Patent EA-002113-B1 (EA)
Title: Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
Inventor: MARFAT ANTHONY
IPC: A61P3/00
Filed: 1997-08-25
Abstract: 1. A compound of the formula I   or a pharmaceutically acceptable salt thereof, wherein: R is H, C1-C9 alkyl, -(CH2)m (5 to 10 membered heterocyclyl) wherein m is 0 to 2; or -(Z1)b(Z2)c(C6-C10 aryl) wherein b and c are independently 0 or 1, Z1 is C1-C6 alkylene or C2-C8 alkenylene, and Z2 is O, S, SO2, or NR12; and wherein: said R groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo; hydroxy; C1-C5 alkyl; C2-C5 alkenyl; C1-C6 alkoxy; trifluoromethyl; nitro; -CO2R12; -C(O)NR12R13; -NR12R13;and -SO2NR12R13; R1 is H, or C1-C9 alkyl optionally substituted by I to 3 substituents independently selected from the group consisting of methyl, ethyl, trifluoromethyl, and halo; R2 is R19; -C(O)NR12(CHR12)mC(O)NR12O(CH2)q(C6-C10) aryl), -C(=NR32)NH(CH2)p(C8-C10 aryl), -C(O)NR8 (CH R12)mC(O)N R12-(CH2)pO R12, -C(O)N R12(CH R12)mS(C1-C4 alkyl); or -Z3-R7; wherein p is 0 to 2, m is 1 to 6, and q is 1 or 2; or R2 is R7 is C1-C10 aryl; or 5 to 10 membered heterocyclyl; wherein said R7 groups are optionally substituted by I to 3 substituents independently selected from halo; trifluoromethyl; cyano; nitro; -CO2 R12; C1-C4 alkoxy; -OC(O)( C1-C4 alkyl); -NR12C(O)( C1-C4 alkyl); -C(O)NH2; -C(O)NHOH; -C(O)O(C1-C4 alkyl); C1-C4 alkyl; -S(O)NR12 wherein n is 0 to 2; benzoyl; -NR12R13;-OR12; C1-C6 alkanoyl; -Y1-(C6-C10 aryl); -C(O)O(C6-C10 aryl); -NH(C6-C10 aryl); -C(O)NH(C6-C10 aryl); -C(O)NR12 O(CH2)N(C6-C10 aryl); wherein n is 1 to 3; and -SO2NH(C6-C10 aryl); R8 is H; or C1-C6 alkyl; each R12 and R13 is independently H or C1-C4 alkyl; R19 is phenyl; naphthyl; pyrrolyl; furanyl; thienyl; oxazolyl; pyridinyl; pyrimidinyl; pyridazinyl; quinolinyl; isoquinolinyl; 5,6,7,8-tetrahydroquinolinyl, or 5,6,7,8- tetrahydroisoquinolinyl; wherein: said R19 groups, except said phenyl, are optionally substituted by 1 to 3 R23 substituents, and wherein said phenyl group is optionally substituted by 1 to 3 substituents independently selected from R23 and R24; each R23 is independently halo; C1-C6 alkyl; C1-C alkoxy; C2-C6 alkylenedioxy; trifluoromethyl; -NR12R13; nitro; -C(NR12)NR12R13; -C(O) NR12R13C(O)R12; -C(NOR12)R13; -C(NCN) NR12R13; -C(NCN)SR12; -(CH2)m(CN) wherein m is 0 to 3; hydroxy; -C(O)R12; -C((O)NR12OR13; -C(O)NR12 NR12R13; -OC(O) NR12R13; -NR12C(O)R12; -C(O)C(O) NR12R13; -CO2R12; -SO2R12; -SO2 NR12R13; -C(O) NR12R13; -NR12SO2R13; and -NR12C(O) NR12R13; each R24 is independently imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadlazolyl; thiadiazolyl; thiazolyl; oxazordinyl; thiazolidinyl; or imidazolidinyl; wherein each of the foregoing R24 substituents is optionally substituted by 1 to 3 R23, substituents; Y1 is O or S; Z3 is selected from the group of -NR12-; -(CH2)m-; -CH2C(O)NH-; -NHCH2C(O)-; -CH2C(Y1)CH2-; -CH=CH-; -C(O)C-; -CH(Y1H)-; -C(Y1)-; -CH2C(Y1)-; -C(Y1)CH2-; -C(Y1)C(Y1)-; -CH2NR12-; -CH2-Y1-;  -C(Y1)NR8(CHR12)n-; -NR8C(Y1)(CHR12)n-; -NHCH2-; -Y1-CH2-; -SOCH2-; -CH2SO-; -SO2CH2-; -CH2SO2-; -OC(Y1)-; -N=N-; -NHSO2-; -SO2NH-; -C(Y1)C(Y1)NH-; -NHC(O)O-; -OC(O)NH-; or -NHC(O)NH-, wherein in said Z3 moieties n is 0 to 4 and m is I to 3. provided that: (1) R1 and R may not both be -H at the same time; (2) when R2 is defined as -Z3-R7, where Z3 is -NHC(=O)- and R7 is isoxazolyl optionally substituted by (C1-C4) alkyl or is unsubstituted benzimidazolyl; then R1 must be ethyl; and (3) when Ra is defined as -Z3-R7, where Z3 is -C(O)NH(CH2)n-where n is 0 to 4, or as -NHC(=0)0-, and where R7 is optionally substituted phenyl; then the optional substituent on the R group is other than -CO2R12, and said R group is other than -(CH2)2-tetrazolyl. 2. The compound of claim 1 wherein R2 is -Z3-R7 wherein Z3 is -C(Y1)NH-; -C(O)CH2-; -NHC(Y1)-; -Y1-CH2-' -OC(O)-; -CH=CH-; or -C(Y1)C(Y1)-; and R7 is an optionally substituted aryl or heteroaryl group selected from phenyl, pyydyl, pyrazinyl, thienyl, pyrimidinyl, 2,4-dioxypyeimidin-5-yl, isoxazolyl, isothiazolyl, pyridazinyl, and 1 ,2,4-triazinyl. 3. The compound of claim 2 wherein R7 is substituted phenyl, 2,6-dihalosubstituted phenyl, or 3,5-dihalo-pyrid-4-yl. 4. The compound of claim 1 wherein R2 is -Z3-R7 wherein Z3 is -C(O)NH(CH2)n- or -NHC(O)(CH2)n-, wherein n is 0 or 1, and R7 is phenyl or pyridyl optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, -CO2CH,, methyl, methoxy, and -C(O)NH2. 5. The compound of claim 1 wherein R2 is -Z3-R7, wherein Z3 is -C(O)NH and R7 is phenyl or pyridyl optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, cyano, carboxy and -OC(O)( C1-C4 alkyl). 6. The compound of claim 1 wherein wherein R2 is R19 wherein R19 is optionally substituted pyrimidinyl or optionally substituted pyridazinyl. 7. The compound of claim 1 wherein R2 is phenyl substituted by R24 wherein said R24 is oxadiazolyl, thiadiazolyl or tetrazolyl wherein said R24 groups are optionally substituted by C1-C2 alkyl, or wherein R, is phenyl substituted by cyanomethyl, hydroxy or formyl. 8. The compound of claim 1 wherein R2 is -Z3-R7 wherein Z3 is -C(Y1)NH-, and R7 is phenyl, pyrazinyl, pyrimidinyl, isoxazolyl, or pyridyl, wherein each of said R7 groups is optionally substituted by 1 to 3 substituents independently selected from halo, methoxycarbonyl, trifluoromethyl, benzoyl, acetyl, dimethylamino, hydroxy, nitro, methyl, cyano, methylsulphonyl, and methylthio. 9. The compound of claim 1 wherein R2 is -C(O)NR8(CHR12)mC(O)NR12(CH2)OR12 or -C(O)NR12(CHR12)mS(C1-C4 alkyl), wherein R8, R12, m and p are as defined in claim 1. 10. The compound of claim 1 selected from the group consisting of: 1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (3,5-dichloro-pyridin-4-yl)-amide; 1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (2,6-dichloro-phenyl)-amide; 1-Cyclobutyl-3-ethyl-1H-indazole-6-carboxylic acid (3,5-dichloro-pyridin-4-yl)-amide; 3-Ethyl-1-isopropyl-1H-indazole-6-carboxylic acid (3,5-dichloro-pyridin-4-yl)-amide; 1-Cyclopropylmethyl-3-ethyl-1H-indazole-6-carboxylic acid (3.5-dichloro-pyridin-4-yl)amide; 1-Cyclohexyl-3-ethyl-1H-indazole-6-carboxylic acid (3,5-dichloro-pyridin-4-yl)amide; 3-Ethyl-1-(4-fluoro-phenyl)-1H-indazole-6-carboxylic acid (3,5-dichloro-pyridin-4-yl)-amide; 1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid hydroxycarbamoylmethyl-amide; 1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (2-methylsulfanyl-ethyl)-amide; 1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid hydroxycarbamoylmethylmethyl-amide; S-1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (1-benzyloxycarbamoyl-ethyl)amide; R-1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (1-hydroxycarbamoyl-ethyl)amide; 1-Cyclopentyl-3-ethyl-6-thiophen-2-yl-1H-indazole; 1-Cyclopentyl-3-ethyl-6- phenyl-1H-indazole; and the pharmaceutically acceptable salts of the foregoing compounds. 11. A compound of the formula   or a pharmaceutically acceptable salt thereof, wherein: R is H, C1-C9 alkyl, -(CH2)m, or -(Z1)b(Z2)c(C6-C10 aryl) wherein b and c are independently 0 or 1, Z, is C1-C6 alkylene or C2-C8 alkenylene, and Z is O, S, SO2, or NR12, and wherein: said R groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, C1 C5 alkyl, C2-C5 alkenyl, C1-C6 alkoxy, trifluoromethyl, nitro, -CO2R12, -C(O)NR12R13, - NR12R13 and -SO2 NR12R13; R1 is H,or C1-C9 alkyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, trifluoromethyl, and halo; each R12 and R13 is independently H or C,-C, alkyl; and X is bromine, -C(O)O(C1-C6 alkyl), carboxy, CH2OH or -C(O)Cl.