IP Library › Granted Patent US 10,590,090

Granted Patent B2

US 10,590,090 · App. 16/228,324 · Granted Mar 17, 2020

2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric SHP2 inhibitors

Inventors: Elena S. Koltun (Redwood City, CA); Kevin Mellem (Redwood City, CA); Adrian Gill (Redwood City, CA); Gert Kiss (Redwood City, CA); Christopher Semko (Redwood City, CA); Naing Aay (Redwood City, CA); Andreas Buckl (Redwood City, CA); Ashutosh Jogalekar (Redwood City, CA); Walter Won (Redwood City, CA)

Assignee: REVOLUTION MEDICINES, INC.

C07D241/20 A61P35/02 A61P35/04 C07D241/18 C07D401/04 C07D403/04 C07D403/12 C07D477/26 C07D487/04

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Quick Facts

Patent No.: US 10,590,090
App. No.: 16/228,324
Granted: Mar 17, 2020
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present disclosure is directed to inhibitors of SHP2, such as pyrazine compounds, and their use in the treatment of disease associated with SHP2 modulation, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. Also disclosed are pharmaceutical compositions comprising the same.

Claims (445)

1. A compound of Formula I-W:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein:

A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;

Y 1 is —S— or a direct bond;

Y 2 is —NR a —, —(CR a 2 ) m —, —C(O)—, —C(R a ) 2 NH—, —(CR a 2 ) m O—, —C(O)N(R a )—, —N(R a )C(O)—, —S(O) 2 N(R a )—, —N(R a )S(O) 2 —, —N(R a )C(O)N(R a )—, —N(R a )C(S)N(R a )—, —C(O)O—, —OC(O)—, —OC(O)N(R a )—, —N(R a )C(O)O—, —C(O)N(R a )O—, —N(R a )C(S)—, —C(S)N(R a )—, or —OC(O)O—; wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 1 is independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more —OH, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is independently —OH, —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, F, Br, I, —C 3 -C 8 cycloalkyl, 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, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R a is independently, at each occurrence, —H, -D, —OH, —C 3 -C 8 cycloalkyl, —C 1 -C 6 alkyl, 3- to 12-membered heterocyclyl, or —(CH 2 ) n -aryl, wherein each alkyl or cycloalkyl is optionally substituted with one or more —NH 2 , or wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;

R b is independently, at each occurrence, —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocycle, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CF 3 , —CHF 2 , or —CH 2 F;

R 3 is independently —H, —C 1 -C 6 alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C 3 -C 8 cycloalkyl, or —(CH 2 ) n —R b , wherein each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, —NH 2 , —OR b , —NHR b , —(CH 2 ) n OH, heterocyclyl, or spiroheterocyclyl; or

R 3 can combine with R a 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 —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NH 2 , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

R 4 is independently —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, aryl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —NH 2 , —OR b , halogen, or oxo; wherein each aryl is optionally substituted with one or more —OH, —NH 2 , or halogen; or

R a and R 4 , together with the atom or atoms to which they are attached, can combine to form a monocyclic or polycyclic C 3 -C 12 cycloalkyl or a monocyclic or polycyclic 3- to 12-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo; wherein the heterocycle optionally comprises —S(O) 2 — in the heterocycle;

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

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

R 7 and R 8 are independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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, —NH 2 , —NO 2 , or —CN;

m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound of claim 1 , wherein the compound is Formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein:

A is 5- to 12-membered monocyclic or polycyclic heterocycloalkyl, aryl, or heteroaryl;

Y 1 is —S— or a direct bond;

R 1 is independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , or —CO 2 R 5 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more —OH, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is independently —OH, —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, 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, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R a is independently, at each occurrence, —H, -D, —OH, —C 3 -C 8 cycloalkyl, or —C 1 -C 6 alkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more —NH 2 , wherein 2 R a , together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;

R b is independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O; wherein each alkyl, cycloalkyl, alkenyl, or heterocycle is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 3 is independently —C 1 -C 6 alkyl or a 3- to 12-membered monocyclic or polycyclic heterocycle, wherein each alkyl or heterocycle is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, or —NH 2 ; or

R 4 is independently —H, -D, or —C 1 -C 6 alkyl, wherein each alkyl is optionally substituted with one or more —OH, —NH 2 , halogen, or oxo; or

R 7 and R 8 are independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, 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, —NH 2 , —NO 2 , or —CN;

m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

3. The compound of claim 1 , wherein the compound is Formula I-W6:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein:

A is a 5- to 12-membered monocyclic or polycyclic heteroaryl;

Y 1 is —S—;

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

R 3 is combined with R a 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 —C 1 -C 6 alkyl, —OH, —NH 2 , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , or —CH 2 F;

R 1 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —OH, halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —C(O)R 5 , or —CO 2 R 5 ;

R 2 is —C 1 -C 6 alkyl;

R b is independently, at each occurrence, —H or —C 1 -C 6 alkyl;

R 4 is —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —C(O)NR 5 R 6 , or —OH, or CN, wherein alkyl is optionally substituted with one or more —OH, —NH 2 , halogen, or oxo; or

R 5 and R 6 are each independently, at each occurrence, —H or —C 1 -C 6 alkyl; and

n is independently, at each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y 1 is —S—.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y 1 is a direct bond.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y 2 is —(NR a )—.

7. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R 3 is —C 1 -C 6 alkyl, which is optionally substituted with one or more —C 1 -C 6 alkyl, —OH, —NH 2 , —OR b , —NHR b , —(CH 2 ) n OH, heterocyclyl, or spiroheterocyclyl.

8. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with —C 1 -C 6 alkyl, —OH, —NH 2 , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , or —CH 2 F.

9. The compound of claim 8 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein 5- to 12-membered spiroheterocycle comprises piperidinyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein 5- to 12-membered spiroheterocycle comprises an oxygen.

11. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with —C 1 -C 6 alkyl, —OH, —NH 2 , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , or —CH 2 F.

12. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R a and R 4 together with the atom to which they are attached combine to form a monocyclic or polycyclic 3- to 12-membered heterocycle.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y 2 is —(CR a 2 ) m —.

14. The compound of claim 13 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with —C 1 -C 6 alkyl, —OH, —NH 2 , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , or —CH 2 F.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y 2 is —C(O)—, —C(R a ) 2 NH—, or —C(O)N(R a )—.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with —C 1 -C 6 alkyl, —OH, —NH 2 , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , or —CH 2 F.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein A is heterocycloalkyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein A is aryl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein A is heteroaryl.

20. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, selected from the group consisting of:

21. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, selected from the group consisting of:

Com-

pound

Structure

A-1

A-2

A-3

A-4

A-5

A-6

A-7

A-8

A-9

A-10

A-11

A-12

A-14

A-15

A-16

A-17

A-18

A-19

A-20

A-21

A-22

A-23

A-24

A-25

A-26

A-27

A-28

A-29

A-30

A-31

A-32

A-33

A-35

A-36

A-37

A-38

A-39

A-40

A-41

A-42

A-43

A-44

A-45

A-46

A-47

A-48

A-49

A-50

A-51

A-52

A-53

A-54

A-55

A-56

A-57

A-58

A-59

A-60

A-61

A-62

A-63

A-64

A-65

A-66

A-67

A-68

A-69

A-70

A-71

A-72

A-73

A-74

A-75

A-76

A-77

A-78

A-79

A-80

A-81

A-82

A-83

A-84

A-85

A-86

A-87

A-88

A-89

A-90

A-91

A-92

A-93

A-94

A-95

A-96

A-97

A-98

A-99

A-100

A-101

A-102

A-103

A-104

A-105

A-106

A-107

A-108

A-109

A-110

A-111

A-112

A-113

A-114

A-115

A-116

A-117

A-118

A-119

A-120

A-121

A-122

A-123

A-124

A-125

A-126

A-127

A-128

A-129

A-130

A-131

A-132

A-133

A-134

A-135

A-136

A-137

A-138

A-139

A-140

A-141

22. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, selected from the group consisting of:

Com-

pound

Structure

A-142

A-143

A-144

A-145

A-146

A-147

A-148

A-149

A-150

A-151

A-152

A-153

A-154

A-155

A-156

A-157

A-158

A-159

A-160

A-161

A-162

A-163

A-164

A-165

A-166

A-167

A-168

A-169

A-170

A-171

A-172

A-173

A-174

A-175

A-176

A-177

A-178

A-179

A-180

A-181

A-182

A-183

A-184

A-185

A-186

A-187

A-188

A-189

A-190

A-191

A-192

A-193

A-194

A-195

A-196

A-197

A-198

A-199

A-200

A-201

A-202

A-203

A-204

A-205

A-206

A-207

A-208

A-209

A-210

A-211

A-212

A-213

A-214

A-215

A-216

A-217

A-218

A-219

A-220

A-221

A-222

A-223

A-224

A-225

A-226

A-227

A-228

A-229

A-230

A-231

A-232

A-233

A-234

A-235

A-236

A-237

A-238

A-239

A-240

A-241

A-242

A-243

A-244

A-245

A-246

A-247

A-248

A-249

A-250

A-251

A-252

A-253

A-254

A-255

A-256

A-257

A-258

A-259

A-260

A-261

A-262

A-263

A-264

A-265

A-266

A-267

A-268

A-269

A-270

A-271

A-272

A-273

A-274

A-275

A-276

A-277

A-278

A-279

A-280

A-281

A-282

A-283

A-284

A-285

A-286

A-287

A-288

A-289

A-290

A-291

A-292

A-293

A-294

A-295

A-296

A-297

A-298

A-299

A-300

A-301

A-302

A-303

A-304

A-305

A-306

A-307

A-308

A-309

23. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is

(A170).

24. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is

(A228).

25. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is

(A266).

26. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is

(A283).

27. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is

(A290).

28. A compound that is

(A170).

29. A compound that is

(A228).

30. A compound that is

(A266).

31. A compound that is

(A283).

32. A compound that is

(A290).

33. A compound of Formula I-W:

or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein:

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

Y 1 is —S— or a direct bond;

Y 2 is —NR a —, —(CR a 2 ) m —, —C(R a ) 2 NH—, —(CR a 2 ) m O—, —C(O)N(R a )—, —N(R a )C(O)—, —S(O) 2 N(R a )—, —N(R a )S(O) 2 —, —N(R a )C(O)N(R a )—, —N(R a )C(S)N(R a )—, —OC(O)N(R a )—, —N(R a )C(O)O—, —C(O)N(R a )O—, —N(R a )C(S)—, or —C(S)N(R a )—; where in the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 1 is independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is independently —OH, —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, F, Br, I, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

R 3 is combined with R a to form a 3- to 12-membered polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NH 2 , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

R 4 is independently —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, or heterocyclyl is optionally substituted with one or more —OH, —NH 2 , —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 , or halogen; or

R 5 and R 6 are independently, at each occurrence, —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR 7 , —SR 7 , halogen, —NR 7 R 8 , —NO 2 , —CF 3 , or —CN;

m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6; and

n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

34. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition of claim 34 , wherein the compound is

(A170), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

36. The pharmaceutical composition of claim 34 , wherein the compound is

(A228), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

37. The pharmaceutical composition of claim 34 , wherein the compound is

(A266), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

38. The pharmaceutical composition of claim 34 , wherein the compound is

(A283), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

39. The pharmaceutical composition of claim 34 , wherein the compound is

(A290), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

40. A method of treating a disease selected from the group consisting of Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

41. The method of claim 40 , wherein the compound is

(A170), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

42. The method of claim 41 , wherein the disease is a cancer of the breast, lung or colon.

43. The method of claim 40 , wherein the compound is

(A228), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

44. The method of claim 43 , wherein the disease is a cancer of the breast, lung or colon.

45. The method of claim 40 , wherein the compound is

(A266), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

46. The method of claim 45 , wherein the disease is a cancer of the breast, lung or colon.

47. The method of claim 40 , wherein the compound is

(A283), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

48. The method of claim 47 , wherein the disease is a cancer of the breast, lung or colon.

49. The method of claim 40 , wherein the compound is

(A290), or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof.

50. The method of claim 49 , wherein the disease is a cancer of the breast, lung or colon.

Assignments (2)

SECURITY INTEREST Recorded Jun 25, 2025

From: REVOLUTION MEDICINES, INC.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS AGENT

Reel/Frame 071721/0025 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 15, 2019

From: JOGALEKAR, ASHUTOSH; WON, WALTER; KOLTUN, ELENA S.; GILL, ADRIAN; MELLEM, KEVIN; AAY, NAING; BUCKL, ANDREAS; SEMKO, CHRISTOPHER; KISS, GERT

To: REVOLUTION MEDICINES, INC.

Reel/Frame 048016/0160 →

Cited By (2)

US 12,565,476 US 12,570,672