N-biphenylmethylindole modulators of PPARG
The invention provides molecular entities that bind with high affinity to PPARG (PPARγ), inhibit kinase-mediated, e.g., cdk5-mediated, phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. In methods of treatment of these conditions using a compound of the invention, the compound can avoid producing side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, in the patient receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
1. A method of inhibiting kinase-mediated phosphorylation of PPARG in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R is H or (C 1 -C 4 )alkyl;
R 1 and R 2 are independently H, or (C 1 -C 6 )alkyl;
R 3 is mono- or multi-substituted arylalkyl, wherein each substituent on R 3 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl, (C 3 -C 9 )cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, haloalkyl, haloalkoxy, nitro, cyano, CO 2 R′, methylenedioxy, OR′, N(R′) 2 , C(O)N(R′) 2 , (C 1 -C 4 )alkyl-S(O) q , SO 2 NR′ 2 , and (C 1 -C 6 )alkoxyl,
wherein R′ is independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, or (C 3 -C 9 )cycloalkyl, or wherein two R′ bonded to an atom together with the atom form a 3-8 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O) q , and wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl is optionally mono- or independently multi-substituted with (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halo, OR′, N(R′) 2 , aryl, or aroyl; and wherein an alkyl or an alkyl group of a cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl can be substituted with oxo;
each of X 1 -X 4 is independently N or is C substituted with an independently selected R 7 or with Z, provided that no more than one of X 1 -X 4 is N, and provided that there is one and only one Z group, present in the ring comprising X 1 ,
Z is a group of formula
wherein a wavy line indicates a point of attachment, each X 5 -X 7 is independently N or is C substituted with an independently selected H or R 4 ; provided that no more than one of X 5 -X 7 is N;
each R 4 is independently halo, nitro, (C 1 -C 6 )fluoroalkyl, R″—(C 1 -C 6 )alkyl, R″O 2 C—(C 0 -C 6 )alkyl, NC—(C 0 -C 6 )alkyl, R″O—(C 0 -C 6 )alkyl, (R″) 2 N—(C 0 -C 6 )alkyl, (R′) 2 NC(═O)—(C 0 -C 6 )alkyl, C-bonded tetrazolyl, 3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl, cyclohexylaminocarbonyl, 2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl, N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl, N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl, (1,2,4-oxadiazol-5(4H)-on)-3-yl, (C 1 -C 6 )alkyl-S(O) q (C 0 -C 6 )alkyl, R′S(O) 2 NHC(O), or R′C(O)NHS(O) 2 , or R 4 is —(C(R″) 2 ) m CO 2 R″, —(C(R″) 2 ) m CON(R″) 2 , or —(C(R″) 2 ) m CN, —O(C(R″) 2 ) m CO 2 R″, —O(C(R″) 2 ) m CON(R″) 2 , or —O(C(R″) 2 ) m CN, wherein m is 1, 2, or 3;
R″ is H, or (C 1 -C 6 ) alkyl, or two R″ together with an atom to which they are bonded form a (C3-C9)cycloalkyl;
q is 0, 1 or 2;
R 5 is H or (C 1 -C 4 )alkyl; R 6 is R 7 ; or R 5 and R 6 taken together form a —CH 2 CH 2 — group; and,
R 7 is H, halo, CO 2 R′, CN, OR′, N(R′) 2 , C(O)N(R′) 2 , (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl optionally substituted with OR′ or N(R′) 2 , C-bonded tetrazolyl, or (C 1 -C 4 )alkyl-S(O) q ; or R 7 is —(C(R′) 2 ) m CO 2 R′ wherein m is 1, 2, or 3.
2. The method of inhibiting kinase-mediated phosphorylation of PPARG in a mammal of claim 1 , comprising administering to the mammal an effective amount of a compound selected from the group consisting of:
3. The method of inhibiting kinase-mediated phosphorylation of PPARG in a mammal of claim 1 , comprising administering to the mammal an effective amount of a compound selected from the group consisting of
4. The method of claim 1 wherein the kinase-mediated phosphorylation of PPARG is cdk5-mediated.
5. The method of claim 4 wherein the effective amount of the compound for inhibiting cdk5-mediated phosphorylation of PPARG does not produce an agonistic effect on PPARG.