Triaryl-oxy-aryloxy-pyrimidine-2,4,6-trione metalloproteinase inhibitors

A compound of the formula

• or a pharmaceutically acceptable salt thereof,
• wherein R1 is selected from the group consisting of hydrogen, (R2)2n+1—(C)n— and (C3-C7)cycloalkyl;
• wherein said (C3-C7)cycloalkyl may be optionally substituted on any ring carbon atom able to support an additional substituent by one to two substituents independently selected from the group consisting of halo, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, R3—, R3—O—, perfluoro(C1-C4)alkoxy , R3—(C1-C4)alkyl-O—, R3—(C═O)—O—, (R3)2N—(C═O)—O—, —NO2, (R3)2N—, R3—(C═O)—(NR4)—, R3—(SO2)—(NR4)—, R3O—(C═O)—(NR4)—, (R3)2—N—(C═O)—(NR4)—, R3—S—, R3—(S═O)—, R3—(SO2)—, (R3)2N—(SO2)—, —CN, R3—(C═O)—, R3—O—(C═O)— and (R3)2N—(C═O)—;
• n is an integer from one to five;
• each R2 is independently selected from the group consisting of halo, (C1-C4)alkenyl, (C1-C4)alkynyl, R3—, R3—O—, perfluoro(C1-C4)alkoxy, R3—(C═O)—O—, (R3)2N—(C═O)—O—, —NO2, (R3)2N—, R3—(SO2)—(NR4)—, (R3)2—N—(C═O)—, R3—(C═O)—(NR4)—, R3O—(C═O)—(NR4)—, (R3)2—N—(C═O)—(NR4)—, R3—S—, R3—(S═O)—, R3—(SO2)—, (R3)2N—(SO2)—, —CN, R3—O—(C═O)—, and R3—(C═O)—;
• wherein not more than three of said R3 may be other than hydrogen and any one carbon atom of said —(C)n— component of the R1 can contain only one bond to a heteroatom;
• wherein a carbon atom of any two R2 may be taken together with the carbons to which they are attached to form a four to ten membered ring;
• each R3 is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C6-C10)aryl, (C3-C7)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
• wherein each R3 may be optionally substituted on any carbon atom able to support an additional substituent by one to three substituents, wherein said substituents are independently selected from the group consisting of halo, hydroxy, amino, —CN, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl-NH—, [(C1-C4)alkyl]2—N—, C6-C10)aryl, (C3-C7)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
• wherein each of said R3 (C3-C7)cycloalkyl and (C1-C10)heterocyclyl may be optionally substituted on any ring carbon atoms capable of supporting two additional substituents with one to two oxo groups per ring;
• wherein each of said R3 (C1-C10)heteroaryl and (C1-C10)heterocyclyl may be optionally substituted on any ring nitrogen atom able to support an additional substituent independently selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkyl-(C═O)—, (C6-C10)aryl, (C3-C7)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
• R4 is selected from the group consisting of hydrogen and (C1-C4)alkyl;
• wherein said R3 may be optionally taken together with said R4 to form a three to eight membered ring;
• X is selected from the group consisting of —O—, >C═O, —S—, >SO2, >S═O, >NR5, —CH2—, —CH2O—, —OCH2—, —CH2S—, —CH2(S═O)—, —CH2SO2—, —SCH2, —(S═O)CH2—, —SO2CH2—, —[N(R5)]CH2—, —CH2[N(R5)]—, —[N(R5)]SO2— and —SO2[N(R5)]—;
• R5 is selected from the group consisting of hydrogen and (C1-C4)alkyl;
• A is (C6-C10)aryl or (C1-C10)heteroaryl;
• Y is selected from the group consisting of a bond, —O—, —S—, >C═O, >SO2, >S═O, —CH2O—, —OCH2—, —CH2S—, —SCH2—, —CH2SO—, —CH2SO2—, —SOCH2—, —SO2CH2—, >NR6, —[N(R6)]CH2—, —CH2[N(R6)]—, —CH2—, —CH═CH—, —C═C—, [N(R6)]—SO2— and —SO2[N(R6)]—;
• R6 is selected from the group consisting of hydrogen and (C1-C4)alkyl;
• B is selected from the group consisting of (C6-C10)aryl, (C3-C7)cycloalkyl, (C1-C10)heterocyclyl and (C1-C10)heteroaryl;
• wherein one or two carbon-carbon single bonds of said B (C3-C7)cycloalkyl or (C1-C10)heterocyclyl may optionally be replaced by carbon-carbon double bonds;
• wherein G is bonded to one ring carbon atom of B;
• wherein each of said A or B may be independently optionally substituted on any of the ring carbon atoms capable of supporting an additional substituent by one or two substituents per ring independently selected from F, Cl, Br, CN, OH, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)perfluoroalkoxy, (C1-C4)alkoxy and (C3-C7)cycloalkyloxy;
• G is —[R7—(CR8R9)p]—;
• wherein the orientation of -B-G-W is -B-[R7—(CR8R9)p]-W or -B-[(CR8R9)p—R7]-W;
• p is an integer from zero to four;
• R7 is independently selected from the group consisting of (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
• wherein each of said (C6-C10)aryl, (C3-C7)cycloalkyl (C1-C10)heteroaryl and (C1-C10)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of supporting an additional substituent by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)perfluoroalkoxy, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, —NH2, —NO2, (C1-C4)alkyl-NH—, [(C1-C4)alkyl]2—N—, (C3-C7)cycloalkyloxy, —(C═O)—OH, —(C═O)—O—(C1-C4)alkyl, —(C═O)—NH2, —(C═O)—NH—(C1-C4)alkyl, and —(C═O)—N[(C1-C4)alkyl]2;
• wherein each of said R7 (C3-C7)cycloalkyl and (C1-C10)heterocyclyl may optionally be substituted on any ring carbon atoms capable of supporting two additional substituents with one to two oxo groups per ring;
• wherein each of said R7 (C1-C10)heteroaryl and (C1-C10)heterocyclyl may optionally be substituted on any ring nitrogen atom able to support an additional substituent independently selected from the group consisting of (C1-C4)alkyl and (C1-C4)alkyl-(C═O)—;
• each of R8 and R9 is independently selected from the group consisting of hydrogen and (C1-C4)alkyl;
• or R8 and R9 may optionally be taken together with the carbon to which they are attached to form a 3 to 8-membered carbocyclic ring;
• W is selected from the group consisting of (C1-C4)alkoxy(C1-C4)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
• wherein each of said W (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of supporting an additional substituent by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)perfluoroalkoxy, (C1-C4)alkoxy, and (C3-C7)cycloalkyloxy;
• wherein each of said W (C3-C7)cycloalkyl and (C1-C10)heterocyclyl may optionally be substituted on any ring carbon atoms capable of supporting two additional substituents with one to two oxo groups per ring;
• wherein each of said W (C1-C10)heteroaryl and (C1-C10)heterocyclyl may optionally be substituted on any ring nitrogen atom able to support an additional substituent independently selected from the group consisting of (C1-C4)alkyl and (C1-C4)alkyl-(C═O)—;
• wherein each (C1-C10)heteroaryl in all occurrences is selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl;
• and
• wherein each (C1-C10)heterocyclyl in all occurrences is selected from the group consisting of 3-azabicycl[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxetanyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydroturanyl, tetrehydropyranyl, 1,2,3,6-tetrahydrpyridinyl, tetrahydrothienyl, tertahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl.