Pyrazolopyridine derivatives and uses thereof
The present disclosure relates to compounds of formula (I) and pharmaceutical compositions and their use in reducing Widely Interspaced Zinc Finger Motifs (WIZ) expression levels, or inducing fetal hemoglobin (HbF) expression, and in the treatment of inherited blood disorders (e.g., hemoglobinopathies, e.g., beta-hemoglobinopathies), such as sickle cell disease and beta-thalassemia.
1. A method of treating or preventing a disorder that is affected by the reduction of WIZ protein levels in a subject in need thereof; inhibiting, reducing, or eliminating the activity of WIZ protein or WIZ protein expression in a subject in need thereof; inducing or promoting fetal hemoglobin in a subject in need thereof; reactivating fetal hemoglobin production or expression in a subject in need thereof; increasing fetal hemoglobin expression in a subject in need thereof; treating a hemoglobinopathy, a sickle cell disease, or beta-thalassemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I″) or a pharmaceutically acceptable salt thereof, wherein:
is a single bond or a double bond;
X is selected from CH, CF, and N;
R x is selected from hydrogen, C 1 -C 6 alkyl, halo, C 1 -C 6 alkoxyl, and C 3 -C 8 cycloalkyl;
R′ is selected from hydrogen and C 1 -C 6 alkyl;
R 1 is selected from hydrogen and C 1 -C 6 alkyl;
each R 2 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, and oxo, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 2a ; or 2 R 2 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
R 2a is selected from C 1 -C 6 alkoxyl and hydroxyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, —SO 2 R 4 , C 1 -C 6 haloalkyl, —C(═O)—O—(R 5 ), —C(═O)—(R 6 ), C 3 -C 10 cycloalkyl, and a 4- to 10-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, wherein the C 1 -C 8 alkyl and C 1 -C 6 haloalkyl are each independently substituted with 0-3 occurrences of R 3a , and wherein the C 3 -C 10 cycloalkyl and 4- to 10-membered heterocyclyl are each independently substituted with 0-3 occurrences of R 3b ;
or
R 3 together with the nitrogen atom to which it is attached and R 2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O and S, which 5- or 6-membered heterocyclyl is substituted with 0-2 occurrences of an oxo group;
each R 3a is independently selected from C 3 -C 10 cycloalkyl, a 4- to 10-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, C 1 -C 6 alkoxyl, hydroxyl, and —C(═O)—NR 7 R 8 , wherein the C 3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C 6 -C 10 aryl are substituted with 0-4 occurrences of R 3b ;
each R 3b is independently selected from C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkyl, —CN, —SO 2 NR 7 R 8 , —SO 2 R 4 , and hydroxyl;
R 4 is selected from C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, C 6 -C 10 aryl, and —NR 4b R 4c , wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 4a ;
R 4a is selected from C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and C 1 -C 6 alkoxyl;
R 4b is selected from hydrogen, and C 1 -C 6 alkyl;
R 4c is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl;
R 5 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl;
R 6 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, a 4- to 10-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and —NR 4b R 4c wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 6a , the C 3 -C 8 cycloalkyl is substituted with 0-1 occurrence of R 6b and the 4- to 10-membered heterocyclyl is substituted with 0-1 occurrence of C 1 -C 6 alkyl;
R 6a is selected from C 6 -C 10 aryl and C 3 -C 8 cycloalkyl;
R 6b is selected from halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, and C 1 -C 6 alkyl;
R 7 is selected from hydrogen and C 1 -C 6 alkyl;
R 8 is selected from hydrogen and C 1 -C 6 alkyl;
or
R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O, and S;
n is 0, 1, 2, 3 or 4;
m is 0, 1 or 2; and
p is 0 or 1.
2. The method of claim 1 , wherein the compound of Formula (I″) is a compound of Formula (I′) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I′) is:
wherein
is a single bond or a double bond;
X is selected from CH, CF, and N;
R′ is selected from hydrogen and C 1 -C 6 alkyl;
R 1 is selected from hydrogen and C 1 -C 6 alkyl;
each R 2 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, and oxo, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 2a ; or 2 R 2 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
R 2a is selected from C 1 -C 6 alkoxyl and hydroxyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, —SO 2 R 4 , C 1 -C 6 haloalkyl, —C(═O)—O—(R 5 ) and —C(═O)—(R 6 ), wherein the C 1 -C 8 alkyl and C 1 -C 6 haloalkyl are independently substituted with 0-3 occurrences of R 3a ;
or
R 3 together with the nitrogen atom to which it is attached and R 2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O and S;
each R 3a is independently selected from C 3 -C 10 cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, C 1 -C 6 alkoxyl, hydroxyl, and —C(═O)—NR 7 R 8 , wherein the C 3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C 6 -C 10 aryl are substituted with 0-4 occurrences of R 3b ;
each R 3b is independently selected from C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkyl, —CN, —SO 2 NR 7 R 8 , —SO 2 R 4 , and hydroxyl;
R 4 is selected from C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 4a ;
R 4a is selected from C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and C 1 -C 6 alkoxyl;
R 5 is selected from C 1 -C 6 alkyl C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl;
R 6 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 6a and the C 3 -C 8 cycloalkyl is substituted with 0-1 occurrence of R 6b ;
R 6a is selected from C 6 -C 10 aryl and C 3 -C 8 cycloalkyl;
R 6b is selected from halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, and C 1 -C 6 alkyl;
R 7 is selected from hydrogen and C 1 -C 6 alkyl;
R 8 is selected from hydrogen and C 1 -C 6 alkyl;
or
R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O, and S;
n is 0, 1, 2, 3 or 4;
m is 0, 1 or 2; and
p is 0 or 1.
3. The method of claim 1 , wherein the compound of Formula (I″) is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is:
wherein
X is selected from CH, CF, and N;
R′ is selected from hydrogen and C 1 -C 6 alkyl;
R 1 is selected from hydrogen and C 1 -C 6 alkyl;
each R 2 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, and oxo, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 2a ; or 2 R 2 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
R 2a is selected from C 1 -C 6 alkoxyl and hydroxyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, —SO 2 R 4 , C 1 -C 6 haloalkyl, —C(═O)—O—(R 5 ) and —C(═O)—(R 6 ), wherein the C 1 -C 8 alkyl and C 1 -C 6 haloalkyl are independently substituted with 0-3 occurrences of R 3a ;
or
R 3 together with the nitrogen atom to which it is attached and R 2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O and S;
each R 3a is independently selected from C 3 -C 10 cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, C 1 -C 6 alkoxyl, hydroxyl, and —C(═O)—NR 7 R 8 , wherein the C 3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C 6 -C 10 aryl are substituted with 0-4 occurrences of R 3b ;
each R 3b is independently selected from C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkyl, —CN, —SO 2 NR 7 R 8 , —SO 2 R 4 , and hydroxyl;
R 4 is selected from C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 4a ;
R 4a is selected from C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and C 1 -C 6 alkoxyl;
R 5 is selected from C 1 -C 6 alkyl C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl;
R 6 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 6a and the C 3 -C 8 cycloalkyl is substituted with 0-1 occurrence of R 6b ;
R 6a is selected from C 6 -C 10 aryl and C 3 -C 8 cycloalkyl;
R 6b is selected from halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, and C 1 -C 6 alkyl;
R 7 is selected from hydrogen and C 1 -C 6 alkyl;
R 8 is selected from hydrogen and C 1 -C 6 alkyl;
or
R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O, and S;
n is 0, 1, 2, 3 or 4;
m is 0, 1 or 2; and
p is 0 or 1.
4. The method of claim 1 , wherein
X is selected from CH, CF, and N;
R′ is selected from hydrogen and C 1 -C 3 alkyl;
R 1 is selected from hydrogen and C 1 -C 3 alkyl;
each R 2 is independently selected from unsubstituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and halo; or 2 R 2 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, —SO 2 R 4 , C 1 -C 6 haloalkyl, —C(═O)—O—(R 5 ) and —C(═O)—(R 6 ), wherein the C 1 -C 8 alkyl and C 1 -C 6 haloalkyl are independently substituted with 0-3 occurrences of R 3a ;
or
R 3 together with the nitrogen atom to which it is attached and R 2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N and O;
each R 3a is independently selected from C 3 -C 10 cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, C 1 -C 6 alkoxyl, hydroxyl, and —C(═O)—NR 7 R 8 , wherein the C 3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C 6 -C 10 aryl are substituted with 0-4 occurrences of R 3b ;
each R 3b is independently selected from C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkyl, —CN, —SO 2 NR 7 R 8 , —SO 2 R 4 , and hydroxyl;
R 4 is selected from C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 4a ;
R 4a is selected from C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and C 1 -C 6 alkoxyl;
R 5 is selected from C 1 -C 6 alkyl C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl;
R 6 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 6a and the C 3 -C 8 cycloalkyl is substituted with 0-1 occurrence of R 6b ;
R 6a is selected from C 6 -C 10 aryl and C 3 -C 8 cycloalkyl;
R 6b is selected from chloro, fluoro, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, and C 1 -C 6 alkyl;
R 7 is selected from hydrogen and C 1 -C 6 alkyl;
R 8 is selected from hydrogen and C 1 -C 6 alkyl;
or
R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O, and S;
n is 0, 1, 2 or 3;
m is 0, 1 or 2; and
p is 0 or 1.
5. The method of claim 1 , wherein
X is selected from CH and N;
R′ is selected from hydrogen and methyl;
R 1 is selected from hydrogen and methyl;
each R 2 is independently selected from unsubstituted C 1 -C 6 alkyl and halo; or 2 R 2 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a C 1 -C 3 alkylene bridging ring;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, —SO 2 R 4 , C 1 -C 6 haloalkyl, —C(═O)—O—(R 5 ) and —C(═O)—(R 6 ), wherein the C 1 -C 8 alkyl and C 1 -C 6 haloalkyl are independently substituted with 0-3 occurrences of R 3a ;
or
R 3 together with the nitrogen atom to which it is attached and R 2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional O heteroatom;
each R 3a is independently selected from C 3 -C 10 cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S and phenyl, wherein the C 3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and phenyl are substituted with 0-4 occurrences of R 3b ;
each R 3b is independently selected from C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkyl, —CN, —SO 2 NR 7 R 8 , —SO 2 R 4 , and hydroxyl;
R 4 is selected from C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 1 occurrence of R 4a ;
R 4a is selected from C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and C 1 -C 6 alkoxyl;
R 5 is selected from C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl;
R 6 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl is substituted with 0-1 occurrence of R 6a and the C 3 -C 8 cycloalkyl is substituted with 0-1 occurrence of R 6b ;
R 6a is selected from C 6 -C 10 aryl and C 3 -C 8 cycloalkyl;
R 6b is selected from chloro, fluoro, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, and C 1 -C 6 alkyl;
R 7 is selected from hydrogen and C 1 -C 6 alkyl;
R 8 is selected from hydrogen and C 1 -C 6 alkyl;
or
R 7 and R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O, and S;
n is 0, 1, 2 or 3;
m is 0, 1 or 2; and
p is 0 or 1.
6. The method of claim 1 , wherein
X is selected from CH and N;
R′ is hydrogen;
R 1 is hydrogen;
each R 2 is independently selected from unsubstituted C 1 -C 3 alkyl;
R 3 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —SO 2 R 4 and unsubstituted C 1 -C 6 haloalkyl, wherein the C 1 -C 6 alkyl is substituted with 0-2 occurrences of R 3a ;
each R 3a is independently selected from C 3 -C 10 cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1 O heteroatom, a 6-membered heteroaryl comprising 1-2 N heteroatoms and phenyl, wherein the C 3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 6-membered heteroaryl and phenyl are substituted with 0-2 occurrences of R 3b ;
each R 3b is independently selected from chloro, fluoro, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl and C 1 -C 6 alkyl;
R 4 is selected from C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl comprising 1 O heteroatom and phenyl, wherein the C 1 -C 6 alkyl is substituted with 1 occurrence of R 4a ;
R 4a is selected from C 3 -C 8 cycloalkyl and phenyl;
n is 0, 1 or 2;
m is 1 or 2; and
p is 1.
7. The method of claim 1 , wherein the compound is of Formula (Ia):
8. The method of claim 1 , wherein R 3 is selected from methyl, ethyl, n-propyl, i-propyl, 2-propanyl, butyl, i-butyl, 2-butanyl, 3-methyl-2-butanyl, i-pentyl, 3-pentanyl, neopentyl, 2,4-dimethylpentanyl, and —CH 2 —(CH 2 ) 0-1 —R 3a .
9. The method of claim 1 , wherein R 3a is C 3 -C 10 cycloalkyl, wherein the C 3 -C 10 cycloalkyl is substituted with 0-4 occurrences of R 3b , wherein each R 3b is independently selected from C 1 -C 6 alkoxyl, chloro, fluoro, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl and C 1 -C 6 alkyl.
10. The method of claim 1 , wherein R 3a is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl
11. The method of claim 1 , wherein is a single bond.
12. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the method is of treating or preventing a disorder that is affected by the reduction of WIZ protein levels in a subject in need thereof.
14. The method of claim 1 , wherein the method is of inhibiting, reducing, or eliminating the activity of WIZ protein or WIZ protein expression.
15. The method of claim 1 , wherein the method is of inducing or promoting fetal hemoglobin in a subject in need thereof.
16. The method of claim 1 , wherein the method is of reactivating fetal hemoglobin production or expression in a subject in need thereof.
17. The method of claim 1 , wherein the method is of increasing fetal hemoglobin expression in a subject in need thereof.
18. The method of claim 1 , wherein the method is of treating a hemoglobinopathy in a subject in need thereof.
19. The method of claim 1 , wherein the method is of treating a sickle cell disease in a subject in need thereof.
20. The method of claim 1 , wherein the method is of treating beta-thalassemia in a subject in need thereof.
21. The method of claim 1 , wherein the compound is selected from the group consisting of
and pharmaceutically acceptable salts thereof.
22. The method of claim 21 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 21 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 21 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
25. The method of claim 21 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
26. The method of claim 19 , wherein the compound is selected from the group consisting of
and pharmaceutically acceptable salts thereof.
27. The method of claim 26 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28. The method of claim 26 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
29. The method of claim 26 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
30. The method of claim 26 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.