CN115260195A - EGFR degradation agent - Google Patents
EGFR degradation agent Download PDFInfo
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- CN115260195A CN115260195A CN202210451380.5A CN202210451380A CN115260195A CN 115260195 A CN115260195 A CN 115260195A CN 202210451380 A CN202210451380 A CN 202210451380A CN 115260195 A CN115260195 A CN 115260195A
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- alkyl
- cancer
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- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 title abstract description 14
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 title abstract description 14
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- ZRBFSULGNPXCMK-UHFFFAOYSA-N isothiocyanic acid;toluene Chemical compound N=C=S.CC1=CC=CC=C1 ZRBFSULGNPXCMK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
The present invention provides novel compounds that degrade the EGFR protein, pharmaceutical compositions containing such compounds, useful intermediates for preparing such compounds, and methods of treating cell proliferative diseases, such as cancer, using the compounds of the invention.
Description
Technical Field
The present invention is in the field of medicinal chemistry and in particular relates to a novel class of compounds which degrade EGFR proteins, pharmaceutical compositions containing said compounds, useful intermediates for preparing said compounds and methods of treating cell proliferative diseases, such as cancer, using the compounds of the invention.
Background
EGFR, i.e., epidermal growth factor receptor (epidermal growth factor receptor), is widely distributed on the cell surface of mammalian epithelial cells, fibroblasts, glial cells, and the like. The EGFR signaling pathway plays an important role in physiological processes such as growth, proliferation and differentiation of cells. EGFR mutations are also one of the most common types of mutations in NSCLC patients, and can account for 40% to 50% of the asian population, among others. EGFR has therefore been one of the hottest targets in the field of drug development.
Currently, EGFR inhibitors on the market are classified into the first, second and third generations. The first generation are reversible targeted drugs such as gefitinib, erlotinib. The second generation is irreversible targeted drugs such as afatinib and dacatinib. Although the first and second generation targeted drugs have remarkable curative effect, most patients have drug resistance after 1-2 years of drug use. Of the patients resistant to EGFR inhibitors, 50% of resistance is associated with the T790M mutation. The third generation EGFR targeting drug oxicetinib can overcome tumor drug resistance caused by T790M mutation, and brings better survival benefit to more lung cancer patients. However, the third generation of targeting drugs inevitably generates drug resistance, and the drug resistance is mainly caused by C797S mutation. The C797S mutation is embodied by mutation of a cysteine residue to serine, which disrupts the binding of the EGFR protein to third generation targeted drugs, thereby failing to prevent phosphorylation of the EGFR protein and activation of downstream signaling pathways. At present, no mature treatment means exists for the response of the drug resistance of the oxitinib, the clinical requirement is urgent, and the invention is generated based on solving the problem.
Disclosure of Invention
The invention aims to provide a novel compound capable of degrading EGFR protein, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound and application of the compound in preparing a medicament for treating cancer.
The invention provides a compound shown in a formula (I-1) or a pharmaceutically acceptable salt thereof,
wherein R is1Selected from H, C1-4Alkyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or 5-7 membered heterocycloalkyl, and said C1-4Alkyl or 5-7 membered heterocycloalkyl optionally substituted with one or more R11Substituted by a group.
X1Is selected from-C (= O) or N;
X2is selected from N or CH;
X3is selected from N or C;
X1and X3Are connected with each other
Represents a single or double bond;
L1is C1-4Alkylene, wherein said C1-4The alkylene group may be further optionally substituted by one or more U groups selected from O, S, NH or NRuaWherein R isuaIs C1-4An alkyl group;
or, L1Is a connecting bond;
R2is H, C1-6Alkyl or C3-5A cycloalkyl group;
L2is C1-4Alkylene oxideWherein said C is1-4The alkylene group may be further optionally substituted with one or more Q groups selected from C ≡ C, O, S, NH, NRqa-NHC (O) -or-C (O) NH-, wherein RqaIs C1-4An alkyl group;
or, L2Is a connecting bond;
ring A is selected from-C6-10Aryl or 6-10 membered heteroaryl;
ring B is C6-10Aryl, 5-10 membered heteroaryl, 5-6 membered heterocycloalkyl, or partially saturated 5-6 membered heterocycloalkyl;
R3selected from H, halogen, C2-4Alkynyl, C1-4Alkyl radical, C1-4Alkoxy radical, C3-5Cycloalkyl, -S (O)2R10、-P(O)(R13)R14Or C6-10An aryl group;
or two adjacent R3Cyclisation to C4-6Cycloalkyl fused to ring a;
R4selected from H, halogen or C1-4An alkyl group;
m and n are each independently selected from 0, 1, 2 or 3;
s and t are each independently selected from 0, 1 or 2;
R5and R6Each independently selected from H or C1-4An alkyl group;
R7and R8Each independently selected from H or C1-4An alkyl group;
or, R7And R8Together with the N atom to which they are attached form a 3-5 membered heterocycloalkyl, said 3-5 membered heterocycloalkyl optionally further substituted with one or more R12Substituted by a group;
R9is selected from C1-4Alkyl or C3-5A cycloalkyl group;
R10is C1-4An alkyl group;
R11selected from OH, halogen, C1-4Alkyl radical, C6-10Aryl or 5-7 membered heteroaryl;
R12selected from OH, halogen or C1-4An alkyl group;
R13and R14Each independently selected from OH or C1-4An alkyl group.
In some embodiments of the invention, L is1Is selected from-CH2-、-CH2CH2-or-CH2NH-; or L1Is a connecting bond.
In some embodiments of the present invention, L is2Is selected from-CH2-、-CH2CH2-、-NHCH2-、-CH2NH-, -NHC (O) -; or L2Is a connecting key.
In some embodiments of the invention, R is as defined above2Is H.
In some embodiments of the invention, the ring B is C6-10And (3) an aryl group.
In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from,
wherein R is1Selected from H, C1-4Alkyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or 5-7 membered heterocycloalkyl, and said C1-4Alkyl or 5-7 membered heterocycloalkyl optionally substituted with one or more R11Substituted by a group.
X1Selected from-C (= O) or N;
X2is selected from N or CH;
X3is selected from N or C;
X1and X3Are connected with each other
Represents a single or double bond;
R2is H;
ring A is selected from C6-10Aryl or 6-10 membered heteroaryl;
ring B is C6-10An aryl group;
R3selected from H, halogen, C2-4Alkynyl, C1-4Alkyl radical, C1-4Alkoxy radical, C3-5Cycloalkyl, -S (O)2R10、-P(O)(R13)R14Or C6-10An aryl group;
or two adjacent R3Cyclisation to C4-6Cycloalkyl is fused to ring a;
R4selected from H, halogen or C1-4An alkyl group;
m and n are each independently selected from 0, 1, 2 or 3;
s and t are each independently selected from 0, 1 or 2;
R5and R6Each independently selected from H or C1-4An alkyl group;
R7and R8Each independently selected from H or C1-4An alkyl group;
or, R7And R8Together with the N atom to which they are attached form a 3-5 membered heterocycloalkyl, said 3-5 membered heterocycloalkyl optionally further substituted with one or more R12Substituted by a group;
R9is selected from C1-4Alkyl or C3-5A cycloalkyl group;
R10is C1-4An alkyl group;
R11selected from OH, halogen, C1-4Alkyl radical, C6-10Aryl or 5-7 membered heteroaryl;
R12selected from OH, halogen or C1-4An alkyl group;
R13and R14Each independently selected from OH or C1-4An alkyl group.
In some embodiments of the present invention, the first and second,
wherein R is1Selected from H, C1-4Alkyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or 5-7 membered heterocycloalkyl, and said C1-4Alkyl or 5-7 membered heterocycloalkyl optionally substituted with one or more R11Substituted by a group;
X1is selected from-C (= O) or N;
X2is selected from N or CH;
X3is selected from N or C;
X1and X3Are connected with each other
Represents a single or double bond;
R2is H, C1-6Alkyl or C3-5A cycloalkyl group;
ring A is selected from C6-10Aryl or 6-10 membered heteroaryl;
ring B is C6-10An aryl group;
R3selected from halogen, C2-4Alkynyl, C1-4Alkyl radical, C1-4Alkoxy radical, C3-5Cycloalkyl, -S (O)2R10、-P(O)(R13)R14Or C6-10An aryl group;
or two adjacent R3Cyclisation to C4-6Cycloalkyl fused to ring a;
R4selected from halogen or C1-4An alkyl group;
m and n are each independently selected from 0, 1, 2 or 3;
s and t are each independently selected from 0, 1 or 2;
R5and R6Each independently selected from H or C1-4An alkyl group;
R7and R8Each independently selected from H or C1-4An alkyl group;
or, R7And R8Together with the N atom to which they are attached form a 3-5 membered heterocycloalkyl, said 3-5 membered heterocycloalkyl optionally further substituted with one or more R12Substituted by a group;
R9is selected from C1-4Alkyl or C3-5A cycloalkyl group;
R10is C1-4An alkyl group;
R11selected from OH, halogen, C1-4Alkyl radical, C6-10Aryl or 5-7 membered heteroaryl;
R12selected from OH, halogen or C1-4An alkyl group;
R13and R14Each independently selected from OH or C1-4An alkyl group.
In some embodiments of the invention, R is as defined above5Is a tert-butyl group.
In some embodiments of the invention, R is as defined above6Is methyl and s is 2.
In some embodiments of the invention, R is as defined above7And R8Each independently selected from H, methyl or ethyl;
or, R7And R8Together with the N atom to which they are attached form an azetidinyl group, said azetidinyl group optionally further substituted with one or more R12Substituted by a group;
R12is F;
t is selected from 0 or 1.
In some embodiments of the invention, R is as defined above9Selected from methyl or cyclopropyl.
In some embodiments of the invention, R is as defined above10Selected from methyl or isopropyl.
In some embodiments of the invention, R is as defined above13And R14Each independently is methyl.
In some embodiments of the invention, R is as defined above1Selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or tetrahydropyranyl, and said methyl or isobutyl group is optionally substituted by one or more R11Substituted by a group;
R11selected from OH, H,Phenyl or pyridyl.
In some embodiments of the invention, R is as defined above1Selected from H, methyl, ethyl, isopropyl,
In some embodiments of the invention, ring A is selected from
In some embodiments of the invention, R is as defined above3Selected from F, cl, ethynyl, methyl, ethyl, methoxy, cyclopropyl, -S (O)2CH3、-P(O)(CH3)CH3Or a phenyl group;
or, two adjacent R3Cyclisation is cyclopentyl fused to ring a, ring a being as defined in any of claims 1 to 9; m is selected from 0, 1 or 2.
In some embodiments of the invention, the structural unit
Is selected from
In some embodiments of the invention, ring B is phenyl.
In some embodiments of the invention, R is as defined above4Selected from Br or methyl; n is selected from 0 or 1.
In some embodiments of the invention, the structural unit
Is selected from
In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from:
wherein R is1、R3、R4、X1、X3M, n and ring a are as defined above.
In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from:
wherein R is1、R3、R4M, n and ring a are as defined above.
In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from:
wherein R is1、R3、R4M and n are as defined above.
The present invention also provides a compound selected from:
the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for treating cancer.
In some embodiments of the invention, the cancer comprises lymphoma, non-hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), acute Myeloid Leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, or melanoma.
In some embodiments of the invention, the cancer is lung cancer.
The invention also provides an intermediate compound shown in a formula (Z-3), a formula (Z-5) or a formula (Z-6) or a stereoisomer and a pharmaceutically acceptable salt thereof,
wherein PG is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl;
R15is selected from H or C1-4An alkyl group;
R2、R3、R4、X1、X2、X3m, n, ring A and ring B are as defined above.
In some embodiments of the invention, the intermediate is selected from the group consisting of:
wherein PG is tert-butyloxycarbonyl;
R15selected from H, methyl or ethyl;
R3、R4m and n are as defined above.
The invention also provides a preparation method of the compound shown in the formula (I),
deprotecting a compound represented by the formula (Z-5) under acidic conditions to give a compound represented by the formula (Z-6), and introducing R1The compound shown in the formula (I) is prepared,
wherein PG is selected from tert-butyloxycarbonyl or benzyloxycarbonyl, and the acid is selected from hydrochloric acid, acetic acid, trifluoroacetic acid or hydrobromic acid;
R1、R2、R3、R4、X1、X2、X3m, n, ring A and ring B are as defined above.
The invention also provides a preparation method of the compound of the formula (Z-5), which is characterized in that,
prepared by acylating a compound represented by the formula (Z-3) or a salt thereof with a compound represented by the formula ((Z-4) or a salt thereof by a condensing agent,
wherein the condensing agent is selected from 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide;
PG、R2、R3、R4、X1、X2、X3m, n, ring A and ring B are as defined above.
The present invention also provides a process for the preparation of a compound of formula (Z-3), characterized in that:
prepared by coupling reaction of a compound represented by the formula (Z-1) or a salt thereof with a compound represented by the formula ((Z-2) or a salt thereof in a palladium/copper catalytic system,
wherein R is15Selected from H or ethyl;
R16is composed of
The palladium/copper catalytic system is a palladium/copper catalytic system which is tetrakis (triphenylphosphine) palladium/thiophene-2-cuprous formate (I), dichlorobis (triphenylphosphine) palladium/thiophene-2-cuprous formate (I) or palladium acetate/bis (2-diphenylphosphinophenyl) ether/thiophene-2-cuprous formate (I);
PG、R4、X1、X2、X3n and ring B are as defined above.
The present invention also provides a process for preparing the above compound or a pharmaceutically acceptable salt thereof, wherein the representative preparation route is as shown in the following scheme:
wherein PG and R15、R16、R1、R2、R3、R4、X1、X2、X3M, n, ring A and ring B are as defined above.
Carrying out coupling reaction on a compound shown in a formula (Z-1) or a salt thereof and a compound shown in a formula ((Z-2) or a salt thereof under a palladium/copper catalytic system to prepare a compound shown in a formula (Z-3), wherein the palladium/copper catalytic system is tetrakis (triphenylphosphine) palladium/thiophene-2-cuprous formate (I), dichlorobis (triphenylphosphine) palladium/thiophene-2-cuprous formate (I) or palladium acetate/bis (2-diphenylphosphinophenyl) ether/thiophene-2-cuprous formate (I);
the compound or the salt thereof shown in the formula (Z-3) and the compound or the salt thereof shown in the formula ((Z-4) are subjected to acylation reaction under the action of a condensing agent and alkali to prepare the compound or the salt thereof, wherein the condensing agent is selected from 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI) or 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU);
deprotecting the compound represented by the formula (Z-5) under acidic conditions to give a compound represented by the formula (Z-6), and introducing R1The preparation of the compound of formula (I), R1The groups may be introduced by nucleophilic substitution reactions, e.g. using R1X is a halogen as a reactant, including but not limited to introduction of 2-methoxyethyl by using 1-iodo-2 methoxyethane, introduction of methanesulfonyl chloride, introduction of methyl iodide to methyl, and the like. The methyl and ethyl can be introduced by formaldehyde and acetaldehyde aqueous solution, and then reduced by sodium borohydride acetate and the like.
Interpretation of terms
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention which are prepared with relatively nontoxic acids or bases. These salts may be prepared during synthesis, isolation, purification of the compounds, or by reacting the free form of the purified compound with a suitable acid or base. When the compound contains relatively acidic functional groups, the compound can be reacted with alkali metal, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including cations based on alkali metal and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, amine cations, and the like. When the compound contains a relatively basic functional group, the compound is reacted with an organic acid or an inorganic acid to obtain an acid addition salt.
The compounds provided herein also include prodrug forms, meaning compounds that are rapidly converted in vivo to the parent compound of the above formula, and which are converted to the compounds of the invention by chemical or biochemical means in an in vivo or in vitro environment, for example by hydrolysis in blood.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of the present invention exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic and other mixtures thereof, all of which are within the scope of the present invention.
The term "enantiomer" refers to stereoisomers that are mirror images of each other.
The term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and a relationship between the molecules that is not a mirror image.
The term "cis-trans isomer" refers to a configuration in which a double bond or a single bond of a ring-forming carbon atom in a molecule does not exist freely in rotation.
Stereoisomers of the compounds of the invention may be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the invention may be prepared by asymmetric catalysis techniques or by chiral auxiliary derivatization techniques. Or a compound with a single spatial configuration is obtained from a mixture by a chiral resolution technology. Or by using chiral starting materials. The separation of optically pure compounds in the present invention is usually accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the separation of chiral compounds.
The invention also includes isotopically-labeled compounds, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) Cl. Compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
When a substituent bond can cross-link to two atoms on a ring, such substituent can be bonded to any atom on the ring.
For example, in
Represents R3Substitution can occur at any position of ring a and, likewise,
represents R4Substitution may occur at any position on ring B.
The term "pharmaceutically acceptable carrier" refers to vehicles generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, depending on the mode of administration and nature of the dosage form, for example, adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antimicrobials, antifungals, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated by one of ordinary skill in the art within the purview of one of ordinary skill in the art based on a variety of factors. Which include but are not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients as may be included in the formulation for a variety of reasons (e.g., to stabilize the active agent, binder, etc.) are well known to those of ordinary skill in the art. The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition. The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to treat a disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prevention. It will be appreciated, however, that the total daily amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a composition of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof of the present invention for use in mammals, particularly humans, may be from 0.001 to 1000mg/kg body weight/day, for example from 0.01 to 100mg/kg body weight/day, for example from 0.01 to 10mg/kg body weight/day.
The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical feasibility, for example, the term "optionally substituted with one or more R11By substituted is meant that the substituent may be substituted by one or more R11Substituted or not with R11And (4) substitution. When any variable (e.g. R)11) Where a compound occurs more than one time in its composition or structure, its definition in each case is independent. For example, if a group is substituted by 0-2R11Substituted, said group may optionally be substituted with up to two R11Substituted, and R in each case11There are separate options.
Unless otherwise specified, "ring" refers to monocyclic and polycyclic rings, saturated, partially saturated or unsaturated, including bicyclic, spirocyclic, bicyclic or bridged rings. Representative "rings" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "hetero" denotesSubstituted or unsubstituted heteroatoms, typically selected from N, O, S, and oxidized forms of heteroatoms, typically including NO, SO, S (O)2The nitrogen atom may be substituted, i.e. NR (R is H or other substituent as defined herein); the number of atoms in a ring is generally defined as the number of ring members, e.g., "5-7 membered heterocycloalkyl" means a mono-, di-, spiro-, hetero-, or bridged heterocyclic ring of 5-7 atoms arranged around, each ring optionally containing 1-3 heteroatoms, i.e., N, O, S, NO, SO, S (O)2Or NR.
Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group, including spiro, fused or bridged cyclic groups, which are identical to fused groups when the bridge atom in the bridged cyclic group is zero. The 3-to 8-membered cycloalkyl group is preferably a 3-to 8-membered monocycloalkyl group, more preferably a 3-to 5-membered monocycloalkyl group, and examples of these monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like;
unless otherwise specified, "heterocycloalkyl" refers to mono-and poly-heterocycloalkyl groups containing a number of heteroatoms in the ring, typically selected from N, O, S, NO, SO, S (O)2And NR. Polyheterocycloalkyl includes spiroheterocyclyl, heterocyclo or bridged heterocyclyl, i.e., bridged heterocyclyl is equivalent to fused heterocyclyl when the bridge atom in the bridged heterocyclyl is zero. 3-8 membered heterocycloalkyl is preferably 3-8 membered monoheterocycloalkyl, examples of which include, but are not limited to, oxiranyl, azetidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1, 3-dioxolane, 1, 4-dioxane, and the like.
Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group that may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom (N, O, S, NO, SO, S (O)2Or NR. ).Preferably 5-12 membered heteroaryl, more preferably 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heteroaryl; preferably comprising carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, and the like pyrazinyl, oxazolyl, benzoxazolyl, isoxazolyl, and the like thiazolyl, furyl, thienyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, thienyl, pyrrolyl, and thienyl,
Unless otherwise specified, the term "alkyl" is used to denote a straight or branched chain saturated hydrocarbon group. Preferably C1-6More preferably C1-4, and examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, n-hexyl, and the like.
Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Preferably C2-8Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Preferably C2-8Alkynyl, examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
Unless otherwise specified, the term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.
It is specifically stated that all combinations of substituents and/or variants thereof herein are permissible only if such combinations result in stable compounds.
In the examples of the invention, the title compound was named after the structural transformation of the compound by means of Chemdraw. If the name of the compound is inconsistent with the structure of the compound, the name of the compound can be determined by integrating related information and assisting a reaction route; otherwise, the given structural formula of the compound is subject to no confirmation. The preparation methods of some compounds in the present invention refer to the preparation methods of the similar compounds described above. It will be understood by those skilled in the art that the ratio of the reactants, the reaction solvent, the reaction temperature, etc. may be appropriately adjusted according to the reactants when the preparation method cited herein is used or referred to.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
Abbreviations and their corresponding chemical names used in the examples of the present invention are as follows:
| abbreviations | Chemical name |
| Boc | Tert-butyloxycarbonyl radical |
| CuTC | Thiophene-2-carboxylic acid cuprous (I) |
| Lawson's reagent | 2, 4-bis (p-methoxyphenyl) -1, 3-dithiodiphosphetane-2, 4 sulfide |
| DMF | N, N-dimethylformamide |
| HATU | 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate |
| DIPEA | N, N-diisopropylethylamine |
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limited in any way. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated methanol (CD 3 OD) and/or deuterated chloroform (CDCl 3) as solvents and Tetramethylsilane (TMS) as internal standard.
LC-MS measurement was performed by Agilent 1260-6125B single square spectrometer or Waters H-Class SQD2 spectrometer (electrospray ionization as ion source). HPLC measurements were performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
Preparative high performance liquid chromatography was performed using Waters 2555-2489 (10 μm, ODS 250 cm. Times.5 cm) or GILSON Trilution LC, a Welch XB-C18 column (5. Mu.m, 21.2. Times.150mm).
The thin layer chromatography silica gel plate is a GF254 silica gel plate of Nicotiana tianjiangyou silica gel development company Limited or a GF254 silica gel plate of Nippon New Material company Limited in Mount Runshan, the specification adopted by TLC is 0.15-0.20 mm, the preparation type is 20x 20cm, and the column chromatography is generally used for forming 200-300-mesh silica gel in chemical engineering as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade.
Example 1
(E) -3- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
step 1: 2-amino-2- (4-bromophenyl) acetic acid (5.0g, 21.8mmol) was dissolved in methanol (100 mL), and thionyl chloride (3.9g, 33.0mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature overnight. The reaction solution is decompressed and concentrated to obtain crude 2-amino-2- (4-bromophenyl) methyl acetate hydrochloride which is directly used for the next reaction.
MS(ESI)M/Z:244.1[M+H]+.
Step 2: methyl 2-amino-2- (4-bromophenyl) acetate hydrochloride (6.2 g, crude) was dissolved in concentrated aqueous ammonia (40 mL) and stirred at room temperature for 2 days. White precipitate was separated out and filtered. The filter cake was dried in vacuo to give 2.6g of 2-amino-2- (4-bromophenyl) acetamide.
MS(ESI)M/Z:229.0[M+H]+.
And 3, step 3: 2-amino-2- (4-bromophenyl) acetamide (2.4 g,10.5 mmol) and tert-butyl 4-piperidone-1-carboxylate (2.1g, 10.5 mmol) were dissolved in ethanol (80 mL), and the reaction was heated to reflux under nitrogen and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was dissolved in methylene chloride (80 mL), NBS (1.9g, 10.7mmol) was added, and the mixture was stirred at room temperature overnight. After dilution with dichloromethane (100 mL), the mixture was washed with saturated aqueous sodium bicarbonate (100 mL. Times.2). The organic phase is dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to give 2.1g of tert-butyl 2- (4-bromophenyl) -3-oxo-1, 4, 8-triazaspiro [4.5] dec-1-ene-8-carboxylate.
MS(ESI)M/Z:408.1[M+H]+.
And 4, step 4: tert-butyl 2- (4-bromophenyl) -3-oxo-1, 4, 8-triazaspiro [4.5] dec-1-ene-8-carboxylate (1.0 g,2.5 mmol) was dissolved in anhydrous toluene (30 mL), and Lawson's reagent (993mg, 2.5 mmol) was added in portions, and the mixture was heated to 100 ℃ and stirred for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to give 800mg of tert-butyl 2- (4-bromophenyl) -3-thio-1, 4, 8-triazaspiro [4.5] dec-1-ene-8-carboxylate.
MS(ESI)M/Z:422.2[M-H]﹣.
And 5: tert-butyl 2- (4-bromophenyl) -3-thioxo-1, 4, 8-triazaspiro [4.5] dec-1-ene-8-carboxylate (400mg, 0.95mmol) and (E) -3-boronic acid pinacol ester-ethyl acrylate (320mg, 1.4 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), and CuTC (360mg, 1.9mmol) and tetrakis (triphenylphosphine) palladium (109mg, 0.09mmol) were added. The reaction was heated to reflux under nitrogen atmosphere and stirred overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with 25% concentrated aqueous ammonia (20 mL. Times.2). The organic phase was washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to give 270mg of (E) -2- (4-bromophenyl) -3- (3-ethoxy-3-oxopropyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:490.4[M+H]+.
Step 6: to a mixed solution of tert-butyl (E) -2- (4-bromophenyl) -3- (3-ethoxy-3-oxopropyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (260mg, 0.53mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added sodium hydroxide (86mg, 2.1mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, the pH of the reaction mixture was adjusted to 5 with 1M diluted hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 245mg of (E) -3- (3- (4-bromophenyl) -8- (tert-butoxycarbonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylic acid.
MS(ESI)M/Z:460.3[M-H]﹣.
And 7: (E) -3- (3- (4-bromophenyl) -8- (tert-butoxycarbonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylic acid (2454 mg, 0.53mmol) and 3-aminoquinoline (115mg, 0.80mmol) were dissolved in DMF (10 mL) and HATU (262mg, 0.69mmol) and DIPEA (205mg, 1.6 mmol) were added. The reaction was stirred at room temperature overnight, poured into water (90 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated brine (80 mL. Times.2), dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to give 190mg of (E) -2- (4-bromophenyl) -3- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:588.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ10.99(s,1H),8.97(d,J＝2.4Hz,1H),8.83(d,J＝2.0Hz,1H),7.99-7.95(m,2H),7.82-7.80(m,2H),7.73-7.71(m,2H),7.68-7.53(m,3H),7.25(d,J＝15.2Hz,1H),3.72(br s,4H),1.73(br s,4H),1.46(s,9H).
And 8: to a solution of (E) -2- (4-bromophenyl) -3- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylic acid tert-butyl ester (180mg, 0.31mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to give 140mg of (E) -3- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:488.3[M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.29(s,1H),9.05(d,J＝2.4Hz,1H),8.85(d,J＝2.4Hz,1H),7.99-7.93(m,2H),7.83-7.73(m,4H),7.69-7.52(m,3H),7.35(d,J＝15.2Hz,1H),3.36(br s,4H),2.03(br s,4H).
And step 9: (E) -3- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide (140mg, 0.29mmol), 36% aqueous formaldehyde (76mg, 0.92mmol) and acetic acid (37mg, 0.62mmol) were dissolved in tetrahydrofuran (15 mL), and sodium borohydride acetate (195mg, 0.92mmol) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (30 mL) was added and extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to give 105mg of the final product (E) -3- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:502.3[M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.01(s,1H),8.97(d,J＝2.4Hz,1H),8.83(d,J＝2.4Hz,1H),7.99-7.95(m,2H),7.82-7.60(m,6H),7.54(d,J＝15.2Hz,1H),7.26(d,J＝15.6Hz,1H),2.85(br s,4H),2.49(br s,3H),1.90(br s,4H).
The following target product was prepared according to the synthesis method of example 1:
example 6
(E) -3- (8-methyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-dien-2-methyl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
starting from 2-amino-2- (p-tolyl) acetic acid, 150mg of the final product (E) -3- (8-methyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-dien-2-methyl) -N- (quinolin-3-yl) acrylamide were prepared according to the procedure of example 1.
MS(ESI)M/Z:438.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.05(s,1H),8.90(d,J＝2.4Hz,1H),8.84(d,J＝2.0Hz,1H),7.99-7.95(m,2H),7.70-7.55(m,5H),7.40(d,J＝8.0Hz,2H),7.30(d,J＝15.2Hz,1H),2.85(br s,4H),2.51(s,3H),2.50(br s,3H),1.85(br s,4H).
Example 7
(E) -3- (8-methyl-3-phenyl-1, 4, 8-triazaspiro [4.5] decane-1, 3-dien-2-methyl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
starting from 2-amino-2-phenylacetic acid, 20mg of the final product (E) -3- (8-methyl-3-phenyl-1, 4, 8-triazaspiro [4.5] decane-1, 3-dien-2-methyl) -N- (quinolin-3-yl) acrylamide were prepared according to the procedure of example 1.
MS(ESI)M/Z:424.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ10.07(s,1H),8.99(s,1H),8.84(d,J＝2.0Hz,1H),7.96(t,J＝8.4Hz,2H),7.77-7.55(m,8H),7.31(d,J＝15.2Hz,1H),2.89(br s,4H),2.50(s,3H),1.89(br s,4H).
Example 8
(E) -3- (8-Ethyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-dien-2-methyl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
step 1: (E) -tert-butyl 2- (3-oxo-3- (quinolin-3-amino) propyl-1-enyl) -3-p-tolyl-1, 4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (303mg, 0.58mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride-containing ethyl acetate (6M, 0.6mL,3.6 mmol) was added thereto and the mixture was stirred at room temperature for 1 hour. A white solid precipitated, which was filtered and dried in vacuo to give 230mg of (E) -N- (quinolin-3-yl) -3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide hydrochloride.
MS(ESI)M/Z:424.2[M+H]+.
Step 2: (E) -N- (quinolin-3-yl) -3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide hydrochloride (100mg, 0.22mmol) and triethylamine (89mg, 0.88mmol) were dissolved in tetrahydrofuran (3 mL), and acetaldehyde (29mg, 0.66mmol) and sodium borohydride acetate (208mg, 0.98mmol) were added and stirred at room temperature overnight. Water (15 mL) was added to dilute the solution, and the solution was extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give 6.8mg of the final product (E) -3- (8-ethyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-methyl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:452.1[M+H]+.
1H NMR(400MHz,CDCl3):δ8.91(br s,2H),8.04(d,J＝8.4Hz,1H),7.83-7.75(m,2H),7.64-7.54(m,4H),7.29-7.23(m,3H),2.99(br s,4H),2.72(q,J＝7.2Hz,2H),2.40(s,3H),2.26(br s,4H),1.23(t,J＝7.2Hz,3H).
The following target product was prepared according to the synthesis method of example 8:
example 12
(E) -3- (8- (2-methoxyethyl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
(E) -N- (quinolin-3-yl) -3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide hydrochloride (50mg, 0.11mmol) was dissolved in N, N-dimethylformamide (6 mL), and potassium carbonate (60mg, 0.44mmol) and 1-iodo-2-methoxyethane (20mg, 0.27mmol) were added in this order, and the reaction was stirred at room temperature overnight. LCMS detection showed disappearance of starting material, quench the reaction with water (10 mL), extract the mixture with ethyl acetate (20 mL × 3 times), combine the organic phases, wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give 14.6mg of the final product (E) -3- (8- (2-methoxyethyl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:482.3[M+H]+.
1H NMR(400MHz,DMSO-d6):δ10.98(s,1H),8.97(s,1H),8.83(s,1H),7.96(t,J＝7.6Hz,2H),7.67-7.54(m,5H),7.39(d,J＝8.0Hz,2H),7.28(d,J＝15.6Hz,1H),3.53(t,J＝6.0Hz,2H),3.28(s,3H),2.83(br s,4H),2.67(br s,2H),2.49(s,3H),1.79(br s,4H).
The following target product was prepared according to the synthesis method of example 12:
example 17
(E) -3- (8- (2- (3, 3-difluoroazetidin-1-yl) -2-oxoethyl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
step 1: (E) -N- (quinolin-3-yl) -3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide hydrochloride (50mg, 0.11mmol) was dissolved in tetrahydrofuran (6 mL), and N, N-diisopropylethylamine (56mg, 0.44mmol) and tert-butyl bromoacetate (21mg, 0.11mmol) were added in this order and stirred at room temperature overnight. LCMS detection showed disappearance of starting material, water (10 mL) was added to the reaction and the mixture was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude tert-butyl (E) -2- (2- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-8-yl) acetate, which was used directly in the next reaction.
MS(ESI)M/Z:538.3[M+H]+.
And 2, step: tert-butyl (E) -2- (2- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-8-yl) acetate (58 mg, crude) was dissolved in tetrahydrofuran and water (3 mL/3 mL), and lithium hydroxide monohydrate (27mg, 0.66mmol) was added and stirred at room temperature overnight. LCMS detection showed disappearance of starting material, water (10 mL) was added to the reaction system, and pH =6-7 was adjusted with 3N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (E) -2- (2- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-8-yl) acetic acid, which was used directly in the next reaction.
MS(ESI)M/Z:482.3[M+H]+.
And 3, step 3: (E) -2- (2- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-8-yl) acetic acid (52 mg, crude) and N, N-diisopropylethylamine (70mg, 0.55mmol) were dissolved in dichloromethane (6 mL), HATU (62mg, 0.11mmol) and 3, 3-difluorotrimethylene imine hydrochloride (14mg, 0.11mmol) were added and stirred at room temperature overnight. LCMS detection showed disappearance of starting material, water (10 mL) was added to the reaction and the mixture was extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to give 22.8mg of the final product (E) -3- (8- (2- (3, 3-difluoroazetidin-1-yl) -2-oxoethyl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:557.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.01(s,1H),8.98(s,1H),8.84(s,1H),7.97(t,J＝7.2Hz,2H),7.69-7.54(m,5H),7.39(d,J＝8.0Hz,2H),7.27(d,J＝15.6Hz,1H),4.77(t,J＝13.2Hz,2H),4.33(t,J＝12.8Hz,2H),3.51(s,2H),2.83(br s,4H),2.41(s,3H),1.99-1.75(m,4H).
Example 18
(E) -N-Ethyl-2- (3-oxo-3- (quinolin-3-ylamino) -propyl-1-en-1-yl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxamide
The reaction process comprises the following steps:
the reaction steps are as follows:
(E) -N- (quinolin-3-yl) -3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide (50mg, 0.12mmol) was dissolved in dichloromethane (6 mL), and triethylamine (26mg, 0.26mmol) and ethyl isocyanate (17mg, 0.24mmol) were added in this order, followed by stirring at room temperature overnight. Upon detection by LCMS, the starting material disappeared, and water (10 mL) was added to the reaction system, and the mixture was extracted with methylene chloride (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give 7.2mg of the final product (E) -N-ethyl-2- (3-oxo-3- (quinolin-3-ylamino) -propyl-1-en-1-yl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxamide.
MS(ESI)M/Z:495.3[M+H]+.
1H NMR(400MHz,CDCl3):δ10.13(s,1H),9.04(s,2H),8.09(d,J＝8.4Hz,1H),7.85-7.77(m,2H),7.66-7.54(m,4H),7.38(d,J＝15.2Hz,1H),7.30(d,J＝8.0Hz,2H),4.73(br s,1H),3.89-3.84(m,4H),3.38(q,J＝7.2Hz,2H),2.42(s,3H),1.89-1.86(m,4H),1.20(t,J＝7.2Hz,3H).
Example 19
(E) -3- (8-acetyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
(E) -N- (quinolin-3-yl) -3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide hydrochloride (100mg, 0.22mmol) was dissolved in dichloromethane (3 mL), and triethylamine (97mg, 0.96mmol) and acetyl chloride (17mg, 0.22mmol) were added in this order, followed by stirring at room temperature for 1 hour. LCMS detection showed disappearance of starting material, water (10 mL) was added to the reaction and the mixture was extracted with dichloromethane (10 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give 23.9mg of the final product (E) -3- (8-acetyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:466.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.01(s,1H),8.98(s,1H),8.83(s,1H),7.97(t,J＝7.2Hz,2H),7.69-7.56(m,5H),7.40(d,J＝8.0Hz,2H),7.28(d,J＝15.6Hz,1H),3.86-3.81(m,4H),2.41(s,3H),2.12(s,3H),1.80(t,J＝5.2Hz,2H),1.69(t,J＝5.2Hz,2H).
The following target product was prepared according to the synthesis method of example 19:
example 24
(E) -N- (6-ethynylpyridin-3-yl) -3- (8-methyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
step 1: (E) -3- (8- (tert-Butoxycarbonyl) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylic acid (100mg, 0.25mmol) was dissolved in dichloromethane (10 mL), N-diisopropylethylamine (97mg, 0.75mmol) and HATU (143mg, 0.38mmol) were added in this order, and after stirring for 0.5 hour, 6-ethynylpyridin-3-amine (33mg, 0.28mmol) was added and stirred at room temperature overnight. The disappearance of starting material was detected by LCMS, quenched by the addition of water (10 mL) and the mixture extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to give 100mg of (E) -2- (3- ((6-ethynylpyridin-3-yl) amino) -3-acrylamido) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:498.3[M+H]+.
And 2, step: tert-butyl (E) -2- (3- ((6-ethynylpyridin-3-yl) amino) -3-acrylamido) -3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (100mg, 0.20mmol) was dissolved in ethyl acetate (3 mL) under ice-cooling, and a hydrogen chloride/ethyl acetate solution (4M, 1mL) was added and stirred at room temperature for 2 hours. LCMS detection shows the disappearance of the raw materials, the reaction solution is decompressed and concentrated to obtain crude (E) -N- (6-ethynylpyridin-3-yl-3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide hydrochloride which is directly used for the next reaction.
MS(ESI)M/Z:398.2[M+H]+.
And 3, step 3: (E) -N- (6-ethynylpyridin-3-yl-3- (3- (p-tolyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) acrylamide hydrochloride (87mg, 0.20mmol) was dissolved in methylene chloride (6 mL), triethylamine (120mg, 1.2mmol) and sodium triacetoxyborohydride (192mg, 0.90mmol) were added, followed by addition of 37% aqueous formaldehyde (50mg, 0.60mmol), and stirring overnight at room temperature. The mixture was extracted with dichloromethane (20 mL. Times.3.) the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by HPLC to give 8.9mg of the final product (E) -N- (6-ethynylpyridin-3-yl) -3- (8-methyl-3- (p-tolyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylamide.
MS(ESI)M/Z:412.0[M+H]+.
1H NMR(400MHz,CDCl3):δ8.68(s,1H),8.48(s,1H),8.36(s,1H),8.17(br s,1H),7.75(d,J＝15.2Hz,1H),7.61(d,J＝8.4Hz,2H),7.30(d,J＝7.6Hz,2H),7.20-7.10(m,1H),3.22(s,1H),2.97(br s,4H),2.56(s,3H),2.43(s,3H),2.20-1.60(m,4H).
The following target product was prepared according to the synthesis method of example 24:
example 30
(E) -3- (8-methyl-4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-en-2-yl) -N- (quinolin-3-yl) acrylamide
The reaction process comprises the following steps:
the reaction steps are as follows:
step 1: methyl 4-aminopiperidine-1-carboxylate-4-carboxylate (1.0 g,3.9 mmol) and 4-methylbenzene isothiocyanate (590 mg,3.9 mmol) were dissolved in 1, 4-dioxane (80 mL), and the reaction system was heated to 90 ℃ under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by slurrying with a mixed solvent of petroleum ether/ethyl acetate (20 mL) in a volume ratio of 5/1 to give 1.3g of tert-butyl 4-oxo-2-thioxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] decane-8-carboxylate.
MS(ESI)M/Z:376.3[M+H]+.
Step 2: tert-butyl 4-oxo-2-thioxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] decane-8-carboxylate (1.3g, 3.5 mmol) and (E) -3-boronic acid pinacol ester-ethyl acrylate (1.3g, 5.8mmol) were dissolved in anhydrous tetrahydrofuran (50 mL), and CuTC (1.3g, 6.9mmol) and tetrakis (triphenylphosphine) palladium (400mg, 0.35mmol) were added. The reaction was heated to reflux under nitrogen atmosphere and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with 25% concentrated aqueous ammonia (50 mL. Times.2). The organic phase was washed with brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to give 600mg of (E) -2- (3-ethoxy-3-oxopropyl-1-en-1-yl) -4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-ene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:442.4[M+H]+.
And step 3: to a mixed solution of tert-butyl (E) -2- (3-ethoxy-3-oxopropyl-1-en-1-yl) -4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-ene-8-carboxylate (500mg, 1.1 mmol) in tetrahydrofuran (16 mL) and water (8 mL) at room temperature was added sodium hydroxide (90mg, 2.3mmol). The reaction system was stirred at room temperature for 2 hours, the pH of the reaction solution was adjusted to 5 with 1M dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL. Times.2 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 160mg of (E) -3- (8- (tert-butoxycarbonyl) -4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-en-2-yl) acrylic acid.
MS(ESI)M/Z:436.0[M+Na]+.
And 4, step 4: (E) -3- (8- (tert-Butoxycarbonyl) -4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-en-2-yl) acrylic acid (150mg, 0.36mmol) and 3-aminoquinoline (58mg, 0.40mmol) were dissolved in DMF (8 mL), and HATU (179mg, 0.47mmol) and DIPEA (140mg, 1.1mmol) were added. The reaction was stirred at room temperature overnight, poured into water (50 mL), and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (40 mL. Times.2), dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/2) to give 145mg of (E) -4-oxo-2- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-ene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:540.3[M+H]+.
And 5: to a solution of (E) -4-oxo-2- (3-oxo-3- (quinolin-3-ylamino) propyl-1-en-1-yl) -3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-ene-8-carboxylic acid tert-butyl ester (145mg, 0.27mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (1.3 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with dichloromethane (20 mL. Times.3). The combined organic phases were washed with brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give crude (E) -3- (4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-en-2-yl) -N- (quinolin-3-yl) acrylamide, which was used directly in the next reaction.
MS(ESI)M/Z:440.2[M+H]+.
Step 6: (E) -3- (4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-en-2-yl) -N- (quinolin-3-yl) acrylamide (120 mg, crude product), 36% aqueous formaldehyde (65mg, 0.81mmol) and acetic acid (33mg, 0.55mmol) were dissolved in tetrahydrofuran (10 mL), and sodium borohydride acetate (171mg, 0.81mmol) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (20 mL) was added and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give 4.5mg of the final product (E) -3- (8-methyl-4-oxo-3- (p-tolyl) -1,3, 8-triazaspiro [4.5] dec-1-en-2-yl) -N- (quinolin-3-yl) acrylamide.
MS(ESI)M/Z:454.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ11.15(s,1H),8.96(s,1H),8.77(s,1H),7.97-7.93(m,2H),7.68-7.57(m,2H),7.41-7.37(m,3H),7.25(d,J＝8.0Hz,2H),6.86(d,J＝15.2Hz,1H),2.84(br s,2H),2.50(br s,2H),2.40(s,3H),2.37(s,3H),2.01-1.91(m,2H),1.67-1.64(m,2H).
Biological test evaluation
Test example 1: evaluation of proliferation inhibitory Effect of the Compound of the present invention on Ba/F3 cell line stably expressing triple mutant epidermal growth factor receptor
In the experiment, the proliferation inhibition effect of the compound on a cell strain stably expressing the triple-mutation epidermal growth factor receptor (EGFR triple mutants) is detected by measuring the content of ATP in cells by adopting a fluorescence method, and the half inhibition concentration IC of the compound on the proliferation inhibition of the triple-mutation epidermal growth factor receptor (EGFR triple mutants) cell strain is obtained50。
1. Experimental materials
RPMI-1640 medium, fetal Bovine Serum (FBS), 100X Pen/Strep, glutaMAX-I Supplement was purchased from GIBCO. Cell Titer-Glo luminescence Cell viability assay reagents were purchased from Promega corporation.
2. Experimental methods
1) Stably transfected Ba/F3 (DEL 19/T790M/C797S and L858R/T790M/C797S) cells were counted using a cytometer and plated at a density of 3000 cells per well in 96 well plates at 100. Mu.l per well. Placing in an incubator (37 ℃,5%2) And incubated overnight.
2) Day 0: to the plate cells, a gradient of 500nL of test compound (starting concentration 30 μ M,10 concentrations, 172 hours (37 ℃,5%2). Blank controls were added 500nL of DMSO per well.
3) Day 3: add 100. Mu.L Cell Titer-Glo reagent to each well, shake for 2 min at 500rpm, centrifuge for 1 min at 1000rpm, incubate in dark for 10 min at room temperature to stabilize the luminescent signal.
4) The luminescence signal was detected with an Envision plate reader (PerkinElmer).
5) Data analysis was performed using GraphPad Prism 6 software to calculate IC of compounds50。
The result of the proliferation inhibition effect of the compound on a Ba/F3 cell line stably expressing a three-mutation epidermal growth factor receptor is shown in Table 1, and the activity data are divided into four intervals of A, B, C and D, and IC50The compound less than or equal to 0.5 mu M is marked by A, and IC is less than 0.5 mu M50The compound less than or equal to 1 mu M is marked by B, and the IC is less than 1 mu M50Compounds less than or equal to 2. Mu.M are labeled with C, IC50> 2. Mu.M marked with D.
TABLE 1 inhibition results of Ba/F3 cell lines stably expressing triple mutant epidermal growth factor receptor
And (4) conclusion: as can be seen from Table 1, the compounds of the present invention have a good inhibitory effect on Ba/F3 cell lines stably expressing the triple mutant epidermal growth factor receptor.
Claims (29)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein R is1Selected from H, C1-4Alkyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or 5-7 membered heterocycloalkyl, and said C1-4Alkyl or 5-7 membered heterocycloalkyl optionally substituted with one or more R11Substituted by a group;
X1is selected from-C (= O) or N;
X2is selected from N or CH;
X3is selected from N or C;
X1and X3Are connected with each other
Represents a single or double bond;
R2is H, C1-6Alkyl or C3-5A cycloalkyl group;
ring A is selected from C6-10Aryl or 6-10 membered heteroaryl;
ring B is C6-10An aryl group;
R3selected from H, halogen, C2-4Alkynyl, C1-4Alkyl radical, C1-4Alkoxy radical, C3-5Cycloalkyl, -S (O)2R10、-P(O)(R13)R14Or C6-10An aryl group;
or two adjacent R3Cyclisation to C4-6Cycloalkyl fused to ring a;
R4selected from H, halogen or C1-4An alkyl group;
m and n are each independently selected from 0, 1, 2 or 3;
s and t are each independently selected from 0, 1 or 2;
R5and R6Each independently selected from H or C1-4An alkyl group;
R7and R8Each independently selected from H or C1-4An alkyl group;
or, R7And R8Together with the N atom to which they are attached form a 3-5 membered heterocycloalkyl, said 3-5 membered heterocycloalkyl optionally further substituted with one or more R12Substituted by a group;
R9is selected from C1-4Alkyl or C3-5A cycloalkyl group;
R10is C1-4An alkyl group;
R11selected from OH, halogen, C1-4Alkyl radical, C6-10Aryl or 5-7 membered heteroaryl;
R12selected from OH, halogen or C1-4An alkyl group;
R13and R14Each independently selected from OH or C1-4An alkyl group.
2. A compound according to claim 1, which is,
wherein R is1Selected from H, C1-4Alkyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or 5-7 membered heterocycloalkyl, and said C1-4Alkyl or 5-7 membered heterocycloalkyl optionally substituted with one or more R11Substituted by a group;
X1is selected from-C (= O) or N;
X2is selected from N or CH;
X3is selected from N or C;
X1and X3Are connected with each other
Represents a single or double bond;
R2is H, C1-6Alkyl or C3-5A cycloalkyl group;
ring A is selected from C6-10Aryl or 6-10 membered heteroaryl;
ring B is C6-10An aryl group;
R3selected from halogen, C2-4Alkynyl, C1-4Alkyl radical, C1-4Alkoxy radical,C3-5Cycloalkyl, -S (O)2R10、-P(O)(R13)R14Or C6-10An aryl group;
or two adjacent R3Cyclisation to C4-6Cycloalkyl is fused to ring a;
R4selected from halogen or C1-4An alkyl group;
m and n are each independently selected from 0, 1, 2 or 3;
s and t are each independently selected from 0, 1 or 2;
R5and R6Each independently selected from H or C1-4An alkyl group;
R7and R8Each independently selected from H or C1-4An alkyl group;
or, R7And R8Together with the N atom to which they are attached form a 3-5 membered heterocycloalkyl, said 3-5 membered heterocycloalkyl optionally further substituted with one or more R12Substituted by a group;
R9is selected from C1-4Alkyl or C3-5A cycloalkyl group;
R10is C1-4An alkyl group;
R11selected from OH, halogen, C1-4Alkyl radical, C6-10Aryl or 5-7 membered heteroaryl;
R12selected from OH, halogen or C1-4An alkyl group;
R13and R14Each independently selected from OH or C1-4An alkyl group.
3. A compound according to claim 1 or 2, wherein R5Is a tert-butyl group.
4. A compound according to any one of claims 1-3, wherein R6Is methyl and s is 2.
5. The compound of any one of claims 1-4, wherein R7And R8Each independently selected from H, methyl or ethyl;
or，R7And R8Together with the N atom to which they are attached form an azetidinyl group, said azetidinyl group optionally further substituted with one or more R12Substituted by a group;
R12is F;
t is selected from 0 or 1.
6. The compound of any one of claims 1-5, wherein R9Selected from methyl or cyclopropyl.
7. The compound of any one of claims 1-6, wherein R10Selected from methyl or isopropyl.
8. The compound of any one of claims 1-7, wherein R13And R14Each independently is methyl.
9. The compound of any one of claims 1-8, wherein R1Selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -C (O) OR5、-(CH2)s-OR6、-(CH2)t-C(O)NR7R8、-C(O)R9、-S(O)2R10Or tetrahydropyranyl, and said methyl or isobutyl group is optionally substituted by one or more R11Substituted by a group;
R11selected from OH, phenyl or pyridyl.
10. The compound of claim 9, wherein R1Selected from H, methyl, ethyl, isopropyl,
11. The compound of any one of claims 1-10, wherein ring a is selected from
12. The compound of any one of claims 1-11, wherein R3Selected from F, cl, ethynyl, methyl, ethyl, methoxy, cyclopropyl, -S (O)2CH3、-P(O)(CH3)CH3Or a phenyl group;
or, two adjacent R3Cyclisation is cyclopentyl fused to ring a, ring a being as defined in any of claims 1 to 10;
m is selected from 0, 1 or 2.
13. A compound according to claim 11 or 12, wherein the building block
Is selected from
14. The compound of any one of claims 1-13, wherein ring B is phenyl.
15. The compound of any one of claims 1-14, wherein R4Selected from Br or methyl;
n is selected from 0 or 1.
16. A compound according to claim 14 or 15, wherein the building block
Is selected from
17. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (II):
wherein R is1、R3、R4、X1、X3M, n and ring a are as defined in any one of claims 1 to 16.
18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from:
wherein R is1、R3、R4M, n and ring a are as defined in claim 17.
19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, selected from:
wherein R is1、R3、R4M and n are as defined in claim 18.
20. A compound, or a pharmaceutically acceptable salt thereof, selected from:
21. a pharmaceutical composition comprising a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
22. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for the treatment of cancer.
23. The use of claim 22, wherein the cancer comprises lymphoma, non-hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), acute Myeloid Leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, or melanoma.
24. The use of claim 23, wherein the cancer is lung cancer.
25. An intermediate compound represented by the formula (Z-3), the formula (Z-5) or the formula (Z-6), or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein PG is selected from tert-butyloxycarbonyl or benzyloxycarbonyl;
R15is selected from H or C1-4An alkyl group;
R2、R3、R4、X1、X2、X3m, n, ring a and ring B are as defined in any one of claims 1 to 20.
26. A compound according to claim 25 selected from:
wherein PG is tert-butyloxycarbonyl;
R15selected from H, methyl or ethyl;
R3、R4m and n are as defined in claim 25.
27. A process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 20,
deprotecting the compound represented by the formula (Z-5) under acidic conditions to give a compound represented by the formula (Z-6), and introducing R1The compound shown in the formula (I) is prepared,
wherein PG is selected from tert-butyloxycarbonyl or benzyloxycarbonyl, and the acid is selected from hydrochloric acid, acetic acid, trifluoroacetic acid or hydrobromic acid;
R1、R2、R3、R4、X1、X2、X3m, n, ring a and ring B are as defined in any one of claims 1 to 20.
28. A process for the preparation of a compound of formula (Z-5) as claimed in claim 27,
prepared by acylating a compound represented by the formula (Z-3) or a salt thereof with a compound represented by the formula ((Z-4) or a salt thereof in the presence of a condensing agent and a base,
wherein the condensing agent is selected from 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide;
PG、R2、R3、R4、X1、X2、X3m, n, ring a and ring B are as defined in claim 27.
29. A process for the preparation of a compound of formula (Z-3) according to claim 28, characterized in that:
prepared by coupling reaction of a compound represented by the formula (Z-1) or a salt thereof with a compound represented by the formula ((Z-2) or a salt thereof under a palladium/copper catalytic system,
wherein R is15Selected from H or ethyl;
R16is composed of
The palladium/copper catalytic system is tetrakis (triphenylphosphine) palladium/thiophene-2-carboxylic acid cuprous (I), dichlorobis (triphenylphosphine) palladium/thiophene-2-carboxylic acid cuprous (I) or palladium acetate/bis (2-diphenylphosphinophenyl) ether/thiophene-2-carboxylic acid cuprous (I);
PG、R4、X1、X2、X3n and ring B are as defined in claim 28.
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| WO2001096337A1 (en) * | 2000-06-14 | 2001-12-20 | Banyu Pharmaceutical Co.,Ltd | 4-oxoimidazolidine-2-spiro-nitrogenous heterocycle compounds |
| WO2015158310A1 (en) * | 2014-04-18 | 2015-10-22 | 山东轩竹医药科技有限公司 | Tyrosine kinase inhibitor and uses thereof |
| CN105073111A (en) * | 2012-10-11 | 2015-11-18 | 默沙东公司 | Substituted spiropiperidinyl compounds useful as gpr120 agonists |
| CN105461695A (en) * | 2014-09-29 | 2016-04-06 | 齐鲁制药有限公司 | Pyrimidine or triazine derivative, and preparation method and use thereof |
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| WO2001096337A1 (en) * | 2000-06-14 | 2001-12-20 | Banyu Pharmaceutical Co.,Ltd | 4-oxoimidazolidine-2-spiro-nitrogenous heterocycle compounds |
| CN105073111A (en) * | 2012-10-11 | 2015-11-18 | 默沙东公司 | Substituted spiropiperidinyl compounds useful as gpr120 agonists |
| WO2015158310A1 (en) * | 2014-04-18 | 2015-10-22 | 山东轩竹医药科技有限公司 | Tyrosine kinase inhibitor and uses thereof |
| CN105461695A (en) * | 2014-09-29 | 2016-04-06 | 齐鲁制药有限公司 | Pyrimidine or triazine derivative, and preparation method and use thereof |
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