PPARG modulators for the treatment of osteoporosis

A method for treatment of a patient afflicted by a progressive bone disease, comprising administering to the patient an effective dose of a compound of formula (I)

• wherein:
• R is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C3-C9)cycloalkyl(C1-C6)alkyl;
• Y1 or Y2 are each independently C or N, provided that when Y1 or Y2 is N, R1 or R2, respectively, is absent;
• R1 is H, (C1-C6)alkyl, (C3-C9)cycloalkyl, or (C1-C6)haloalkyl;
• or R1 and R2 together with the atoms to which they are bonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selected from the group consisting of O, NR, and SOq wherein q is 0, 1, or 2, and optionally mono- or multi-substituted with independently selected (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, halo, oxo, (C1-C6)haloalkyl, nitro, cyano-(C0-C6)alkyl, R′O2C—(C0-C6)alkyl, methylenedioxy, R′O—(C0-C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)—(C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)alkyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, aryl, aroyl, or SO2NR′2;
• R2 is H or (C1-C6)alkyl;
• R3 is optionally mono- or multi-substituted (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C1-C6)alkyl, (3-9 membered)heteroaryl, or (3-9 membered)heteroaryl(C1-C6)alkyl;
• wherein if present each substituent on R3 is independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, 3-9 membered mono- and bicyclic heterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano, CO2R′, methylenedioxy, OR′, N(R′)2, C(O)N(R′)2, (C1-C6)alkyl-S(O)q, SO2NR′2, and (C1-C6)alkoxyl;
• and provided that group R3N(R)C(═O)— can be bonded to any one of the four carbon atoms of the phenyl ring not bonded to N1 or Y1;
• wherein each R′ is independently H, (C1-C6) alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or wherein two R′ bonded to an atom together with the atom form a 3-9 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O)q;
• wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl of R′ is optionally mono- or independently multi-substituted with (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halo, oxo, aryl, or aroyl;
• each of X1-X5 is independently N or CH, or is C substituted with an independently selected R4 or is C substituted with Z, provided that no more than two of X1-X5 are N, and provided that there is no more than one Z group bonded to the ring comprising X1—X5;
• each R4 is independently halo, nitro, (C1-C6)fluoroalkyl, R′—(C0-C6)alkyl, R′O2C—(C0-C6)alkyl, NC—(C0-C6)alkyl, R′O—(C0-C6)alkyl, (R′)2N—(C0-C6)alkyl, (R′)2NC(═O)—(C0-C6)alkyl, R′C(═O)N(R′)—(C0-C6)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, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, R'S(O)2NHC(O), R′C(O)NHS(O)2, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, (C1-C6)alkyl or (C3-C9)cycloalkyl-(C0-C6)alkyl, wherein any alkyl or cycloalkyl is optionally mono- or independently multi-substituted with R′, OR′, N(R′)2, C-bonded tetrazolyl, (C1-C6)alkyl-S(O)q(C0-C6)alkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl;
• or R4 is —(C(R″)2)mCO2R′, —(C(R″)2)mCON(R′)2, —(C(R″)2)mCN, —O(C(R″)2)mCO2R′, —O(C(R″)2)mCON(R′)2, or —O(C(R″)2)mCN, wherein m is 1, 2, or 3;
• R″ is H, halo, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C6) alkyl, or two R″ together with an atom to which they are bonded form a 3- to 9-membered ring;
• Z is a group of formula
• wherein a wavy line indicates a point of bonding, each of Z1-Z5 is independently N or is C substituted with an independently selected H or R4;
• provided that no more than two of Z1-Z5 are N;
• Y is (C1-C2) alkyl, or sulfur;
• when Y is (C1-C2)alkyl, R5 and R6 are independently H or (C1-C4)alkyl or independently each R5 and R6 together with the carbon atom to which they are bonded form a carbonyl, or, one R5 group can further be bonded to X5 to form a 4- to 8-membered ring;
• and,
• when Y is sulfur, R5 and R6 are both oxygen;
• or a pharmaceutically acceptable salt thereof;
• wherein R3—NRCO— is substituted at position 5 or 6 of the ring.