US 2006/0217374 A1 · Fused heterocyclic derivates as ppar modulators

Abstract

The present invention is directed to a method of treatment by modulating a peroxisome proliferator activated receptor by employing a compound of Structural Formula (I). The variables in I are defined herein. Also included are compounds, methods of making compounds, and pharmaceutical compositions. The compounds of the present invention are believed to be effective in treating and preventing Syndrome X, Type H diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, atherosclerosis, and other disorders related to Syndrome X and cardiovascular diseases.

A compound represented by the following Structural Formula:

and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
(a) T1 is selected from the group consisting of
(b) R1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkenyl, aryl-C0-4-alkyl, aryl-C1-6-heteroalkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl, wherein C1-C8 alkyl, C1-C8 alkenyl, aryl-C0-4-alkyl, aryl-C1-6-heteroalkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl are each optionally substituted with from one to three substituents independently selected from R1′;
(c) R1′, R26, R27, R28, R31, Z14′, and Z15′ are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C1-C6 alkyl, C1-C6 alkyl-COOR12, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkyloxy, C3-C7 cycloalkyl, optionally substituted aryloxy, optionally substituted aryl-C0-4-alkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, C(O)R13, COOR14, OC(O)R15, OS(O)2R16, N(R17)2, NR18C(O)R19, NR20SO2R21, SR22, S(O)R23, S(O)2R24, and S(O)2N(R25)2;
R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and aryl;
(d) R2 is selected from the group consisting of C0-C8 alkyl and C1-6-heteroalkyl;
(e) X is selected from the group consisting of a bond, O, S, S(O)2 and N;
(f) U is an aliphatic linker wherein one carbon atom of the aliphatic linker may be replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with R30;
(g) Y is selected from the group consisting of C, O, S, NH and a single bond;
(h) E is C(R3)(R4)A or A and wherein
(i) A is selected from the group consisting of C0-C6 alkylcarboxyl, C0-C6 alkyltetrazole, C1-C6 alkylnitrile, C0-C6 alkylcarboxamide, C0-C6 alkylsulfonamide and C0-C6 alkylacylsulfonamide;
wherein C0-C6 alkylsulfonamide, C0-C6 alkylacylsulfonamide and C0-C6 alkyltetrazole are each optionally substituted with from one to two groups independently selected from R7;
(ii) each R7 is independently selected from the group consisting of hydrogen, C1-C6 haloalkyl, aryl-C0-C4 alkyl and C1-C6 alkyl, wherein such alkyl and arylalkyl are each optionally substituted with from one to two groups independently selected from R7′;
each R7′ is independently selected from halo, C1-C6 alkyl, and haloC1-C6 alkyl;
(iii) R3 is selected from the group consisting of hydrogen, C1-C5 alkyl, and C1-C5 alkoxy;
and
(iv) R4 is selected from the group consisting of hydrogen, C1-C5 alkyl, C1-C5 alkoxy, aryloxy, C3-C6 cycloalkyl, and aryl C0-C4 alkyl, and R3 and R4 are optionally combined to form a C3-C4 cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and aryl-alkyl are each optionally substituted with one to three each independently selected from R26;
(i) B is selected from the group consisting of S and O, wherein when Z is C then B is N;
(j) Z is selected from the group consisting of N and C;
(k) Z1 and Z2 are each independently N or C with the proviso that at least one of Z1 and Z2 is N;
(l) Z3 is N or O;
(m) Z4 is selected from the group consisting of N, S, and O, wherein when Z4 is N and n2 is 1, T1 is not
(n) Z5 is S or O;
(O) Z12 is selected from the group consisting of hydrogen and -Z13C0-C3alkylZ14;
(p) Z13 is selected from the group consisting of a single bond, CO, CO2, CONZ15, and SO2;
(q) Z14 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl is each optionally substituted with from one to three substituents independently selected from Z14′;
(r) Z15 is selected from the group consisting of hydrogen, aryl, and heteroaryl, wherein the aryl and heteroaryl is each optionally substituted with from one to three substituents independently selected from Z15′;
(s) W is independently selected from the group consisting of S and O;
(t) n2 is 1 to 3;
(u) R8 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, oxo, sulfo, and halo;
(v) R9 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, halo, aryl-C0-C4 alkyl, heteroaryl, C1-C6 allyl, oxo, sulfo, and OR29, and R8 and R9 together optionally combine to form a fused C5-C6 ring with the carbons to which they are attached, and wherein aryl-C0-C4 alkyl, heteroaryl are each optionally substituted with from one to three independently selected from R27;
R29 is selected from the group consisting of hydrogen and C1-C4 alkyl;
(w) R10, R11 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C1-C6 alkyl, C0-C6 alkyl-COOR12″, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkyloxy, C3-C7 cycloalkyl, aryl-C0-4-alkyl, aryl-C1-6-heteroalkyl, heteroaryl-C0-4-alkyl, C3-C6 cycloalkylaryl-C0-2-alkyl, aryloxy, C(O)R13′, COOR14′, OC(O)R15′, OS(O)2R16′, N(R17′)2, NR18′C(O)R19′, NR20′SO2R21′, SR22′, S(O)R23′, S(O)2R24′, and S(O)2N(R25′)2;
and wherein aryl-C0-4-alkyl, aryl-C1-6-heteroalkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl are each optionally substituted with from one to three independently selected from R28;
(x) R12′, R12″, R13′, R14′, R15′, R16′, R17′, R18′, R19′, R20′, R21′, R22′, R23′, R24′, and R25′ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and aryl;
(y) R30 is selected from the group consisting of C1-C6 alkyl, aryl-C0-4-alkyl, aryl-C1-6-heteroalkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl, and wherein C1-C6 alkyl, aryl-C0-4-alkyl, aryl-C1-6-heteroalkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl are each optionally substituted with from one to three substituents each independently selected from R31;
(z) R32 is selected from the group consisting of a bond, hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxo;
(aa) R33 is selected from the group consisting of C2-C8 alkyl, C1-C8 alkoxy, phenyl, thiophene, pyridine, piperidine,
wherein the C2-C8 alkyl, C1-C8 alkoxy, phenyl, thiophene, pyridine, piperidine,
are each optionally substituted with R10 and R11;
(bb) AL is selected from the group consisting of a fused C3-C8 carbocyclic and a fused phenyl;
(cc) “- - - -” are each independently an optional bond to form a double bond at the indicated position;
(dd) wherein when Z4 is N, Z2 and Z3 are each N;

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Fused heterocyclic derivates as ppar modulators

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Fused heterocyclic derivates as ppar modulators

Life of this patent

Abstract

Claims41