Phenethanolamine derivatives for treatment of respiratory diseases

1. A compound of formula (II):

or a salt thereof, wherein

m is an integer of from 2 to 8;

n is an integer of from 2 to 5;

with the proviso that m+n is 4 to 10;

R 1a , R 2a , and R 3a are each independently either the same as R 1 , R 2 , and R 3 respectively as defined below or represent a precursor for said group R 1 , R 2 , or R 3 ;

R 1 is selected from hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl,

—XC(O)NR 9 R 10 , —XNR 8 C(O)R 9 , —XNR 8 C(O)NR 9 R 10 , —XNR 8 SO 2 R 9 , —XSO 2 NR 11 R 12 , XNR 8 SO 2 R 9 R 10 ,

—XNR 9 R 10 , XN + R 8 R 9 R 10 , —XNR 8 C(O)OR 9 , —XCO 2 R 9 , —XNR 8 C(O)NR 8 C(O)NR 9 R 10 , —XSR 9 , XSOR 9 , and —XSO 2 R 9 ;

or R 1 is selected from —X-aryl, —X-hetaryl, and —X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl,

C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —SO 2 NH 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkylC 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, or

C 1-6 haloalkyl;

X is —(CH 2 ) p — or C 2-6 alkenylene;

p is an integer from 0 to 6,

R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)- and R 8 and R 9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C 1-6 alkyl,

C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —CO 2 H, —CO 2 (C 1-4 alkyl),

—NH 2 , —NH(C 1-6 alkyl), aryl(C 1-6 alkyl)-, aryl(C 2-6 alkenyl)-, aryl(C 2-6 alkynyl)-, hetaryl(C 1-6 alkyl)-, —NHSO 2 aryl, —NH(hetarylC 1-6 alkyl), —NHSO 2 hetaryl, —NHSO 2 (C 1-6 alkyl), —NHC(O)aryl, or —NHC(O)hetaryl:

R 10 is selected from hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl;

R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)-, or R 11 and R 12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

and R 11 and R 12 are each optionally substituted by one or two groups independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;

where R 1 is —XNR 8 C(O)NR 9 R 10 , R 8 and R 9 may, together with the —NC(O)N— portion of the group R 1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring;

where R 1 is —XNR 8 C(O)OR 9 , R 8 and R 9 may, together with the —NC(O)O— portion of the group R 1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring;

where R 1 is —XC(O)NR 9 R 10 or —XNR 8 C(O)NR 9 R 10 , R 9 and R 10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

R 2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 3 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4; and,

R 6 and R 7 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 6 and R 7 is not more than 4;

and R 13 , R 14 , and R 15 are each independently either hydrogen or a protecting group provided that at least one of R 13 , R 14 , and R 15 is a protecting group, and R 19 is hydrogen or a protecting group.

2. A compound of formula (II) according to claim 1 or a salt thereof wherein R 1 is selected from hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl, —XNR 8 (C)OR 9 , —XNR 8 C(O)NR 9 R 10 , —XNR 8 SO 2 R 9 , —XSO 2 NR 11 R 12 , —XNR 9 R 10 , —XNR 8 C(O)OR 9 , XSR 9 , XSOR 9 , XSO 2 R 9 , or from X-aryl, X-hetaryl or X-aryloxy, optionally substituted.

3. A compound of formula (II) according to claim 1 or a salt thereof wherein X is (CH 2 ) p wherein p is zero.

4. A compound of formula (II) according to claim 1 or a salt thereof wherein R 1 is selected from hydrogen, C 1-4 alkyl, hydroxy, halo, —NR 8 C(O)NR 9 R 10 , and —NR 8 SO 2 R 9 .

5. A compound of formula (II) according to claim 1 or a salt thereof wherein R 2 and R 3 are independently selected from hydrogen, halogen, haloC 1-6 alkyl, C 1-6 alkyl, and phenyl or substituted phenyl.

6. A compound of formula (II) according to claim 1 or a salt thereof wherein R 1 is not XNR 8 SO 2 R 9 R 10 , XN + R 8 R 9 R 10 , —XCO 2 R 9 , —XNR 8 C(O)NR 8 C(O)NR 9 R 10 , —XSR 9 , XSOR 9 , or —XSO 2 R 9 .

7. A compound of formula (II) according to claim 1 or a salt thereof wherein the group R 1 is attached to the meta-position relative to the —OCR 6 R 7 — link.

8. A compound of formula (II) according to claim 1 or a salt thereof wherein the groups R 2 and R 3 are each independently attached to the ortho-position relative to the —OCR 6 R 7 -link.

9. A compound of formula (II) according to claim 8 or a salt thereof wherein R 1 represents a substituent other than hydrogen, attached to the meta-position relative to the —OCR 6 R 7 -link, and R 2 and R 3 each represent hydrogen.

10. A compound of formula (II) according to claim 1 or a salt thereof wherein R 1 represents hydrogen and R 2 and R 3 each represent a substituent at least one of which is other than hydrogen, and R 2 and R 3 are each independently attached to the ortho- or meta-positions relative to the —OCR 6 R 7 -link.

11. A compound of formula (II) according to claim 10 , or a salt thereof, wherein R 2 and R 3 each represent halogen attached to the ortho position relative to the —OCR 6 R 7 -link.

12. A compound of formula (II) according to claim 1 or a salt thereof wherein R 4 and R 5 are independently selected from hydrogen and methyl.

13. A compound of formula (II) according to claim 1 or a salt thereof wherein R 6 and R 7 are independently selected from hydrogen and methyl.

14. A compound of formula (II) according to claim 1 or a salt thereof wherein m is 4, 5 or 6, and n is 2 or 3.

15. A compound according to claim 1 wherein R 13 and R 14 together represent a protecting group R 16 R 17 C═ as in the compound of formula (III):

or a salt thereof, wherein R 1a , R 2a , R 3a , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, and n are as defined for the compound of formula (II).

16. A compound selected from the group consisting of:

N-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]-N′-phenylurea; and

(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol;

N-cyclohexyl-N′-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea;

N-(1,1′-biphenyl-4-yl)-N′-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea;

N-cyclopropyl-3′-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]-1,1′-biphenyl-2-sulfonamide;

(1R)-2-{[6-(2-[{3-(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-ylmethyl)amino]-phenyl}methoxy]ethoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol;

N-{3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}hexyl)oxy]ethoxy)methyl]phenyl}-3-[(phenylsulfonyl)amino]benzamide;

N-(3-{[({3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-ethyl]amino}hexyl)oxy]ethoxy)methyl]phenyl}amino)carbonyl]amino}phenyl)-pyridine-3-carboxamide;

N-cyclohexyl-3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]-N-({[2-(trimethylsilyl)ethyl]-oxy}methyl)benzenesulfonamide;

3′-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}hexyl)oxy]ethoxy)methyl]-1,1′-biphenyl-3-ol;

(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{2-[(3-iodobenzyl)oxy]-ethoxy}hexyl)amino]ethanol;

N-{3-[(2-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethoxy)methyl]phenyl}-N′-[3-(phenylethynyl)phenyl]urea;

(1R)-2-{[6-(2-{[3′-{2,4-bis[(1,1-dimethylethyl)oxy]pyrimidin-5-yl}-1,1′-biphenyl-3-yl]methoxy}ethoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol; and

cyclopentyl 3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-ethyl]amino}hexyl)oxy]ethoxy)methyl]phenylcarbamate.

17. A compound of formula (IV):

or a salt thereof, wherein

m is an integer of from 2 to 8;

n is an integer of from 2 to 5;

with the proviso that m+n is 4 to 10;

R 1a , R 2a , and R 3a are each independently either the same as R 1 , R 2 , and R 3 respectively as defined below or represent a precursor for said group R 1 , R 2 , or R 3 ;

R 1 is selected from hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl,

—XC(O)NR 9 R 10 , —XNR 8 C(O)R 9 , —XNR 8 C(O)NR 9 R 10 , —XNR 8 SO 2 R 9 , —XSO 2 NR 11 R 12 , XNR 8 SO 2 R 9 R 10 ,

—XNR 9 R 10 , XN + R 8 R 9 R 10 , —XNR 8 C(O)OR 9 , —XCO 2 R 9 , —XNR 8 C(O)NR 8 C(O)NR 9 R 10 , —XSR 9 , XSOR 9 , and —XSO 2 R 9 ;

or R 1 is selected from —X-aryl, —X-hetaryl, and —X-(aryloxy), each optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl,

C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —SO 2 NH 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —SO 2 NH(C 3-7 cycloalkylC 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), or hetaryl optionally substituted by 1 or 2 groups independently selected from hydroxy, C 1-6 alkoxy, halo, C 1-6 alkyl, or

C 1-6 haloalkyl;

X is —(CH 2 ) p — or C 2-6 alkenylene;

p is an integer from 0 to 6,

R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)- and R 8 and R 9 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C 1-6 alkyl,

C 1-6 haloalkyl, —NHC(O)(C 1-6 alkyl), —SO 2 (C 1-6 alkyl), —SO 2 (aryl), —CO 2 H, —CO 2 (C 1-4 alkyl),

—NH 2 , —NH(C 1-6 alkyl), aryl(C 1-6 alkyl)-, aryl(C 2-6 alkenyl)-, aryl(C 2-6 alkynyl)-, hetaryl(C 1-6 alkyl)-, —NHSO 2 aryl, —NH(hetarylC 1-6 alkyl), —NHSO 2 hetaryl, —NHSO 2 (C 1-6 alkyl), —NHC(O)aryl, or —NHC(O)hetaryl:

R 10 is selected from hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl;

R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl, hetaryl, hetaryl(C 1-6 alkyl)- and aryl(C 1-6 alkyl)-, or R 11 and R 12 , together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

and R 11 and R 12 are each optionally substituted by one or two groups independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;

where R 1 is —XNR 8 C(O)NR 9 R 10 , R 8 and R 9 may, together with the —NC(O)N— portion of the group R 1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring;

where R 1 is —XNR 8 C(O)OR 9 , R 8 and R 9 may, together with the —NC(O)O— portion of the group R 1 to which they are bonded, form a 5-, 6- or 7-membered saturated or unsaturated ring;

where R 1 is —XC(O)NR 9 R 10 or —XNR 8 C(O)NR 9 R 10 , R 9 and R 10 may, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

R 2 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 3 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo, aryl, aryl(C 1-6 alkyl)-, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 4 and R 5 is not more than 4; and,

R 6 and R 7 are independently selected from hydrogen and C 1-4 alkyl with the proviso that the total number of carbon atoms in R 6 and R 7 is not more than 4;

and R 13 , R 14 , and R 15 are each independently either hydrogen or a protecting group provided that at least one of R 13 , R 14 , and R 15 is a protecting group, and R 19 is hydrogen or a protecting group.

18. A compound selected from the group consisting of:

(5R)-3-(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one;

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{2-[(3-nitrobenzyl)oxy]-ethoxy}hexyl)-1,3-oxazolidin-2-one;

N-(3-{[2-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)-N′-phenylurea;

N-cyclohexyl-M-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea;

N-(1,1′-biphenyl-4-yl)-N′-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea;

(5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one;

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{[(3-nitrophenyl)-methyl]oxy}ethoxy]hexyl}-1,3-oxazolidin-2-one;

N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-[(phenylsulfonyl)amino]-benzamide;

3-amino-N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]benzamide;

N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-nitrobenzamide;

N-(3-aminophenyl)-N′-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]urea;

N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N′-(3-nitrophenyl)urea;

N-cyclohexyl-3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)-N-({[2-(trimethylsilyl)ethyl]oxy}-methyl)benzenesulfonamide;

N-{3-[({[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]amino}carbonyl)amino]-phenyl}pyridine-3-carboxamide;

cyclopentyl 3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenylcarbamate;

N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N′-[3-(phenylethynyl)phenyl]urea;

1,1-dimethylethyl cyclopropyl{[3′-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)-1,1′-biphenyl-2-yl]sulfonyl}carbamate;

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{2-([3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy)ethoxy}hexyl)-1,3-oxazolidin-2-one;

(5R)-3-[6-(2-[{3-[(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-ylmethyl)amino]-phenyl}methoxy]ethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one;

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{(3-iodophenyl)methoxy}ethoxy]hexyl}-1,3-oxazolidin-2-one;

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{(3′-hydroxy-1,1′-biphenyl-3-yl)methoxy}ethoxy]hexyl}-1,3-oxazolidin-2-one; and

(5R)-3-{6-[2-{(3′-{2,4-bis[(1,1-dimethylethyl)oxy]pyrimidin-5-yl}-1,1′-biphenyl-3-yl)methoxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.

19. A compound according to claim 17 wherein R 13 and R 14 are independently selected from an ester.

20. A compound according to claim 17 wherein R 15 represents a group selected from benzyl, α-methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, trichloroacetyl, and trifluoroacetyl.

21. A compound of according to claim 17 wherein R 19 represents a trialkylsilyl group.