Biphenyl derivatives

A method of studying a biological system or sample having a muscarinic receptor or a β2 adrenergic receptor, the method comprising:

• (a) contacting the biological system or sample with a muscarinic receptor-antagonizing or a β2 adrenergic receptor-agonizing amount of a compound of formula I:
• wherein
• a is 0 or an integer of from 1 to 3;
• each R1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, −OR1a, —C(O)OR1b, —SR1c, —S(O)R1d, —S(O)2R1e and —NR1fR1g;
• each of R1a, R1b, R1c, R1d, R1e, R1f and R1g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
• b is 0 or an integer of from 1 to 3;
• each R2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR2a, —C(O)OR2b, —SR2c, —S(O)R2d, —S(O)2R2e and —NR2fR2g;
• each of R2a, R2b, R2c, R2d, R2e, R2f and R2g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
• W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring and represents O or NWa;
• Wa is hydrogen or (1-4C)alkyl;
• c is 0 or an integer of from 1 to 4;
• each R3 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR3a, —C(O)OR3b, —SR3c, —S(O)R3d, —S(O)2R3e and —NR3fR3g;
• or two R3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;
• each of R3a, R3b, R3c, R3d, R3e, R3f and R3g is independently hydrogen or (1-4C)alkyl;
• R4 is a divalent group of the formula:
• —(R4a)d-(A1)e—(R4b)f-Q-(R4c)g-(A2)h (R4d)i—
• wherein
• d, e, f, g, h and i are each independently selected from 0 and 1;
• R4a, R4b, R4c and R4d are each independently selected from (1-10C)alkylene, (2-10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
• A1 and A2 are each independently selected from (3-7C)cycloalkylene, (6-10C)arylene, —O—(6-10C)arylene, (6-10C)arylene-O—, (2-9C)heteroarylene, —O—(2-9C)heteroarylene, (2-9C)heteroarylene-O— and (3-6C)heterocyclene, wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S—(1-4C)alkyl, —S(O)—(1-4C)alkyl, —S(O)2—(1-4C)alkyl, —C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy;
• Q is selected from a bond, —O—, —C(O)O—, —OC(O)—, —S—, —S(O)—, —S(O)2—, —N(Qa)C(O)—, —C(O)N(Qb)—, —N(Qc)S(O)2—, —S(O)2N(Qd)—, —N(Qe)C(O)N(Qf)—, —N(Qg)S(O)2N(Qh)—, —OC(O)N(Qi)—, —N(Qj)C(O)O— and —N(Qk);
• Qa, Qb, Qc, Qd, Qe, Qf, Qg, Qh, Qi, Qi and Qk are each independently selected from hydrogen, (1-6C)alkyl, A3 and (1-4C)alkylene-A4, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy;
• or together with the nitrogen atom and the group R4b or R4c to which they are attached, form a 4-6 membered azacycloalkylene group;
• A3 and A4 are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
• provided that R4 contains from 4 to 16 contiguous atoms in the shortest chain between the two nitrogen atoms to which R4 is attached;
• R5 represents hydrogen or (1-4C)alkyl;
• R6 is —NR6aCR6b(O) or —CR6cR6dOR6e and R7 is hydrogen;
• or R6 and R7 together form —NR7aC(O)—CR7b═CR7c—, —CR7d═CR7e—C(O)—NR7f—, —NR7gC(O)—CR7hR7i—CR7jR7k— or —CR7lR7m—CR7nR7o—C(O)—NR7p—;
• each of R6a, R6b, R6c, R6d and R6e is independently hydrogen or (1-4C)alkyl;
• and
• each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7k, R7m, R7n, R7o and R7p is independently hydrogen or (1-4C)alkyl;
• or a pharmaceutically acceptable salt or solvate or stereoisomer thereof;
• and
• (b) measuring an effect caused by the compound of formula I on the biological system or sample.

A method of antagonizing a muscarinic receptor or agonizing a β2 adrenergic receptor in a biological system or sample, the method comprising:

• (a) contacting a biological system or sample having a muscarinic receptor or a β2 adrenergic receptor with a muscarinic receptor-antagonizing or a β2 adrenergic receptor-agonizing amount of a compound of formula I:
• wherein
• a is 0 or an integer of from 1 to 3;
• each R1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR1a, —C(O)OR1b, —SR1c, —S(O)R1d, —S(O)2R1e and —NR1fR1g;
• each of R1a, R1b, R1c, R1d, R1e, R1f and R1g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
• b is 0 or an integer of from 1 to 3;
• each R2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR2a, —C(O)OR2b, —SR2c, —S(O)R2d, —S(O)2R2e and —NR2fR2g;
• each of R2a, R2b, R2c, R2d, R2e, R2f and R2g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
• W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring and represents O or NWa;
• Wa is hydrogen or (1-4C)alkyl;
• c is 0 or an integer of from 1 to 4;
• each R3 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR3a, —C(O)OR3b, —SR3c, —S(O)R3d, —S(O)2R3e and —NR3fR3g;
• or two R3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;
• each of R3a, R3b, R3c, R3d, R3e, R3f and R3g is independently hydrogen or (1-4C)alkyl;
• R4 is a divalent group of the formula:
• —(R4a)d-(A1)e—(R4b)f-Q-(R4c)g-(A2)h−(R4d)i−
• wherein
• d, e, f, g, h and i are each independently selected from 0 and 1;
• R4a, R4b, R4c and R4d are each independently selected from (1-10C)alkylene, (2-10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;
• A1 and A2 are each independently selected from (3-7C)cycloalkylene, (6-10C)arylene, —O—(6-10C)arylene, (6-10C)arylene-O—, (2-9C)heteroarylene, —O—(2-9C)heteroarylene, (2-9C)heteroarylene-O— and (3-6C)heterocyclene, wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —S—(1-4C)alkyl, —S(O)—(1-4C)alkyl, —S(O)2-(1-4)alkyl, —C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy;
• Q is selected from a bond, —O—, —C(O)O—, —OC(O)—, —S—, —S(O)—, —S(O)2—, —N(Qa)C(O)—, —C(O)N(Qb)—, —N(Qc)S(O)2—, —S(O)2N(Qd)—, —N(Qe)C(O)N(Qf)—, —N(Qg)S(O)2N(Qh)—, —OC(O)N(Qi)—, —N(Qj)C(O)O— and —N(Qk);
• Qa, Qb, Qc, Qd, Qe, Qf, Qg, Qh, Qi, Qj and Qk are each independently selected from hydrogen, (1-6C)alkyl, A3 and (1-4C)alkylene-A4, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy;
• or together with the nitrogen atom and the group R4b or R4c to which they are attached, form a 4-6 membered azacycloalkylene group;
• A3 and A4 are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1 -4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;
• provided that R4 contains from 4 to 16 contiguous atoms in the shortest chain between the two nitrogen atoms to which R4 is attached;
• R5 represents hydrogen or (1-4C)alkyl;
• R6 is —NR6aCR6b(O) or —CR6cCR6dOR6e and R7 is hydrogen;
• or R6 and R7 together form —NR7aC(O)—CR7b═CR7c —, —CR7d═CR7e—C(O)—NR7f—, —NR7gC(O)—CR7hR7i—CR7jR7k—or —CR7lR7m—CR7nR7o—C(O)—NR7p—;
• each of R6a, R6b, R6c, R6d and R6e is independently hydrogen or (1-4C)alkyl;
• and
• each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7o and R7p is independently hydrogen or (1-4C)alkyl;
• or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.