US 11,673,901 B2
Polycyclic compounds as allosteric SHP2 inhibitors
Elena S. Koltun, Redwood City, CA (US); Naing N. Aay, Redwood City, CA (US); Andreas Buckl, Redwood City, CA (US); Kevin T. Mellem, Redwood City, CA (US); Brian R. Blank, Redwood City, CA (US); Jennifer Pitzen, Redwood City, CA (US); Gang Wang, Redwood City, CA (US); Ashutosh S. Jogalekar, Redwood City, CA (US); Walter S. Won, Redwood City, CA (US); Christos Tzitzilonis, Redwood City, CA (US); Jie Jack Li, Redwood City, CA (US); Adrian Liam Gill, Redwood City, CA (US); and James Joseph Cregg, Redwood City, CA (US)
Assigned to REVOLUTION MEDICINES, INC., Redwood City, CA (US)
Filed by Revolution Medicines, Inc., Redwood City, CA (US)
Filed on Jun. 11, 2020, as Appl. No. 16/899,446.
Application 16/899,446 is a continuation of application No. PCT/US2018/065817, filed on Dec. 14, 2018.
Claims priority of provisional application 62/599,583, filed on Dec. 15, 2017.
Claims priority of provisional application 62/678,891, filed on May 31, 2018.
Prior Publication US 2020/0407372 A1, Dec. 31, 2020
Int. Cl. C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 487/14 (2006.01); C07D 519/00 (2006.01); A61K 31/519 (2006.01); A61K 31/437 (2006.01); A61P 35/00 (2006.01)
CPC C07D 519/00 (2013.01) [C07D 471/04 (2013.01); C07D 487/04 (2013.01)] 19 Claims
 
1. A compound of the Formula II′:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
A is cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;
R1 is independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —OH, —OR6, halogen, —NO2, —CN, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, —C(O)R5, —CO2R5, —C(O)NR5R6, —NR5C(O)R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, or spiroheterocyclyl is optionally substituted with one or more —OH, halogen, —NO2, oxo, ═O, —CN, —R5, —OR5, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, heterocycle, aryl, or heteroaryl;
Y1 is —S—, a direct bond, —NH—, —S(O)2—, —S(O)2—NH—, —C(═CH2)—, —CH2—, or —S(O)—;
X1 is N or CR2;
X2 is N or CH;
B, including the atoms at the points of attachment, is

OG Complex Work Unit Chemistry
Y2 is —NRa—; wherein the bond on the left side of Y2, as drawn, is bound to the ring and the bond on the right side of the Y2 moiety, as drawn, is bound to R3;
Rb is independently, at each occurrence, —H, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or —(CH2)n-aryl is optionally substituted with one or more —OH, halogen, —NO2, oxo, —CN, —R5, —OR5, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, —C(O)NR5R6, —NR5C(O)R6, heterocycle, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CF3, —CHF2, or —CH2F;
R2 is independently —H, —NH2, —ORb, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, halogen, —C(O)ORb, —C3-C8cycloalkyl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, halogen, —NO2, oxo, —R5, —OR5, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, heterocycle, aryl, or heteroaryl;
R3 combines with Ra to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more —C1-C6alkyl, halogen, —OH, —ORb, —NH2, —NHRb, optionally substituted heteroaryl, optionally substituted heterocyclyl, —(CH2)nNH2, —(CH2)nOH, —COORb, —CONHRb, —CONH(CH2)nCOORb, —NHCOORb, —CF3, —CHF2, —CH2F, or ═O; wherein the heteroaryl and heterocyclyl are optionally substituted with —CN;
R5 and R6 are independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR7, —SR7, halogen, —NR7R8, —NO2, —CF3, or —CN;
R7 and R8 are independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more —OH, —SH, —NH2, —NO2, or —CN;
m is independently 1, 2, 3, 4, 5 or 6; and
n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.