Azabicycloalkane compounds
This invention provides compounds of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β 2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Such compounds are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.
1. A compound of formula I:
wherein
R 1 represents —CH 2 CH 2 —, —CH═CH—, —CH 2 CH 2 CH 2 —, —CH 2 CH(OCH 3 )— or
R 2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents; provided that when R 2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X − , is present;
R 3 represents —OC(O)CR 3a R 3b R 3c or —NHC(O)R 3d ;
R 3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
R 3b represents phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
R 3c represents hydrogen, phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
or R 3b and R 3c together with R 3a and the carbon atom to which they are attached form a group of formula (a):
wherein R 3e represents —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —CH 2 O—, or —CH 2 S—;
R 3d represents an indazol-3-yl group which is unsubstituted or substituted with (1-4C)alkyl at the 1-position;
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; or R 4d represents (1-6C)alkylene-NHC(O)-(1-6C)alkylene;
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 substituents 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;
wherein the (2-9C)heteroarylene group is selected from pyrrolylene, imidazolylene, thiazolylene, oxazolylene, furylene, thiophenylene, triazolylene, pyrazolylene, isoxazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, indolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, benzthiazolylene, quinolinylene, isoquinolinylene, quinazolinylene, and quinoxalinylene;
wherein the (3-6C)heterocyclene group is selected from pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, 1,4-dioxanylene, morpholinylene, thiomorpholinylene, piperazinylene, 3-pyrrolinylene, and tetrahydrofuranylene;
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 substituents 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;
wherein the (2-9C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl;
wherein the (3-6C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
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 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 R 1 represents —CH 2 CH 2 —.
5. The compound of claim 1 , wherein R 1 represents —CH═CH.
6. The compound of claim 1 , wherein R 1 represents an oxiran-1,2-diyl group.
7. The compound of claim 1 , wherein R 3 represents —OC(O)CR 3a R 3b R 3c .
8. The compound of claim 7 , wherein R 3a is hydroxy; and R 3b and R 3c are both thien-2-yl.
9. The compound of claim 7 , wherein R 3a is hydroxymethyl; and R 3b is phenyl; and R 3c is hydrogen.
10. The compound of claim 1 , wherein R 3 represents —NHC(O)R 3d .
11. 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 —.
12. 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.
13. The compound of claim 12 , wherein R 4 is —(CH 2 ) 8 —, —(CH 2 ) 9 , and —(CH 2 ) 10 —.
14. 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.
15. 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.
16. The compound of claim 1 , wherein Q is —N(Q a )C(O)— or —C(O)N(Q b )-.
17. The compound of claim 16 , 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.
18. A compound of formula II:
wherein
R 2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents; provided that when R 2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X − , is present;
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; or R 4d represents (1-6C)alkylene-NHC(O)-(1-6C)alkylene;
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 substituents 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;
wherein the (2-9C)heteroarylene group is selected from pyrrolylene, imidazolylene, thiazolylene, oxazolylene, furylene, thiophenylene, triazolylene, pyrazolylene, isoxazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, indolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, benzthiazolylene, quinolinylene, isoquinolinylene, quinazolinylene, and quinoxalinylene;
wherein the (3-6C)heterocyclene group is selected from pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, 1,4-dioxanylene, morpholinylene, thiomorpholinylene, piperazinylene, 3-pyrrolinylene, and tetrahydrofuranylene;
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 substituents 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;
wherein the (2-9C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl;
wherein the (3-6C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
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 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 stereoisomer thereof.
19. A compound of formula III:
wherein
R 1 represents —CH 2 CH 2 —, —CH═CH—, —CH 2 CH 2 CH 2 —, —CH 2 CH(OCH 3 )— or
R 2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents; provided that when R 2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X − , is present;
R 3 represents —OC(O)CR 3a R 3b R 3c or —NHC(O)R 3d ;
R 3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
R 3b represents phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
R 3c represents hydrogen, phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
or R 3b and R 3c together with R 3a and the carbon atom to which they are attached form a group of formula (a):
wherein R 3c represents —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —CH 2 O—, or —CH 2 S—;
R 3d represents an indazol-3-yl group which is unsubstituted or substituted with (1-4C)alkyl at the 1-position;
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; or R 4d represents (1-6C)alkylene-NHC(O)-(1-6C)alkylene;
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 substituents 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;
wherein the (2-9C)heteroarylene group is selected from pyrrolylene, imidazolylene, thiazolylene, oxazolylene, furylene, thiophenylene, triazolylene, pyrazolylene, isoxazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, indolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, benzthiazolylene, quinolinylene, isoquinolinylene, quinazolinylene, and quinoxalinylene;
wherein the (3-6C)heterocyclene group is selected from pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, 1,4-dioxanylene, morpholinylene, thiomorpholinylene, piperazinylene, 3-pyrrolinylene, and tetrahydrofuranylene;
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 substituents 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;
wherein the (2-9C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl;
wherein the (3-6C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
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;
or a pharmaceutically acceptable salt or stereoisomer thereof.
20. A compound of formula IV:
wherein
R 1 represents —CH 2 CH 2 —, —CH═CH—, —CH 2 CH 2 CH 2 —, —CH 2 CH(OCH 3 )— or
R 2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents; provided that when R 2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X − , is present;
R 3 represents —OC(O)CR 3a R 3b R 3c or —NHC(O)R 3d ;
R 3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
R 3b represents phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
R 3c represents hydrogen, phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
or R 3b and R 3c together with R 3a and the carbon atom to which they are attached form a group of formula (a):
wherein R 3e represents —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —CH 2 O—, or —CH 2 S—;
R 3d represents an indazol-3-yl group which is unsubstituted or substituted with (1-4C)alkyl at the 1-position;
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; or R 4d represents (1-6C)alkylene-NHC(O)-(1-6C)alkylene;
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 substituents 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;
wherein the (2-9C)heteroarylene group is selected from pyrrolylene, imidazolylene, thiazolylene, oxazolylene, furylene, thiophenylene, triazolylene, pyrazolylene, isoxazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, indolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, benzthiazolylene, quinolinylene, isoquinolinylene, quinazolinylene, and quinoxalinylene;
wherein the (3-6C)heterocyclene group is selected from pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, 1,4-dioxanylene, morpholinylene, thiomorpholinylene, piperazinylene, 3-pyrrolinylene, and tetrahydrofuranylene;
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 substituents 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;
wherein the (2-9C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl;
wherein the (3-6C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
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;
or a pharmaceutically acceptable salt or stereoisomer thereof.
21. A compound of formula V:
wherein
R 1 represents —CH 2 CH 2 —, —CH═CH—, —CH 2 CH 2 CH 2 —, —CH 2 CH(OCH 3 )— or
R 2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents; provided that when R 2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X − , is present;
R 3 represents —OC(O)CR 3a R 3b R 3c or —NHC(O)R 3d ;
R 3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
R 3b represents phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
R 3c represents hydrogen, phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl; wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (3-5C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl;
wherein the (3-5C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
or R 3b and R 3c together with R 3a and the carbon atom to which they are attached form a group of formula (a):
wherein R 3e represents —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —CH 2 O—, or —CH 2 S—;
R 3d represents an indazol-3-yl group which is unsubstituted or substituted with (1-4C)alkyl at the 1-position;
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; or R 4d represents (1-6C)alkylene-NHC(O)-(1-6C)alkylene;
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 substituents 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;
wherein the (2-9C)heteroarylene group is selected from pyrrolylene, imidazolylene, thiazolylene, oxazolylene, furylene, thiophenylene, triazolylene, pyrazolylene, isoxazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, indolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, benzthiazolylene, quinolinylene, isoquinolinylene, quinazolinylene, and quinoxalinylene;
wherein the (3-6C)heterocyclene group is selected from pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, 1,4-dioxanylene, morpholinylene, thiomorpholinylene, piperazinylene, 3-pyrrolinylene, and tetrahydrofuranylene;
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 substituents 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;
wherein the (2-9C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl;
wherein the (3-6C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
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;
or a pharmaceutically acceptable salt or stereoisomer thereof.
22. The compound of any one of claims 18 , 19 , 20 or 21 , 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.
23. The compound of any one of claims 18 , 19 , 20 or 21 , 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.
24. The compound of any one of claims 18 , 19 , 20 or 21 , wherein R 4 is a divalent group of the formula: —(R 4a ) d — where R 4a is (4-10C)alkylene.
25. The compound of claim 24 , wherein R 4 is —(CH 2 ) 8 —, —(CH 2 ) 9 , and —(CH 2 ) 10 —.
26. The compound of any one of claims 18 , 19 , 20 or 21 , 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.
27. The compound of any one of claims 18 , 19 , 20 or 21 , 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; A2 is (6-10C)arylene or (2-9C)heteroarylene; and R 4d is (1-10C)alkylene.
28. The compound of any one of claims 18 , 19 , 20 or 21 , wherein Q is —N(Q a )C(O)— or —C(O)N(Q b )-.
29. The compound of claim 28 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.
30. The compound of any one of claims 18 , 19 , 20 or 21 , 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)(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 —;
—(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 —.
31. A compound of formula Ic:
in which:
R 1 represents —CH 2 CH 2 —, —CH═CH—, —CH 2 CH 2 CH 2 —, —CH 2 CH(OCH 3 )— or
R 3′ represents —CH 2 CH(R 3 )CH 2 —;
R 3 represents —OC(O)CR 3a R 3b R 3c or —NHC(O)R 3d ;
R 3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
R 3b represents a (5-6C)cycloalkyl group that is unsubstituted or substituted by methyl, or a phenyl or thienyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group, and
R 3c represents a hydrogen atom or a phenyl or thienyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group;
or R 3b and R 3c together with R 3a and the carbon atom to which they are attached form a group of formula
in which R 3e represents O, S or CH 2 ;
R 3d represents an indazol-3-yl group, which may bear a (1-4C)alkyl group at the 1-position;
R 2′ represents —NR 2a — or —N + R 2b R 2c —X − ;
R 2c represents (1-6C)alkyl, which may bear a hydroxy substituent or from one to three fluoro substituents;
X − represents a pharmaceutically-acceptable anion;
each of R 2a and R 2b independently represents a group of formula
wherein:
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 the group consisting of (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 the group consisting of (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 substituents 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 the group consisting of halogen, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (2-9C)heteroarylene group is selected from pyrrolylene, imidazolylene, thiazolylene, oxazolylene, furylene, thiophenylene, triazolylene, pyrazolylene, isoxazolylene, isothiazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, indolylene, benzofuranylene, benzothiophenylene, benzimidazolylene, benzthiazolylene, quinolinylene, isoquinolinylene, quinazolinylene, and quinoxalinylene;
wherein the (3-6C)heterocyclene group is selected from pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, 1,4-dioxanylene, morpholinylene, thiomorpholinylene, piperazinylene, 3-pyrrolinylene, and tetrahydrofuranylene;
Q is selected from the group consisting of 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 the group consisting of 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 substituents 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 the group consisting of halogen, (1-4C)alkyl and (1-4C)alkoxy;
wherein the (2-9C)heteroaryl group is selected from pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl;
wherein the (3-6C)heterocyclyl group is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-pyrrolinyl, and tetrahydrofuranyl;
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 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 o and R 7p is independently hydrogen or (1-4C)alkyl;
or a pharmaceutically-acceptable salt or stereoisomer thereof.
32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a of a compound of any one of claims 1 , 18 , 19 , 20 , 21 or 31 .
33. The pharmaceutical composition of claim 32 , wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.
34. The pharmaceutical composition of claim 32 , wherein the composition further comprises a therapeutically effective amount of a PDE 4 inhibitor.