Multi-substitued selective androgen receptor modulators and methods of use thereof

A selective androgen receptor modulator (SARM) compound represented by the structure of formula I:

• wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;
• G is O or S;
• T is OH, OR, —NHCOCH3, or NHCOR;
• R is alkyl, haloalkyl, dihaloalkyl, tihaloalkyl, CH2F, CHF2, CF3, CF2CF3;
• aryl, phenyl, halogen, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or
• R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
• Z is NO2, CN, COR, COOH, or CONHR;
• Y is CF3 F, Br, Cl, I, CN, or SnR3;
• Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR;
• or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
• n is an integer of 1-4, and
• m is an integer of 1-3;
• or its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

A selective androgen receptor modulator (SARM) compound represented by the structure of formula V:

• wherein
• R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or
• R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3;
• aryl, phenyl, halogen, alkenyl or OH;
• Z is NO2, CN, COR, COOH, or CONHR;
• Y is CF3, F, Br, Cl, I, CN, or SnR3;
• Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR;
• or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
• n is an integer of 1-4;
• and
• m is an integer of 1-3.

A selective androgen receptor modulator (SARM) compound represented by the structure of formula V:

• wherein
• R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or
• R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3;
• aryl, phenyl, halogen, alkenyl or OH;
• Z is NO2, CN, COR, COOH, or CONHR;
• Y is CF3, F, Br, Cl, I, CN, or SnR3;
• Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR;
• or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
• n is an integer of 1-4;
• and
• m is an integer of 1-3;
• or its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

A process for preparing a selective androgen receptor modulator (SARM) compound represented by the structure of formula I:

• wherein X is a O, NH, S, Se, PR, or NR;
• G is O or S;
• T is OH, OR, —NHCOCH3, or NHCOR;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
• Z is NO2, CN, COR, COOH, or CONHR,
• Y is CF3,F, Br, Cl, I, CN, or SnR3;
• Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R, SO2R, SR;
• or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
• n is an integer of 1-4;
• and
• m is an integer of 1-3;
• said process comprising the step of coupling a compound of formula VII:
• wherein Z, Y, G, R1, T, R3 and m are as define above and L is a leaving group, with a compound of formula VIII:
• wherein Q, X R2 and n are as defined above.