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KR-20260068103-A - RAS inhibitors

KR20260068103AKR 20260068103 AKR20260068103 AKR 20260068103AKR-20260068103-A

Abstract

(I) The present invention provides a compound having a structure represented by formula (I) that can be used as a RAS inhibitor, a pharmaceutical composition comprising said compound, a method for preparing said compound, and a use of said compound in cancer treatment.

Inventors

  • 샹 얼창
  • 정 아이준
  • 동 춘란
  • 종 보유
  • 장 토니 얀타오
  • 송 구앙린
  • 지앙 준
  • 왕 롱페이
  • 호우 풀리앙
  • 왕 지파
  • 왕 헝

Assignees

  • 타이리간드 바이오사이언스 (상하이) 리미티드

Dates

Publication Date
20260513
Application Date
20240906
Priority Date
20230908

Claims (20)

  1. Compounds of Formula (II), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates: (II) Here: M is selected from N and CR 8 ; W is selected from N and CR 9 ; Z is selected from N and CR 10 ; X is selected from S or Se; Each Q is independently selected from CR 6 and N; Y is selected from O, S, Se and NR a ; B is selected from 4-7-membered 1-ring heterocycloalkyls comprising 1 to 3 heteroatoms independently selected from N, O, P, S, and Se, and 6-12-membered polycyclic heterocycloalkyls comprising 1 to 4 heteroatoms independently selected from N, O, P, S, and Se, provided that the ring atom attached to the pyrimidine ring portion of the molecule is a nitrogen heteroatom; R1 is selected from H, halogen, -CN, -OH, -NH2 , -B(OH)2, oxo, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -OC1-6 alkyl, -C(O) -C1-6 alkyl, -C(O)N( Rb ) 2 , wherein the C1-6 alkyl present is optionally substituted with a halogen, deuterium, OH, or -OC1-6 alkyl; R2 are each independently selected from H, D, -C1-6 alkyl and -( CH2 ) n - C3-6 cycloalkyl, or two R2s form a C3-4 cycloalkyl together with the carbon atoms to which they are attached, wherein the C1-6 alkyl, C3-6 cycloalkyl or C3-4 cycloalkyl are each independently and optionally substituted with a halogen, D, optionally a C1-6 alkyl substituted with a halogen or D, or optionally a -OC1-6 alkyl substituted with a halogen or D; R3 is selected from -C1-6 alkyl and -( CH2 ) n - C3-6 cycloalkyl, each of which is independently and optionally substituted with a halogen, D, optionally a C1-6 alkyl substituted with a halogen or D, or optionally a -OC1-6 alkyl substituted with a halogen or D; R4 is selected from H, D, halogen, -CN, -OH, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, -OC 3-6 cycloalkyl, and -(CH 2 ) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, or C 3-6 cycloalkyl present herein are each independently and optionally substituted with D, halogen, CN, or -OC 1-6 alkyl, or Two R4s attached to the same carbon atom form =C( Rc ) 2 , or two R4s attached to the same ring carbon atom form a spiro C3-6 cycloalkyl or a spiro 4-7 heterocycloalkyl together with the ring carbon atom to which they are attached, wherein each Rc is independently selected from -C1-6 alkyls substituted with H, a halogen, and optionally a halogen, and the spiro C3-6 cycloalkyl or spiro 4-7 heterocycloalkyl is optionally substituted with a halogen and optionally a halogen-substituted -C1-6 alkyl; R5 is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, and -( CH2 ) n - C3-6 cycloalkyl, wherein -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, or C3-6 cycloalkyl are each independently and optionally substituted with D, halogen, CN, -OC1-6 alkyl, or -O-CON( Rb ) 2 ; R6 and R7 are each independently selected from H, D, halogen, CN, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -OC1-6 alkyl, -SC1-6 alkyl, and -Se- C1-6 alkyl, wherein the -C1-6 alkyl , -C2-6 alkenyl, and -C2-6 alkynyl present herein are each independently and optionally substituted with halogen, -OC1-6 alkyl, or D; R8 is selected from H, D, halogen, CN, NO2 , -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, and -OR b , wherein -C1-6 alkyl, -C2-6 alkenyl, and -C2-6 alkynyl are each independently and optionally substituted with a halogen, CN, or -OC1-6 alkyl; or R8 is -( CH2 ) n -C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with a halogen or CN; R 10 is selected from H, D, halogen, CN, NO 2 , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, and -OR b , wherein -C 1-6 alkyl, -C 2-6 alkenyl, and -C 2-6 alkynyl are each independently and optionally substituted with a halogen or CN; R9 is selected from H, halogen, CN, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -ORb , and -O-CON( Rb ) 2 , wherein -C1-6 alkyl, -C2-6 alkenyl, and -C2-6 alkynyl are each independently and optionally substituted with a halogen or CN; R is selected from H, and optionally halogen-substituted -C 1-6 alkyls; Rb is selected from H, optionally halogen-substituted -C 1-6 alkyl, -OH, -OC 1-6 alkyl or deuterium, and -C 3-6 cycloalkyl, or two Rb attached to the same N atom form a 4-7-membered heterocycloalkyl optionally substituted with a halogen or -C 1-6 alkyl together with the N atom to which they are attached; n and p are each independently integers from 0 to 3; and m and t are each independently integers from 0 to 8.
  2. Compound of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates: (I) Here: M is selected from N and CR 8 ; W is selected from N and CR 9 ; Z is selected from N and CR 10 ; Y is selected from O, S, Se, and NR a ; B is selected from 5-7-membered 1-ring heterocycloalkyls comprising 1 to 3 heteroatoms independently selected from N, O, P, S, and Se, and 6-12-membered polycyclic heterocycloalkyls comprising 1 to 4 heteroatoms independently selected from N, O, P, S, and Se, provided that the ring atom attached to the pyrimidine ring portion of the molecule is a nitrogen heteroatom; R1 is selected from H, halogen, -CN, -OH, -B(OH) 2 , -C1-6 alkyl, -OC1-6 alkyl, and -C(O)N( Rb ) 2 , wherein the C1-6 alkyl present is optionally substituted with a halogen; R2 is each independently selected from H, D, -C1-6 alkyl and -( CH2 ) n - C3-6 cycloalkyl, or two R2s form a C3-4 cycloalkyl together with the carbon atoms to which they are attached, wherein the C1-6 alkyl, C3-6 cycloalkyl or C3-4 cycloalkyl is each independently and optionally substituted with a halogen, D, optionally a C1-6 alkyl substituted with a halogen or D, or optionally a -OC1-6 alkyl substituted with a halogen or D; R3 is selected from -C1-6 alkyl and -( CH2 ) n - C3-6 cycloalkyl, each of which is independently and optionally substituted with a halogen, D, optionally a C1-6 alkyl substituted with a halogen or D, or optionally a -OC1-6 alkyl substituted with a halogen or D; R4 is selected from H, D, halogen, -CN, -OH, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, -OC 3-6 cycloalkyl, and -(CH 2 ) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, or C 3-6 cycloalkyl present herein are each independently and optionally substituted with D, halogen, CN, or -OC 1-6 alkyl, or Two R4s attached to the same ring carbon atom form =C( Rc ) 2 , or two R4s attached to the same ring carbon atom form a spiro C3-6 cycloalkyl or a spiro 4-7 heterocycloalkyl together with the ring carbon atom to which they are attached, wherein each Rc is independently selected from -C1-6 alkyls substituted with H, a halogen, and optionally a halogen, and the spiro C3-6 cycloalkyl or spiro 4-7 heterocycloalkyl is optionally substituted with a halogen and optionally a halogen-substituted -C1-6 alkyl; R5 is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, and -( CH2 ) n - C3-6 cycloalkyl, wherein -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, or C3-6 cycloalkyl are each independently and optionally substituted with D, halogen, CN, -OC1-6 alkyl, or -O-CON( Rb ) 2 ; R6 and R7 are each independently selected from H, D, halogen, CN, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -OC1-6 alkyl, -SC1-6 alkyl, and -Se- C1-6 alkyl, wherein each of the -C1-6 alkyl, -C2-6 alkenyl , and -C2-6 alkynyl present herein is independently and optionally substituted with a halogen; R8 and R10 are each independently selected from H, D, halogen, CN, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, and -OR b , wherein -C1-6 alkyl, -C2-6 alkenyl, and -C2-6 alkynyl are each independently and optionally substituted with halogen or CN; R9 is selected from H, halogen, CN, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -ORb , and -O-CON( Rb ) 2 , wherein -C1-6 alkyl, -C2-6 alkenyl, and -C2-6 alkynyl are each independently and optionally substituted with a halogen or CN; R a and R b are each independently selected from -C 1-6 alkyls substituted with H and optionally halogens; n and p are each independently integers from 0 to 3; and m and t are each independently integers from 0 to 8.
  3. In claim 1 or 2, Z is a compound, stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein Z is C-CN.
  4. In any one of paragraphs 1 through 3, The benzo-fusion ring fragment containing Z is and, where R6 is each independently selected from H and a halogen, and the halogen is preferably F, a compound, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate.
  5. A compound, stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein M is a C-halogen-substituted C1-6 alkyl, a C-halogen-substituted C2-6 alkenyl, a C-halogen, C-CN, or C- NO2 , and preferably M is a C-halogen-substituted C1-6 alkyl or a C-halogen.
  6. A compound, stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein W is selected from N, C-halogen or CO-optionally halogen-substituted C 1-3 alkyl; or W is selected from C-halogen or CC 1-3 alkyl.
  7. In any one of claims 1 to 6, B is a compound, stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is a 5-7-membered unicyclic heterocycloalkyl comprising one nitrogen atom, a 5-7-membered unicyclic heterocycloalkyl comprising one nitrogen atom and one O atom, an 8-10-membered spiroheterocycloalkyl, or an 8-10-membered fused heterocycloalkyl comprising one-three nitrogen atoms and 0-1 O atoms, each optionally substituted with 0-3 groups independently selected from -OH, NH2 , CN, halogen, -C1-6 alkyl, -CO- C1-6 alkyl, and -CON( Rb ) 2 .
  8. In Paragraph 7, B is , Selected from, where R1 is each independently selected from -OH and optionally halogen-substituted -C 1-6 alkyls; or B is , , Selected from, wherein R1 adjacent to the nitrogen atom on the five-membered ring is selected from -COC1-6 alkyl, -CONH2 , -CONHC1-6 alkyl, and -CON( C1-6 alkyl) 2 , and the remaining R1 is selected from H, NH2 , CN, halogen, and -C1-6 alkyl; or B is And, where one R1 is selected from halogens, CN, and halogen-substituted -C1-6 alkyls, preferably existing at the para position of the ring N atom, and another R A compound selected from H, -OH, optionally halogen-substituted -C 1-6 alkyl or optionally halogen-substituted -OC 1-6 alkyl, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.
  9. In any one of paragraphs 1 through 6, B is and, for example and, here R1 adjacent to the nitrogen atom of the five-membered ring is selected from -C(O) -C1-6 alkyl and -C(O)N( Rb ) 2 , preferably -C(O)N( Rb ) 2 , and each Rb is independently a -C1-6 alkyl or -C3-6 cycloalkyl selectively substituted with H, one or more halogens, deuterium, or -C1-6 alkyl, preferably each Rb is independently a -C1-3 alkyl selectively substituted with H or one or more deuterium, most preferably each Rb is independently a -C1-3 alkyl substituted with one or more deuterium, for example, R1 is -C(O) CH3 , -C(O)N(CH₃)(CH₂CH₂F), -C(O)N(CH₃)₂, -C(O)N(CH₃)(cyclopropyl), -C(O)NH( CH3 ), -C(O)N(CD₃)₂, -C(O)N(CH₃)(CH₂CH₂OCH₃); or two Rb groups , together with the nitrogen atoms to which they are attached, form a 4-7-membered heterocycloalkyl group optionally substituted with a halogen or a -C1-6 alkyl, e.g., azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, and R1 at the meta position of the nitrogen atom on the five-membered ring is selected from H, halogen , CN, -OH, -NH2, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -OC1-6 alkyl, and -C1-6 alkyl- OC1-6 alkyl, preferably selected from H, halogen, -CN, -OH, NH2 , -C1-3 alkyl, -C2-4 alkenyl, -C2-4 alkynyl, -OC1-3 alkyl, and -C1-3 alkyl- OC1-3 alkyl, more preferably selected from -C1-3 alkyl- OC1-3 alkyl, wherein the alkyl present is optionally substituted with one or more halogens, OH, or deuterium, preferably substituted with one or more deuterium, and R1 at this position is, for example, but not limited thereto, H, F, Cl, -OH, -NH 2 , -CN, -OCH₃, -CH₃, -ethynyl, -CH₂F, -CHF₂, -O-CD₃, -CH₂OH, -CH₂-CH₃, -O-CH₂-CH₃, -CH₂-O-CH₃, -CD₂-O-CD₃, -CH₂-O-CD₃, -CH₂-OCH₂CH₃, R1 at the ortho position of the nitrogen to which B is connected to the rest of the molecule is selected from H or -C1-6 alkyl, preferably H or -C1-3 alkyl, e.g., H, -CH3 or -CH2CH₃ ; Preferably, B is , , , A compound, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate selected from, wherein R1 is as defined in this claim, provided that each is not H.
  10. In any one of claims 1 to 9, Y is O, a compound, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof.
  11. A compound, stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof, wherein each R2 is independently H or D in any one of claims 1 to 10.
  12. In any one of claims 1 to 11, R3 is a compound, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof, wherein R3 is a -C1-6 alkyl.
  13. In any one of claims 1 to 12, R 4 is selected from halogens, -OC 1-6 alkyls, and -C 1-6 alkyls, wherein each C 1-6 alkyl present therein is independently and optionally substituted with a halogen, or Two R⁴ groups attached to the same carbon atom form =C( Rc ) ₂ , where each Rc is independently selected from H, a halogen, and optionally a -C 1-6 alkyl group substituted with a halogen, or Two R4 groups attached to the same ring carbon atom form a spiro C3-6 cycloalkyl together with the ring carbon atom to which they are attached, and the spiro C3-6 cycloalkyl is optionally substituted with a halogen and optionally substituted with a halogen-substituted -C1-6 alkyl; Preferably, the R4 substitution occurs at the para position of the ring N atom, in a compound, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate.
  14. In any one of claims 1 to 13, R5 is a compound, stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate selected from -C1-6 alkyl, -deuteriumated C1-6 alkyl and -C3-6 cycloalkyl, preferably selected from -C1-3 alkyl and -deuteriumated C1-3 alkyl.
  15. In any one of paragraphs 1 through 14, the structural fragment silver and preferably and, where R2 is each independently selected from H and D; R3 is selected from -C1-3 alkyl; m is 1 or 2; A compound, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein R4 is a halogen, optionally a halogen-substituted -C1-3 alkyl, or two R4s attached to the same carbon atom form =C( Rc ) 2 , where each Rc is independently selected from H, a halogen, and optionally a halogen-substituted -C1 - ₃ alkyl, or two R4s attached to the same ring carbon atom form an optionally halogen-substituted spiro C3-4 cycloalkyl together with the ring carbon atom to which they are attached, and R5 is a -C1-3 alkyl or a -C1-3 alkyl substituted with one or more deuteriums.
  16. In paragraph 15, structural fragment silver A compound, its stereoisomer, tautomeric, stable isotopic variant, pharmaceutically acceptable salt, or solvate selected from.
  17. In claim 1 or 2, a compound, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate having the following sub-formula: Here, each group has the meaning as defined in any one of claims 1 to 15, and preferably X is selected from S and Se; Each Q is independently selected from CR 6 and N; R 6 is each independently selected from H and halogen; A benzo-fusion ring segment containing Z is preferably and, where R6 is each independently selected from H and a halogen, and the halogen is preferably F; M is selected from N and CR 8 ; W is selected from N and CR 9 ; R 7 is H and; R8 is a C1-3 alkyl substituted with a halogen (preferably F), a C2-4 alkenyl substituted with a halogen (preferably F), CN, NO2 , or a halogen (preferably Cl); or R8 is a -C1-6 alkyl- OC1-6 alkyl, preferably a -C1-3 alkyl- OC1-3 alkyl; R9 is selected from F, Cl, and -O-optionally halogen-substituted C 1-3 alkyls; In the case of formulas IA-1, IA-2, and II-2, one of R1 is -OH and the other is -C 1-3 alkyl; In the case of Formula II-1, one R1 is selected from halogen, CN, or halogen-substituted -C 1-6 alkyl, preferably present at the para position of the ring N atom, and the other is selected from H, -OH, optionally halogen-substituted -C 1-6 alkyl or -OC 1-6 alkyl; For formulas IA-3 and II-3', R1 adjacent to the nitrogen atom on the five-membered ring is selected from -COC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, and -CON(C 1-6 alkyl) 2 , and the remaining R1 is selected from H, NH 2 , CN, halogen, and -C 1-6 alkyl; Y is O and; R 2 is each independently selected from H and D; R3 is -C 1-3 alkyl and; R4 is selected from halogens, -OC 1-3 alkyls, and -C 1-3 alkyls, wherein the C 1-3 alkyls present are each independently and optionally substituted with a halogen, or Two R⁴ groups attached to the same carbon atom form =C( Rc ) ₂ , where each Rc is independently selected from H, a halogen, or optionally a halogen-substituted -C 1-3 alkyl, or Two R4 groups attached to the same ring carbon atom form a spiro C3-4 cycloalkyl together with the ring carbon atom to which they are attached, and the spiro C3-4 cycloalkyl is optionally substituted with a halogen and optionally a halogen-substituted -C1-3 alkyl; R5 is selected from -C1-3 alkyl and -deuterated C1-3 alkyl; m is an integer from 1 to 2, and p is an integer from 0 to 2; Preferably, R* is located at the para position of the ring nitrogen atom; preferably, structural segment Is And; More preferably, structural fragments silver Selected from.
  18. In claim 1, a compound having the following general formula, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or solvate: Here, A fused heterocyclic fragment possessing R 1 is and, here R1 adjacent to the nitrogen atom on the five-membered ring is selected from -C(O) -C1-6 alkyl and -C(O)N( Rb ) 2 , preferably -C(O)N( Rb ) 2 , where each Rb is independently a -C1-6 alkyl selectively substituted with H, one or more halogens, deuterium, or -C3-6 cycloalkyl, preferably each Rb is independently a -C1-3 alkyl selectively substituted with H or one or more deuterium, most preferably each Rb is independently a -C1-3 alkyl selectively substituted with one or more deuterium, for example, R1 is -C(O) CH3 , -C(O)N(CH₃)(CH₂CH₂F), -C(O)N(CH₃)₂, -C(O)N(CH₃)(cyclopropyl), -C(O)NH(CH₃), -C(O)N(CD₃)₂, -C(O)N(CH₃)(CH₂CH₂OCH₃); or two R₅b , together with the nitrogen atoms to which they are attached, form a 4-7-membered heterocycloalkyl group optionally substituted with a halogen or a -C 1-6 alkyl, e.g., azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl; R1 at the meta position of the nitrogen atom on the five-membered ring is selected from H, halogen, CN, -OH, -NH2 , -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -OC1-6 alkyl, and -C1-6 alkyl- OC1-6 alkyl, preferably selected from H, halogen, -CN, -OH, NH2 , -C1-3 alkyl, -C2-4 alkynyl, -C2-4 alkenyl, -OC1-3 alkyl, and -C1-3 alkyl- OC1-3 alkyl, more preferably selected from -C1-3 alkyl- OC1-3 alkyl, wherein the alkyl present is optionally substituted with one or more halogens, OH, or deuterium, preferably substituted with one or more deuterium, and R1 at this position is, for example, but not limited thereto, H, F, Cl, -OH, -NH 2 , -CN, -OCH₃, -CH₃, -ethynyl, -CH 2 F, -CHF₂, -O-CD₃, -CH₂OH, -CH₂-CH₃, -O-CH₂-CH₃, -CH₂-O-CH₃, -CD₂-O-CD₃, -CH₂-O-CD₃, -CH₂-O-CH₂CH₃, The R1 at the ortho position of the nitrogen to which this fragment is connected to the rest of the molecule is selected from H or -C 1-6 alkyl, preferably H or -C 1-3 alkyl, e.g., H, -CH 3 or -CH 2 CH₃; Specifically, the short story is , , , It may be, wherein R1 is defined as described herein, provided that each is not H; R6 is each independently selected from H and a halogen (preferably F); and the fragment having R6 is preferably And; M is CR 8 and; W is CR 9 and; R 7 is H; R8 is a C1-3 alkyl (e.g., CF3 ) substituted with a halogen (preferably Cl), optionally a halogen (preferably F), a -C2-4 alkenyl, CN, NO2 , or -C1-6 alkyl- OC1-6 alkyl (preferably a -C1-3 alkyl- OC1-3 alkyl, e.g., -CH2 -O-CH₃) substituted with a halogen; preferably a C1-3 alkyl substituted with a halogen, e.g., Cl and CF3 ; R9 is selected from halogens, -C1-3 alkyls, -OH, and optionally halogen-substituted -OC1 - ₃ alkyls; preferably selected from halogens and -C1-3 alkyls; e.g., F, Cl, CH3 , and -O- CH3 ; Y is O and; R 2 is each independently selected from H and D; R3 is -C 1-3 alkyl and; R4 is a -C1-3 alkyl substituted with a halogen, or two R4s attached to the same carbon atom form =C( Rc ) 2 , where each Rc is independently selected from H and a halogen; R5 is selected from -C1-3 alkyl and -deuterated C1-3 alkyl; m is an integer from 1 to 2.
  19. A compound selected from the compounds of the examples, or a pharmaceutically acceptable salt or solvate thereof.
  20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, stereoisomers, tautomers, stable isotope variants thereof, pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable excipients.

Description

RAS inhibitors Cross-reference The present application claims priority to Chinese patent application 2023111641130 filed September 8, 2023; Chinese patent application 2024102175790 filed February 27, 2024; Chinese patent application 2024106366320 filed May 21, 2024; Chinese patent application 2024111178533 filed August 14, 2024; and Chinese patent application 2024112398386 filed September 5, 2024. Technology field The present invention relates to the field of pharmaceutical chemistry. More specifically, the present invention relates to a group of compounds having a novel structure that can be used as RAS inhibitors, pharmaceutical compositions comprising such compounds, methods for preparing such compounds, and the use of such compounds in the treatment of cancer or tumors. RAS, a rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. Specifically, under normal physiological conditions, RAS is activated by growth factors and various other extracellular signals and plays a role in regulating functions such as cell growth, survival, migration, and differentiation. These regulatory functions of RAS are performed through a switching between the GDP-bound state and the GTP-bound state, i.e., a "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13:394-401). RAS bound to GDP exists in an inactive, dormant, or off state, during which the signaling system is switched off but becomes activated upon exposure to certain probiotic stimuli, such as pro-growth stimuli. For example, it can be induced by guanine nucleotide exchange factor (GEF) to release GDP and bind to GTP, resulting in the RAS being "switched on" and subsequently converted to an active form. This allows the RAS to recruit and activate various downstream effectors for signaling and transmit signals from the cell surface to the cytoplasm. This controls numerous important cellular processes such as differentiation, survival, and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357). Ras possesses GTPase activity, which allows it to cleave the terminal phosphate of GTP to convert it to GDP, thereby enabling it to convert itself into an inactive state. However, the endogenous GTPase activity of RAS is very low, and the exogenous protein GAP (GTPase-activating protein) is required to convert GTP-RAS to GDP-RAS. GAP interacts with RAS to facilitate the conversion of GTP to GDP. Therefore, if any RAS gene mutation affects the interaction between RAS and GAP or influences the conversion from GTP to GDP, it will result in RAS remaining in a prolonged active state. Consequently, this continuously transmits signals for growth and division to cells, stimulates continuous cell proliferation, and ultimately leads to the formation and development of tumors. Among the genes associated with human tumors, there are three universally expressed Ras genes known as H-RAS, K-RAS, and N-RAS, which encode highly homologous HRAS, NRAS, and KRAS proteins of approximately 21 KDa, respectively. In 1982, researchers first discovered that RAS is activated by mutations in cancer cell lines (Chang, E.H. et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large-scale genome sequencing studies across different cancer types revealed that RAS proteins were mutated in over 30% of cancer types, with the highest mutation rates observed particularly in pancreatic cancer (>90%), colon cancer (45%), and lung cancer (35%). Transgenic and genetically engineered mouse models have also revealed that mutated RAS proteins are sufficient to induce and trigger multiple types of cancer. Furthermore, RAS oncogenes play a key role in the maintenance and progression of tumors in various cancer types, such as in RAS-mutated cancer cell lines and animal models of cancer, where RNA interference has been demonstrated to slow tumor growth. Due to these findings, RAS oncogenes have become a widely recognized and highly attractive target for anticancer drugs in the pharmaceutical field. Studies have shown that RAS mutations are most commonly observed in KRAS, and that KRAS mutations can be observed in about 85% of cancers driven by RAS mutations; the majority of RAS mutations occur in codons G12, G13, and Q61, where about 80% of these KRAS mutations also occur in glycine of codon 12, such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, and Q61H mutation. KRAS mutations are frequently found in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma, and can also be found in 25% of patients with non-small cell lung cancer (McCormick, F. et al., Clinical Cancer Research 21(8), 1797-1801, 2015). Therefore, KRAS mutant proteins have become the most important branch in RAS drug target research, and the