Diamine derivatives as inhibitors of leukotriene A4 hydrolase

1. A compound having Formula (I):

wherein:

R is the group:

n 1 , n 2 , and n 3 are each independently 0 to 2;

r is 0 to 4;

q is 0 to 2;

R 1v , R 1w , R 1x , R 1y and R 1z are each independently hydrogen or fluoro;

R 2 and R 7 , together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 2 and R 7 , together with the nitrogens to which they are attached and one of R 5a , R 5b and R 5c , form an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

or R 2 and R 5a , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

or R 2 and R 5b , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

R 3 is —O—, —R 12 —O—, or —O—R 12 ;

R 4 is a direct bond or an optionally substituted straight or branched alkylene chain;

each R 5a , R 5b , R 5c , R 6a , R 6b and R 6c are each independently hydrogen, alkyl, haloalkyl or hydroxyalkyl;

or any one of R 5a and R 6a together, R 5b and R 6b together, and R 5c and R 6c together can be an oxo group;

R 7 is hydrogen, —R 13 —OR 10 , —R 13 —C(═O)R 10 , —R 13 —C(═O)OR 10 , —R 13 —C(═O)—R 13 —N(R 10 )R 11 —R 13 —N(R 10 )C(═O)N(R 10 )R 11 , alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl;

R 8 is aralkyl optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, optionally substituted heteroaryl, hydroxyiminoalkyl, —R 13 —OR 10 , —R 13 —C(═O)R 10 , —R 13 —C(═O)OR 10 , —R 13 —C(═O)—R 13 —N(R 10 )R 11 , —R 13 —C(═O)N(R 10 )—R 14 —N(R 10 )R 11 , —R 13 —S(═O) t N(R 10 )R 11 (where t is 1 or 2), —R 13 —N(R 10 )R 11 , —R 13 —N(R 10 )C(═O)R 10 , —R 13 —N(R 10 )C(═O)—R 13 —N(R 10 )R 11 , —R 13 —N(R 10 )—R 13 —C(═O)OR 10 , —R 13 —N(R 10 )C(═O)—R 14 —S(═O) t N(R 10 )R 11 (where t is 1 or 2), —R 13 —N(R 10 )C(═O)—R 13 —N(R 10 )C(═O)R 10 , —R 13 —N(R 10 )C(═O)—R 13 —N(R 10 )—R 14 —N(R 10 )R 11 , —R 13 —N(R 10 )S(═O) t N(R 10 )R 11 (where t is 1 or 2), and —R 13 —O—R 14 —C(═O)OR 10 ;

each R 9 is independently —O—R 10 , alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl;

each R 10 and R 11 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

or R 10 and R 11 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

R 12 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

each R 13 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and

each R 14 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

as a single stereoisomer or as a mixture of stereoisomers;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein:

R 2 and R 7 , together with the nitrogens to which they are attached and one of R 5a , R 5b and R 5c , form an optionally substituted 6- to 10-membered bridged N-heterocyclyl.

3. A compound according to claim 2 having the following formula (I-1):

4. A compound according to claim 3 wherein:

R 4 is an optionally substituted straight or branched alkylene chain;

R 8 is aralkyl optionally substituted with one or more substituents selected from the group consisting of —R 13 —OR 10 , —R 13 —C(═O)R 10 , —R 13 —C(═O)OR 10 and —R 13 —C(═O)N(R 10 )R 11 ;

each R 9 is independently alkyl, halo or —O—R 10

R 12 is an optionally substituted straight or branched alkylene chain;

and

each R 13 is a direct bond or an optionally substituted straight or branched alkylene chain.

5. A compound according to claim 4 wherein:

r is 0;

R 8 is benzyl substituted with one or more substituents selected from —R 13 —OR 10 and —R 13 —C(═O)OR 10 ;

R 10 is hydrogen, alkyl or optionally substituted aryl; and

R 12 is C 1-6 alkylene.

6. A compound according to claim 1 wherein:

R 2 and R 7 , together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl.

7. A compound according to claim 6 , having the following formula (I-2):

8. A compound according to claim 6 having the following formula (I-3):

9. A compound according to claim 1 wherein:

R 2 and R 5a , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

or R 2 and R 5b , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl.

10. A compound according to claim 9 which is of formula (I-4) or formula (I-5):

11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 .

12. The compound of claim 1 , wherein R 3 is —O—R 12 — and R 4 is an optionally substituted straight or branched C 1 -C 6 alkylene chain.

13. The compound of claim 3 , wherein R 3 is —O—R 12 — and R 4 is an optionally substituted straight or branched C 1 -C 6 alkylene chain.

14. The compound of claim 6 , wherein R 3 is —O—R 12 — and R 4 is an optionally substituted straight or branched C 1 -C 6 alkylene chain.

15. The compound of claim 9 , wherein R 3 is —O—R 12 — and R 4 is an optionally substituted straight or branched C 1 -C 6 alkylene chain.

16. The compound of claim 1 , wherein n 1 , n 2 , and n 3 are each independently 0 to 1.

17. The compound of claim 3 , wherein n 1 , n 2 , and n 3 are each independently 0 to 1.

18. The compound of claim 6 , wherein n 1 , n 2 , and n 3 are each independently 0 to 1.

19. The compound of claim 9 , wherein n 1 , n 2 , and n 3 are each independently 0 to 1.

20. A compound selected from the following:

4-[[(1S,4S)-5-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(2-fluoroethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(2,2,3,3,4,4,4-heptafluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-[(7,7,8,8,8-pentafluorooctyl)oxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(difluoromethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(2,2,3,4,4,4-hexafluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(3,3,4,4,4-pentafluorobutyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(4,4,5,5,5-pentafluoropentyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(4,4,4-trifluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(3,3,3-trifluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

methyl 4-[[(1S,4S)-5-[[4-(3,3,4,4,4-pentafluorobutyl)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate;

methyl 2-methoxy-4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate;

methyl 2-methoxy-4-[[(1S,4S)-5-[[4-(2,2,3,3,4,4,4-heptafluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate;

3-methoxy-4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

4-[[(1S,4S)-5-[[4-(2,2,3,3,4,4,4-heptafluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]-3-methoxybenzoic acid;

3-methoxy-4-[[(1S,4S)-5-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

2-methoxy-4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid;

2-methoxy-4-[[(1S,4S)-5-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid; and

4-[[(1S,4S)-5-[[4-(2,2,3,3,4,4,4-heptafluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]-2-methoxybenzoic acid,

as a single stereoisomer or as a mixture of stereoisomers;

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 , wherein the compound is 4-[[(1S,4S)-5-[[4-(4,4,4-trifluorobutoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic as a single stereoisomer or as a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.