Heterocyclic analgesic compounds and methods of use thereof

A compound represented by B:

• 23
• wherein
• m is independently for each occurrence 1, 2, 3 or 4;
• n is 1 or 2;
• Ar represents aryl, or heteroaryl;
• R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
• Ar and R2 may be connected through a covalent bond;
• R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
• wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;
• R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
• R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
• a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in B;
• any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond;
• X represents C(R3)2, O, S, SO, SO2, NR2, NC(O)OR2, or C═O;
• and
• the stereochemical configuration at any stereocenter of a compound represented by B is R or S.

A compound represented by C:

• 24
• wherein
• m is independently for each occurrence 1, 2, 3 or 4;
• y is 0, 1 or 2;
• Ar represents aryl, or heteroaryl;
• R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
• Ar and R2 may be connected through a covalent bond;
• R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
• R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
• R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
• a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in C;
• any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond;
• and
• the stereochemical configuration at any stereocenter of a compound represented by C is R, S, or a mixture of these configurations.

A compound represented by D:

• 25
• wherein
• m is independently for each occurrence 1, 2, 3 or 4;
• y is 0, 1 or 2;
• Ar represents aryl, or heteroaryl;
• R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
• Ar and R2 may be connected through a covalent bond;
• R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
• R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
• R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
• a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in D;
• any two geminal or vicinal instances of R1 and R6 may be connected through a covalent bond;
• and
• the stereochemical configuration at any stereocenter of a compound represented by D is R or S.

A compound represented by E:

• 26
• wherein
• m is independently for each occurrence 1, 2, 3 or 4;
• n is 1 or 2;
• Ar represents aryl, or heteroaryl;
• R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
• Ar and R2 may be connected through a covalent bond;
• R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
• wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;
• R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
• R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
• a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in E;
• any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond;
• X represents C(R3)2, O, S, SO, SO2, NR2, NC(O)OR2, or C═O;
• and
• the stereochemical configuration at any stereocenter of a compound represented by E is R, S, or a mixture of these configurations.

A compound represented by F:

• 27
• wherein
• m is independently for each occurrence 1, 2, 3 or 4;
• y is 0, 1, or 2;
• Ar represents aryl, or heteroaryl;
• R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
• Ar and R2 may be connected through a covalent bond;
• R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
• R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
• R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
• Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
• a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in F;
• any two geminal or vicinal instances of R1 and R6 may be connected through a covalent bond;
• X represents O, S, SO, SO2, NR2, NC(O)OR2, or C═O;
• and
• the stereochemical configuration at any stereocenter of a compound represented by F is R, S, or a mixture of these configurations.