US 11,739,093 B2
Substituted pyrazolopyrazines, imidazopyrazines and [1,2,4]triazolopyrazines as allosteric SHP2 inhibitors
Brian R. Blank, Redwood City, CA (US); Jennifer Pitzen, Redwood City, CA (US); Gang Wang, Redwood City, CA (US); Walter S. Won, Redwood City, CA (US); Christos Tzitzilonis, Redwood City, CA (US); Jie Jack Li, Redwood City, CA (US); Elena S. Koltun, Redwood City, CA (US); Naing Aay, Redwood City, CA (US); Andreas Buckl, Redwood City, CA (US); Kevin Mellem, Redwood City, CA (US); Christopher Semko, Redwood City, CA (US); Ash Jogalekar, Redwood City, CA (US); Gert Kiss, Redwood City, CA (US); and Adrian Gill, Redwood City, CA (US)
Assigned to REVOLUTION MEDICINES, INC., Redwood City, CA (US)
Filed by Revolution Medicines, Inc., Redwood City, CA (US)
Filed on Jul. 22, 2019, as Appl. No. 16/518,798.
Application 16/518,798 is a continuation of application No. PCT/US2018/013023, filed on Jan. 9, 2018.
Claims priority of provisional application 62/449,530, filed on Jan. 23, 2017.
Prior Publication US 2020/0017511 A1, Jan. 16, 2020
Int. Cl. A61K 31/4985 (2006.01); C07D 487/04 (2006.01); C07D 471/04 (2006.01); C07D 513/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/04 (2013.01) [C07D 471/04 (2013.01); C07D 513/04 (2013.01); C07D 519/00 (2013.01)] 18 Claims
 
1. A compound of Formula IV:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:

OG Complex Work Unit Chemistry
is:

OG Complex Work Unit Chemistry
wherein ring B is optionally substituted on any available carbon with one or two substituents independently selected from the group consisting of C1-C6 alkyl, CH2F, CHF2, CF3, (CH2)nNH2, (CH2)nOH, heterocyclyl, and heteroaryl;
R2 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR5R6, OH, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or heterocyclyl;
wherein the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of nitrogen, phosphorous, oxygen, and sulfur;
wherein the heterocyclyl is not attached via a nitrogen atom; and
wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NR5R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR5, ═O, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, heterocyclyl, aryl, heteroaryl, and R5;
Y2 is —NRa', —NRaC(O)—, —NRaC(O)NRa—, —NRaC(O)O—, —NRaC(S)—, —NRaC(S)NRa—, or —NRaS(O)2—, wherein the bond on the left side of Y2 is bound to the ring and the bond on the right side of Y2 is bound to R3;
R3 and Ra, together with the atom(s) to which they are attached, form a monocyclic or polycyclic 3- to 12-membered heterocyclyl or a spirocyclic 5- to 12-membered heterocyclyl;
wherein the monocyclic or polycyclic 3- to 12-membered heterocyclyl or spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, CH2F, CHF2, CF3, (CH2)nNH2, (CH2)nOH, ═O, heterocyclyl, and heteroaryl;
R4 is:

OG Complex Work Unit Chemistry
wherein:
Y1 is a direct bond, —CH2—, —C(═CH2)—, —NH—, —S—, —S(O)—, —S(O)2—, or —S(O)2NH—;
ring A is a monocyclic or polycyclic 5- to 12-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
each R1 is independently H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C(O)R5, C(O)OR5, NR5R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR5, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, C3-C8 cycloalkyl, or C4-C8 cycloalkenyl;
wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and C4-C8 cycloalkenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, NR5R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR5, ═O, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, heterocyclyl, aryl, heteroaryl, and R5;
each R5 is independently H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR7R8, OR7, SR7, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
each R6 is independently H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR7R8, OR7, SR7, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
each R7 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, and 3- to 12-membered monocyclic or polycyclic heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO2, NH2, OH, and SH;
each R8 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;
wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, and 3- to 12-membered monocyclic or polycyclic heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO2, NH2, OH, and SH; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
with the provisos that:
(1) the heteroaryl of ring A is not furanyl or thiophenyl; and
(2) Ra and R3, together with the atom(s) to which they are attached, do not form an optionally substituted piperazinyl.
 
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.