Bi-functional pyrazolopyridine compounds

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

X is selected from:

wherein R 1 is selected from CH 2 OH, CH 2 CH 2 OH, N(H)C(O)H, and N(H)S(O 2 )CH 3 , and R 2 is H;

or X is a bicyclic, fused heterocyclic ring selected from the group of:

wherein said bicyclic fused heterocyclic ring is optionally substituted with one, two, or three additional substituents independently selected from alkyl, oxo, and OH;

R 3 is selected from C 4-12 alkylene, C 4-12 alkenylene, C 4-12 alkynylene, R 4 —O—R 4 , R 4 —N(R 8 )—R 4 , C 3-6 cycloalkylene, R 4 —C 3-6 cycloalkylene, C 3-6 cycloalkylene-R 4 , R 4 —C 3-6 cycloalkylene-R 4 , phenylene, R 4 -phenylene, phenylene-R 4 , R 4 -phenylene-R 4 , R 4 -phenylene-O—R 4 , R 4 -phenylene-N(R 8 )—R 4 , R 4 -phenylene-phenylene, Het, R 4 —Het, R 4 -Het-phenylene, Het-R 4 , R 4 -Het-R 4 , R 4 —O-Het R 4 -phenylene-O-Het, R 4 phenylene-C(O)—Het, and R 4 -phenylene-N(R 8 )-Het;

wherein said alkylene, alkenylene, alkynylene, cycloalkylene, or arylene is optionally substituted with 1, 2, or 3 substituents selected from halo, oxo, and OR 8 ;

Het is 5-membered or 6-membered saturated or unsaturated heterocyclene selected from the group of:

and wherein said 5-membered or 6-membered saturated or unsaturated heterocyclene is optionally substituted with 1, 2, or 3 substituents selected from halo, alkyl, alkoxy, oxo, and OH;

R 4 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene wherein each R 4 is optionally substituted with 1, 2, or 3 substituents selected from halo, oxo, and OR 8 ; with the proviso that the total number of carbon atoms in the C 1-10 alkylene, O 2-10 alkenylene, or C 2-10 alkynylene chains of two R 4 groups in any definition of R 3 is not greater than 12;

Y is C(O), C(O)N(R 8 )CH 2 , N(R 8 )C(O), O—C(O)N(R 8 )CH 2 , N(R 8 )C(O)N(R 8 )CH 2 , or SO 2 N(R 8 )CH 2 ;

R 5 is alkyl;

R 6 is H or alkyl;

R 7 is selected from unsubstituted C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, and a heterocyclic group selected from formulas (i), (ii), and (iii):

wherein Z is O, S, S(O) 2 , NH, or N—R 7a , and

R 7a is selected from alkyl, C(O)alkyl, C(O)NH 2 , C(O)N(H)alkyl, and C(O)N(alkyl) 2 ; and R 8 is H or alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 2 OH and R 2 is H.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is selected from:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 4-12 alkylene, C 4-12 alkenylene, C 4-12 alkynylene, R 4 —O—R 4 , and R 4 —N(R 8 )—R 4 , wherein said alkylene, alkenylene, or alkynylene are each optionally substituted with 1, 2, or 3 substituents selected from halo, oxo, and OR 8 .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 5-8 alkylene, C 5-8 alkenylene, C 5-8 alkynylene, R 4 —O—R 4 , and R 4 —N(R 8 )—R 4 wherein each C 5-8 alkylene, C 5-8 alkenylene, C 5-8 alkynylene is optionally substituted with 1 or 2 substituents selected from halo, oxo, and OR 8 ; and each R 4 is selected from C 1-4 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, each optionally substituted with 1 or 2 substituents selected from halo, oxo, and OR 8 .

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted C 5-8 alkylene.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from phenylene, R 4 -phenylene, phenylene-R 4 , R 4 -phenylene-R 4 , Het, R 4 -Het, and R 4 -Het-R 4 .

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from R 4 -phenylene, Het, R 4 -Het, and R 4 -Het-R 4 .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from R 4 -phenylene, R 4 -phenylene-R 4 , Het, R 4 -Het, and R 4 -Het-R 4 .

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from R 4 -phenylene, Het, and R 4 -Het.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is C(O)N(R 8 )CH 2 .

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —CH 2 CH 3 .

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is —CH 2 CH 3 .

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is

15. A compound selected from

N-[[1,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-yl]methyl]-3-[2-[[(R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]propyl]benzamide;

(R)—N-[[1,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[2-[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]-2-methylpropyl]benzamide;

(R)—N-[[1,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[2-[[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]-2-methylpropyl]benzamide;

(R)—N-[[1,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[[[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]methyl]benzamide;

(R)—N-[[1,6-diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[[[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl]ethyl]amino]methyl]benzamide;

(R)—N-[[1,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]benzamide;

(R)—N-[[1,6-diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]benzamide;

(R)—N-[[1,6-diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[5-[[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pentyl]benzamide;

(R)—N-[[1,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-8-[[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]octanamide;

(R)-1-((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4-(5-((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)urea;

(R)-1-((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4-(5-((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)phenyl)urea;

(R)-3-(((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)amino)-4-((4-(5-((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dhydroquinolin-5-yl)ethyl)amino)pentyl)phenyl)amino)cyclobut-3-ene-1,2-dione;

(R)-1-((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4-(4-((6-((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)butyl)phenyl)urea;

(R)-1-((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4-(5-((2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)urea;

(R)-1-Ethyl-N-[4′-[[[2-(3-formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]methyl]biphenyl-4-yl]-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

(R)-8-[2-[2-[4-[1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carbonyl]piperazin-1-yl]ethylamino]-1-hydroxyethyl]-5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one;

(R)—N-[[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-6-[4-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]butoxy]nicotinamide;

(R)—N-((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino) H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4-(5-((2-hydroxy-2-(4-hydroxy-3-(methylsulfonamido)phenyl)ethyl)amino)pentyl)benzamide;

(R)-6-((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl((1,6-diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)carbamate;

or a pharmaceutically acceptable salt thereof.

16. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

17. The composition according to claim 16 , wherein said composition is suitable for inhalation.

18. The composition according to claim 16 further comprising a therapeutically active agent selected from anti-inflammatory agents, anticholinergic agents, peroxisome proliferator-activated receptor agonists, epithelial sodium channel blockers, kinase inhibitors, protease inhibitors, antiinfective agents and antihistamines.