US 12,458,640 B2
Pyrazolo[3,4-b]pyrazine SHP2 phosphatase inhibitors
Steven Howard, Cambridge (GB); John Walter Liebeschuetz, Cambridge (GB); and Tadashi Shimamura, Tsukuba (JP)
Assigned to OTSUKA PHARMACEUTICAL CO., LTD., Tokyo (JP); and TAIHO PHARMACEUTICAL CO., LTD., Tokyo (JP)
Appl. No. 17/753,048
Filed by OTSUKA PHARMACEUTICAL CO., LTD., Tokyo (JP); and TAIHO PHARMACEUTICAL CO., LTD., Tokyo (JP)
PCT Filed Aug. 20, 2020, PCT No. PCT/IB2020/057815
§ 371(c)(1), (2) Date Feb. 16, 2022,
PCT Pub. No. WO2021/033153, PCT Pub. Date Feb. 25, 2021.
Claims priority of application No. 1911928 (GB), filed on Aug. 20, 2019.
Prior Publication US 2023/0049719 A1, Feb. 16, 2023
Int. Cl. A61K 31/4985 (2006.01); A61K 9/00 (2006.01); A61K 9/19 (2006.01); A61K 9/20 (2006.01); A61K 9/48 (2006.01); A61K 45/06 (2006.01); A61K 47/10 (2017.01); A61K 47/26 (2006.01); A61P 35/00 (2006.01); C07D 487/04 (2006.01); C07D 519/00 (2006.01)
CPC A61K 31/4985 (2013.01) [A61K 9/0019 (2013.01); A61K 9/19 (2013.01); A61K 9/2013 (2013.01); A61K 9/2018 (2013.01); A61K 9/4825 (2013.01); A61K 45/06 (2013.01); A61K 47/10 (2013.01); A61K 47/26 (2013.01); A61P 35/00 (2018.01); C07D 487/04 (2013.01); C07D 519/00 (2013.01)] 33 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or hydroxyl;
R2 and R3 are independently selected from hydrogen, halogen, C1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl and —CN;
X is O or CR4R5;
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, C1-4alkyl, C1-4alkoxy and haloC1-4alkyl;
R6 and R7 join to form a Ring A which is optionally substituted by one or more R10 groups;
Ring A is either:
(i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S, or
(ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
(iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S;
R8 is selected from haloC1-4alkyl, —CH3 and halogen;
R9 is selected from hydrogen, C1-4alkyl, haloC1-4alkyl and halogen;
R10 are independently selected from halogen, cyano, cyanoC1-4alkyl, hydroxyl, ═O (oxo), C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, hydroxylC1-4alkyl, C1-4alkoxyC1-4alkylene, C1-4alkylsulfone, amino, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkylene, —C1-4alkylene-C(═O)NH(2-q)(C1-6 alkyl)q), —C0-4alkylene-NHC(═O)C1-6alkyl, sulfonamideC0-4alkylene, 3 to 6 membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, and S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted with 3 to 6 membered cycloalkyl, C1-4alkyl substituted with optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, and S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted with optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S where the optional substituent is selected from C1-4alkyl, and optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S where the optional substituent is selected from C1-4alkyl; and
q is selected from 0, 1 and 2.