Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof

A process for preparing a compound of formula (14),

• or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
• wherein:
• Ra is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl, propargyl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3;
• Rb is H;
• Z2 is NH;
• R1 and R2 are each H;
• R3 and R4 are independently selected from H, F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)2CN, —CH2CN, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CONHCH2CH3, —CONHCH(CH3)2, —CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3) COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, —S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino;
• R5 is selected from H, C1-C9 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle, C6-C9 aryl, C6-C9 heteroaryl, —(C1-C6 alkyldiyl)-(C3-C9 cycloalkyl), —(C1-C6 alkyldiyl)-(C3-C9 heterocycle), C(O)Rb, C(O)NRa, SO2Ra, and SO2NRa, optionally substituted with one or more of halogen, CN, ORa, N(Ra)2, C1-C9 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle, C6-C9 aryl, C6-C9 heteroaryl, C(O)Rb, C(O)NRa, SO2Ra, and SO2NRa;
• each R6 and R7 is independently F or Cl;
• m is selected from 0, 1, 2, 3, and 4;
• and
• n is selected from 0, 1, 2, 3, and 4;
• the process comprising:
• (a) contacting a compound of formula:
• with a compound of formula X—R5, wherein X is I, Br, or —OTf, thereby synthesizing a compound having formula (12):
• (b) cyclizing the compound of formula (12) with a compound of formula:
• wherein X1 is Br or I, thereby synthesizing a compound having formula (13)
• wherein X1 is I or Br;
• and
• (c) reacting the compound of formula (13) with a compound having formula
• (d) contacting the compound of step (c) with an acid to remove the Boc moiety thereby synthesizing a free amine;
• and
• (e) contacting the compound of step (d) with a compound of formula I—Ra;
• thereby synthesizing a compound having formula (14).