Substituted pyrazolopyrazines, imidazopyrazines and [1,2,4]triazolopyrazines as allosteric SHP2 inhibitors

1. A compound of Formula IV:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

wherein:

is:

wherein ring B is optionally substituted on any available carbon with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , (CH 2 ) n OH, heterocyclyl, and heteroaryl;

R 2 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 5 R 6 , OH, C 3 -C 8 cycloalkyl, C 4 -C 8 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 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NR 5 R 6 , NR 5 S(O)R 6 , NR 5 S(O)NR 5 R 6 , NR 5 S(O) 2 R 6 , NR 5 S(O) 2 NR 5 R 6 , OR 5 , ═O, SR 5 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , heterocyclyl, aryl, heteroaryl, and R 5 ;

Y 2 is —NR a ', —NR a C(O)—, —NR a C(O)NR a —, —NR a C(O)O—, —NR a C(S)—, —NR a C(S)NR a —, or —NR a S(O) 2 —, wherein the bond on the left side of Y 2 is bound to the ring and the bond on the right side of Y 2 is bound to R 3 ;

R 3 and R a , 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 C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , (CH 2 ) n OH, ═O, heterocyclyl, and heteroaryl;

R 4 is:

wherein:

Y 1 is a direct bond, —CH 2 —, —C(═CH 2 )—, —NH—, —S—, —S(O)—, —S(O) 2 —, or —S(O) 2 NH—;

ring A is a monocyclic or polycyclic 5- to 12-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and

each R 1 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R 5 , C(O)OR 5 , NR 5 R 6 , NR 5 S(O)R 6 , NR 5 S(O)NR 5 R 6 , NR 5 S(O) 2 R 6 , NR 5 S(O) 2 NR 5 R 6 , OR 5 , SR 5 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, or C 4 -C 8 cycloalkenyl;

wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and C 4 -C 8 cycloalkenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , NR 5 R 6 , NR 5 S(O)R 6 , NR 5 S(O)NR 5 R 6 , NR 5 S(O) 2 R 6 , NR 5 S(O) 2 NR 5 R 6 , OR 5 , ═O, SR 5 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , heterocyclyl, aryl, heteroaryl, and R 5 ;

each R 5 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 7 R 8 , OR 7 , SR 7 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;

each R 6 is independently H, D, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 7 R 8 , OR 7 , SR 7 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;

each R 7 is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;

wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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, NO 2 , NH 2 , OH, and SH;

each R 8 is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl;

wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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, NO 2 , NH 2 , 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) R a and R 3 , together with the atom(s) to which they are attached, do not form an optionally substituted piperazinyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring B is optionally substituted on any available carbon with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is C 1 -C 6 alkyl;

wherein the C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NR 5 R 6 , and OR 5 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is CH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y 2 is —NR a —, wherein the bond on the left side of Y 2 is bound to the ring and the bond on the right side of Y 2 is bound to R 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 and R a , together with the atom(s) to which they are attached, form a monocyclic or polycyclic 3- to 12-membered heterocyclyl;

wherein the monocyclic or polycyclic 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 and R a , together with the atom(s) to which they are attached, form a spirocyclic 5- to 12-membered heterocyclyl;

wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH.

8. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents.

9. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more NH 2 substituents.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y 1 is a direct bond.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y 1 is —S—.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring A is a monocyclic or polycyclic aryl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein ring A is a monocyclic or polycyclic heteroaryl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 1 is independently H, halogen, or NR 5 R 6 .

15. The compound of claim 1 , wherein the compound is of Formula IV-Q:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

wherein:

is:

wherein ring B is optionally substituted on any available carbon with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH;

R 2 is H, C 1 -C 6 alkyl, NR 5 R 6 , or OH;

wherein the C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NR 5 R 6 , or OR 5 ;

Y 2 is —NR a —, wherein the bond on the left side of Y 2 is bound to the ring and the bond on the right side of Y 2 is bound to R 3 ;

R 3 and R a , 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 C 1 -C 6 alkyl, CH 2 F, CHF 2 , CF 3 , (CH 2 ) n NH 2 , and (CH 2 ) n OH;

R 4 is:

wherein:

Y 1 is a direct bond or —S—;

ring A is a monocyclic or polycyclic aryl or heteroaryl; and

each R 1 is independently H, halogen, CN, C 1 -C 6 alkyl, NR 5 R 6 , or OR 5 ;

each R 5 is independently H or C 1 -C 6 alkyl; and

each R 6 is independently H or C 1 -C 6 alkyl.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

17. A compound, or a stereoisomer thereof, wherein the compound, or a stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.

18. The compound of claim 17 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.