CN112851663A - Fused heterocyclic compound and application thereof - Google Patents

Fused heterocyclic compound and application thereof Download PDF

Info

Publication number
CN112851663A
CN112851663A CN201911098350.5A CN201911098350A CN112851663A CN 112851663 A CN112851663 A CN 112851663A CN 201911098350 A CN201911098350 A CN 201911098350A CN 112851663 A CN112851663 A CN 112851663A
Authority
CN
China
Prior art keywords
base
substituted
compound
optionally substituted
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201911098350.5A
Other languages
Chinese (zh)
Other versions
CN112851663B (en
Inventor
方华祥
张晓林
刘呈祥
陶进峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Borui Biomedical Suzhou Co ltd
Original Assignee
Borui Biomedical Suzhou Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Borui Biomedical Suzhou Co ltd filed Critical Borui Biomedical Suzhou Co ltd
Priority to CN201911098350.5A priority Critical patent/CN112851663B/en
Publication of CN112851663A publication Critical patent/CN112851663A/en
Application granted granted Critical
Publication of CN112851663B publication Critical patent/CN112851663B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a heterocyclic compound and application thereof. The compound is a compound shown as a formula I, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a hydrate, a solvate, a metabolite or a prodrug thereof, wherein R is1～R2And A, E, L and the K group are defined in the specification. The compound can be used for preparing a medicament for treating and/or preventing cancers.

Description

Fused heterocyclic compound and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a heterocyclic compound and application thereof.
Background
In the field of cancer research, KRAS is one of the most well-known oncogenes, and the oncogene RAS is mutated in human tumors, accounting for about one-third of all malignant mutations in humans. The RAS family includes HRAS, NRAS and KRAS. KRAS is the major subtype of the RAS protein family, with mutations accounting for 86% of all RAS protein mutations and prevalent in pancreatic, colorectal and lung cancers. KRAS gene mutation is existed in 15-30% of patients with non-small cell lung cancer (NSCLC), wherein lung adenocarcinoma accounts for 30-50% and is higher than EGFR, ALK and the like; the probability of KRAS gene mutation abnormality of colorectal cancer patients is 30-35%; in pancreatic cancer, more than 90% of patients present KRAS gene mutations. The KRAS signal pathway is an important anti-tumor pathway, and targeting KRAS signals is becoming an important field for discovering anti-tumor drugs. However, due to the lack of a good small molecule binding cavity on the surface of the KRAS protein, the research and development of KRAS-based small molecule inhibitors is one of the difficulties in the field of medicine, and currently, no KRAS inhibitor drugs are available on the market all over the world, so that the research and development of new KRAS small molecule inhibitors have huge clinical value and broad market prospect.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a compound with a novel structure, a pharmaceutical composition thereof and application thereof. The compound provided by the invention has KRAS G12C inhibitory activity, and provides a new commercial choice for KRAS G12C inhibitors.
The invention solves the technical problem through the following technical scheme.
According to a first aspect of the present invention, there is provided a compound comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof:
Figure BDA0002269062660000021
wherein,
a is selected from optionally substituted by 0-3R3Substituted C5-C8Mono-heterocycloalkyl optionally substituted with 0-3R3Substituted C6-C12Bridged heterocycloalkyl, or optionally substituted with 0-3R3Substituted C6-C12Spiroheterocycloalkyl when interrupted by multiple R3When substituted, R3May be the same or different
L is independently selected from the group consisting of a single bond, - (CH)2)n-、-O(CH2)n-、-N(R4)n-, C ═ O or C (O) C (R)4)n-, where n is independently selected from 0 to 3, when represented by a plurality of R4When substituted, R4May be the same or different;
said K is independently selected from hydrogen, -N (R)3)2、-C(O)-N(R3)2、-OR3、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R3Substituted when by more than one R3When substituted, R3May be the same or different;
the R is1Independently selected from hydrogen, -N (R)3)2、-C(O)-N(R3)2、-OR3、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R3Substituted when by more than one R3When substituted, R3May be the same or different;
the R is2Selected from H, halogen, cyano, hydroxy, amino, optionally substituted with 0-3R3Substituted byC1-C8Alkyl, optionally substituted with 0-3R3Substituted C1-C8Heteroalkyl, optionally with 0-3R3Substituted C1-C8Alkoxy, optionally substituted with 0-3R3Substituted C1-C3Haloalkoxy, optionally substituted with 0-3R3Substituted C3-C8Cycloalkyl optionally substituted by 0-3R3Substituted C3-C12Heterocycloalkyl optionally substituted with 0-3R3Substituted C2-C4Alkenyl or optionally substituted with 0-3R3Substituted C2-C4Alkynyl when interrupted by multiple R3When substituted, R3May be the same or different;
said E is independently
Figure BDA0002269062660000022
Or
Figure BDA0002269062660000023
Wherein R isaIndependently is hydrogen or C1-C3An alkyl group; rbIndependently of one another is hydrogen, C1-C3Alkyl, alkylaminoalkyl, dialkylaminoalkyl or heterocyclylalkyl groups; m is 0 or 1; p is 1 or 2; when in use
Figure BDA0002269062660000031
In the case of three bonds, m is equal to 0 and P is equal to 1; when in use
Figure BDA0002269062660000032
When it is a double bond, m is equal to 1 and P is equal to 2, when there are more than one RaOr RbWhen substituted, RaOr RbMay be the same or different;
"hetero" represents a heteroatom or group of heteroatoms, and the "hetero" of the above-mentioned mesoheteroalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, heteroaryl are each independently selected from-C (═ O) N (R)4)-、-N(R4)-、-NH-、N、 -O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-and-N (R)4)C(＝O)N(R4)-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2 and 3, respectively.
In some embodiments of the invention, A is optionally substituted with 0-7R3Substituted by
Figure BDA0002269062660000033
Figure BDA0002269062660000034
Figure BDA0002269062660000035
More preferably
Figure BDA0002269062660000036
Other variables are as defined herein.
In some embodiments of the invention, K is optionally substituted with 0-7R3Substituted H, CN, methoxy, ethyl, isopropyl,
Figure BDA0002269062660000037
Figure BDA0002269062660000041
Figure BDA0002269062660000042
And
Figure BDA0002269062660000051
other variables are as defined herein.
In some embodiments of the invention, L is independently selected from the group consisting of a single bond, - (CH)2)n-、-O(CH2)n-、 -N(R4)n-, C ═ O or C (O) C (R)4)n-, more preferably-O-, OCH2-or-NH-, other variables being as defined hereinThe definition of the invention;
in some embodiments of the invention, R is1Is optionally substituted by 0 to 7R3Substituted by
Figure BDA0002269062660000052
A base,
Figure BDA0002269062660000053
A base,
Figure BDA0002269062660000054
A base,
Figure BDA0002269062660000055
A base,
Figure BDA0002269062660000056
A base,
Figure BDA0002269062660000057
A base,
Figure BDA0002269062660000058
A base,
Figure BDA0002269062660000059
A base,
Figure BDA00022690626600000510
A base,
Figure BDA00022690626600000511
A base,
Figure BDA00022690626600000512
A base,
Figure BDA00022690626600000513
A base,
Figure BDA00022690626600000514
A base,
Figure BDA00022690626600000515
A base,
Figure BDA00022690626600000516
A base,
Figure BDA00022690626600000517
A base,
Figure BDA00022690626600000518
A base,
Figure BDA00022690626600000519
A base,
Figure BDA00022690626600000520
A base,
Figure BDA00022690626600000521
A base,
Figure BDA00022690626600000522
A base,
Figure BDA00022690626600000523
A base,
Figure BDA00022690626600000524
A base,
Figure BDA00022690626600000525
A base,
Figure BDA00022690626600000526
A base,
Figure BDA00022690626600000527
A base,
Figure BDA00022690626600000528
A base,
Figure BDA00022690626600000529
A base,
Figure BDA00022690626600000530
A base,
Figure BDA00022690626600000531
A base,
Figure BDA00022690626600000532
A base,
Figure BDA00022690626600000533
A base,
Figure BDA00022690626600000534
A base,
Figure BDA00022690626600000553
A base,
Figure BDA00022690626600000535
A base,
Figure BDA00022690626600000536
A base,
Figure BDA00022690626600000537
A base,
Figure BDA00022690626600000538
A base,
Figure BDA00022690626600000539
A base,
Figure BDA00022690626600000540
A base,
Figure BDA00022690626600000541
A base,
Figure BDA00022690626600000542
A base,
Figure BDA00022690626600000543
A base,
Figure BDA00022690626600000544
A base,
Figure BDA00022690626600000545
A base,
Figure BDA00022690626600000546
A base,
Figure BDA00022690626600000547
A base,
Figure BDA00022690626600000548
A base,
Figure BDA00022690626600000549
A base,
Figure BDA00022690626600000550
A base,
Figure BDA00022690626600000551
A base,
Figure BDA00022690626600000552
A base,
Figure BDA0002269062660000061
A base,
Figure BDA0002269062660000062
Methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, cyclopentenyl, cyclohexenyl, and other variables as defined herein.
In some embodiments of the invention, R is2Is selected from H, F, Cl, Br, I, CN, OH, NH2， CONH2、CH3、CH3CH2、(CH3)2CH. Cyclopropyl, methoxy, ethoxy, isopropoxy, CF3、 CHF2、CH2CHF2，CH2CH2F. Cyclopentyl, cyclohexyl, morpholinyl, vinyl, ethynyl, more preferably H, F, Cl, CN, CH3Methoxy, CF3Or CHF2Other variables are as defined herein.
In some embodiments of the invention, E is independently selected from
Figure BDA0002269062660000063
Wherein R isaIs H, F, CH3, RbIs H, CH3, CH2F、CHF2、
Figure BDA0002269062660000064
Figure BDA0002269062660000065
More preferably
Figure BDA0002269062660000066
Figure BDA0002269062660000067
For other variables as defined herein.
In some embodiments of the invention, R is3Independently selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl radical, C2-C4Alkynyl, -OR9、-SR9、-C(O)OR9、-C(O)N(R9)2、-N(R9)2In which C is1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl and C2-C4Alkynyl is optionally substituted by one OR more cyano, hydroxy, halogen, -OR4Heteroaryl or R4Instead, the other variables are as defined herein.
In some embodiments of the invention, R is4Independently selected from hydrogen, chlorine, fluorine, amino, hydrogen radical, hydroxyl, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl of said C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl radical 56-C6Heteroaryl is selected from optionally substituted with 1,2 or 3R. Wherein R is selected from the group consisting of hydrogen, chloro, fluoro, amino, hydro, hydroxy, methyl, ethyl, propyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CH2OH、-OCH2CH3、-OCH2CHF2N (CH3)2, NH (CH3) or-OCH2CF3The other variables are as defined herein.
In some embodiments of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, is selected from
Figure BDA0002269062660000071
Wherein R is1、R2、R3、Ra、RbAnd K is as defined above in the invention.
Thus, throughout this specification, the skilled person will be able to refer to R as described for compounds of formula I, formula II or formula III1～R4And A, L, K and substituents thereof are selected to provide stable compounds of formula I, formula II or formula III, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, and methods of the invention,Or a metabolite thereof, or a prodrug thereof.
In some embodiments of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, is selected from
Figure BDA0002269062660000081
Figure BDA0002269062660000091
Figure BDA0002269062660000101
Figure BDA0002269062660000111
Figure BDA0002269062660000121
Figure BDA0002269062660000131
In the present invention, a person skilled in the art can select the groups and substituents of the compounds represented by formula I, formula II or formula III to provide stable compounds represented by formula I, formula II or formula III, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, including but not limited to I-1 to I-148 described in the examples of the present invention.
The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. Further, many equivalent modifications, substitutions, or equivalents of the various solvents, solvent combinations, and ratios of solvent combinations described herein are intended to be included within the scope of the present invention.
According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, and at least one pharmaceutically acceptable excipient.
The pharmaceutically acceptable excipients may be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical adjuvant may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
Oral administration of the compounds of the invention is preferred. Intravenous administration of the compounds of the invention is also preferred. Depending on the circumstances, other routes of administration may be applied or even preferred. For example, transdermal administration may be highly desirable for patients who are forgetful or whose oral medications are irritable. In particular cases, the compounds of the invention may also be administered by transdermal, intramuscular, intranasal or intrarectal routes. The route of administration may vary in any manner, limited by the physical nature of the drug, the convenience of the patient and caregiver, and other relevant circumstances.
According to a third aspect of the present invention, the present invention provides a use of the compound (the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof) or a pharmaceutical composition thereof in preparing a medicament for treating diseases caused by KRAS G12C mutation. The compound provided by the invention can be used for treating and/or preventing one or more diseases related to KRAS G12C activity, and has good clinical application and medical application.
According to a fourth aspect of the present invention, the present invention provides a use of the compound (the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof) or a pharmaceutical composition thereof in preparation of a drug of a KRAS G12C inhibitor. The compound provided by the invention has good KRAS G12C inhibitory activity, can be effectively used as a KRAS G12C inhibitor and is used as a therapeutic drug of the KRAS G12C inhibitor.
According to a fifth aspect of the present invention, the present invention provides a use of the compound (the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof) or a pharmaceutical composition thereof in preparation of a medicament for treating and/or preventing cancer, where the compound according to the present invention can be used for treating and/or preventing cancer, and cancers which can be treated and/or prevented include, but are not limited to, pancreatic cancer, colorectal cancer, and lung cancer.
Terms and definitions
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group including straight and branched chain groups of 1 to 20 carbon atoms, such as straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In this context "alkyl" may be a monovalent, divalent or trivalent radical. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the various branched chain isomers thereof and the like. Non-limiting examples also include methylene, methine, ethylene, ethylidene, propylidene, butylidene, and various branched isomers thereof. Alkyl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, or 3 to 6 ring atoms, or may be a 3,4, 5, 6 membered ring. Non-limiting examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. The cyclic group may be optionally substituted or unsubstituted.
"Heterocycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O)m(wherein m is 0, 1, or 2) but does not include the ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably 3 to 12 ring atoms of which 1-4 are heteroatoms, more preferably a heterocycloalkyl ring comprising 3 to 10 ring atoms, most preferably a 5 or 6 membered ring of which 1-4 are heteroatoms, more preferably 1-3 are heteroatoms, most preferably 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused, or bridged heterocyclic groups.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share a common atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a completely shared electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)P(wherein p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. Spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group or a double spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic group. Wherein "a-membered/b-membered single spiroheterocyclyl" means an a-membered unitSpiro heterocyclic groups in which the ring and the b-membered monocyclic ring share one atom with each other. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: diazaspiro [3.3]Heptane.
"bridged heterocyclyl" refers to a 5 to 14-membered, or 5 to 18-membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a completely co-extensive pi-electron aromatic system in which one or more ring atoms are selected from heteroatoms of nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: diazabicyclo [3.1.1] heptane.
"haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms, and examples of preferred alkyl or alkoxy groups include, but are not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxy.
"aryl" means a monocyclic, bicyclic, and tricyclic carbon ring system containing 6 to 14 ring atoms in which at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6 to 10 or 6 to 7 ring atoms.
"heteroaryl" means monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl and quinolyl. Preferably, the heteroaryl group is a ring system of 5 to 10 ring atoms.
"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example: "heterocyclyl group optionally substituted with alkyl" means that alkyl may, but need not, be present, and this description includes the case where the heterocyclyl group is substituted with alkyl and the case where the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including similar acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; also included are Salts of amino acids (e.g., arginine, etc.), and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
"pharmaceutical composition" means a mixture containing one or more compounds of formula I, as described herein, or a pharmaceutically acceptable salt, or stereoisomer, or tautomer, or hydrate, or solvate, or metabolite, or prodrug thereof, in combination with other chemical components, as well as other components, such as pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The invention synthesizes a series of novel compounds, and related enzyme and cell activity tests show that the compounds have excellent cell activity and IC for cell proliferation in vitro50Values reached the nM range. Can be applied to various tumors. The compound shown in the formula I has a very good inhibition effect on KRAS G12C mutant human non-small cell lung cancer cell NCI-H358. The compound provided by the invention can be used as a medicine prepared into a KRAS G12C inhibitor, is used for preventing and/or treating KRAS G12C mutant diseases, and is used for preparing a medicine for treating and/or preventing cancers, wherein the cancers to be treated and/or prevented include but are not limited to pancreatic cancer, colorectal cancer and lung cancer.
Compared with the prior art, the invention has the following advantages and effects:
the invention provides a compound which comprises a compound shown as a formula I, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a hydrate, a solvate, a metabolite or a prodrug thereof; also provided are compositions comprising the compounds. The compound or the pharmaceutical composition has application in preparing medicines for treating diseases caused by KRAS G12C mutation, or preparing KRAS G12C inhibitor medicines, or preparing medicines for treating and/or preventing cancers, and specific effects are shown in specific examples.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.
The preparation of the compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, can be accomplished by the following exemplary methods and procedures of the related publications used by those skilled in the art, which, however, are not intended to limit the scope of the present invention.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDC 1)3) Deuterated methanol (CD)3OD) internal standard as Tetramethylsilane (TMS) chemical shift is 10-6(ppm) is given as a unit.
MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6110) or Shimadzu SQD (ESI) mass spectrometer (manufacturer: Shimadzu, model: 2020).
HPLC measurements were carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5wn, column) and a Waters 2695-.
The thin layer chromatography silica gel plate is Qingdao sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5 mm.
Column chromatography generally uses Qingdao ocean 200-mesh and 300-mesh silica gel as a carrier.
Known starting materials of the present invention can be synthesized using or following methods known in the art, companies such as Shaoyuan chemical technology (Accela ChemBio Inc), Beijing coupled chemicals, and the like.
In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L. The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction temperature was room temperature and the temperature range was 20 ℃ to 30 ℃ unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the petroleum ether and the ethyl acetate system is adjusted according to different polarities of the compounds, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.
The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, their combinations with other chemical synthetic methods to form embodiments, and equivalents known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the invention without departing from the spirit and scope of the invention. The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise indicated, each substituent has the definition as described herein.
Scheme A:
Figure BDA0002269062660000211
in scheme a above, compound 1A and oxalyl chloride are reacted to provide compound 1B. The compound 1B and S-methylisothiouronium sulfate are used for obtaining a compound 1C under the condition that sodium hydroxide is used as alkali. Heating cesium carbonate serving as base in a DMF solution for more than 90 ℃ to obtain a compound 1D through intramolecular ring closure, refluxing the compound 1D by phosphorus oxychloride to obtain a compound 1E, performing substitution reaction on the compound 1E and a piperazine derivative to obtain 1F, performing suzuki reaction or substitution reaction on the obtained 1F to obtain a compound 1G, oxidizing the compound 1G by m-chloroperoxybenzoic acid to obtain 1H, performing substitution reaction on the 1H to obtain 1I, and removing Boc from the 1I under the condition of TFA to obtain 1J, 1J and proper acryloyl chloride to obtain the compound shown in the formula 1K.
Example 1: preparation of Compound represented by formula I-1
Figure BDA0002269062660000221
The synthetic route is as follows:
Figure BDA0002269062660000231
the preparation method comprises the following steps:
the first step is as follows: synthesis of Compound I-1B
Starting material 1-1A (42g,200mmol) was dissolved in DCM (300mL) and several drops of DMF were added, cooled to 0 to 5 deg.C, at which point oxalyl chloride (30.5g,240 mmol) was slowly added dropwise and stirred at room temperature for 3 hours after TLC indicated the reaction was complete and was spin dried to give crude compound 1-1B (45.1g, light yellow liquid) in 100% yield and used in the next step without further purification.
The second step is that: synthesis of Compound I-1C
Dissolving sodium hydroxide (18.5g,463mmol) in water (400mL), cooling to 0 ℃, adding S-methylisothiourea hydrogen sulfate (51.5g,185mmol) slowly in batches, stirring the mixture at 0 ℃ for 30 minutes, dissolving compound 1-1B (22.8g,100mmol) obtained in the previous step in ethyl ether (100mL), dropwise adding the solution at 0-5 ℃ to the reaction mixture, reacting at room temperature for 1 hour after the completion of the addition, separating an organic layer after TLC shows that the reaction is completed, extracting the aqueous layer with ethyl acetate (100mL 2), combining the organic layers, washing the saturated sodium chloride solution, drying the organic layer with anhydrous sodium sulfate, and drying to obtain compound 1-1C (23.7g, light yellow solid), wherein the yield: 84 percent.
MS m/z(ESI):282[M+1].
The third step: synthesis of Compound I-1D
Compound 1-1C (14.1g, 50mmol) was dissolved in DMF (100ml) and cesium carbonate (24.4g,75mmol) was added, after which time the mixture was warmed to 90 degrees and stirred for 12 hours. After TLC indicated completion, the reaction mixture was cooled to room temperature, poured into ice water, adjusted to pH 3-4 with 3N hydrochloric acid, and a large amount of solid precipitated, filtered, washed with water, and dried to give compound 1-1D (9.5g, yellow solid) in 77.2% yield.
MS m/z(ESI):246[M+1].
The fourth step: synthesis of Compound I-1E
Compound 1-1D (12.3, 50mmol) was added to phosphorus oxychloride (120ml), and after addition was complete, the mixture was heated to reflux and reacted overnight. After TLC showed the reaction was complete, the reaction solution was concentrated in vacuo, the resulting residue was dissolved in dichloromethane (300ml), then washed with saturated sodium bicarbonate (250ml), saturated sodium chloride (250ml) and water (150ml), the organic phase was separated, anhydrous sodium sulfate was washed, and concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1(V: V volume ratio)) to give compound I-1E (9.9g, pale yellow solid) in yield: 81 percent.
MS m/z(ESI):264[M+1].
The fifth step: synthesis of Compound I-1F
Compound I-1E (9g,34.4mmol) was added to acetonitrile (100ml) at room temperature, followed by addition of (S) -4-N-tert-butoxycarbonyl-2-methylpiperazine (9.6g, 52mmol) and DIEA (6.7g,52mmol), followed by reflux reaction for 3 hours, TLC showed the reaction to be complete, the reaction solution was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1(V: V volume ratio)) to give compound I-1F (9g, pale yellow solid) in yield: and (3) 63.3%.
MS m/z(ESI):428[M+1].
And a sixth step: synthesis of Compound I-1G
Compound 1G (4.14G,10mmol) was added to dioxane (40mL) and water (10mL) at room temperature, potassium phosphate (4.2G,20mmol), the compound 2-fluoro-6-methoxyphenylboronic acid (2.5G,15mmol) and Pd (dppf)2Cl2 dichloromethane complex (816mg,1mmol) were added, and the reaction was allowed to react at 100 ℃ for 12 hours under nitrogen protection and TLC indicated the end of the reaction. Saturated sodium bicarbonate (50mL) was added and extracted with dichloromethane (2 × 20mL), the organic phases were combined and dried over anhydrous sodium sulfate, the drying agent was removed by filtration, desolventization under reduced pressure was performed, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1(V: V volume ratio)) to give compound I-1G (3.1G, pale yellow solid), yield: 61.3 percent.
MS m/z(ESI):518[M+1].
The seventh step: synthesis of Compound I-1H
Compound I-1G (2.5G,5mmol) was added to DCM (50ml) at room temperature, after dissolution with stirring m-chloroperoxybenzoic acid (2.6G,15mmol) was added, the resulting mixture was allowed to continue to react overnight at room temperature, TLC showed the end of the reaction, saturated sodium sulfite solution (200ml) was added, stirring was carried out for half an hour, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50ml x 3), the organic phases were combined, washed successively with saturated sodium bicarbonate (50ml), saturated sodium chloride (50ml) and water (50ml), the organic phase was separated, anhydrous sodium sulfate was washed clean and concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1(V: V vol.%) to give compound I-1H (2.5G, pale yellow solid) with yield: 93 percent.
MS m/z(ESI):550[M+1].
Eighth step: synthesis of Compound I-1I
Compound I-1G (1.4G,2.5mmol) and 5-hydroxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (1.2G, 7.5mmol) were added to DMF (30ml) at room temperature, followed by addition of cesium carbonate (2.4,7.5mmol), after which the mixture was warmed to 90 ℃ and stirred for 12 hours. After TLC showed completion, the reaction mixture was cooled to room temperature, the reaction mixture was poured into water (150ml), the aqueous phase was extracted with ethyl acetate (50ml × 3), after combining the organic phases, the organic phase was washed successively with saturated sodium bicarbonate (50ml), saturated sodium chloride (50ml) and water (50ml), the organic phase was separated off, after being cleaned with anhydrous sodium sulfate, concentrated, and the residue obtained was purified by silica gel column chromatography (dichloromethane/methanol: 50/1(V: V vol.)) to give compound I-1I (1.1g, pale yellow solid) with yield: 67%.
MS m/z(ESI):634[M+1].
The ninth step: synthesis of Compound I-1J
Compound I-1H (619mg,1mmol) was dissolved in ethyl acetate (5mL) at room temperature, then a solution of ethyl acetate hydrochloride (4N, 5mL) was added and the mixture was stirred at room temperature for 2 hours. The solution turned from clear to turbid and a solid precipitated out. The reaction was monitored by TLC, after completion of the reaction, the reaction solution was cooled to 0 ℃, left to stand for 1 hour, filtered, and the solid was washed with ether and dried to give the hydrochloride of compound I-1J (516mg, white solid) in yield: 93 percent.
MS m/z(ESI):534[M+1].
The tenth step: synthesis of Compound I-1
The hydrochloride of Compound I-1I obtained in the previous step (516mg,0.93mmol) was dissolved in dichloromethane (10ml), cooled to-10 ℃ and added with triethylamine (200mg,2mmol) and acryloyl chloride (85mg, 0.93mmol) in that order, allowed to naturally warm to room temperature for 1 hour, after which time TLC indicated the completion of the reaction. The reaction was quenched by addition of MeOH (1 mL). The resulting residue was isolated and purified by preparative HPLC to give Compound I-1K (150mg, white solid). Yield: 24 percent.
MS m/z(ESI):588[M+1].
The eleventh step: synthesis of Compound I-1
Compound I-1K (150mg,0.26mmol) was dissolved in dichloromethane (10ml), then cooled to-10 deg.C, boron tribromide (130mg,0.52mmol) was added slowly, then allowed to warm to room temperature naturally for 1 hour, after which time TLC indicated the end of the reaction. The reaction was quenched by addition of MeOH (1 mL). The resulting residue was isolated and purified by preparative TLC to give Compound I-1(35mg, yellow solid). Yield: 24 percent.
MS m/z(ESI):573[M+1].
HNMR:(400MHz,CD3OD)8.25-8.22(m,1H),7.36-7.24(m,2H),7.08-7.03 (m,2H),6.79-6.70(m,3H),6.29-6.25(m,1H),5.81-5.79(m,1H),4.68-4.67(m, 1H),4.24-4.21(m,2H),3.82-3.64(m,5H),3.30-3.25(m,1H),2.85-2.83(m,4H), 2.55(s,3H),1.30(d,J＝6.8MHz,3H).
TABLE 1-the following compounds are obtained by reference to the scheme of example 1
Figure BDA0002269062660000271
Figure BDA0002269062660000281
EXAMPLE 2 pharmacodynamic assay
Activity measurement of the compound of the invention on high-expression KRAS G12C human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2
The following methods were used to determine the effect of the compounds of the invention on tumor cell proliferation.
For KRAS G12C subtype, high-expression KRAS G12C human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2 were used for cancer cell activity inhibition assay, and NCI-H358 cells were cultured in DMEM medium containing 10% fetal calf serum, 100U penicillin and 100yg/mL streptomycin. Cultured at 37 ℃ in 5% CO2In the incubator. Cancer Cell Activity by Using Cell
Figure BDA0002269062660000282
The Cell growth inhibition was assessed by measuring the amount of ATP using a kit (luminecent Cell Viability Assay kit, methods of use see manufacturer's instructions).
The experimental method is operated according to the steps of the kit specification, and is briefly as follows: test samples were prepared by first dissolving test compounds in DMSO as stock solutions and then diluting the stock solutions in a gradient of the corresponding cell culture medium to give final concentrations of compounds in the range of 30uM to 0.01 nM. Tumor cells in logarithmic growth phase were seeded at appropriate density into 96-well cell culture plates at 37 ℃ in 5% CO2After overnight in the incubator, cells were incubated for a further 72 hours after addition of test compound samples. After incubation, the appropriate volume of Cell Titer-Glo ∘ R reagent was added to each well and incubated at 37 ℃ for 1-4 hours, followed by reading the absorbance values at 450nM for each well of the sample on a microplate reader. Percent inhibition of compound at each concentration point was calculated by comparison with absorbance values of control (0.3% DMSO), followed by non-linear regression analysis in GraphPad Prism 5 software at compound concentration log-inhibition to obtain IC of compound inhibition of cell proliferation50The values, experimental results are shown in table 2.
TABLE 2 IC inhibition of human non-small cell Lung cancer cells NCI-H358 and human pancreatic cancer cells Mia Paca-2 by Compounds of formula I of the invention50Data of
Figure BDA0002269062660000291
+ represents more than 10 μ M; the table of ++ is not less than 10 μ M and is greater than 1 μ M; the table of +++ is not less than 1 μ M
As can be seen from Table 2, the compound disclosed by the invention has a very good inhibition effect on KRAS G12C mutant human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2 cells, and the activity of part of the compound is less than 1 mu M, so that the compound can be used as a medicament for preparing KRAS G12C inhibitors.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
It should be noted that the above embodiments belong to the same inventive concept, and the description of each embodiment has a certain emphasis, and reference may be made to the description in other embodiments where the description in individual embodiments is not detailed. The invention is not to be considered as limited to the particular embodiments shown, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (12)

1. A fused heterocyclic compound, comprising a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof:
Figure FDA0002269062650000011
wherein,
a is selected from optionally substituted by 0-3R3Substituted C5-C8Mono-heterocycloalkyl optionally substituted with 0-3R3Substituted C6-C12Bridged heterocycloalkyl, or optionally substituted with 0-3R3Substituted C6-C12Spiroheterocycloalkyl, when substituted with multiple R3, R3 may be the same or different
L is independently selected from the group consisting of a single bond, - (CH)2)n-、-O(CH2)n-、-N(R4)n-, C ═ O or C (O) C (R)4)n-, whereinn is independently selected from 0 to 3, when R is more than one4When substituted, R4May be the same or different;
said K is independently selected from hydrogen, -N (R)3)2、-C(O)-N(R3)2、-OR3、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R3Substituted when by more than one R3When substituted, R3May be the same or different;
the R is1Independently selected from hydrogen, -N (R)3)2、-C(O)-N(R3)2、-OR3、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R3Substituted when by more than one R3When substituted, R3May be the same or different;
the R is2Selected from H, halogen, cyano, hydroxy, amino, optionally substituted with 0-3R3Substituted C1-C8Alkyl, optionally substituted with 0-3R3Substituted C1-C8Heteroalkyl, optionally with 0-3R3Substituted C1-C8Alkoxy, optionally substituted with 0-3R3Substituted C1-C3Haloalkoxy, optionally substituted with 0-3R3Substituted C3-C8Cycloalkyl optionally substituted by 0-3R3Substituted C3-C12Heterocycloalkyl optionally substituted with 0-3R3Substituted C2-C4Alkenyl or optionally substituted with 0-3R3Substituted C2-C4Alkynyl when being pluralR is3When substituted, R3May be the same or different;
said E is independently
Figure FDA0002269062650000023
Or
Figure FDA0002269062650000024
Wherein R isaIndependently is hydrogen or C1-C3An alkyl group; rbIndependently of one another is hydrogen, C1-C3Alkyl, alkylaminoalkyl, dialkylaminoalkyl or heterocyclylalkyl groups; m is 0 or 1; p is 1 or 2; when in use
Figure FDA0002269062650000025
In the case of three bonds, m is equal to 0 and P is equal to 1; when in use
Figure FDA0002269062650000026
When it is a double bond, m is equal to 1 and P is equal to 2, when there are more than one RaOr RbWhen substituted, RaOr RbMay be the same or different;
"hetero" represents a heteroatom or group of heteroatoms, the "hetero" of the above-mentioned mesoheteroalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, heteroaryl being independently selected from-C (═ O) N (R4) -, -N (R4) -, -NH-, N, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) 2-and-N (R4) C (═ O) N (R4) -;
in any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2 and 3, respectively.
2. The compound of claim 1, wherein the compound is selected from compounds of formulae II and III, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof;
Figure FDA0002269062650000021
3. the compound of any one of claims 1-2, wherein a is optionally substituted with 0-7R3Substituted by
Figure FDA0002269062650000022
Figure FDA0002269062650000031
4. The compound of any one of claims 1-2, wherein K is optionally substituted with 0-7R3Substituted H, CN, methoxy, ethyl, isopropyl,
Figure FDA0002269062650000032
Figure FDA0002269062650000033
Figure FDA0002269062650000041
5. The compound of any one of claims 1-2, wherein E is independently selected from
Figure FDA0002269062650000042
Wherein R isaIs H, F, CH3；RbIs H, CH3，CH2F、CHF2、
Figure FDA0002269062650000043
6. As claimed in any one of claims 1-2The compound of (1), wherein R is1Is optionally substituted by 0 to 7R3Substituted by
Figure FDA0002269062650000044
A base,
Figure FDA0002269062650000045
A base,
Figure FDA0002269062650000046
A base,
Figure FDA0002269062650000047
A base,
Figure FDA0002269062650000048
A base,
Figure FDA0002269062650000049
A base,
Figure FDA00022690626500000410
A base,
Figure FDA00022690626500000411
A base,
Figure FDA00022690626500000412
A base,
Figure FDA00022690626500000413
A base,
Figure FDA00022690626500000414
A base,
Figure FDA00022690626500000415
A base,
Figure FDA00022690626500000416
A base,
Figure FDA00022690626500000417
A base,
Figure FDA00022690626500000418
A base,
Figure FDA00022690626500000419
A base,
Figure FDA00022690626500000420
A base,
Figure FDA00022690626500000421
A base,
Figure FDA00022690626500000422
A base,
Figure FDA00022690626500000423
A base,
Figure FDA00022690626500000424
A base,
Figure FDA00022690626500000425
A base,
Figure FDA00022690626500000426
A base,
Figure FDA00022690626500000427
A base,
Figure FDA00022690626500000428
A base,
Figure FDA00022690626500000429
A base,
Figure FDA00022690626500000430
A base,
Figure FDA00022690626500000431
A base,
Figure FDA00022690626500000432
A base,
Figure FDA00022690626500000433
A base,
Figure FDA00022690626500000434
A base,
Figure FDA00022690626500000435
A base,
Figure FDA0002269062650000051
A base,
Figure FDA0002269062650000052
A base,
Figure FDA0002269062650000053
A base,
Figure FDA0002269062650000054
A base,
Figure FDA0002269062650000056
A base,
Figure FDA0002269062650000055
A base,
Figure FDA0002269062650000057
A base,
Figure FDA0002269062650000058
A base,
Figure FDA0002269062650000059
A base,
Figure FDA00022690626500000510
A base,
Figure FDA00022690626500000511
A base,
Figure FDA00022690626500000512
A base,
Figure FDA00022690626500000513
A base,
Figure FDA00022690626500000514
A base,
Figure FDA00022690626500000515
A base,
Figure FDA00022690626500000516
A base,
Figure FDA00022690626500000517
A base,
Figure FDA00022690626500000518
A base,
Figure FDA00022690626500000519
A base,
Figure FDA00022690626500000520
A base,
Figure FDA00022690626500000521
A base,
Figure FDA00022690626500000522
Methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, cyclopentenyl, cyclohexenyl.
7. A compound according to any one of claims 1 to 2, wherein R is2Is H, F, Cl, Br, I, CN, OH, NH2，CONH2，CH3、CH3CH2、(CH3)2CH. Cyclopropyl, methoxy, ethoxy, isopropoxy, CF3、CHF2、CH2CHF2，CH2CH2F. Cyclopentyl, cyclohexyl, morpholinyl, vinyl, ethynyl.
8. A compound according to any one of claims 1 to 2, wherein R is3Independently selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl radical, C2-C4Alkynyl, -OR4、-SR4、-C(O)OR4、-C(O)N(R4)2、-N(R4)2In which C is1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl and C2-C4Alkynyl is optionally substituted by one OR more cyano, hydroxy, halogen, -OR4Heteroaryl or R4And (4) substituting.
9. A compound according to any one of claims 1 to 2, wherein R is4Independently selected from hydrogen, chlorine, fluorineAmino, hydrogen, hydroxyl, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl of said C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl or C5-C6Heteroaryl is selected from optionally substituted with 1,2 or 3R; wherein R is selected from the group consisting of hydrogen, chloro, fluoro, amino, hydro, hydroxy, methyl, ethyl, propyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CH2OH、-OCH2CH3、-OCH2CHF2、N(CH3)2、NH(CH3) or-OCH2CF3。
10. A pharmaceutical composition comprising an effective amount of a compound of claims 1-8, comprising: one or more of a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt of said compound of formula I, formula II or formula III, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, as claimed in claims 1-9, and at least one pharmaceutically acceptable excipient.
11. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament comprising a medicament for the treatment of a disease caused by a mutation in KRAS G12C, or a KRAS G12C inhibitor medicament, or a medicament for the treatment and/or prevention of cancer.
12. The use of claim 11, wherein the cancer comprises lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.
CN201911098350.5A 2019-11-12 2019-11-12 Parallel heterocyclic compound and application thereof Active CN112851663B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911098350.5A CN112851663B (en) 2019-11-12 2019-11-12 Parallel heterocyclic compound and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911098350.5A CN112851663B (en) 2019-11-12 2019-11-12 Parallel heterocyclic compound and application thereof

Publications (2)

Publication Number Publication Date
CN112851663A true CN112851663A (en) 2021-05-28
CN112851663B CN112851663B (en) 2023-07-18

Family

ID=75984520

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911098350.5A Active CN112851663B (en) 2019-11-12 2019-11-12 Parallel heterocyclic compound and application thereof

Country Status (1)

Country Link
CN (1) CN112851663B (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112876471A (en) * 2020-01-07 2021-06-01 广州百霆医药科技有限公司 Pyridopyrimidine KRAS G12C mutant protein inhibitor
WO2022135470A1 (en) * 2020-12-22 2022-06-30 上海科州药物研发有限公司 Preparation and application method of heterocyclic compound as kras inhibitor
WO2022247760A1 (en) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment
WO2023077441A1 (en) * 2021-11-05 2023-05-11 Ranok Therapeutics (Hangzhou) Co. Ltd. Methods and compositions for targeted protein degradation
WO2024081674A1 (en) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Combination therapies for the treatment of cancer
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2025067459A2 (en) 2023-09-29 2025-04-03 D3 Bio (Wuxi) Co., Ltd. Therapies for the treatment of cancer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190233440A1 (en) * 2018-02-01 2019-08-01 Pfizer Inc. Substituted Quinazoline and Pyridopyrimidine Derivatives Useful as Anticancer Agents
CN110267957A (en) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 Quinazoline compounds
CN110256421A (en) * 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 KRAS-G12C inhibitors
WO2019213516A1 (en) * 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
CN113423703A (en) * 2019-05-29 2021-09-21 上海翰森生物医药科技有限公司 Nitrogen-containing heterocyclic derivative regulator, and preparation method and application thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110267957A (en) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 Quinazoline compounds
US20190233440A1 (en) * 2018-02-01 2019-08-01 Pfizer Inc. Substituted Quinazoline and Pyridopyrimidine Derivatives Useful as Anticancer Agents
TW201942115A (en) * 2018-02-01 2019-11-01 美商輝瑞股份有限公司 Substituted quinazoline and pyridopyrimidine derivatives useful as anticancer agents
WO2019213516A1 (en) * 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
CN113423703A (en) * 2019-05-29 2021-09-21 上海翰森生物医药科技有限公司 Nitrogen-containing heterocyclic derivative regulator, and preparation method and application thereof
CN110256421A (en) * 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 KRAS-G12C inhibitors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112876471A (en) * 2020-01-07 2021-06-01 广州百霆医药科技有限公司 Pyridopyrimidine KRAS G12C mutant protein inhibitor
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022135470A1 (en) * 2020-12-22 2022-06-30 上海科州药物研发有限公司 Preparation and application method of heterocyclic compound as kras inhibitor
WO2022247760A1 (en) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment
WO2023077441A1 (en) * 2021-11-05 2023-05-11 Ranok Therapeutics (Hangzhou) Co. Ltd. Methods and compositions for targeted protein degradation
WO2024081674A1 (en) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Combination therapies for the treatment of cancer
WO2025067459A2 (en) 2023-09-29 2025-04-03 D3 Bio (Wuxi) Co., Ltd. Therapies for the treatment of cancer

Also Published As

Publication number Publication date
CN112851663B (en) 2023-07-18

Similar Documents

Publication Publication Date Title
CN113024544B (en) Cyano-containing heterocyclic compound and application thereof
CN112300194B (en) Condensed ring pyridone compounds, preparation method and application
CN112745335A (en) Tri-heterocyclic compound and application thereof
CN114163457B (en) Pyrimido five-membered nitrogen heterocyclic compound and its use
CN111484477B (en) Benzopyridone heterocyclic compound and application thereof
CN112300173B (en) Nitrogen-containing polycyclic compounds, preparation method and application
CN112851663A (en) Fused heterocyclic compound and application thereof
CN113527299B (en) Nitrogen-containing condensed ring compound, preparation method and application
CN112707905A (en) Tri-heterocyclic compound and preparation method and application thereof
AU2020446002A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
CN116162099A (en) Heterocyclic derivative and preparation method and application thereof
CN112300153B (en) Heterocyclic compound, pharmaceutical composition and application
CN110092745B (en) Compound containing aromatic ring and application thereof
WO2022135432A1 (en) Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof
CN115028648B (en) Tri-fused ring compound and pharmaceutical composition and application thereof
CN116157401B (en) Heterocyclic derivatives and preparation methods and uses thereof
JP7041821B2 (en) Amino-substituted nitrogen-containing condensed ring compound, its preparation method and use
TW202527946A (en) Tricyclic compounds and their medical uses
CN115677730B (en) 8-Oxo-3-azabicyclo[3.2.1]octane compounds or their salts and preparation methods and uses thereof
CN114605390A (en) Compound with CDK kinase inhibitory activity, pharmaceutical composition and use thereof
WO2022063297A1 (en) Quinazoline derivative, preparation method therefor and use thereof
CN115160309A (en) KRAS G12C Preparation and application of mutant protein heterocyclic inhibitor
CN115433207A (en) Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof
CN113045569A (en) Compounds useful as RET kinase inhibitors and uses thereof
CN111247143B (en) Pyridoquinazoline derivatives useful as inhibitors of protein kinases

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant