Organic compounds
Compounds of formula I: in free or salt or solvate form, where R 1 , R 2 , R 3 and R 20 have the meanings as indicated in the specification, are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described. These compounds are useful for the treatment of inflammatory or obstructive airways diseases such as pulmonary hypertension, pulmonary fibrosis, liver fibrosis, cancer, muscle diseases such as muscle atrophies and muscle dystrophies, and systemic skeletal disorders such as osteoporosis.
1. A compound of Formula I,
wherein
X is N;
R 1 is selected from aryl, heterocyclyl, C 1 -C 7 alkyl, C 3 -C 10 -cycloalkyl, C 5 -C 10 cycloalkenyl, C(O)NR 5 R 6 , halo, C 1 -C 7 alkoxy, alkylthio, hydroxyl, C 1 -C 7 alkylcarbonyl, carboxy, carbonyl, cyano and sulfonamide, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted by one or more substituents each independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 8 cycloalkyl and C 1 -C 6 alkoxy;
R 2 is independently selected from H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, NR 7 R 8 and Z;
R 3 is independently selected from H, halogen, C 2 -C 7 alkynyl, aryl and heterocyclyl, wherein the alkynyl group is optionally substituted by one or more groups independently selected from hydroxy, cyano, amino, C 1 -C 7 alkylamino and halogen, and wherein the aryl and heterocyclyl groups are optionally substituted by one or more R x groups and each R x is independently selected from C 1 -C 7 alkyl; hydroxyl; carbonyl; aminocarbonyl; C 1 -C 7 alkylaminocarbonyl; amino; C 1 -C 7 alkylamino; C 1 -C 7 alkylthio; sulfonylamino; carbonylamino; C 1 -C 7 alkylcarbonylamino; C 1 -C 7 alkylaminocarbonyl; C 1 -C 7 alkylcarbonyl; halogen; oxo; carboxyl; C 1 -C 7 alkoxy; benzyloxy; C 1 -C 7 alkoxycarbonyl; aminosulfonyl; cyano; sulfonyl; sulfanyl; sulfoxide; -L-C 3 -C 10 -cycloalkyl, -L- C 5 -C 10 cycloalkenyl; -L-aryl; -L-het; carbonyloxy; C 1 -C 7 aminoalkyl; C 1 -C 7 alkylamino-C 1 -C 7 alkyl; C 1 -C 7 alkylamino-C 1 -C 7 alkoxy; C 1 -C 7 alkylamino- C 1 -C 7 alkylcarbonyl; and a group of the formula: P—NH-Q-T, wherein each R x group itself is optionally substituted by one or more groups each independently selected from OH, COOH, halogen, C 1 -C 7 alkyl, aryl, amino, C 1 -C 7 alkylamino, het, cyano, sulfonyl, sulfanyl, sulfoxide, hydroxy-C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkoxycarbonyl and C 1 -C 7 alkylamino-C 1 -C 7 alkyl; or
when two R x groups are present, they may be joined together to form a ring system fused to R 3 , the ring system being optionally substituted by one or more groups eachindependently selected from hydroxyl, C 1 -C 7 alkyl, aryl, amino, C 1 -C 7 alkylamino, heterocyclyl, cyano, halo, sulfonyl, sulfanyl, sulfoxide, hydroxy-C 1 -C 7 alkyl, C 1 -C 7 alkoxy and C 1 -C 7 alkylamino-C 1 -C 7 alkyl;
each L is independently a bond, —C(O)—, —C(O)NH—, a C 1 -C 6 alkylene linker, a C 1 -C 6 alkylenecarbonyl linker or a C 1 -C 6 alkyleneoxy linker;
P is —C(O)—, a C 1 -C 6 alkylene linker, a C 1 -C 6 alkylenecarbonyl linker or a C 1 -C 6 alkyleneoxy linker;
Q is —C(O)—, a C 1 -C 6 alkylene linker or a C 1 -C 6 alkylenecarbonyl linker;
T is aryl, het, NR a R b or C 3 -C 8 cycloalkyl;
R a and R b are each independently selected from H and C 1 -C 6 alkyl;
R 5 , R 6 and R 7 are each independently selected from H and C 1 -C 6 alkyl;
R 8 is selected from C 5 -C 7 cycloalkyl and a 5- or 6-membered heterocyclic group, each optionally substituted by one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and OH;
Z is selected from 5- or 6-membered heteroaryl and aryl, each being optionally substituted by one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, OH, CN, halo, —C(O)H, —C(O)OC 1 -C 6 alkyl, —C(O)NR 9 R 10 , —(CH 2 ) p NR 11 R 12 , —(CH 2 ) n het, —NR 13 C(O)C 1 -C 6 alkyl, —S(O) 2 NHR 14 and —NR 14 S(O) 2 C 1 -C 6 alkyl, wherein each alkyl group is optionally substituted by OH, COOR c and halogen;
each het is independently a 5- or 6-membered heterocyclic group optionally substituted by one or more groups each independently selected from OH, C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
R c is H or C 1 -C 6 alkyl;
n and p are each independently 0, 1 or 2;
R 9 , R 11 , R 13 and R 14 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl and C 3 -C 8 cycloalkyl;
R 10 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —(CH 2 ) m NR 15 R 16 , —(CH 2 ) t COOR d and C 5 -C 7 cycloalkyl optionally substituted by one or more groups independently selected from OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; or
R 9 and R 10 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic group which optionally contains one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more groups independently selected from OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
m is 2 or 3;
t is 1, 2 or 3;
R d is H or C 1 -C 6 alkyl;
R 12 is selected from H, C 1 -C 6 alkyl and (CH 2 ) q NR 17 R 18 ;
q is 2, 3 or 4;
R 15 , R 16 , R 17 and R 18 are each independently selected from H and C 1 -C 3 alkyl; or
R 15 and R 16 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic group which optionally contains one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more groups independently selected from OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; or
R 17 and R 18 , together with the nitrogen atom to which they are attached, form a 5-or 6-membered heterocyclic group which optionally contains one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more groups independently selected from OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
R 20 is selected from H, halo, NR 21 R 22 and OR 23 ; and
R 21 , R 22 and R 23 are each independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cyclolkyl; or R 21 and R 22 , together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered N-containing heterocyclic group;
provided that when R 3 is other than H, R 2 is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cyclolkyl; and when R 3 is H, R 2 is halogen, NR 7 R 8 or Z.
2. A compound according to claim 1 , wherein R 1 is selected from C(O)NR 5 R 6 , C 1 -C 6 alkoxy, C 5 -C 6 cycloalkenyl, halogen, 5- or 6-membered heteroaryl and aryl, wherein the cycloalkenyl, heteroaryl and aryl groups are optionally substituted by one or more groups independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
3. A compound according to claim 1 , wherein R 3 is H, optionally substituted phenyl or optionally substituted pyridinyl.
4. A compound according to claim 3 , wherein R 3 is H, phenyl or pyridinyl, wherein the phenyl and pyridinyl groups are optionally substituted by one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, CN, halo, —C(O)H, —C(O)OC 1 -C 6 alkyl, —C(O)NR 9 R 10 , —(CH 2 ) p NR 11 R 12 , —(CH 2 ) n het, —NR 13 C(O)C 1 -C 6 alkyl and —NR 14 S(O) 2 C 1 -C 6 alkyl;
R 9 , R 11 , R 13 and R 14 are each independently selected from H and C 1 -C 3 alkyl;
R 10 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —(CH 2 ) m NR 15 R 16 and C 5 -C 7 cycloalkyl optionally substituted by one or more groups independently selected from OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; or
R 9 and R 10 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic group which optionally contains one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more groups independently selected from OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy; and
m is 2 or 3.
5. A compound according to claim 1 which is a compound of Formula X
where R 3 and T are as shown below:
R 3
T
Cl
Cl
Cl
Cl
Cl
Cl
6. A compound according to claim 1 which is a compound of Formula Y
where R 2 and T are as shown below:
R 2
T
CF 3
7. A pharmaceutical composition including a compound according to any of claim 1 and one or more pharmaceutically acceptable excipients, diluents and/or carriers.
8. A process for preparing a compound of Formula I comprising the step of:
(a) reacting a compound of Formula II
where R 2 and R 3 are as defined in claim 1 and A 1 is a halogen atom, with a compound of Formula III
where X, R 1 and R 20 are as defined in claim 1 and L 1 is a boronic acid or boronic anhydride group; or
(b) reacting a compound of Formula IV
where X, R 1 , R 3 and R 20 are as defined in claim 1 and A 3 is a halogen atom, with a compound having the formula R 2 L 2 , where R 2 is as defined in claim 1 and L 2 is a boronic acid or boronic anhydride group; or
(c) reacting a compound of Formula V
where X, R 1 , R 2 and R 20 are as defined in claim 1 and A 7 is a halogen atom, with a compound having the formula R 3 L 3 , where R 3 is as defined in claim 1 and L 3 is a boronic acid or boronic anhydride group.