Substituted pyrazolopyrazines, imidazopyrazines and [1,2,4]triazolopyrazines as allosteric SHP2 inhibitors
The present disclosure is directed to inhibitors of SHP2 having the formula: and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.
1. A method for modulating SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of 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 monocyclic or polycyclic 3- to 12-membered 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 monocyclic or polycyclic 3- to 12-membered 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 method of claim 1 , wherein the subject has a disease associated with modulation of SHP2 activity selected from the group consisting of acute myeloid leukemia, breast cancer, colon cancer, juvenile myelomonocytic leukemia, LEOPARD syndrome, lung cancer, melanoma, neuroblastoma, and Noonan syndrome.
3. The method of claim 1 , 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.
4. The method of claim 1 , 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 .
5. The method of claim 1 , wherein R 2 is CH 3 .
6. The method of claim 1 , 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 .
7. The method of claim 1 , 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.
8. The method of claim 1 , 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.
9. The method of claim 8 , wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents.
10. The method of claim 8 , wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more NH 2 substituents.
11. The method of claim 1 , wherein Y 1 is a direct bond.
12. The method of claim 1 , wherein Y 1 is —S—.
13. The method of claim 1 , wherein ring A is a monocyclic or polycyclic aryl.
14. The method of claim 1 , wherein ring A is a monocyclic or polycyclic heteroaryl.
15. The method of claim 1 , wherein each R 1 is independently H, halogen, or NR 5 R 6 .
16. The method 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.
17. The method of claim 1 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof.
18. The method of claim 17 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof.
19. A method for modulating SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 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 monocyclic or polycyclic 3- to 12-membered 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 monocyclic or polycyclic 3- to 12-membered 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.
20. The method of claim 19 , wherein the subject has a disease associated with modulation of SHP2 activity selected from the group consisting of acute myeloid leukemia, breast cancer, colon cancer, juvenile myelomonocytic leukemia, LEOPARD syndrome, lung cancer, melanoma, neuroblastoma, and Noonan syndrome.
21. The method of claim 19 , 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.
22. The method of claim 19 , 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 .
23. The method of claim 19 , wherein R 2 is CH 3 .
24. The method of claim 19 , 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 .
25. The method of claim 19 , 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.
26. The method of claim 19 , 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.
27. The method of claim 26 , wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents.
28. The method of claim 26 , wherein the spirocyclic 5- to 12-membered heterocyclyl is optionally substituted with one or more NH 2 substituents.
29. The method of claim 19 , wherein Y 1 is a direct bond.
30. The method of claim 19 , wherein Y 1 is —S—.
31. The method of claim 19 , wherein ring A is a monocyclic or polycyclic aryl.
32. The method of claim 19 , wherein ring A is a monocyclic or polycyclic heteroaryl.
33. The method of claim 19 , wherein each R 1 is independently H, halogen, or NR 5 R 6 .
34. The method of claim 19 , 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.
35. The method of claim 19 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof.
36. The method of claim 35 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof.