CN114685460A - KRAS G12C inhibitor and application thereof in medicines - Google Patents
KRAS G12C inhibitor and application thereof in medicines Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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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- 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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- 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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- 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
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a novel compound having KRAS G12C modulating activity. The invention also relates to a method for preparing the compounds and a pharmaceutical composition containing the compoundsA pharmaceutical composition.
Description
Technical Field
The present invention relates to a novel compound having KRAS G12C modulating activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Clinical data show that RAS is the gene with the highest mutation rate in human tumors, with mutations in RAS occurring in about 20-30% of all tumors, about 98% of pancreatic cancers, 52% of colon cancers, 43% of multiple myeloma, and 32% of lung adenocarcinomas. The most common mode of mutation in RAS is point mutation, often occurring at codons 12, 13, 61, with mutations most common again at codon 12. The KRAS-G12C mutation accounted for approximately 10-20% of the KRAS mutation, and 14% in non-small cell lung cancer. At present, drug research and development aiming at KRAS mutation is one of the current new drug research hotspots.
Disclosure of Invention
The present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
X2Selected from N or CR7,R7Selected from H, halogen, C1-6Alkyl, substituted C1-6Alkyl radical, C2-6Alkenyl, substituted C2-6Alkenyl radical, C3-6Cycloalkyl or substituted C3-6A cycloalkyl group;
X3selected from N or CR8;R8Selected from H, hydroxy or oxo, C2-6Alkenyl radical, C1-6Alkoxy radical, C3-10Cycloalkyl oxy, C1-6Alkyl, 4-10 membered heterocyclyl substituted C1-6Alkyl radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylthio radical, C2-6Alkynyl, C1-6Alkylamino, amino, C1-6Aminoalkyl, carbamoyl, C1-6Carbamoylalkyl, C1-6Carboxyalkyl, cyano, C1-6Cyanoalkyl, halogen, C1-6Haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, cyano-substituted cyclopropyl C1-6Alkylene oxide radical of said C1-6Alkoxy is optionally further selected from halogen, hydroxy, C1-6Alkoxy radical, C3-8Cycloalkyl, substituted with a substituent;
l is selected from the group consisting of a bond, C1-6Alkylene radical, C2-6Alkenylene radical, C2-6Alkynylene, O (CH)2)0-3、S(CH2)0-3Or NRa(CH2)0-3Said C is1-6Alkylene radical, C2-6Alkenylene radical, C2-6Alkynylene, O (CH)2)0-3、S(CH2)0-3Or NRa(CH2)0-3Optionally further substituted with one or more RaSubstitution;
R1selected from H, -ORa、-OC(O)N(Ra)2、-N(Ra)2、-NRaC(O)Ra、-NRaC(O)N(Ra)2、-NRaS(O)Ra、-NRaS(O)2Ra、-S(=O)Ra、-S(=O)2Ra、-SRa、-S(Ra)5、-C(=O)Ra、-C(=O)ORa、-C(=O)N(Ra)2、C3-14Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C3-14Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl optionally further substituted with one or more R9Substitution; r9Selected from H, cyano, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -C0-6alkylene-ORa、-C0-6alkylene-OC (O) N (R)a)2、-C0-6alkylene-N (R)a)2、-C0-6alkylene-NRaC(O)Ra、-C0-6alkylene-NRaC(O)N(Ra)2、-C0-6alkylene-NRaS(O)Ra、-C0-6alkylene-NRaS(O)2Ra、-C0-6alkylene-S (═ O) Ra、-C0-6alkylene-S (═ O)2Ra、-C0-6alkylene-SRa、-C0-6alkylene-S (R)a)5、-C0-6alkylene-C (═ O) Ra、-C0-6alkylene-C (═ O) ORa、-C0-6alkylene-C (═ O) N (R)a)2、C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl), said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more RaSubstituted;
R3Selected from H, C2-6Alkenyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkyl, 4-10 membered heterocyclyl substituted C1-6Alkyl radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylthio radical, C2-6Alkynyl, C1-6Alkylamino, amino, C1-6Aminoalkyl, carbamoyl, C1-6Carbamoylalkyl, C1-6Carboxyalkyl, cyano, C1-6Cyanoalkyl, halogen, C1-6Haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or oxo; preferably H, halogen or C1-3An alkyl group; more preferably H;
R4、R5or R6Each independently selected from H, cyano, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -C0-6alkylene-ORa、-C0-6alkylene-OC (O) N (R)a)2、-C0-6alkylene-N (R)a)2、-C0-6alkylene-NRaC(O)Ra、-C0-6alkylene-NRaC(O)N(Ra)2、-C0-6alkylene-NRaS(O)Ra、-C0-6alkylene-NRaS(O)2Ra、-C0-6alkylene-S (═ O) Ra、-C0-6alkylene-S (═ O)2Ra、-C0-6alkylene-SRa、-C0-6alkylene-S (R)a)5、-C0-6alkylene-C (═ O) Ra、-C0-6alkylene-C (═ O) ORa、-C0-6alkylene-C (═ O) N (R)a)2、C2-6Alkenyl radical、C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl), said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more RaSubstituted;
each RaEach independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Heteroalkyl group, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
m is selected from 0, 1,2 or 3.
In some embodiments, X in formula (I)2Selected from N or CR7,R7Selected from H, halogen, C3-6Cycloalkyl or C1-3An alkenyl group.
In some embodiments, X in formula (I)3Selected from N or CR8,R8Selected from H, halogen, C1-6Alkoxy radical, C3-8Cycloalkyloxy, cyano-substituted cyclopropyl C1-6Alkylene oxide radical of said C1-6Alkoxy is optionally further selected from halogen, hydroxy, methoxy, C3-8Cycloalkyl substituents.
In some embodiments, R in formula (I)4、R5Or R6Each independently selected from H, ═ O, halogen and C1-6An alkyl group.
In some embodiments, formula (I) is selected from formula (IA):
wherein the substituents are as defined for formula (I).
In some embodiments, the compound of formula (I) is selected from:
the invention also provides a pharmaceutical composition, which is characterized by comprising at least one compound shown as the formula (I) in a therapeutically effective amount and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition, which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown in the formula (I) and pharmaceutically acceptable auxiliary materials is 0.0001: 1-10.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of a medicament.
The invention further provides a preferable technical scheme of the application:
preferably, the application is the application in preparing a medicament for treating and/or preventing cancer.
Preferably, the use is for the manufacture of a medicament for the treatment of a disease mediated by KRAS G12C. Preferably, the disease is cancer.
Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The invention also provides a method for treating and/or preventing diseases, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in a therapeutically effective amount.
The invention also provides a method for treating and/or preventing KRAS G12C mediated diseases, which comprises administering at least one compound represented by structural formula (I) or a pharmaceutical composition containing the compound to a subject in a therapeutically effective amount.
Unless otherwise indicated, general chemical terms used in the structural formulae have the usual meanings.
For example, the term "halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise specified, "alkyl" includes straight or branched chain monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Similarly, "radical1-8Alkyl group "of"1-8"refers to a group comprising 1,2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
“C1-3Alkylene "means a straight or branched chain divalent saturated hydrocarbon group, such as methylene, 1, 2-ethylene, 1, 3-propylene or 1, 2-isopropylene.
In the present invention, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition that includes "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "aryl", as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group of atoms including carbocyclic rings, having a fully conjugated pi-electron system. Preferably, aryl is a 6 to 10 membered monocyclic or bicyclic aromatic ring group. Preferably phenyl or naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
The term "heterocyclyl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring system composed of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the nitrogen or sulfur heteroatom may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl.
The term "heteroaryl", in the present invention, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-to 14-membered benzo-fused heteroaromatic ring system or polycyclic heteroaromatic ring system, which consists of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may optionally be oxidized and the heteroatoms may optionally be quaternized. The heteroaryl group may be attached at any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl group may be fused to an aryl, heterocyclyl, or heteroaryl ring, wherein the ring to which the parent structure is attached is cycloalkyl.
The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents, respectively. Typical substituents include, but are not limited to, H, -ORa、-OC(O)N(Ra)2、-N(Ra)2、-NRaC(O)Ra、-NRaC(O)N(Ra)2、-NRaS(O)Ra、-NRaS(O)2Ra、-S(=O)Ra、-S(=O)2Ra、-SRa、-S(Ra)5、-C(=O)Ra、-C(=O)ORa、-C(=O)N(Ra)2、C3-14Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C3-14Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl optionally further substituted with one or more R1Substitution; r1Selected from H, cyano, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -C0-6Alkylene-ORa、-C0-6alkylene-OC (O) N (R)a)2、-C0-6alkylene-N (R)a)2、-C0-6alkylene-NRaC(O)Ra、-C0-6alkylene-NRaC(O)N(Ra)2、-C0-6alkylene-NRaS(O)Ra、-C0-6alkylene-NRaS(O)2Ra、-C0-6alkylene-S (═ O) Ra、-C0-6alkylene-S (═ O)2Ra、-C0-6alkylene-SRa、-C0-6alkylene-S (R)a)5、-C0-6alkylene-C (═ O) Ra、-C0-6alkylene-C (═ O) ORa、-C0-6alkylene-C (═ O) N (R)a)2、C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl), said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclic group), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more RaAnd (4) substituting. Each RaEach independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Heteroalkyl group, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl. In some embodiments, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3、-SC2H5Formaldehyde group, -C (OCH)3) Cyano, nitro, -CF3、-OCF3Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
Examples of substituted alkyl groups include, but are not limited to, 2, 3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, phenylmethyl, dioxolanylmethyl, and piperazinylmethyl.
Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2, 3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
Since the compounds of formula (I) are intended for pharmaceutical use, it is preferred to use them in a certain purity, for example, at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
Prodrugs of the compounds of the present invention are included within the scope of the invention. In general, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
When a tautomer exists in the compound of formula (I), the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.
Certain therapeutic advantages may be provided when compounds of formula (I) are replaced with heavier isotopes such as deuterium, for example, which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When solvates or polymorphs exist of the compounds of formula (I) and pharmaceutically acceptable salts thereof, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.
The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as methods for preparing the compounds of the invention are also part of the invention. In addition, some crystalline forms of the compounds may exist as polymorphs and as such are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.
The pharmaceutical composition provided by the invention comprises a compound shown as a formula (I) (or pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials.
Detailed Description
In order to make the above-mentioned contents clearer and clearer, the present invention will be further illustrated by the following examples. The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art.
All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise indicated.
Synthesis of intermediate M
Step 1: synthesis of Compound M-2
Commercially available starting material M-1(10.0g) was dissolved in THF (60mL), then DIEA (14mL) and carbonyldiimidazole (10.4g) were added and reacted at room temperature for 3 h. LCMS confirmed complete conversion of starting material to intermediate. Adding ammonia water (90mL) into the other bottle, cooling to 0 ℃, dropwise adding the previous reaction liquid into the reaction bottle while stirring, and after the reaction is finished for 10min, sampling and detecting to show that the reaction liquid is converted into the product. Ethyl acetate (100mL) was added and the mixture was extracted, followed by washing with a saturated aqueous sodium chloride solution (60 mL. times.2) and separation. Adding anhydrous sodium sulfate and drying. Filtration and concentration gave M-2(9.6g, 96.9% yield) ESI-MS M/z 233.21[ M + H ]]+。
Step 2: synthesis of Compound M-3
Raw material M-2(9.6g) was added to a reaction flask, DMF (100mL) was added to dissolve, the temperature was reduced to 0 ℃ and NaH (4.1g) was added to react at 0 ℃ for 0.5h, then carbonyldiimidazole (10.1g) was added to react at 75 ℃ for 5 h. Sampling and detection showed conversion to product. Cooling, then adding water to precipitate a solid, filtering, washing the filter cake three times with water and EA, and finally drying to obtain a yellow solid M-3(8.1g, 75.5% yield) ESI-MS M/z 259.31[ M + H ]]+。
And step 3: synthesis of Compound M-4
The starting material M-3(8.0g) was charged into a reaction flask, and POCl was added thereto with stirring3(60mL), DIEA (12mL) was added and the reaction was carried out at 110 ℃ for 2 hours. Sampling revealed most conversion to product, solvent was spun dry, then added to crushed ice and extracted with EA. The organic phase was concentrated and slurried with PE: EA 2:1 and filtered to give M-4(3.8g, 41.7% yield) ESI-MS M/z 295.33[ M + H ] as a yellow solid]+。
And 4, step 4: synthesis of Compound M-5
The reaction flask was charged with M-4(3.75g), dissolved in DCM (30mL) and THF (10mL), charged with DIEA (6mL), cooled to 0 deg.C, and then charged with (S) -2- (piperazin-2-yl) acetonitrile (2.1 g). The reaction was continued at this temperature for 0.3 h. Sampling showed substantial conversion of the starting material to the product, and the solvent was spun dry to give crude yellow solid M-5(6.8g, crop) ESI-MS M/z 384.07[ M + H)]+。
And 5: synthesis of Compound M-6
The crude M-5(6.8g, loud) was added to the reaction flask, DCM (50mL) was added and DIEA (6mL) was added and (Boc) was added at 0 deg.C2O (3.5 g). After the addition, the reaction was allowed to return to room temperature for 14 h. Sampling showed that the starting material was essentially converted to the product, water and DCM were added, extracted, dried and concentrated. Flash column chromatography with DCM: MeOH 40:1 for developing solvent to give M-6(5.4g, 87.4% yield) ESI-MS M/z 484.02[ M + H ] 484.02]+。
Step 6: synthesis of intermediate M
A reaction flask was charged with M-6(5.4g) and CH3CN (50mL) was dissolved, followed by DIEA (6mL) and(s) -1-methyl-2-pyrrolidinemethanol (3.8 g). The reaction is carried out for 14h at the temperature of 80 ℃. Sampling and detecting show that most of the raw materials are converted into the product, the solvent is firstly dried by spinning, then water and DCM are added for extraction, and the mixture is dried and concentrated. Flash column chromatography with DCM: MeOH 15:1 as developing solvent gave yellow solid M (4.1g, 65.8% yield) ESI-MS M/z 563.28[ M + H]+。
Example 1: synthesis of Compound 1
Step 1: synthesis of Compound 1-2
Commercially available starting materials 1-1(2.11g) and methyltriphenylphosphonium bromide (7.14g) were charged into a reaction flask, dissolved in THF (25mL), and potassium tert-butoxide (2.24g) was dissolved in THF (25mL) and added to the reaction mixture at 0 ℃ to complete the reaction and allowed to return to room temperature for 3 hours. And (5) detecting by using a sampling point plate, and indicating that the raw materials are completely reacted. Adding EA and water, extracting, drying, and concentrating. The column was passed through a flash column and the developing solvent petroleum ether to give 1-2(1.65g, 79.3% yield) as a colorless liquid.
Step 2: synthesis of Compounds 1-3
DCM (30mL) was added to the reaction flask, the temperature was reduced to 0 deg.C, diethyl zinc solution (28.7mL) and trifluoroacetic acid (2.1mL) were added thereto, and after completion of the addition at 0 deg.C, reaction was carried out for 15min, CH was added2I2(7.69g), continuing to react at 0 ℃ for 15min, dissolving the compound 1-2(1.5g) in DCM (15mL), adding into the reaction solution, continuing to react at 0 ℃ for 15min, finally returning to room temperature for reaction for 3h,and (5) detecting by using a sampling point plate, and indicating that the raw materials are completely reacted. The reaction was quenched by addition of aqueous ammonium chloride, then extracted with DCM, dried and concentrated. The column was passed through a flash column and the developing solvent was petroleum ether to obtain a colorless liquid 1-3(1.4g, 87.6% yield).
And step 3: synthesis of Compounds 1-4
1-3(1.4000g), pinacol diboron ester (3.18g), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.51g), potassium acetate (1.85g) and 1,4-dioxane (25mL) were charged into a reaction flask, and reacted at 95 ℃ for 8 hours under nitrogen atmosphere after nitrogen substitution. And (5) detecting by using a sampling point plate, indicating that the raw materials completely react, adding EA and water for extraction, drying and concentrating. The column was run with flash, developing the solvent from PE to PE: EA 50:1 to give a pale yellow liquid 1-4(1.1g, 64.8% yield).
And 4, step 4: synthesis of Compounds 1-5
Intermediate M (0.2G), 1-4(0.14G), potassium phosphate (0.23G), Sphos-Pd-G2(0.026G), cyclopentyl methyl ether (4mL) and water (0.4mL) were added to a reaction flask, and reacted at 100 ℃ for 4h under nitrogen after nitrogen substitution. Sampling and detecting to show that the raw materials completely react, adding EA and water for extraction, drying and concentrating. Separated on large plate and the developer is purified with DCM: MeOH: ammonia 15: 1: 0.15, take 1-5(0.14g, yield: 62.9%) ESI-MS M/z 627.42[ M + H ] of the yellow solid]+。
And 5: synthesis of Compounds 1-6
To a reaction flask were added compound 1-5(0.14g), DCM (1.5mL) and trifluoroacetic acid (1.5mL) and reacted at room temperature for 0.5 h. Sampling and detecting to show that the reaction of the raw materials is complete. Adding DCM and water for extraction, drying and concentrating. To give the crude compound 1-6(120mg, crop) ESI-MS M/z 527.25[ M + H ]]+。
Step 6: synthesis of Compound 1
Adding 1-5(120mg) into a reaction bottle, adding DCM (3mL) for dissolving, adding DIEA (81mg), cooling to 0 ℃, taking acryloyl chloride (23mg), diluting, slowly adding into the reaction solution, and continuing to react at the temperature for 10min after the addition is finished. LCMS shows the reaction of the raw materials is complete, 10mL of dichloromethane is added, and then the mixture is washed with 20mL of saturated aqueous sodium chloride solution multiplied by 2 and separated. Adding anhydrous sodium sulfate, drying, filtering, concentrating, and separating with preparative plateTo the separated developing solvent was added DCM: MeOH: ammonia 18:1:0.18 to obtain white solid 1(60mg, 49.3% yield) ESI-MS M/z:581[ M + H]+,1H NMR(500MHz,CDCl3)δ7.55–7.47(m,1H),7.21(d,J=7.7Hz,1H),7.09(t,J=7.5Hz,1H),7.04(ddd,J=8.8,6.5,2.7Hz,1H),6.80(d,J=7.3Hz,1H),6.53(s,1H),6.34(d,J=16.7Hz,1H),5.77(d,J=10.4Hz,1H),4.55(ddd,J=10.8,4.6,1.8Hz,1H),4.38–4.18(m,3H),4.07–3.87(m,1H),3.83–3.47(m,2H),3.40–3.28(m,1H),3.08(t,J=7.3Hz,1H),2.95(ddt,J=23.6,16.1,7.9Hz,3H),2.72(s,2H),2.47(t,J=5.6Hz,3H),2.31–2.20(m,1H),2.04–1.90(m,3H),1.83–1.65(m,3H),1.29–1.15(m,1H),0.63–0.53(m,2H),0.52–0.46(m,1H),0.45–0.38(m,1H).
Example 2: synthesis of Compound 2
The crude product 1-6 (100mg) was added to the reaction flask, dissolved in DMF (4mL), DIEA (0.2mL) was added, followed by 2-fluoroacrylic acid (18mg), and HATU (72mg) was added and the reaction was continued at that temperature for 10 min. LCMS shows that the raw materials completely react, and after the reaction is finished, EA (100mL) is added into the system, and then the system is washed twice by saturated sodium bicarbonate aqueous solution, and then washed by saturated sodium chloride aqueous solution 20mL multiplied by 2 for liquid separation. Dried over anhydrous sodium sulfate, filtered, concentrated, separated on prep. plate, and the developing solvent is washed with DCM: MeOH: ammonia 18:1:0.18, and taken to a white solid 2(43mg, 37.7% yield) ESI-MS M/z:599[ M + H ] ESI-MS M/z]+,1H NMR(500MHz,CDCl3)δ7.57(dd,J=8.5,3.7Hz,1H),7.29(d,J=7.5Hz,1H),7.21–7.10(m,2H),6.88(d,J=7.5Hz,1H),5.45(d,J=47.5Hz,1H),5.27(dd,J=17.0,3.7Hz,1H),4.68(dt,J=10.4,4.8Hz,1H),4.45(dt,J=11.8,6.5Hz,1H),4.42–4.26(m,2H),3.30(s,1H),3.04(qt,J=16.7,8.2Hz,4H),2.89(s,2H),2.64(d,J=3.9Hz,3H),2.46(d,J=9.2Hz,1H),2.19–2.09(m,1H),2.03(q,J=9.9,8.7Hz,2H),1.97–1.80(m,3H),0.64(dp,J=13.4,5.0Hz,2H),0.60–0.53(m,2H),0.48(ddt,J=10.1,6.8,3.6Hz,1H)。
The following examples were synthesized using the methods described above, or analogous methods using the corresponding intermediates.
Pharmacological experiment
Example 1: cell proliferation inhibition assay
MIA PaCa-2 cells were plated on 96-well ultra-low adsorption plates at 600 cells, 160. mu.L/well. After overnight incubation, compound solutions of graded concentrations were prepared, and 40 μ L of test compound DMSO solutions of each concentration were added to each well of cells, respectively, at final concentrations of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.12, 0.025, 0nM (final DMSO concentrations were all 0.25%). 37 ℃ and 5% CO2And (5) incubating for 96 h. Adding 50 mu L of Cell-titer Glo working solution into each hole, shaking and uniformly mixing, incubating at room temperature for 10min, reading a Luminescence value of Luminescence by using a multifunctional microplate reader, and converting the Luminescence value reading into an inhibition percentage:
percent inhibition is (max-reading)/(max-min) 100.
"maximum" is DMSO control; "minimum" indicates a cell-free control group.
Curve fitting was performed with Graphpad Prism software and IC was obtained50The value is obtained.
The compounds of the invention have good activity. EXAMPLES IC OF COMPOUNDS ON MIA PaCa-2 CELL INHIBITION50See table 1 for data.
TABLE 1
Name of Compound | IC50(nM) |
1 | 1.09 |
2 | 11 |
Example 2: cell proliferation inhibition assay
H358 cells were plated onto 96-well ultra low-adsorption plates at 2000 cells, 190. mu.L/well. After overnight incubation, compound solutions of graded concentrations were prepared, and 10 μ L of test compound DMSO solutions at each concentration were added to each well of cells to give final concentrations of 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, and 0nM (final DMSO concentrations were all 0.25%). Incubation was carried out at 37 ℃ for 96h with 5% CO 2. Adding 50 mu L of Cell-titer Glo working solution into each hole, shaking and uniformly mixing, incubating at room temperature for 10min, reading a Luminescence value of Luminescence by using a multifunctional microplate reader, and converting the Luminescence value reading into an inhibition percentage:
percent inhibition is (max-reading)/(max-min) 100.
"maximum" is DMSO control; "minimum" indicates a cell-free control group.
Curve fitting was performed using Graphpad Prism software and IC was obtained50The value is obtained.
The compounds of the invention have good activity. IC inhibition of H358 cells by Compounds of the examples50See table 2 for data.
TABLE 2
Compound (I)Name (R) | IC50(nM) |
1 | 2.3 |
2 | 22 |
While the present invention has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims.
Claims (10)
1. A compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
X2Selected from N or CR7,R7Selected from H, halogen, C1-6Alkyl, substituted C1-6Alkyl radical, C2-6Alkenyl, substituted C2-6Alkenyl radical, C3-6Cycloalkyl or substituted C3-6A cycloalkyl group;
X3selected from N or CR8;R8Selected from H, hydroxy or oxo, C2-6Alkenyl radical, C1-6Alkoxy radical, C3-10Cycloalkanoyloxy groupBase, C1-6Alkyl, 4-10 membered heterocyclyl substituted C1-6Alkyl radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylthio radical, C2-6Alkynyl, C1-6Alkylamino, amino, C1-6Aminoalkyl, carbamoyl, C1-6Carbamoylalkyl, C1-6Carboxyalkyl, cyano, C1-6Cyanoalkyl, halogen, C1-6Haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted 4-to 10-membered heterocyclyl, cyano-substituted cyclopropyl C1-6Alkylene oxide group of said C1-6Alkoxy is optionally further selected from halogen, hydroxy, C1-6Alkoxy radical, C3-8Cycloalkyl, substituted with a substituent;
l is selected from the group consisting of a bond, C1-6Alkylene radical, C2-6Alkenylene radical, C2-6Alkynylene, O (CH)2)0-3、S(CH2)0-3Or NRa(CH2)0-3Said C is1-6Alkylene radical, C2-6Alkenylene radical, C2-6Alkynylene, O (CH)2)0-3、S(CH2)0-3Or NRa(CH2)0-3Optionally further substituted by one or more RaSubstitution;
R1selected from H, -ORa、-OC(O)N(Ra)2、-N(Ra)2、-NRaC(O)Ra、-NRaC(O)N(Ra)2、-NRaS(O)Ra、-NRaS(O)2Ra、-S(=O)Ra、-S(=O)2Ra、-SRa、-S(Ra)5、-C(=O)Ra、-C(=O)ORa、-C(=O)N(Ra)2、C3-14Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C3-14Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl optionally further substituted with one or more R9Substitution;R9selected from H, cyano, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -C0-6alkylene-ORa、-C0-6alkylene-OC (O) N (R)a)2、-C0-6alkylene-N (R)a)2、-C0-6alkylene-NRaC(O)Ra、-C0-6alkylene-NRaC(O)N(Ra)2、-C0-6alkylene-NRaS(O)Ra、-C0-6alkylene-NRaS(O)2Ra、-C0-6alkylene-S (═ O) Ra、-C0-6alkylene-S (═ O)2Ra、-C0-6alkylene-SRa、-C0-6alkylene-S (R)a)5、-C0-6alkylene-C (═ O) Ra、-C0-6alkylene-C (═ O) ORa、-C0-6alkylene-C (═ O) N (R)a)2、C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl), said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more RaSubstituted;
R3Selected from H, C2-6Alkenyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkyl, 4-10 membered heterocyclyl substituted C1-6Alkyl radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylthio radical, C2-6Alkynyl, C1-6Alkylamino, amino, C1-6Aminoalkyl, carbamoyl, C1-6Carbamoylalkyl, C1-6Carboxyalkyl, cyano, C1-6Cyanoalkyl, halogen, C1-6Haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or oxo; preferably H, halogen or C1-3An alkyl group; more preferably H;
R4、R5or R6Each independently selected from H, cyano, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -C0-6alkylene-ORa、-C0-6alkylene-OC (O) N (R)a)2、-C0-6alkylene-N (R)a)2、-C0-6alkylene-NRaC(O)Ra、-C0-6alkylene-NRaC(O)N(Ra)2、-C0-6alkylene-NRaS(O)Ra、-C0-6alkylene-NRaS(O)2Ra、-C0-6alkylene-S (═ O) Ra、-C0-6alkylene-S (═ O)2Ra、-C0-6alkylene-SRa、-C0-6alkylene-S (R)a)5、-C0-6alkylene-C (═ O) Ra、-C0-6alkylene-C (═ O) ORa、-C0-6alkylene-C (═ O) N (R)a)2、C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl), said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C0-6alkylene-C3-14Cycloalkyl, -C0-6Alkylene- (3-to 14-membered heterocyclyl), -C0-6alkylene-C6-14Aryl or-C0-6Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more RaSubstituted;
each RaEach independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Aminoalkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Heteroalkyl group, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
m is selected from 0, 1,2 or 3.
2. The compound of claim 1, wherein X is2Selected from N or CR7,R7Selected from H, halogen, C3-6Cycloalkyl or C1-3An alkenyl group.
3. A compound according to claim 1 or 2, characterised in that X3Selected from N or CR8,R8Selected from H, halogen, C1-6Alkoxy radical, C3-8Cycloalkyloxy, cyano-substituted cyclopropyl C1-6Alkylene oxide radical of said C1-6Alkoxy is optionally further selected from halogen, hydroxy, methoxy, C3-8Cycloalkyl substituents.
6. A compound according to any one of claims 1 to 5, wherein R is4、R5Or R6Each independently selected from H, ═ O, halogen and C1-6An alkyl group.
9. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient.
10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament.
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WO2023030495A1 (en) * | 2021-09-03 | 2023-03-09 | Ascentage Pharma (Suzhou) Co., Ltd. | Kras inhibitors |
WO2023039240A1 (en) * | 2021-09-13 | 2023-03-16 | Biomea Fusion, Inc. | IRREVERSIBLE INHIBITORS OF KRas |
WO2023114733A1 (en) * | 2021-12-13 | 2023-06-22 | Quanta Therapeutics, Inc. | Kras modulators and uses thereof |
US11912723B2 (en) | 2022-02-09 | 2024-02-27 | Quanta Therapeutics, Inc. | KRAS modulators and uses thereof |
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WO2023030495A1 (en) * | 2021-09-03 | 2023-03-09 | Ascentage Pharma (Suzhou) Co., Ltd. | Kras inhibitors |
WO2023039240A1 (en) * | 2021-09-13 | 2023-03-16 | Biomea Fusion, Inc. | IRREVERSIBLE INHIBITORS OF KRas |
WO2023114733A1 (en) * | 2021-12-13 | 2023-06-22 | Quanta Therapeutics, Inc. | Kras modulators and uses thereof |
US11912723B2 (en) | 2022-02-09 | 2024-02-27 | Quanta Therapeutics, Inc. | KRAS modulators and uses thereof |
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