Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation

A method of making a compound of Formula Ia:

• comprising reacting a compound of Formula VIII
• with a compound of Formula (II)
• Ar—YH Formula II,
• in the presence of a base with a solvent to provide the compound of Formula Ia;
• wherein
• R1 is C1-C6 alkyl or C3-C6 cycloalkyl
• R2 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
• Y is O, S or NR5,
• n is 2, 3, or 4;
• Ar is selected from the group consisting of phenyl and a 6-membered heteroaryl ring containing up to three N atoms, wherein said Ar being optionally substituted at any available position by 1 to 5 independently selected R3 groups, and
• optionally fused to a 5- or 6-membered saturated carbocyclic ring,
• a 5- or 6-membered unsaturated carbocyclic ring, or
• a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from the group consisting of N, O and S,
• wherein said fused ring may be optionally substituted at any available position by 1 to 4 independently selected R4 groups;
• R3 is selected from the group consisting of
• hydroxy,
• SH,
• halo,
• CN,
• NO2,
• C(═O)OH,
• C(═O)OC1-C6 alkyl,
• C(═O)—OC3-C6 cycloalkyl,
• NR6R7,
• C(═O)NR6R7,
• C(═S)NR6R7,
• C1-C6 alkyl optionally substituted with halo, OH, NR6R7, or C1-C6 alkoxy,
• C1-C6 haloalkyl,
• C1-C6 alkoxy,
• C1-C6 thioalkyl,
• C2-C6 alkenyl,
• C1-C6 haloalkoxy,
• C3-C8 cycloalkyl,
• C3-C8 cycloalkoxy,
• phenoxy optionally substituted on the phenyl ring with halo, C1-C6 alkyl, or C1-C6 alkoxy, and
• a mono or bicyclic ring radical selected from the group consisting of
• a) phenyl optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from the group consisting of N, O and S, and
• b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from the group consisting of N, O or S, optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from the group consisting of N, O and S,
• said mono or bicyclic ring radical being optionally substituted with up to 5 groups independently selected from the group consisting of
• halo,
• hydroxy,
• oxo,
• CN,
• C1-C6 alkyl optionally substituted with halo, OH, NR6R7, or C1-C6 alkoxy,
• C1-C6 haloalkyl,
• C1-C6 alkoxy,
• C1-C6 thioalkyl,
• C1-C6 haloalkoxy,
• C3-C8 cycloalkyl,
• C3-C8 cycloalkoxy,
• C1-C6 acyl,
• C(═O)OH,
• CH2C(═O)OH,
• NR6R7,
• C(═O)NR6R7,
• C(═O)OC1-C6 alkyl, and
• C(═O)OC3-C6 cycloalkyl;
• R4 is selected from the group consisting of
• oxo,
• hydroxy,
• halo,
• CN,
• NR6R7,
• C1-C6 alkyl optionally substituted with OH, NR6R7, or C1-C6 alkoxy,
• C1-C6 haloalkyl,
• C1-C6 alkoxy,
• C1-C6 thioalkyl,
• C1-C6 haloalkoxy,
• C3-C8 cycloalkyl, and
• C3-C8 cycloalkoxy;
• R5 is selected from the group consisting of
• H,
• C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl,
• C1-C6 acyl,
• benzyl optionally substituted with halo, C1-C6 alkoxy, (C1-C6)alkyl, CN, NH2, N[(C1-C3)alkyl]2, NO2, or CF3,
• C3-C6 cycloalkyl, and
• C(═O)OC1-C6 alkyl;
• R6 and R7 are independently selected from the group consisting of
• H,
• C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl,
• C1-C6 acyl,
• benzyl optionally substituted with halo, C1-C6 alkoxy, (C1-C6)alkyl, CN, NH2, N[(C1-C3)alkyl]2, NO2, or CF3,
• C3-C6 cycloalkyl, and
• phenyl optionally substituted with halo, C1-C6 alkoxy, (C1-C6)alkyl, CN, N[(C1-C3)alkyl]2, NO2, or CF3,
• or
• R6 and R7 may be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring optionally interrupted by NR6 or O;
• and
• Lg is a leaving group.

A method of making a compound of Formula Ia:

• comprising reacting a compound of Formula XI
• with a compound of Formula (II)
• Ar—Lg,
• in the presence of a base and/or a palladium catalyst and in the presence of a solvent to provide the compound of Formula Ia;
• wherein
• R1 is C1-C6 alkyl or C3-C6 cycloalkyl
• R2 is H, C1-C6 alkyl, or C3-C6 cycloalkyl;
• Y is O, S or NR5,
• n is 2, 3, or 4;
• Ar is selected from the group consisting of phenyl and a 6-membered heteroaryl ring containing up to three N atoms, wherein said Ar being optionally substituted at any available position by 1 to 5 independently selected R3 groups, and
• optionally fused to a 5- or 6-membered saturated carbocyclic ring,
• a 5- or 6-membered unsaturated carbocyclic ring, or
• a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from the group consisting of N, O and S,
• wherein said fused ring may be optionally substituted at any available position by 1 to 4 independently selected R4 groups;
• R3 is selected from the group consisting of
• hydroxy,
• SH,
• halo,
• CN,
• NO2,
• C(═O)OH,
• C(═O)OC1-C6 alkyl,
• C(═O)—OC3-C6 cycloalkyl,
• NR6R7,
• C(═O)NR6R7,
• C(═S)NR6R7,
• C1-C6 alkyl optionally substituted with halo, OH, NR6R7, or C1-C6 alkoxy,
• C1-C6 haloalkyl,
• C1-C6 alkoxy,
• C1-C6 thioalkyl,
• C2-C6 alkenyl,
• C1-C6 haloalkoxy,
• C3-C8 cycloalkyl,
• C3-C8 cycloalkoxy,
• phenoxy optionally substituted on the phenyl ring with halo, C1-C6 alkyl, or C1-C6 alkoxy, and
• a mono or bicyclic ring radical selected from the group consisting of
• a) phenyl optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from the group consisting of N, O and S, and
• b) a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from the group consisting of N, O or S, optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocylic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from the group consisting of N, O and S,
• said mono or bicyclic ring radical being optionally substituted with up to 5 groups independently selected from the group consisting of
• halo,
• hydroxy,
• oxo,
• CN,
• C1-C6 alkyl optionally substituted with halo, OH, NR6R7, or C1-C6 alkoxy,
• C1-C6 haloalkyl,
• C1-C6 alkoxy,
• C1-C6 thioalkyl,
• C1-C6 haloalkoxy,
• C3-C8 cycloalkyl,
• C3-C8 cycloalkoxy,
• C1-C6 acyl,
• C(═O)OH,
• CH2C(═O)OH,
• NR6R7,
• C(═O)NR6R7,
• C(═)OC1-C6 alkyl, and
• C(═O)OC3-C6 cycloalkyl;
• R4 is selected from the group consisting of
• oxo,
• hydroxy,
• halo,
• CN,
• NR6R7,
• C1-C6 alkyl optionally substituted with OH, NR6R7, or C1-C6 alkoxy,
• C1-C6 haloalkyl,
• C1-C6 alkoxy,
• C1-C6 thioalkyl,
• C1-C6 haloalkoxy,
• C3-C8 cycloalkyl, and
• C3-C8 cycloalkoxy;
• R5 is selected from the group consisting of
• H,
• C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl,
• C1-C6 acyl,
• benzyl optionally substituted with halo, C1-C6 alkoxy, (C1-C6)alkyl, CN, NH2, N[(C1-C3)alkyl]2, NO2, or CF3,
• C3-C6 cycloalkyl, and
• C(═O)OC1-C6 alkyl;
• R6 and R7 are independently selected from the group consisting of
• H,
• C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl,
• C1-C6 acyl,
• benzyl optionally substituted with halo, C1-C6 alkoxy, (C1-C6)alkyl, CN, NH2, N[(C1-C3)alkyl]2, NO2, or CF3,
• C3-C6 cycloalkyl, and
• phenyl optionally substituted with halo, C1-C6 alkoxy, (C1-C6)alkyl, CN, N[(C1-C3)alkyl]2, NO2, or CF3,
• or
• R6 and R7 may be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring optionally interrupted by NR5 or O;
• and
• Lg is a leaving group.