Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof
View Patent ↗Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ;
R 1 , R 2 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 1 and R 6 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 2 and R 8 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or
R 6 and R 7 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
provided that R 2 is not —CF 3 or —CHF 2 ,
provided that R 6 is not —CF 3 or —CHF 2 ; and
provided that R 1 is not —NR B C(O)R A , —NR B SO 2 R A , or —(CR z R z ) n C(O)N(R B ) 2 ; wherein each R z is independently hydrogen or fluoro; and n is 0, 1, 2, 3, or 4.
2. The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein R 1 is not hydrogen.
4. The compound of claim 1 , wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are not hydrogen.
5. The compound of claim 1 , wherein R 1 is not hydrogen.
6. The compound of claim 5 , wherein R 1 is —OR A .
7. The compound of claim 6 , wherein R 1 is —OR A , wherein R A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.
8. The compound of claim 7 , wherein R 1 is —OR A , wherein R A is optionally substituted C 1-6 alkyl.
9. The compound of claim 8 , wherein R 1 is —O-propyl, —O-isopropyl, —O-isobutyl, or —O-isoamyl.
10. The compound of claim 8 , wherein R 1 is —OR A , wherein R A is substituted C 1-6 alkyl.
11. The compound of claim 10 , wherein R 1 is —O—C 1-6 alkyl-carbocyclyl or —O—C 1-6 alkyl-heterocyclyl.
12. The compound of claim 1 , wherein R 6 is hydrogen, —OR A , halo, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclic.
13. The compound of claim 12 , wherein R 6 is halo.
14. The compound of claim 13 , wherein R 6 is fluoro or chloro.
15. The compound of claim 1 , wherein R 2 is hydrogen.
16. The compound of claim 1 , wherein R 7 and R 8 are hydrogen.
17. The compound of claim 1 , wherein R 3 is C 1-4 alkyl.
18. The compound of claim 17 , wherein R 3 is methyl.
19. The compound of claim 1 , wherein R 3 is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, or cyclobutyl.
20. The compound of claim 1 , wherein R 4 is hydrogen or optionally substituted C 1-6 alkyl.
21. The compound of claim 1 , wherein R 5 is hydrogen or optionally substituted C 1-4 alkyl.
22. The compound of claim 1 , wherein R x is methyl, ethyl, propyl, butyl, isopropyl, hydroxyethyl methoxyethyl, cyclopropyl, or cyclobutyl.
23. The compound of claim 22 , wherein R x is methyl.
24. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
25. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
26. A kit or packaged pharmaceutical comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and instructions for use thereof.
27. The compound of claim 1 , wherein the compound is of Formula (II-a) or (II-b):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is optionally substituted alkoxyalkyl, —OR A , —N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , or —NR B C(O)OR A ; and
R 2 is halogen.
28. The compound of claim 27 , wherein R 1 is —OR A , —N(R B ) 2 , or optionally substituted alkoxyalkyl.
29. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
30. A pharmaceutical composition comprising a compound of claim 24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
31. A pharmaceutical composition comprising a compound of claim 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.