WO2023153748A1 - Inhibiteur de sos1 et dérivé de celui-ci - Google Patents

Inhibiteur de sos1 et dérivé de celui-ci Download PDF

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WO2023153748A1
WO2023153748A1 PCT/KR2023/001685 KR2023001685W WO2023153748A1 WO 2023153748 A1 WO2023153748 A1 WO 2023153748A1 KR 2023001685 W KR2023001685 W KR 2023001685W WO 2023153748 A1 WO2023153748 A1 WO 2023153748A1
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amine
ethyl
carbon atoms
dimethoxy
amino
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Korean (ko)
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심태보
윤정혁
한혜정
김규태
남기엽
류성식
신인재
조한나
김남경
이지원
김철희
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(주)파로스아이바이오
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to SOS1 inhibitors and derivatives thereof.
  • RAS proteins have been well known as small GTPases that play an important role in signaling pathways related to cell differentiation, proliferation and survival.
  • the RAS family has three isoforms, HRAS, NRAS, and KRAS, and is well known as an oncogene whose mutations are found in various carcinomas.
  • high frequency of RAS mutations has been reported in carcinomas with high lethality (lung cancer, colorectal cancer, and pancreatic cancer), and 85% of RAS-driven cancers are known to be caused by KRAS mutations.
  • K-Ras+GDP As a strategy to prevent activation of K-Ras by inhibiting binding to K-Ras using a compound that binds to a protein that activates RAS, SOS1, a type of RasGEF, binds to K-Ras+GDP to remove GDP and activate GTP do. It binds to the SOS1 protein and inhibits the transition from KRAS-GDP-bound state to KRAS-GTP-bound state, blocking downstream signaling pathways.
  • An object of the present invention is to provide a compound represented by Formula 1 below, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof;
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • X 3 is sulfur (S) or carbon (C)
  • X 4 is a direct bond or carbon ( C)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • R 3 is alkoxy having 1 to 10 carbon atoms; halogen; vinyl;
  • B is hydrogen; tertbutyloxycarbonyl; alkylene having 1 to 3 carbon atoms substituted with acetamide; unsubstituted or substituted heteroaryl having 4 to 10 carbon atoms (wherein, at least one substituted heteroaryl is is substituted with a substituent of tertbutyloxycarbonyl); or -R 31 R 32 ;
  • R 31 is alkenylene having 2 to 5 carbon atoms;
  • R 32 is hydrogen; trimethylsilyl; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms (the substituted substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is halogen; unsubstituted or substituted with at least one halogen) Alkyl of 1 to 3; Alkoxy of 1 to 3 carbon atoms; Acetamide;)
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • Another aspect of the present invention is the treatment and prevention of tumor diseases containing the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable diastereomers thereof as active ingredients. And to provide a pharmaceutical composition for relief.
  • One aspect of the present invention provides a compound represented by Formula 1 below, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof;
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • X 3 is sulfur (S) or carbon (C)
  • X 4 is a direct bond or carbon ( C)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • R 3 is alkoxy having 1 to 10 carbon atoms; halogen; vinyl;
  • B is hydrogen; tertbutyloxycarbonyl; alkylene having 1 to 3 carbon atoms substituted with acetamide; unsubstituted or substituted heteroaryl having 4 to 10 carbon atoms (wherein, at least one substituted heteroaryl is is substituted with a substituent of tertbutyloxycarbonyl); or -R 31 R 32 ;
  • R 31 is alkenylene having 2 to 5 carbon atoms;
  • R 32 is hydrogen; trimethylsilyl; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms (the substituted substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is halogen; unsubstituted or substituted with at least one halogen) Alkyl of 1 to 3; Alkoxy of 1 to 3 carbon atoms; Acetamide;)
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • Formula 1 is Formula 1-1 below,
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • Formula 1 is Formula 1-2 below,
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • R 3 is alkoxy having 1 to 10 carbon atoms; halogen; vinyl;
  • B is hydrogen; tertbutyloxycarbonyl; alkylene having 1 to 3 carbon atoms substituted with acetamide; unsubstituted or substituted heteroaryl having 4 to 10 carbon atoms (wherein, at least one substituted heteroaryl is is substituted with a substituent of, and the substituent is tertbutyloxycarbonyl); or -R 31 R 32 ;
  • R 31 is alkenylene having 2 to 5 carbon atoms; or alkynylene having 2 to 5 carbon atoms;
  • R 32 is hydrogen; trimethylsilyl; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms (the substituted substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is halogen; unsubstituted or substituted with at least one halogen) Alkyl of 1 to 3; Alkoxy of 1 to 3 carbon atoms; Acetamide;)
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • the compound may be selected from the group consisting of;
  • a tumor containing a compound of any one of the above, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof as an active ingredient. It provides a pharmaceutical composition for disease treatment, prevention and alleviation.
  • the active ingredient may inhibit the activity of SOS1.
  • the tumor disease is gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, appendix It may be any one of thyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, and fibroadenoma.
  • Another aspect of the present invention is to treat patients with tumor disease with the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable diastereomers thereof as active ingredients. It provides a method for treating tumor disease comprising administering a pharmaceutical composition for disease treatment, prevention and alleviation.
  • Another aspect of the present invention is the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for treating, preventing and alleviating tumor diseases.
  • Use of the diastereomers is provided.
  • the compound of the present invention has an excellent ability to inhibit the activity of SOS1, and therefore diseases caused by abnormal cell growth. It is useful as a prevention, alleviation or treatment of
  • Abnormal cell growth diseases that can be prevented and treated by the compounds according to the present invention include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerotic adenoma, uterine cancer, cervical cancer, head and neck cancer , esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia (acute myelogenous leukemia), multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hodgkin's disease and non-Hodgkin's lymphoma, or various neoplastic diseases selected from fibroadenomas and the like.
  • leukemia acute myelogenous leukemia
  • multiple myeloma blood cancer
  • lymphoma such as Hodgkin's disease and non-Hodgkin's lympho
  • Figure 1 shows the experimental results of Experimental Example 9, and it can be confirmed that the compound of the present invention has excellent tumor volume and mass reduction effects, ie, anticancer effects, in an animal model transplanted with AsPC-1 cell line.
  • One aspect of the present invention provides a compound represented by Formula 1 below, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof;
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • X 3 is sulfur (S) or carbon (C)
  • X 4 is a direct bond or carbon ( C)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • R 3 is alkoxy having 1 to 10 carbon atoms; halogen; vinyl;
  • B is hydrogen; tertbutyloxycarbonyl; alkylene having 1 to 3 carbon atoms substituted with acetamide; unsubstituted or substituted heteroaryl having 4 to 10 carbon atoms (wherein, at least one substituted heteroaryl is is substituted with a substituent of tertbutyloxycarbonyl); or -R 31 R 32 ;
  • R 31 is alkenylene having 2 to 5 carbon atoms;
  • R 32 is hydrogen; trimethylsilyl; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms (the substituted substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is halogen; unsubstituted or substituted with at least one halogen) Alkyl of 1 to 3; Alkoxy of 1 to 3 carbon atoms; Acetamide;)
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • Formula 1 is Formula 1-1 below,
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • Formula 1 is Formula 1-2 below,
  • X 1 is carbon (C) or nitrogen (N)
  • X 2 is carbon (C) or nitrogen (N)
  • R 1 is hydrogen; Alkyl having 1 to 20 carbon atoms; alkenyl having 1 to 20 carbon atoms; cyano (-CN); amide (-CONH2); Cycloalkyl having 3 to 10 carbon atoms; or halogen;
  • R 2 is -R 21 R 22 , and R 21 is linear or branched alkylene having 1 to 20 carbon atoms;
  • R 22 is alkyl having 1 to 5 carbon atoms; hydroxy (-OH); Cycloalkyl having 5 to 10 carbon atoms; Heterocycloalkyl having 5 to 10 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; or unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms;
  • the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is hydroxy (-OH); halogen; straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, unsubstituted or substituted with at least one halogen; straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms; nitro (-NO 2 ); Cycloalkyl having 3 to 6 carbon atoms; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is straight chain or branched chain alkyl having 1 to 5 carbon atoms; straight chain or branched chain alkoxy having 1 to 5 carbon atoms; (Wherein A is hydrogen; or tertbutyloxycarbonyl); or -NR 221 R 222
  • R 223 and R 224 are each independently hydrogen; unsubstituted or substituted aryl having 6 to 10 carbon atoms; Or unsubstituted or substituted heteroaryl having 3 to 5 carbon atoms (the substituted aryl and substituted heteroaryl are substituted with at least one substituent, wherein the substituent is an alkyl having 1 to 3 carbon atoms, unsubstituted, or at least one alkoxy having 1 to 3 carbon atoms substituted with a halogen of cyano; ; ; amine; (Where A is hydrogen; or tertbutyloxycarbonyl;))
  • R 3 is alkoxy having 1 to 10 carbon atoms; halogen; vinyl;
  • B is hydrogen; tertbutyloxycarbonyl; alkylene having 1 to 3 carbon atoms substituted with acetamide; unsubstituted or substituted heteroaryl having 4 to 10 carbon atoms (wherein, at least one substituted heteroaryl is is substituted with a substituent of, and the substituent is tertbutyloxycarbonyl); or -R 31 R 32 ;
  • R 31 is alkenylene having 2 to 5 carbon atoms; or alkynylene having 2 to 5 carbon atoms;
  • R 32 is hydrogen; trimethylsilyl; unsubstituted or substituted aryl having 6 to 30 carbon atoms; Unsubstituted or substituted heteroaryl having 4 to 20 carbon atoms (the substituted substituted aryl and substituted heteroaryl are substituted with at least one substituent, and the substituent is halogen; unsubstituted or substituted with at least one halogen) Alkyl of 1 to 3; Alkoxy of 1 to 3 carbon atoms; Acetamide;)
  • heterocycloalkyl and heteroaryl include at least one of O, S, and N;
  • Y is hydrogen; or alkoxy having 1 to 20 carbon atoms
  • the compound may be selected from the group consisting of;
  • Another aspect of the present invention is the treatment and prevention of tumor diseases containing the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable diastereomers thereof as active ingredients. And it provides a pharmaceutical composition for relief.
  • the active ingredient may inhibit the activity of SOS1, and specifically, the active ingredient may inhibit the growth of abnormal cells through SOS1 inhibition.
  • the compound is 1 ⁇ M When treated at this concentration, the activity of SOS1 may be inhibited by 90%.
  • the tumor disease is gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, appendix It may be any one of thyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, and fibroadenoma.
  • Another aspect of the present invention provides a method for preparing the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable diastereomers thereof.
  • the prepared compound may be selected from the group consisting of;
  • Another aspect of the present invention is to treat patients with tumor disease with the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable diastereomers thereof as active ingredients. It provides a method for treating tumor disease comprising administering a pharmaceutical composition for disease treatment, prevention and alleviation.
  • Another aspect of the present invention is the above compounds, pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for treating, preventing and alleviating tumor diseases.
  • Use of the diastereomers is provided.
  • the present invention is characterized by a method for preparing the compound represented by Formula 1, and a representative method for preparing the compound is as follows.
  • Examples 4, 5, 6, 7, and 8 were also synthesized in the same reaction by changing only acetylene.
  • Example 28 tert-Butyl (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4- d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate;
  • Examples 29, 30, and 31 were also synthesized in the same reaction by changing only the boronic acid.
  • Example 33 was also synthesized by the same reaction.
  • Example 37 was also synthesized in the same reaction by changing only the boronic acid.
  • Examples 44, 45, 46, 47, 48, 49, and 50 were also synthesized in the same reaction by changing only the boronic acid.
  • Examples 52, 53, 54, 55, 56, and 57 were also synthesized in the same reaction by changing only the aniline.
  • Examples 59, 60, 61, 62, 63, 64, 64, 65, 66, 67, and 68 were also synthesized in the same reaction by changing only the boronic acid.
  • Example 70 2-chloro-6,7-dimethoxy-N-(3,4,5-trimethoxybenzyl)quinazolin-4-amine;
  • Examples 70 and 71 were also synthesized by the same reaction.
  • Example 72 6,7-dimethoxy-N-(4-methoxybenzyl)-2-vinylquinazolin-4-amine;
  • Examples 73 and 74 were also synthesized by the same reaction.
  • Example 75 2-Cyclopropyl-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxyquinazolin-4-amine;
  • Example 76 2-Cyclopropyl-N-(1-(3-fluoro-5-methylphenyl)ethyl)-6,7-dimethoxyquinazolin-4-amine;
  • Example 77 2-cyclopropyl-6,7-dimethoxy-N-(1-(3-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine;
  • Example 90 2-cyclopropyl-6,7-dimethoxy-N-(3-methoxybenzyl)quinazolin-4-amine;
  • Examples 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, and 95 were also synthesized by the same reaction.
  • novel compound represented by Chemical Formula 1 according to the present invention can be formulated in various forms depending on the purpose.
  • the following exemplifies some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Formulation Example 2 Tablet (wet granulation)
  • the active ingredient After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture is hardened to No. 10 using a suitable device. Filled in 5 gelatin capsules.
  • An injection was prepared by containing 100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na 2 HPO 4 12H 2 O, and 2974 mg of distilled water.
  • the experimental results were as follows.
  • the activity value was expressed in three stages.
  • the activity value was expressed in three stages.
  • Example 24 O Example 27 O Example 30 O Example 31 X Example 32 O Example 33 O Example 34 O Example 38 O Example 39 O Example 40 O Example 41 O Example 46 ⁇ Example 47 ⁇ Example 48 ⁇ Example 49 O Example 50 O Example 58 O Example 59 O Example 63 O Example 65 O Example 66 O Example 67 O Example 69 X Example 72 X Example 75 O Example 76 O Example 77 O Example 78 O Example 79 X Example 80 O Example 81 O Example 82 O Example 83 O Example 84 O Example 85 O Example 86 O Example 87 O Example 88 X Example 89 X Example 90 X Example 91 X Example 92 O Example 93 O Example 94 X Example 95 X
  • Example 24 50% inhibition
  • Example 27 0% inhibition
  • Example 30 0% inhibition
  • Example 31 0% inhibition
  • Example 32 0% inhibition
  • Example 33 0% inhibition
  • Example 34 0% inhibition
  • Example 38 40% inhibition
  • Example 39 50% inhibition
  • Example 40 40% inhibition
  • Example 41 40% inhibition
  • Example 58 0% inhibition
  • Example 65 0% inhibition
  • Example 66 0% inhibition
  • Example 67 0% inhibition
  • Example 69 20% inhibition
  • Example 72 20% inhibition
  • Dispense 10000 cells per well of a 96-well plate After cell stabilization, 1/3 serially diluted compounds were treated with 0.5% DMSO and incubated for 72 hours. When cell titer glo is treated, luciferase degrades luciferin only in the presence of ATP, resulting in luminescence. Luminescence values were measured using Envision (perkinelmer). Based on the measured luminescence value, the concentration of the compound that kills the cells was calculated to obtain the GI50 value.
  • the experimental results were as follows.
  • the activity value was expressed in three stages.
  • liver microsomes Two types of liver microsomes (Human, Mouse, 0.5 mg/ml), 0.1 M phosphate buffer (pH 7.4), and 1 ⁇ M concentration of the compound were pre-incubated at 37 ° C for 5 minutes, and then NADPH Regeneration system solution was added. Incubate at 37 o C for 30 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard (chloropropamide) was added, centrifuged for 5 minutes (15,000 rpm, 4 o C), and the supernatant was injected into the LC-MS/MS system to detect the substrate drug. Metabolic stability was evaluated by analyzing
  • Human liver microsomes (0.25 mg/ml) and 0.1 M phosphate buffer (pH 7.4) were mixed with substrate drug cocktails of 5 drug metabolizing enzymes at concentrations of 0, 0.1, 0.5, 2, and 10 ⁇ M at 37 ° C. After pre-incubation for 5 minutes, NADPH Regeneration system solution was added and incubated at 37 o C for 15 minutes. Then, to terminate the reaction, an acetonitrile solution containing an internal standard (terfenadine) was added, centrifuged for 5 minutes (15,000 rpm, 4 o C), and the supernatant was injected into the LC-MS/MS system to detect the substrate drug. By simultaneously analyzing the metabolites of the compound, drug metabolizing enzyme inhibitory ability is evaluated.
  • the hERG-HEK single cell dispensed in the dedicated chip (8-well) is giga-sealed to the single hole located on the bottom of the well, and then the whole-cell is made by making a hole in the cell, and the hERG channel current can be measured. make it happen
  • cell membrane voltage (holding potential) of cells in an external buffer solution without test substance was -80 mV for 51 msec, -40 mV for 500 msec, +40 mV for 500 msec and -40 mV for 500 msec.
  • the magnitude (nA) of the peak current by the activated hERG channel was measured.
  • the same cells measured in the previous step were reacted with the cells for 60 sec, starting with the lowest concentration of the test substance, 0.01 ⁇ M, and then the peak current size of the hERG channel was measured. Stabilization was confirmed by measuring the current magnitude at No. 12 before treatment with the following concentrations. Concentration-specific experiments were conducted in this order. The degree of inhibition of the hERG channel activity of the test substance was calculated as %hERG activity.
  • %hERG activity magnitude of current after administration of test substance / magnitude of current before administration of test substance * 100
  • the AUC inf value was 413.39 ng*h/mL, and the average retention time (MRT) obtained therefrom was 0.54 hours, and the half-life (t 1/2 ) was calculated as 0.91 h.
  • MRT average retention time
  • t 1/2 half-life
  • the AUC inf value was 1077.84 ng*h/mL
  • the average retention time (MRT) obtained therefrom was 3.35 hours
  • the half-life (t 1/2 ) was calculated as 3.44 hours.
  • the maximum blood concentration (C max ) in the body is 541.29 ng/mL at 0.08 hours (T max ; time of maximum plasma concentration).
  • T max time of maximum plasma concentration
  • mice 6- to 7-week-old BALB/C nude mice were xenotransplanted with AsPC-1 having a KRAS mutation, and were used as an animal model.
  • As a control drug BI-3406 known as an SOS1 inhibitor was used.
  • the drug was orally administered at a dose of 20 mpk and 40 mpk (mg/kg) once a day.
  • Compound No. 40 of the present invention has a tumor volume and mass reduction effect in an animal model transplanted with AsPC-1 cell line, that is, It was found that the anticancer effect was excellent.
  • the derivative compound according to the present invention has excellent ability to inhibit proliferation of various cancer cells and tumor growth inhibitory effect in cancer-induced animal models, that is, excellent anti-cancer efficacy.
  • the derivative compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal cell growth, that is, tumor or cancer diseases.

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Abstract

La présente invention concerne un inhibiteur de SOS1 et un dérivé de celui-ci. L'invention concerne un composé ou un sel, hydrate, solvate, tautomère, énantiomère ou diastéréoisomère pharmaceutiquement acceptable de celui-ci qui a une excellente capacité à inhiber l'activité SOS1, et peut ainsi être utilisé de manière avantageuse en tant qu'agent pour prévenir, soulager ou traiter une maladie provoquée par une croissance cellulaire anormale, la maladie à croissance cellulaire anormale pouvant comprendre divers types de maladies tumorales choisies parmi le cancer gastrique, le cancer du poumon, le cancer du foie, le cancer colorectal, le cancer de l'intestin grêle, le cancer du pancréas, le cancer du cerveau, le cancer des os, le mélanome, le cancer du sein, l'adénose sclérosante, le cancer de l'utérus, le cancer du col de l'utérus, le cancer de la tête et du cou, le cancer de l'œsophage, le cancer de la thyroïde, le cancer de la parathyroïde, le cancer du rein, le sarcome, le cancer de la prostate, le cancer de l'urètre, le cancer de la vessie, la leucémie (leucémie myéloïde aiguë), le myélome multiple, les hémopathies malignes telles que le syndrome myélodysplasique, les lymphomes tels que la maladie de Hodgkin et le lymphome non hodgkinien ou les fibroadénomes.
PCT/KR2023/001685 2022-02-10 2023-02-07 Inhibiteur de sos1 et dérivé de celui-ci WO2023153748A1 (fr)

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