Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders

A compound having formula Ia:

• or a pharmaceutically acceptable salt or metabolite thereof, wherein
• W is selected from the group consisting of —OR13, —OCH2OR13, —OCH(CH3)OR13, —OCH2OC(O)R13, —OCH(CH3)OC(O)R13, —OCH2OC(O)OR13, —OCH(CH3)OC(O)OR13, and —NR14R14, wherein each R13 is independently selected from C1-C6 alkyl optionally substituted with one or two groups independently selected from —CO2H, —CONH2, NH2, —OH, —OAc, NHAc and phenyl;
• and wherein each R14 is independently selected from H and R13 wherein
• Z is selected from the group consisting of CH2 and C═O;
• R1 is selected from the group consisting of Cl, Br, F and C1-4 alkyl, wherein said C1-4alkyl is linear or branched and is optionally substituted with 1-3 halogens independently selected from F and Cl, 1 phenyl which is optionally substituted with 1-3 halogens, or a mixture thereof;
• Ar is Aryl, wherein Aryl is in each instance optionally substituted with 1-5 substituents independently selected from (a) halogen, (b) C1-5alkyl, (c) C2-5alkenyl, (d) C2-5alkynyl, (e) —OC1-5alkyl, (f) —OC2-5alkenyl, (g) —OC2-5alkynyl, (h) —SOxC1-5alkyl, (i) —SOxNRaRb, (j) —SOxphenyl, (k) —C(O)C1-3alkyl, and (l) —C(O)NRaRb, wherein in each instance, each alkyl, alkenyl and alkynyl is linear or branched and is optionally substituted witb (a) 1-5 halogen atoms, (b) 1-2 groups independently selected from —OC1-3alkyl, which is linear or branched and is optionally substituted with 1-5 halogens, or (c) a mixture thereof, and wherein phenyl is optionally substituted with 1-3 substituents independently selected from halogen, C1-3alkyl, and C1-3alkoxy, wherein C1-3alkyl and C1-3alkoxy are linear or branched and are optionally substituted with 1-5 halogens;
• x is selected from 0, 1 and 2;
• Aryl is a carbocyclic 6-10 membered monocyclic or bicyclic aromatic ring system;
• Hetcyc is a 5- or 6-membered saturated or partly saturated monocyclic heterocyle having 1-4 heteroatoms independently selected from N, S, and O in the ring, wherein N may optionally be NRa and S may optionally be SO or SO2;
• Benzoheterocycle contains a 5 or 6-membered heterocyclic ring which may be saturated, partly unsaturated or aromatic, and a benzene ring, wherein said heterocyclic ring and said benzene ring are fused together, wherein said heterocyclic ring contains 1-3 heteroatoms independently selected from O, S and N in the ring, where N may optionally be NRa, and S may optionally be SO or SO2;
• Ra and Rb are independently selected from the group consisting of H, C1-5alkyl, C2-5alkenyl, C2-5alkynyl, —C(O)C1-5alkyl, —C(O)C2-5alkenyl, —C(O)C2-5alkynyl, SOxC1-5alkyl, SOxphenyl, SOxNRdRe, —C(O)NRdRe, halogen, and phenyl, wherein in all instances, alkyl, alkenyl, and alkynyl are linear or branched and are optionally substituted with (a) 1-5 halogen atoms, (b) 1-3 groups independently selected from —OCH3, —OCF3 and phenyl, or (c) a mixture thereof, wherein phenyl in all occurrences is optionally substituted with 1-3 substituents independently selected from halogen, C1-3alkyl, and C1-3alkoxy, said C1-3alkyl and C1-3alkoxy being linear or branched and optionally substituted with 1-5 halogens;
• Rd and Re are independently selected from H;
• C1-5alkyl, C2-5alkenyl, C2-5alkynyl, and phenyl, wherein said alkyl, alkenyl, and alkynyl are linear or branched and are optionally substituted with (a) 1-5 halogen atoms, (b) 1-3 groups independently selected from —OCH3, —OCF3 and phenyl, or (c) a mixture thereof, wherein phenyl in all occurrences is optionally substituted with 1-3 substituents independently selected from halogen, C1-3alkyl, and C1-3alkoxy, said C1-3alkyl and C1-3alkoxy being linear or branched and optionally substituted with 1-5 halogens;
• X and Y are independently selected from the group consisting of O and S;
• n is an integer from 1-6;
• R2 is selected from the group consisting of Cl, Br, F and C1-4alkyl, wherein said C1-4alkyl is optionally substituted with 1-3 halogens,
• R4 is selected from the group consisting of Benzoheterocycle, C3-8Cycloalkyl, Hetcyc, —OC3-8Cycloalkyl and Rc;
• wherein Benzoheterocycle, C3-8Cycloalkyl, Hetcyc and —OC3-8Cycloalkyl are each optionally substituted with 1-3 groups independently selected from halogen, C1-5alkyl, C2-5alkenyl, C2-5alkynyl, —OC1-5alkyl, —OC2-5alkenyl, —OC2-5alkynyl, C3-8Cycloalkyl, —SOxC1-5alkyl, —SOxNRaRb, —SOxphenyl, C(O)C1-3alkyl and —C(O)NRaRb, wherein in all instances, said C1-5alkyl, C2-5alkenyl, and C2-5alkynyl groups are linear or branched and are optionally substituted with 1-3 halogens, and wherein Hetcyc, —OC3-8Cycloalkyl and C3-8Cycloalkyl may optionally have a C3-6-spiro-cycloalkyl substituent on the ring, wherein the spiro-cycloalkyl group is optionally substituted with 1-2 groups independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy and halogen;
• wherein Rc is selected from the group consisting of halogen, —OH, —OSO2C1-8alkyl, —OSO2C3-8Cycloalkyl, —OSO2Ar, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, —OC1-8alkyl, —OC2-8alkenyl, —OC2-8alkynyl, and Aryl, wherein said —OSO2C1-8alkyl, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, —OC1-8alkyl, —OC2-8alkenyl, and —OC2-8alkynyl are linear or branched, and are optionally substituted with (a) 1-5 halogens, (b) 1-2 groups independently selected from —OC1-3alkyl, which are linear or branched and which are optionally substituted with 1-5 halogens, (c) 1 group selected from Aryl and C3-8Cycloalkyl, or (d) a mixture of one or more of (a), (b) and (c), and Aryl and C3-8Cycloalkyl are each optionally substituted as defined under Ar for Aryl and R4 for C3-8Cycloalkyl;
• or alternatively R4 and the adjacent substituent R3 or R5 may be connected to form a 5- or 6-membered heterocyclic ring that may be saturated, partly unsaturated or aromatic fused to the benzene ring, wherein the 5-or 6-membered fused ring contains 1-3 heteroatoms independently selected from O, S, and N, where N may optionally be NRa and S may optionally be SO or SO2, said fused ring optiomally also containing 1-2 C═O groups in the ring, wherein said 5- or 6-membered heterocyclic fused ring is optionally substituted with 1-2 groups independently selected from R3.