Patent EA-004229-B1 (EA)
Title: Oxamic acids and derivatives as thyroid receptor ligands
Inventor: CHIANG YUAN-CHING PHOEBE
IPC: C07C235/74
Filed: 2000-02-21
Abstract: 1. A compound of the Formula a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug, or said isomer, wherein: R<1>, R<2> and R<3> are each independently hydrogen, halogen, C1-6 alkyl, trifluoromethyl, -CN, -OCF3 or-OC1-6 alkyl; R<4> is hydrogen, C1-12 alkyl optionally substituted with one to three substituents independently selected from Group Z, C2-12 alkenyl, halogen, -CN, aryl, heteroaryl, C3-10 cycloalkyl, heterocycloalkyl, -S(O)2NR<9>R<10>, -C(O)NR<9>R<10>, -(C1-6 alkyl)-NR<9>R<10>, NR<9>C(O)R<10>, -NR<9>C(O)NR<9>R<10>, -NR<9>S(O)2R<10>, -(C1-6 alkyl)-OR<11>, (O)R<11> or -S(O)aR<12>, provided that, where R<5> is not fluoro, R<4> is -S(O)2NR<9>R<10>, -C(O)NR<9>R<10>, -(C1-6 alkyl)-NR<9>R<10>, -NR<9>C(O)R<10>, -NR<9>C(O)NR<9>R<10>, -NR<9>S(O)2R<10>, -(C1-6 alkyl)-OR<11>, -OR<11> or S(O)aR<12>; Or R<3> and R<4> may be taken together to form a carbocyclic ring A of the formula- (CH2)b- or a heterocyclic ring A selected from the group consisting of -Q-(CH2)c- and (CH2)j-Q-(CH2)k- wherein Q is O, S or NR<17>, wherein said carbocyclic ring A and said heterocyclic ring A are each independently optionally substituted with one or more substituents independently selected from C1-4 alkyl, halide or oxo; R<5> is fluoro, hydroxy, C1-4 alkoxy or OC(O)R<9>; or R<4> and R<5> may be taken together to form a heterocyclic ring B selected from the group consisting of -CR<9>=CR<10>-NH-, -N=CR<9>-NH-, -CR<9>=CH-O- and -CR'=CH-S-; R<6> is hydrogen, halogen, C1-4 alkyl, or trifluoromethyl; R<7> is hydrogen or C1-6 alkyl; R<8> is-OR<9> or -NR<19>R<20>; R<9> and R<10> for each occurrence are independently (A) hydrogen, (B) C1-12 alkyl optionally substituted with one or more substituents independently selected from Group V, (C) C2-12 alkenyl, (D) C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-5 alkynyl, C3-10 cycloalkyl, -CN, -NR<13>3R<14>, oxo, -OR<18>-COOR<18> or aryl optionally substituted with X and Y, (E) aryl optionally substituted with X and Y, or (F) het optionally substituted with X and Y; or R<9> and R<10> for any occurrence may be taken together to form a heterocyclic ring C optionally further containing a second heterogroup selected from the group consisting of -O-, -NR<13>- and -S-, and optionally further substituted with one or more substituents independently selected from C1-5 alkyl, oxo, -NR<13>R<14>, -OR<18>-C(O)2R<18>, -CN, -C(O)R<9>, aryl optionally substituted with X and Y, het optionally substituted with X and Y, C5-6 spirocycloalkyl, and a carbocyclic ring B selected from the group consisting of 5-, 6-, 7- and 8-membered partially and fully saturated, and unsaturated carbocyclic rings, and including any bicyclic group in which said carbocyclic ring B is fused to a carbocyclic ring C selected from the group consisting of 5-, 6-, 7- and 8-membered partially and fully saturated, and unsaturated carbocyclic rings; R<11> is C1-12 alkyl optionally substituted with one or more substituents independently selected from Group V, C2-12 alkenyl, C3-10 cycloalkyl, trifluoromethyl, difluoromethyl, monofluoromethyl, aryl optionally substituted with X and Y, het optionally substituted with X and Y, -C(O)NR<9>R<10> or-C(O)R<9>; R<12> is C1-12 alkyl optionally substituted with one or more substituents independently selected from Group V, C2-12 alkenyl, C3-10 cycloalkyl, aryl optionally substituted with X and Y, or het optionally substituted with X and Y; R<13> and R<14> for each occurrence are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, -(C1-6 alkyl)-C1-6alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, (C1-4 alkyl)-aryl optionally substituted with X and Y, -(C1-4 alkyl)-heterocycle optionally substituted with X and Y, -(C1-4 alkyl)-halo, -(C1-4 alkyl)-poly-halo, -(C1-4 alkyl)-CONR<15>R<16> or C3-10 cycloalkyl; R<15> and R<16> for each occurrence are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl or aryl optionally substituted with X and Y; R<17> is hydrogen, C1-6 alkyl, -COR<9> or -SO2R<9>; R<18> is hydrogen, C1-6 alkyl, C2-6 alkenyl, -(C1-6 alkyl)-C1-6 alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, -(C1-4 alkyl)-aryl optionally substituted with X and Y, -(C1-4 alkyl)-heterocycle optionally substituted with X and Y, -(C1-4 alkyl)-hydroxy, -(C1-4 alkyl)-halo, -(C1-4 alkyl)-poly-halo, -(C1-4 alkyl)-CONR<15>R<16>, -(C1-4 alkyl)-(C1-4 alkoxy) or C3-10 cycloalkyl; R<19> is hydrogen or C1-6 alkyl; R<20> is hydrogen or C1-6 alkyl; W is O, S (O)d, CH2 or NR<9>; Group Z is C2-6 alkenyl, C2-6 alkynyl, halogen, -CF3, -OCF3, hydroxy, oxo, -CN, aryl, heteroaryl, C3-10 cycloalkyl, hetercycloalkyl, -S(O)aR<12>, -S(O)2NR<9>R<10>, -C(O)R<9>R<10>, and -NR<9>R<10>; Group V is halogen, -NR<13>R<14>, -OCF3, -OR<9>, oxo, trifluoromethyl, -CN, C3-10 cycloalkyl, aryl optionally substituted with X and Y, and het optionally substituted with X and Y; het for each occurrence is a heterocyclic ring D selected from the group consisting of 4-, 5-, 6-, 7- and 8-membered partially and fully saturated, and unsaturated, heterocyclic rings containing from one to four heteroatoms independently selected from the group consisting of N, O and S, and including any bicyclic group in which said heterocyclic ring D is fused to a benzene ring or a heterocyclic ring E selected from the group consisting of 4-, 5-, 6-, 7- and 8-membered partial and fully saturated, and unsaturated, heterocyclic rings containing from one to four heteroatoms independently selected from the group consisting of N, O and S; X and Y for each occurrence are independently (A) hydrogen, (B) halogen, (C) trifluoromethyl, (D)-OCF3, (E)-CN, (F)C, alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF3 and phenyl, (G) C1-6 alkoxy, (H) aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF3, C1-4 alkyl and C1-4 alkoxy, (I)-C(O)2R<13>, (J)-C(O)NR<13>R<14>, (K)-C(O)R<14>, (L)-NR<13>C(O)NR<13>R<14> and (M)-NR<13>C(O)R<14>; or X and Y for any occurrence in the same variable may be taken together to form (a) a carbocyclic ring D of the formula- (CH2)e- or (b) a heterocyclic ring F selected from the group consisting of -O(CH2)fO-, (CH2)gNH- and -CH=CHNH-; a and d are each independently 0,1 or 2; b is 3,4,5,6 or 7; c, f, g, j and k are each independently 2,3,4,5 or 6; and e is 3,4,5,6 or 7. 2. A compound or pharmaceutically acceptable salt as defined in claim 1 wherein W is oxygen. 3. A compound or pharmaceutically acceptable salt as defined in claim 2 wherein R<1> is located at the 3 position, R<2> is located at the 5 position, R<3> is located at the 2' position, R<4> is located at the 3' position, R<5> is located at the 4' position and R<6> is located at the 5' position. 4. A compound or pharmaceutically acceptable salt as defined in claim 3 wherein R<1> and R<2> are each independently hydrogen, C1-6 alkyl, bromo, or chloro, R<3> is hydrogen, R<4> is-C(O)NR<9>R<10>, -S(O)2NR<9>R<10>, or S(O)aR<12>, or R<3> and R<4> are taken together to form to said carbocyclic ring A of the formula- (CH2)b- or said heterocyclic ring A selected from the group consisting of -Q-(CH2)c- and -(CH2)j-Q-(CH2)k-wherein Q is O, S or NR<17>, wherein said carbocyclic ring A and said heterocyclic ring A are each independently optionally substituted with one or more substituents independently selected from C1-4 alkyl, halide or oxo, R<5> is fluoro or hydroxy, R<8> is hydroxy, methoxy, ethoxy, isopropoxy, NH2, or NH (CH3), R<6> and R<7> are each hydrogen. 5. A compound or pharmaceutically acceptable salt as defined in claim 4 wherein R<3> and R<4> are taken together to form said carbocyclic ring A of the formula (CH2)b-optionally substituted with one or more substituents independently selected from C1-4 alkyl, halide or oxo. 6. A compound or pharmaceutically acceptable salt as defined in claim 5 wherein R<1> and R<2> are each independently methyl or chloro, R<3> and R<4> taken together form-(CH2)3-, -CH2-C(CH3)2-CH2-, or -(CH2)4-, R<5> is hydroxy, and R<8> is hydroxy or ethoxy. 7. A compound or pharmaceutically acceptable salt as defined in claim 4 wherein R<4> is-C(O)NR<9>R<10>. 8. A compound or pharmaceutically acceptable salt as defined in claim 7 wherein R<1> and R<2> are each independently methyl or chloro, R<5> is hydroxy, R<8> is hydroxy or ethoxy, R<9> is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, n-pentyl, hexyl, 4-fluorophenyl, -CH2-2-thienyl, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclohexyl, endo-2-norbornyl, exo-2-norbornyl, (S)-1-phenylethyl, (R)-1-phenylethyl, -CH2-2-chlorophenyl, -CH2-4-chlorophenyl, -CH2-4fluorophenyl, -CH2-3-chloro-4-fluorophenyi, -CH2-2-chloro-4-fluorophenyl, -CH2-2-fluoro-4-chlorophenyl, -CH2-3,4-difluorophenyl, -CH2-4-isopropylphenyl, -CH2-2,3-dichlorophenyl, -CH2-2,4-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3-trifluoromethyl-4-chlorophenyl, 4-phenylphenyl, 3-(2,4-dimethyl) pentyl, (R)-1-(1-naphthyl)ethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, (R)-1-(naphthyl) ethyl, (R)-2-(1-naphthyl) ethyl, -CH2-(1-naphthyl), (R)-1-cyclohexylethyl, (S)-1-cyclohexylethyl, -CH2-3,4-methylenedioxyphenyl, -CH2-4-t-butylphenyl, -CH2-2,3-dichlorophenyl, 1-indanyl, (R)-1-indanyl, (S)-1-indanyl, 5-indanyl, 1-(1,2,3,4-tetrahydronaphthyl) or (R)-1-cyclohexylethyl, and R<10> is hydrogen, methyl, or ethyl, or R<9> and R<10> are taken together with the nitrogen atom to which they are attached to form N(CH2)7, N (CH2)6, N(CH2)5, N(CH2)4, morpholine, 9. A compound or pharmaceutically acceptable salt as defined in claim 4 wherein R<4> is-S (O)2NR<9>R<10>. 10. A compound or pharmaceutically acceptable salt as defined in claim 9 wherein R<1> and R<2> are each independently methyl or