Imidazole based lxr modulators

A compound according to one of the following formulas,

• or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein,
• (A) R1 is -L1-R5, wherein
• L1 is a bond, L5, L6, -L5-L6-L5-, or -L6-L5-L6-, wherein
• each L5 is independently —[C(R15)2]m—, wherein
• each R15 is independently hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, or (C1-C6)haloalkyl;
• and
• each L6 is independently —CS—, —CO—, —SO2—, —O—, —CON(R11)—, —CONR11N(R11)—, —C(═NR11)—, —C(═NOR11)—, or —C(═NN(R11)2)—, -aryl-, —C3-C8cycloalkyl-, -heteroaryl-, or -heterocyclyl-;
• wherein the aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more R14;
• or each L6 is independently C2-C6 alidiyl,
• wherein the alidiyl chain is optionally interrupted by —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C(R11)2O—, —C(R11)2NR11—, —C≡C—, —O—, —S—, —N(R10)CO—, —N(R10)CO2—, —CON(R10)—, —CO—, —CO2—, —OC(═O)—, —OC(═O)N(R10)—, —SO2—, —N(R10)SO2—, or —SO2N(R10);
• and
• R5 is aryl, heterocyclyl, heteroaryl, —(C3-C6)cycloalkyl, —C, or —B—C,
• wherein
• B is —[C(R15)2]m— or —C3-C8 cycloalkyl-;
• and
• C is halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, —SO2R11, —SR11, —SO2N(R11)2, —SO2NR11COR11, —C≡N, —C(O)OR11, —CON(R11)2, or —N(R11)2,
• wherein R5 is optionally substituted with one or more R5a, wherein
• each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-C1-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11, SO2N(R11)2, SO2NR11COR11, C≡N, C(O)OR11, CON(R11)2, CON(R11)11 OR11, OCON(R11)2, NR11COR11, NR11CON(R11)2, NR11COOR11, or N(R11)2, wherein
• each R5a is optionally substituted with one or more groups which independently are -halogen, —C1-C6 alkyl, aryloxy C0-6alkylSO2R11, C0-6 alkylCOOR11, C0-6alkoxyaryl, C1-C6 haloalkyl, —SO2R11, —OR11, —SR11, —N3, —SO2R11, —COR11, —SO2N(R11)2, —SO2NR11COR11, —C≡N, —C(O)OR11, —CON(R11)2, —CON(R11)OR11, —OCON(R11)2, —NR11COR11, —NR11CON(R11)2, —NR11COOR11 or —N(R11)2;
• R2 and R21 are -L3-R7, wherein
• each L3 is independently a bond or —(CH2)m—V1—(CH2)n—, wherein
• n is 0-6;
• and
• V1 is —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C(R11)2O—, —C(R11)2NR11—, —C≡C—, —O—, —S—, —NR11—, —N(R10)CO—, —N(R10)CO2—, —OCO—, —CO—, —CS—, —CONR10—, —C(═N—R11)—, —C(═N—OR11)—, —C[═N—N(R11)2], —CO2—, —OC(═O)—, —OC(═O)N(R10)—, —SO2—, —N(R10)SO2—, —SO2N(R10)—, —NR10CONR10—, —NR10CSNR1—, C3-C6 cycloalkyl, or C3-C6 cyclohaloalkyl;
• or each L3 is independently C2-C6 alidiyl,
• wherein the alidiyl chain is optionally interrupted by —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C(R11)2O—, —C(R11)2NR11—, —C≡C—, —O—, —S—, —N(R11CO—, —N(R10)CO2—, —NR11—, —CON(R10)—, —CO—, —CO2—, —OC(═O)—, —OC(═O)N(R11)—, —SO2—, —N(R11)SO2—, or —SO2N(R11)—;
• and
• each R7 is independently hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl, -Z, —Y—Z, or —X—Y—Z, wherein
• X is —O—;
• Y is —[C(R15)2]m—, C2-C6 alkenyl, or —C3-C8cycloalkyl;
• and
• Z is —H, halogen, —OR11, —C(═O)R11, —C(═O)OR11, —C(═O)N(R11)2, —N(R11)2, —C(═N—OH)R11, —C(═S)N(R11)2, —CN, —S(═O)2N(R11)2, —C(═O)N(R11)N(R11)2, —C(═O)N(R11)(OR11), —OC(═O)—R11, or —OC(═O)—N(R11)2,
• wherein R7 is optionally substituted with one or more R7a, wherein
• R7a is halogen, haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, arylC0-C6 alkylcarboxy, C(R11)═C(R11)—COOH, aryl, heteroaryl, heterocyclyl, heterocyclyloxy, heteroaryloxy, —Z′, —Y′—Z′, or —X′—Y′—Z′, wherein
• X′ is —O—;
• Y′ is —[C(R15)2]m or —C3-C8cycloalkyl;
• and
• Z′ is —H, halogen, —OR11, —SR11, —S(═O)2R11, —C(═O)R11, —C(═O)OR11, —C(═O)N(R11)2, —N(R11)2, —N(R11)C(═O)R11, —S(═O)2N(R11)C(═O)R11, —CN, —S(═O)2N(R11)2, —C(═O)N(R11)N(R11)2, —C(═O)N(R11)(OR11), —OC(═O)—R1, —OC(═O)—OR11, —N(R11)C(═O)—R11, or —N(R11)S(O═)2R11,
• wherein each R7a is optionally substituted with one or more R5,
• wherein each R5 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkyl(OR11), C0-C6 alkylOR11, C0-C6 alkylCON(R11)2, CO—C6 alkylCOR11, C0-C6 alkylCOOR11, or C0-C6 alkylSO2R11,
• provided that R2 and R21 are not simultaneously hydrogen;
• R3 is -L-R6, wherein
• L is a bond, —X3—(CH2)—X3—, —(CH2)m—X3—(CH2)n— or —(CH2)1+w—Y3—(CH2)w—, wherein
• n is 0-6;
• each w is independently 0-5;
• and
• each X3 is independently a bond, —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C≡C—, —CO—, —CS—, —CONR10—, —C(═N)(R11)—, —C(═N—OR11)—, —C[═N—N(R11)2], —CO2—, —SO2—, or —SO2N(Ro)—;
• and
• Y3 is —O—, —S—, —NR7—, —N(R10)CO—, —N(R10)CO2—, —OCO—, —OC(═O)N(R10)—, —NR10CONRo—, —N(R10)SO2—, or —NR10CSNR10—;
• or L is C2-6 alidiyl chain wherein the alidiyl chain is optionally interrupted by —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C(R11)2-0—, —C(R11)2NR11—, —C≡C—, —O—, —S—, —N(R10)CO—, —N(R10)CO2—, —CON(R10)—, —CO—, —CO2—, —OC(═O)—, —OC(═O)N(R10)—, —SO2—, —N(R10)SO2—, or —SO2N(R10);
• and
• R6 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, —CN, —C(═O)R11, —C(═O)OR11, —C(═O)N(R11)2, —N(R11)2, —SO2R11, —S(═O)2N(R11)2, —C(═O)N(R11)N(R11)2, or —C(═O)N(R11)(OR11), wherein
• the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6a, wherein
• each R6a is independently —Z″, —Y″—Z″, or —X″—Y″—Z″, wherein
• X″ is —O—;
• Y″ is —[C(R15)2]m—, —C2-C6 alkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein
• the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z″;
• Z″ is —H, —CN, halogen, —OR11, —C(═O)R11, —C(═O)OR11, —C(═O)N(R11)2, —N(R11)2, —N3, —SO2R11, —S(═O)2N(R11)2, —C(═O)N(R11)N(R11)2, —N(R11)C(═O)N(R11)2, —OC(═O)—OR11, —C(═O)N(R11)(OR11), —OC(═O)—R11, —OC(═O)—N(R11)2, or —N(R11)COR11;
• and
• G is a group of the formula,
• wherein
• J is aryl, heteroaryl, or absent;
• K is aryl, heteroaryl, or absent;
• provided that
• (i) if K is absent, then q is 1 and R4 is bonded directly to L2;
• and
• each R4 and R41 is independently halogen, oxo, nitro, CR11═CR11COOR11, aryloxy, aralkyloxy, aryloxyalkyl, arylC0-C6 alkylcarboxy, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -G1, -E-G1′ or -D-E-G1, wherein
• D is —O—;
• E is —[C(R15)2]m— or —C3-C8cycloalkyl;
• and
• G1 is —C1-C6 alkyl, —C1-C6 haloalkyl, —COR11, —COOR11, —CON(R11)2, —C≡N, —OR11, —OCON(R11)2, —OCOOR11, —N3, —NR11COR11, —NR11SO2R11, —N(R11)2, —NR11COOR11, —SO2R11, —SO2NR11COR11, —SO2N(R11)2, —SOR11, or —SR11;
• wherein each R4 is optionally substituted with one or more R4a,
• wherein each R4a is independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, C1-C6 alkoxyaryl, arylC0-C6 alkylcarboxy, -G′, -E′-G1, or -D′-E′-G′, wherein
• D′ is —O—;
• E′ is —[C(R15)2]m— or —C3-C8cycloalkyl-;
• and
• G′ is —H, -halogen, —COR11, —COOR11, —C≡N, —OR11, —NR11SO2R1, —SO2R11, —SO2N(R11)2, or —SR11;
• L2 is a bond or —[C(R15)2]m—-V2—[C(R15)2]n—, wherein
• V2 is independently —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C(R11)2O—, —C(R11)2NR11—, —C≡C—, —O—, —SO2—, —N(R10)CO—, —N(R10)CO2—, —CON(R10)—, —CON(R11)—, —CON(R11)O—, —CO—, —CS—, —CO2—, —OC(═O)—, —OC(═O)N(R10)—, —N(R10)SO2—, —SO2N(R10)—, —NR10CONR10—, —NR10CSNR10—, C3-C6 cycloalkyl-, or C3-C6 cyclohaloalkyl,
• or V2 is C2-6 alidiyl,
• wherein alidiyl chain is optionally interrupted by —C(R11)2—, —C(R11)2C(R11)2—, —C(R11)═C(R11)—, —C(R11)2O—, —C(R11)2NR11—, —C(R11)2NR11—, —C(R11)2NR11—, —C≡C—, —O—, —S—, —N(R10)CO—, —N(R10)CO2—, —CON(R10)—, —CON(R11)—, —CON(R11)O—, —CO—, —CO2—, —OC(═O)—, —OC(═O)N(R10)—, —SO2—, —N(R10)SO2— or —SO2N(R10)—;
• or V2 is aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more R9, wherein
• each R9 is independently halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkyloxy, C0-C6 alkyl or C1-C6 alkylCOOR11;
• each m is 0, 1, 2, 3, 4, 5, or 6;
• q is 0, 1, 2, 3, 4, or 5, provided that q is 0 if and only if K is not phenyl;
• and
• q′ is 0, 1, 2, 3, or 4,
• each R10 is independently —R11, —C(═O)R11, —CO2R11, or —SO2R11;
• each R11 is independently -hydrogen, —C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-C1-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, —C1-C6 haloalkyl, —N(R12)2, aryl, —(C1-C6)alkyl-aryl, heteroaryl, —(C1-C6)alkyl-heteroaryl, heterocyclyl, or —(C1-C6)alkyl-heterocyclyl,
• wherein any of R11 is optionally substituted with one or more radicals of R12;
• each R12 is independently halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)C═O(OR13);
• C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, CO—C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, C0-6alkoxyaryl, arylC0-6 alkylcarboxy, -C0-C6 alkylN(R13)2, NR13SO2R13, or —OC-6 alkylCOOR13;
• each R13 is independently hydrogen, C1-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-C1-C6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-;
• each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(R11)2, CO—C6 alkylCONR11OR11, C0-C6 alkylOR11, or C0-C6 alkylCOOR11;
• and
• (B) provided that
• (i) when L2 is a bond, both J and K are not absent;
• (ii) if the compound If defined by formula IIa, then
• a) if J is phenyl and K is thienyl, furyl, or thiazoyl and q is 0, then R1 is not 4-(NH2SO2)phenyl, 4-(NH2SO2)-3-fluorophenyl, p-(CH3SO2)phenyl-, or 4p-(CH3SO2)-3-fluorophenyl-;
• and
• b) if R5 is pyridyl or phenyl optionally substituted with one or more R5a and L1 is a bond, then G is not p-(NH2SO2)phenyl or p-(CH3SO2)phenyl-;
• (iii) if the compound is defined by formula IIc or IId, then G is not p-(NH2SO2)phenyl or p-(CH3SO2)phenyl-;
• (iv) the compound is not 1-(biphenyl-4-yl)-2,5-diphenyl-1H-imidazole.