Biphenyl derivatives
This invention provides biphenyl derivatives of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both β 2 adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.
1 . A compound of formula I:
wherein:
a is 0 or an integer of from 1 to 3;
each R 1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 1a , —C(O)OR 1b , SR 1c , —S(O)R 1d , —S(O) 2 R 1e and —NR 1f R 1g ;
each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 1g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
b is 0 or an integer of from 1 to 3;
each R 2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 2a , —C(O)OR 2b , SR 2c , —S(O)R 2d , S(O) 2 R 2e and —NR 2f R 2g ;
each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g 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 NW a ;
W a is hydrogen or (1-4C)alkyl;
c is 0 or an integer of from 1 to 4;
each R 3 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 3a , —C(O)OR 3b , —SR 3c , —S(O)R 3d , —S(O) 2 R 3e and —NR 3f R 3g ; or two R 3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;
each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g is independently hydrogen or (1-4C)alkyl;
R 4 is a divalent group of the formula:
—(R 4a ) d -(A 1 ) e -(R 4b ) f -Q-(R 4c ) g -A 2 ) h -(R 4d ) i —
wherein
d, e, f, g, h and i are each independently selected from 0 and 1;
R 4a , R 4b , R 4c and R 4d 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;
A 1 and A 2 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(Q a )C(O)—, —C(O)N(Q b )-, —N(Q c )S(O) 2 —, —S(O) 2 N(Q d )-, —N(Q e )C(O)N(Q f )-, —N(Q g )S(O) 2 N(Q h )-, —OC(O)N(Q i )-, —N(Q j )C(O)O— and —N(Q k );
Q a , Q b , Q c , Q d , Q e , Q f , Q g , Q h , Q i , Q j and Q k are each independently selected from hydrogen, (1-6C)alkyl, A 3 and (1-4C)alkylene-A 4 , 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 R 4b or R 4c to which they are attached, form a 4-6 membered azacycloalkylene group;
A 3 and A 4 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 the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 4 to 16;
R 5 represents hydrogen or (1-4C)alkyl;
R 6 is —NR 6a CR 6b (O) or —CR 6c R 6d OR 6e and R 7 is hydrogen; or R 6 and R 7 together form —NR 7a C(O)—CR 7b ═CR 7c —, —CR 7d ═CR 7e —C(O)—NR 7f —, —NR 7g C(O)—CR 7h R 7i —CR 7j R 7k — or —CR 7l R 7m —CR 7n R 7o —C(O)—NR 7p —;
each of R 6a , R 6b , R 6c , R 6d and R 6e is independently hydrogen or (1-4C)alkyl; and
each of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , R 7i , R 7j , R 7k , R 7l , R 7m , R 7n , R 7o and R 7p is independently hydrogen or (1-4C)alkyl;
or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
2 . The compound of claim 1 , wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 8 to 14.
3 . The compound of claim 2 , wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is 8, 9, 10 or 11.
4 . The compound of claim 1 , wherein W is attached to the piperidine ring at the 4-position with respect to the nitrogen atom.
5 . The compound of claim 1 , wherein a, b, and c are each 0, and W a and R 5 are both hydrogen.
6 . The compound of claim 1 , wherein W represents O.
7 . The compound of claim 1 , wherein R 6 is —NHCHO or —CH 2 OH and R 7 is hydrogen; or R 6 and R 7 together form —NHC(O)—CH═CH—, —CH═CH—C(O)—NH—, —CH 2 —CH 2 —C(O)NH— or —NHC(O)—CH 2 —CH 2 —.
8 . The compound of claim 1 , wherein R 4 is a divalent group of the formula: —(R 4a ) d — where R 4a is (4-10C)alkylene.
9 . The compound of claim 8 , wherein R 4 is —(CH 2 ) 8 —, —(CH 2 ) 9 , and —(CH 2 ) 10 —.
10 . The compound of claim 1 , wherein R 4 is a divalent group of the formula:
—(R 4a ) d -(A 2 ) h -(R 4d ) i —
wherein R 4a is (1-10C)alkylene; A 2 is (6-10C)arylene or (2-9C)heteroarylene; and R 4d is (1-10C)alkylene.
11 . The compound of claim 1 , wherein R 4 is a divalent group of the formula:
—(R 4a ) d -Q-(A 2 ) h -(R 4d ) i —
wherein Q is —O— or —N(Q k )-; Q k is hydrogen or (1-3C)alkyl; R 4a is (1-10C)alkylene; A 2 is (6-10C)arylene or (2-9C)heteroarylene; and R 4d is (1-10C)alkylene.
12 . The compound of claim 1 , wherein Q is —N(Q a )C(O)— or —C(O)N(Q b )-.
13 . The compound of claim 12 , wherein R 4 is selected from:
wherein m is an integer from 2 to 10; and n is an integer from 2 to 10; provided that m+n is an integer from 4 to 12;
wherein o is an integer from 2 to 7; and p is an integer from 1 to 6; provided that o+p is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally 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;
wherein q is an integer from 2 to 6; r is an integer from 1 to 5; and s is an integer from 1 to 5; provided that q+r+s is an integer from 4 to 8; and wherein the phen-1,4-ylene group is optionally 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;
wherein t is an integer from 2 to 10; and u is an integer from 2 to 10; provided that t+u is an integer from 4 to 12;
wherein v is an integer from 2 to 7; and w is an integer from 1 to 6; provided that v+w is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally 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; and
wherein x is an integer from 2 to 6; y is an integer from 1 to 5; and z is an integer from 1 to 5; provided that x+y+z is an integer from 4 to 8; and wherein the phen-1,4-ylene group is optionally 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.
14 . A compound of formula II:
wherein
W represents O or NW a ;
W a is hydrogen or (1-4C)alkyl;
R 4 is a divalent group of the formula:
—(R 4a ) d -(A 1 ) e -(R 4b ) f -Q-(R 4c ) g -A 2 ) h -(R 4d ) i —
wherein
d, e, f, g, h and i are each independently selected from 0 and 1;
R 4a , R 4b , R 4c and R 4d 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;
A 1 and A 2 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(Q a )C(O), —C(O)N(Q b )-, —N(Q c )S(O) 2 —, —S(O) 2 N(Q d )-, N(Q e )C(O)N(Q f )-, —N(Q g )S(O) 2 N(Q h )-, —OC(O)N(Q i )-, —N(Q j )C(O)O— and —N(Q k );
Q a , Q b , Q c , Q d , Q e , Q f , Q g , Q h , Q i , Q j and Q k are each independently selected from hydrogen, (1-6C)alkyl, A 3 and (1-4C)alkylene-A 4 , 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 R 4b or R 4c , to which they are attached, form a 4-6 membered azacycloalkylene group;
A 3 and A 4 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 the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 4 to 14;
or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
15 . A compound of formula III:
wherein
W represents O or NW a ;
W a is hydrogen or (1-4C)alkyl;
R 4 is a divalent group of the formula:
—(R 4a ) d -(A 1 ) e -(R 4b ) f -Q-(R 4c ) g -A 2 ) h -(R 4d ) i —
wherein
d, e, f, g, h and i are each independently selected from 0 and 1;
R 4a , R 4b , R 4c and R 4d 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;
A 1 and A 2 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(Q a )C(O)—, C(O)N(Q b )-, N(Q c )S(O) 2 —, —S(O) 2 N(Q d )-, N(Q e )C(O)N(Q f )-, —N(Q g )S(O) 2 N(Q h )-, —OC(O)N(Q i )-, —N(Q j )C(O)O— and N(Q k );
Q a , Q b , Q c , Q d , Q e , Q f , Q g , Q h , Q i , Q j and Q k are each independently selected from hydrogen, (1-6C)alkyl, A 3 and (1-4C)alkylene-A 4 , 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 R 4b or R 4c to which they are attached, form a 4-6 membered azacycloalkylene group;
A 3 and A 4 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 the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 4 to 14;
or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
16 . A compound of formula IV:
wherein
W represents O or NW 3 ;
W a is hydrogen or (1-4C)alkyl;
R 4 is a divalent group of the formula:
—(R 4a ) d -(A 1 ) e -(R 4b ) f -Q-(R 4c ) g -A 2 ) h -(R 4d ) i —
wherein
d, e, f, g, h and i are each independently selected from 0 and 1;
R 4a , R 4b , R 4c and R 4d 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;
A 1 and A 2 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(Q a )C(O)—, —C(O)N(Q b ), —N(Q c )S(O) 2 —, —S(O) 2 N(Q d )-, —N(Q e )C(O)N(Q f )-, —N(Q g )S(O) 2 N(Q h )-, —OC(O)N(Q i )-, —N(Q j )C(O)O— and —N(Q k );
Q a , Q b , Q c , Q d , Q e , Q f , Q g , Q h , Q i , Q j and Q k are each independently selected from hydrogen, (1-6C)alkyl, A 3 and (1-4C)alkylene-A 4 , 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 R 4b or R 4c to which they are attached, form a 4-6 membered azacycloalkylene group;
A 3 and A 4 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 the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 4 to 14;
or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
17 . The compound of any one of claims 14 , 15 or 16 , wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 8 to 14.
18 . The compound of any one of claims 14 , 15 or 16 , wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is 8, 9, 10 or 11.
19 . The compound of any one of claims 14 , 15 or 16 , wherein W represents O.
20 . The compound of any one of claims 14 , 15 or 16 , wherein R 4 is a divalent group of the formula: —(R 4a ) d — where R 4a is (4-10C)alkylene.
21 . The compound of claim 20 , wherein R 4 is —(CH 2 ) 8 —, —(CH 2 ) 9 , and —(CH 2 ) 10 —.
22 . The compound of any one of claims 14 , 15 or 16 , wherein R 4 is a divalent group of the formula:
—(R 4a ) d -(A 2 ) h -(R 4d ) i —
wherein R 4a is (1-10C)alkylene; A 2 is (6-10C)arylene or (2-9C)heteroarylene; and R 4d is (1-10C)alkylene.
23 . The compound of any one of claims 14 , 15 or 16, wherein R 4 is a divalent group of the formula:
—(R 4a ) d -(A 2 ) h -(R 4d ) i —
wherein Q is —O— or —N(Q k )-; Q k is hydrogen or (1-3C)alkyl; R 4a is (1-10C)alkylene; A 2 is (6-10C)arylene or (2-9C)heteroarylene; and R 4d is (1-10C)alkylene.
24 . The compound of any one of claims 14 , 15 or 16 , wherein Q is —N(Q a )C(O)— or —C(O)N(Q b )-.
25 . The compound of claim 24 wherein R 4 is selected from:
wherein m is an integer from 2 to 10; and n is an integer from 2 to 10; provided that m+n is an integer from 4 to 12;
wherein o is an integer from 2 to 7; and p is an integer from 1 to 6; provided that o+p is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally 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;
wherein q is an integer from 2 to 6; r is an integer from 1 to 5; and s is an integer from 1 to 5; provided that q+r+s is an integer from 4 to 8; and wherein the phen-1,4-ylene group is optionally 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;
wherein t is an integer from 2 to 10; and u is an integer from 2 to 10; provided that v+U is an integer from 4 to 12;
wherein v is an integer from 2 to 7; and w is an integer from 1 to 6; provided that v+w is an integer from 3 to 8; and wherein the phen-1,4-ylene group is optionally 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)(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy; and
wherein x is an integer from 2 to 6; y is an integer from 1 to 5; and z is an integer from 1 to 5; provided that x+y+z is an integer from 4 to 8; and wherein the phen-1,4-ylene group is optionally 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.
26 . The compound of any one of claims 14 , 15 or 16 , wherein R 4 is selected from:
—(CH 2 ) 7 —;
—(CH 2 ) 8 —;
—(CH 2 ) 9 —;
—(CH 2 ) 10 —;
—(CH 2 ) 11 —;
—(CH 2 ) 2 C(O)NH(CH 2 ) 5 —;
—(CH 2 ) 2 N(CH 3 )C(O)(CH 2 ) 5 —;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)NH(CH 2 ) 5 —;
—(CH 2 ) 3 NHC(O)NH(CH 2 ) 5 —;
—(CH 2 ) 2 C(O)NHCH 2 (cyclohex-1,3-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)(cis-cyclopent-1,3-ylene)-;
—(CH 2 ) 2 NHC(O)NH(phen-1,4-ylene)(CH 2 ) 2 —;
1-[-(CH 2 ) 2 C(O)](piperidin-4-yl)(CH 2 ) 2 —;
—(CH 2 ) 2 NHC(O)(trans-cyclohex-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)(cis-cyclopent-1,3-ylene)-;
—(CH 2 ) 2 NH(phen-1,4-ylene)(CH 2 ) 2 —;
1-[-(CH 2 ) 2 NHC(O)](piperidin-4-yl)(CH 2 ) 2 —;
—CH 2 (phen-1,4-ylene)NH(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NHCH 2 (phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NHCH 2 (pyrid-2,6-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(cis-cyclohex-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(trans-cyclohex-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)(cis-cyclopent-1,3-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)(trans-cyclohex-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)C*H(CH 3 )— ((S)-isomer);
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)C*H(CH 3 )— ((R)-isomer);
2-[(S)-(—CH 2 -](pyrrolidin-1-yl)C(O)(CH 2 ) 4 —;
2-[(S)-(—CH 2 -](pyrrolidin-1-yl)C(O)(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(4-chlorophen-1,3-ylene)CH 2 —;
—CH 2 (2-fluorophen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(4-methylphen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(6-chlorophen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2-chlorophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2,6-dichlorophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)NHCH 2 (phen-1,3-ylene)CH 2 —;
4-[-CH 2 -](piperidin-1-yl)C(O)(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)N(CH 2 CH 3 )(phen-1,4-ylene)CH 2 —;
1-[-(CH 2 ) 2 NHC(O)](piperidin-4-yl)-;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 NHC(O)(thien-2,5-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)(3-nitrophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)(trans-cyclohex-1,4-ylene)-;
1-[-CH 2 (2-fluorophen-1,3-ylene)CH 2 ](piperidin-4-yl)-;
5-[-(CH 2 ) 2 NHC(O)](pyrid-2-yl)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 3 (thien-2,5-ylene)(CH 2 ) 3 —;
—(CH 2 ) 2 (phen-1,4-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—CH 2 (phen-1,2-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
1-[-CH 2 (2-fluorophen-1,3-ylene)CH 2 ](piperidin-4-yl)(CH 2 ) 2 —;
1-[-CH 2 (2-fluorophen-1,3-ylene)CH 2 ](piperidin-4-yl)CH 2 —;
—(CH 2 ) 2 C(O)NH(3-chlorophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2-(CF 3 O-)phen-1,4-ylene)CH 2 —;
—(CH 2 ) 3 (phen-1,3-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 S(O) 2 NH(CH 2 ) 5 —;
CH 2 (phen-1,3-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 C(O)NH(2-iodophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2-chloro-5-methoxyphen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2-chloro-6-methylphen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(CH 2 ) 5 —;
—(CH 2 ) 2 N(CH 3 )S(O) 2 (phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2-bromophen-1,4-ylene)CH 2 —;
—(CH 2 ) 3 (phen-1,4-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 3 (phen-1,2-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
1-[-CH 2 (2-fluorophen-1,3-ylene)CH 2 ](piperidin-4-yl)(CH 2 ) 3 —;
—(CH 2 ) 2 C(O)NH(2-methoxyphen-1,4-ylene)CH 2 —;
—(CH 2 ) 5 NH(phen-1,4-ylene)(CH 2 ) 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)CH(CH 3 )CH 2 —;
—(CH 2 ) 2 -(trans-cyclohex-1,4-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 C(O)NH(2-fluorophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,3-ylene)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 C(O)NH(2,5-difluorophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)(phen-1,4-ylene)(CH 2 ) 2 —;
1-[-CH 2 (pyrid-2,6-ylene)CH 2 ](piperidin-4-yl)CH 2 —;
—(CH 2 ) 3 NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 NH(naphth-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 3 O(phen-1,4-ylene)CH 2 —;
1-[-(CH 2 ) 3 ](piperidin-4-yl)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 3 (phen-1,4-ylene)NHC(O)(CH 2 ) 2 —;
—(CH 2 ) 3 O(phen-1,4-ylene)(CH 2 ) 2 —;
2-[-(CH 2 ) 2 ](benzimidazol-5-yl)CH 2 —;
—(CH 2 ) 2 -(trans-cyclohex-1,4-ylene)NHC(O)(CH 2 ) 2 —;
—(CH 2 ) 2 -(trans-cyclohex-1,4-ylene)NHC(O)(CH 2 ) 4 —;
—(CH 2 ) 2 -(trans-cyclohex-1,4-ylene)NHC(O)(CH 2 ) 5 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)(CH 2 ) 2 —;
—(CH 2 ) 2 NHC(O)NH(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )(CH 2 ) 2 (cis-cyclohex-1,4-ylene)-;
—(CH 2 ) 2 C(O)NH(2,3,5,6-tetrafluorophen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2,6-diiodophen-1,4-ylene)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)(CH 2 ) 3 —;
4-[-(CH 2 ) 2 ]piperidin-1-yl)C(O)(CH 2 ) 4 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)(CH 2 ) 5 —;
—(CH 2 ) 2 C(O)NHCH 2 (phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)NHCH 2 (phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(2-methylphen-1,4-ylene)CH 2 —;
1-[-(CH 2 ) 3 O(phen-1,4-ylene)(CH 2 ) 2 ](piperidin-4-yl)CH 2 —;
—(CH 2 ) 2 C(O)NHCH 2 (phen-1,3-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 O(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)CH 2 O(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)CH 2 O(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 N(CH 3 )C(O)(fur-2,5-ylene)CH 2 —;
10-(CH 2 ) 2 N(CH 3 )C(O)(thien-2,5-ylene)CH 2 —;
—(CH 2 ) 2 O(phen-1,4-ylene)O(CH 2 ) 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)CH 2 O(phen-1,2-ylene)CH 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)CH 2 O(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)CH 2 O(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)(fur-2,5-ylene)CH 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)(thien-2,5-ylene)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)CH 2 O(phen-1,2-ylene)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)CH 2 O(phen-1,3-ylene)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)CH 2 O(phen-1,4-ylene)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)(fur-2,5-ylene)CH 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)(thien-2,5-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)CH 2 O(phen-1,2-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)CH 2 O(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)CH 2 O(phen-1,4-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)(fur-2,5-ylene)CH 2 —;
—(CH 2 ) 2 (phen-1,4-ylene)NHC(O)(thien-2,5-ylene)CH 2 —;
—(CH 2 ) 2 (trans-cyclohex-1,4-ylene)NHC(O)(phen-1,3-ylene)CH 2 —;
—(CH 2 ) 3 O(phen-1,3-ylene)CH 2 —;
—CH 2 CH(OH)CH 2 NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 4 NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)CH 2 NHC(O)CH 2 —;
—(CH 2 ) 2 C(O)NH(phen-1,4-ylene)(CH 2 ) 2 NHC(O)CH 2 —;
—(CH 2 ) 2 C(O)NHCH 2 (trans-cyclohex-1,4-ylene)CH 2 —;
—(CH 2 ) 2 NHC(O)(CH 2 ) 5 —;
—(CH 2 ) 2 O(phen-1,3-ylene)O(CH 2 ) 2 —;
—(CH 2 ) 2 O(phen-1,2-ylene)O(CH 2 ) 2 —;
—CH 2 (phen-1,2-ylene)O(phen-1,2-ylene)CH 2 —;
—(CH 2 ) 2 C(O)NH(CH 2 ) 6 —;
—(CH 2 ) 3 (phen-1,4-ylene)(CH 2 ) 3 —;
—(CH 2 ) 3 (phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 4 (phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 3 (furan-2,5-ylene)(CH 2 ) 3 —;
—(CH 2 ) 2 N(CH 3 )C(O)NH(phen-1,4-ylene)(CH 2 ) 2 —;
4-[-(CH 2 ) 2 ](piperidin-1-yl)C(O)NH(phen-1,4-ylene)(CH 2 ) 2 —;
—(CH 2 ) 3 (phen-1,3-ylene)(CH 2 ) 3 —;
—(CH 2 ) 3 (tetrahydrofuran-2,5-ylene)(CH 2 ) 3 —; and
—(CH 2 ) 2 O(phen-1,4-ylene)C(O)(CH 2 ) 2 —.
27 . A compound of formula I:
wherein:
a is 0 or an integer of from 1 to 3;
each R 1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 1a , —C(O)OR 1b , SR 1c , —S(O)R 1d , S(O) 2 R 1e , and —NR 1f R 1g ;
each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 1g is independently hydrogen or (1-4C)alkyl;
b is 0 or an integer of from 1 to 3;
each R 2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 2a , —C(O)OR 2b , SR 2c , —S(O)R 2d , —S(O) 2 R 2e and —NR 2f R 2g ;
each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g is independently hydrogen or (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 NW a ;
W a is hydrogen or (1-4C)alkyl;
c is 0 or an integer of from 1 to 4;
each R 3 is a substituent on carbon independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 3a , —C(O)OR 3b , SR 3c , —S(O)R 3d , —S(O) 2 R 3e , and NR 3f R 3g ;
each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g is independently hydrogen or (1-4C)alkyl;
R 4 is a divalent group of the formula:
—(R 4a ) d -(A 1 ) e -(R 4b ) f -Q-(R 4c ) g -A 2 ) h -(R 4d ) i —
wherein
d, e, f, g, h and i are each independently selected from 0 and 1;
R 4a , R 4b , R 4c and R 4d 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;
A 1 and A 2 are each independently selected from (3-7C)cycloalkylene, (6-10C)arylene, (2-9C)heteroarylene 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 and (1-4C)alkoxy;
Q is selected from a bond, —O—, —C(O)O—, —OC(O)—, —S—, —S(O)—, —S(O) 2 —, —N(Q a )C(O), —C(O)N(Q b )-, —N(Q c )S(O) 2 —, —S(O) 2 N(Q d )-, N(Q e )C(O)N(Q f )-, —N(Q g )S(O) 2 N(Q h )-, —OC(O)N(Q i )- and —N(Q j )C(O)O—;
Q a , Q b , Q c , Q d , Q e , Q f , Q g , Q h , Q i and Q j are each independently selected from hydrogen, (1-6C)alkyl, A 3 and (1-4C)alkylene-A 4 ; 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 R 4b or R 4c to which they are attached, form a 4-6 membered azacycloalkylene group;
A 3 and A 4 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 the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 8 to 14;
R 5 represents hydrogen or (1-4C)alkyl;
R 6 is —NR 6a CR 6b (O) and R 7 is hydrogen, or R 6 and R 7 together form —NR 7a C(O)—CR 7b ═CR 7c —, —CR 7d ═CR 7e —C(O)—NR 7f —, —NR 7g C(O)—CR 7h R 7i —CR 7j R 7k — or —CR 7l R 7m —CR 7n R 7o —C(O)—NR 7p —;
each of R 6a and R 6b is independently hydrogen or (1-4C)alkyl; and
each of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , R 7i , R 7j , R 7k , R 7l , R 7m , R 7n , R 7o and R 7p is independently hydrogen or (1-4C)alkyl;
or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
28 . A compound selected from:
1-biphenyl-2-yl-3-(1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl)urea;
biphenyl-2-ylcarbamic acid 1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2-hydroxyethylamino]nonyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl}ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-({6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]hexanoyl}methylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentyl}-ureido)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentyl}-ureido)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]nonyl}piperidin-4-yl ester;
1-biphenyl-2-yl-3-(1-{9-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]nonyl}piperidin-4-yl)urea;
biphenyl-2-ylcarbamic acid 1-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexylmethyl)carbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentylsulfamoyl}-ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzenesulfonyl)methylamino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}benzyl)ureido]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-fluoro-3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}piperidin-1-ylmethyl)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenoxy)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}piperidin-1-yl)-propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{7-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]heptyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{8-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]octyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)ureido]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}piperidin-1-yl)-3-oxopropyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexanecarbonyl)amino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-({(1R,3S)-3-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-cyclopentanecarbonyl}amino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{5-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentyl}ureido)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(3-{5-[2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentyl}ureido)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}piperidine-1-carbonyl)amino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}-phenylamino)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzylcarbamoyl)ethyl]piperidin-4-yl ester;
3-[4-(3-biphenyl-2-yl-ureido)piperidin-1-yl]-N-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenyl)propionamide;
biphenyl-2-ylcarbamic acid 1-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-l)ethylamino]methyl}pyridin-2-ylmethyl)carbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-cyclopentanecarbonyl}amino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoyl)methylamino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl 1-cyclohexanecarbonyl)methylamino]-ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{(S)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{(R)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-((S)-1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentanoyl}pyrrolidin-2-ylmethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[(S)-1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoyl)pyrrolidin-2-ylmethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2-hydroxy-ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{(R)-1-[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2-hydroxy-ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-chloro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
N-{2-[4-(3-biphenyl-2-yl-ureido)-piperidin-1-yl]ethyl}-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}benzamide;
1-biphenyl-2-yl-3-{1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}piperidin-1-yl)-3-oxo-propyl]piperidin-4-yl}urea;
3-[4-(3-biphenyl-2-yl-ureido)piperidin-1-yl]-N-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzyl)propionamide;
biphenyl-2-ylcarbamic acid 1-(2-fluoro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-4-methyl-phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2,6-dichloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}benzoyl)-piperidin-4-ylmethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2-hydroxyethylamino]methyl}-benzoylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[ethyl-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenyl)carbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]piperidin-1-yl}-3-oxo-propyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)amino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-3-nitro-benzoyl)methylamino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}-cyclohexylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-({4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]cyclohexanecarbonyl}-methylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-fluoro-3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]piperidin-1-ylmethyl}benzyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}pyridine-3-carbonyl)amino]ethyl}piperidin-4-yl ester,
biphenyl-2-ylcarbamic acid 1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}-thiophen-2-yl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxy-ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-fluoro-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}piperidin-1-ylmethyl)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-trifluoromethoxy-phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidin-4-yl ester,
biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(S)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-iodo-phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-6-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{5-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-bromo-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)-phenyl]propyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-fluoro-3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}piperidin-1-ylmethyl)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methoxy-phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[5-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)pentyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)-piperidin-4-yl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-1-methyl-ethyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)cyclohexyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-fluoro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)phenyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2,5-difluoro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}-benzoylamino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[6-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}piperidin-1-ylmethyl)pyridin-2-ylmethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}-naphthalen-1-ylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoyl)piperidin-4-yl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propionylamino}phenyl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-1H-benzoimidazol-2-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propionylamino}cyclohexyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentanoylamino}cyclohexyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-hexanoylamino}cyclohexyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(1-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propionyl}piperidin-4-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenyl)ureido]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(2-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]cyclohexyl}-ethyl)methylamino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2,3,5,6-tetrafluoro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)-ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2,6-diiodo-phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(1-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-butyryl}piperidin-4-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentanoyl}piperidin-4-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(1-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-hexanoyl}piperidin-4-yl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2-hydroxyethylamino]methyl}-benzylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzyl)ureido]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzyl)-ureido]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methyl-phenylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(3-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}piperidin-1-yl)ethyl]phenoxy}propyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}-benzylcarbamoyl)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetyl]methylamino}ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetyl]methylamino}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}furan-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)methylamino]ethyl}-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)cyclohexyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}furan-2-carbonyl)amino]cyclohexyl}-ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)amino]cyclohexyl}-ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidin-4-yl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-(1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidin-4-yl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidin-4-yl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}furan-2-carbonyl)piperidin-4-yl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}thiophene-2-carbonyl)piperidin-4-yl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)phenyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)phenyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)-piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}furan-2-carbonyl)amino]phenyl}ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-thiophene-2-carbonyl)amino]phenyl}-ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-benzoylamino)cyclohexyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)-propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-hydroxy-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)butyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-({2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]acetylamino}-methyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(2-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]acetyl amino}ethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-cyclohexylmethyl)carbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]hexanoylamino}-ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-{2-[(S)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenoxy)benzyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]hexylcarbamoyl}ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)butyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}furan-2-yl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)-1-methylureido]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylcarbamoyl)piperidin-4-yl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(3-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}tetrahydrofuran-2-yl)propyl]piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethylcarbamoyl}phenoxy)ethyl]piperidin-4-yl ester;
(5-bromobiphenyl-2-yl)carbamic acid 1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}-piperidin-4-yl ester;
(2′-fluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}-piperidin-4-yl ester;
(3′-chloro-3,5-difluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethylamino]nonyl}piperidin-4-yl ester;
(3′,5′-dichloro-3,5-difluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethylamino]nonyl}piperidin-4-yl ester;
(3,5-difluorobiphenyl-2-yl)carbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-phenylcarbamoyl)ethyl]-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}phenylcarbamoyl)-ethyl]-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-(3-formylamino-4-hydroxy-phenyl)-2-hydroxyethylamino]nonyl}-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl}-ethyl)-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentylcarbamoyl}ethyl)-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]hexanoylamino}ethyl)-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{6-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]hexanoylamino}ethyl)-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}benzoylamino)ethyl]-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzoylamino)ethyl]-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-4-methylpiperidin-4-yl ester;
4-(biphenyl-2-ylcarbamoyloxy)-1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethylamino]nonyl}-1-azoniabicyclo[2.2.2]octane;
biphenyl-2-ylcarbamic acid 8-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}-8-azabicyclo[3.2.1]oct-3-yl ester;
7-(biphenyl-2-ylcarbamoyloxy)-9-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethylamino]nonyl}-9-methyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonane; and
biphenyl-2-ylcarbamic acid 9-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}-3-oxa-9-aza-tricyclo[3.3.1.0*2,4*]non-7-yl ester;
or a pharmaceutically acceptable salt or solvate thereof.
29 . Biphenyl-2-ylcarbamic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.
30 . Biphenyl-2-ylcarbamic acid 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]pentylcarbamoyl}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.
31 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1 , 14 , 15 , 16 , 27 , 28 , 29 or 30 .
32 . The pharmaceutical composition of claim 31 , wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.
33 . The pharmaceutical composition of claim 31 , wherein the composition further comprises a therapeutically effective amount of a PDE 4 inhibitor.
34 . A method for treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1 , 14 , 15 , 16 , 27 , 28 , 29 or 30 .
35 . A method of providing bronchodilation in a patient, the method comprising administering to a patient requiring bronchodilation a therapeutically effective amount of a compound of any one of claims 1 , 14 , 15 , 16 , 27 , 28 , 29 or 30 .
36 . A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1 , 14 , 15 , 16 , 27 , 28 , 29 or 30 .
37 . A method for treating a pulmonary disorder, the method comprising administering a compound having both muscarinic receptor antagonist and β 2 -adrenergic receptor agonist activity.
38 . The method of claim 37 , wherein the compound has a K i for the M 3 muscarinic receptor of less than about 100 nM and an EC 50 for the β 2 adrenergic receptor of less than about 100 nM.
39 . The method of claim 37 or claim 38 , wherein the compound has a ratio of the K i for the M 3 muscarinic receptor to the EC 50 for the β 2 adrenergic receptor is from about 30:1 to about 1:30.
40 . A method of studying a biological system or sample comprising a muscarinic receptor or a β 2 adrenergic receptor, the method comprising:
(a) contacting the biological system or sample with a compound of claim 1; and
(b) determining the effects caused by the compound of claim 1 on the biological system or sample.
41 . A process for preparing a compound of formula I:
wherein:
a is 0 or an integer of from 1 to 3;
each R 1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 1a , —C(O)OR 1b , —SR 1c , —S(O)R 1d , —S(O) 2 R 1e and —NR 1f R 1g ;
each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 1g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
b is 0 or an integer of from 1 to 3;
each R 2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 2a , —C(O)OR 2b , —SR 2c , —S(O)R 2d , —S(O) 2 R 2e and NR 2f R 2g ;
each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g 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 NW a ;
W a is hydrogen or (1-4C)alkyl;
c is 0 or an integer of from 1 to 4;
each R 3 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 3a , —C(O)OR 3b , —SR 3c , —S(O)R 3d S(O) 2 R 3e and —NR 3f R 3g ; or two R 3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;
each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g is independently hydrogen or (1-4C)alkyl;
R 4 is a divalent group of the formula:
—(R 4a ) d -(A 1 ) e -(R 4b ) f -Q-(R 4c ) g -A 2 ) h -(R 4d ) i —
wherein
d, e, f, g, h and i are each independently selected from 0 and 1;
R 4a , R 4b , R 4c and R 4d 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;
A 1 and A 2 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(Q a )C(O)—, —C(O)N(Q b )-, —N(Q c )S(O) 2 —, —S(O) 2 N(Q d )-, —N(Q e )C(O)N(Q f )-, —N(Q g )S(O) 2 N(Q h )-, —OC(O)N(Q i )-, —N(Q j )C(O)O— and —N(Q k );
Q a , Q b , Q c , Q d , Q e , Q f , Q g , Q h , Q i , Q j and Q k are each independently selected from hydrogen, (1-6C)alkyl, A 3 and (1-4C)alkylene-A 4 , 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 R 4b or R 4c to which they are attached, form a 4-6 membered azacycloalkylene group;
A 3 and A 4 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 the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R 4 is attached is in the range of from 4 to 14;
R 5 represents hydrogen or (1-4C)alkyl;
R 6 is —NR 6a CR 6b (O) or —CR 6c R 6d OR 6e and R 7 is hydrogen; or R 6 and R 7 together form —NR 7a C(O)—CR 7b ═CR 7c —, —CR 7d ═CR 7e C(O)—NR 7f —, —NR 7g C(O)—CR 7h R 7i —CR 7j R 7k — or —CR 7l R 7m —CR 7n R 7o — C(O)—NR 7p —;
each of R 6a , R 6b , R 6c , R 6d and R 6e is independently hydrogen or (1-4C)alkyl; and
each of R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , R 7i , R 7j , R 7k , R 7l , R 7m , R 7n , R 7o and R 7p is independently hydrogen or (1-4C)alkyl;
or a stereoisomer thereof; the process comprising:
(a) reacting a compound of formula 1:
or a salt thereof; with a compound of formula 2:
wherein X 1 represents a leaving group, and P 1 and P 2 each independently represent a hydrogen atom or a hydroxyl-protecting group;
(b) reacting a compound of formula 3:
salt thereof; with a compound of formula 4:
wherein X 2 represents a leaving group, and P 3 and P 4 each independently represent a hydrogen atom or a hydroxyl-protecting group;
(c) coupling a compound of formula 5:
with a compound of formula 6:
wherein X Qa and X Qb each independently represent functional groups that couple to form a group Q, P 5a represents a hydrogen atom or an amino-protecting group; and P 5b and P 6 each independently represent a hydrogen atom or a hydroxyl-protecting group;
(d) for a compound of formula I wherein R 5 represents a hydrogen atom, reacting a compound of formula 3 with a compound of formula 7:
or a hydrate thereof (e.g., a glyoxal), in the presence of a reducing agent, wherein P 7 represents a hydrogen atom or a hydroxyl-protecting group;
(e) reacting a compound of formula 1 with a compound of formula 8:
or a hydrate thereof, in the presence of a reducing agent, wherein P 8 and P 9 each independently represent a hydrogen atom or a hydroxyl-protecting group, P 10 represents a hydrogen atom or an amino-protecting group, and R 4′ represents a residue that, together with the carbon to which it is attached, affords a group R 4 upon completion of the reaction;
(f) reacting a compound of formula 9:
wherein X 3 represents a leaving group, with a compound of formula 10:
wherein P 11 and P 12 each independently represent a hydrogen atom or a hydroxyl-protecting group, and P 13 represents a hydrogen atom or an amino-protecting group; or
(g) reacting a compound of formula 11:
or a hydrate thereof; wherein R 4′ represents a residue that, together with the carbon to which it is attached, affords a group R 4 upon completion of the reaction; with a compound of formula 10 in the presence of a reducing agent; and then
removing any protecting group P 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , P 12 or P 13 to provide a compound of formula I.
42 . The process of claim 41 , wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.
43 . The product prepared by the process of claim 41 or 42 .