Oxamic acids and derivatives as thyroid receptor ligands

A compound of the Formula

• 26
• a prodrug thereof;
• a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug, or said isomer, wherein:
• R1, R2 and R3 are each independently hydrogen, halogen, C1-6 alkyl, trifluoromethyl, —CN, —OCF3 or —OC1-6 alkyl;
• R4 is hydrogen, C1-12 alkyl optionally substituted with one to three substitutents independently selected from Group Z, C2-12 alkenyl, halogen, —CN, aryl, heteroaryl, C3-10 cycloalkyl, heterocycloalkyl, —S(O)2NR9R10, —C(O)NR9R10, —(C1-6 alkyl)-NR9R10, —NR9C(O)R10, —NR9C(O)NR9R10, —NR9S(O)2R10, —(C1-6 alkyl)—OR11, —OR11 or —S(O)aR12, provided that, where R5 is not fluoro, R4 is —S(O)2NR9R10, —C(O)NR9R10, —(C1-6 alkyl)-NR9R10, —NR9C(O)R10, —NR9C(O)NR9R10, —NR9S(O)2R10, —(C1-6alkyl)-OR11, —OR11 or —S(O)aR12;
• or R3 and R4 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 NR17, 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;
• R5 is fluoro, hydroxy, C1-4 alkoxy or OC(O)R9;
• or R4 and R5 may be taken together to form a heterocyclic ring B selected from the group consisting of —CR9═CR10—NH—, —N═CR9—NH—, —CR9═CH—O— and —CR9═CH—S—;
• R6 is hydrogen, halogen, C1-4 alkyl or trifluoromethyl;
• R7 is hydrogen or C1-6 alkyl;
• R8 is —OR9 or —NR19R20;
• R9 and R10 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, —NR13R14, oxo, —OR18, —COOR18 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 R9 and R10 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—, —NR13— and —S—, and optionally further substituted with one or more substituents independently selected from C1-5 alkyl, oxo, —NR13R14, —OR18, —C(O)2R18, —CN, —C(O) R9, 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;
• R11 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)NR9R10 or —C(O)R9;
• R12 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;
• R13 and R14 for each occurrence are independently 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)-CONR15R16 or C3-10 cycloalkyl;
• R15 and R16 for each occurrence are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl or aryl optionally substituted with X and Y;
• R17 is hydrogen, C1-6 alkyl, —COR9 or —SO2R9;
• R18 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)-CONR15R16, —(C1-4 alkyl)-(C1-4 alkoxy) or C3-10 cycloalkyl;
• R19 is hydrogen or C1-6 alkyl;
• R20 is hydrogen or C1-6 alkyl;
• W is O, S(O)d, CH2 or NR9;
• Group Z is C2-6 alkenyl, C2-6 alkynyl, halogen, —CF3, —OCF3, hydroxy, oxo, —CN, aryl, heteroaryl, C3-10 cycloalkyl, hetercycloalkyl, —S(O)aR12, —S(O)2NR9R10, —C(O)R9R10, and —NR9R10;
• Group V is halogen, —NR13R14, —OCF3, —OR9, 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 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;
• X and Y for each occurrence are independently (A) hydrogen, (B) halogen, (C) trifluoromethyl, (D) —OCF3, (E) —CN, (F) C1-6 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)2R13, (J) —C(O)NR13R14, (K) —C(O)R13, (L) —NR13C(O)NR13R14 and (M) —NR13C(O)R14;
• 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.