WO2024041621A1 - Inhibiteurs de protéines mutantes k-ras - Google Patents

Inhibiteurs de protéines mutantes k-ras Download PDF

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Publication number
WO2024041621A1
WO2024041621A1 PCT/CN2023/114824 CN2023114824W WO2024041621A1 WO 2024041621 A1 WO2024041621 A1 WO 2024041621A1 CN 2023114824 W CN2023114824 W CN 2023114824W WO 2024041621 A1 WO2024041621 A1 WO 2024041621A1
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membered
alkyl
haloc
alkynyl
alkenyl
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PCT/CN2023/114824
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English (en)
Inventor
Hongwei Yang
Cunbo Ma
Peng Wang
Panliang GAO
Huifeng HAN
Runze LI
Dan Liu
Yanping Wang
Wei LONG
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Jacobio Pharmaceuticals Co., Ltd.
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Publication of WO2024041621A1 publication Critical patent/WO2024041621A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to compounds that inhibit the activity of multiple forms of K-Ras protein including K-Ras wild type and K-Ras mutant types, compositions comprising the same, and the methods of using the same.
  • K-Ras Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP-bound active
  • Aberrant expression of K-Ras accounts for up to ⁇ 20%of all cancers and oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras.
  • K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence are present in 88%of all pancreatic adenocarcinoma patients, 50%of all colorectal adenocarcinoma patients, and 32%lung adenocarcinoma patients.
  • a recent publication also suggested wild type K-Ras inhibition could be a viable therapeutic strategy to treat K-Ras wild type dependent cancers.
  • Allele-specific K-Ras G12C inhibitors such as sotorasib (AMG510) or adagrasib (MRTX849) , are currently changing the treatment paradigm for patients with K-Ras G12C mutated non-small cell lung cancer and colorectal cancer.
  • sotorasib AMG510
  • MRTX849 adagrasib
  • K-Ras inhibitors have the potential to address broad patient populations, including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant and K-Ras wild type amplified cancers.
  • a compound of formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
  • composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof as defined herein; and a pharmaceutically acceptable excipient.
  • Also provided herein is a method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or formula (II) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a PROTAC molecule thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
  • a compound of formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof:
  • R X11 and R X12 together with the carbon atom to which they are both attached forms a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R SX1 ;
  • X 2 at each occurrence is independently selected from N or CR 1 ;
  • Ring A is selected from a 3-10 membered carbocyclic ring, 3-10 membered heterocyclic ring, 6-10 membered aryl ring, 5-10 membered heteroaryl ring;
  • two R S1 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S11 ;
  • R S1 together with the atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S12 ;
  • n 1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • R 3 is selected from
  • R 31 and R 32 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S33 ;
  • R 33 and R 34 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S34 ;
  • R 35 and R 36 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S35 ;
  • R 38 and R 39 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S310 ;
  • R 310 and R 311 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S316 ;
  • n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 3 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 4 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 5 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 6 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring;
  • two R S31 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S311 ;
  • R S31 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S312 ;
  • m 3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • two R S32 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S321 ;
  • R S32 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S322 ;
  • n 4 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 37 is selected from -N (R 37A ) 2 or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally independently substituted with one or more R S37 ;
  • two R S38 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S381 ;
  • R S38 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S382 ;
  • n 8 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • two R S39 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S391 ;
  • R S39 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S392 ;
  • n 9 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • two R S315 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S3151 ;
  • R S315 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S3152 ;
  • n 10 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, is independently unsubstituted or substituted with one or more R S4 ;
  • Z at each occurrence is independently selected from C or N;
  • Ring E at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;
  • Ring E at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;
  • R 1B , R 1D , R S1B , R S1D , R S31B , R S31D , R S32B , R S32D , R S38B , R S38D , R S39B , R S39D , R S315B , R S315D , R S4B , R S4D , R 5B and R 5D is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, haloC 2-6 alkenyl, -C 2-6 alkynyl, haloC 2-6 alkynyl, -N (R A ) 2 , -OR A , -SR A , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered
  • Each of (R A , R B , R C and R D ) is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered ary
  • R SX1 , R S11 , R S12 , R S13 , R S33 , R S34 , R S35 , R S316 , R S311 , R S312 , R S313 , R S321 , R S322 , R S323 , R S37 , R S310 , R S381 , R S382 , R S383 , R S391 , R S392 , R S393 , R S3151 , R S3152 , R S3153 , R SS and R SA is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -NO 2 , -N 3 , oxo, -NH 2 , -NH (C 1-6 alkyl) , -N (
  • Each of heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S.
  • X 1 at each occurrence is independently selected from -C (R X11 ) (R X12 ) -, -NR X13 -, -O-or -S-;
  • R X11 or R X12 is independently selected from hydrogen, deuterium, halogen or -C 1-6 alkyl; wherein said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
  • R X13 is selected from hydrogen, deuterium or -C 1-6 alkyl; wherein said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
  • R X2 is selected from hydrogen, deuterium, or methyl.
  • R S1 is selected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly; wherein said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
  • R S1 is selected from -F, -CH 3 or -OH.
  • the compound is selected from any one of the following formulas inTable B:
  • a compound of formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof:
  • R X11 and R X12 together with the carbon atom to which they are both attached forms a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R SX1 ;
  • X 2 at each occurrence is independently selected from N or CR 1 ;
  • R 81 and R 82 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S81 ;
  • R 81 and R S8 together with the atoms to which they are respectively attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S82 ;
  • n 7 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Ring M is selected from a 6-10 membered aryl ring or 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • n 8 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • two R S2 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S21 ;
  • R S2 together with the atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S22 ;
  • n 2 is selected from 0, 1, 2, 3, 4 or 5;
  • R 3 is selected from
  • R 31 and R 32 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S33 ;
  • R 33 and R 34 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S34 ;
  • R 35 and R 36 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S35 ;
  • R 38 and R 39 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S310 ;
  • R 310 and R 311 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S316 ;
  • n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 3 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 4 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 5 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 6 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring;
  • two R S31 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S311 ;
  • R S31 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S312 ;
  • m 3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • two R S32 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S321 ;
  • R S32 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S322 ;
  • n 4 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 37 is selected from -N (R 37A ) 2 or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally independently substituted with one or more R S37 ;
  • two R S38 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S381 ;
  • R S38 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S382 ;
  • n 8 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • two R S39 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S391 ;
  • R S39 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S392 ;
  • n 9 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • two R S315 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S3151 ;
  • R S315 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently unsubstituted or substituted with one or more R S3152 ;
  • n 10 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, is independently unsubstituted or substituted with one or more R S4 ;
  • Z at each occurrence is independently selected from C or N;
  • Ring E at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;
  • Ring E at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;
  • R 1B , R 1D , R S2B , R S2D , R S31B , R S31D , R S32B , R S32D , R S38B , R S38D , R S39B , R S315B , R S315D , R S39D , R S4B , R S4D , R 5B , R 5D , R 8B , R 8D , R S8B and R S8D is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, haloC 2-6 alkenyl, -C 2-6 alkynyl, haloC 2-6 alkynyl, -N (R A ) 2 , -OR A , -SR A , 3-10 membered cycloalkyl, 3-10 membered cycloalken
  • Each of (R A , R B , R C and R D ) is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered ary
  • R SX1 , R S21 , R S22 , R S23 , R S33 , R S34 , R S35 , R S37 , R S310 , R S316 , R S311 , R S312 , R S313 , R S321 , R S322 , R S323 , R S381 , R S382 , R S383 , R S391 , R S392 , R S393 , R S3151 , R S3152 , R S3153 , R S81 , R S82 , R SS and R SA is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -NO 2 , -N 3 , oxo, -NH 2 , -NH (C 1-6
  • Each of heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S.
  • R 81 is selected from hydrogen or deuterium; R 82 is selected from methyl or cyclopropyl.
  • Ring M is selected from a 5 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N.
  • ring M is 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, and said 6 membered heteroaryl is substituted with one -NH 2 or -OH and further optionally substituted with one or more R S8 .
  • the moiety of is selected from
  • n 9 is selected from 0, 1, 2, 3, or 4;
  • R S8 is selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
  • R S8 is selected from -NHCH 3 .
  • n 8 is selected from 0 or 1
  • n 9 is selected from 0 or 1.
  • the moiety of is selected from
  • R 3 is selected from
  • Ring B or ring C is a 4-6 membered heterocyclic ring optionally further containing 1 or 2 heteroatoms selected from N or O;
  • Ring D is a 3 membered carbocyclic ring
  • R 37 is selected from -N (R 37A ) 2 or a 6 membered heterocyclyl, wherein said 6 membered heterocyclyl is optionally independently substituted with 1, 2 or 3 R S37 ;
  • R 37A is selected from hydrogen, deuterium, or -C 1-6 alkyl.
  • R 37A is selected from hydrogen, deuterium, or -C 1-3 alkyl.
  • the moiety of is selected from:
  • the moiety of is selected from:
  • Ring I is a 4-6 membered cycloalkyl ring.
  • Ring J is a 4-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S.
  • the moiety of is selected from:
  • R S381 is selected from hydrogen or R S38 ;
  • m 81 is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • R S381 is selected from hydrogen, deuterium, -C 1-6 alkyl or 3-6 membered cycloalkyl wherein, said -C 1-6 alkyl or 3-6 membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
  • n 9 is selected from 0, 1 or 2.
  • n 1
  • n 1
  • the moiety of is selected from:
  • R S394 is selected from hydrogen or R S391 .
  • R S39 is selected from halogen
  • R S39 is selected from -F.
  • R S391 is selected from hydrogen, deuterium, halogen, or -C 1-6 alkyl; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
  • R S391 is selected from hydrogen, deuterium, -F, or -CH 3 .
  • the moiety of is selected from:
  • the moiety of is selected from:
  • Ring B is a 4-6 membered heterocyclic ring containing the fused N atom.
  • Ring C is a 4-6 membered heterocyclic ring containing the fused N atom.
  • the moiety of is selected from:
  • two R S31 together with the carbon atom to which they are both attached form or cyclopropyl; wherein, said or cyclopropyl is independently unsubstituted or substituted with 1, 2 or 3 R S311 ; or
  • two adjacent R S31 together with the carbon atoms to which they are respectively attached form a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring or a 5-10 membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, O or S, wherein, each of rings is independently unsubstituted or substituted with 1, 2 or 3 R S312 .
  • the moiety of is selected from:
  • Ring G is selected from a 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, or S;
  • Ring H is selected from a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S;
  • R S36 is same as R S31 ;
  • R S314 is selected from hydrogen or R S311 ;
  • n 31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • m 33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • m 34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n 5 is selected from 0, 1, 2, 3, 4, 5, or 6;
  • n 6 is selected from 0, 1, 2, 3, 4, 5, or 6.
  • the moiety of is selected from:
  • n 31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • n 32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • m 33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • m 34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n 5 is selected from 0, 1, 2, 3, 4, 5, or 6;
  • n 6 is selected from 0, 1, 2, 3, 4, 5, or 6.
  • R S311 is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
  • R S312 is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
  • R S314 is independently selected from hydrogen, deuterium, halogen, -C 1-6 alkyl, wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
  • R S311 is independently selected from deuterium, -F or -OCH 3 ;
  • R S312 is independently selected from deuterium, -F, -OCH 3 , or -CH 2 OCH 3 ;
  • R S314 is independently selected from hydrogen, deuterium, -F, -CH 3 , -CH 2 OCH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CHF 2 , -CH 2 CH (CH 3 ) 2 .
  • R S36 is selected from deuterium or -F.
  • n 31 is selected from 0 or 1;
  • n 32 is selected from 0 or 1;
  • m 33 is selected from 0 or 1;
  • n 34 is selected from 0 or 1;
  • m 5 is selected from 0 or 1;
  • n 6 is selected from 0 or 1.
  • the moiety of is selected from:
  • the moiety of is selected from:
  • Ring K is a 4-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O atom.
  • the moiety of is selected from:
  • ring L is selected from a 4-6 membered heterocyclic ring optionally further comtaining 1 or 2 heteroatoms selected from N or O.
  • the moiety of is selected from:
  • R S315 is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
  • the moiety of is selected from:
  • the moiety of is selected from:
  • R 4 is selected from phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl, said phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl , benzothiaphenyl or benzothiozolyl is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 R S4 .
  • n 7 is selected from 0, 1, 2 or, 3;
  • R S4a is selected from -OH or -NH 2 ;
  • R S4b is selected from hydrogen, deuterium, halogen
  • R S4c is selected from hydrogen, deuterium, -C 1-3 alkyl, -C 2-3 alkenyl or -C 2-3 alkynyl;
  • R S4d is selected from hydrogen, deuterium or halogen
  • R S4e is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
  • R S4f is selected from -OH or -NH 2 ;
  • R S4g is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
  • R S4h is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
  • R S4i is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
  • R S4j is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
  • R S4k is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
  • R S4l is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
  • R S4m is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
  • R S4n is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
  • R S4o is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
  • R S4p is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl.
  • n 7 is selected from 0;
  • R S4a is selected from -OH or -NH 2 ;
  • R S4b is selected from -F
  • R S4c is selected from ethyl, ethenyl or ethynyl
  • R S4d is selected from hydrogen, or -F;
  • R S4e is selected from -F
  • R S4f is selected from -NH 2 ;
  • R S4g is selected from hydrogen, -F, or methyl
  • R S4h is selected from hydrogen, -F or methyl
  • R S4i is selected from -I or -CF 3 ;
  • R S4j is selected from -CN
  • R S4k is selected from hydrogen
  • R S4l is selected from methyl
  • R S4m is selected from -CF 3 , -OCF 2 Cl, -OCF 3 or -CF 2 H;
  • R S4n is selected from hydrogen, -F, or methyl
  • R S4o is selected from hydrogen, -F or methyl
  • R S4p is selected from hydrogen, -F, or methyl.
  • R 4a is selected from
  • R 4c is selected from hydrogen, -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C 0-6 alkylene- (3-20 membered carbocyclyl) , -C 0-6 alkylene- (3-20 membered heterocyclyl) , -C 0-6 alkylene- (6-10 membered aryl) or -C 0-6 alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j ;
  • R 4a is selected from the following Table E:
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [81] , and a pharmaceutically acceptable excipient.
  • a method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [81] , or the pharmaceutical composition of [71] to a subject in need thereof.
  • a method for treating cancer in a subject in need thereof comprising:
  • the cancer is associated with at least one of K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification.
  • halogen or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include -F, -Cl and -Br.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
  • -C 1-6 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • C 1-3 as in C 1-3 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • haloalkyl such as -C 1-6 haloalkyl, -C 1-4 haloalkyl or -C 1-3 haloalkyl
  • an alkyl chain such as -C 1-6 alkyl, -C 1-4 alkyl or -C 1-3 alkyl
  • examples include trifluoromethyl, difluoromethyl and fluoromethyl.
  • alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
  • alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkenyl contains from 2 to 6 carbon atoms.
  • Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkynyl contains from 2 to 6 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.
  • aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • heterocyclic refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone and oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclicheteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
  • cycloalkyl refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms.
  • Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instan
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers.
  • the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
  • the invention includes all possible stereoisomers of the compound.
  • Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule.
  • the compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds in present invention or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier of conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
  • the compounds of Formula I or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
  • the compound in the present invention could be synthesized and the activity could be tested according to the pharmacological experiments.
  • INT 1 was synthesized with 2- (4-fluorophenyl) acetic acid as starting material.
  • the isomers were separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-SA column (2 cm ⁇ 25 cm, 5 um) ; mobile phase, Hex (0.2%isopropylamine) /EtOH (55: 45) ; Flowing rate: 20mL/min.
  • GDP-loaded HIS-KRAS (G12V, aa 1-169) was pre-incubated with a compound in the presence of 10nM GDP in a 384-well plate (Greiner) for 15 min, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPY TM FL GTP (Invitrogen) and MAb (monoclonal antibody) Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 10-15nM GDP-loaded HIS-KRAS (G12V) , 5 nM GDP, 0.5 ⁇ M SOS1 ExD, 80 nM BODIPY TM FL GTP, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 °C.

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Abstract

L'invention concerne des inhibiteurs de protéines mutantes K-Ras de formule (I), une composition les contenant et leur utilisation.
PCT/CN2023/114824 2022-08-25 2023-08-25 Inhibiteurs de protéines mutantes k-ras WO2024041621A1 (fr)

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