CN112409337A - Substituted pyrazine derivative and application thereof - Google Patents

Substituted pyrazine derivative and application thereof Download PDF

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CN112409337A
CN112409337A CN202011514324.9A CN202011514324A CN112409337A CN 112409337 A CN112409337 A CN 112409337A CN 202011514324 A CN202011514324 A CN 202011514324A CN 112409337 A CN112409337 A CN 112409337A
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substituted
pyrazine derivative
represents hydrogen
phenyl
ethyl
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李寒
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention provides a substituted pyrazine derivative with a chemical structure shown in a formula 1, a pharmaceutical preparation containing the substituted pyrazine derivative, and application of the substituted pyrazine derivative in preparing RET kinase inhibitors,

Description

Substituted pyrazine derivative and application thereof
Technical Field
The invention relates to a pyrazine derivative, in particular to a cyclohexanone-substituted pyrazine derivative and application thereof as an RET inhibitor.
Background
The RET protein is a receptor tyrosine kinase RTK and is also a transmembrane glycoprotein, expressed by the proto-oncogene RET (rearranged reduced transduction) located on chromosome 10, plays an important role in the development of the renal and enteric nervous systems during the embryonic stage, and is also critical in various tissue homeostasis, such as neurons, neuroendocrine, hematopoietic tissues and male germ cells. Unlike other RTKs, RET does not bind directly to the ligand molecule: such as neurotropic hormone (artemin), glial cell line-derived neurotrophic factor (GDNF), neurturin and persephin, which are ligands belonging to the GNDF Family (GFLs). These ligand GFLs generally bind to GDNF family receptor alpha (GFR alpha), and the resulting GFLs-GFR alpha complex mediates the auto-dimerization of RET proteins, causing a trans autophosphorylation reaction of tyrosine on the intracellular domain, recruitment of related adaptor proteins, activation of a cascade of signaling such as cell proliferation, and related signaling pathways including MAPK, PI3K, JAK-STAT, PKA, PKC, and the like.
There are two major oncogenic activation mechanisms of RET: one is that chromosomal rearrangements produce new fusion proteins, usually a fusion of the kinase domain of RET and a protein comprising a self-dimerization domain; the second is that the RET mutation directly or indirectly activates the kinase activity of RET. These alterations at the somatic or germ cell level are involved in the pathogenesis of a variety of cancers. RET chromosomal rearrangements are present in 5% -10% of papillary thyroid carcinoma patients; while 60% of the myeloid thyroid medullary cancers have RET point mutations; among all NSCLC patients, there is probably 1-2% with RET fusion proteins, with KIF5B-RET being the most common.
In summary, aberrant RET expression or activation is found in a variety of tumors and gastrointestinal disorders such as irritable bowel syndrome. RET inhibitors are therefore of potential clinical value in neoplastic or bowel disorder diseases.
Disclosure of Invention
The invention provides a substituted pyrazine derivative with a novel structure and application thereof in RET inhibitors.
The technical scheme for solving the technical problems is as follows:
a substituted pyrazine derivative having the chemical structure according to formula i:
Figure RE-GDA0002886868270000021
wherein Q represents Q1、Q2Any one of:
Figure RE-GDA0002886868270000022
R1represents hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C3-C6 cycloalkyl, phenyl which is unsubstituted or substituted by 1,2, 3 or 4 halogens;
RXindependently of one another, hydrogen, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;
y represents hydrogen, halogen, hydroxyl, mercapto, cyano, amino, C1-C3 acyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylamino, aryl or heteroaryl which are unsubstituted or substituted by halogen;
and pharmaceutically acceptable salts, tautomers, geometric isomers and optically active forms thereof.
Preferred substituents for each variable in formula 1 of the present invention are as follows:
R1preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3、-CH2CHF2、 -CH2CHCl2、-CH2CCl3、-CCl3、-CBr3、-CH2CBr3、-CH2CHBr2Vinyl, propenyl, allyl, 1-methylprop-2-en-1-yl, but-2-en-1-yl, ethynyl, propynyl, phenyl or phenyl substituted with 1,2, 3 or 4 of F, Cl or Br.
R1More preferably hydrogen and methylAlkyl, ethyl, isopropyl, -CF3、-CH2CF3Vinyl, propenyl, allyl, phenyl or phenyl substituted with 1 or 2F, Cl or Br.
RXPreferably, independently of one another, represents hydrogen, -F, -Cl, -Br, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, -CF3、-CH2CF3、-CH2CHF2、-CH2CHCl2、-CH2CCl3、-CCl3、-CBr3、 -CH2CBr3、-CH2CHBr2、-O-CF3、-O-CH2CF3、-O-CH2CHF2、-O-CH2CHCl2、 -O-CH2CCl3、-O-CCl3、-O-CBr3、-O-CH2CBr3or-O-CH2CHBr2。
RXMore preferably, each independently of the others, represents hydrogen, -F, -Cl, -Br, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, -CF3or-CH2CF3。
Y preferably represents hydrogen, halogen, hydroxyl, mercapto, cyano, amino, formyl, acetyl, methyl, ethyl, isopropyl, n-propyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, methylamino, ethylamino, one of the following groups unsubstituted or substituted by 1,2 or 3 halogen atoms: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl.
Y more preferably represents hydrogen, halogen, hydroxy, mercapto, cyano, amino, formyl, acetyl, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, one of the following groups unsubstituted or substituted with 1,2 or 3 of F, Cl or Br: phenyl, naphthyl, pyridyl or pyrimidinyl.
In the definitions of the compounds of the above general formula and in all the formulae below, the term "combination" means that two or more substituents are linked in the stated order to give a combination of substituents, such as alkoxy, for example alkyl-O-, alkylthio for alkyl-S-, alkylsulfinyl for alkyl-S (O) -, alkylsulfonyl for alkyl-S (O)2-and so on;
the terms used above, whether used alone or in compound words, represent the following substituents:
alkyl groups: alkyl groups having more than two carbon atoms may be straight chain or branched. Cn-Cm alkyl represents an alkyl group having n to m carbon atoms, such as the alkyl group in the compound word "alkoxy, alkylthio, alkylamino, alkylsulfoxide, alkylsulfonyl, alkoxyalkyl, phenylalkyl" and the like may be-CH2-、 -CH2CH2-、-CH(CH3)-、-C(CH3)2-and the like. Alkyl groups are, for example, C1 alkyl-methyl; c2 alkyl-ethyl; c3 alkyl-propyl such as n-propyl or isopropyl;
similarly, alkenyl is, for example, vinyl, allyl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-3-en-1-yl, 1-methylbut-3-en-1-yl and 1-methylbut-2-en-1-yl.
Alkynyl is, for example, ethynyl, propargyl, but-2-yn-1-yl, but-3-yn-1-yl, 1-methylbut-3-yn-1-yl. Multiple bonds may be at any position per unsaturated group.
Cycloalkyl is a carbocyclic saturated ring system having, for example, three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Halogen is fluorine, chlorine, bromine or iodine.
Meanwhile, the substituent and the connecting site which are not marked with a specific connecting position in the group can be connected and substituted at any position on the ring which can be connected or substituted.
The substituted pyrazine derivative provided by the invention can be synthesized by the following route:
route one:
Figure RE-GDA0002886868270000051
and a second route:
Figure RE-GDA0002886868270000052
the term "pharmaceutically acceptable salt" refers to a salt or complex of a compound according to the invention. Examples of such salts include, but are not limited to, base addition salts formed by reacting the pyrazine derivatives of the invention with organic or inorganic bases such as hydroxides, carbonates or bicarbonates of metal cations selected from the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (e.g. calcium or magnesium). Also included are salts formed from acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) and organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid).
The present invention includes within its scope pharmaceutically acceptable salts, complexes, hydrates, solvates or polymorphs, tautomers, geometrical isomers, optically active forms and pharmaceutically active derivatives of the compounds of the invention. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially (substitially) pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the synthetic procedures used to prepare these compounds, or during the use of racemization or epimerization procedures well known to those skilled in the art, the products of these procedures can be mixtures of stereoisomers. Many organic compounds exist in optically active forms that have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center.
"pharmaceutically active derivative" as disclosed herein refers to any active compound that can be directly or indirectly provided for administration to a subject. The term "indirectly" also encompasses metabolic molecules of the compounds according to the invention.
The term "effective amount" includes "a prophylactically effective amount" as well as "a therapeutically effective amount".
In a specific embodiment, the present invention provides a pharmaceutical formulation comprising at least one pyrazine derivative of the invention, or pharmaceutically acceptable salts, tautomers, geometrical isomers and optically active forms thereof, as active ingredient, together with a pharmaceutically acceptable carrier.
The pharmaceutical compositions of the invention may contain one or more compounds of the invention in any of the forms described herein. The compositions of the present invention may further comprise one or more pharmaceutically acceptable additional ingredients, such as alum, stabilizers, antimicrobials, buffering agents, coloring agents, flavoring agents, adjuvants and the like.
The compounds of the present invention, together with adjuvants, carriers, diluents or excipients conventionally employed, may be presented in the form of pharmaceutical compositions and unit dosages thereof, and may be employed in solid form, such as tablets or filled capsules, or in liquid form, such as solutions, suspensions, emulsions, elixirs or capsules filled therewith, for all oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may contain conventional proportions of the ingredients, with or without other active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient, commensurate with the intended dosage range to be employed. The composition according to the invention is preferably oral.
The compositions of the present invention may be liquid preparations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles with buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain additives including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Non-aqueous carriers include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol and ethyl alcohol. Preservatives include, but are not limited to, methylparaben or propylparaben and sorbic acid. Other materials and processing techniques, etc., are set forth in "Pharmaceutical sciences and Practice" (Reming ton: The Science & Practice of Pharmacy,22 th edition, 2012, Lloyd, Ed. Allen, Pharmaceutical Press), and are hereby incorporated by reference.
The solid composition of the present invention may be in the form of a tablet or troche formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binders, fillers, lubricants, disintegrants, and wetting agents. Binders include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silicon dioxide. Disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Wetting agents include, but are not limited to, sodium lauryl sulfate. Tablets may be coated according to methods well known in the art.
Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art.
The compositions of the present invention may also be formulated as suppositories, which may contain a suppository base including, but not limited to, cocoa butter or glycerides. The compositions of the present invention may also be formulated for inhalation in forms including, but not limited to, solutions, suspensions or emulsions which may be administered as a dry powder or in an aerosol form using a propellant, such as dichlorodifluoromethane or trichlorofluoromethane.
The compositions of the present invention may also be formulated in transdermal formulations comprising aqueous or non-aqueous vehicles including, but not limited to, creams, ointments, lotions, pastes, salves, patches or films.
The compositions of the present invention may also be formulated for parenteral administration, including but not limited to by injection or continuous infusion.
Formulations for injection may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents including, but not limited to, suspending, stabilizing and dispersing agents. The compositions may also be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water.
The compositions of the present invention may also be formulated as a long acting formulation, which may be administered by implantation or by intramuscular injection.
The compositions may be formulated with suitable polymeric or hydrophobic materials (e.g. emulsions in acceptable oils), ion exchange resins or sparingly soluble derivatives (e.g. sparingly soluble salts).
The compositions of the present invention may also be formulated as liposomal formulations. The liposome formulation can comprise liposomes that penetrate the cell or stratum corneum of interest and fuse with the cell membrane, resulting in delivery of the liposome contents into the cell. Other suitable formulations may use niosomes. Niosomes are lipid vesicles similar to liposomes, with membranes composed primarily of non-ionic lipids, some of which are effective in transporting compounds across the stratum corneum.
The compounds of the present invention may also be administered in a sustained release form or from a slow release drug delivery system. Descriptions of representative sustained release materials can also be found in the incorporated materials of Remington's Pharmaceutical Sciences.
Administration mode: the compositions of the present invention may be administered in any manner, including but not limited to oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, inhalation, oral or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intraarticular. The compositions of the invention may also be administered in the form of implants, which allow for slow release of the composition and slow controlled administration of intravenous infusion.
Detailed Description
The principles and features of this invention are described below in conjunction with examples, which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
A, B, C compound
In view of the economic and diversity of the compounds, we prefer to synthesize compounds in which selected portions are listed in index table a and index table B. The compounds in index table a and index table B are only for better illustration of the present invention, but do not limit the present invention, and it should not be understood to limit the scope of the above-mentioned subject matter of the present invention to the following compounds for those skilled in the art.
In index Table A and index Table B, the abbreviations represent the following meanings:
me represents a methyl group; et represents an ethyl group; nPr represents n-propyl; iPr represents an isopropyl group;
bn represents a benzyl group, i.e. a phenylmethyl group.
TABLE A
Figure RE-GDA0002886868270000091
Figure RE-GDA0002886868270000092
Figure RE-GDA0002886868270000101
Figure RE-GDA0002886868270000111
Figure RE-GDA0002886868270000121
Figure RE-GDA0002886868270000131
Figure RE-GDA0002886868270000141
The structural general formulas of the compounds I-B-1 to I-B-50 are shown in the table B, the specific substituent definition of the compounds I-B-1 to I-B-50 is shown in the table A, the substituent is shown in the I-A-1 row in the table 1 if the compound I-B-1 is shown in the formula I-B, the substituent is shown in the I-A-2 row in the table 1 if the compound I-B-2 is shown in the formula I-B, and the like.
Second, synthetic method
Example 1: the synthetic route of compound I-A-1 is as follows:
Figure RE-GDA0002886868270000142
step 1): to a solution of compound A-1-1(0.83g,5mmol) in DMF (20ml) was added N-bromosuccinimide (1g,5.5mmol) and after stirring the reaction mixture at room temperature for 1 hour, the reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with water (5 × 20mL) followed by brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave crude product A-1-2(1.08g,4.25mmol) in 88% yield;
step 2): to a stirring solution of A-1-2(1g,4mmol) in toluene was added 4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl-4-cyclohexanone (0.89g,4mmol,1 equiv.) and the resulting mixture was purged under nitrogenAnd (5) aerating for 20 minutes. Pd (PPh)3)4(0.225g,0.08mmol,0.05 eq.) was then added to the mixture and the mixture was further vented under nitrogen for 10 minutes. The resulting mixture was heated at 110 ℃ for 16 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (200mL) and extracted with EtOAc (2X 200 mL). The combined organic layers were washed with water (200mL) and brine (100mL) and washed with Na2SO4Drying, filtering and concentrating under reduced pressure to obtain product A-1-3(0.84g,3.2mol), yield 80%;
step 3): to A-1-3(0.78g,3mmol,1.0 equiv.) of CH2Cl2To a solution (20mL) were added pyridine (0.36g,4.5mmol,1.5 equiv.) and n-propyl chloride (0.35g,4.5mmol,1.5 equiv.). The reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS and found to be complete after 18 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were washed with brine (30mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product, which was purified by reverse phase column chromatography to give 0.74g of Compound I-A-1 (yield 81%).
Example 2: the synthetic route for compound I-A-12 is as follows:
Figure RE-GDA0002886868270000151
step 1): to a solution of compound A-12-1(1.07g,4mmol) in DMF (10ml) was added N-bromosuccinimide (0.87g,4.8mmol,1.2 equiv.) and the reaction mixture was stirred at room temperature for 1 hour and the reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with water (5 × 20mL) followed by brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave crude product A-12-2 (1.22g,3.52mmol) in 88% yield;
step 2): to a solution of Compound A-12-2(1.0g,3mmol) in dioxane (10ml) was added 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -cyclohexanone (0.81g,3.6mmol,1.2 equiv.), Na2CO3(0.64g,6mmol,2 equiv.), Pd (PPh)3)4(0.15g,0.15mmol,0.05 equiv.). Reaction mixture with N2The atmosphere was deoxygenated and the mixture was heated at 80 ℃ for 18 hours. The reaction was monitored by NMR and LCMS. The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purifying the crude product by supercritical fluid chromatography to obtain white solid A-12-3(0.74g,2.04mmol, 68%) as white solid;
step 3): to a solution of A-12-3(0.72g,2.0mmol,1.0 equiv) in toluene (15mL) was added pyridine (0.24g,3mmol,1.5 equiv.) and vinyl chloride (0.2g,3mmol,1.5 equiv.) and the reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS and found to be complete after 18 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were washed with brine (30mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a crude product which was purified by reverse phase column chromatography to give 684mg of Compound I-A-12 (yield 82%).
Example 3: the synthetic route of compound I-A-30 is as follows:
Figure RE-GDA0002886868270000161
step 1): compound A-30-1(1.12g,2mmol) was dissolved in tetrahydrofuran, N-bromosuccinimide (0.43g,2.4mmol,1.2 equiv.) was added thereto, and after stirring the reaction mixture at room temperature for 1 hour, the reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with water (5 × 20mL) followed by brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave crude product A-30-2 (0.84g,1.8mmol) in 90% yield;
step 2): to a solution of compound a-30-2(0.7g,1.5mmol) in toluene was added 4-tri-n-butyltin-cyclohexanone) (0.77g,2mmol,1.3 equiv.), and the resulting mixture was vented under nitrogen for 20 minutes. Pd (PPh)3)4(0.18g,0.15mmol,0.1 equiv.) is then added to the mixture andthe mixture was further vented under nitrogen for 10 minutes. The resulting mixture was heated at 110 ℃ for 16 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (200mL) and extracted with EtOAc (2X 200 mL). The combined organic layers were washed with water (200mL) and brine (100mL) and washed with Na2SO4Drying, filtering and concentrating under reduced pressure to give product A-30-3(0.53g,1.1mmol) in 70% yield;
step 3): compound A-30-3(0.48g,1mmol) was dissolved in DMF, to which were added pyridine (0.12g,1.5mmol,1.5 equiv.) and 3,4, 5-trichlorobromobenzene (0.28g,1.5mmol,1.5 equiv.). The reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS and found to be complete after 18 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were washed with brine (30mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product, which was purified by reverse phase column chromatography to give 0.53g of compound I-A-30 (yield 81%).
Example 4 Synthesis of Compound I-A-46 the route is as follows:
Figure RE-GDA0002886868270000171
step 1): to a solution of 2-chloro-6-aminopyrazine (0.52g,4mmol) in toluene was added pyridin-4-ylboronic acid (0.49g,4mmol) in H2Na in O (10mL)2CO3(0.76g,7.2mmol,1.8 equiv.), Pd (PPh)3)4(0.12g,0.1mmol,0.025 equiv.). Reaction mixture with N2The atmosphere was deoxygenated and the mixture was heated at 100 ℃ for 18 hours. The reaction was monitored by NMR. The reaction mixture was filtered through celite, washing with ethyl acetate (2 × 20 mL). The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purifying the crude product on silica gel by Combiflash to obtain 0.55g of A-46-1 compound with the yield of 81 percent;
step 2): compound A-46-1(0.5g,3.0mmol) was dissolved in tetrahydrofuran, N-bromosuccinimide (0.55g,3.0mmol,1 eq) was added thereto, and after stirring the reaction mixture at room temperature for 1 hour, the reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with water (5 × 20mL) followed by brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave crude product A-46-2 (0.68g,2.7mmol) in 90% yield;
step 3): to a solution of compound A-46-2(0.625g,2.5mmol) in DMF was added 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -cyclohexanone (0.68g,3.0mmol,1.2 equiv.), Na2CO3(0.48g,5mmol,2 equiv.), PdCl2(PPh3)2(0.18g,0.25mmol,0.1 equiv.). Reaction mixture with N2The atmosphere was deoxygenated and the mixture was stirred at 80 ℃ overnight. The reaction was monitored by NMR and LCMS and found to be complete after 18 hours. The reaction mixture was cooled to room temperature, diluted with water (50mL), and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (20mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a crude product which was purified by SFC to give 0.43g (1.63mmol) of Compound A-46-3 as a white solid in 65% yield;
step 4): compound A-46-3(0.4g,1.6mmol) was dissolved in tetrahydrofuran, N-bromosuccinimide (0.16g,1.6mmol,1 equiv.) was added thereto, and after stirring the reaction mixture at room temperature for 1 hour, the reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with water (5 × 20mL) followed by brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave crude product A-46-4 (0.50g,1.44mmol) in 90% yield;
step 5): preparing 2-ethoxytetrazole into a Grignard reagent, dissolving a compound A-46-4 (0.50g,1.44mmol) in tetrahydrofuran, adding the Grignard reagent into a tetrahydrofuran solution of the compound A-46-4, controlling the molar ratio of the compound A-46-4 to the Grignard reagent to be (1.1-1.3): 1, the reaction temperature to be 55-60 ℃, and reacting for 1-2 h to obtain a product compound A-46-5 (0.4g, 1.1mmol) of Suzuki coupling reaction, wherein the yield is 78%;
step 6): compound A-46-5(0.36g,1.0mmol) was dissolved in DMF, to which was added pyridine (0.12g,1.5mmol,1.5 equiv.) and 1, 4-p-bromobenzene (0.35g,1.5mmol,1.5 equiv.). The reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS and found to be complete after 18 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were washed with brine (30mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product, which was purified by reverse phase column chromatography to give 0.31g of Compound I-A-46 (yield 79%).
All the compounds referred to in the present invention can be synthesized by methods similar to examples 1 to 4, and if the above synthetic methods are not suitable for obtaining the substituted pyrazine derivatives and/or necessary intermediates according to the present invention, suitable preparation methods known to those skilled in the art should be used. In general, the synthetic route for any single derivative will depend on the particular substituents per molecule and the availability of the necessary intermediates; these factors are also understood by those skilled in the art.
Application and activity
Evaluation of in vitro inhibitory activity of wild-type, V804M mutant kinase:
by using33Determination of IC by P-isotopically labelled kinase Activity test (Reaction Biology Corp)50Values were evaluated for the ability of the test compound to inhibit human wild-type, V804M mutant RET.
Buffer conditions: 20mM hydroxyethylpiperazine ethanethiosulfonic acid (Hepes) (pH 7.5),10mM MgCl2Ethylene glycol bisaminoethyl ether tetraacetic acid (EGTA) at 1mM, polyoxyethylene lauryl ether (Brij35) at 0.02% 0.02mg/mL Bovine Serum Albumin (BSA), sodium vanadate (Na) at 0.1mM3VO4) 2mM Dithiothreitol (DTT), 1% DMSO.
Compound treatment: test compounds were dissolved in 100% DMSO and serially diluted by Integra Viaflo Assist with DMSO to the specified concentrations.
The test steps are as follows: the substrate is dissolved in fresh buffer, the test kinase is added to it and gently mixed well. The DMSO solution containing the test compound was added using an acoustic technique (Echo 550)The mixed reaction solution was incubated at room temperature for 20 minutes. The concentration of the compound in the reaction solution was 3. mu.M, 1. mu.M, 0.333. mu.M, 0.1. mu.M, 0.0370. mu.M, 0.0123. mu.M, 4.12nM,1.37nM,0.457nM, 0.152 nM. After incubation for 15 min, the reaction was started by adding 33P-ATP (activity 0.01. mu. Ci/. mu.l, Km concentration). After the reaction was carried out at room temperature for 120 minutes, the radioactivity was detected by the filter binding method. Kinase activity data are presented as a comparison of kinase activity with test compound and blank (DMSO only) and IC was obtained by curve fitting Prism4 software (GraphPad)50The values and experimental results are shown in table 1.
Table 1: results of in vitro screening assays for Compounds of the invention
Figure RE-GDA0002886868270000201
Figure RE-GDA0002886868270000211
Figure RE-GDA0002886868270000221
As can be seen from the data in table 1, the compounds of the present invention showed good inhibitory activity against both wild type, V804M mutant RET.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (10)

1. A substituted pyrazine derivative having the chemical structure according to formula i:
Figure DEST_PATH_IMAGE001
formula I;
wherein Q represents Q1、Q2Any one of:
Figure DEST_PATH_IMAGE003
；
R1represents hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C3-C6 cycloalkyl, phenyl which is unsubstituted or substituted by 1,2, 3 or 4 halogens;
RXindependently of one another, hydrogen, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;
y represents hydrogen, halogen, hydroxyl, mercapto, cyano, amino, C1-C3 acyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylamino, aryl or heteroaryl which are unsubstituted or substituted by halogen;
and pharmaceutically acceptable salts, tautomers, geometric isomers and optically active forms thereof.
2. A pyrazine derivative according to claim 1,
R1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, -CF3、-CH2CF3、-CH2CHF2、-CH2CHCl2、-CH2CCl3、-CCl3、-CBr3、-CH2CBr3、-CH2CHBr2Vinyl, propenyl, allyl, 1-methylprop-2-en-1-yl, but-2-en-1-yl, ethynyl, propynyl, phenyl or phenyl substituted with 1,2, 3 or 4 of F, Cl or Br.
3. A pyrazine derivative according to claim 2,
R1represents hydrogen, methyl, ethyl, isopropyl, -CF3、-CH2CF3Vinyl and propyleneAryl, allyl, phenyl or phenyl substituted with 1 or 2F, Cl or Br.
4. A pyrazine derivative according to any of claims 1 to 3,
RXindependently of one another, represents hydrogen, -F, -Cl, -Br, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, -CF3、-CH2CF3、-CH2CHF2、-CH2CHCl2、-CH2CCl3、-CCl3、-CBr3、-CH2CBr3、-CH2CHBr2、-O-CF3、-O-CH2CF3、-O-CH2CHF2、-O-CH2CHCl2、-O-CH2CCl3、-O-CCl3、-O-CBr3、-O-CH2CBr3or-O-CH2CHBr2。
5. A pyrazine derivative according to claim 4,
RXindependently of one another, represents hydrogen, -F, -Cl, -Br, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, -CF3or-CH2CF3。
6. A pyrazine derivative according to any of claims 1 to 5,
y represents hydrogen, halogen, hydroxyl, mercapto, cyano, amino, formyl, acetyl, methyl, ethyl, isopropyl, n-propyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, methylamino, ethylamino, one of the following groups unsubstituted or substituted by 1,2 or 3 halogen atoms: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl.
7. A pyrazine derivative according to claim 6,
y represents hydrogen, halogen, hydroxy, mercapto, cyano, amino, formyl, acetyl, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, one of the following unsubstituted or substituted with 1,2 or 3 of F, Cl or Br: phenyl, naphthyl, pyridyl or pyrimidinyl.
8. A pharmaceutical formulation comprising as an active ingredient a therapeutically effective amount of a substituted pyrazine derivative according to any of claims 1 to 7, or pharmaceutically acceptable salts, tautomers, geometrical isomers and optically active forms thereof, together with a pharmaceutically acceptable carrier.
9. Use of substituted pyrazine derivatives according to any of claims 1 to 7 for the preparation of RET kinase inhibitors.
10. Use of a pharmaceutical formulation according to claim 8 for the preparation of a RET kinase inhibitor.
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