CN109516999B - Compounds useful as protein kinase modulators and uses thereof - Google Patents
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/18—Bridged systems
Abstract
The invention discloses a compound shown in a formula I, wherein each symbol is defined in the claims. The compound shown in the formula I has good inhibitory activity on ALK, ROS1 and/or TRK kinase, can be used for preparing medicines for inhibiting ALK, ROS1 and/or TRK kinase, and is used for treating cancers, pains, neurological diseases, autoimmune diseases or inflammation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound used as a protein kinase regulator, a pharmaceutical composition containing the compound, and application of the compound in preparing medicines for regulating protein kinase activity or treating protein kinase related diseases.
Background
Malignant tumors are one of the main killers of human health, and the latest edition of the world cancer report predicts that global cancer cases will show a rapid growth situation, which is increased from 1400 million people in 2012 to 1900 million people in 2025 year and reaches 2400 million people in 2035 year. Reports also show that developing countries in africa, asia, and central and south america have the most severe forms of cancer. In 2012, a total of 1400 million cancer cases and 820 million people died all over the world. Among them, 307 new cancer patients and about 220 million deaths in china account for 21.9% and 26.8% of the total global amount, respectively (global cancer report 2014). At present, the awareness level and the treatment means of human beings on the tumors are remarkably developed, and effective control on part of the tumors can be achieved. However, because the formation mechanism of tumor is very complex, most malignant tumor cells have multiple pathways for growth, so that the cancer cells have extremely strong vitality, and the inhibition of one or part of the pathways cannot completely eliminate the cancer cells. Whereas chemotherapy often causes mutations in oncogene genes, resulting in drug resistance, in addition to the usual focal metastasis.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80% to 85% of all lung cancer patients, with some patients being accompanied by genetic mutations. Anaplastic Lymphoma Kinase (ALK) rearrangement, a receptor-type protein of the insulin receptor superfamily, is present in 2-5% of NSCLC cases. ALK was initially discovered as an activated fused oncogene in anaplastic large cell lymphoma, and subsequently, continued research has resulted in the discovery of fused forms of ALK in a variety of cancers, including systemic dysplasia, inflammatory myofibrocyte cancer, non-small cell lung cancer, and the like. The mutant and aberrant activity of ALK in various cancers has made it a drug target for the treatment of ALK-positive cancers.
Crizotinib (Crizotinib), developed by pfeizu pharmaceutical limited, usa, was clinically validated to be effective in reducing the size of malignant tumors in patients with advanced gene mutant non-small cell lung cancer (NSCLC). However, crizotinib may exhibit the following side effects: visual impairment, gastrointestinal side effects, 16% of patients develop elevated levels of grade 3-4 liver transaminase, and in addition, patients who are ALK-positive after an initial phase of crizotinib treatment sensitization typically develop resistance after 1-2 years of treatment. Currently, three second-generation ALK inhibitors, such as ceritinib, alectinib, and brigitinib, are sequentially approved by the FDA for the treatment of crizotinib-resistant patients. Although acquired drug resistant patients have gained many benefits from these marketed drugs, the efficacy of these therapies is often limited by some side effects or tumor reacquiring resistance problems, and there is an urgent need to develop new, highly effective, broad-spectrum kinase inhibitors.
Patent document WO2017004342a1 discloses a series of highly active compounds which have high inhibitory activity against drug-resistant mutations caused by crizotinib and also have excellent inhibitory activity against drug-resistant mutations caused by the use of a second-generation ALK inhibitor. The compound disclosed therein, TPX-0005, is an effective orally available small molecule kinase inhibitor against the ALK, ROS1 and TRK families. The molecule can effectively bind to ATP binding sites of ALK, ROS1 and TRK kinase, and plays a role in inhibiting the ALK, ROS1 and TRK kinase. More importantly, it can bind to the mutants of these proteins, such as ALK G1202R, ALK L1196M, ROS 1G 2032R and TRKA G595R, and at the same time, has the potential to comprehensively solve the drug tolerance problem related to acquired drug resistance mutation after targeting ALK, ROS1 and NTRK families, and can solve the bypass and EMT mechanism. Since bypassing and EMT are common drug resistance mechanisms in targeted therapy, TPX-0005 will have potential in the future to overcome the problem of drug resistance at other therapeutic targets such as EGFR through combination therapy. Currently, it has been performed in clinical i/ii trials and is FDA-qualified for orphan drug use in treating non-small cell lung adenocarcinoma patients carrying rearrangements of ALK, ROS1 or NTRK oncogenes.
Although TPX-0005 has achieved relatively good effects in clinical I/II experiments, in order to meet the urgent clinical requirement of drug resistance and benefit a large number of patients, the development of new compounds with high activity and/or better pharmacodynamic/pharmacokinetic properties has become an urgent key problem to be solved for the development of novel antitumor drugs.
Disclosure of Invention
The invention provides a compound shown as a formula I, or a tautomer thereof, or a racemate, a racemic mixture, a meso mixture and a racemic mixture, or an enantiomer, a diastereoisomer, a mixture of enantiomer and diastereoisomer, or a pharmaceutically acceptable salt thereof:
in formula I:
M1selected from the group consisting of CR9Or N;
M2selected from the group consisting of CR10Or N;
X1、X2and X3Each independently selected from O, S, NR11S (O) or S (O)2；
W is selected from C (O), S (O), C (S) or S (O)2；
C (O) is
S (O) is
C (S) is
S(O)2Is composed of
Z1、Z2、Z3、Z4、Z5、Z6And Z7Each independently selected from N, NH or CR11And Z is1、Z2、Z3、 Z4、Z5、Z6And Z7At least one of which is N or NH;
R1、R2、R9、R10and R11Each independently selected from the group consisting of H, deuterium, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphonyl, carboxyl, amino, sulfonyl, phosphonyl, phosphono, amino,
Wherein the H in the alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl and phosphonyl can be mono-or polysubstituted, and the substituent is selected from fluorine, chlorine, bromine, amino, acetyl, cyano, carboxyl, sulfonyl, phosphonyl, C1-6Alkoxy group of (C)1-4Alkyl of (C)3-6Cycloalkyl, fluoroalkyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, deuterated monofluoroMethoxy or deuterated difluoromethoxy;
R3、R4、R5、R6、R7and R8Each independently selected from the group consisting of H, deuterium, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphonyl, carboxyl, amino, sulfonyl, phosphono, amino,
Wherein the H in the alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl and phosphonyl can be mono-or polysubstituted, and the substituent is selected from fluorine, chlorine, bromine, amino, acetyl, cyano, carboxyl, sulfonyl, phosphonyl, C1-6Alkoxy group of (C)1-4Alkyl of (C)3-6Cycloalkyl, fluoroalkyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, deuterated monofluoromethoxy or deuterated difluoromethoxy of (a);
R12and R13Each independently selected from alkyl, haloalkyl, cycloalkyl, halocycloalkyl, aryl or heteroaryl;
m is 1 or 2;
n is 1 or 2.
The invention also provides a compound shown as a formula II, or a tautomer thereof, or a racemate, a racemic mixture, a meso mixture and a racemic mixture, or an enantiomer, a diastereoisomer, a mixture of enantiomer and diastereoisomer, or a pharmaceutically acceptable salt thereof:
in formula II:
a is a 3-8 membered ring, wherein the ring is selected from a carbocyclic ring or a heterocyclic ring;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
The invention also provides a compound shown as a formula III, or a tautomer thereof, or a racemate, a racemic mixture, a meso mixture and a racemic mixture, or an enantiomer, a diastereoisomer, a mixture of enantiomer and diastereoisomer, or a pharmaceutically acceptable salt thereof:
in formula III:
b is a 3-8 membered ring, wherein the ring is selected from a carbocyclic ring or a heterocyclic ring;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
The invention also provides a compound shown as a formula IV, or a tautomer thereof, or a racemate, a racemic mixture, a meso mixture and a racemic mixture, or an enantiomer, a diastereoisomer, a mixture of enantiomer and diastereoisomer, or a pharmaceutically acceptable salt thereof:
in formula IV:
c is a 3-8 membered ring, wherein the ring is selected from carbocycle or heterocycle;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
The invention also provides a compound shown as the formula V, or a tautomer thereof, or a racemate, a racemic mixture, a meso mixture and a racemic mixture, or an enantiomer, a diastereoisomer, a mixture of enantiomer and diastereoisomer, or a pharmaceutically acceptable salt thereof:
in formula V:
A. b is respectively independent 3-8 membered ring, wherein the ring is selected from carbocycle or heterocycle;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
The invention also provides a compound shown as a formula VI, or a tautomer thereof, or a racemate, a raceme, a mixture of a meso form and a raceme, or an enantiomer, a diastereomer, a mixture of an enantiomer and a diastereomer, or a pharmaceutically acceptable salt thereof:
in formula VI:
B. c is respectively independent 3-8 membered ring, wherein the ring is selected from carbocycle or heterocycle;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
The invention also provides a compound shown in the formula VII, or a tautomer thereof, or a racemate, a raceme, a mixture of a meso form and a raceme, or an enantiomer, a diastereomer, a mixture of an enantiomer and a diastereomer, or a pharmaceutically acceptable salt thereof:
in formula VII:
A. c is respectively independent 3-8 membered ring, wherein the ring is selected from carbocycle or heterocycle;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
The invention also provides a compound of formula viii, or a tautomer thereof, or a mixture of racemates, racemics and meso and racemates thereof, or enantiomers, diastereomers and mixtures of enantiomers and diastereomers thereof, or a pharmaceutically acceptable salt thereof:
in formula VIII:
A. b, C is independently 3-8 membered ring, wherein the ring is selected from carbocycle or heterocycle;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、 R6、R7、R8m and n are as defined in formula I.
Further defined, in formula I-formula VIII, R1Selected from deuterium, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphonyl, hydroxyl, carboxyl, amino, alkylamino, dialkylamino, alkylamino, dialkylamino, alkylamino, dialkylamino,
Wherein said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphonyl, alkoxy, haloalkoxy, alkylamino, acyl, ester, alkenyl, alkynyl, aryl, heteroaryl, sulfonyl, phosphonyl, or phosphonyl,
Wherein H may be mono-or polysubstituted, and the substituent is selected from the group consisting of fluorine, chlorine, bromine, amino, acetyl, cyano, carboxyl, sulfonyl, phosphonyl, C1-6Alkoxy group of (C)1-4Alkyl of (C)3-6Is selected from the group consisting of cycloalkyl, fluoroalkyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, deuterated monofluoromethoxy, and deuterated difluoromethoxy.
Further defined, in formula I, formula III, formula IV, formula VI, R3Is deuterium.
Further defined, in the formula I, the formula II, the formula IV and the formula VII, R5Is deuterium.
Further limited by formula I, formula IV wherein R3、R5Are all deuterium.
The invention further provides a specific compound, or a tautomer thereof, or inner racemate, racemate and mixture of inner and racemate, or enantiomer, diastereomer and mixture of enantiomer and diastereomer thereof, or a pharmaceutically acceptable salt thereof, optionally selected from the group consisting of:
these particular compounds are effective in inhibiting ALK, ROS1 and/or TRK kinase activity. Can be used as ALK/ROS1/TRK kinase inhibitor for treating ALK/ROS1/TRK related diseases. In particular to a therapeutic drug for non-small cell lung cancer.
Wherein, the pharmaceutically acceptable salt can be inorganic acid salt or organic acid salt, for example, the inorganic acid salt can be selected from hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic acid salt may be selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier;
and the number of the first and second groups,
the above compounds, or tautomers thereof, or racemates, racemates and mixtures of meso and racemic forms thereof, or enantiomers, diastereomers and mixtures of enantiomers and diastereomers thereof, or pharmaceutically acceptable salts thereof, or crystalline forms, hydrates or solvates, prodrugs or isotopic variations thereof.
The use of a compound as described above, or a tautomer thereof, or a racemate, racemate and mixture of meso and racemate, or an enantiomer, diastereomer and mixture of enantiomer and diastereomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, pain, neurological diseases, autoimmune diseases or inflammation. Such cancers include, but are not limited to: lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, renal cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or carcinoma of large intestine.
The use of a compound as described above, or a tautomer thereof, or a racemate, a racemate or a mixture of both the meso and the racemate, or an enantiomer, diastereomer, or a mixture of the enantiomer and diastereomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting cell proliferation.
The use of a compound as described above, or a tautomer thereof, or a racemate, racemate and mixture of meso and racemate, or an enantiomer, diastereomer and mixture of enantiomer and diastereomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
The compound, or the tautomer thereof, or the racemate, the racemate and the mixture of the meso and the racemate, or the enantiomer, the diastereomer and the mixture of the enantiomer and the diastereomer thereof, or the pharmaceutically acceptable salt thereof, and the application of the compound, or the tautomer, or the mixture of the meso and the racemate, in preparing the medicine for inhibiting ALK, ROS1 and/or TRK kinase.
The use of the compound described above, or a tautomer thereof, or a racemate, a racemate and a mixture of the meso and the racemate, or an enantiomer, a diastereomer and a mixture of the enantiomer and the diastereomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of non-small cell lung cancer.
Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below.
"alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms consisting only of carbon and hydrogen atoms. "alkyl" is preferably an alkyl group of 1 to 6 carbon atoms, i.e.C1-C6Alkyl, more preferably C1-C4An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl and the like.
"alkoxy" refers to a group of formula-OR, wherein R is an alkyl group as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.
"halo (halo)" means a fluoro, chloro, bromo, or iodo substituent.
"haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogens are replaced with the same or different halogen. Examples of haloalkyl groups include-CH2Cl、-CH2CF3、-CH2CCl3Perfluoroalkyl (e.g., -CF)3) And the like.
"haloalkoxy" refers to a group of the formula-OR, wherein R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2, 2-trifluoroethoxy, and the like.
"cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of mono-or bicyclic rings having 3 to 12, preferably 3 to 10, more preferably 3 to 6 ring atoms. The cycloalkyl group can be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
"Cycloalkoxy" refers to a group of formula-OR, wherein R is cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
"acyl" refers to a group of formula-C (O) R, wherein R is alkyl as defined herein. Exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl, and the like.
An ester group refers to a group of formula-C (O) OR, wherein R is an alkyl group as defined herein. Exemplary ester groups include-C (O) OMe, -C (O) OEt, and the like.
"alkylthio" refers to a group of formula-SRa, wherein Ra is H or alkyl as herein defined.
"alkylamino" refers to a group of formula-NRaRb, wherein Ra is H or alkyl as defined herein and Rb is alkyl as defined herein.
"cycloalkylamino" refers to a group of formula-NRaRb, wherein Ra is H, alkyl as defined herein, or cycloalkyl as defined herein, and Rb is cycloalkyl as defined herein.
"heteroaryl" refers to a monocyclic, bicyclic or tricyclic group of 5 to 12 ring atoms containing at least 1 aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, the remaining ring atoms being C, it being understood that the point of attachment of the heteroaryl group should be on the aromatic ring. The heteroaryl group preferably has specifically 5 to 8 ring atoms, and more preferably has 5 to 6 ring atoms. Examples of heteroaryl groups include, but are not limited to: imidazolyl group,
Azolyl radical, iso
Oxazolyl, thiazolyl, isothiazolyl,
Oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzofuranyl
Azolyl, benzo
Oxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza-azanyl
Radical diaza
Mesityl, acridinyl and the like.
The solvate referred to in the present invention means a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate out of a solvent or crystallize out. For example, complexes formed with water are known as hydrates; others include alcoholates, ketonates, and the like. The solvates include solvates of the compounds of formula I-formula VIII of the present invention and salts and stereoisomers thereof.
The stereoisomers mentioned in the present invention mean that the compounds of the formulae I to VIII according to the invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compounds of formula I-formula VIII contain more than one chiral center, diastereoisomers may be present. Stereoisomers of the present invention include resolved optically pure specific isomers as well as mixtures of non-corresponding isomers. Diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.
Prodrugs as referred to herein are intended to include known amino and carboxyl protecting groups, and are intended to be hydrolyzed under physiological conditions or released via enzymatic reaction to give the parent compound. Specific prodrug preparation methods can be referred to in the art (Saulnier, M.G.; Frannesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.ChemLett.1994,4, 1985-oz 1990; and Greenwald, R.B.; Choe, Y.H.; Conover, C.D.; Shum, K.; Wu D.; Royzen, M.J.Med.Chem.2000, 43, 475.).
The compound shown in the formula I-formula VIII can effectively inhibit the activity of ALK, ROS1 and/or TRK kinase. Can be used as ALK/ROS1/TRK kinase inhibitor for treating ALK/ROS1/TRK related diseases. In particular to a therapeutic drug for non-small cell lung cancer.
The compounds of formula I-VIII of the present invention, or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, may be formulated with one or more pharmaceutically acceptable carriers for administration in a suitable dosage form. These dosage forms include those suitable for oral, rectal, topical, oral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
The pharmaceutical compositions of the present invention may be formulated, dosed and administered in a manner consistent with medical practice specifications. The "effective amount" of a compound to be administered will depend on the particular condition being treated, the individual being treated, the cause of the condition, the target site for the drug, and the mode of administration.
The pharmaceutical composition may further comprise an additional therapeutic agent, the additional therapeutic agent being an agent for cancer, cardiovascular disease, inflammation, infection, immunological disease, cell proliferative disease, viral disease, metabolic disease or organ transplantation.
Detailed Description
The technical solution of the present invention is further described below with reference to specific examples, but the scope of the present invention is not limited thereto.
Example 1
Target compound:
the synthetic route is as follows:
specific synthetic process
Synthesis of Compound 2
Tetraethyl titanate (24g, 84mmol) was added dropwise to a solution of compound 1(5.0g, 32.4mmol) and R-tert-butylsulfenamide (3.9g, 32.4mmol) in dichloromethane (150mL) with stirring at room temperature under a nitrogen atmosphere at room temperature, after the addition was completed, the reaction was stirred at room temperature overnight, water (100mL) was added to quench the reaction, the reaction was filtered through celite, the cake was washed with dichloromethane (300mL), the layers were separated, and the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography (PE: EA ═ 1:1) to give 2.8g of a yellow solid.
Characterization data:1H NMR(400MHz，CDCl3)：δ12.78(s，1H)，7.32(dd,J＝3.2，9.6Hz， 1H)，7.26(m,1H)，6.93(dd,J＝3.2，9.6Hz，1H)，2.79(s，3H)，1.34(s，9H)。 MS m/z(ESI):258.1[M+H]+。
synthesis of Compound 3
Dissolving compound 2(9g, 35mmol) in anhydrous tetrahydrofuran (50mL), cooling to-50 deg.C under nitrogen protection, and adding NaBD in batches4(4.5g, 105mmol), after addition, warmed to room temperature, stirred for 2 hours, spot TLC plate, starting material disappeared, water (50mL) was added, extracted with ethyl acetate (100mL × 3), organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and silica gel column chromatography (PE: EA ═ 2:1) afforded 7.5g yellow solid with 97% deuteration.
Characterization data:1H NMR(400MHz，CDCl3)：δ9.05(s，1H)，6.77(dd,J＝3.2，8.8Hz， 1H)，6.56(m,1H)，6.42(dd,J＝3.2，8.8Hz，1H)，5.01(s，1H)，1.50(s，3H)，1.26(s，9H)。MS m/z(ESI):261.1[M+H]+。
synthesis of Compound 4
Saturated 1, 4-dioxane hydrochloride solution (20mL) was slowly added to a solution of compound 3(7.5g, 28.8mmol) in dichloromethane (100mL) at room temperature, stirred at room temperature for 2 hours, the starting material disappeared, the solution was removed, ether was added to the residue, stirred for 10 minutes, and filtered to give 5.2g of a gray solid.
Characterization data:1H NMR(400MHz，DMSO-d6)：δ10.19(br s,1H),8.42(br s,3H),7.29(d, J＝3.2，9.6Hz，1H),7.01(m,1H)，6.92(m，1H)，1.45(s，3H)。MS m/z(ESI):157.1[M+H]+。
synthesis of Compound 6
Cesium carbonate (65.7g, 202mmol) was added to a solution of compound 5(15g, 108mmol) and ethyl 3-ethoxyacrylate (29.2g, 203mmol) in N, N-dimethylformamide at room temperature under nitrogen protection, warmed to 110 ℃ and stirred for 8h, and TLC (PE: EA ═ 1:1) showed disappearance of compound 5. The reaction solution was cooled to room temperature, filtered through celite, the filter cake was washed with ethyl acetate (200mL), most of the ethyl acetate was removed by rotary evaporation, the residue was taken up in water (200mL) and adjusted to pH 4 with acetic acid, a solid precipitated, filtered and dried to give 6 as a white solid (17g, 85%).
Characterization data:1H NMR(400MHz，DMSO-d6)：δ8.54(d,J＝8.0Hz,1H)，8.12(s,1H),6.13 (d,J＝8.0Hz,1H)，4.27(q,J＝7.2Hz,2H)，1.28(t,J＝7.2Hz,3H)。MS m/z(ESI):208.1 [M+H]+。
synthesis of Compound 7
Phosphorus oxychloride (58g, 380mmol) was added to a solution of compound 6(16g, 76mmol) in acetonitrile at room temperature under nitrogen, warmed to 100 ℃ and stirred for 2h, and compound 6 was shown to disappear by TLC (PE: EA ═ 1: 1). The reaction solution was cooled to room temperature, introduced into crushed ice, stirred for 20 minutes, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to give 7(10g, 62%) as a white solid.
Characterization data:1H NMR(400MHz，DMSO-d6)：δ9.33(d,J＝7.2Hz,1H)，8.66(s,1H), 7.41(d,J＝7.2Hz,1H)，4.31(q,J＝7.2Hz,2H)，1.32(t,J＝7.2Hz,3H)。MS m/z(ESI):226.1 [M+H]+。
synthesis of Compound 8
Compound 4(2g, 10.5mmol) and compound 7(2.4g, 10.5mmol) were added sequentially to n-butanol (50mL), followed by diisopropylethylamine (10.8g, 84mmol), warmed to 120 ℃ and stirred overnight, TLC showed disappearance of the starting material, n-butanol was removed under reduced pressure, water (50mL) was added to the residue, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (PE: EA ═ 1:1) to give white solid 8(3.1g), deuterium substitution rate 97%.
Characterization data:1H NMR(400MHz，CDCl3)：δ9.10(br s,1H)，8.25(s,1H)，,8.16(d,J＝ 7.6Hz,1H)，6.94(m,1H),6.94(m,1H)，6.84(m,1H)，6.08(d,J＝7.6Hz,1H)，5.52(br s, 1H)，4.43(m,2H)，1.42(t,J＝7.2Hz,3H)。MS m/z(ESI):346.1[M+H]+。
synthesis of Compound 9
Compound 8(2.5g, 7.2mmol) and compound (R) -1- (BOC-amino) -2-propanol (1.9g, 10.8mmol) were added sequentially to dry dichloromethane (10mL), followed by toluene (50mL), heated to concentrate water, and then dry dichloromethane (50mL) was added. Under the protection of nitrogen, triphenylphosphine is added, the mixture is stirred until the triphenylphosphine is completely dissolved, DEAD is dropwise added, and heat is released in the process. After the addition was complete, the mixture was stirred at room temperature overnight, 2N aqueous sodium hydroxide (30mL) was added, extracted with dichloromethane (50mL × 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and chromatographed on silica gel (PE: EA ═ 5:1) to give 9(1.8g) as a white solid. 80% pure, used directly in the next step. MS M/z (ESI) 503.1[ M + H]+。
Synthesis of Compound 10
The crude compound 9(2.6g) obtained in the previous step was dissolved in methanol/tetrahydrofuran (60mL/20mL), and then 2N aqueous lithium hydroxide (20mL) was added, the temperature was raised to 70 ℃ and the mixture was stirred overnight, the point TLC plate showed disappearance of the starting material 9, the solution was spun off, the pH was adjusted to 5 with 2N aqueous hydrochloric acid, dichloromethane was extracted (50mL × 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (PE: EA ═ 2:1) to obtain a white solid 10(1.8 g). 90% pure, used directly in the next step. MS M/z (ESI) 475.2[ M + H]+。
Synthesis of Compound 11
The crude compound 10(1.8g) obtained in the previous step was dissolved in dichloromethane (100mL), and a saturated 1, 4-dioxane hydrochloride solution (20mL) was slowly added thereto at room temperature, and stirred at room temperature for 2 hours, whereupon the starting material disappeared, the solution was removed, ether was added to the residue, stirred for 10 minutes, and filtered to obtain 1.2g of a gray solid. 95% pure, used directly in the next step. MS M/z (ESI) 375.1[ M + H]+。
Synthesis of target Compound TRN020201
Compound 11(200mg, 0.42mmol) in DMF (3mL) was added to a mixed solution of diisopropylethylamine (426mg, 3.3mmol) in DMF (6mL) and DCM (14mL) under nitrogen protection, then FDPP (169mg, 0.44mmol) was added, stirred at room temperature for 2 hours, 2N aqueous sodium carbonate (10mL) was added to the reaction solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (DCM: MeOH ═ 20:1) to give TRN020201(108mg) as a white solid.
Characterization data:1H NMR(400MHz，DMSO-d6)：δ9.81(d,J＝6.4Hz,1H)，8.81(s,1H),8.57 (d,J＝7.6Hz,1H)，8.04(s,1H),7.14(d,J＝3.2,9.6Hz,1H)，6.98(m，2H)，,6.36(d,J＝7.6Hz, 1H)，4.48(m，1H),3.90(m，1H),3.13(m，1H),1.45(m，6H)。LC-MS m/z(ESI):357.1 [M+H]+。
example 2
Target compound:
example 2 synthesis of the object compound, with reference to example 1, except that the compound (R) -1- (BOC-amino) -2-propanol in the synthesis step of compound 9 was replaced with:
example 2 target compound: MS M/z (ESI) 383.1[ M + H ]]+。
Example 3
Target compound:
example 3 synthesis of the object compound, with reference to example 1, except that the compound (R) -1- (BOC-amino) -2-propanol in the synthesis step of compound 9 was replaced with:
example 3 target compound: MS M/z (ESI) 369.2[ M + H ]]+。
Example 4
Target compound:
example 4 synthesis of the object compound, with reference to example 1, except that the compound (R) -1- (BOC-amino) -2-propanol in the synthesis step of compound 9 was replaced with:
example 4 target compound: MS M/z (ESI) 397.2[ M + H]+。
Example 5
Target compound:
example 5 synthesis of the object compound, with reference to example 1, except that the compound (R) -1- (BOC-amino) -2-propanol in the synthesis step of compound 9 was replaced with:
example 5 target compound: MS M/z (ESI) 411.2[ M + H ]]+。
Specific compounds synthesized include the following:
effect test examples measurement of biological Activity
The activity of the target compound TRN020201 on Anaplastic Lymphoma Kinase (ALK) was detected at ATP Km concentration using the Caliper Mobility Shift Assay method. The Caliper Mobility Shift Assay method is the Mobility-detection technique (Mobility-Shift Assay) by Caliper corporation.
In vitro activity of each compound on Anaplastic Lymphoma Kinase (ALK) was tested at Km concentration using Caliper Mobility Shift Assay and bioactivity screening of compounds was repeated at 10 concentrations using Staurosporine (Staurosporine) as a control.
Experimental materials:
anaplastic Lymphoma Kinase (ALK) (Carna, Cat. No.08-105, Lot. No. 08CBS-0112);
peptide FAM-P22(GL Biochem, Cat. No.112393, Lot. No. P080401-XY 112393);
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)；
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)；
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)；
96-well test plates (Corning Corp., Cat.3365, Lot.No. 22008026);
384-well test plates (Corning Corp., Cat.3573, Lot.No. 12608008);
staurosporine (Staurosporine) (Sigma, Cat. No. S4400-1MG, Lot. No.046 K4080).
Test sample
Each sample was prepared as a 10mM solution.
Experimental methods
Firstly, preparing 1.25x basic kinase buffer solution and quenching buffer solution for experimental kinase
1. Containing no manganese dichloride (MnCl)2) 1.25 Xkinase basic buffer solution
HEPES solution at a concentration of 62.5mM, pH 7.5,
a Brij-35 concentration of 0.001875%,
magnesium dichloride (MgCl) at a concentration of 12.5mM2) The solution is prepared by mixing a solvent and a solvent,
DTT solution with concentration of 2.5 mM;
2. containing manganese dichloride (MnCl)2) 1.25 Xkinase basic buffer solution
HEPES solution at a concentration of 62.5mM, pH 7.5,
a Brij-35 concentration of 0.001875%,
magnesium dichloride (MgCl) at a concentration of 12.5mM2) The solution is prepared by mixing a solvent and a solvent,
manganese dichloride (MnCl) at a concentration of 12.5mM2) The solution is prepared by mixing a solvent and a solvent,
DTT solution with concentration of 2.5 mM;
3. quench buffer solution
HEPES solution at a concentration of 100mM, pH 7.5,
brij-35 at a concentration of 0.015%,
surface agent No. 3 with a concentration of 0.2%,
EDTA solution at a concentration of 50 mM.
Secondly, preparing compounds for experimental kinases
Serial (serial) dilutions of compounds
1. Pipetting 5 microliter of compound solution with concentration of 10mM, transferring the solution into a test tube, adding 95 microliter of DMSO, and diluting to compound concentration of 500. mu.M;
2. transferring the compound in the test tube to one of the wells of a 96-well storage plate, transferring 30 μ L of the compound to the next adjacent well, and adding 60 μ L of DMSO for dilution, thereby obtaining 10 compound solutions with the concentration of 500 μ M to 0.025 μ M by serial dilution;
3. in the same 96-well test plate, 60 mu L of DMSO is added into each row of wells for DMSO control;
4. from each well, 5. mu.L of the solution was transferred to another 96-well test plate and 45. mu.L of H was added2O；
5. Transfer 70 μ L of 250mM EDTA for low control;
6. transfer 5 μ L of each well to 384-well assay plates; the A1 with low control in the 96-well plate was transferred to A1 and A2 in the 384-well plate, and the A2 with the highest concentration of compound in the 96-well plate was transferred to A3 and A4 in the 384-well plate, and so on.
Thus, this assay plate contained 5 Xcompound in 10% DMSO, with an initial concentration of 50. mu.M.
III, kinase reaction
1. Preparation of 2.5 Xenzyme solution
Adding kinase to a 1.25 Xbasic buffer solution of kinase;
2. preparation of 2.5 Xpeptide solution
Adding FAM-labeled peptide and ATP to 1.25x kinase basal buffer;
3. transfer 2.5 Xkinase solution to assay tray
Now 5 μ L of compound in 10% DMSO in assay dish;
add 10. mu.L of 2.5 Xenzyme solution to each well of a 384-well assay plate;
incubating for 10 minutes at room temperature;
4. transfer 2.5 Xpeptide solution to analysis tray
Add 10. mu.L of 2.5 Xpeptide solution to each well of a 384-well assay plate;
5. enzymatic reaction and quenching
Incubating at 28 ℃ for a period of 1 hour in this experiment;
add 25 μ L of quench buffer to stop the reaction;
6. caliper reading data
The Caliper collects data;
7. fitting of curves
Copying data from the Caliper;
conversion value to inhibition value:
percent inhibition (max-transformed value)/(max-min) 100,
wherein the maximum represents DMSO control; minimum represents low control (low control);
fitting the data to Xlfit to obtain IC50Value of
The following equation is used:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
inhibitory Activity IC of the obtained test sample on Anaplastic Lymphoma Kinase (ALK)50The (nM) values are shown in the table below:
| Compound ID | Top Conc.(uM) | ALK IC50(nM) |
| Staurosporine | 1 | 14.42 |
| TPX-0005 | 10 | 14.64 |
| EXAMPLE 1 object Compound | 10 | 7.90 |
| EXAMPLE 2 object Compounds | 10 | 1.01 |
| EXAMPLE 3 object Compounds | 10 | 7.80 |
| EXAMPLE 4 object Compounds | 10 | 8.92 |
| EXAMPLE 5 object Compounds | 10 | 25.63 |
As can be seen from the above table, Staurosporine and TPX-0005 were used as control samples in vitro bioactivity screening. The compounds we synthesized, such as example 1, example 2, example 3 and example 4, all showed better inhibitory ability to Anaplastic Lymphoma Kinase (ALK) compared to the control.
The compounds of the invention are also effective in inhibiting the activity of ROS1 and TRK kinase as measured.
Pharmacokinetic experiment of rat
Purpose of the experiment: the pharmacokinetic behavior of rats after administration of the experimental compounds was studied.
Experimental animals: SD rat grade, SPF grade.
Animal sex is number: male, 18.
Body weight range: 180 and 250 grams.
The source is as follows: shanghai Spiral-BiKai laboratory animals Co., Ltd.
The experimental process comprises the following steps:
(1) animal dose: each compound IV (administered intravenously) was administered in an amount of 2mg and PO (administered orally) in an amount of 10 mg.
(2) Collecting and processing samples:
blood is collected by jugular venipuncture, about 0.25mL of each sample is collected, EDTA-K2 is anticoagulated, and the samples are placed on ice after collection. The blood sampling time points were as follows:
IV: before administration, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.
PO: before administration, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration.
Blood samples were collected and placed on ice and plasma was centrifuged (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ℃). The collected plasma was stored in a-80 ℃ freezer before analysis.
(3) Pharmacokinetic analysis:
according to the blood concentration data of the medicine, Phoenix is used
7.0 calculation of pharmacokinetic parameters, providing parameters such as AUC (0-t), AUC (0- ∞), MRT (0- ∞), Cmax, Tmax and t1/2, as well as their mean and standard deviation.
For samples with concentrations below the lower limit of quantitation, the pharmacokinetic parameters were calculated as non-quantifiable (BLQ).
Experiments have shown (see table below) that the compounds of the invention have better pharmacokinetic properties than the control sample TPX-0005.
Comparison of PK parameters for the example Compounds and TPX-0005 control
The above description is only an example of the present invention, and is not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or other related fields directly or indirectly are included in the scope of the present invention.
Claims (11)
1. A compound of formula I:
in formula I:
M1selected from CH or N;
M2is CH;
X1is NH or O;
X2selected from NH, O or S;
X3selected from O or NH;
w is selected from C (O), C (S) or S (O)2；
Z1、Z2、Z3、Z4、Z5、Z6And Z7Middle Z1、Z4、Z6Is N, Z2、Z3、Z5And Z7Is C or CH;
R1、R2each independently selected from H, halogen, and at least one selected from halogen;
R3selected from deuterium;
R4is selected from methyl;
R5、R6each independently selected from H, methyl, ethyl;
R7、R8each independently selected from H, methyl, ethyl;
m is 1;
n is 1.
2. A compound of formula III:
in formula III:
b is any one of a cyclopropyl ring and a cyclobutyl ring;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R7、R8m, n are as defined in claim 1.
3. A compound of formula IV:
in formula IV:
c is any one of a cyclopropyl ring and a cyclobutyl ring;
M1、M2、X1、X2、X3、W、Z1、Z2、Z3、Z4、Z5、Z6、Z7、R1、R2、R3、R4、R5、R6m, n are as defined in claim 1.
4. A compound or a pharmaceutically acceptable salt thereof for use as a protein kinase modulator, wherein the compound is selected from any one of the following compounds:
5. the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, and the inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic acid salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
6. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
and, a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
7. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, pain, a neurological disease, an autoimmune disease or inflammation.
8. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cell proliferation.
9. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
10. Use of a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting ALK, ROS1 and/or TRK kinase.
11. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.
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