Compounds and methods for modulation of estrogen receptors

A compound having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein
• a is 0, 1 or 2;
• One of A and B is N, and the other is CH or CR;
• D is —(CH2)r — or —(CH2)nC(═O)(CH2)m—;
• R1 represents one or two substituents independently selected from —X—Y;
• R2 is C1-8 alkyl, C6-12aryl, C7-12aralkyl, —C(═O)R5, a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from O, NRc and S(O)q, or a bicyclic ring system contain a five- or six-membered heterocycle fused to phenyl, wherein each of the above groups are optionally substituted with one to three substituents independently selected from —X—Y or R4;
• and
• R3 is hydrogen, —R6, —(CH2)sC(═O)R6, —(CH2)sC(═O)R6, —(CH2)sC(═O)NR6R7, —(CH2)sC(═O)NR6(CH2)nC(═O)R7R8, —(CH2)sNR6C(═O)R7, —(CH2)sNR6C(═O)NR7R8, —(CH2)sNR6R7, —(CH2)sOR6, —(CH2)sSOqR6 or —(CH2)sSO2NR6R7;
• and wherein
• R4 is at each occurrence independently halogen, hydroxy, carboxy, C1-6alkyl, C1-4alkoxy, C1-4haloalkyl, acyloxy, C1-4thio, C1-4alkylsulfinyl, C1-4alkylsulfonyl, (hydroxy)C1-4alkyl, C6-12aryl, C7-12aralkyl, —C(═O)OH, —C(═O)OR, —OC(═O)R, —C(═O)NHR, —C(═O)NRR, —C(═O)NHOR, —SO2NHC, —NHSO2R, —CN, —NO2, C1-4alkylamino, C1-4dialkylamino, —NHC(═O)R, NHC(═O)(CH2)s(five- or six-membered heterocycle), a five- or six-membered heterocycle, or a five-or six-membered heterocycle fused to phenyl;
• R5, R6, R7 and R8 are at each occurrence independently hydrogen, C1-8alkyl, C6-12aryl, C7-12aralkyl, or a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from 0, NRc and S(O)q, wherein each of the above groups are optionally substituted with one to three substituents independently selected from R4;
• X is at each occurrence independently
• a direct bond;
• —(CH2)nZ(CH2)m—;
• —O(CH2)nZ(CH2)m—;
• —S(CH2)nZ(CH2)m—;
• —NRc(CH2)nZ(CH2)m—;
• —O(CH2)nCRaRb—;
• —NRc(CH2)nCRaRb—;
• —OCHRcCHRd—;
• or
• —SCHRcCHRd—;
• Y is at each occurrence independently
• halogen;
• —Re;
• —NReRf;
• optionally fused on adjacent carbon atoms with one or two phenyl or cycloalkyl rings, and with each carbon optionally and independently substituted with carbonyl or with one or two substituents independently selected from R4, with any two R4 substituents on a single carbon atom optionally being taken together to form a five- or six-membered heterocycle, and with each nitrogen atom optionally and independently substituted with R4, wherein W is —NR3—, —O—, —S— or —CReRf—;
• or a bridged or fused C5-12bicyclic amine optionally substituted with one to three substituents independently selected from R4;
• or where —X—Y is
• Z is CH2, CH=CH, C═C, O, NRc, S(O)q, C(═O), C(OH)Rc,
• C(═O)NRc,NRcC(═O), C(═O)NRc, NRcC(═O) or
• G is O, S or NRe;
• n and m are at each occurrence independently 0, 1, 2 or 3;
• p is at each occurrence independently 1, 2 or 3;
• q is at each occurrence independently 0, 1 or 2;
• r is at each occurrence independently 1, 2, 3, 4 or 5;
• s is at each occurrence independently 0, 1, 2, 3 or 4;
• R is at each occurrence independently C1-6alkyl;
• Ra and Rb are at each occurrence independently C1-8alkyl or taken together form a C3-8cyclic alkyl;
• Rc and Rd are at each occurrence independently hydrogen or C1-4alkyl;
• and
• Re and Rf are at each occurrence independently hydrogen, C6-12aryl, C1-8alkyl, C7-12aralkyl, a five- or six-membered heterocycle, or a five- or six membered heterocycle fused to phenyl;
• or wherein Re or Rf form a 3-8 membered nitrogen-containing heterocyclic alkyl with Ra or Rb;
• and wherein each Re and Rf are optionally substituted with up to three substituents independently selected from R4.