Pyrazolo[3,4-b]pyridine compounds, and their use as pde4 inhibitors

Abstract

The invention provides a compound of formula (I) or a salt thereof: wherein Ar has the sub-formula (w), (y), (z1) or (z2): wherein the several groups are defined herein below, and the use of these compounds as inhibitors of phosphodiesterase type IV (PDE4).

1 - 52 . (canceled) 
   
   
       53 . A compound of formula (I) or a salt thereof: 
     
       
         
         
             
             
         
       
       wherein Ar has the sub-formula (w), (y), (z1) or (z2): 
     
     
       
         
         
             
             
         
       
       wherein:
 Q 1  is NH or NMe, and Q 2  is —C(O)—, —S(O) 2 —, —C(O)NH— or —C(O)NMe-; 
 or when Q 1  is a bond or —O—, then Q 2  is a bond; 
 or when Q 1  is —C(O)— then Q 2  is NH or NMe; 
 or when Q 1  is —S(O) 2 — then Q 2  is NH, NMe or a bond; 
 Q 3  is a bond, NH or NMe; 
 L is (CH 2 ) n  wherein n is 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; 
 or L is —(CH 2 ) m   1 —O—(CH 2 ) m   2 —, wherein it is the —(CH 2 ) m   2 — which is bonded to the NR 5 R 6  group, and wherein m 1  is 1, 2, 3, 4, 5, 6, 7, 8 or 9, and m 2  is 2, 3, 4, 5, 6, 7, 8 or 9; provided that m 1 +m 2  is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and provided that when m 1  is 1 then Q 2  is —C(O)— and Q 3  is a bond; 
 R 5  is a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, —CH 2 CH 2 OH, —CH 2 CH(Me)OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 OMe, or —CH 2 CH 2 CH 2 OMe; 
 R 6  is C 1-4 alkyl, or R 6  is C 1-4 alkyl substituted by one OH or OC 1-3  alkyl substituent which is not substituted at the alkyl carbon atom which is bonded to the nitrogen atom of the NR 5 R 6  group; 
 or R 5  and R 6  taken together are —(CH 2 ) 2 —X—(CH 2 ) 2 —, —(CH 2 ) 2 —X—(CH 2 ) 3 —, —(CH 2 ) p 1 —, —CHR 7a —(CH 2 ) p   2 —, or —(CH 2 ) p   3 —CHR 7b —(CH 2 ) p   4 —; in which: 
 X is O or NR 8  wherein R 8  is hydrogen or C 1-3 alkyl; 
 R 7a  is —CH 2 OH, —CH 2 OC 1-3 alkyl, —CH 2 CH 2 OH, —CH 2 CH 2 OC 1-3 alkyl, or C 1-3 alkyl; 
 R 7b  is OH, OC 1-3 alkyl, —CH 2 OH, —CH 2 OC 1-3 alkyl, —CH 2 CH 2 OH, —CH 2 CH 2 OC 1-3 alkyl, or C 1-3 alkyl; 
 p 1  is 4, 5 or 6, 
 p 2  is 3, 4 or 5, 
 p 3  is 1 or 2 and p 4  is 2, 3 or 4, provided that p 3 +p 4  is 3, 4 or 5; 
 and wherein, in sub-formula (y): 
 A, B, D, E and F independently are C—H or nitrogen (N); wherein one or two of A, B, D, E and F are nitrogen (N) and the remainder of A, B, D, E and F are C—H; 
 the Q 1 -Q 2 -L-NR 5 R 6  group of sub-formula (y) is substituted at a ring carbon atom of the six-membered heteroaryl ring of sub-formula (y); 
 and wherein sub-formulae (z1) and (z2) are connected to the carbonyl carbon atom of formula (I) at a ring carbon atom within (z1) and (z2); 
 and wherein, in sub-formulae (z1) and (z2):
 G is O or S or NR 9  wherein R 9  is a hydrogen atom (H) or methyl; 
 J is C—R 9J , C-[connection to carbonyl carbon atom of formula (I)], or nitrogen (N), 
 M is C—R 9M , C-[connection to carbonyl carbon atom of formula (I)], or nitrogen (N), and 
 Q is C—R 9Q , C-[connection to carbonyl carbon atom of formula (I)], or nitrogen (N); 
 
 no more than two of J, M and Q are nitrogen (N); 
 R 9J , R 9M  and R 9Q  independently are a hydrogen atom (H) or methyl; provided that no more than one of R 9J , R 9M  and R 9Q  is methyl; 
 R 1  is C 1-3 alkyl, —CH 2 —C 1-2 fluoroalkyl, or —CH 2 CH 2 OH; 
 R 2  is a hydrogen atom (H), methyl, ethyl, n-propyl, isopropyl, n-butyl, C 1-2 fluoroalkyl, cyclopropyl, cyclobutyl, or (cyclopropyl)methyl-; 
 R 4  is a hydrogen atom (H), methyl or ethyl; and 
 R 3  is optionally substituted C 4-7 cycloalkyl, or optionally substituted mono-unsaturated-C 5-7 cycloalkenyl, or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc), or a bicyclic group of sub-formula (ee); 
 
     
     
       
         
         
             
             
         
       
       in which n 1  and n 2  independently are 1 or 2; and in which Y is O, S, SO 2 , or NR 10 ; where R 10  is a hydrogen atom (H), methyl, C(O)NH 2 , C(O)-methyl, or C(O)—C 1  fluoroalkyl;
 wherein, when R 3  is optionally substituted C 4-7 cycloalkyl, then R 3  is C 4-7 cycloalkyl optionally substituted on a ring carbon(s) with one or two substituents independently being: oxo (═O); OH; methoxy; C 1  fluoroalkoxy; NH 2 ; C 1-2 alkyl; C 1 fluoroalkyl; —CH 2 OH; —CH(Me)OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —C(O)OH; —C(O)NHR 24  wherein R 24  is H or methyl; —C(O)R 25  wherein R 25  is methyl; fluoro; hydroxyimino (═N—OH); or (C 1-2 alkoxy)imino (═N—OR 26  where R 26  is C 1-2 alkyl); and wherein any OH, methoxy, fluoroalkoxy or NH 2  substituent is not bonded to the R 3  ring carbon bonded to the —NH— group of formula (I); 
 or when R 3  is the optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc), then R 3  is the heterocyclic group of sub-formula (aa), (bb) or (cc) optionally substituted on a ring carbon(s) with one or two oxo (═O) substituents; or 
 or when R 3  is optionally substituted mono-unsaturated-C 5-7 cycloalkenyl, then the cycloalkenyl is optionally substituted on a ring carbon with one substituent being fluoro or methyl, and the R 3  ring carbon bonded to the —NH— group of formula (I) does not partake in the cycloalkenyl double bond; 
 or when R 3  is the heterocyclic group of sub-formula (aa) and Y is NR 10 , then R 10  is not C(O)-methyl, or C(O)—C 1  fluoroalkyl; and 
 when R 3  is the heterocyclic group of sub-formula (bb) and Y is NR 10 , then R 10  is not methyl; and 
 when R 3  is the heterocyclic group of sub-formula (cc), then Y is O, S, SO 2  or NR 10  wherein R 10  is H or methyl; 
 and wherein: 
 when R 3  is optionally substituted C 4-7 cycloalkyl, then any —C(O)NHR 24  or —C(O)R 25  substituent on a ring carbon is: at the 3-position of a R 3  cyclobutyl ring; or 
 
       at the 3- or 4-position of a R 3  cyclopentyl ring; or at the 4-position of a R 3  cyclohexyl ring; or at the 3-, 4-, 5- or 6-position of a R 3  cycloheptyl ring wherein, in this connection, the 1-position of the R 3  cycloalkyl ring is deemed to be the connection point to the —NH— in formula (I), that is the ring atom connecting to the —NH— in formula (I);
 and wherein: 
 when R 3  is optionally substituted C 4-7 cycloalkyl, then any OH, methoxy, fluoroalkoxy, —CH 2 OH, —CH(Me)OH, —CH 2 CH 2 OH, —CH 2 NH 2 , or —C(O)OH substituent on a ring carbon is: at the 3-position of a R 3  cyclobutyl ring; or at the 3- or 4-position of a R 3  cyclopentyl ring; or at the 3-, 4- or 5-position of a R 3  cyclohexyl ring; or at the 3-, 4-, 5- or 6-position of a R 3  cycloheptyl ring. 
 
     
   
   
       54 . A compound or salt as claimed in  claim 53 , wherein R 1  is ethyl. 
   
   
       55 . A compound or salt as claimed in  claim 53 , wherein R 2  is ethyl. 
   
   
       56 . A compound or salt as claimed in  claim 53 , wherein, when R 3  is a heterocyclic group of sub-formula (aa), (bb) or (cc), then Y is O or NR 10 . 
   
   
       57 . A compound or salt as claimed in  claim 53 , wherein, when R 3  is a heterocyclic group of sub-formula (aa), (bb) or (cc), then R 3  is the heterocyclic group of sub-formula (bb) and n 1  is 1. 
   
   
       58 . A compound or salt as claimed in  claim 53 , wherein NHR 3  is sub-formula (c), (h), (k2), (k3), (n), (o), (o2), (p9) or (p13). 
     
       
         
         
             
             
         
       
     
   
   
       59 . A compound or salt as claimed in  claim 58 , wherein R 3  is tetrahydro-2H-pyran-4-yl or 1-(aminocarbonyl)-4-piperidinyl. 
   
   
       60 . A compound or a salt thereof as claimed in  claim 53 , wherein R 4  is hydrogen. 
   
   
       61 . A compound or salt thereof as claimed in  claim 53 , wherein Ar has the sub-formula (w). 
   
   
       62 . A compound or salt thereof as claimed in  claim 53 , herein Q 3  is a bond. 
   
   
       63 . A compound or salt thereof as claimed in  claim 53 , wherein L is (CH 2 ) n . 
   
   
       64 . A compound or salt thereof as claimed in  claim 53 , wherein n is 6, 7, 8 or 9. 
   
   
       65 . A compound or a salt thereof, which is: 
     4-({1,6-diethyl-5-[({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)-methyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}amino)-1-piperidinecarboxamide, 
     4-[(1,6-diethyl-5-{[(8-{(2R)-2-[(methyloxy)methyl]-1-pyrrolidinyl}octanoyl)amino]methyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]-1-piperidinecarboxamide, 
     4-[(1,6-diethyl-5-{[(8-{(2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}-octanoyl)amino]methyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]-1-piperidinecarboxamide, 
     N-{[1,6-d]ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-8-[(2-hydroxyethyl)(methyl)amino]octanamide, 
     N-{[1,6-d]ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-8-{(2R)-2-[(methyloxy)methyl]-1-pyrrolidinyl}octanamide, or 
     N-{[1,6-d]ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-8-{(2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}octanamide. 
   
   
       66 . A method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as defined in  claim 53  or a pharmaceutically acceptable salt thereof. 
   
   
       67 . A method as claimed in  claim 66 , wherein the disease is chronic obstructive pulmonary disease (COPD), asthma or rhinitis (such as allergic and/or non-allergic rhinitis) in a human. 
   
   
       68 . A pharmaceutically acceptable composition comprising a compound or pharmaceutically acceptable salt of formula (I) according to  claim 53  and a pharmaceutically acceptable excipient.