Azabicycloalkane compounds

1. A process for preparing 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; and wherein the heteroaryl and heterocyclyl groups contain 1 or 2 ring heteroatoms selected independently from oxygen, nitrogen and sulfur;

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; and wherein the heteroaryl and heterocyclyl groups contain 1 or 2 ring heteroatoms selected independently from oxygen, nitrogen and sulfur;

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;

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(O)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;

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 salt or stereoisomer thereof; the process comprising:

(a) reacting a compound of formula 1:

wherein R 2a represents hydrogen or R 2 ; or a salt or protected derivative thereof; with a compound of formula 2:

wherein X 1 represents a leaving group, and P 1 and P 2 each independently represent hydrogen or a hydroxy-protecting group;

(b) reacting a compound of formula 3:

wherein P 3 represents hydrogen or an amino-protecting group, or salt or protected derivative thereof; with a compound of formula 4:

wherein X 2 represents a leaving group, and P 4 and P 5 each independently represent hydrogen or a hydroxy-protecting group;

(c) coupling a compound of formula 5:

or a salt or protected derivative thereof; 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 6 represents hydrogen or an amino-protecting group; and P 7 and P 8 each independently represent hydrogen or a hydroxy-protecting group;

(d) for a compound of formula I wherein R 5 represents hydrogen, reacting a compound of formula 3 with a compound of formula 7:

or a hydrate thereof (e.g., a glyoxal), wherein P 9 represents hydrogen or a hydroxy-protecting group, in the presence of a reducing agent;

(e) reacting a compound of formula 1 with a compound of formula 8:

or a salt or hydrate or protected derivative thereof, in the presence of a reducing agent, wherein P 10 and P 11 each independently represent hydrogen or a hydroxy-protecting group; P 12 represents hydrogen 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, or a salt or protected derivative thereof with a compound of formula 10:

wherein P 13 and P 14 each independently represent hydrogen or a hydroxy-protecting group, and P 15 represents hydrogen or an amino-protecting group;

(g) reacting a compound of formula 11:

with a reducing agent; wherein P 16 represents hydrogen or an amino-protecting group; and P 17 represents hydrogen or a hydroxy-protecting group; or a salt or protected derivative thereof;

(h) reacting a compound of formula 12:

or a salt or hydrate or protected derivative thereof; wherein R 4″ represents a residue that, together with the carbon to which it is attached, affords an R 4 group upon completion of the reaction; with a compound of formula 10 in the presence of a reducing agent;

and then removing any protecting groups to provide a compound of formula I or a salt or stereoisomer thereof.

2. The process of claim 1 , wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.

3. The process of claim 1 , wherein the compound of formula I is a compound having formula II:

or a salt or stereoisomer thereof.

4. The process of claim 1 , wherein the compound of formula I is a compound having formula III:

or a salt or stereoisomer thereof.

5. The process of claim 1 , wherein the compound of formula I is a compound having formula IV:

or a salt or stereoisomer thereof.

6. The process of claim 1 , wherein the compound of formula I is a compound having formula V:

or a salt or stereoisomer thereof.

7. The process of claim 1 , wherein R 4 is a divalent group of the formula: —(R 4a ) d — where R 4a is (4-10C)alkylene.

8. The process 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.

9. The process of claim 1 , 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.