- 6 or a heterocyclyl-Ci-β alkyl group can be prepared by the reaction, conveniently in the presence of a suitable base as defined above, of a compound of Formula IX.
Z- alkyl wherein X, Y, R2, R3, n, q and Q have any of the meanings defined above and Z is a suitable leaving group with an appropriate amine or heterocycle.
A suitable leaving group Z is, for example, a halogen group such as fluoro, chloro or bromo, a C?-6 alkanesulfonyloxy group such as methanesulfonyloxy or an arylsulfonyloxy group such as 4-toluenesulfonyloxy. The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined above and at a temperature in the range, for example from 20 to 200 ° C, conveniently in the range of 50 to 150 ° C. The following biological tests and examples serve to illustrate the present invention. Biological Tests The following tests can be used to measure the inhibitory effects of p38 kinase, the inhibitors of TNF and antiarthritics of the compounds of the present invention: In vitro enzymatic test The ability of the compounds of the invention to inhibit the enzyme p38 kinase was assessed . The activity of the test compounds against each of the p38a and p38β isoforms of the enzyme was determined. Human recombinant MKK6 was isolated (Access Number
GenBank G1209672) from clone Image 45578 (Genomics,
1996, 33, 151) and was used to produce protein in the form of a GST fused protein in a pGEX vector using procedures analogous to those described by J. Han et al. , Journal of Biological Chemistry, 1996, 271, 2886-2891. P38a (GenBank accession number G529039) and p38β (Accession number GenBank G1469305) were isolated by PCR amplification of human lymphoblastoid cDNA [Accession number GenBank GM1416) and human fetal brain cDNA [synthesized from mRNA (Clontech, no of catalog 6525-1) using a Gibco superguide cDNA synthesis kit respectively using pligonucleotides designed for the 5 'and 3' ends of the human p38a and p38ß genes using methods analogous to those described by J. Han et al. , Biochimica et Biophysica Acta. 1995, 1265, 224-227 and Y. Jiang et al. , Journal of Biological Chemistry, 1996, 271, 17920-17926. Both isoforms of the p38 protein were expressed in e coli in PET vectors. Human recombinant p38a and p38β isoforms were produced as 6His, 5 'c-myc labeled proteins. The MKK6 and p38 proteins were purified using standard protocols: GST MKK6 was purified using a glutathione sepharose column and the p38 proteins were purified using nickel chelate columns. The p38 enzymes were activated before use by incubation with MKK6 for 3 hours at 30 ° C. The non-activated coli-expressed MKK6 retained sufficient activity to fully activate the p38 isoforms. The incubation of activation comprises p38a (10 μl of 10 mg / ml) or p38β (10 μl of 5 mg / ml) together with MKK6 (10 μl of 1 mg / ml), "Kinase Regulator" [100 μl; regulator pH 7.4 comprising Tris (50 mM), EGTA (0.1 mM), sodium orthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (30 μl of 50 mM Mg (OCOCH3) 2 and 0.5 mM ATP). produced enough p38 enzyme activated for three microtiter plates.The test compounds were solubilized in DMSO and 10 μl of a diluted sample of 1:10 in a Kinase Regulator was added to a well on a Microtiter plate. individual dose, the compound was tested at 10 μM, then "Kinase Test Mix" [30 μl; comprising Myelin Basic Protein (Gibco BRL cat # 1322B-010; 1 ml of a 3.33 mg / ml solution in water), activated p38 enzyme (50 μl) and "Kinase Regulator" (2 ml) followed by \ ATP Marking '[10 μl, comprising ATP 50 μl, 3P ATP 0.1 μCi (Amersham International cat # BFIOOO) and 50 mM Mg (OCOCH3) 2] The plates were incubated at room temperature with gentle shaking. containing P38a were incubated for 90 minutes and the plates containing p38β were incubated for 45 minutes The incubation was stopped by the addition of 50 μl of 20% trichloroacetic acid (TCA) The precipitated protein was phosphorylated by p38 kinase and the Test compounds were assessed for their ability to inhibit this phosphorylation.The plates were filtered using a Canberra Packard Unifilter and washed with 2% TCA, dried overnight and counted in a Top Count scintillation counter. test were initially tested at an individual dose and the active compounds were reexamined to allow determination of the I-In Vitro Cell-Based Assay (i) PBMC values The ability of the compounds of this invention to inhibit the production of TNFα was assessed using human peripheral blood mononuclear cells that They synthesize and secrete TNFα when stimulated with lipopolysaccharides. Peripheral blood mononuclear cells
(PBMC) were isolated from heparinized human blood (10 units / ml heparin) by density centrifugation
(Lymphoprep ™; Nycomed). The mononuclear cells were resuspended in a culture medium [RPMI 1640 medium
(Gibco) supplemented with 50 units / ml of penicillin,
50 μg / ml streptomycin, 2 M glutamine and 1% heat-inactivated human AB serum (Sigma H-1513)]. The compounds were solubilized in DMSO at a concentration of 50 mM, diluted 1: 100 in a culture medium and subsequently serially diluted in a culture medium containing 1% DMSO. PBMC (2.4xl05 cells in
160 μl of culture medium) were incubated with 20 μl of various concentrations of the test compound (cultures in triplicate) or 20 μl of a culture medium containing 1% DMSO (control wells) for 30 minutes at 37 ° C in a humidified incubator (5% C02 / 95% air) (Falcon 3072, 96 well flat bottom tissue culture plates). 20 μl of lipopolysaccharide [LPS E. Coli 0111: B4 (Sigma L-4130) final concentration of 10 μg / ml] solubilized in a culture medium was added to appropriate wells. 20 μl of the culture medium was added to control wells with "one medium alone". Six "LPS alone" and four "one medium only" controls were included in each 96-well plate. Various concentrations of a known TNFa inhibitor were included in each test, ie an inhibitor of the type IV PDE enzyme (for example see Semmler, J. Wachtel, H and Endres, S., Int. J. Immunopharmac. (1993) , I5 (3), 409-413) or a pro-NFa convertase inhibitor (e.g., see McGeehan, GM et al., Nature (1994) 370, 558-561). Plates were incubated for 7 hours at 37 ° C (humidified incubator) after which 100 μl of the supernatant from each well was removed and stored at -70 ° C (96-well round bottom plates; Corning 25850). TNFa levels were determined in each sample using a human TNFa ELISA
(see WO92 / 10190 and Current Protocols in Molecular Biology, vol. 2 by Frederick M. Ausbel et al., John Wiley and Sons
Inc.). % inhibition = (single-medium LPS only) - (single-medium test concentration) xl00 (LPS only - medium alone) (ii) (Total Human Blood) The ability of the compounds of this invention to inhibit TNFa production It was also assessed on a total human blood test. Total human blood secretes TNFα when stimulated with LPS. This property of the blood forms the basis of a test that is used as a secondary test for test compounds that are profiled as active in the PBMC test. Heparinized human blood (10 units / ml) was obtained from volunteers. 160 μl of whole blood was added to 96-well round bottom plates (Corning 25850). The compounds were solubilized and serially diluted in RPMI 1640 medium (Gibco) supplemented with 50 units / ml penicillin, 50 μg / ml streptomycin and 2mM glutamine, as detailed above, 20 μl of each concentration of test to appropriate wells (cultures in triplicate). 20 μl of RPMI 1640 medium supplemented with antibiotics and glutamine were added to control wells. The plates were incubated for 30 minutes at 37 ° C (humidified incubator), before the addition of 20 μl of LPS
(final concentration 10 μg / ml). The RPMI 1640 medium was added to control wells. Six controls of "LPS alone" and four of "one medium alone" were included in each plate. A known inhibitor of synthesis / secretion of TNFa was included in each test. The plates were incubated for 6 hours at 37 ° C (humidified incubator). Plates were centrifuged (2000 rpm for 10 minutes and 100 μl of plasma was removed and stored at -70 ° C (Corning plates 25850). TNFa levels were measured by ELISA (see WO92 / 10190 and Current Protocols in Molecular Biology. , vol 2 by Frederick M. Ausbel et al., John Wiley and Sons Inc.) The paired antibodies that were used in the ELIZA were obtained from R &D Systems (catalog nos. MAB610 anti-human TNFα coating antibody, antibody that detects biotinylated TNFα biotinylated BAF210) Ex vivo / In vivo Assay The ability of the compounds of this invention as ex vivo TNFa inhibitors was evaluated in rat or mouse Briefly, groups of Wistar male Alderley Park (AP) rats (180 -210 g) were dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route, for example peroral (po), intraperitoneal (ip) or subcutaneous
(s.c.) Ninety minutes later the rats were sacrificed using a concentration of C02 and were bled by means of the posterior vena cava in 5 units of sodium heparin / ml of blood. The blood samples were placed immediately on ice and centrifuged at 2000 rpm for 10 minutes at 4 ° C and the harvested plasmas were frozen at -20 ° C for subsequent tests on their effect on TNFa production by human blood stimulated with LPS The rat plasma samples were thawed and 175 μl of each sample was added to a layout design pattern on a 96 well round bottom plate (Corning 25850). 50 μl of heparinized human blood was added after each well was mixed on the plate, incubated for 30 minutes at 37 ° C (humidified incubator). LPS 25 μl was added; final concentration of 10 μg / ml) to the wells and incubation continued for an additional 5.5 hours. The control wells were incubated with 25 μl of a medium alone. The plates were then centrifuged for 10 minutes at 2000 rpm and 200 μl of the supernatants were transferred to a 96-well plate and frozen at -20 ° C for subsequent analysis of TNF concentration by ELISA. Analysis of data by dedicated software calculations for each compound / dose:% inhibition of TNFa = (average TNFa (Controls) -TNFa mean (Treated) xlOO Mean TNFa (Controls) Alternatively, mice could be used instead of rats in the above procedure: Testing as an antiarthritic agent The activity of a compound as an antiarthritic agent was tested as follows: Native type II acid-soluble collagen was shown to be arthritogenic in rats by
Trentha, et al. [1]; caused polyarthritis when administered in incomplete Freunds adjuvants. This is now known as collagen-induced arthritis (CIS) and similar conditions can be induced in mice and primates. Recent studies have shown that anti-TNF monoclonal antibodies [2] and mixed fused TMF receptor IgG proteins [3] improve established CIA indicating that TNF plays a key role in the pathophysiology of CIA. In addition, the surprising reported efficiency for anti-TNF monoclonal antibodies in recent clinical trials of rheumatoid arthritis indicate that TNF plays a major role in this chronic inflammatory disease. Thus the CIA in DBA / 1 mice as described in references 2 and 3 is a tertiary model that can be used to demonstrate the anti-arthritic activity of a compound. See also reference 4. 1. Trentham, D.E. et al. , (1977) J. Exp. Med., 146, 857. 2. Williams, R.O. et al. , (1992) Proc. Nati Acad. Sci., 89, 9784. 3. Williams, R.O. et al. , (1995) Immunology, 84, 433. 4. Badger, M. B. et al. , (1996) The Journal of
Pharmacology and Experimental Therapeutics, 279, 1453-1461. Although the pharmacological properties of the compounds of Formula I vary with the structural change as expected, in general a compound of Formula I gives about 30% inhibition of p38a and / or p38β of concentrations up to 10 μM. No physiologically unacceptable toxicity was observed at the effective dose of the tested compounds of the present invention. By way of example, the compound N-. { 6- [N- (3-dimethylaminopropyl) -N-methylamino] pyrid-3-yl} -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide has an I of approximately 0.05 μM against p38a and an I or approximately 5 μM in the Total Human Blood test. According to a further aspect of the invention there is provided a pharmaceutical composition comprising an amide derivative of Formula I, or an in vivo or pharmaceutically acceptable cleavable ester thereof, as defined above in association with a pharmaceutically acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or dispersible granules, syrups or elixirs), for local use (e.g. as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation, for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, the compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration in humans will generally contain, for example, 0.5 mg to 0.5 g of active agent compound with an appropriate and convenient amount of excipients which may vary from about 5 to about 98% by weight of the composition total. The size of the dose for therapeutic or prophylactic purposes of a compound of Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, in accordance with well-known principles of the invention. medicine.
When using a compound of Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kilogram of body weight is received, if required in divided doses. . In general, lower doses are administered when a parenteral route is used. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg of body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example 0.5 mg to 25 mg per kg of body weight will be used. However, oral administration is preferred, particularly in the form of a tablet. Typically, the unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. According to a further aspect of the invention there is provided an amide derivative of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, as defined above for use in a method of treatment of the human or animal body by therapy . According to a further aspect of the invention, there is provided the use of an amide derivative of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, as defined above in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines. In a further aspect the present invention provides a method for treating diseases or medical conditions mediated by cytokines comprising administering to a warm-blooded animal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or in vivo cleavable ester thereof. . In a further aspect of the present invention there is provided the use of a compound of Formula I or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8. In a further aspect the present invention provides a method for treating diseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. In a further aspect the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by TNF which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or inbred ester in vivo of the invention. same. In a further aspect of the present invention there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in the manufacture of a medicament for use to inhibit TNF, IL-1, IL -6 or IL-8. In a further aspect of the present invention there is provided a method for inhibiting TNF, IL-1, IL-6 or IL-8 comprising administering to a warm-blooded animal an effective amount of a compound of Formula I, or a salt pharmaceutically acceptable or in vivo cleavable ester thereof. In a further aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in the manufacture of a medicament of use for inhibiting TNF. In a further aspect the present invention provides a method for inhibiting TNF, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or ester cleavable in vivo thereof. In a further aspect the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by p38 kinase In a further aspect the present invention provides a method for treating diseases or medical conditions mediated by p38 kinase comprising administering to a warm-blooded animal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or in vivo cleavable ester of the same. In a further aspect the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in the manufacture of a medicament for use in the production of an inhibitory effect of p38 kinase. In a further aspect the present invention provides a method for 'providing an inhibitory effect of p38 kinase comprising administering to a warm-blooded animal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or in vivo cleavable ester thereof. . In a further aspect the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, asthma, Irritable bowel, multiple sclerosis, AIDS, septic shock, ischemic heart disease or psoriasis. In a further aspect the present invention provides a method for treating rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease or psoriasis comprising administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof. The compounds of this invention can be used in combination with other drugs and therapies used in the treatment of affective states that would benefit from the inhibition of cytokines, in particular TNF and IL-1. For example, the compounds of Formula I could be used in combination with drug therapies used in the treatment of rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease, psoriasis and the other states. affective mentioned earlier in this specification. For example, by virtue of their ability to inhibit cytokines, the compounds of Formula I are of value in the treatment of some inflammatory and non-inflammatory diseases that are currently treated with a non-steroidal anti-inflammatory drug inhibiting cyclooxygenase.
(NSAIDs) such as indomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of a compound of Formula I with an NSAID may result in a reduction in the amount of the last agent needed to produce a therapeutic effect. This reduces the likelihood of adverse side effects of NSAIDs such as gastrointestinal effects. Thus according to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in conjunction or mixture with a non-steroidal anti-inflammatory agent inhibiting cyclooxygenase, and a pharmaceutically acceptable diluent or carrier. The compounds of the invention can also be used with anti-inflammatory agents such as an inhibitor of the enzyme 5-lipoxygenase.
The compounds of Formula I can also be used in the treatment of conditions such as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate, steroids and penicillinamine, and under conditions such as osteoarthritis in combination with steroids. The compounds of the present invention can also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, antidegradant and / or repair agents such as Diacerhein, hyaluronic and acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril. The compounds of Formula I can be used in the treatment of asthma in combination with antiasthmatic agents such as bronchodilators and leukotriene antagonists. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within their approved dosage range. Sequential use is contemplated, when a combination formulation is inappropriate. Although the compounds of Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful where inhibiting the effects of cytokines is required. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. The invention will now be illustrated in the following non-limiting examples, in which, unless otherwise indicated: (i) the operations were carried out at room temperature, i.e., in the range of 17 to 25 ° C and under an atmosphere of an inert gas such as argon unless otherwise indicated; (ii) the evaporations were carried out by rotary evaporation under vacuum and the work-up procedures were carried out after the removal of residual solids by filtration; (iii) column chromatography (by the instantaneous process) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 reverse phase silica (Art. 9303) obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) was performed on C-18 reversed phase silica, for example on a Dynamax C-18 60A preparative reverse phase column; (iv) the returns are given for illustration only and are not necessarily the maximum obtainable;
(v) in general, the final products of Formula I have satisfactory microanalysis and their structures were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrum techniques; mass spectrum data (FAB) by fast atom bombardment was obtained using a Platform spectrometer and, where appropriate, negative ion data and positive ion data were collected; the chemical change NMR values were measured on the delta scale [the proton magnetic resonance spectra were determined using a Varian Gemini 2000 spectrometer operating at a field strength of 300MHz or a Bruker AM250 spectrometer operating at a field strength of 250MHz]; the following abbreviations have been used: s, singlet; d, double; t, triple; m, multiple; br, broad; (vi) the intermediates were not fully characterized generally and the purity was assessed by thin layer chromatography, HPLC, infra red (IR) and / or NMR analysis; (vii) the melting points are not corrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil bath apparatus; the melting points for the final products of Formula I were determined after crystallization from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, together or as a mixture; and (viii) the following abbreviations have been used: DMF N, N-dimethylformamide DMSO dimethylsulfoxide THF tetrahydrofuran Example 1 N- < 4-propylphenyl) -5- (4-cyanobenzamido) -2-methylbenzamide 4-n-Propylaniline (0.11 g) was added to a stirred suspension of 5- (4-cyanobenzamido) -2-methylbenzoyl chloride (0.224 g) , triethylamine (0.21 ml) and methylene chloride (5 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. Thus, the title compound (0.049 g) was obtained; NMR spectrum: (DMSOd6) 0.87 (t, 3H), 1.56 (m, 2H), 2.33 (s, 3H), 2.48 (m, 2H), 7.13 (d, 2H), 7.28 (d, 1H), 7.63 (m, 2H), 7.83 (, 3H), 8.01 (d, 1H), 8.1 (m, 2H); Mass Spectrum: M + H + 398. The 5- (4-cyanobenzamido) -2-methylbenzoyl chloride used as an initial material was prepared as follows: 4-cyanobenzoyl chloride (4.50 g) was added to a stirred suspension of? aethyl-5-amino-2-methylbenzoate (J. Med.
Chem., 1991, 3_4, 2176-2186; 3 g), triethylamine (2.54 ml) and methylene chloride (100 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was acidified by the addition of IN aqueous hydrochloric acid solution and the mixture was stirred at room temperature for 30 minutes. The resulting solid was isolated and dried under vacuum at 40 ° C to give methyl-5- (4-cyanobenzamidol-2-methylbenzoate (5.32 g); NMR spectrum: (DMSOdβ) 2.47 (s, 3H), 3.83 (s) , 3H), 7.31 (d, 1H), 7.88 (d, 1H), 8.0 (d, 2H), 8.1 (d, 2H), 8.27 (s, 1H), 10.57 (s 1H), Mass Spectrum: M + H + 295. A mixture of a portion (3 g) of the material thus obtained, 2N aqueous sodium hydroxide solution (20.4 ml), water (10 ml) and methanol (80 ml) was stirred at room temperature for 16 hours. Then it was heated at 50 ° C for 5 hours, the resulting solution was evaporated and the residue was partitioned between ethyl acetate and water.The aqueous phase was acidified to pH 5 by the addition of IN aqueous hydrochloric acid solution and the The resulting solid was isolated and dried under vacuum at 40 ° C. Thus, 5- (4-cyanobenzamido) -2-methylbenzoic acid (1.79 g) was obtained: NMR spectrum: (DMSOdβ) 2.45 (s, 3H), 7.24 (d, 1H), 7.84 (m, 1H), 8.02 (m, 4H), 8.26 (s, 1H), 10.41 (d, 1H); mass ectro: MH "279. Oxalyl chloride (0.104 g) was added dropwise to a stirred mixture of 5- (4-cyanobenzamido) -2-methylbenzoic acid (0.21 g), DMF (a few drops) and sodium chloride. methylene (10 ml) that had been cooled to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 4 hours. The mixture was evaporated to give the required starting material which was used without further purification. Example 2 Using an analogous procedure to that described in Example 1, the appropriate benzoyl chloride was reacted with the appropriate aniline to give the compounds described in Table I. Table I
Notes a) The product gave the following data: NMR spectrum: (DMSOdβ) 0.87 (t, 3H), 1.52-1.56 (m, 2H), 2.32 (s, 3H), 2.48-2.53 (, 2H), 7.13 ( d, 2H), 7.26 (d, 1H), 7.51-7.63, 7.8 (d, 1H) 7.86 (s, 1H), 7.95 (d, 2H), 10.21 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M + H + 373. The 5-benzamido-2-methylbenzoyl chloride used as starting material was prepared from methyl 5-amino-2-methylbenzoate and benzoyl chloride using procedures analogous to those described in the of Example I which is concerned with the preparation of starting materials.
This was obtained in turn: methyl-5-benzamido-2-methylbenzoate. NMR spectrum: (DMSOdβ) 2.43 (s, 3H), 3.83 (s, 3H), 7.29
(d, 1H), 7.49-7.61 (m, 3H), 7.88 (d, 1H), 7.95 (d, 2H), 8.29
(s, 1H), 10.33 (s, 1H); Mass Spectrum: M + H + 270; 5-benzamido-2-methylbenzoate NMR spectrum: (DMSOdβ) 2.43 (s,
3H), 7.24 (d, 1H), 7.44-7.6 (m, 3H), 7.84 (d, 1H), 7.94 (d, 2H), 8.25 (s, 1H), 10.39 (s, 1H), 12.80 (s) , 1 HOUR); Mass Spectrum: M + H + 254; and 5-benzamido-2-methylbenzoyl chloride which was used without further purification. b) after the reaction mixture had been stirred at room temperature for 16 hours, the mixture was filtered and the filtrate was washed in turn with an aqueous hydrochloric acid solution IN and a solution of saturated aqueous sodium bicarbonate. The organic phase was evaporated and the residue was triturated under a mixture of isohexane and ethyl acetate. The resulting solid was isolated, washed with diethyl ether and dried. The product thus obtained gave the following data. NMR spectrum: (DMSOdβ) 2.33 (s, 3H), 3.72 (s, 6H), 6.9 (d, 1H), 7.25 (d, 2H), 7.43-7.58 (m, 4H), 7.78 (d, 1H) , 7.87 (s, 1H), 7.95 (d, 2H), 10.13 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M + H 391. c) After the reaction mixture had been stirred at room temperature for 16 hours, the mixture was filtered and the filtrate was washed in turn with IN aqueous hydrochloric acid solution and a solution of saturated aqueous sodium bicarbonate. The organic phase was evaporated and the residue was triturated under a mixture of isohexane and ethyl acetate. The resulting solid was isolated, washed with diethyl ether and dried. The product thus obtained gave the following data: Mass Spectrum: M + H + 416. EXAMPLE 3 N- [3- (4-Methylpiperazin-1-ylmethyl) phenyl] -2-methyl-5- (2-morpholinopyrid-4) ylcarbonylamino) benzamide Using an analogous procedure to that described in Example 1, 1,2-morpholinopyridine-4-carbonyl chloride was reacted with N- [3- (4-methylpiperazin-1-ylmethyl) phenyl] -5-amino- 2-methylbenzamide. The residue was purified by column chromatography on an ion exchange column (SColu column isolute from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a mixture of 99: 1 methanol and a hydroxide solution. of saturated aqueous ammonium as eluent. Thus the title compound was obtained with 27% yield; Mass Spectrum: M + H + 529. The 2-morpholinopyridine-4-carbonyl chloride used as an initial material was prepared as follows: 2-chloropyridine-4-carbonyl chloride (11.2 g) was added to a stirred mixture of tert. -potassium butoxide (7.15 g) and THF (50 ml) that had been cooled to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated. 2-chloropyridine-4-carboxylic acid tert-butyl ester (10.5 g); NMR spectrum: (CDC13) 1.6 (s, 9H), 7.72 (d, 1H), 7.82 (s, 1H), 8.51 (d, 1H). After the repetition of the previous reaction, a mixture of the pyridine-4-carboxylate thus produced (18.3 g) and morpholine (30 ml) was stirred and heated at 100 ° C for 40 hours. The mixture was poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by column chromatography on silica using initially a 5: 1 mixture of isohexane and ethyl acetate and then a 10: 3 mixture of the same solvents as eluents. Thus, tert-butyl 2-morpholinopyridine-4-carboxylate (15 g) was obtained; NMR spectrum: (DMSOdβ) 1.52 (s, 9H), 3.46-3.55 (m, 4H) 3.62-3.7 (m, 4H), 7.09 (d, 1H), 7.13 (s, 1H), 8.24 (d, 1H) ). A mixture of the material thus obtained, water (10 ml) and trifluoroacetic acid (90 ml) was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was triturated under a mixture of isohexane and ethyl acetate.
The resulting solid was isolated, washed with ethyl acetate and dried to give 2-morpholinopyridine-4-carboxylic acid (13.2 g); NMR spectrum: (DMSOdβ) 3.46-3.51 (m, 4H), 3.62-3.7 (m, 4H), 7.07 (d, 1H), 7.25 (s, 1H), 8.24 (d '1H). The material thus obtained was reacted with oxalyl chloride using a procedure analogous to that described in the last paragraph of the portion of Example 1 which is concerned with the preparation of starting materials. Thus, 2-morpholinopyridine-4-carbonyl chloride was obtained which was used without further purification. N- [3- (4-Methylpiperazin-l-ylmethyl) phenyl] -5-amino-2-methylbenzamide used as an initial material was prepared as follows: A mixture of 3-nitrobenzyl chloride (1 g) and N- methylpiperazine (3 ml) was stirred and heated at 100 ° C for 4 hours. The mixture was cooled to room temperature and partitioned between methylene chloride and water. The organic phase was evaporated to give 3- (4-methylpiperazin-1-ylmethyl) nitrobenzene
(1.05 g); NMR spectrum: (DMSOdβ) 2.14 (s, 3H), 2.31-2.38 (m, 8H), 3.57 (s, 2H), 7.6 (t, 1H), 7.54 (d, 1H), 8.07-8.13 (m, 2H). Iron powder (2.47 g) was added to a stirred suspension of the material thus obtained in a mixture of ethanol (30 ml), water (2 ml) and acetic acid (0.5 ml). The mixture was stirred and heated to reflux for 4 hours. The mixture was cooled to room temperature. Water (30 ml) was added and the resulting mixture was basified by the addition of sodium carbonate. The mixture was filtered and the filtrate was evaporated. The residue was triturated under water. The resulting solid was isolated and dried under vacuum at 40 ° C. Thus, 3- (4-methylpiperazin-1-yl ethyl) aniline (0.51 g) was obtained; NMR spectrum: (DMSOdβ) 2.11 (s, 3H), 2.24-2.36 (m, 8H), 3.28 (s, 2H), 4.92 (s, 2H), 6.37-6.41 (m, 2H), 6.49 (s, 1H), 7.9 (t, 1H). Oxalyl chloride (0.31 g) was added dropwise to a stirred mixture of 2-methyl-5-nitrobenzoic acid (0.4 g), DMF (a few drops) and methylene chloride (25 ml) which had been cooled to 0 °. C. The mixture was allowed to warm to room temperature and was stirred for five hours. The mixture was evaporated to give 2-methyl-5-nitrobenzoyl chloride which was dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of 3- (4-methylpiperazin-1-ylmethyl) aniline ( 0.44 g), triethylamine (0.49 g) and methylene chloride (10 ml). The mixture was stirred at room temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99: 1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. Thus, N- [3- (4-methylpiperazin-1-ylmethyl) phenyl] -2-methyl-5-nitrobenzamide (0.46 g) was obtained; Mass Spectrum: M + H + 369. A mixture of the 5-nitrobenzamide thus obtained, iron powder (2.79 g), water (1 ml), acetic acid (0.25 ml) and ethanol (15 ml) was stirred and heated to reflux for 5 hours. The mixture was cooled to room temperature. Water (50 ml) was added and the mixture was made basic by the addition of sodium carbonate. The resulting mixture was filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99: 1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. Thus, N- [3- (4-methylpiperazin-1-ylmethyl) phenyl] -5-amino-2-methylbenzamide (0.194 g) was obtained; NMR spectrum: (CDC13) 2.28 (s, 3H), 2.37 (s, 3H), 2.42-2.58 (m, 8H), 3.5 (s, 2H), 3.64 (s broad, 2H), 5.29 (s, 1H) ), 6.67-6.81 (m, 2H), 7.02 (t, 1H), 7.10 (d, 1H), 7.3-7.6 (m, 1H); Mass Spectrum: M + H + 339. Example 4 N- [6- (4-ethylpiperazin-1-yl) pyrid-3-yl] -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) enamide 2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzoic acid (0.162 g) to a stirred mixture of 5-amino-2- (4-ethylpiperazin-1-yl) pyridine (0.093 g), diisopropylethylamine (0.232 g), 2- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (V) (0.176 g) and DMF (10 ml) and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated. The residue was triturated under a mixture of isohexane and ethyl acetate. The resulting solid was isolated and dried under vacuum at 40 ° C to give the title compound (0.071 g); NMR spectrum: (DMSOdβ) 1.02 (t, 3H), 2.34 (m, 2H), 2.4-2.46 (m, 4H), 3.38 3.42 (m, 4H), 3.5-3.53 (m, 4H), 3.69-3.71 (, 4H), 6.82 (d, 1H), 7.08 (d, 2H), 7.22 (s, 1H), 7.62 (d, 1H), 7.82-7.98 (m, 3H), 8.28 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M + H + 550.and 352. The 2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzoic acid used as an initial material was prepared as follows:
Using a procedure analogous to that described in the last paragraph of the portion of Example 3 which is concerned with the preparation of starting materials, methyl 2-chloro-5-nitrobenzoate was reduced to give methyl 5-amino-2-chlorobenzoate with 38% of performance; NMR spectrum: (DMS0d6) 3.79 (s, 3H), 5.46 (s, 2H), 6.66 (d, 1H), 6.97 (s, 1H), 7.1 (d, 1H).
Using an analogous procedure to that described in Example 1, 1,2-morpholinopyridine-4-carbonyl chloride was reacted with methyl 5-amino-2-chlorobenzoate. The reaction product was triturated under a mixture of isohexane and ethyl acetate. The resulting solid was isolated and washed with diethyl ether. Thus methyl 2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzoate was obtained in 63% yield; NMR spectrum: (DMSOd6) 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 3.86 (s, 3H), 7.09 (d, 1H), 7.23 (s, 1H), 7.56 (d. 1H) 7.96 (d, 1H), 8.25 8.28 (m, 2H), 10.55 (s, 1H); Mass Spectrum: M + H + 376 and 378. A mixture of the methyl benzoate thus obtained (3 g), 2N aqueous sodium hydroxide solution (16 ml), the water (25 ml) and methanol (100 ml) was stirred at room temperature for 16 hours. The resulting solution was evaporated and the residue acidified to pHl by the addition of IN aqueous hydrochloric acid solution. Water (1 ml) and methanol (1 ml) were added and the mixture was stirred for 1 hour. The resulting solid was isolated and dried under vacuum at 40 ° C to give the required starting material (2.83 g); NMR spectrum: (DMSOdβ) 3.62-3.74 (m, 8H), 7.21 (d, 1H), 7.53 (d, 1H), 7.63 (s, 1H), 8.01 (d, 1H), 8.21 (d, 1H) , 8.28 (s, 1H), 10.98 (s, 1H); Mass Spectrum: M-H ~ 360 and 362. The 5-amino-2- (4-ethylpiperazin-1-yl) pyridine used as an initial material was prepared as follows:
A mixture of 2-chloro-5-nitropyridine (1 g) and N-ethylpiperazine (4 ml) was stirred and heated at 100 ° C for 16 hours. The mixture was cooled to room temperature and poured into water. The resulting solid was isolated, washed in turn with water and with diethyl ether and dried under vacuum at 40 ° C. Thus, 2- (4-ethylpiperazin-1-yl) -5-nitropyridine (0.22 g) was obtained; NMR spectrum: (DMS0d6) 1.01 (t, 3H), 2.33-2.41 (m, 2H), 2.42-2.44 (m, 4H), 3.71-3.75 (m, 4H), 6.91 (d, 1H), 8.17 ( d, 1H), 8.92 (s, 1H). A mixture of the material thus obtained, 10% palladium on carbon (0.095 g) and methanol (20 ml) was stirred under an atmosphere of hydrogen gas. After the cessation of hydrogen uptake, the catalyst was removed by filtration and the filtrate was evaporated. Thus the required initial material (0.18 g) was obtained; NMR spectrum: (DMSOdβ) 1.0 (t, 3H), 2.28-2.36 (m, 2H), 2.38-2.41 (m, 4H), 3.15-3.21 (m, 4H), 4.5 (broad s, 2H), 6.58 (d, 1H), 6.85 (d, 1H), 7.57 (s, 1H); Mass Spectrum: M + H + 207. Example 5 Using a procedure analogous to that described in
Example 4, the appropriate 5-aminopyridine was reacted with 2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzoic acid to give the compounds described in Table II.
Table II
Notes a) The product gave the following data: NMR spectrum: (DMSOdβ) 2.4-2.49 (m, 8H), 2.98 (s, 3H), 3.48-3.53 (m, 4H), 3.66-3.72 (m, 6H) , 6.61 (m, 1H), 7.1 (d, 1H), 7.23 (s, 1H), 7.53 (d, 1H), 7.78-7.82 (m, 1H), 7.88-7.93 (m, 2H), 8.27- 8.38 (m, 2H), 10.26 (s, 1H), 10.51 (s, 1H); Mass Spectrum: M + H + 538 and 540. The 5-amino-2- [N- (2-dimethylaminoethyl) -N-methylamino] pyridine used as an initial material was prepared from 2-chloro-5-nitropyridine and N- (2-dimethylaminoethyl) -N-methylamine using procedures analogous to those described in the portion of Example 4 which is concerned with the preparation of 5-amino-2- (4-ethylpiperazin-1-yl) pyridine. The initial material required gave the following data:
NMR spectrum: (DMSOdβ) 2.35 (t, 2H), 2.48 (s, 6H), 2.82 (s, 3H), 3.32-3.44 (m, 6H), 6.4 (m, 1H), 6.84-6.9 (m, 1H), 7.53-7.56 (m, 1H); Mass Spectrum: M + H + 195. b) The product was purified by column chromatography on a column SCX ion exchange isolute using initially methanol and then a 99: 1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. The product gave the following data: Mass Spectrum: M + H + 552 and 554. The 5-amino-2-2- [N- (3-dimethylaminopropyl) -N-methylaminopropyl) -N-methylamino] pyridine used as a material Initial preparation was prepared from 2-chloro-5-nitropyridine and N- (3-methylaminopropyl) -n-methylamine using procedures analogous to those described in the portion of Example 4 which is concerned with the preparation of 5-amino-2- (4-ethylpiperazin-1-yl) pyridine. The initial material required gave the following data: NMR spectrum: (DMSOdβ) 1.48-56 (, 2H), 2.08 (s, 6H), 2.16 (t, 2H), 2.49 (s, 3H), 3.29-3.36 (, 2H), 4.28 (s broad, 2H), 6.37-6.42 (m, 1H), 6.84-6.9 (m, 1H), 7.53 (s, 1H); Mass Spectrum: M + H + 209. c) The product gave the following data: Spectrum of
NMR: (DMSOdβ) 2.19 (s, 3H), 2.36-2.39 (m, 4H), 3.39-3.43 (m,
4H), 3.39-3.52 (m, 4H), 3.68-3.71 (m, 4H), 6.84 (d, 1H), 7.08
(d, 1H), 7.23 (s, 1H), 7.52 (d, 1H), 7.84-7.94 (m, 3H), 8.27 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M + H + 536 and 538.
The 5-amino-2- (4-methylpiperazin-1-yl) pyridine used as an initial material was prepared from 2-chloro-5-nitropyridine and N-methylpiperazine using procedures analogous to those described in the portion of Example 4 which is concerned with the preparation of 5-amino-2- (4-ethylpiperazin-1-yl) pyridine. The initial material gave the following data: NMR spectrum: (DMSOdβ) 2.26 (s, 3H), 2.47-2.49 (m, 4H), 3.21-3.25 (m, 4H), 6.6 (d, 1H), 6.9 (d , 1H), 7..57 (s, 1H); Mass Spectrum: M + H + 193. d) The product was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99: 1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent . The product gave the following data: Mass Spectrum: M + H + 550 and 552. The 5-amino-2- (4-methylpiperazin-1-yl) pyridine used as an initial material was prepared from 2-chloro-5 -nitropyridine and N-methylhomopiperazine using procedures analogous to those described in the portion of Example 4 which is concerned with the preparation of 5-amino-2- (4-ethylpiperazin-1-yl) pyridine. The initial material gave the following data: Mass Spectrum: M + H + 207.
Example 6 N- [3- (4-Methylpiperazin-1-ylmethyl) phenyl] -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide Using an analogous procedure to that described in Example 4, it was reacted - (4-methylpiperazin-1-ylmethyl) aniline with 2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzoic acid to give the title compound in 32% yield; NMR spectrum: (DMSOdβ) 2.13 (s, 3H), 2.31-2.35 (m, 8H), 3.42 (s, 2H) 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 7.02 (d , 1H), 7.1 (d, 1H), 7.22-7.3 (m, 2H), 7.57-7.65 (m, 3H), 7.84-7.94 (m, 2H), 8.28 (d, 1H), 10.47 (s, 1H) ), 10.52 (s, 1H); Mass Spectrum: M + H + 549 and 551. EXAMPLE 7 Pharmaceutical Compositions The following illustrates the representative pharmaceutical dosage forms of the invention as defined herein (referred to as the active ingredient "Compound X"), for therapeutic or prophylactic use in human: (a) Tablet I mg / tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% w / v paste) 2.25 Magnesium stearate; 3.0 (b) Tablet II mg / tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% w / v paste) 2.25 Magnesium stearate 3.0
(c) Tablet III mg / tablet
Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% w / v paste) 0.75 Magnesium stearate 1.0
(d) Capsule mg / capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium ... 1.5
(e) Injection I (50 mg / ml)
Compound X 5.0% p / v
1M sodium hydroxide solution 15.0% v / v 0.1M hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w / v
Water for injection up to 100% (f) Injection II (10 mg / ml) Compound X • 1.0% w / v Sodium phosphate BP 3.6% w / v 0.1 M sodium hydroxide solution 15.0% v / v
Water for 100% injection (g) Injection III (1 mg / ml, regulated at pH6)
Compound X 0.1% w / v Sodium phosphate BP 2.26% w / v
Citric acid 0.38% p / v
Polyethylene glycol 400 3.5% w / v
Water for 100% injection (h) Aerosol I mg / ml Compound X 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0 Dichlorodifluoroethane 490.0
(i) Aerosol II mg / ml Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j) Aerosol III mg / ml
Compound X 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane; 1086.0 Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg / ml Compound X 2.5 Soy lecithin, 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6
(1) Ointment ml Compound X 40 mg Ethanol 300 μl Water 300 μl l-Dodecylazacycloheptan-2-one 50 μl Propylene glycol up to 1 ml
Note The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. Tablets (a) - (c) can be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h) - (k) can be used in conjunction with standard metered dose aerosol dispensers, and the sorbitan triolate suspension agents and soy lecithin can be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.
Claims (6)
- R2 is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, Ci-β alkoxycarbon, Ci-β alkenyl alkyl of C2-β, C2-β alkynyl, Ci-β alkoxy, C-alkylamino ? 6 or di- [Ci-β] amino alkyl; R3 is hydrogen, halogen, C? -6 alkyl or C? _6 alkoxy; Q is 0, 1, 2, 3 or 4; and Q is aryl, aryloxy, aryl-C6-6 alkoxy, arylamino, N-Ci-β-arylamino alkyl, Ci-β arylamino, N-Ci-β-arylamino-Ci-β alkylamino , aroylamino, arylsulfonylamino, N-arylcarbamoyl, N-arylsulfamoyl, aryl-C2-β-alkanoylamino, C3-7 cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-Ci-β-alkoxy, heteroarylamino, N-Ci-β-heteroarylamino , C 1-6 heteroaryl-alkylamino, C 1-6 N-alkyl-heteroaryl-alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylcarbamoyl, N-heteroarylsulphamoyl, heteroaryl-C 2 ß-alkanoylamino, heterocyclyl, heterocyclyloxy, heterocyclyl-alkoxy of Ci-β, heterocyclylamino, N-Ci-β-heterocyclylamino-alkyl, heterocyclyl-Ci-β-alkylamino, C-6-Ci-β-heterocyclyl-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylcarbamoyl, N -heterocyclylsulfamoyl or C2-e heterocyclyl-alkanoylamino, and Q is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, C? -6 alkyl, C2-b alkenyl, C2-b alkynyl, alkoxy of C? _6, Ci-β alkylthio, C? -6 alkylsulfinyl, C? -6 alkylsulfonyl, C? -e alkylamino, di- [Ci-b] amino alkyl, C? _6 alkoxycarbonyl, N -alkylcarbamoyl of C? _6, N, N-di- [alkylcarbamoyl of C? -6] carbamoyl, alkanoyl of C2-6, alkanoyloxy of C2-6, alkanoylamino of Ci-β, N-alkylsulfamoyl of Ci-β, N , N-di- [C? _6] alkyl sulphamoyl, C? _? Alkylsulfonylamino, N-Ci-β-alkylsulfonylamino of Ci-β, halogen-Ci-β alkyl, hydroxy-Ci-β alkyl, Ci-β-alkyloxy-Ci-β alkyl, cyano-Ci-β-alkyl, amino-C-β-alkyl, Ci-β-alkylamino Ci-β alkyl, di- [Ci-β alkyl] amino- C?-βalkyl, C?-C6carboxy-alkyl, C?-6-alkoxycarbonyl of C? _-alkyl, carbamoyl-Ci-e alkyl, N-alkylcarbamoyl of Ci-β-alkylamino C de-6, N, N-di- [Ci-β alkyl] carbamoyl-C?-6-alkyl, halo-C 2 -β-alkoxy / hydroxy-C 2 -β alkoxy, Ci-β-alkoxy -C2-6 alkoxy, Ci-β cyano-alkoxy, C? -6 alkoxy / Ci-β-alkoxy-Ci-β alkoxy, Ci-β-carbamoyl-alkoxy, N-alkylcarbamoyl e-Ci-β, N, N-di- [Ci-β] alkylcarbamoyl-C?-6-alkoxy, C 2 -β-alkylamino / C?-6-alkoxy-C 2 -β alkoxy alkoxy; di- [Ci-β alkyl] amino-C2-β alkoxy, C2-5 haloalkylamino, C2-β hydroxy-alkylamino, Ci-β-alkylamino of C?-β-cyano-alkylamino of C? βß, carboxy-alkylamino of Ci-β, alkoxycarbonyl of Ci-β-alkylamino of Cα-e, carbamoyl-alkylamino of Ci-β, N-alkylcarbamoyl of Ci-β-alkylamino of Cα-6 / N, N- di- [C6-6 alkyl] carbamoyl-C-6 alkylamino, C2-6 amino-alkylamino, C6-6 alkylamino of C2-6 alkylamino, di- [Ci-β] amino alkyl -alkylamino of C2-β, N-C alquilo-6-halogenoalkylamino of C?-6, N-Ci-β-hydroxy-alkylamino of C2-6 / N-C alquilo-6-alkoxy alkyl of C? -6-C2-6 alkylamino, N-C? -6-cyano-alkylamino of? -β? N-Ci-β-carboxy-alkylamino of Ci-β, N-C 1 -β-alkoxycarbonyl of Ci-e-alkylamino of Ci-β, N-C alquilo-6-carbamoyl-alkylamino of C ? 6, N-C 1-6 alkyl-N-alkylcarbamoyl of C? -6-Ci-β-alkylamino, N-Ci-β-N alkyl, N-di- [Ci-β alkyl] carbamoyl-alkylamino of Ci-β, N-C?-6-amino-alkylamino of C 2 -β / N-Ci-β-alkylamino of C ?6-alkylamino of C2-6 / N-alkyl of Ci-β- di- [Ci-β alkyl] amino-alkylamino of C2-β? Halogen-C2-β-alkanoylamino / hydroxy-alkanoylamino of C2-β-Ci-β-alkanoylamino of C2-β-cyano-C2-β-alkanoylamino, C2-β-carboxy-alkanoylamino / C6-alkoxylamino of C2-6 / Carbamoyl-C2-β-alkanoylamino, N-alkylcarbamoyl of Ci-β-alkanoylamino of C2-β, N, N-di- [Ci-β alkyl] carbamoyl-C2-β-alkanoylamino, C2-6 amino-alkanoylamino / C?-6 alkylamino - C2-6alkylamino / Ci- [beta] -amino-alkanoylamino di-C2-6 / aryl, aryl-Ci-β-aryl, ary-C?-βalkoxy, aryloxy, arylamino, N-alkyl of C? -6-arylamino, arylalkyl of Ci-β, N-Ci-β-aryl-alkylamino of Ci-β, aroylamino, arylsulfonylamino, N-arylsulfamoyl, aryl-C2-β / β-heteroaryl alkanoylamino, heteroaryl-C6-6alkyl, heteroaryloxy, heteroaryl-Ci-βalkoxy, heteroarylamino, N-Ci-β-heteroarylamino-alkyl, heteroaryl-C-6alkylamino, N-C6-6-heteroaryl-alkylamino of Ci-β, heteroarylcarbonylamino, heteroarylsulfonylamino, N-heteroarylsulfamoyl, heteroaryl-C2-β-alkanoylamino, heteroaryl-Ci-β-alkyloxy-Ci-β-heteroaryl-alkylamino of Ci-β-C alquilo-6-alkyl, N -alkyl Ci-β-heteroaryl-alkylamino of Ci-β-Ci-β alkyl, hetero cyclyl, heterocyclyl-C6-6alkyl, heterocyclyloxy, heterocyclyl-Ci-βalkoxy, heterocyclylamino, N-Ci-β-heterocyclylamino-alkyl, heterocyclyl-Ci-β-alkylamino, N-Ci-β-heterocyclyl- alkyl C 1-6 alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-C 2-6 alkanoylamino / heterocyclyl-Ci-β-alkyloxy-C 6 -alkyl, heterocyclyl-C 1-6 -alkylamino-C 1 -alkylamino 6 and N-C 1-6 alkyl-heterocyclyl-C 1-6 alkylamino-C 1-6 alkyl, or Q is substituted with an alkylenedioxy group of C 1-3, and wherein any of the substituents on Q defined above that comprise a CH group that is attached to 2 carbon atoms or a group of CH3 that is attached to a carbon atom can optionally carry in each of the CH2 or CH3 groups a substituent selected from hydroxy, amino, Ci alkoxy -β, C? _ß alkylamino, di- [Ci-β] amino and heterocyclyl alkyl, and wherein any aryl, heteroaryl or heterocyclyl group in a Q substituent may optionally carry 1 or 2 substituents selected from hydroxy, halogen, Ci-β alkyl, C? _ alkoxy, carboxy, Ci-β, N-alkylcarbamoyl alkoxycarbonyl, C? -6, N, N-di- [Ci-β] alkyl carbamoyl, C 2-6 alkanoyl, amino, Ci-β alkylamino, di- [Ci-e] amino alkyl, halogen-Ci alkyl -e, hydroxy-Ci-βalkyl, C?-6alkyl-C alquilo-6alkyl, cyano-C alquilo-6alkyl, Ci-β-aminoalkyl, Ci-β-alkyl-C-alkylamino? -6, di- [Ci-β alkyl] amino-C-6 alkyl, aryl and aryl-Ci-β alkyl; or a pharmaceutically acceptable salt or an indole ester in vivo thereof, wherein X is CH or N; And it is CH or N; m is 0, 1, 2, or 3; R1 is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, Ci-β alkyl, C2-β alkenyl, C2-alqu alkynyl, C? _ Alkoxy, Ci-β alkylthio , Ci-β alkylsulfinyl, Ci-β alkylsulfonyl, C? -6 alkylamino, di- [C? -6] amino alkyl, C? -6 alkoxycarbonyl, C? _6 N-alkylcarbamoyl, N, N -di- [Ci-β] alkyl carbamoyl, C2-6 alkanoyl, C2-6 alkanoyloxy / Ci-β-alkanoylamino, N-alkylsulfamoyl of C6-6, N, N-di- [Ci-β alkyl] ] sulphamoyl, Ci-β alkanesulphonylamino, Ci-β-alkanesulfonyloamino N-α6 alkyl, halogen-C alquilo-6 alkyl, C?-6 hydroxyalkyl, C? _6-C alco-C alco alkyl alkoxy β, Ci-β cyanoalkyl, Ci-β aminoalkyl, Ci-βalkylamino-C alquilo-βalkyl, di- [C?-βalkyl] amino-C?-βalkyl, Ci-β-carboxyalkyl, Ci-β alkoxycarbonyl, Ci-6 alkyl, C6-6 carbamoylalkyl, Ci-β-N-alkylcarbamoyl-Ci-β alkyl, N, N-di- [Ci-β alkyl] carbamoyl-alkyl Ci -β, halogen-C2-6 alkoxy / hydroxy-C2-alkoxy, Ci-e-alkoxy of C2-β / cyano-Ci-β-alkoxy, Ci-β-carboxy-alkoxy, Ci-alkoxycarbonyl -β-Ci-β alkoxy, the carbamoyl-C 1-6 alkoxy, N-alkylcarbamoyl of C? -d-alkoxy of C? -6, N, N-di- [Ci-e alkyl] carbamoyl-alkoxy of C? -6, C2_6 amino-alkoxy? C2-6 Ci-β-alkylamino of C2-β- di- [C de-e] alkyl] amino-C2-6 alkoxy / halogen-C2-β alkylamino, C2-β hydroxy-alkylamino, Ci-e alkoxy -alkylamino of C2-6, cyano-alkylamino of Ci-β, carboxy-alkylamino of Ci-β, alkoxycarbonyl of C? -6-alkylamino of C? _6, carbarmoyl-alkylamino of Ci-β, N-alkylcarbamoyl of Ci-? β-C 1-6 alkylamino, N, N-di- [Ci-β alkyl] carbamoyl-C 1-6 alkylamino, C 2 ß amino-alkylamino, C 2-6 alkylamino d-β-alkylamino, di- [ C6-6 alkylamino-C2-6alkylamino, C6-6-halogenoalkylamino-C6-6alkylamino, N-C2-7alkylamino-C2-βalkylamino-hydroxylamino, -C1 -6-alkoxy of Ci-β-alkylamino of C2-β / N-alkyl-cyano of Ci-β-alkylamino of Ci-β, N-alkyl-carboxy of C?-6-alkylamino of C ? 6, N-Ci-β-alkoxycarbonyl of Ci-β-alkylamino of Ci-β, N-alkyl-carbamoyl of C?-6-alkylamino of Ci-β, N-alkyl of Ci-β-N-alkylcarbamoyl of Ci-β-alkylamino of Ci-β, N-alkyl of Ci-β-N, N-di- [Ci-β] alkylcarbamoyl-alkylamino of Ci-βN-alkyl-amino of Ci-β-alkylamino of C2-β, N-C 1 -C 6 -alkylamino of C?-6-alkylamino of C-β / N-C 1 -C 6 alkyl-di- [C de _] alkyl] amino-alkylamino alkyl? Halogen-C2-β-alkanoylamino / C2-β-hydroxy-alkanoylamino, C2-β-C2-β-alkanoylamino d-β-alkanoylamino alkoxy, C2-β-alkanoylamino C2-β alkoxycarbonyl carboxy-alkanoylamino-Ci-β-alkanoylamino alkoxy C2-ß / carbamoyl-C2_6 alkanoylamino, N-alkylcarbamoyl of C-β, C2-6 alkanoylamino, N, N-di- [C? _] Alkyl] carbamoyl-C2-6 alkanoylamino / C2 amino-alkanoylamino -β, Ci-β-alkanoylamino alkylamino of C2-6, or di- [C6-6] alkylamino-alkanoylamino of C2-6 / or R1 is aryl, aryl-C1-6alkyl, aryl-alkoxy Ci-β, aryloxy, arylamino, N-Cι-6-arylamino alkyl, C? _6 arylarylamino, Ci-β-arylalkyl Ci-β alkylamino, aroylamino, arylsulfonylamino, N-arylsulfamoyl , C2_6 aryl-alkanoylamino, heteroaryl, C6_6-heteroaryl-alkyl, heteroaryloxy, heteroaryl-C-β-alkoxy, heteroarylamino, N-Ci-β-heteroarylamino alkyl, heteroaryl-alkylamino-Ci-, N- Ci-β-heteroaryl-Ci-β alkylamino alkyl, heteroarylcarbonylamino- heteroarylsulphonylamino, N-heteroarylsulphamoyl, Ci-β heteroaryl-alkynylamino, Ci-β-Ci-β-alkyloxy-heteroaryl, C?-6-alkyl-heteroaryl-Ci-β-alkyl, Ci-β-N-alkyl -heteroaryl-alkylamino of C? -6-Ci-β alkyl, heterocyclyl, heterocyclyl-Ci-β alkyl, heterocyclyloxy, heterocyclyl-Ci-β alkoxy, heterocyclylamino, N-Ci-β-heterocyclylamino-alkyl, heterocyclyl- Ci-e alkylamino, N-C 1-6 -heterocyclyl-C 1-6 -heterocycliccarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, C 2 -6 -heterocyclic-C 1-6 -alkanoylamino, heterocyclyl-C 6 -alkoxy-C 6 -alkyl, heterocyclyl -alkylamino of Ci-β-alkyl of Ci-e or N-alkyl of C? -6-heterocyclyl-alkylamino of C? -6-alkyl of C? -6 or (R1) m, is an alkylenedioxy group of C1- 3, and wherein any of the R1 substituents defined above that comprise a CH2 group that is attached to 2 carbon atoms or to a group of CH3 that is attached to a carbon atom can optionally carry in each of the CH2 or CH3 groups a substituent selected from hydroxy, amino, C? _ alkoxy, C?-6 alkylamino, di- [C? -6] alkyl amino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent R1 can optionally carry 1 or 2 substituents selected from hydroxy, halogen, Ci-β alkyl, Ci-β alkoxy, boxi, Ci-β alkoxycarbonyl, N-alkylcarbamoyl of C? -6, N, N-di- [Ci-β] alkyl carbamoyl, C2-β alkanoyl, amino, Ci-βalkylamino, di- [alkyl] of C? _6] amino, haloalkyl of Ci-β, hydroxy-alkyl of Ci-β, alkoxy of C? -6-Ci-β alkyl, cyano-C? -6 alkyl, amino-Ci-β alkyl , Ci-β-alkylamino of Ci-β, di- [C de-6 alkyl] aminoalkyl of C?-6, aryl and aryl-C alquilo-6 alkyl, n is 0, 1, 2 or 3; R 2 is the hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy alkoxycarbonyl of C 1 e, Ci-β alkyl, C 2-6 alkenyl, C 2 β alkynyl, Ci-β alkoxy, alkylamino C? -6 or di- [C? _6] amino alkyl; R3 is hydrogen, halogen, Ci-β alkyl or alkoxy q is O, 1, 2, 3 or 4; and Q is aryl, aryloxy, aryl-Ci-β alkoxy, arylamino, Ci-β-arylamino N-alkyl, C?-6 aryl-alkyloxy, Ci-β-arylarylkylamino β, aroylamino, arylsulfonylamino, N-arylcarbamoyl, N-arylsulfamoyl, aryl-C2-6 alkanoylamino, C3-7 cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-C6-6 alkoxy, heteroarylamino, N-C6-alkyl -heteroarylamino, heteroaryl-alkylamino of C? _ß, N-Ci-β-heteroaryl-alkylamino of Ci-β, heteroarylcarbonylamino, heteroarylsulfonylamino, N-heteroarylcarbamoyl, N-heteroarylsulfamoyl, heteroaryl-C2-6 alkanoylamino / heterocyclyl, heterocyclyloxy, heterocyclyl-C6-alkoxy, heterocyclylamino, N-C6-heterocyclylamino-N-alkyl, C6-6-heterocyclyl-alkylamino, N-C6-6-heterocyclyl-C6-alkylamino , heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylcarbamoyl, N-heterocyclylsulphamoyl or heterocyclyl-C2-β-alkanoylamino and Q is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, Ci-β alkyl, C2-6 alkenyl / C2-β alkynyl, C? alkoxy 6, C? _6 alkylthio, C-_6 alkylsulfinyl Ci-e * arylsulfonyl, Ci-e alkylamino, di- [Ci-β] amino alkyl, C?-6 alkoxycarbonyl, C N-alkylcarbamoyl? -β, N, N-di- [C?-6-alkylcarbamoyl] carbamoyl, C2-β alkanoyl / C2-6 alkanoyloxy / Ci-e alkanoylamino, N-alkylsulfamoyl of Ci-β, N, N-di - [Ci-β] sulphamoyl alkyl, C? _ alca-alkylsulfonylamino, Ci-β-alkylsulfonylamino N-Ci-β alkyl, halo-Ci-β alkyl, hydroxyC de _6 alkyl, Ci-alkoxy e-Ci-e alkyl, cyanoC6-alkyl, amino-Ci-β alkyl, Ci-β-alkylamino of Ci-β, di- [Ci-β alkyl] amino-C-alkyl ? -6, Ci-β -carboxy-alkyl, Ci-β-alkyloxycarbonyl? -C? Alkyl, C? _6 carbamoyl-C6-6alkyl, N-alkylcarbamoyl of C? _6-Ci-β alkyl, N, N - di- [Ci-β alkyl] carbamoyl-C?-6alkyl, halogen-Cz-alkoxy, hydroxy-C 2-6 alkoxy / α-6-C 2-6 alkoxy / cyano-alkoxy CI-6? carboxy-C6-alkoxy, Ci-β-alkoxy-C6-6 alkoxycarbonyl, C-β- carbamoyl-alkoxy, Ci-β-alkoxy-N-alkylcarbamoyl of Ci-e, N, N-di- [C] -6] alkylcarbamoylcarbamoyl-C?-6alkoxy, C 2 -β-alkylamino / C?-6-alkoxy-C 2 -alkoxy, di- [C?-6alkyl] amino-alkoxy of C2-6 / halogen-C2- [beta] alkylamino, C2-6 hydroxy-alkylamino, Ci-β-alkylamino of C2-β, cyano-alkylamino of C [beta], carboxy-alkylamino of Ci-[beta], alkoxycarbonyl of Ci-β-alkylamino of Ci-β, carbamoyl-C 1-6 alkylamino, N-alkylcarbamoyl of Ci-β-alkylamino of C β-β, N, N-di- [Ci-β] alkyl carbamoyl-alkylamino C? -6, C2-β amino-alkylamino, C? -6-alkylamino of C2-e, di- [C? -6] alkyl amino-alkylamino of C2-β, N-alkyl of Ci-? β-halogenoalkylamino of Ci-β, N-C 1 -β-hydroxy-alkylamino of C 2 -β, N-C 1-6 alkyl-C? _-alkylamino of C 2-6 alkylamino, N-alkyl of Ci-β-cyano-alkylamino of Ci-6, N-alkyl of C?-6-carboxy-alkylam of C? -6, N-C 1-6 alkyl-alkoxycarbonyl of C? -6-Ci-β-alkylamino, N-C 1-6 alkyl-carbamoyl-alkylamino, N-C 1-6 alkyl ß-N-al qui 1 carbamoi Ci-ß-alkyloamino of Ci-β, N-alkyl of Ci-β-N / N-di- [C?-6 alkyl] carbamoyl-Ci-β-alkylamino, N-C 1 -β-amino-alkylamino of C 2 -β, C-β-β-alkylamino of Ci-β-alkylamino of C2-β, N-alkyl of Ci-β-di- [C-alkyl of C ? -6] C2-6 amino-alkylamino, C2_6 halogen-alkanoylamino, C2-6-hydroxy-alkanoylamino * C2_6 Ci-β-alkanoylamino alkoxy, C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C3-C3-C3-C3-C2-C3 alkanoylamino C 2-6 -alkanoylamino of C2-β, C2-6 carbamoyl-alkanoylamino / N-alkylcarbamoyl of Ci-β-C2-6 alkanoylamino / N, N-di- [Ci-β alkyl] carbamoyl- C2-6 alkanoylamino, C2-6 amino-alkanoylamino, Ci-β-alkanoylamino alkylamino of C2-β, di- [C6-6 alkyl] amino-alkanoylamino of C2-6 / aryl, arylalkyl of C? _ß, aryl-Ci-β alkoxy, aryloxy, arylamino, N-C? -β-arylamino alkyl, arylamino of C? -6, N-alkyl of Ci-β-aryl- Ci-β, aroylamino, arylsulfonylamino, N-arylsulphamoyl, aryl-C2-6alkylaminoylamino, heteroaryl, heteroaryl-C6-6alkyl, heteroaryloxy, heteroaryl-C1-6alkoxy, heteroarylamino, N-C6-6alkylamino β-heteroarylamino, heteroaryl-Ci-β-alkylamino, Ci-β-heteroaryl-alkylamino of Ci-β, heteroarylcarbonylamino, heteroarylsulfonylamino, N-heteroarylsulfamoyl, heteroaryl-C2-β-alkanoylamino, heteroaryl-C alco-alkoxy β-Ci-β alkyl, Ci-β-alkyl-heteroaryl-Ci-β-alkyl, N-Ci-β-heteroaryl-alkylamino of Ci-β-C alquilo-6 alkyl, heterocyclyl, heterocyclyl-alkyl of Ci-ß, heterocyclyloxy, heterocyclyl-C6-alkoxy, heterocyclylamino, N-Ci-β-heterocyclylamino-alkyl, Ci-β-heterocyclic-alkylamino, C-β-β-heterocyclyl-C-alkylamino N-alkyl? _ß, heter occylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulphamoyl, heterocyclyl-C2_6 alkanoylamino, heterocyclyl-C6-6alkyl-C6-6alkyl, heterocyclyl-C6-6alkylamino-C6-6alkyl and Ci-N-alkyl -β-C6-6-C6-alkyl-heterocyclyl-alkylamino, or Q is substituted with an C1-3 alkylenedioxy group, and wherein any of the substituents on Q defined above that comprise a CH2 group that is attached to 2 carbon atoms or to a group of CH3 which is attached to a carbon atom may optionally carry in each of the groups CH2 or CH3 a substituent selected from hydroxy, amino, hydroxy, Ci-β alkoxy, alkyloxy Ci-β, di- [Ci-β] amino and heterocyclyl alkyl, and wherein any aryl, heteroaryl or heterocyclyl group in a Q substituent may optionally carry 1 or 2 substituents selected from hydroxy, halogen, cycloalkyl, β, Ci-β alkoxy, carboxy, alkoxycarbonyl of Cj.- β-N-alkylcarbamoyl of Ci-β, N, N-di- [C?-β-alkyl] carbamoyl, C 2-6 alkanoyl amino, Ci-β alkylamino, di- [Ci-β] alkyl amino, halogen -Ci-βalkyl, C 1-6 hydroxyalkyl, C? -6alkyl-C? -isalkyloxy, cyano-Ci-βalkyl, Ci-β-aminoalkyl, Ci-β-alkyl-alkylamino C1-6, di- [Ci-β alkyl] amino-C6-6 alkyl, aryl and aryl-C6-alkyl; or a pharmaceutically acceptable salt or an in-vivo unfolding ester thereof. 2. The amide derivative of Formula I according to claim 1, characterized in that RJ is selected from halogen and Ci-β alkyl, or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof. 3. The amide derivative of Formula I according to claim 1, characterized in that X is CH or N; And it is CH or N; is CH or N: Y is CH or N: R3 is hydrogen, fluoro, chloro, bromo, methyl or ethyl; m is 0, 1 or 2; R 1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethyl inomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy , 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, -methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) N-methylamino, N- (3-aminopropyl) -N-methylamino, N- (2 -methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino, N- (2-dimethylaminoethyl) ) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-diet ilaminopropil) -N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-metilhomopiperazinilo, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetilpiperazinilmetilo , pyrrolidinyloxy, 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- (piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ethoxy or 3- (4 -acetylpiperazinyl) propoxy; n is 0 or 1; R2 is fluoro, chloro, bromo, methyl or ethyl; q is 0; and Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazoyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl. , quinoxalinyl or naphthyridinyl optionally carrying 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethyla inomethyl, • dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy , 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, p iperidinilo, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-metilhomopiperazinilo, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetilpiperazinilmetilo, pyrrolidinyloxy, 1-metilpirrolidiniloxi, piperidinyloxy, 1-metilpiperidiniloxi, 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- ( piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ethoxy and 3- (4-acetylpiperazinyl) propoxy; or a pharmaceutically acceptable salt thereof. 4. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is hydrogen, chlorine or methyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3- methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- (2 -methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino), N- (2- dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaneopropyl) -N-methylamino, N- (3-d) ietilaminopropyl) -N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin -l-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl 4-acetyl-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-l- il) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy or 3- (4-acetylpiperazin-1-yl) propoxy; n is 0; q is 0; and Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl optionally bearing 1 or 2 substituents selected from the group from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy , methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy , 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-di-ethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetyl-piperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morfol inometilo, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4- Ioxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methyl-piperazin-1-yl) ethoxy, 3- (4-methyl-piperazin-1-yl) -propoxy, 2- (4-acetyl-piperazin-1-yl) ethoxy and 3- (4-acetyl-piperazin-1-yl) propoxy; or a pharmaceutically acceptable salt thereof. 5. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is hydrogen, chlorine or methyl; m is 1 and R1 is selected from diethylaminomethyl, N- (3-dimethylaminopropyl) -N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- ethylpiperazin-l-yl, homopiperazin-l-yl, 4-methylhomopiperazin-l-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-l-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-l-ylmethyl, 3-hydroxypyrrolidin -1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2, 2-dimethylpropylaminomethyl, 2- ( l-methylpyrrolidin-2-ylethyl) aminomethyl, 3-pyrrolidin-1-yl-propylaminomethyl, 2-morpholinoethylaminomethyl, 3-orpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl, 3- (4-methylpiperazin-1-ylpropyl) aminomethyl and 2-pyridylmethoxy; n is 0; q is 0; and Q is 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. 6. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is hydrogen, chlorine or methyl; m is 1 and R1 is N- (3-dimethylaminopropyl) -limetilamino, 4-methylpiperazin-l-yl, 4-methylhomopiperazin-l-yl, 4-methylpiperazin-l-ylmethyl or pyrrolidin-3-yloxy; n is 0; q is 0; and Q is 2-morpholinopyrid-4-yl; or a pharmaceutically acceptable salt thereof. 7. The amide derivative of Formula I according to claim 1, characterized in that X is CH or N; And it is CH or N; R3 is fluorine, chlorine, bromine, methyl or ethyl; And it is CH or N; R3 is fluoro, chloro, bromo, methyl or ethyl; m is 0, 1 6 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2- methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- (2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3 -ethylaminopropyl) -N-methylamino, N- (2-dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-diethylaminopropyl ) -N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, homopiperazinilmetilo, 4-metilhomopiperazinilmetilo, 4-acetilpiperazinilmet ilo, pyrrolidinyloxy, 1-ethylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinylox ?, homopiperidinyloxy, 1-methylhomopiperidinyloxy, 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, - (morpholinyl) ethoxy, 3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- (piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4- acetylpiperazinyl) ethoxy, 3- (4-acetylpiperazinyl) propoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethyl, 2- (1-methylpyrrolidinylethyl) aminomethyl, 3-pyrrolidinylpropylaminomethyl, 2-morpholinylethylaminomethyl, 3-morpholinylpropylamminomethyl, 2- piperaziniletilaminometilo, 3- (4-metilpiperazinilopropil) aminomethyl, pyridylmethoxy, i idazolilmetoxi, thiazolylmethoxy and 2-metiltiazolilmetoxi; n is 0 or 1. R2 is fluoro, chloro, bromo, methyl or ethyl; q is 0; and Q is phenyl, indenyl, indanyl, tetrahydronaphthyl, fluorophenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl. , benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl which optionally carry 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy , propoxy, isopropoxy, cyclopentyloxy, methylenedioxy, methylamino, ethylamino, diethylamino, dimethylamino, acetamido, propionamido, methanesulfonamido, N-methylmethanesulfonamido, aminomethyl, methylaminomethyl, ethylaminomethyl, diethylaminomethyl, dimethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, -ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, phenyl, furyl, thienyl, pyridyl, pyridylmethyl , pyridylmethoxy, azetidinyl, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholino, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-metilhomopiperazinilo, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetilpiperazinilmetilo, pyrrolidinyloxy , 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy,
- 2- (pyrrolidinyl) ethoxy, 3- (pyrrolidinyl) propoxy, 2- (piperidinyl) ethoxy, 3- (piperidinyl) propoxy, 2- (morpholinyl) ethoxy, '3- (morpholinyl) propoxy, 2- (piperazinyl) ethoxy, 3- (piperazinyl) propoxy, 2- (4-methylpiperazinyl) ethoxy, 3- (4-methylpiperazinyl) propoxy, 2- (4-acetylpiperazinyl) ethoxy and 3- (4-acetylpiperazinyl) propoxy, and wherein any phenyl group, furyl, thienyl, pyridyl or heterocyclyl in a Q substituent may carry 1 or 2 substituents selected from fluoro, chloro, methyl and methoxy or a pharmaceutically acceptable salt thereof. 8. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is chloro or methyl; m is 0, 1 or 2; R1 is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3- methylaminopropylamino, '3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N- (2-aminoethyl) -N-methylamino, N- (3-aminopropyl) -N-methylamino, N- ( 2-methylaminoethyl) -N-methylamino, N- (2-ethylaminoethyl) -N-methylamino, N- (3-methylaminopropyl) -N-methylamino, N- (3-ethylaminopropyl) -N-methylamino, N- (2- dimethylaminoethyl) -N-methylamino, N- (2-diethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, N- (3-di ethylaminopropyl) -timetilamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l -yl, homopiperazin-1-yl, 4-methylhomopiperazin-l-yl, 4-acetylpiperazin-l-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl, 4 -acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidine -1-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy or 3- (4-acetylpiperazin-1-yl) propoxy; n is 0; q is 0; and Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl optionally bearing 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino , ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, -methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl , 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l-yl, homopiperazin-1-yl, 4-methylhomopiperazin -l-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-yl-propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-l-yl-propoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-acetylpiperazin-1-yl) ethoxy and 3- (4-acetylpiperazin-1-yl) propoxy; or a pharmaceutically acceptable salt thereof. 9. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 or 2; R is hydroxy, fluoro, chloro, methyl, ethyl, propyl, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 4- dimethylaminobutylamino, 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino, N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) - N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl, homopiperazin-1-yl, yl 4-methylhomopiperazin-l-, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hidroxipirrolidin- l-ylmethyl, 4- (2-hydroxyethyl) piperazin-l-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, l-benzylpiperidine-4 -yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-yl-propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazyl-l-ylpropoxy , 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-l-yl) propoxy, 2-hydroxy-3-pyrrolidin-l-yl-propoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy -3-morpholinopropoxy, 4-piperidyl-ylamino, l-methylpiperidin-4-ylamino, l-benzylpiperidin-4-ylamino, 2-pyrrolidin-l-ylethylamino, 3-pyrrolidin-l-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino , 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropyl ino, 2- (4-methyl-piperazin-1-yl) -ethylamino, 3- (4-methyl-piperazin-1-yl-propylamino, 2- (1-methylpyrrolidin-2-yl) -ethylamino, 3- (1-methylpyrrolidin-2-yl) propylamino, 2-dimethylaminoethylamino-methyl, 3-dimetilaminopropilaminometilo, 3-dimethylamino-2, 2-dimetilpropilaminometilo, 2- (l-methylpyrrolidin-2-ylethyl) -aminometilo, 3-pyrrolidin-l-ilpropilaminometilo, 2-morpholinoethylaminomethyl, 3- morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl, 3- (4-methylpiperazin-1-ylpropyl) aminomethyl or 2-pyridylmethoxy; n is 0; q is 0; and Q is 2-pyridyl, 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl,
- 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, morpholino, piperidino,
- 4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methyl-piperazin-1-yl; or pharmaceutically acceptable salt thereof 10. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 and R1 is selected from diethylaminomethyl, N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) - N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, yl 4-ethylpiperazin-l-yl 4-methylhomopiperazin-l-yl 4-methylpiperazin-l-, homopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-l-ylmethyl, 4-methylhomopiperazin-1- ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-l-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3- dimetilaminopropilaminometilo, 3-dimethylamino-2, 2-dimetilpropilaminometilo, 2- (l-methylpyrrolidin-2-ylethyl) aminomethyl, 3-pifrolidin-1-ilpropilaminometilo, 2-morfolinoetila inometilo, 3-morpholinopropylaminomethyl, 2-piperazin-1-iletilaminometilo, 3- (4-methyl-piperazin-1-ylpropyl) aminomethyl and 2-pyridylmethoxy; n is 0; q is 0; and Q is 3-pyridyl or 4-pyridyl bearing a substituent selected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. 11. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 and R1 is selected from diethylaminomethyl, N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl , 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, N-methylpyrrolidin 3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, homopiperidin-4-yloxy, N-methylhomopiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, -dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaninomethyl, 2- (1-methylpyrrolidin-2-ylethyl) -aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl , 3- (4-methylpiperazin-1-ylpropyl) aminomethyl, 2-pyridylmethoxy, 4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy; n is 0; q is 0; and Q is phenyl carrying 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido, N-methylmethanesulfonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin- 1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl, or Q is 1-fluorenyl or 4-dibenzofuranyl, or Q is 3-pyridyl or 4-pyridyl bearing a substituent selected from azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin -1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl; or a pharmaceutically acceptable salt thereof 12. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 and R1 is N- (2-dimethylaminoethyl) -N-methylamino, N- (3-dimethylaminopropyl) -N-methylamino, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-methylhomopiperazin-1-yl, or 4-methyl-piperazin-1-ylmethyl; n is 0; q is 0; and Q is 2- (pyrrolidin-1-yl) pyrid-4-yl, 2- (3-pyrrolin-1-yl) pyrid-4-yl, 2-piperidinopyrid-4-yl, 2-morpholinopyrid-4-yl , 1-fluorenyl, dibenzofuran-4-yl, 3-acetamidophenyl or 3- (2-furyl) phenyl; or a pharmaceutically acceptable salt thereof 13. The amide derivative of Formula I according to claim 1, characterized in that X is CH; And it is CH or N; R3 is chloro or methyl; m is 1 and Rx is N- (3-dimethylaminopropyl) -trinethylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-methylpiperazin-1-ylmethyl; n is 0; q is 0; and Q is 2-morpholinopyrid-4-yl; or a pharmaceutically acceptable salt thereof 14. The amide derivative of Formula I according to claim 1, selected from: N- [3- (4-methylpiperazin-l-ylmethyl) phenyl] -2-methyl-
- 5- (2-morpholinopyrid-4-) ilcarbonylamino) benzamide, N- [
- 6- (4-ethylpiperazin-1-yl) pyrid-3-yl] -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide, N- [6- (4- methylpiperazin-1-yl) pyrid-3-yl] -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide and -. { 6- [N- (3-dimethylaminopropyl) -N-methylamino] pyrid-3-yl} -2-chloro-5- (2-morpholinopyrid-4-ylcarbonylamino) benzamide; or a pharmaceutically acceptable salt thereof. 15. The process for the preparation of an amide derivative of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, according to claim 1, characterized in that it comprises: a) reacting an aniline of the Formula II II with a benzoic acid of Formula III, or an activated derivative thereof under conditions that form standard amide bonds, wherein the variable groups are as defined in claim 1 and wherein any functional group is protected, if necessary, and: (i) eliminating any protecting group; (ii) optionally forming a pharmaceutically acceptable salt or ester cleavable in vivo; (b) reacting an aniline of Formula VI with a carboxylic acid of Formula V, or a reactive derivative thereof, H02C - (CH2) q-Q under standard amide bond forming conditions, wherein the variable groups are as defined in claim 1 and wherein any group functional is protected, if necessary, and: (i) eliminate any protective group; and (ii) optionally forming a pharmaceutically acceptable salt or cleavable ester in vivo; (c) an amide derivative of Formula I wherein R1 or a substituent on Q is C6-6 alkoxy or substituted Ci-β alkoxy, C6-6 alkylthio, Ci-β alkylamino, di- [alkyl] of C? _6] amino, or substituted Ci-β alkylamino can be prepared by alkylation, conveniently in the presence of a suitable base, or of an amide derivative of Formula I characterized in that R1 or a substituent on Q is hydroxy, mercapto, or amino as appropriate. (d) an amide derivative of Formula I characterized in that a substituent on Q is amino, Ci-β-di- [C? _] amino alkyl, substituted Ci-β alkylamino or an N-linked heterocyclyl group preparing by the reaction, conveniently in the presence of a suitable base, of an amide derivative of Formula I, characterized in that a substituent on Q is a suitable leaving group with an appropriate amine; (e) an amide derivative of Formula I characterized in that R1 or a substituent on Q is Ci-a alkanoylamino or substituted C2-β-alkanoylamino can be prepared by the acylation of a compound of Formula I, wherein R1 or a substituent on Q is amino; (f) an amide derivative of Formula I characterized in that R1 or a substituent on Q is C6_6 alkanesulfonylamino can be prepared by the reaction of a compound of Formula I, wherein R1 or a substituent on Q is amino with a Ci-β alkanesulfonic acid, or an activated derivative thereof; (g) an amide derivative of Formula I wherein R1 or a substituent on Q is carboxy, carboxyC1-βalkyl, Ci-βalkoxycarboxy, Ci-βcarboxyalkylamino, Ci-N-alkyl β-carboxy-alkylamino of Ci-β, or carboxy-alkanoylamino of C 2-6 can be prepared by cleavage of a compound of the formula I wherein R 1 or a substituent on Q is C 1 -C 6 alkoxycarbonyl, alkoxy- carbonyl of Ci-β- Ci-β alkyl, Ci-β alkoxy of Ci-β alkoxy, Ci-β-alkylamino of C2-6A alkyloxycarbonyl Ci-β-alkylaminocarboxyl of Ci-β-alkylamino of Ci-ß or Ci-β-alkanoylamino alkoxycarbonyl of C2-β as appropriate; or (h) an amide derivative of Formula I, characterized in that R1 is amino-Ci-β alkyl, Ci-β-alkylamino of C?-6 alkyl, di- [C?-6 alkyl] amino-alkyl of C? _ ß, or a heterocyclyl-C? _ß alkyl group, can be prepared by the reaction, conveniently in the presence of a suitable base, of a compound of the formula IX Z-alkyl wherein X, Y, R2, R3, n, q and Q have any of the meanings defined in claim 1 and Z is a suitable leaving group with an appropriate amine or heterocycle. 16. The pharmaceutical composition characterized in that it comprises an amide derivative of Formula I, or an in vivo or pharmaceutically acceptable cleavable ester thereof, according to claim 1 in association with a pharmaceutically acceptable diluent or carrier 17. The use of a amide derivative according to Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, according to claim 1 in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines. 18. The method for treating diseases or medical conditions mediated by cytokines comprising administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, in accordance with claim 1
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0002472.9 | 2000-02-03 | ||
| GB9906277.0 | 2000-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01009308A true MXPA01009308A (en) | 2002-03-26 |
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