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WO2025000265A1 - Composés hétérocycliques utiles en tant qu'inhibiteurs de sos1 - Google Patents

Composés hétérocycliques utiles en tant qu'inhibiteurs de sos1 Download PDF

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Publication number
WO2025000265A1
WO2025000265A1 PCT/CN2023/103169 CN2023103169W WO2025000265A1 WO 2025000265 A1 WO2025000265 A1 WO 2025000265A1 CN 2023103169 W CN2023103169 W CN 2023103169W WO 2025000265 A1 WO2025000265 A1 WO 2025000265A1
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Prior art keywords
phenyl
mmol
trifluoromethyl
ethyl
group
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PCT/CN2023/103169
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Inventor
Haiquan Fang
Xiaolei Liu
Lei Zhang
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Silexon Ai Technology Co Ltd
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Silexon Ai Technology Co Ltd
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Priority to PCT/CN2023/103169 priority Critical patent/WO2025000265A1/fr
Publication of WO2025000265A1 publication Critical patent/WO2025000265A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • 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
    • C07D471/20—Spiro-condensed systems

Definitions

  • the present invention relates to heterocyclic compounds and use thereof.
  • the present invention relates to a compound of Formula (I) , a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, a solvate thereof, a crystal form thereof, a metabolite thereof, or a prodrug thereof.
  • the present invention also relates to a composition containing, but not limited to, a compound of Formula (I) , and a pharmaceutically acceptable carrier thereof, and use for treating or preventing SOS1-associated disease.
  • the present invention also relates to a PROTAC comprising a compound of Formula (I) , a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, a solvate thereof, a crystal form thereof, a metabolite thereof, or a prodrug thereof.
  • the RAS proteins are members of a family of membrane anchored, small GTPase proteins that participate in the transduction of extracellular stimuli to intracellular signaling, play an important role in cell proliferation, cell survival, cell adhesion, and cell motility (Young, A et al., Adv. Cancer Res., 2009, 102, 1-17) (Julian Downward et al., Nature Reviews Cancer, 2003, 3, 11-22) .
  • the RAS family consists of four proteins: NRAS (neuroblastoma RAS viral oncogene homolog) , HRAS (Harvey murine sarcoma virus oncogene) and splice variants K-RAS4A/K-RAS4B (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) (Dhirendra K. Simanshu et al., Cell, 2017, 170, 17-33) .
  • RAS proteins act as molecular switches that cycle between an active, GTP bound state and an inactive, GDP-bound state.
  • GTPase activating proteins facilitate hydrolysis of GTP by RAS while guanine nucleotide exchange factors (GEFs) catalyze GDP dissociation (Vetter et al., Science 2001, 294, 1299-1304) (K. Scheffzek et al., Science, 1997, 277, 333-338) .
  • GEFs guanine nucleotide exchange factors
  • This regulation through GAPs and GEFs is the mechanism whereby activation and deactivation are tightly regulated under normal conditions.
  • Active RAS interacts with effector proteins and activates downstream cellular signal transduction pathways such as the RAF-MEK-ERK, PI3K-AKT-mTOR, and RalGDS pathways (McCormick et al., Curr. Opin.
  • SOS guanine nucleotide exchange factor Son of Sevenless
  • PPIs protein-protein interactions
  • SOS protein consists of an N-terminal domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a core catalytic domain (SOScat) that includes a RAS exchanger motif (Rem) domain and a Cdc25 domain, and a C-terminal region
  • the catalytic core of SOS accommodates two RAS molecules: the catalytic site in the CDC25 domain binds GDP-RAS to promote nucleotide release, and the allosteric site interact with GTP-RAS which leads to a marked enhancement of SOS1 catalytic GEF function (Lu et al., Chem Med Chem, 2015, 11, 8, 814-821) .
  • the SOS family encompasses two highly homologous, ubiquitously expressed members, SOS1 and SOS2 (Baltanás et al., Biochim. Biophys. Acta Rev. Cancer, 2020, 1874, 188445) .
  • SOS1 decreases proliferation rate and survival of tumor cells carrying a KRAS mutation (Xiaona et al., Blood, 2016, 128, 1543) (Jeng HH et al., Nature communications 2012, 3, 1168) . All in all, these published data suggest that SOS1 as a potential therapeutic target in RAS-mutated cancers.
  • SOS1 is also a GEF for the activation of the GTPases RAC1 (Ras-Related C3 Botulinum Toxin Substrate 1) .
  • Dysregulated RAC1-SOS1 signaling includes RAC-GEF overexpression, gain-of-function genetic alterations in signaling components, or excessive upstream input that leads to RAC1 signaling hyperactivation, are implicated in the pathogenesis of a variety of human cancer and other diseases (Mariana et al., Front. Cell Dev. Biol., 2020, 25, 118) .
  • a number of recent studies have started to reveal recurrent SOS1 gene alterations in many sporadic tumors, including lung adenocarcinoma (LUAD) , uterine corpus endometrial carcinoma (UCEC) , urothelial bladder cancer (BLCA) , lung squamous cell carcinoma (LUSC) , liver hepatocellular carcinoma (LIHC) , acute myeloid leukemia (AML) , lower grade glioma (LGG) and cutaneous melanoma (SKMC) (Dirk Kessler et al., Current Opinion in Chemical Biology, 2021, 62, 109-118) .
  • LAD lung adenocarcinoma
  • UCEC uterine corpus endometrial carcinoma
  • BLCA urothelial bladder cancer
  • LUSC lung squamous cell carcinoma
  • LIHC liver hepatocellular carcinoma
  • AML acute myeloid leukemia
  • LGG lower grade glioma
  • the SOS1 gene alterations found in specific association with different human tumor types include gene amplifications, gain-of-function mutations, or overexpression of SOS1 gene products that result in GEF hyperactivation and subsequent hyperactivation of RAS signaling, driving tumor formation (Diana et al., Mol Cancer Res, 2019, 17, 4, 1002-1012) .
  • gain of function genetic alterations or mutations in different SOS1 domains have been identified in inherited RASopathies such as Noonan syndrome (NS) , cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (HGF-1) (Fernando et al., BBA -Reviews on Cancer, 2020, 1874, 188445) .
  • SOS1 inhibition may be a therapeutic avenue for the treatment of SOS1-mutant cancers and other SOS1-activated diseases.
  • selective inhibition of SOS1 may represent a viable approach for treating diseases dependent on the SOS1 activity.
  • the present disclosure provides a compound represented by Formula (I) , a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, a solvate thereof, a crystal form thereof, a metabolite thereof, or a prodrug thereof,
  • R 1 is selected from the group consisting of 6-to 10-membered aryl and 5-to 10- membered heteroaryl; and the 6-to 10-membered aryl and 5-to 10-membered heteroaryl is substituted with one or more substituents consisting of H, halo, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of halo, -OH, -C 1-3 alkyl, and -C 1-3 alkoxy;
  • R 2 is selected from the group consisting of -C 1-3 alkyl, -C 2-3 alkenyl, and -C 2-3 alkynyl;
  • R 3 is selected from the group consisting of H, -OH, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy;
  • X is absent, CH 2 , or carbonyl
  • R 4 is selected from the group consisting of H, -C 1-3 alkyl-C (O) -, -C 1-3 alkyl, and -C 1-3 halo alkyl; when R 4 is -C 1-3 alkyl, one or two R 4 is connected to the N atom to which R 4 is connected;
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle;
  • the 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, or C 3-10 carbonaceous saturated cycle optionally contains independently one or more heteroatoms consisting of O, S, and N;
  • the 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1- 3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, -C 1-3 alkoxy, and -C (O) O-C 1-3 alkyl;
  • R 6 is selected from the group consisting of H, -C 1-3 alkyl, -C 1-3 alkyl-C (O) -, and oxo;
  • p1 and p2 each independently is 0, 1, or 2;
  • t 0, 1 or 2.
  • X is absent, CH 2 , or carbonyl.
  • X is absent.
  • X is CH 2 .
  • X is carbonyl, that is
  • R 1 is selected from the group consisting of 6-to 10-membered aryl and 5-to 10-membered heteroaryl; and the 6-to 10-membered aryl and 5-to 10-membered heteroaryl is substituted with one or more substituents consisting of H, halo, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of halo, -OH, -C 1-3 alkyl, and -C 1-3 alkoxy.
  • R 1 is 6-to 10-membered aryl; and the 6-to 10-membered aryl is substituted with one or more substituents consisting of halo, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of halo, -OH, -C 1-3 alkyl, and -C 1-3 alkoxy.
  • the 6-to 10-membered aryl is phenyl; and the phenyl is independently substituted with one or more substituents consisting of H, F, Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of F, -CH 3 , -OH, and -OCH 3 .
  • the 6-to 10-membered aryl is phenyl; and the phenyl is independently substituted with one, two, or three groups consisting of H, F, Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of F, -CH 3 , -OH, and -OCH 3 .
  • R 1 is selected from the group consisting of:
  • R 1 is 5-to 10-membered heteroaryl; and the 5-to 10-membered heteroaryl is substituted with one or more substituents consisting of halo, -NH 2 , -C 1-3 alkyl, and -C 1-3 haloalky.
  • R 1 is 5-to 10-membered heteroaryl, the 5-to 10-membered heteroaryl is each of which is independently substituted with one or two substituents consisting of -NH 2 , and -CF 3 , .
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of -C 1-3 alkyl, -C 2-3 alkenyl, and -C 2-3 alkynyl.
  • R 2 is selected from the group consisting of -CH 3 , and -C ⁇ CCH 3 .
  • R 3 is selected from the group consisting of H, -OH, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy.
  • R 3 is selected from the group consisting of H, OH, -C 1-3 alkyl, and -C 1-3 alkoxy.
  • R 3 is selected from the group consisting of H, OH, -CH 3 , and -OCH 3 .
  • R 4 is selected from the group consisting of H, C 1-3 alkyl-C (O) -, and -C 1-3 alkyl; when R 4 is -C 1-3 alkyl, one or two R 4 is connected to the N atom to which R 4 is connected.
  • R 4 is selected from the group consisting of H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , CH 3 -C (O) -, CH 3 CH 2 -C (O) -, and CH 3 CH 2 CH 2 -C (O) -.
  • R 4 is selected from the group consisting of H, -CH 3 , and CH 3 -C (O) -.
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle; the 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, or C 3-10 carbonaceous saturated cycle optionally contains independently one or more heteroatoms consisting of O, S, and N; and the 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, -C 1-3 alkoxy, and -C (O) O-C 1-3 alky.
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, and 5-to 10-membered heteroaryl, and the 5-to 10-membered heteroaryl contains at least one nitrogen atom.
  • R 5 is selected from the group consisting of phenyl and pyridinyl; and the phenyl or pyridinyl is optionally substituted with one or more substituents consisting of F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 F, -CHF 2 , -C (O) O-CH 3 , and -C (O) O-CH 2 CH 3 .
  • R 5 is selected from the group consisting of:
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains at least one oxygen atom
  • the C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy.
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains one oxygen atom
  • the C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of F, Cl, Br, OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH, -CH 2 CH 2 OH, and oxo.
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains one oxygen atom
  • the C 3-10 carbonaceous saturated cycle contains an oxygen atom and is optionally substituted with one or more substituents consisting of F, OH, -CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH, and oxo.
  • R 5 is selected from the group consisting of:
  • R 5 is C 1-12 straight or branched carbonaceous chain; and the C 1-12 straight or branched carbonaceous chain contains at least one O atom.
  • R 5 is C 1-6 straight or branched carbonaceous chain; and the C 1-6 straight or branched carbonaceous chain contains one O atom.
  • R 5 is selected from the group consisting of
  • R 6 is selected from the group consisting of H, -C 1-3 alkyl, -C 1-3 alkyl-C (O) -, and oxo.
  • R 6 is selected from the group consisting of H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , CH 3 -C (O) -, CH 3 CH 2 -C (O) -, CH 3 CH 2 CH 2 -C (O) -, and oxo.
  • R 6 is selected from the group consisting of H, -CH 3 , CH 3 -C (O) -, and oxo.
  • R 6 is a substituent that appears on any possible position of the spiro for example R 6 also may be a substituent that appears on the position below:
  • p1 and p2 each independently is 0, 1, or 2.
  • p1 is 0.
  • p1 is 1.
  • p1 is 2.
  • p2 is 0.
  • p2 is 1.
  • p2 is 2.
  • p1 is 1, and p2 is 1.
  • p1 is 1, and p2 is 2.
  • p1 is 2, and p2 is 1.
  • p1 is 2.
  • p2 is 0.
  • t is 0.
  • t is 1.
  • t is 2.
  • the moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is 6-membered aryl, and the 6-membered aryl is substituted with one or more substituents selected from the group consisting of halo, -CN, and -C 1-3 haloalkyl;
  • R 2 is -C 1-3 alkyl
  • R 3 is -C 1-3 alkyl
  • R 4 is -C 1-3 alkyl
  • R 5 is is optionally substituted with one or more substitutes selected from the group consisting of -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, and oxo;
  • p1 is 2, and p2 is 1;
  • R 6 is H
  • R 1 is 6-membered aryl, and the 6-membered aryl is substituted with two substituents selected from the group consisting of F, -CF 3 , -CH 3 , and -CN.
  • R 2 is -CH 3 .
  • R 3 is -CH 3 .
  • R 5 is is optionally substituted with one or more substitutes selected from the group consisting of -CHF 2 , -CH 2 F, -CH 2 OH, and oxo.
  • R 1 is selected from the group consisting of 6-to 10-membered aryl and 5-to 10-membered heteroaryl; and the 6-to 10-membered aryl and 5-to 10-membered heteroaryl is substituted with one or more substituents consisting of H, halo, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of halo, -OH, -C 1-3 alkyl, and -C 1-3 alkoxy;
  • R 2 is selected from the group consisting of -C 1-3 alkyl, -C 2-3 alkenyl, and -C 2-3 alkynyl;
  • R 3 is selected from the group consisting of H, -OH, -C 1-3 alkyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy;
  • R 4 is selected from the group consisting of H, C 1-3 alkyl-C (O) -, and -C 1-3 alkyl; when R 4 is -C 1-3 alkyl, one or two R 4 is connected to the N atom to which R 4 is connected;
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle;
  • the 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, or C 3-10 carbonaceous saturated cycle optionally contains independently one or more heteroatoms consisting of O, S, and N;
  • the 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1- 3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy;
  • R 6 is selected from the group consisting of H, -C 1-3 alkyl, -C 1-3 alkyl-C (O) -, and oxo;
  • p1 and p2 each independently is 0, 1, or 2;
  • t 0, 1 or 2.
  • R 1 is 6-to 10-membered aryl; and the 6-to 10-membered aryl is substituted with one or more substituents consisting of halo, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of halo, -OH, -C 1-3 alkyl, and -C 1-3 alkoxy.
  • R 1 is 6-to 10-membered aryl; the 6-to 10-membered aryl is phenyl; and the phenyl is independently substituted with one or more substituents consisting of H, F, Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of F, -CH 3 , -OH, and -OCH 3 .
  • R 1 is 6-to 10-membered aryl; the 6-to 10-membered aryl is phenyl; and the phenyl is independently substituted with one, two, or three groups consisting of H, F, Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CF 3 , -NH 2 , -CN, and -SF 5 , each of which is independently substituted with one or more substituents consisting of F, -CH 3 , -OH, and -OCH 3 .
  • R 1 is selected from the group consisting of:
  • R 1 is 5-to 10-membered heteroaryl; and the 5-to 10-membered heteroaryl is substituted with one or more substituents consisting of halo, -NH 2 , -C 1-3 alkyl, and -C 1-3 haloalky.
  • R 1 is 5-to 10-membered heteroaryl, the 5-to 10-membered heteroaryl is each of which is independently substituted with one or two substituents consisting of -NH 2 , and -CF 3 , .
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of -C 1-3 alkyl, -C 2-3 alkenyl, and -C 2-3 alkynyl.
  • R 2 is selected from the group consisting of -CH 3 , and -C ⁇ CCH 3 .
  • R 3 is selected from the group consisting of H, -OH, -C 1-3 alkyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy.
  • R 3 is selected from the group consisting of H, OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , and -OCH 2 CH 2 CH 3 .
  • R 4 is selected from the group consisting of H, C 1-3 alkyl-C (O) -, and -C 1-3 alkyl; when R 4 is -C 1-3 alkyl, one or two R 4 is connected to the N atom to which R 4 is connected.
  • R 4 is selected from the group consisting of H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , CH 3 -C (O) -, CH 3 CH 2 -C (O) -, and CH 3 CH 2 CH 2 -C (O) -.
  • R 4 is selected from the group consisting of H, -CH 3 , and CH 3 -C (O) -.
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle; the 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, or C 3-10 carbonaceous saturated cycle optionally contains independently one or more heteroatoms consisting of O, S, and N; and the 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, -C 1-3 alkoxy, and -C (O) O-C 1-3 alky.
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, and 5-to 10-membered heteroaryl, and the 5-to 10-membered heteroaryl contains at least one nitrogen atom.
  • R 5 is selected from the group consisting of phenyl and pyridinyl; and the phenyl or pyridinyl is optionally substituted with one or more substituents consisting of F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 F, -CHF 2 , -C (O) O-CH 3 , and -C (O) O-CH 2 CH 3 .
  • R 5 is selected from the group consisting of:
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains at least one oxygen atom
  • the C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy.
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains one oxygen atom
  • the C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of F, Cl, Br, OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH, -CH 2 CH 2 OH, and oxo.
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains one oxygen atom
  • the C 3-10 carbonaceous saturated cycle contains an oxygen atom and is optionally substituted with one or more substituents consisting of F, OH, -CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH, and oxo.
  • R 5 is selected from the group consisting of:
  • R 5 is C 1-12 straight or branched carbonaceous chain; and the C 1-12 straight or branched carbonaceous chain contains at least one O atom.
  • R 5 is C 1-6 straight or branched carbonaceous chain; and the C 1-6 straight or branched carbonaceous chain contains one O atom.
  • R 5 is selected from the group consisting of
  • R 6 is selected from the group consisting of H, -C 1-3 alkyl, -C 1-3 alkyl-C (O) -, and oxo.
  • R 6 is selected from the group consisting of H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , CH 3 -C (O) -, CH 3 CH 2 -C (O) -, CH 3 CH 2 CH 2 -C (O) -, and oxo.
  • R 6 is selected from the group consisting of H, -CH 3 , CH 3 -C (O) -, and oxo.
  • R 6 is a substituent that appears on any possible position of the spiro for example R 6 also may be a substituent that appears on the position below:
  • p1 and p2 each independently is 0, 1, or 2.
  • p1 is 0.
  • p1 is 1.
  • p1 is 2.
  • p2 is 0.
  • p2 is 1.
  • p2 is 2.
  • p1 is 1, and p2 is 1.
  • p1 is 1, and p2 is 2.
  • p1 is 2, and p2 is 1.
  • p1 is 2.
  • p2 is 0.
  • t is 0, 1 or 2.
  • t is 0.
  • t is 1.
  • t is 2.
  • the moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is 6-to 10-membered aryl; and the 6-to 10-membered aryl is substituted with one or more substituents consisting of halo, -C 1-3 alkyl, and -C 1-3 haloalkyl;
  • R 2 is -C 1-3 alkyl
  • R 3 is H or -C 1-3 alkyl
  • R 4 is H or -C 1-3 alkyl
  • R 5 is selected from the group consisting of 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle;
  • the 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, or C 3-10 carbonaceous saturated cycle optionally contains independently one or more heteroatoms consisting of O, S, and N;
  • the 6-to 10-membered aryl, 5-to 10-membered heteroaryl, C 1-12 straight or branched carbonaceous chain, and C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of halo, OH, oxo, -C 1- 3 alkyl, -C 1-3 haloalkyl, -C 1-3 hydroxyalkyl, and -C 1-3 alkoxy;
  • R 6 is selected from the group consisting of H, -C 1-3 alkyl, -C 1-3 alkyl-C (O) -, and oxo;
  • p1 and p2 each independently is 0, 1, or 2;
  • t 0, 1 or 2.
  • the 6-to 10-membered aryl is phenyl; and the phenyl is independently substituted with one, two, or three groups consisting of F, -CH 3 , -CF 3 , -NH 2 , -CN, and -SF 5 .
  • R 1 is selected from the group consisting of:
  • R 2 is -CH 3 .
  • R 3 is H or -CH 3 .
  • R 4 is H or -CH 3 .
  • R 5 is selected from the group consisting of phenyl and pyridinyl; and the phenyl or pyridinyl is optionally substituted with one or more substituents consisting of F, Cl, Br, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 F, -CHF 2 , -C (O) O-CH 3 , and -C (O) O-CH 2 CH 3 .
  • R 5 is selected from the group consisting of:
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains one oxygen atom
  • the C 3-10 carbonaceous saturated cycle is optionally substituted with one or more substituents consisting of F, Cl, Br, OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH, -CH 2 CH 2 OH, and oxo.
  • R 5 is C 3-10 carbonaceous saturated cycle
  • the C 3-10 carbonaceous saturated cycle contains one oxygen atom
  • the C 3-10 carbonaceous saturated cycle contains an oxygen atom and is optionally substituted with one or more substituents consisting of F, OH, -CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH, and oxo.
  • R 5 is C 1-6 straight or branched carbonaceous chain; and the C 1-6 straight or branched carbonaceous chain contains one O atom.
  • R 6 is selected from the group consisting of H, -CH 3 , CH 3 -C (O) -, and oxo.
  • p1 and p2 each independently is 0, 1, or 2.
  • p1 is 0.
  • p1 is 1.
  • p1 is 2.
  • p2 is 0.
  • p2 is 1.
  • p2 is 2.
  • p1 is 1, and p2 is 1.
  • p1 is 1, and p2 is 2.
  • p1 is 2, and p2 is 1.
  • p1 is 2.
  • p2 is 0.
  • t is 0, 1 or 2.
  • t is 0.
  • t is 1.
  • t is 2.
  • the moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the present disclosure also provides a compound represented by Formula (I) , a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, a solvate thereof, a crystal form thereof, a metabolite thereof or a prodrug thereof, wherein the compound is:
  • the present disclosure provides the compounds of the present disclosure for use in therapy.
  • the present disclosure provides methods for inhibiting SOS1 protein in a subject, comprising administering to the subject (preferably, a therapeutically effective amount of) at least one of the compounds of the present disclosure.
  • the present disclosure provides methods for inhibiting the interaction of SOS1 and RAS family proteins in a subject, comprising administering to the subject (preferably, a therapeutically effective amount of) at least one of the compounds of the present disclosure.
  • the present disclosure provides methods for inhibiting the interaction of SOS1 and RAC1 proteins in a subject, comprising administering to the subject (preferably, a therapeutically effective amount of) at least one of the compounds of the present disclosure.
  • the present disclosure provides methods for treating or preventing diseases, e.g., a SOS l-associated disease, e.g., a disease mediated through SOS1, e.g., neoplastic diseases (such as cancer, particularly cancer that are dependent on the SOS1 activity) , infectious disease, or RASopathy disease mediated through SOS1, comprising administering to the subject (preferably, a therapeutically effective amount of) at least one of the compounds of the present disclosure.
  • diseases e.g., a SOS l-associated disease, e.g., a disease mediated through SOS1, e.g., neoplastic diseases (such as cancer, particularly cancer that are dependent on the SOS1 activity) , infectious disease, or RASopathy disease mediated through SOS1, comprising administering to the subject (preferably, a therapeutically effective amount of) at least one of the compounds of the present disclosure.
  • the present disclosure provides methods for inhibiting, blocking, reducing or decreasing SOS1 activation for the reduction of tumor growth and/or tumor metastasis in a subject, wherein the method comprises administering to the subject an effective amount of a compound or a pharmaceutical composition of the present disclosure.
  • the aforementioned subject is treated with an additional therapy.
  • the additional therapy may be one or more selected from therapy using one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy and a mastectomy) , chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, and monoclonal antibody therapy.
  • the therapeutic agents include, but not limited to, inhibitors of EGFR and/or of mutants thereof, inhibitors of ErB2 and/or of mutants thereof, inhibitors of ALK and/or of mutants thereof, inhibitors of BCR-ABL and/or of mutants thereof, inhibitors of FGFR1/2/3 and/or of mutants thereof, inhibitors of MEK /or of mutants thereof, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, RAS inhibitors, KRAS inhibitors, KRAS G12C inhibitors, K and RAS G12D inhibitors, ERK1/2 inhibitors, SHP2 inhibitors, Focal Adhesion Kinase (FAK) inhibitors, PI3K inhibitors, mTOR inhibitors, immune check point inhibitors, inhibitors of epigenetic mechanism such as histone methyl transferases (HMTs) , DNA methyl transferases (DNMTs)
  • At least one of the compounds of the present disclosure can also be used in combination with an additional therapy.
  • the additional therapy may be optionally includes one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy and a mastectomy) , chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing.
  • the therapeutic agents are as described above.
  • the compounds of the present disclosure are administered as a raw chemical or are formulated as pharmaceutical compositions.
  • the present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises (preferably, a therapeutically effective amount of) at least one (such as at least two) of the compounds of the present disclosure and optionally one or more pharmaceutically acceptable carriers.
  • the pharmaceutical compositions of the present disclosure comprise a compound of Formula (I) , Formula (II-1) , Formula (II-2) , Formula (II-3) , Formula (III) , or Formula (III-1) , or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a first compound of Formula (I) , Formula (II-1) , Formula (II-2) , Formula (II-3) , Formula (III) , or Formula (III-1) , or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.
  • the pharmaceutical compositions of the present disclosure also comprise one or more other therapeutically active compounds.
  • the pharmaceutical compositions of the present disclosure also comprise a compound represented by Formula (I) , Formula (II-1) , Formula (II-2) , Formula (II-3) , Formula (III) , or Formula (III-1) , or a pharmaceutically acceptable salt thereof, as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the present disclosure provides a pharmaceutical composition for preventing or treating a SOS l-associated disease, wherein the pharmaceutical composition comprises (preferably, a therapeutically effective amount of) at least one (such as at least two) of the compounds of the present disclosure and optionally one or more pharmaceutically acceptable carriers.
  • the present disclosure provides a PROTAC, comprising the compound represented by Formula (I) , the pharmaceutically acceptable salt thereof, the tautomer thereof, the stereoisomer thereof, the solvate thereof, the crystal form thereof, the metabolite thereof or the prodrug thereof as defined above.
  • the present disclosure provides a pharmaceutical composition for preventing or treating a SOS l-associated disease, wherein the pharmaceutical composition comprises (preferably, a therapeutically effective amount of) at least one of the compounds of the present disclosure and at least one of additional therapeutically active agents, and optionally one or more pharmaceutically acceptable carriers.
  • additional therapeutically active agents include, but are not limited to, an anti-viral agent, a chemotherapeutic agent, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, a tyrosine kinase inhibitor, or an immuno-oncology agent.
  • the immuno-oncology agents include but not limited to small molecule drug, antibody, or other biologic molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • the immuno-oncology agents could antagonist of a protein that inhibits T cell and/or NK cell activation.
  • the antibody is a monoclonal antibody.
  • the pharmaceutical composition is a composition suitable for oral, rectal, topical, or 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 of the present disclosure may be prepared by any of the methods well known in the art of pharmacy.
  • each dosage unit contains from about 0.01 mg to about 2000 mg of one or more compounds of the present disclosure, for example, from about 0.01 mg to about 1000 mg, from about 0.02 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 2 mg to about 1000 mg, from about 3 mg to about 1000 mg, from about 4 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 1 mg to 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 400 mg to about 500 mg, for example about
  • each dosage unit contains from about 0.1 mg to about 100 mg of one or more compounds of the present disclosure, for example from about 0.5 mg to about 100 mg, from about 1 mg to about 100 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 0.5 mg to about 90 mg, from about 0.5 mg to about 80 mg, from about 0.5 mg to about 70 mg, from about 0.5 mg to about 60 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, from about 1 mg to about 90 mg, from about 5 mg to about 90 mg, from about 10 mg to about 80 mg, from about 20 mg to about 70 mg, from about 30 mg to about 60 mg, or from about 40 mg to about 50 mg.
  • the pharmaceutical composition of the present disclosure may have a dosage level of between 0.001-1000 mg/kg body weight/day, for example, 0.01-900 mg/kg body weight/day, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.05-900 mg/kg body weight/day, 0.05-800 mg/kg body weight/day, 0.05-700 mg/kg body weight/day, 0.05-600 mg/kg body weight/day, 0.05-500 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the present disclosure provides at least one of the compounds of the present disclosure for use as SOS1 inhibitor.
  • the present disclosure provides at least one of the compounds of the present disclosure for use in treating or preventing a SOSl-associated disease (e.g. hyperproliferative disorders, RASopathies) , especially wherein the inhibition of the interaction of SOS1-RAS family proteins/RAC1 is of therapeutic benefit, particularly cancer that are dependent on the SOS1 activity.
  • a SOSl-associated disease e.g. hyperproliferative disorders, RASopathies
  • Hyperproliferative disorders include, but are not limited to, psoriasis, keloids, other hyperplasias affecting the skin, benign prostate hyperplasia (BPH) , restenosis after angioplastic surgery, and cancer.
  • BPH benign prostate hyperplasia
  • the present disclosure provides use of the compound of the present disclosure in the manufacture of a medicament for preventing or treating a SOS l-associated disease.
  • the compounds of the present disclosure are used as a sole active ingredient or in combination with other active ingredients.
  • the afore-mentioned SOS l-associated disease is selected from cancers exhibiting one or more of the following molecular features: alterations in RAS-family proteins, alterations in components of RAS signaling (such as SOS1, MDM2, receptor tyrosine kinases such as EGFR, VEGFR1/2/3, ErB2/3/4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TRKA/B/C, RET, and c-MET, GAPs such as NF1/2) , alterations in RAC1 protein, and alterations in RAC1 signaling components.
  • the alterations include, but are not limited to, mutation, gene amplification, and over-expression.
  • the afore-mentioned SOS l-associated disease is a disease having an activating RAS mutation (such as one at position G12, G13, Q61 or A146) , e.g. a KRAS, HRAS or NRAS G12C-mutated cancer, a KRAS, HRAS or NRAS G12D-mutated cancer, a KRAS, HRAS or NRAS G12V-mutated cancer, a KRAS, HRAS or NRAS G12S-mutated cancer, a KRAS, HRAS or NRAS G12A-mutated cancer, a KRAS, HRAS or NRAS G12D-mutated cancer, a KRAS, HRAS or NRAS G12V-mutated cancer, a KRAS, HRAS or NRAS G13D-mutated cancer, a KRS, HRAS or NRAS G13C-mutated cancer, a KRAS, HRAS or NRAS Q61X-mutated
  • the afore-mentioned SOS l-associated disease is a disease having an activating SOS1 mutation (such as SOS1 N233S, N233Y, D309Y, P478L, or G604V mutation) , such as lung cancer.
  • an activating SOS1 mutation such as SOS1 N233S, N233Y, D309Y, P478L, or G604V mutation
  • the afore-mentioned SOS l-associated disease is a disease having a loss-of-function mutation in the neurofibromin (NF-1) gene or neurofibromin 2 (NF-2) gene.
  • the afore-mentioned SOS l-associated disease is selected from RASopathies, which is a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS/MAPK signaling pathway, such as neurofbromatosis type 1 (NF1) , Legius syndrome (LS) , Noonan syndrome (NS) , neurofbromatosis-Noonan syndrome (NFNS) , Noonan syndrome-like (NSL) , Noonan syndrome with multiple lentigines (NSML) , formerly known as LEOPARD syndrome, Noonan syndrome-like with loose anagen hair (NSLSH) also known as Mazzanti syndrome, Costello syndrome (CS) , cardiofaciocutaneous (CFC) syndrome, hereditary gingival fibromatosis type 1 (HGF-1) , capillary malformation-arteriovenous malformation syndrome (CM-AVM) , intellectual disability associated with autism spectrum disorder and juvenile myelomonocytic
  • the compounds of the present disclosure exhibit desirable stability, bioavailability, therapeutic index, and toxicity values.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • a dash “-” at the front or end of a chemical group is used, as matter of convenience, to indicate a point of attachment for a substituent.
  • -OH is attached through the oxygen atom;
  • chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • the term “about” directed to that value or parameter per se, includes the indicated amount ⁇ 10%, ⁇ 5%, or ⁇ 1%. Also, the term “about X” includes description of “X” .
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • the term “m-n membered” ring wherein m and n are integers and n is greater than m, refers to a ring containing m to n atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to a linear or branched-chain alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • C 1-6 alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • C 1-3 alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups can contain 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • Examples of “C 1-6 alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy (e.g.
  • C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) .
  • aryl refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • cyano refers to -CN.
  • cycloalkyl refers to a monovalent or divalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl group may contain 3 to 14 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • the cycloalkyl group may be saturated or partially unsaturated. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system.
  • the cycloalkyl group may be saturated or partially unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • the cycloalkyl group may be saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which can be arranged as a fused, spiro or bridged ring system.
  • fused ring refers to a ring system having two rings sharing two adjacent atoms
  • spiro ring refers to a ring systems having two rings connected through one single common atom
  • bridged ring refers to a ring system with two rings sharing three or more atoms.
  • fused carbocyclyl examples include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl and the like.
  • spiro carbocyclyl examples include, but are not limited to, spiro [5.5] undecanyl, spiro-pentadienyl, spiro [3.6] -decanyl, and the like.
  • bridged carbocyclyl examples include, but are not limited to bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [3.3.3] undecanyl, and the like.
  • halo refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. If a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ( "di” ) or three ( “tri” ) halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl examples include -CH 2 CF 3 , -CH 2 F, difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ) .
  • haloalkenyl refers to an alkenyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • haloalkynyl refers to an alkynyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • haloalkoxyl refers to an alkoxyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • heteroatom refers to nitrogen, oxygen, sulfur or phosphorus, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • heteroalkyl refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, P, and S.
  • the heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkenyl refers to an alkenyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, P, and S.
  • the heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkynyl refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, P, and S.
  • the heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one, two, three or more heteroatoms independently selected from N, O, P, and S.
  • the heteroaryl group can be monocyclic.
  • Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, heteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • the heteroaryl group also includes polycyclic groups in which an heterocyclyl ring is fused to one or more aryl or heteroaryl ring, where the radical or point of attachment is on the aryl or heteroaryl ring.
  • polycyclic heteroaryl examples include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, thienyl, 2, 3-dihydrobenzofuranyl, pyridyl, pyridazinyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetra
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one, two, three or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .
  • Heterocyclyl group may be monocyclic.
  • monocyclic heterocyclyl include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, azetidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, 3, 6-dihydro-2
  • Heterocyclyl group may be polycyclic, including the fused, spiro and bridged ring systems.
  • the fused heterocyclyl group includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1, 2-a] pyridinyl, furo [3, 4-d] pyrimidinyl, pyrrolo [3, 4-d] pyrimidinyl, dihydrofuro [3, 4-b
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, 5-aza-spiro [2.4] heptanyl, 6-aza-spiro [2.5] octanyl, 6-aza-spiro [3.4] octanyl, 2-oxa-6-aza-spiro [3.3] heptanyl, 2-oxa-6-aza-spiro [3.4] octanyl, 6-aza-spiro [3.5] nonanyl, 7-aza-spiro [3.5] nonanyl, 1-oxa-7-aza-spiro [3.5] nonanyl, 3, 8-dioxa-1-azaspiro [4.5] dec-1-enyl and the like.
  • bridged heterocyclyl examples include, but are not limited to, 3-aza-bicyclo [3.1.0] hexanyl, 8-aza-bicyclo [3.2.1] octanyl, 1-aza-bicyclo [2.2.2] octanyl, 2-aza-bicyclo [2.2.1] heptanyl, 1, 4-diazabicyclo [2.2.2] octanyl, 3-oxabicyclo [3.1.1] heptane and the like.
  • hydroxyl refers to —OH.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the substituents may include, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • PROTAC proteolysis targeting chimera
  • This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein.
  • PROTAC is a strategy that utilizes the ubiquitin ⁇ protease system to target a specific protein and induce its degradation in the cell.
  • the normal physiological function of the ubiquitin-protease system is responsible for clearing denatured, mutated, or harmful proteins in cells.
  • PROTAC takes advantage of the cell's own protein destruction mechanism to remove specifically targeted proteins from cells (Cell Biochem Funct. 2019, 37, 21-30) .
  • crystal or “crystal form” , or “crystalline” refer to the ions or molecules, in a certain way, are arranged periodically in three-dimensional space, and have recurrence at certain intervals. Due to the difference of the periodic arrangement, there can be a variety of crystal forms, that is, polymorph phenomenon.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well-known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage, etc. of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with mammals for a period.
  • prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because , in some situations, they may be easier to administer than the patent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
  • the current disclosed compounds are capable to form acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • the term “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 of Formula (I) 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 compounds of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical acceptable carrier according to conventional pharmaceutical compounding techniques.
  • the pharmaceutical acceptable 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 disclosure 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 of the present disclosure 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.
  • the pharmaceutical acceptable 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 acceptable carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the pharmaceutical composition of the present disclosure 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, surfactant 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 or l000mg.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical acceptable carrier.
  • the amount of the compounds of the present disclosure in the unit dosage form will vary depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of the individual subject) , the particular route of administration, the actual compound administered and its relative activity, and the severity of the subject's symptoms.
  • compositions of the present disclosure 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 disclosure 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 syringeability.
  • 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 disclosure 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 disclosure 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 the present disclosure 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, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, 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.
  • subject , “individual” or “patient” is used interchangeably, and refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans. In some embodiments, patient is a human.
  • RAS family proteins refers to NRAS (neuroblastoma RAS viral oncogene homolog) , HRAS (Harvey murine sarcoma virus oncogene) and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) and any mutant thereof.
  • disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
  • inhibitor refers to a decrease in the baseline activity of a biological activity or process.
  • Inhibition of activity of SOS1 thereof refers to a decrease in SOS1 activity as compared to the activity of that enzyme in the absence of the compound of the present disclosure.
  • the subject matter disclosed herein can be utilized to inhibit undesired cellular proliferation and/or anchorage-independent cell growth.
  • SOS1-associated disease refers to disease which harbor hyperactive or aberrantly activated signaling pathways involving SOS1.
  • cancer encompass all forms of cancers, including but not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias. Examples include but are not limited to breast cancer, bladder cancer, bladder carcinoma, uterine cancer, brain tumors, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, liver cancer (including HCC) , laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, kidney cancer (including RCC) , thyroid cancer, acute lymphocytic leukemia, acute myeloid leukemia, ependymoma, Ewing’s sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid cancer, and nephroblastoma (Wilm’s tumor) .
  • Compounds of the present disclosure may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -or, as (D) -or (L) -for amino acids.
  • the present disclosure includes all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-) , (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved by conventional techniques, such as, chromatography and fractional crystallization.
  • stereoisomer or “stereoisomeric form” refers to a compound containing the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the current disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers” , which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • enantiomers represent a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1: 1 mixture of a pair of enantiomers is a "racemic” mixture.
  • a mixture of enantiomers at a ratio other than 1: 1 is a "scalemic" mixture.
  • diastereoisomers represent stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Tautomer or “tautomeric isomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present disclosure includes tautomers of any compounds of the present disclosure.
  • Tautomeric isomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. As the same, the imidic acid containing compounds are understood to include their amide tautomers.
  • any formula or structure provided herein also represents unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have the same structures as depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes include isotopes, such as, but not limited to, of hydrogen ( 2 H (deuterium, D) , 3 H (tritium) ) , carbon ( 11 C, 13 C, 14 C) , nitrogen ( 15 N) , oxygen ( 17 O, 18 O) , phosphorous ( 31 P, 32 P) , fluorine ( 18 F) , chlorine ( 36 Cl) , and iodine ( 125 I) .
  • isotopically labelled compounds may have usages in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) in drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., amorphous, crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvated form is a hydrate; and if the solvent is alcohol, the solvated form is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • the compounds of the present disclosure 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 term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical 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 term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the term “pharmaceutically acceptable carrier” refers to a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier” as used herein includes both one and more than one such carrier.
  • pharmaceutically acceptable carrier also encompasses “pharmaceutically acceptable excipient” and “pharmaceutically acceptable diluent” .
  • the particular carrier used in the pharmaceutical compositions of the present disclosure will depend upon the means and purpose for which the compounds of the present disclosure is being applied.
  • the pharmaceutical acceptable 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 acceptable carriers are employed.
  • tablets may be coated by standard aqueous or non-aqueous techniques.
  • the compounds of the present disclosure may be synthesized by varieties of methods by those skilled in the art of organic chemistry, and general synthetic schemes for preparing compounds of the present invention are described herein. These schemes are illustrative and not meant to limit the possible methodologies one skilled in the art to prepare the compounds of the present disclosure. Different methods preparing the current disclosed compounds will be evident to those skilled in the art. General schemes to prepare the compounds of the present invention are given in the Examples section set out hereinafter. Preparation of homochiral examples may be realized by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products or diastereomers by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically or diastereomerically enriched products.
  • the compounds of the present disclosure may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.
  • compounds and intermediates provided herein may be prepared using the methods described in PCT/CN2021/142533, PCT/CN2022/113750, and PCT/CN2022/143068.
  • non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • a person skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.
  • Step 1 1- (5- (trifluoromethyl) -1H-pyrazol-3-yl) ethan-1-one
  • Step 2 (R, Z) -2-methyl-N- (1- (5- (trifluoromethyl) -1H-pyrazol-3-yl) ethylidene) propane-2-sulfinamide
  • Step 3 (R, Z) -N- (1- (1- (4-methoxybenzyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) ethylidene) -2-methylpropane-2-sulfinamide
  • Step 4 (R) -N- ( (R) -1- (1- (4-methoxybenzyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) ethyl) -2-methylpropane-2-sulfinamide
  • Step 5 (R) -1- (1- (4-methoxybenzyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) ethan-1-amine hydrochloride
  • Step 1 2- (trimethylsilyl) ethyl 4-bromo-6- (trifluoromethyl) -1H-indazole-1-carboxylate
  • Step 2 2- (trimethylsilyl) ethyl 4-acetyl-6- (trifluoromethyl) -1H-indazole-1-carboxylate
  • Step 3 (R, Z) -2-methyl-N- (1- (6- (trifluoromethyl) -1H-indazol-4-yl) ethylidene) propane-2-sulfinamide
  • Step 4 (R) -2-methyl-N- ( (Z) -1- (1- (tetrahydro-2H-pyran-2-yl) -6- (trifluoromethyl) -1H-indazol-4-yl) ethylidene) propane-2-sulfinamide
  • Step 5 2-methyl-N- ( (1R) -1- (1- (tetrahydro-2H-pyran-2-yl) -6- (trifluoromethyl) -1H-indazol-4-yl) ethyl) propane-2-sulfinamide
  • Step 6 (R) -1- (6- (trifluoromethyl) -1H-indazol-4-yl) ethan-1-amine hydrochloride
  • Step 1 (R, Z) -N- (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylidene) -2-methylpropane-2-sulfinamide
  • Step 2 (R) -N- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide
  • Step 3 (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride
  • Step 1 1- (3- (pentafluoro-l6-sulfaneyl) phenyl) ethan-1-one
  • Step 2 (R, Z) -2-methyl-N- (1- (3- (pentafluoro-l6-sulfaneyl) phenyl) ethylidene) propane-2-sulfinamide
  • Step 3 (R) -2-methyl-N- ( (R) -1- (3- (pentafluoro-l6-sulfaneyl) phenyl) ethyl) propane-2-sulfinamide
  • Step 4 (R) -1- (3- (pentafluoro-l6-sulfaneyl) phenyl) ethan-1-amine hydrochloride
  • Step 1 tert-butyl (3-bromo-5-iodophenyl) carbamate
  • Step 2 ethyl 2- (3-bromo-5- ( (tert-butoxycarbonyl) amino) phenyl) -2, 2-difluoroacetate
  • Step 3 tert-butyl (3-bromo-5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) carbamate
  • Step 4 tert-butyl (3-acetyl-5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) carbamate
  • Step 5 1- (3-amino-5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethan-1-one hydrochloride
  • Step 6 benzyl (3-acetyl-5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) carbamate
  • Step 7 benzyl (R, Z) - (3- (1- ( (tert-butylsulfinyl) imino) ethyl) -5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) carbamate
  • Step 8 benzyl (3- ( (R) -1- ( ( (R) -tert-butylsulfinyl) amino) ethyl) -5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) carbamate
  • Step 9 benzyl (R) - (3- (1-aminoethyl) -5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) carbamate hydrochloride
  • Step 1 3-bromo-2-fluoro-5- (trifluoromethyl) benzaldehyde
  • Step 2 (R, Z) -N- (3-bromo-2-fluoro-5- (trifluoromethyl) benzylidene) -2-methylpropane-2-sulfinamide
  • Step 3 (R) -N- ( (R) -1- (3-bromo-2-fluoro-5- (trifluoromethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide
  • Step 4 (R) -1- (3-bromo-2-fluoro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride
  • Step 1 ethyl 2- (3-bromo-5-nitrophenyl) -2, 2-difluoroacetate
  • Step 4 1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethan-1-one
  • Step 5 (R, Z) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethylidene) -2-methylpropane-2-sulfinamide
  • Step 6 (R) -N- ( (R) -1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -2-methylpropane-2-sulfinamide
  • Step 7 (R) -1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethan-1-amine hydrochloride
  • Step 1 1-bromo-3- (1, 1-difluoroethyl) -2-fluorobenzene
  • Step 2 1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-one
  • Step 3 (R, E) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethylidene) -2-methylpropane-2-sulfinamide
  • Step 4 (R) -N- ( (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
  • Step 5 (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethan-1-amine hydrochloride
  • Step 1 1- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) ethan-1-one
  • the reaction was detected by LCMS.
  • the resulting mixture was cooled to r.t and quenched with 20 mL of sat. KF and stirred for 30 minutes. Brown solid was precipitated out after 10 mins, then filtered through a pad of celite and the filter cake was washed with ethyl acetate (10 mL ⁇ 3) .
  • the filtrate was partitioned between ethyl acetate (50 mL) , extracted with ethyl acetate (30 mL ⁇ 3) .
  • the organic phases were combined, dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 N- ( (R) -1- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide
  • Step 3 tert-butyl (6- ( (1R) -1- ( (tert-butylsulfinyl) amino) ethyl) -4- (trifluoromethyl) pyridine-2-yl) carbamate
  • Step 4 (R) -6- (1-aminoethyl) -4- (trifluoromethyl) pyridin-2-amine
  • Step 1 methyl 3- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) -1-methyl-5- oxopyrrolidine-3-carboxylate
  • Step 2 methyl 3- (5- (1, 3-dioxolan-2-yl) -6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylpyrimidin-4-yl) -1-methyl-5-oxopyrrolidine-3-carboxylate
  • Step 3 methyl 3- (6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -5-formyl-2-methylpyrimidin-4-yl) -1-methyl-5-oxopyrrolidine-3-carboxylate
  • Step 4 4- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6- (2-fluorophenyl) -1', 2-dimethyl-5, 6-dihydro-7H-spiro [pyrido [4, 3-d] pyrimidine-8, 3'-pyrrolidine] -5', 7-dione
  • Step 1 1- (tert-butyl) 2-methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) pyrrolidine-1, 2-dicarboxylate
  • Step 2 1- (tert-butyl) 2-methyl 2- (5- (1, 3-dioxolan-2-yl) -6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylpyrimidin-4-yl) pyrrolidine-1, 2-dicarboxylate
  • Step 3 1- (tert-butyl) 2-methyl 2- (6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -5-formyl-2-methylpyrimidin-4-yl) pyrrolidine-1, 2-dicarboxylate
  • Step 4 tert-butyl 4- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6- (2-fluorophenyl) -2-methyl-7-oxo-6, 7-dihydro-5H-spiro [pyrido [4, 3-d] pyrimidine-8, 2'-pyrrolidine] -1'-carboxylate
  • Step 5 4- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6- (2-fluorophenyl) -2-methyl-5, 6-dihydro-7H-spiro [pyrido [4, 3-d] pyrimidine-8, 2'-pyrrolidin] -7-one
  • Step 1 methyl 3- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) -1-methyl-5-oxopyrrolidine-3-carboxylate
  • Step 2 methyl 3- (5- (1, 3-dioxolan-2-yl) -6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylpyrimidin-4-yl) -1-methyl-5-oxopyrrolidine-3-carboxylate
  • Step 3 4- (5- (1, 3-dioxolan-2-yl) -6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylpyrimidin-4-yl) -4- (hydroxymethyl) -1-methylpyrrolidin-2-one
  • Step 4 4- (5- (1, 3-dioxolan-2-yl) -6- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylpyrimidin-4-yl) -4- (azidomethyl) -1-methylpyrrolidin-2-one
  • the reaction mixture was diluted with water (5.0 mL) and extracted with DCM (10 mL x 2) . The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL) and NaN 3 (208 mg, 3.20 mmol) was added at room temperature. The resulting mixture was stirred at 100 °C for 3 hrs. LCMS showed the reaction was complete. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to dryness.
  • Step 5 benzyl (4-fluoro-3- ( (1R) -1- ( (6- (2-fluorophenyl) -2- (methylthio) -7-oxo-6, 7-dihydro-5H-spiro [pyrido [4, 3-d] pyrimidine-8, 3'-pyrrolidin] -4-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate
  • Step 6 4- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -1', 2-dimethyl-6, 7-dihydro-5H-spiro [pyrido [4, 3-d] pyrimidine-8, 3'-pyrrolidin] -5'-one
  • Step 7 4- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6- (2-fluorophenyl) -1', 2-dimethyl-6, 7-dihydro-5H-spiro [pyrido [4, 3-d] pyrimidine-8, 3'-pyrrolidin] -5'-one
  • Example 5 According to the procedures of Example 1-4, the title compound of Example 5 was afforded.
  • Step 1 tert-butyl (R) -4'- ( (1- (5- ( ( (benzyloxy) carbonyl) amino) -2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 2 benzyl (R) - (4-fluoro-3- (1- ( (6'- (2-fluorophenyl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -4'-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate
  • Step 3 benzyl (R) - (4-fluoro-3- (1- ( (6'- (2-fluorophenyl) -1, 2'-dimethyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -4'-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) carbamate
  • Step 4 (R) -4'- ( (1- (5-amino-2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 tert-butyl (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2- fluorophenyl) -2'-methoxy-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 2 (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'-methoxy-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 3 (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'-methoxy-1-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 tert-butyl (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'- (methylsulfonyl) -7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 2 tert-butyl (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'-hydroxy-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 3 (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'-hydroxy-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 4 (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (2-fluorophenyl) -2'-hydroxy-1-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 rel-benzyl ( (3S, 4R) -3-hydroxytetrahydro-2H-pyran-4-yl) carbamate
  • Step 2 rel-benzyl ( (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) carbamate
  • Step 3 rel- (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-amine
  • Step 4 tert-butyl 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 5 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) -2'-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 6 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 rel- (3R, 4R) -4- ( ( (benzyloxy) carbonyl) amino) tetrahydro-2H-pyran-3-yl 4-nitrobenzoate
  • Step 2 rel-benzyl ( (3R, 4R) -3-hydroxytetrahydro-2H-pyran-4-yl) carbamate
  • Step 3 rel-benzyl ( (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) carbamate
  • Step 4 rel- (3R, 4R) -3-fluorotetrahydro-2H-pyran-4-amine
  • Step 5 rel-tert-butyl 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (3R, 4S) -3-fluorotetrahydro-2H-pyran-4-yl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 6 rel-4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (3R, 4S) -3-fluorotetrahydro-2H-pyran-4-yl) -2'-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 7 rel-4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (3R, 4S) -3-fluorotetrahydro-2H-pyran-4-yl) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 tert-butyl (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (3-methoxypropyl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3- d] pyrimidine] -1-carboxylate
  • Step 2 (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (3-methoxypropyl) -2'-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 3 (R) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- (3- methoxypropyl) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 tert-butyl (R) -6'- (2-ethoxyethyl) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 2 (R) -6'- (2-ethoxyethyl) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2'-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 3 (R) -6'- (2-ethoxyethyl) -4'- ( (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Example 27 According to the procedures of Example 27, the title compounds of Example 28 and Example 29 were afforded.
  • Step 1 (2R, 4R) -N-benzyl-2-methyltetrahydro-2H-pyran-4-amine and (2R, 4S) -N-benzyl-2-methyltetrahydro-2H-pyran-4-amine
  • Step 3 tert-butyl 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (2R, 4R) -2-methyltetrahydro-2H-pyran-4-yl) -2'- (methylthio) -7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 4 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (2R, 4R) -2-methyltetrahydro-2H-pyran-4-yl) -2'- (methylthio) -5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 5 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -1-methyl-6'- ( (2R, 4R) -2-methyltetrahydro-2H-pyran-4-yl) -2'- (methylthio) -5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 6 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -1-methyl-6'- ( (2R, 4R) -2-methyltetrahydro-2H-pyran-4-yl) -5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 1 tert-butyl 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (2R, 4R) -2-methyltetrahydro-2H-pyran-4-yl) -2'- (methylthio) -7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate
  • Step 2 4'- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamino) -6'- ( (2R, 4S) -2- methyltetrahydro-2H-pyran-4-yl) -2'- (methylthio) -5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7' (6'H) -one
  • Step 3 4'- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamino) -1-methyl-6'- ( (2R, 4S) -2-methyltetrahydro-2H-pyran-4-yl) -2'- (methylthio) -5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7' (6'H) -one
  • Step 4 4'- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamino) -1-methyl-6'- ( (2R, 4S) -2-methyltetrahydro-2H-pyran-4-yl) -5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7' (6'H) -one (SLXN-3731-trans)
  • Step 1 1-tert-butyl 3-methyl 3-aminopyrrolidine-1, 3-dicarboxylate
  • Step 2 1-tert-butyl 3-methyl 3- (benzyloxycarbonylamino) pyrrolidine-1, 3-dicarboxylate
  • Step 3 1-benzyl 7-tert-butyl 3-methyl 4-oxo-1, 7-diazaspiro [4.4] nonane-1, 3, 7-tricarboxylate
  • Step 4 6'-benzyl 1-tert-butyl 2'-methyl-4'-oxo-3', 4'-dihydrospiro [pyrrolidine-3, 7'-pyrrolo [3, 4-d] pyrimidine] -1, 6' (5'H) -dicarboxylate
  • Step 5 6'-benzyl 1-tert-butyl 4'- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamino) -2'-methylspiro [pyrrolidine-3, 7'-pyrrolo [3, 4-d] pyrimidine] -1, 6' (5'H) -dicarboxylate
  • Step 6 tert-butyl 4'- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamino) -2'-methyl-5', 6'-dihydrospiro [pyrrolidine-3, 7'-pyrrolo [3, 4-d] pyrimidine] -1-carboxylate
  • Step 7 tert-butyl 4'- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethylamino) -2'-methyl-6'- (tetrahydro-2H-pyran-4-yl) -5', 6'-dihydrospiro [pyrrolidine-3, 7'-pyrrolo [3, 4-d] pyrimidine] -1-carboxylate
  • Step 8 N- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -2'-methyl-6'- (tetrahydro-2H-pyran-4-yl) -5', 6'-dihydrospiro [pyrrolidine-3, 7'-pyrrolo [3, 4-d] pyrimidin] -4'-amine
  • Step 9 N- ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -1, 2'-dimethyl-6'- (tetrahydro-2H-pyran-4-yl) -5', 6'-dihydrospiro [pyrrolidine-3, 7'-pyrrolo [3, 4-d] pyrimidin] -4'-amine
  • Step 1 tert-butyl 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (1s, 4S) -4-hydroxy-4-methylcyclohexyl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine] -1-carboxylate and tert-butyl 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (1r, 4R) -4-hydroxy-4-methylcyclohexyl) -2'-methyl-7'-oxo-6', 7'-dihydro-5'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidine]
  • Step 2 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (1s, 4S) -4-hydroxy-4-methylcyclohexyl) -2'-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one and 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (1r, 4R) -4-hydroxy-4-methylcyclohexyl) -2'-methyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • Step 3 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (1s, 4S) -4-hydroxy-4-methylcyclohexyl) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one and 4'- ( ( (R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -6'- ( (1r, 4R) -4-hydroxy-4-methylcyclohexyl) -1, 2'-dimethyl-5', 6'-dihydro-7'H-spiro [azetidine-3, 8'-pyrido [4, 3-d] pyrimidin] -7'-one
  • test compounds bind to SOS1 and impair SOS1-KRAS G12D interaction were measured by HTRF assay using Cisbio KRAS G12D/SOS1 binding kit (Cat. No. 63ADK000CB21PEH) .
  • Cisbio KRAS G12D/SOS1 binding kit Cat. No. 63ADK000CB21PEH
  • the interaction between Tag2-KRAS G12D and Tag1-SOS1 was detected by energy transfer from Terbium cryptate (HTRF donor) labelled on anti-Tag1 and XL665 (HTRF acceptor) labelled on anti-Tag2.
  • HTRF donor Terbium cryptate
  • HTRF acceptor XL665
  • Test compounds are diluted in DMSO and prepared for 11 concentrations, then transferred to 384 assay plate by Liquid Handler. 5 ⁇ L of Tag2-KRAS G12D, 5 ⁇ L of Tag1-SOS1 and GTP were mixed with diluted compounds, incubated at 25 ⁇ for 15 min. A volume of 10 ⁇ L of the anti-Tag1-Tb and anti-Tag2-XL665 mixture were then added to the assay plate, the mixture was further incubated at 4 ⁇ for 3 hours. The fluorescent signal was read on an BMG2014 Plate Reader. The IC 50 was determined from non-linear regression equation by Graphpad Prism8. The results for exemplary compounds of Formula (I) are as shown in Table 1 and Table 2.
  • test compounds were measured in H358 cell lines (ATCC CRL-5807) using the following protocol:
  • the plasma concentrations of test compounds following single intravenous (IV, 1 mg/kg) and oral (PO, 8 mg/kg) administrations were determined in ICR mouse using LC-MS/MS.
  • the PK parameters were calculated by
  • SyncroPatch 384i/384 automated patch clamp system was used to evaluate the in vitro inhibitory effect of the test articles on the hERG channel current. The concentration response relationship was determined for each test article at 5 concentrations in duplicate to calculate the IC50.

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Abstract

L'invention concerne des composés hétérocycliques et leur utilisation, en particulier un composé représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, un tautomère de celui-ci, un stéréoisomère de celui-ci, un solvate de celui-ci, une forme cristalline de celui-ci, un métabolite de celui-ci ou un promédicament de celui-ci. L'invention concerne en outre un PROTAC comprenant un composé de formule (I), un sel pharmaceutiquement acceptable de celui-ci, un tautomère de celui-ci, un stéréoisomère de celui-ci, un solvate de celui-ci, une forme cristalline de celui-ci, un métabolite de celui-ci ou un promédicament de celui-ci. Les composés hétérocycliques peuvent être utilisés pour prévenir ou traiter une maladie associée à SOS1.
PCT/CN2023/103169 2023-06-28 2023-06-28 Composés hétérocycliques utiles en tant qu'inhibiteurs de sos1 Pending WO2025000265A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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WO2016064960A1 (fr) * 2014-10-22 2016-04-28 Incyte Corporation Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
WO2019191470A1 (fr) * 2018-03-30 2019-10-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et leurs méthodes d'utilisation pour le traitement du cancer
WO2020139992A1 (fr) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
CN115745955A (zh) * 2021-09-03 2023-03-07 四川科伦博泰生物医药股份有限公司 嘧啶酮类化合物、其制备方法及其在医药上的应用
WO2023109929A1 (fr) * 2021-12-17 2023-06-22 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique ayant une activité antitumorale et son utilisation
WO2023125737A1 (fr) * 2021-12-29 2023-07-06 Silexon Ai Technology Co., Ltd. Composés hétérocycliques et leur utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016064960A1 (fr) * 2014-10-22 2016-04-28 Incyte Corporation Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
WO2019191470A1 (fr) * 2018-03-30 2019-10-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et leurs méthodes d'utilisation pour le traitement du cancer
WO2020139992A1 (fr) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
CN115745955A (zh) * 2021-09-03 2023-03-07 四川科伦博泰生物医药股份有限公司 嘧啶酮类化合物、其制备方法及其在医药上的应用
WO2023109929A1 (fr) * 2021-12-17 2023-06-22 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique ayant une activité antitumorale et son utilisation
WO2023125737A1 (fr) * 2021-12-29 2023-07-06 Silexon Ai Technology Co., Ltd. Composés hétérocycliques et leur utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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