CN112851663B - Parallel heterocyclic compound and application thereof - Google Patents

Parallel heterocyclic compound and application thereof Download PDF

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CN112851663B
CN112851663B CN201911098350.5A CN201911098350A CN112851663B CN 112851663 B CN112851663 B CN 112851663B CN 201911098350 A CN201911098350 A CN 201911098350A CN 112851663 B CN112851663 B CN 112851663B
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cancer
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medicament
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CN112851663A (en
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方华祥
张晓林
刘呈祥
陶进峰
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Brightgene Bio Medical Technology Co Ltd
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    • 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

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Abstract

The invention relates to a heterocyclic compound and application thereof. The compound is a compound shown in a 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, wherein R is 1 ～R 2 And A, E, L and K groups are as defined in the specification. The compound provided by the invention can be used for preparing medicines for treating and/or preventing cancers.

Description

Parallel heterocyclic compound and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a parallel heterocyclic compound and application thereof.
Background
In the field of cancer research, KRAS is one of the most well known oncogenes, which is frequently mutated in human tumors, accounting for about one third of all human malignant tumor mutations. The RAS family includes HRAS, NRAS, and KRAS. KRAS is a major subtype of the RAS protein family, with mutations accounting for 86% of all RAS protein mutations, and is frequently found in pancreatic, colorectal and lung cancers. 15 to 30 percent of patients in non-small cell lung cancer (NSCLC) have KRAS gene mutation, wherein lung adenocarcinoma accounts for 30 to 50 percent 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 have KRAS gene mutations. KRAS signaling pathway is an important antitumor pathway, targeting KRAS signaling is becoming an important area of anti-tumor drug discovery. However, due to the lack of good small molecule binding cavities on the surface of KRAS protein, the research and development of small molecule inhibitors based on KRAS is one of the difficulties in the field of medicine, and no KRAS inhibitor drugs are marketed worldwide at present, so that the research and development of new KRAS small molecule inhibitors has great 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 problems through the following technical proposal.
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:
wherein,,
the A is selected from the group consisting of optionally 0 to 3R 3 Substituted C 5 -C 8 Mono-heterocycloalkyl, optionally substituted with 0 to 3R 3 Substituted C 6 -C 12 Bridged heterocycloalkyl, or optionally substituted with 0 to 3R 3 Substituted C 6 -C 12 Spiroheterocycloalkyl, when substituted with a plurality of R 3 R is R when substituted 3 May be the same or different
The L is independently selected from single bond, - (CH) 2 ) n -、-O(CH 2 ) n -、-N(R 4 ) n -, c=o or C (O) C (R 4 ) n -, wherein n is independently selected from 0 to 3, when plural R's are used 4 R is R when substituted 4 May be the same or different;
the K is independently selected from hydrogen, -N (R) 3 ) 2 、-C(O)-N(R 3 ) 2 、-OR 3 、C 3 -C 8 Cycloalkyl, C 3 -C 12 Heterocycloalkyl, C 6 -C 12 Aryl, or C 5 -C 13 Heteroaryl, said C 3 -C 8 Cycloalkyl, C 3 -C 12 Heterocycloalkyl, C 6 -C 12 Aryl or C 5 -C 13 Heteroaryl is optionally substituted with one or more R 3 Substituted by a plurality of R 3 R is R when substituted 3 May be the same or different;
the R is 1 Independently selected from hydrogen, -N (R) 3 ) 2 、-C(O)-N(R 3 ) 2 、-OR 3 、C 3 -C 8 Cycloalkyl, C 3 -C 12 Heterocycloalkyl, C 6 -C 12 Aryl, or C 5 -C 13 Heteroaryl, said C 3 -C 8 Cycloalkyl, C 3 -C 12 Heterocycloalkyl, C 6 -C 12 Aryl or C 5 -C 13 Heteroaryl is optionally substituted with one or more R 3 Substituted by a plurality of R 3 R is R when substituted 3 May be the same or different;
the R is 2 Selected from H, halogen, cyano, hydroxy, amino, optionally substituted with 0 to 3R 3 Substituted C 1 -C 8 Alkyl, optionally substituted with 0 to 3R 3 Substituted C 1 -C 8 Heteroalkyl, optionally substituted with 0 to 3R 3 Substituted C 1 -C 8 Alkoxy, optionally substituted with 0 to 3R 3 Substituted C 1 -C 3 Haloalkoxy, optionally substituted with 0 to 3R 3 Substituted C 3 -C 8 Cycloalkyl, optionally substituted with 0 to 3R 3 Substituted C 3 -C 12 Heterocycloalkyl, optionally substituted with 0 to 3R 3 Substituted C 2 -C 4 Alkenyl or optionally substituted with 0 to 3R 3 Substituted C 2 -C 4 Alkynyl, when substituted by a plurality of R 3 R is R when substituted 3 May be the same or different;
the E is independentlyOr->Wherein R is a Independently hydrogen or C 1- C 3 An alkyl group; r is R b Independently hydrogen, C 1- C 3 Alkyl, alkylaminoalkyl, dialkylaminoalkyl or heterocyclylalkyl; m is 0 or 1; p is 1 or 2; when->In the case of triple bond, m is equal to 0 and P is equal to 1; when->In the case of double bonds, m is equal to 1 and P is equal to 2, when it is substituted by a plurality of R a Or R is b R is R when substituted a Or R is b May be the same or different;
"hetero" means a heteroatom or a heteroatom group, where the "hetero" groups of the above-mentioned heteroalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, heteroaryl groups are each independently selected from the group consisting of-C (=O) N (R) 4 )-、-N(R 4 )-、-NH-、N、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2 -and-N (R) 4 )C(＝O)N(R 4 )-；
In either case, the number of heteroatoms or groups of heteroatoms are each independently selected from 1,2 and 3.
In some embodiments of the invention, A is optionally substituted with 0 to 7R 3 Substituted
More preferably +.>
The other variables are as defined herein.
In some embodiments of the invention, the K is optionally substituted with 0 to 7R 3 Substituted H, CN, methoxy, ethyl, isopropyl,
The other variables are as defined herein.
In some embodiments of the invention, the L is independently selected from a single bond, - (CH) 2 ) n -、-O(CH 2 ) n -、-N(R 4 ) n -, c=o or C (O) C (R 4 ) n -, more preferably-O-, OCH 2 -or-NH-, the other variables being as defined herein;
in some aspects of the invention, the R 1 Is optionally substituted with 0 to 7R 3 SubstitutedBase, & gt>A base group,Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>A base group,Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>A base group,Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>A base group,Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>A base group,Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>Base, & gt>A base group,Base, & gt>Base, & gt>Base, & gt>Base, & gt>Methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, cyclopentenyl, cyclohexenyl, and other variables are as defined herein.
In some aspects of the invention, the R 2 Is selected from H, F, cl, br, I, CN, OH, NH 2 ，CONH 2 、CH 3 、CH 3 CH 2 、(CH 3 ) 2 CH. Cyclopropyl, methoxy, ethoxy, isopropoxy, CF 3 、CHF 2 、CH 2 CHF 2 ，CH 2 CH 2 F. Cyclopentyl, cyclohexyl, morpholinyl, vinyl, ethynyl, more preferably H, F, cl, CN, CH 3 Methoxy, CF 3 Or CHF 2 The other variables are as defined herein.
In some embodiments of the invention, the E is independently selected fromWherein R is a H, F, CH3, R b Is H, CH3, CH 2 F、CHF2、/> More preferably-> For other variables as defined herein.
In some aspects of the invention, the R 3 Independently selected from hydrogen, halogen, hydroxy, amino, cyano, and C 1 -C 8 Alkyl, C 2 -C 8 Heteroalkyl, C 5 -C 6 Cycloalkyl, C 4 -C 6 Heterocycloalkyl and C 5 -C 6 Heteroaryl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, -OR 9 、-SR 9 、-C(O)OR 9 、-C(O)N(R 9 ) 2 、-N(R 9 ) 2 Wherein C 1 -C 8 Alkyl, C 2 -C 8 Heteroalkyl, C 5 -C 6 Cycloalkyl, C 4 -C 6 Heterocycloalkyl and C 5 -C 6 Heteroaryl, C 2 -C 4 Alkenyl and C 2 -C 4 Alkynyl is optionally substituted with one OR more cyano, hydroxy, halogen, -OR 4 Heteroaryl or R 4 Instead, the other variables are as defined herein.
In some aspects of the invention, the R 4 Independently selected from hydrogen, chlorine, fluorine, amino, hydrogen, hydroxy, C 1 -C 8 Alkyl, C 2 -C 8 Heteroalkyl, C 5 -C 6 Cycloalkyl, C 4 -C 6 Heterocycloalkyl and C 5 -C 6 Heteroaryl, said C 1 -C 8 Alkyl, C 2 -C 8 Heteroalkyl, C 5 -C 6 Cycloalkyl, C 4 -C 6 Heterocycloalkyl and C 5 -C 6 Heteroaryl is selected from optionally substituted with 1,2 or 3R. Wherein R is selected from hydrogen, chlorine, fluorine, amino, hydrogen, hydroxy, methyl, ethylPropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CH 2 OH、-OCH 2 CH 3 、-OCH 2 CHF 2 N (CH 3) 2, NH (CH 3) or-OCH 2 CF 3 The other variables are as defined herein.
In some embodiments of the invention, the compound described above, 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
Wherein R is 1 、R 2 、R 3 、R a 、R b And K is as defined above for the present invention.
Thus, throughout this specification, one skilled in the art will be able to apply R to compounds of formula I, formula II or formula III 1 ～R 4 And A, L, K and substituents thereof are selected to provide a stable compound of formula I, formula II or formula 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, as described in the examples of the invention.
In some embodiments of the invention, the compound described above, 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
/>
In the present invention, the groups described in formula I, formula II or formula III and substituents thereof may be selected by those skilled in the art to provide stable compounds of 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 of the reaction steps described in the present invention is not particularly limited, and any solvent which dissolves the starting materials to some extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by 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 can be those excipients 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 means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. 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 excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill 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, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (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, ointments, 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 formulations which may 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; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The compounds of the present invention are preferably administered orally. Intravenous administration of the compounds of the present invention is also preferred. Other routes of administration may be applied or even preferred, depending on the circumstances. For example, transdermal administration may be highly desirable for patients who are forgetful or are irritated with oral medications. In particular cases, the compounds of the invention may also be administered by the transdermal, intramuscular, intranasal or intrarectal route. The route of administration may vary in any manner, limited by the physical nature of the drug, the convenience of the patient and caretaker, and other relevant circumstances.
According to a third aspect of the present invention there is provided the use 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) or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of a disease caused by a 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, there is provided the use 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) or a pharmaceutical composition thereof, in the manufacture of a KRAS G12C inhibitor medicament. The compound provided by the invention has good KRAS G12C inhibition activity, can be effectively used as a KRAS G12C inhibitor and can be used as a therapeutic drug of the KRAS G12C inhibitor.
According to a fifth aspect of the present invention there is provided the use 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, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of cancer, wherein the use of a compound of the present invention may be used in the treatment and/or prophylaxis of cancer, wherein the cancers that may be used in the treatment and/or prophylaxis include, but are not limited to, pancreatic cancer, colorectal cancer, lung cancer.
Terminology and definitions
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, which may be, for example, 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. "alkyl" herein 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 various branched isomers thereof, and the like. Non-limiting examples also include methylene, ethylene, propylene, butylene, and various branched isomers thereof. The alkyl group 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 cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. The cyclic group may be optionally substituted or unsubstituted.
"Heterocyclyl" refers to 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 of the ring atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is 0, 1, or 2) but notcomprising-O-O-, a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. Preferably 3 to 12 ring atoms, of which 1-4 are heteroatoms, more preferably the heterocycloalkyl ring contains 3 to 10 ring atoms, most preferably 5-or 6-membered rings, 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 heterocyclyl groups include spiro, fused, or bridged heterocyclic groups.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds within the ring, but no ring having a completely common electron, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) P (wherein p is selected from the group consisting of 0, 1, and 2), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and is preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group. More preferably 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 single spiro heterocyclyl. Wherein "a-membered/b-membered Shan Luo heterocyclyl" refers to a spiroheterocyclyl in which the a-membered monocyclic 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" means 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 of the rings may contain one or more double bonds, but none of the rings has a completely shared pi electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or sulfur heteroatoms and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclyl" 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 halogen atoms, which may be the same or different, examples of preferred alkyl or alkoxy groups include, but are not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxy.
"aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains rings of 3 to 7 atoms and has one or more points of attachment to the remainder 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, sulfur, wherein each ring system contains a ring of 5 to 7 atoms and has one or more points of attachment to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, and quinolinyl. 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. For example: by "optionally alkyl-substituted heterocyclic group" is meant that an alkyl group may be, but is not required to be, present, and this description includes both cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the invention prepared from the compounds of the invention which have been found to have a particular substituent with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure 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 the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure 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 organic acid salts including 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, and methanesulfonic acid; also included are salts of amino acids such as arginine and the like, 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 basic and acidic functionalities that can be converted to either base or acid addition salts. Preferably, the salt is contacted with a base or acid in a conventional manner to isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
"pharmaceutical composition" means a mixture containing one or more compounds of formula I described herein, 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 other chemical components, as well as other components such as pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The invention synthesizes a series of new compounds, and the activity test of related enzymes and cells shows that the compounds of the invention have excellent cell activity and IC for cell proliferation in vitro 50 The values reached nM. Can be well applied to various tumors. The compound shown in the formula I has very good inhibition effect on the NCI-H358 of the KRAS G12C mutant human non-small cell lung cancer cell. The compound provided by the invention can be used as a medicament for preparing a KRAS G12C inhibitor, is used for preventing and/or treating KRAS G12C mutation diseases, and is used for preparing a medicament for treating and/or preventing cancers, wherein the cancers 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 in a formula I, or pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite or prodrug thereof; compositions comprising the compounds are also provided. The compound or the pharmaceutical composition has the application in preparing medicines for treating diseases caused by KRAS G12C mutation, KRAS G12C inhibitor medicines or medicines for treating and/or preventing cancers, and specific effects are shown in specific examples.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. 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 compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, may be accomplished by the exemplary methods described in the following examples and related published literature procedures used by those skilled in the art, but these examples are not limiting the scope of the invention.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was performed using Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instruments with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDC 1) 3 ) Deuterated methanol (CD) 3 OD) internal standard Tetramethylsilane (TMS) chemical shift was 10 -6 (ppm) is given as a unit.
MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: agilent, model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (manufacturer: shimadzu, model: 2020).
HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunforc C18, 150X4.6mm,5wn, column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18, 150X4.6mm,5ym column).
The thin layer chromatography silica gel plate uses Qingdao ocean 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-0.5mm silica gel plate.
Column chromatography generally uses 200-300 mesh silica gel of Qingdao ocean as carrier.
The known starting materials of the present invention can be synthesized using or according to methods known in the art, from Shaoguan chemical technology (Accela ChemBio Inc), beijing coupling chemicals, and the like.
In the examples, unless otherwise specified, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume. The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 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 agents of a: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate systems, and the volume ratio of the solvent is adjusted according to the polarity of the compounds.
The system of eluent for column chromatography and the system of developing agent for thin layer chromatography used for purifying the compound include a: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of triethylamine, acidic or alkaline reagent and the like can be added for regulation.
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. 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 set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The following synthetic schemes describe the steps for preparing the disclosed compounds. Unless otherwise indicated, each substituent has the definition as described herein.
Scheme a:
in scheme A above, compound 1A is reacted with oxalyl chloride to give compound 1B. The compound 1B and S-methyl isothiourea sulfate are used for obtaining a compound 1C under the condition of taking sodium hydroxide as a base. And (3) taking cesium carbonate as a base in a DMF solution of the compound 1C, heating for more than 90 degrees, closing a ring in a molecule to obtain a compound 1D, refluxing the compound 1D by phosphorus oxychloride to obtain a compound 1E, carrying out substitution reaction on the compound 1E and piperazine derivatives to obtain a compound 1F, carrying out suzuki reaction or substitution reaction on the obtained compound 1F to obtain a compound 1G, oxidizing the compound 1G by m-chloroperoxybenzoic acid to obtain a 1H, carrying out substitution reaction on the 1H to obtain a 1I, removing Boc from the 1I under the TFA condition to obtain a 1J, and carrying out appropriate acryloyl chloride reaction to obtain the compound of the formula 1K.
Example 1: preparation of Compounds of formula I-1
The synthetic route is as follows:
the preparation method comprises the following steps:
the first step: synthesis of Compound I-1B
Raw material 1-1A (42 g,200 mmol) was dissolved in DCM (300 mL), then a few drops of DMF was added, cooled to 0 to 5℃and oxalyl chloride (30.5 g,240 mmol) was slowly added dropwise at this temperature, then stirred at room temperature for 3 hours.
And a second step of: synthesis of Compound I-1C
Sodium hydroxide (18.5 g,463 mmol) was dissolved in water (400 mL), then cooled to 0 ℃, S-methylisothiourea sulfate hydrogen (51.5 g,185 mmol) was slowly added in portions, the mixture was stirred for 30 minutes at 0 ℃ after the addition was completed, then compound 1-1B (22.8 g,100 mmol) obtained in the previous step was dissolved in diethyl ether (100 mL), and this solution was slowly added dropwise to the reaction mixture at 0-5 ℃, after the addition was completed, the reaction was slowly warmed to room temperature for 1 hour, after TLC showed the reaction was completed, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 ml×2), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spun dry to obtain compound 1-1C (23.7 g, pale yellow solid), yield: 84%.
MS m/z(ESI):282[M+1].
And a third step of: synthesis of Compound I-1D
Compound 1-1C (14.1 g,50 mmol) was dissolved in DMF (100 ml) and cesium carbonate (24.4 g,75 mmol) was added, after which the mixture was warmed to 90℃and stirred for 12 hours. After completion of TLC, the reaction mixture was cooled to room temperature, then poured into ice water, pH was adjusted to 3-4 with 3N hydrochloric acid, a large amount of solid was precipitated, filtered, washed with water and dried to give Compound 1-1D (9.5 g, yellow solid) in 77.2% yield.
MS m/z(ESI):246[M+1].
Fourth step: synthesis of Compounds I-1E
Compounds 1-1D (12.3, 50 mmol) were added to phosphorus oxychloride (120 ml) and after addition the mixture was warmed to reflux and reacted overnight. After TLC showed that the reaction was completed, the reaction solution was concentrated in vacuo, the resulting residue was dissolved with methylene chloride (300 ml), then washed with saturated sodium bicarbonate (250 ml), saturated sodium chloride (250 ml) and water (150 ml), respectively, the organic phase was separated, the anhydrous sodium sulfate was washed clean, 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 (9.9 g, pale yellow solid), yield: 81%.
MS m/z(ESI):264[M+1].
Fifth step: synthesis of Compound I-1F
Compound I-1E (9 g,34.4 mmol) was added to acetonitrile (100 ml) at room temperature, followed by (S) -4-N-t-butoxycarbonyl-2-methylpiperazine (9.6 g,52 mmol) and DIEA (6.7 g,52 mmol), then the reaction was refluxed for 3 hours, TLC showed the reaction was completed, the reaction solution was concentrated under vacuum, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1 (V: V volume ratio)) to give compound I-1F (9 g, pale yellow solid), yield: 63.3%.
MS m/z(ESI):428[M+1].
Sixth step: synthesis of Compound I-1G
Compound 1G (4.14G, 10 mmol) was added to dioxane (40 mL) and water (10 mL) at room temperature, followed by potassium phosphate (4.2G, 20 mmol), compound 2-fluoro-6-methoxyphenylboronic acid (2.5G, 15 mmol) and Pd (dppf) 2Cl2 dichloromethane complex (816 mg,1 mmol), and the reaction was allowed to react under nitrogen at 100deg.C for 12 hours, and TLC showed the end of the reaction. Saturated sodium bicarbonate (50 mL) was added, and extracted with dichloromethane (2×20 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, desolventized under reduced pressure, and the residue 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%.
MS m/z(ESI):518[M+1].
Seventh step: synthesis of Compound I-1H
Compound I-1G (2.5G, 5 mmol) was added to DCM (50 ml), m-chloroperoxybenzoic acid (2.6G, 15 mmol) was added after stirring to dissolve, the resulting mixture continued to react overnight at room temperature, TLC showed the end of the reaction, saturated sodium sulfite solution (200 ml) was added, stirring for half an hour, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 ml x 3), the organic phases were combined, the organic phase was washed successively with saturated sodium bicarbonate (50 ml), saturated sodium chloride (50 ml) and water (50 ml), the organic phase was separated, the anhydrous sodium sulfate was purified, and concentrated, the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1 (V: V volume ratio)), to give compound I-1H (2.5G, pale yellow solid), yield: 93%.
MS m/z(ESI):550[M+1].
Eighth step: synthesis of Compound I-1I
Compound I-1G (1.4G, 2.5 mmol) and 5-hydroxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (1.2G, 7.5 mmol) were added to DMF (30 ml) at room temperature, cesium carbonate (2.4, 7.5 mmol) was then added, the mixture was warmed to 90℃after completion of the addition and stirred for 12 hours. After TLC showed completion, the reaction mixture was cooled to room temperature, the reaction solution was poured into water (150 ml), the aqueous phase was extracted with ethyl acetate (50 ml×3), the organic phases were combined, the organic phase was washed successively with saturated sodium bicarbonate (50 ml), saturated sodium chloride (50 ml) and water (50 ml), the organic phase was separated, the anhydrous sodium sulfate was cleaned, concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1 (V: V volume ratio)), to give compound I-1I (1.1 g, pale yellow solid), yield: 67%.
MS m/z(ESI):634[M+1].
Ninth step: synthesis of Compound I-1J
Compound I-1H (619 mg,1 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, then ethyl acetate hydrochloride solution (4N, 5 mL) was added and the mixture was stirred at room temperature for 2 hours. The solution turned from clear to cloudy and a solid precipitated. TLC monitoring reaction, after the reaction, the reaction liquid is cooled to 0 ℃, kept stand for 1 hour, filtered, and the solid is washed by diethyl ether and dried to obtain hydrochloride (516 mg, white solid) of the compound I-1J, yield: 93%.
MS m/z(ESI):534[M+1].
Tenth step: synthesis of Compound I-1
The hydrochloride salt of compound I-1I (516 mg,0.93 mmol) obtained in the previous step was dissolved in methylene chloride (10 ml), then cooled to-10℃and triethylamine (200 mg,2 mmol) and acryloyl chloride (85 mg,0.93 mmol) were added in this order, and then naturally warmed to room temperature for 1 hour, after which TLC showed the end of the reaction. The reaction was quenched by the addition of MeOH (1 mL). The residue obtained by spin-drying the reaction mixture was separated and purified by preparative HPLC to give compound I-1K (150 mg, white solid). Yield: 24%.
MS m/z(ESI):588[M+1].
Eleventh step: synthesis of Compound I-1
Compound I-1K (150 mg,0.26 mmol) was dissolved in dichloromethane (10 ml), then cooled to-10deg.C, boron tribromide (130 mg,0.52 mmol) was slowly added, then allowed to react naturally to room temperature for 1 hour, after which TLC showed the end of the reaction. The reaction was quenched by the addition of MeOH (1 mL). The residue obtained by spin-drying the reaction mixture was purified by preparative TLC to give compound I-1 (35 mg, yellow solid). Yield: 24%.
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 were obtained with reference to the scheme of example 1
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Example 2: pharmacodynamic test
Activity measurement of the inventive compound on human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2 highly expressing KRAS G12C
The following methods were used to determine the effect of the compounds of the invention on tumor cell proliferation.
For KRAS G12C subtype, compound inhibition activity assay was performed using high expression KRAS G12C human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2, NCI-H358 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U penicillin and 100yg/mL streptomycin. Culturing at 37 degree 5% CO 2 The incubator. Cancer Cell Activity by employing CellThe kit (Luminescent Cell Viability Assay kit, methods of use see manufacturer's instructions) measures the amount of ATP to assess cell growth inhibition.
The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were prepared by first dissolving in DMSO to prepare stock solutions, and then performing gradient dilution with medium corresponding to the cells to prepare test samples, with the final concentration of the compounds ranging from 30uM to 0.01nM. Tumor cells in the logarithmic growth phase were seeded at appropriate density in 96-well cell culture plates at 37℃with 5% CO 2 After overnight incubation in the incubator, the cells were further cultured for 72 hours after the test compound sample was added. After the cultivation is completed, a suitable volume of Cell is added to each wellReagents 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. By and withComparing absorbance values of control group (0.3% DMSO) to calculate percentage inhibition rate of compound at each concentration point, and performing nonlinear regression analysis on the inhibition rate in GraphPad Prism 5 software according to the compound concentration logarithm, to obtain IC of compound for inhibiting cell proliferation 50 Values, experimental results are shown in table 2.
TABLE 2 IC for inhibiting human non-small cell lung cancer cells NCI-H358 and human pancreatic cancer cells Mia Paca-2 by the compounds of formula I of the present invention 50 Data
+ represents greater than 10 μm; the++ table is not less than 10. Mu.M, but greater than 1. Mu.M; ++ + watch book less than 1 mu M
As can be seen from Table 2, the compounds shown in the invention have very good inhibition effect on KRAS G12C mutated human non-small cell lung cancer cells NCI-H358 and human pancreatic cancer cells Mia Paca-2 cells, and the activity of part of the compounds is smaller than 1 mu M, so that the compounds can be used as medicaments for preparing KRAS G12C inhibitors.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. 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 foregoing embodiments all belong to the same inventive concept, and the descriptions of the embodiments have emphasis, and where the descriptions of the individual embodiments are not exhaustive, reference may be made to the descriptions of the other embodiments. The present invention is not limited to the preferred embodiments, but is intended to cover modifications, equivalent arrangements, improvements, etc. within the spirit and principles of the present invention.

Claims (7)

1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein,,
a is
L is a single bond;
k is
R 1 Is optionally substituted with 0 to 7R 3 SubstitutedA radical of the formula R 3 Independently halogen or hydroxy;
R 2 f, br or I;
e is
2. A compound as shown below, or a pharmaceutically acceptable salt or stereoisomer thereof:
3. a pharmaceutical composition comprising an effective amount of one or more of the compounds of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament, wherein the medicament is a medicament for the treatment of a disease caused by KRAS G12C mutation.
5. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament, wherein the medicament is a KRAS G12C inhibitor.
6. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament, wherein the medicament is a medicament for the treatment and/or prophylaxis of cancer.
7. The use of claim 6, wherein the cancer is selected from lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, cholangiocarcinoma, breast cancer, colon cancer, leukemia, and melanoma.
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