Sorbitol dehydrogenase inhibitors

A compound of the formula I

• or a pharmaceutically acceptable salt of said compound, wherein:
• R1 is formyl, acetyl, propionyl, carbamoyl or —C(OH)R4R5;
• R4 and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C1-C3)alkyl;
• R2 is hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy;
• R3 is a radical of the formula
• wherein said radical of formula R3a is additionally substituted on the ring by R6, R7 and R8;
• G and G1 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen;
• or
• G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
• q is 0 or 1;
• X is a covalent bond, —(C═NR10)—, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C1-C4)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C1-C4)alkylenylcarbonyl, sulfonyl-(C1-C4)alkylenylcarbonyl or carbonyl(C0-C4)alkylenylcarbonyl;
• wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl and thio(C1-C4)alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl or Ar;
• said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar;
• and said carbonyl(C0-C4)alkylenylcarbonyl in the definition of X is optionally substituted indepedently with up to three (C1-C4)alkyl, benzyl or Ar;
• R10 is hydrogen or (C1-C4)alkyl;
• R9 is (C3-C7)cycloalkyl, Ar1—(C0-C3)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
• provided that when q=0 and X is a covalent bond, oxycarbonyl or (C1-C4)alkylenylcarbonyl, then R9 is not (C1-C6)alkyl;
• Ar and Ar1 are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocyclic ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
• Ar and Ar1 are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to a total of four substituents independently selected from R11, R12, R13 and R14;
• wherein R11, R12, R13 and R14 are each taken separately and are each independently halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R15R16, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (C0-C4)alkylsulfamoyl, N—(C0-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, N-phenylcarbamoyl, N—(C1-C4)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, 8-(C1-C4)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definition of R11, R12, R13 and R14 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of R11, R12, R13 and R14 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said morpholinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from (C1-C4)alkyl;
• said pyrrolidinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C1-C3)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said piperazinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to three substituents independently selected from (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, (C0-C4)alkylsulfamoyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said triazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said tetrazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy-(C2-C3)alkyl or (C1-C4)alkyl optionally substituted with up to five fluoro;
• and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R11, R12, R13 and R4 are optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4))alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• or
• R11 and R12 are taken together on adjacent carbon atoms and are —CH2OC(CH3)2OCH2— or —O—(CH2)p—O—, and R13 and R14 are taken separately and are each independently hydrogen or (C1-C4)alkyl;
• p is 1, 2 or 3;
• R15 and R16 are taken separately and are each independently hydrogen, (C1-C4)alkyl optionally substituted with up to five fluoro;
• or R15 and R16 are taken separately and R15 is hydrogen and R16 is (C3-C6)cycloalkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl;
• or R15 and R16 are taken together and are (C3-C6)alkylene;
• G3 and G4 are taken together and are (C1-C3)alkylene;
• r is 0 or 1;
• and R18, R19, R20 and G5 are hydrogen;
• or
• G4 and G5 are taken together and are (C1-C3)alkylene;
• r is 0 or 1;
• and R18, R19, R20 and G3 are hydrogen;
• R17 is SO2NR21R22, CONR21R22, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, Ar2-sulfonyl, Ar2-sufinyl and (C1-C6)alkyl;
• R21 and R22 are taken separately and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl and Ar2—(C0-C4)alkylenyl;
• or
• R21 and R22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl;
• said azetidinyl in the definition of R21 and R22 is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said pyrrolidinyl, piperidinyl, azepinyl in the definition of R21 and R22 are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said morpholinyl in the definition of R21 and R22 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said piperazinyl in the definition of R21 and R22 is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, (C1-C4)alkoxycarbonyl and (C1-C4)alkyl optionally substituted with up to five fluoro;
• said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R21 and R22 are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R21 and R22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R21 and R22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
• and
• Ar2 is independently defined as set forth for Ar and Ar1 above;
• said Ar2 is optionally independently substituted as set forth for Ar and Ar1 above.