US 2026/0042764 A1 · COMPOSITIONS AND METHODS FOR INHIBITION OF KRAS

A compound represented by Formula II′:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 is selected from H, C1-6alkyl, and a 3-6 membered carbocycle, wherein any C1-6 alkyl is unsubstituted or is substituted with one or more R13;
R3 is selected from a 4-9 membered heterocycle that is unsubstituted or substituted with one or more R10;
R4 is H;
R5 is selected from H, halogen, —CN, —OR12, a 3-6 membered heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a monocyclic or bicyclic heteroaryl, wherein the heteroaryl is substituted with one or more R15;
R7 is selected from halogen;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R10 is independently selected from deuterium, —OR12, ═O, —C(O)(C1-6alkylene)CN, —C(O)(C1-6alkylene)OH, —C(O)(C1-6alkyl), —C(O)O(C1-6alkyl), —C(O)N(R14)2, —C(O)OR14, —C(O)(3-6 membered carbocycle), —C(O)(3-8 membered heterocycle), —C(O)(5-6 membered heteroaryl), —C(O)O(3-6 membered carbocycle), —C(O)O(3-6 membered heterocycle), —C(O)O(C1-6alkylene) (3-6 membered heterocycle), —S(O)2(C1-6alkyl), halogen, a 5-6 membered heteroaryl, a 3-6 membered carbocycle, a 3-6 membered heterocycle, and C1-6alkyl, wherein any C1-6alkyl is optionally deuterated and is unsubstituted or substituted with one or more R20, wherein any 3-6 membered carbocycle, 5-6 membered heteroaryl, or 3-6 or 3-8 membered heterocycle is unsubstituted or substituted with one or more R12 or R20, and wherein two R10 s optionally join together to form, together with the atom(s) to which they are attached, a 3-6 membered carbocycle or heterocycle;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from a 3-6 membered carbocycle, a 3-6 membered heterocycle, C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6 alkyl is optionally deuterated;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —OC1-6haloalkyl, ═O, —CN, —NH2, —NHC1-6alkyl, —C(O)(C1-6alkyl), a 3-6 membered carbocycle, phenyl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
and
Ra and Rb are each independently selected from deuterium, halogen, C1-6 alkyl, a 3-6 membered carbocycle, —OR12, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13.

16 more elements

A compound represented by Formula II:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 is selected from H, C1-6alkyl, and a 3-6 membered carbocycle, wherein any C1-6 alkyl is unsubstituted or is substituted with one or more R13;
R3 is selected from a 4-9 membered heterocycle that is unsubstituted or substituted with one or more R10, provided that (i) when the heterocycle contains a nitrogen atom, the nitrogen atom is substituted with R10, or (ii) the heterocycle does not comprise an —NH-moiety;
R4 is H;
R5 is selected from H, halogen, —CN, —OR12, a 3-6 membered heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a monocyclic or bicyclic heteroaryl, wherein the heteroaryl lis substituted with one or more R15;
R7 is selected from halogen;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R10 is independently selected from deuterium, —OR12, ═O, —C(O)(C1-6alkylene)CN, —C(O)(C1-6alkylene)OH, —C(O)(C1-6alkyl), —C(O)O(C1-6alkyl), —C(O)N(R14)2, —C(O)OR14, —C(O)(3-6 membered carbocycle), —C(O)(3-8 membered heterocycle), —C(O)(5-6 membered heteroaryl), —C(O)O(3-6 membered carbocycle), —C(O)O(3-6 membered heterocycle), —C(O)O(C1-6alkylene) (3-6 membered heterocycle), —S(O)2(C1-6alkyl), halogen, a 5-6 membered heteroaryl, a 3-6 membered carbocycle, and C1-6alkyl, wherein any C1-6alkyl is optionally deuterated and is unsubstituted or substituted with one or more R20, wherein any 3-6 membered carbocycle, 5-6 membered heteroaryl, or 3-6 or 3-8 membered heterocycle is unsubstituted or substituted with one or more R12 or R20, and wherein two R10 s optionally join together to form, together with the atom(s) to which they are attached, a 3-6 membered carbocycle or heterocycle;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from a 3-6 membered carbocycle, a 3-6 membered heterocycle, C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6 alkyl is optionally deuterated;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —OC1-6haloalkyl, ═O, —CN, —NH2, —NHC1-6alkyl, —C(O)(C1-6alkyl), a 3-6 membered carbocycle, phenyl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
and
Ra and Rb are each independently selected from deuterium, halogen, C1-6 alkyl, a 3-6 membered carbocycle, —OR12, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13.

16 more elements

A compound represented by Formula III′:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 and R3, together with the nitrogen atom to which they are attached, form a 4-10 membered heterocycle that is unsubstituted or is substituted with one or more R11;
R4 is H;
R5 is selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a monocyclic or bicyclic heteroaryl, wherein the heteroaryl is substituted with one or more R15;
R7 is selected from halogen;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R11 is independently selected from deuterium, —OR12, ═O, ═N(R14), —C(O)(C1-6alkylene)CN, —C(O)(C1-6alkylene)OR14, —C(O)(C1-6alkyl), —C(O)O(C1-6alkyl), —C(O)N(R14)2, —C(O)(3-6 membered carbocycle or heterocycle), —S(O)2(C1-6alkyl), —N(R14)C(O)(C1-6alkyl), —N(R14)C(O)(C1-6alkylene)OR14, halogen, —CN, a 3-6 membered carbocycle or heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl, carbocycle, heterocycle, or heteroaryl is unsubstituted or substituted with one or more R20;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —CN, —NH2, —NHC1-6alkyl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
and
Ra and Rb are each independently selected from deuterium, halogen, C1-6 alkyl, a 3-6 membered carbocycle, —OR12, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13.

15 more elements

A compound represented by Formula III:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 and R3, together with the nitrogen atom to which they are attached, form a 4-10 membered heterocycle that is unsubstituted or is substituted with one or more R11, provided that when the heterocycle contains an additional nitrogen atom, the additional nitrogen atom is substituted with R11;
R4 is H;
R5 is selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a monocyclic or bicyclic heteroaryl, wherein the heteroaryl is substituted with one or more R15;
R7 is selected from halogen;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R11 is independently selected from deuterium, —OR12, ═O, ═N(R14), —C(O)(C1-6alkylene)CN, —C(O)(C1-6alkylene)OR14, —C(O)(C1-6alkyl), —C(O)O(C1-6alkyl), —C(O)N(R14)2, —C(O)(3-6 membered carbocycle or heterocycle), —S(O)2(C1-6alkyl), —N(R14)C(O)(C1-6alkyl), —N(R14)C(O)(C1-6alkylene)OR14, halogen, —CN, a 3-6 membered carbocycle or heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl, carbocycle, heterocycle, or heteroaryl is unsubstituted or substituted with one or more R20;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —CN, —NH2, —NHC1-6alkyl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
and
Ra and Rb are each independently selected from deuterium, halogen, C1-6 alkyl, a 3-6 membered carbocycle, —OR12, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13.

15 more elements

A compound represented by Formula I:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 is selected from H and C1-6alkyl, wherein any C1-6 alkyl is unsubstituted or is substituted with one or more R13;
R3 is selected from a 3-11 membered carbocycle that is unsubstituted or substituted with one or more R10;
R4 is H;
R5 is selected from H, halogen, —CN, —OR12, a 3-6 membered heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a bicyclic heteroaryl substituted with one or more R15;
R7 is selected from halogen, —CN, and H;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R10 is independently selected from —OR12, —C(O)(C1-6alkylene)CN, —C(O)(C1-6alkylene)OH, —C(O)(C1-6alkyl), —C(O)N(R14)2, —S(O)2(C1-6alkyl), halogen, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R20;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —CN, —NH2, —NHC1-6alkyl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
and
Ra and Rb are each independently selected from deuterium, halogen, C1-6 alkyl, a 3-6 membered carbocycle, —OR12, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13.

16 more elements

A compound represented by Formula IV:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 is selected from H, C1-6alkyl, and a 3-6 membered carbocycle, wherein any C1-6 alkyl is unsubstituted or is substituted with one or more R13;
R3 is selected from C1-6alkyl that is unsubstituted or is substituted with one or more R10;
R4 is H;
R5 is selected from H, halogen, —CN, —OR12, a 3-6 membered heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a bicyclic heteroaryl substituted with one or more R15;
R7 is selected from halogen, —CN, and H;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R10 is independently selected from —OR14, ═O, —CN, —N(R14)2, a 3-6 membered carbocycle, a 3-6 membered heterocycle, a 5-6 membered heteroaryl, phenyl, —S(O)2(C1-6alkyl), —N(R14)C(O)(C1-6alkyl), C1-6alkyl, and halogen, wherein any C1-6alkyl is unsubstituted or substituted with one or more R20, any 3-6 membered carbocycle is unsubstituted or substituted with one or more R12, and any 3-6 membered heterocycle or 5-6 membered heteroaryl is unsubstituted or substituted with one or more ═O, R12, or R13;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —CN, —NH2, —NHC1-6alkyl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
and
Ra and Rb are each independently selected from halogen, C1-6 alkyl, —OR12, and H, wherein any C1-6alkyl is unsubstituted or is substituted with one or more R13, and wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle.

16 more elements

A compound represented by Formula VI:

or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein:
R1 is selected from —OR8 and
R2 is selected from H, C1-6 alkyl, and a 3-6 membered carbocycle, wherein any C1-6 alkyl is unsubstituted or is substituted with one or more R13;
R4 is H;
R5 is selected from H, halogen, —CN, —OR12, a 3-6 membered heterocycle, a 5-6 membered heteroaryl, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
R6 is a monocyclic or bicyclic heteroaryl, wherein the heteroaryl is substituted with one or more R15;
R7 is selected from H and halogen;
R8 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6alkyl;
each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13;
each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen;
each R14 is independently selected from a 3-6 membered carbocycle, a 3-6 membered heterocycle, C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl is optionally deuterated;
each R15 is independently selected from deuterium, halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13;
each R20 is independently selected from —OH, —OC1-6alkyl, —O, —CN, —NH2, —NHC1-6alkyl, —C(O)(C1-6alkyl), a 3-6 membered carbocycle, a 5-6 membered aryl, and halogen;
R27 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R28;
each R28 is independently selected from C1-6alkyl and halogen;
Ra and Rb are each independently selected from deuterium, halogen, C1-6 alkyl, —OR12, a 3-6 membered carbocycle, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13;
each Rd is independently selected from H, halogen, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R20;
Re is selected from
Rf is selected from H, halogen, and C1-6alkyl;
Rg and Rh are independently selected from H and C1-6alkyl;
and
Rj is selected from C1-6alkyl,
provided that Rc is not

20 more elements

A compound capable of inhibiting a wild-type KRAS protein or a KRAS protein having a Q61H, G13D, G12D, G12V, G12C, G12S, G12A, or G12R mutation in both its active (GTP-bound) and inactive (GDP-bound) state.

Compositions and methods for inhibition of kras

Life of this patent

Compositions and methods for inhibition of kras

Life of this patent

Abstract

Claims349