CN115960105A - KRAS G12D inhibitor and application thereof in medicines - Google Patents
KRAS G12D inhibitor and application thereof in medicines Download PDFInfo
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Abstract
The invention relates to a compound shown as a general formula (I), a tautomer, a deuteron or a medicinal salt thereof, and the compound has KRAS G12D regulation activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Description
Technical Field
The invention relates to a compound shown in a general formula (I), a tautomer, a deuteron compound or a medicinal salt thereof, which has KRAS inhibiting activity, particularly KRAS G12D inhibiting 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 a point mutation, often occurring at codon 12, 13, 61, with mutations most common again at codon 12, e.g., G12C, G12D or G12V.
At present, drug research and development aiming at KRAS mutation is one of the current new drug research hotspots. The KRAS G12C inhibitors AMG510 (WO 2018217651 A1) and MRTX849 (WO 2019099524 A1) have entered late clinical stages; while MIRATI has advanced in the development of G12D inhibitors (WO 2021041671 A1).
Based on the importance of aberrant KRAS activation in cancer progression and the prevalence of KRAS gene mutations in human cancers, KRAS has been a target of interest to drug developers. Despite advances in this area, there remains a need in the art for improved KRAS Gl2D mutein inhibitors.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defect of KRAS Gl2D mutein-based inhibitor in the prior art, and provides a compound shown in a general formula (I) and application thereof. The compound shown in the general formula (I) has a good inhibition effect on KRAS Gl2D mutant protein.
The invention provides a compound shown as a general formula (I), a tautomer, a deuteron or a medicinal salt thereof:
wherein the content of the first and second substances,
X 1 selected from the group consisting of CR 6 Or N; r is 6 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl radical, C 3-6 Cycloalkyl or substituted C 3-6 A cycloalkyl group;
X 2 selected from the group consisting of CR 7 Or N; r is 7 Selected from H, halogen, cyano or C 1-6 An alkyl group;
X 3 selected from the group consisting of CR 8 Or N; r is 8 Selected from H, halogen, cyano or C 1-6 An alkyl group;
l is selected from the group consisting of a bond, O, NR 9 Or C 1-4 Alkylene radical of the formula C 1-4 Alkylene is optionally substituted by one or more R 9 Substitution; r is 9 Selected from H, halogen, cyano or C 1-6 Alkyl, or two R on the same carbon atom 9 Together with the atoms to which they are attached form a 3-6 membered cycloalkyl group;
R 1 selected from absent, or R 1 、R 7 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo;
R 2 selected from absent, or R 2 、R 8 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo;
R 3 selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by one or more R 10 Substitution;
R 4 selected from H, halogen, C 1-6 Alkyl OR-OR 11 Said R is 11 Is selected from C 1-6 Alkyl or C 3-8 Cycloalkyl radical, R 11 Optionally substituted by one or more groups selected from hydroxy, halogen, C 1-3 Alkyl radical, C 1-3 Alkoxy or cyclopropyl;
R 5 selected from aryl or heteroaryl, optionally further substituted by one or more R 10 Substitution;
R 10 selected from H, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (= O) R a 、-C 0-6 alkylene-S (= O) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (= O) R a 、-C 0-6 alkylene-C (= O) OR a 、-C 0-6 alkylene-C (= O) N (R) a ) 2 、
C 2-6 Alkenyl radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl), said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R a Substituted;
each R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Halogenated alkyl radical、C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
and the compound of the formula (I) is not
In some embodiments of the invention, the compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof, is selected from compounds of formula (IA) or (IB) below:
preferably a
Wherein, the substituent R 3 ，R 4 ，R 5 ，R 6 ，R 10 As defined in formula (I).
In some embodiments of the invention, the R is 5 Is selected from
In some embodiments of the invention, L is a bond and R is 3 Is cycloalkyl, said cycloalkyl being further substituted by one or more R 10 Substitution; the R is 10 Is selected from-C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl radical, -C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 or-C 0-6 Alkylene- (5-to 14-membered heteroaryl), said-C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R a Substituted; the R is a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 A haloalkoxy group.
In some embodiments of the invention, L is selected from a bond or C 1-4 Alkylene group, said R 3 Selected from heterocyclyl or heteroaryl, optionally further substituted by one or more R 10 Substitution; said R is 10 Selected from H, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a or-C 0-6 alkylene-NR a C(O)N(R a ) Said R is a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl or C 1-6 A haloalkyl group.
In some embodiments of the invention, R is 1 、R 7 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more substituents selected from H, halogen, cyano, C 1-6 Alkyl or oxo.
In some embodiments of the invention, R is 1 Is notAre present.
In some embodiments of the invention, the R is 2 、R 8 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo.
In some embodiments of the invention, R is 2 Is absent.
In some embodiments of the invention, R is 4 Is halogen, preferably F.
In some embodiments of the invention, the compound of formula (I) is selected from:
the invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound shown in the formula (I), a tautomer, a deuteron or a pharmaceutically acceptable salt thereof, and optionally further comprises pharmaceutically acceptable auxiliary materials.
The invention provides application of a compound shown as a formula (I), a tautomer, a deuteron or a medicinal salt thereof, or a medicinal composition thereof in preparing medicines.
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, said use is for the manufacture of a medicament for the treatment and/or prevention of a disease mediated by KRAS G12D.
Preferably, the KRAS G12D mediated 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 a therapeutically effective amount of at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object.
The invention also provides a method for treating and/or preventing KRAS G12D mediated diseases, which comprises administering at least one compound shown in the structural formula (I), a tautomer, a deuteron or a medicinal salt thereof or a medicinal composition containing the compound to a treatment object in a therapeutically effective amount.
The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least any one of the compounds represented by structural formula (I), tautomers, deuterons or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the same.
Preferably, in the above method, the KRAS G12D mediated disease is cancer.
Preferably, in the above method, 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, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
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, "C 1-6 Alkyl group "of" 1-6 "refers to a group comprising 1,2, 3, 4,5, or 6 carbon atoms arranged in a straight or branched chain.
The term "alkylene" refers to a divalent alkyl linking group. By alkylene is meant formally an alkane in which the two C-H bonds are replaced by the point of attachment of the alkylene to the remainder of the compound. Similarly, C 1-6 "C" in alkylene 1-6 "refers to an alkylene group containing 1,2, 3, 4,5, or 6 carbon atoms, including but not limited to methylene, 1, 2-ethylene, 1, 3-propylene, or 1, 2-isopropylene.
"alkoxy" refers to the oxygen ether form of the aforementioned straight or branched chain alkyl groups, i.e., -O-alkyl.
The term "aryl", as used herein, unless otherwise indicated, refers to unsubstituted or substituted aromatic groups comprising 6 to 14 members of a single or fused ring. 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 group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted stabilizing 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 comprising 3 to 14 carbon atoms 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 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, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, -C 0-6 alkylene-OR b 、-C 0-6 alkylene-OC (O) N (R) b ) 2 、-C 0-6 alkylene-N (R) b ) 2 、-C 0-6 alkylene-NR b C(O)R b 、-C 0-6 alkylene-NR b C(O)N(R b ) 2 、-C 0-6 alkylene-NR b S(O)R b 、-C 0-6 alkylene-NR b S(O) 2 R b 、-C 0-6 alkylene-S (= O) R b 、-C 0-6 alkylene-S (= O) 2 R b 、-C 0-6 alkylene-SR b 、-C 0-6 alkylene-S (R) b ) 5 、-C 0-6 alkylene-C (= O) R b 、-C 0-6 alkylene-C (= O) OR b 、-C 0-6 alkylene-C (= O) N (R) b ) 2 、
C 2-6 Alkenyl radical、C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl), said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R b And (4) substituting. Each R b Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl. In some embodiments of the present invention, the, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde group, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
When the number of one linking group is 0, e.g. - (CH) 2 ) 0 -represents that the linking group is a bond.
When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Non-toxic organic bases which can be derivatized to form pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, oxalic, propionic, glycolic, hydroiodic, perchloric, cyclohexanesulfonic, salicylic, 2-naphthalenesulfonic, saccharinic, trifluoroacetic, tartaric, and p-toluenesulfonic acids and the like. Preferably, citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. More preferably formic acid and hydrochloric acid.
Prodrugs of the compounds of the 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.
The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.
When the compounds of formula (I) exist as tautomers, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.
Certain therapeutic advantages may be provided when compounds of formula (I) are substituted with heavier isotopes such as deuterium, for example, resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient may be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (ii) (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.
The term "effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The synthesis scheme is as follows:
step A: compound I-1 under basic conditions such as Cs 2 CO 3 Under the action of the catalyst and benzyl alcohol, performing substitution reaction to obtain a compound I-2, wherein Bn is a protective group;
and B: reaction of Compound I-2 with Compound I in the presence of Pd catalyst, e.g. SphosPdG2
Introduction of R by Suzuki coupling reaction 5 A group;
step C: removing a Bn protecting group from the compound I-3 through palladium-carbon hydrogenation to obtain a compound I-4;
step D: the compound I-4 reacts with trifluoromethanesulfonic anhydride under the action of alkaline conditions such as triethylamine to introduce a Tf protecting group, and then a target product I-5 is obtained.
Step E: compound I-5 with Pd on a catalyst such as Pd (PPh) 3 ) 2 Cl 2 And copper catalysts, e.g. CuI, with compounds
Alkyne is introduced through Sonogashira coupling reaction; />
Step F: the compound I-6 can be used for removing a TG protecting group under the action of acidic conditions such as TFA to obtain the target compound I.
Detailed Description
In order to make the above clear and definite, 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 temperatures are in degrees celsius unless otherwise indicated.
The following abbreviations are used in the examples:
DABCO: triethylene diamine;
DIEA: n, N-diisopropylethylamine;
DCM is dichloromethane;
a Dioxane: dioxane;
ESI-MS: electrospray ionization mass spectrometry;
tf2O: trifluoromethanesulfonic anhydride;
EtOH: ethanol;
HOAc: glacial acetic acid;
MeOH: methanol;
POCl3: phosphorus oxychloride;
THF: tetrahydrofuran;
TFA: trifluoroacetic acid;
TEA: triethylamine;
LiAlH4: lithium aluminum hydride;
TBAF: tetrabutylammonium fluoride;
SphosPdG2: chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II);
Pre-HPLC: preparing a high-performance liquid phase;
Pre-TLC: and (4) preparing a thin-layer plate.
Synthesis of intermediate M1:
step 1: synthesis of Compound M1-2
To compounds M1-1 (40 g), HOAc (77 g), etOH (400 mL) and H at room temperature 2 To a mixture of O (160 mL) was added iron powder (27 g) in portions. The resulting mixture was stirred at room temperature for 2 hours, then neutralized with a NaOH (5N) solution. The mixture was then extracted with ethyl acetate and the organic layer was washed with brine and over Na 2 SO 4 Dried and concentrated in vacuo to give the desired crude product as a brown oil (34g, 98% yield), compound M1-2.ESI-MS m/z:190[ 2 ], [ M ] +H] + 。
Step 2: synthesis of Compound M1-3
2, 2-trichloroethane-1, 1-diol (66.4 g) was mixed with Na 2 SO 4 (503.4 g) was dissolved in water (560 mL) and then warmed to 55 ℃. Water (240 mL) containing Compound M1-2 (34 g) and 35% HCl (72 mL) were added, and an aqueous solution (100 mL) of hydroxylamine hydrochloride (81.4 g) was further added. The resulting mixture was stirred at 90 ℃ for 3 hours and a yellow precipitate formed. The mixture was cooled to room temperature. The solid was collected by filtration, washed with water, and air-dried to give the product as a tan solid (47g, 99% yield), compound M1-3.ESI-MS m/z:261[ 2 ], [ M ] +H ]] + 。
And 3, step 3: synthesis of Compound M1-4
Compound M1-3 (47 g) was added to concentrated sulfuric acid (300 mL) at 60 ℃, the temperature was raised to 90 ℃ and maintained for 3 hours, the reaction was complete, the reaction mixture was cooled to room temperature and poured into ice water. The yellow precipitate was collected by filtration and dried to give the product as a black solid (43g, 99% yield), compound M1-4.
And 4, step 4: synthesis of Compound M1-5
To a solution of compounds M1-4 (43 g) in NaOH (2N) at 0 ℃ was added H 2 O 2 The solution (30%, 80 mL) and the resulting mixture was stirred at 0 ℃ for 30min. After stirring at room temperature for an additional 2 hours to complete the reaction, the mixture was poured into ice water and acidified with concentrated HCl solution, and the precipitate was collected by filtration and air dried to give the product (20g, 49% yield) as a white solid, compound M1-5.ESI-MS m/z of 233[ 2 ], [ M ] +H] + 。
And 6: synthesis of Compound M1-6
Di (imidazol-1-yl) methanone (2.70 g) was added to crude compound M1-5 (4.0 g) in THF (20 mL) at room temperature, N-ethyl-N-isopropylpropan-2-amine (1.4 g) was added thereto, and the mixture was transferred to 50 ℃ for reaction for 2 hours. Compound M1-6 was substantially completely converted to the intermediate product, and the mixture was then added dropwise to ice-cold aqueous ammonia (35 mL) and stirred for 5min to complete the reaction. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, over Na 2 SO 4 Dried and concentrated in vacuo, and the residue purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 70) to give the desired target product compound M1-6 (1.6 g) as a brown solid.
And 7: synthesis of Compounds M1-7
A mixture of the compounds M1-6 and urea was reacted at 200 ℃ with stirring for 3 hours. The mixture was cooled to room temperature, the solid was washed with ethyl acetate and dried to give the desired crude solid product M1-7 (209mg, 78% yield).
And 8: synthesis of Compound M1-8
DIPEA was added to M1-7 POCl at room temperature 3 To the solution of (1), refluxing was carried out at 110 ℃ for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo to remove POCl 3 The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =100:1 to 50).
And step 9: synthesis of Compound M1
Dissolve M1-8 (3.0 g) in 1 at room temperatureTo a solution of 4-dioxane (20 ml) was added tert-butyl (1R, 5S) -3, 8-diazacyclo [ 3.2.1%]Octane-8-carboxylate (1.6 g) and DIPEA (2.8 g), and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =75 to 65) to afford the desired product M1 as a yellow solid (2.5g, 57% yield). ESI-MS m/z:471[ 2 ], [ M ] +H] + 。
Synthesis of intermediate M2:
step 1: synthesis of Compound M2-1
2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butanol (390.00 mL), triethylamine (128.27 mL), powdered 4A molecular sieves (90.00 mL) (preactivated), and reflux at room temperature for half an hour (inner temperature 87 ℃) under nitrogen were added sequentially. Then naturally cooling to room temperature, then adding DPPA (99.44 mL), heating to reflux, and keeping the temperature for reaction for 5 hours. Cooling the reaction mixture to below 40 ℃, and then adding 500mL of EA for dilution; continuously cooling to room temperature, assisting filtration with diatomite, and filtering and removing the added molecular sieve; washing the filter residue with 1500mL of EA for multiple times, and draining; collecting the filtrate, washing with 700mL of water and 700mL of saturated saline solution in sequence, and separating the liquid; drying the organic phase with anhydrous sodium sulfate; filtration, removal of the drying agent, concentration, column chromatography purification of the concentrate (PE/EA = 30. ESI-MS m/z:247.1[ 2 ] M + H] + 。
Step 2: synthesis of Compound M2-2
Compound M2-1 (65.00 g) was dissolved in CH at room temperature 3 CN (82.00 mL), cooled in a water bath, added hydrochloric acid (4M in dioxane) (38.43 g) slowly, and stirred at room temperature for about 16 hours to react, white solid precipitated out and was in suspension. The reaction mixture was filtered and the filter cake was rinsed with a small amount of acetonitrile, drained and the filtrate discarded. The filter cake was collected and added to a mixture of 700mL of saturated aqueous sodium bicarbonate and 700mL of ethyl acetateAlkalizing, extracting and separating liquid; extracting the water phase with 350mL of ethyl acetate, and separating liquid; mixing ethyl acetate phases, adding 300mL of saturated sodium chloride aqueous solution, washing, and separating liquid; the organic phase was dried over anhydrous sodium sulfate, filtered, dried over sodium sulfate and concentrated to give the desired product M2-2 as a yellowish solid powder (36.3 g, 94.0% yield). ESI-MS m/z:147.1[ 2 ], [ M + H ]] + 。
And step 3: synthesis of Compound M2-3
Compound M2-2 (36.00 g) was dissolved in acetonitrile (180.00 mL) at room temperature, and NIS (66.32 g) and p-toluenesulfonic acid (2.12 g) were added thereto, and the mixture was heated and incubated at 70 ℃ under nitrogen. Cooling the reaction liquid to 50 ℃, adding 900mL of water, separating out white solid powder, and pulping for half an hour; filter and rinse the filter cake with water and pump dry. The filter cake was collected, added with 1200mL of ethyl acetate to dissolve completely, and then washed twice with 350mL of saturated aqueous sodium sulfite solution, then washed with 350mL of saturated brine, separated, dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated to give M2-3 as a pale yellow solid particle (63.2 g, yield 94.43%). ESI-MS m/z of 272.9[ 2 ], [ M + H ]] + 。
And 4, step 4: synthesis of Compound M2-4
Compound M2-3 (57.50 g) was dissolved in DMF (22.00 mL) at room temperature, zinc cyanide (32.22 g), palladium tetratriphenylphosphine (12.19 g) and powdered
Molecular sieves (20.00 mL) were added and the reaction was allowed to proceed for about 7 hours at 100 ℃ under nitrogen. And removing the oil bath, naturally cooling to room temperature, and waiting for post-treatment. Filtering with diatomite, filtering the reaction mixture, and draining; collecting filtrate, and concentrating at 60-70 ℃ to obtain a light yellow solid crude product. Rinsing the filter residue by using 500mL of ethyl acetate, and draining; collecting rinsing liquid, combining the rinsing liquid with the crude product, and concentrating again until no liquid is distilled out; the crude solid was concentrated by dissolving in 700mL of ethyl acetate, and then washed 3 times with 250mL of saturated sodium chloride each time, followed by separation. Drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to obtain light yellow solid, adding 160mL of PE/EA =3/1 mixture, pulping for half an hour, filtering, and draining. Collecting filter cakes, carrying out water bath at 45 ℃, concentrating, and drawing by a high vacuum oil pump until the weight is constant; the expected product M2-4 was finally obtained as a pale yellow solid (36.1 g, 99.7% yield). ESI-MS m/z 172.0[ 2 ] M + H] + 。
And 5: synthesis of Compound M2-5
Concentrated sulfuric acid (61.37 mL) was added to a 500mL single-neck flask at room temperature, the mixture was cooled to 10 ℃ or lower in an ice-water bath, and after the addition of the compound M2-4 (39.30 g) in portions, the mixture was stirred for 10 minutes, and then the mixture was kept at 60 ℃ in an oil bath under a nitrogen atmosphere to react for about 1 hour. The reaction was cooled to room temperature and then carefully added to 1100mL of ice-water mixture, and diluted to quench, with a small amount of yellow solid precipitated. Stirring for 10min, and filtering; collecting the filter cake, pulping for 20 minutes by using 50mL of saturated sodium bicarbonate aqueous solution, filtering again, collecting the two filtrates, and combining; then sodium carbonate solid was slowly added to adjust the pH to about 7, and a white-like solid powder precipitated. Stirring for half an hour, filtering, and draining; the filter cake was rinsed with 100mL of water each time, drained, and rinsed 2 times total. The filter cake was collected, placed in a vacuum oven and dried to constant weight at 55 ℃ to give the desired product M2-5 (33.6 g, 77.37% yield) as a beige solid powder. ESI-MS m/z of 190.0[ 2 ] M + H] + 。
And 6: synthesis of Compound M2-6
Adding tetrahydrofuran (470.00 mL) at room temperature, replacing with nitrogen, adding sodium hydride (10.00 g) under the protection of micro nitrogen flow, heating by using an oil bath, keeping the temperature at 40-45 ℃, and stirring for 15 minutes; then, compound M2-5 (18.95 g) was added in portions, after the addition was completed, mechanical stirring was performed under heat for 20 minutes, then CDI (24.31 g) was carefully added in portions, after the addition was completed, stirring was performed for 15 minutes, and then the mixture was heated in an oil bath and subjected to reflux reaction under heat. Cooling the reaction solution to below 10 ℃ by using an ice water bath, then adding 500mL of saturated ammonium chloride aqueous solution to precipitate pale yellow solid, and adding 1000mL of water; then transferring the mixture to a 5L beaker, and adding 3000mL of water; stirring for 1 hour, filtering and pumping to dry; the filter cake was collected, placed in a vacuum oven, and dried to constant weight at 50-55 ℃ to give the desired product M2-6 (18.3 g, 84.93% yield) as a pale yellow solid powder. ESI-MS m/z:216.0[ 2 ] M + H] + 。
And 7: synthesis of Compound M2-7
Compound M2-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl at room temperature 3 (180.00 mL) was heated and maintained at 100 ℃ for about 2.5 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to remove phosphorus oxychloride, and was taken 2 times with 100mL of DCM; the concentrated residue was dissolved in 400mL of dichloromethane, and then added dropwise to 500mL of a saturated aqueous sodium bicarbonate solution, followed by cooling with ice water; stirring for 15 minutes, and separating liquid; extracting and separating the water phase by using 300mL of dichloromethane; the dichloromethane phases are combined, washed by 300mL of saturated sodium chloride aqueous solution and separated; dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate purified by silica gel column (PE/EA = 90/10-75/25) to give the desired product M2-7 as an off-white solid powder (10.95 g, 51.94% yield). ESI-MS m/z:251.9[ 2 ], [ M ] +H] + 。
And 8: synthesis of Compound M2-8
Compound M2-7 (10.50 g) and DIEA (17.18 mL) were dissolved in DCM (120.00 mL) at room temperature, cooled in a water bath, tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (9.27 g) was added in portions, and the reaction was stirred at room temperature for about 10 minutes. And adding 120mL of dichloromethane, washing with 100mL of water and 100mL of saturated aqueous sodium chloride solution in sequence, separating, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating, and purifying the concentrate by using a silica gel column (PE/EA = 90/10-75/25) and pulping (40mL EA +160mL PE) to obtain the target compound M2-8 (15.9 g, yield 89.26%) as a white solid powder.
And step 9: synthesis of Compound M2-9
THF (80.00 mL) and benzyl alcohol (1.60 g) were added to a reaction flask at room temperature, the temperature was reduced to 0 ℃ and NaH (0.59 g) was added thereto, and after completion of the reaction, the mixture was allowed to return to room temperature for 0.4h, and then cooled to 0 ℃ and compound M2-8 (5.30 g) was added thereto, and after completion of the reaction, the mixture was allowed to return to room temperature for 1h. Adding water into the reaction solution to quench and react, extracting with EA, drying the organic phase and concentrating. The concentrate was purified by silica gel column (PE. PE: EA = 1) to obtain the target product M2-9 (5.60 g, yield 90.51%) as a yellow oil. ESI-MS m/z 500[ 2 ], [ M ] +H] + 。
Step 10: synthesis of Compound M2-10
At room temperature, compound M2-9 (1.90 g), 2- [6- (methoxymethyloxy) methoxyYl) -8- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) naphthalen-1-yl]Ethynyltripropyl-2-silane (2.82 g), sphosPdG2 (0.27 g), K 3 PO 4 (2.42 g) was dissolved in a mixed solution of 1,4-dioxane (30.00 mL) and water (5.00 mL), and the mixture was reacted at 95 ℃ for 10 hours under nitrogen atmosphere after nitrogen substitution. The reaction mixture was extracted with EA and water, dried and concentrated. The concentrate was purified by silica gel column (PE. PE: EA = 3) to obtain the target product M2-10 (1.80 g, yield 39.85%) as a yellow oil. ESI-MS m/z:902[ 2 ], [ M ] +H] + 。
Step 11: synthesis of Compound M2-11
M2-10 (1.80 g), methanol (25.00 mL) and Pd/C (0.92 g) were added to a reaction flask at room temperature, and the mixture was reacted at room temperature for 12 hours under hydrogen protection after hydrogen substitution. The reaction mixture was filtered, the filter residue was washed with methanol, the filtrate was concentrated and purified by column chromatography to give the title compound M2-11 (0.60g, 37.38%) as a yellow solid. ESI-MS m/z:812[ 2 ], [ M ] +H] + 。
Step 12: synthesis of Compound M2
At room temperature, M2-11 (600.00 mg), dry DCM (8.00 mL) and DIEA (0.40 mL) were added to the reaction flask, the reaction mixture was cooled to-10 deg.C, and Tf was taken 2 O (0.16 mL) was dissolved in DCM and slowly added to the reaction mixture, and the reaction was allowed to return to room temperature for 2h. The reaction was directly concentrated, and the concentrate was purified by a silica gel column (PE. PE: EA = 8. ESI-MS m/z:944 2[ 2 ], [ M ] +H] + 。
Example 1: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octyl-3-yl) -2- ((1- ((dimethylamino) methyl) cyclopropyl) ethynyl) -8-fluoroquinazolin-7-yl) naphthalen-2-ol
Step 1: synthesis of Compound 1-1
The compound 1-methoxycarbonylcyclopropane-1-carboxylic acid (5.00 g) was dissolved in DCM (80.00 mL) at room temperature, DMF (0.27 mL) was added in an ice bath, and oxalyl chloride (8.81 mL) was added dropwise thereto, followed by stirring at 35 ℃ for 3h after the addition. And finally, directly concentrating the reaction mixture to obtain a crude product of the target compound 1-1, wherein the crude product is directly used for the next reaction.
Step 2: synthesis of Compound 1-2
Crude 1-1 (5.64 g) was dissolved in DCM (80.00 mL) at room temperature, TEA (24.11 mL) and dimethylamine hydrochloride (5.66 g) were added in an ice bath, and after addition was stirred at room temperature for 1h. Water was added to the reaction mixture to extract, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column chromatography to obtain the objective compound 1-2 (5.4 g, yield 91%).
And step 3: synthesis of Compounds 1-3
At room temperature, compound 1-2 (5.4 g) was dissolved in THF (120 mL), cooled to-20 deg.C and LiAlH was added in portions 4 (4.0 g), after the addition was completed, the temperature was slowly returned to room temperature, and the mixture was stirred for 3 hours. After completion of the reaction, 4.0g of water, 4.0g of a 15% aqueous NaOH solution, and 12.0g of water were gradually added in this order under ice-bath conditions, and stirring was continued for 1 hour. The mixture was filtered and the filtrate was concentrated. The concentrate was purified by silica gel column (MeOH: DCM = 0-30%) to obtain the target compounds 1-3 (2.5g, 61%). ESI-MS m/z:130[ 2 ], [ M ] +H] + 。
And 4, step 4: synthesis of Compounds 1-4
DMSO (2.34 g) was dissolved in DCM (30 mL) at room temperature, and oxalyl chloride (1.9 g) was added dropwise thereto at-78 ℃ and stirred for 30min. A solution of compound 1-3 (1.3 g) in DCM (10 mL) was added dropwise at-78 deg.C and stirred for 1h. Triethylamine (3.1 g) was added dropwise thereto at-78 ℃ and slowly returned to room temperature after completion of the addition. Adding water into the reaction solution, extracting, separating liquid, and removing the water phase. The organic phase was concentrated to give crude target compounds 1-4.
And 5: synthesis of Compounds 1-5
The crude compounds 1-4 above and potassium carbonate (2.8 g) were dissolved in methanol (10 mL) at room temperature and stirred at room temperature for 15min. Dimethyl (1-diazo-2-oxopropyl) phosphonate (2.5 g) was added dropwise thereto and the mixture was stirred at room temperature overnight after the addition. Adding toluene and water into the reaction solution for extraction, separating liquid, washing an organic phase once by using a saturated potassium carbonate solution, and drying by using anhydrous sodium sulfate to obtain a crude product of the target compound 1-5.
And 6: synthesis of Compounds 1-6
Intermediate M1 (1.4 g), benzyl alcohol (0.65 g), cesium carbonate (3.9 g), and DABCO (50 mg) were dissolved in a mixed solution of DMF (10 mL) and THF (10 mL) at room temperature, and stirred at room temperature overnight. Adding water and EA into the reaction mixture, extracting, separating liquid, drying the organic phase and concentrating. The concentrate was purified by silica gel column (EA: PE = 0-30%) to obtain the target compounds 1-6 (1.9g, 115%). ESI-MS m/z:543, 545[ M ] +H] + 。
And 7: synthesis of Compounds 1-7
Compound 1-6 (1.8 g), (3- ((tert-butyldimethylsilyl) oxy) naphthalen-1-yl) boronic acid pinacol ester (2.5 g), sphosPdG2 (0.24 g), potassium phosphate (2.1 g) were dissolved in a mixed solution of 1,4-dioxane (18 mL) and water (2 mL) at room temperature, and stirred at 100 ℃ for 1h. After the reaction is finished, adding water and EA into the reaction solution, extracting, separating liquid, drying the organic phase and concentrating. The concentrate was purified by silica gel column (MeOH: DCM = 0-10%) to obtain the objective compounds 1-7 (1.9 g, yield 80%).
And 8: synthesis of Compounds 1 to 8
Compounds 1-7 (1.9 g) were dissolved in methanol (40 mL) at room temperature, 10% wet palladium on carbon (0.2 g) was added under nitrogen, and the mixture was replaced with hydrogen and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to give crude products of the objective compounds 1 to 8 (1.5 g, yield 88%).
And step 9: synthesis of Compounds 1-9
The crude compounds 1-8 (1.4 g) were dissolved in DCM (15 mL) at room temperature, triethylamine (1.0 mL) was added under ice-bath conditions, and trifluoromethanesulfonic anhydride (0.5 mL) was added slowly dropwise, after addition was complete, and stirred at 0 deg.C for 1h. The reaction solution was directly concentrated, and the concentrate was purified by a silica gel column (EA: PE = 0-50%) to obtain the objective compounds 1-9 (1.37 g, yield 81%). ESI-MS m/z:763[ 2 ] M + H] + 。
Step 10: synthesis of Compounds 1-10
Compounds 1-9 (80 mg), pd (PPh) were added at room temperature 3 ) 2 Cl 2 (11 mg), cuI (6 mg), and triethylamine (40 mg) were dissolved in a toluene solution of the compounds 1 to 5, and stirred at 50 ℃ for 2 hours.Water and EA were added to the reaction mixture, followed by extraction, liquid separation, drying of the organic phase, concentration, and purification of the concentrate by column chromatography (EA: PE = 20-50%) to obtain 1-10 (5 mg) of the objective compound. ESI-MS m/z:737[ alpha ], [ M ] +H] + 。
Step 11: synthesis of Compounds 1-11
Compound 1-10 (5 mg) was dissolved in THF (5 mL) at room temperature, triethylamine trihydrofluoride salt (0.1 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 30min. And concentrating the reaction solution to obtain crude products of the target compounds 1-11.
Step 12: synthesis of Compound 1
The crude compounds 1-11 were dissolved in DCM (5 mL) at room temperature, and trifluoroacetic acid (3 mL) was added dropwise thereto and stirred at room temperature for 30min. The reaction was concentrated to give crude compound 1. The crude compound 1 was purified using a reverse phase preparative column (ACN: H) 2 O =5-50%, plus 0.1% tfa) to give target compound 1 (2.1 mg). ESI-MS m/z:522[ 2 ], [ M ] +H] + 。 1 H NMR(500MHz,MeOD)δ7.97(d,J＝8.7Hz,1H),7.77(d,J＝8.4Hz,1H),7.64-7.59(m,1H),7.46-7.41(m,2H),7.27(d,J＝2.0Hz,1H),7.23(t,J＝7.6Hz,1H),7.13(d,J＝2.2Hz,1H),4.71(t,J＝15.2Hz,2H),4.24(s,2H),3.88-3.81(m,2H),3.07(s,6H),2.10-1.98(m,2H),1.69-1.57(m,2H),1.45(q,J＝4.7Hz,2H),1.25(d,J＝2.0Hz,2H),0.90(t,J＝6.8Hz,2H)。
Example 2: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- (isoindol-2-ylmethyl) cyclopropyl) ethynyl) quinazolin-7-yl) naphthalen-2-ol
Detailed synthetic procedures for Compounds 2-1 to 2-4 reference is made to example 1.
And 5: synthesis of Compounds 2-5
The crude compound 2-4 (2.0 g) and potassium carbonate (2.75 g) were dissolved in methanol (20 mL) at room temperature, and stirred at room temperature for 15min. To this was added dropwise dimethyl (1-diazo-2-oxopropyl) phosphonate (2.49 g), which was stirred at room temperature for 2h. Adding EA to the reaction solutionWater, extraction, separation, drying of the organic phase and concentration, purification of the concentrate by column chromatography (MeOH: DCM = 0-20%) gave the desired compound 2-5 (1.4 g, 70% yield). ESI-MS m/z:198[ deg. ] M + H] + 。
Step 6: synthesis of Compounds 2 to 6
Compounds 1-9 (200 mg), pd (PPh) were added at room temperature 3 ) 2 Cl 2 (37 mg), cuI (15 mg), triethylamine (80 mg), and Compound 2-5 (207 mg) were dissolved in DMF (10 mL), and stirred at 40 ℃ for 1h. Water and EA were added to the reaction solution, followed by extraction, liquid separation, concentration of the organic phase, and purification of the concentrate by column chromatography (EA: PE = 20-50%) to obtain the objective compound 2-6 (100 mg, yield 47%). ESI-MS m/z:811[ 2 ] M + H] + 。
Detailed synthetic procedures for compounds 2-7 and target compound 2 reference is made to example 1. Compound 2ESI-MS m/z:596[ M + H ]] + 。 1 H NMR(500MHz,DMSO)δ7.98(d,J＝8.7Hz,1H),7.82(d,J＝8.2Hz,1H),7.60-7.53(m,1H),7.45(dd,J＝14.2,6.3Hz,3H),7.38(dd,J＝8.4,5.6Hz,3H),7.29(s,1H),7.28-7.22(m,1H),7.11(d,J＝2.1Hz,1H),4.96(s,2H),4.76(s,2H),4.47(t,J＝14.8Hz,2H),4.21(s,2H),3.73(dd,J＝25.2,11.9Hz,4H),2.00(d,J＝10.6Hz,4H),1.33(s,4H)。
Example 3: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octyl-3-yl) -8-fluoro-2- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) ethynyl) quinazolin-7-yl) -5-ethynylnaphthalen-2-ol
Detailed synthetic procedures for Compounds 3-1 to 3-6 reference is made to example 1. Compound 3-6ESI-MS m/z:886[ 2 ], [ M + H ]] + 。
And 7: synthesis of Compounds 3-7
Compound 3-6 (110 mg) was dissolved in THF (5 mL) at room temperature, TBAF (1M/THF, 0.12 mL) was added dropwise, and the mixture was stirred at room temperature for 30min. The reaction was concentrated, and the concentrate was purified by column chromatography (MeOH: DCM = 0-200%) to obtain the objective compound 3-7 (80 mg, yield 90%). ESI-MS m/z:730[ 2 ], [ M ] +H] + 。
Step 8 synthesis procedure for target compound 3 reference example 1 was made. ESI-MS m/z [ 585 ], [ M ] +H ]] + 。
Example 4: synthesis of the compound 4- (4- ((1R, 5S) -3, 8-diazacyclo [3.2.1] octan-3-yl) -8-fluoro-2- ((1- ((3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) ethynyl) quinazolin-7-yl) naphthalen-2-ol
Step 1: synthesis of Compound 4-1
1-Methoxycarbonylcyclopropane-1-carboxylic acid (5000.00 mg) was dissolved in DCM (50.00 mL) at room temperature, oxalyl chloride (11.74 mL) was added, DMF (0.03 mL) was added, the temperature was raised to 35 ℃ and the reaction was carried out for 1 hour. After concentration, DCM (50.00 mL) was added, the temperature was reduced to 0 ℃ and TEA (24.11 mL) was added followed by 3-fluoropyrrolidine (3091.46 mg) for 2 hours. The reaction mixture was directly stirred and subjected to silica gel column purification (EA: PE = 1) to obtain the target compound 4-1 (6000.00 mg, yield 80.36%) as a yellow oil.
Step 2: synthesis of Compound 4-2
At room temperature, compound 4-1 (6.20 g) and THF (70.00 mL) were added to the flask and the temperature was reduced to-5 deg.C, LAH (2.5M/THF) (1.64 g) was added in portions, and after 10min addition, the reaction was allowed to return to room temperature for 2h. The reaction mixture was transferred to a low temperature and quenched with 1.6mL of water, 1.6mL of 15% aqueous sodium hydroxide solution was added, 4.8mL of water was added, stirring was carried out for 10min, anhydrous magnesium sulfate was added, stirring was carried out for 10min, and then filtration was carried out, the filter cake was washed twice with DCM, the mother liquor was concentrated, and purification was carried out with a silica gel column (DCM to DCM: EA =3: 1) to obtain the target compound 4-2 as a pale yellow oil (4.02 g, yield 80.56%).
And step 3: synthesis of Compound 4-3
At room temperature, dry DCM (15.00 mL) was added to a dry reaction flask, dry DMSO (2.46 mL) was added, the temperature was reduced to-78 deg.C under nitrogen, 2M oxalyl chloride (1.47 mL) was added slowly, reaction was continued at that temperature for 0.5h, compound 4-2 (2.00 g) was dissolved in DCM (15.00 mL) and then added slowly to the reaction mixture, reaction was continued at that temperature for 1h, TEA (4.81 mL) was added finally, and after stirring at that temperature for 0.3h, the reaction was returned to room temperature. Water and DCM were added for extraction, and the organic phase was dried and concentrated to give crude compound 4-3 (1.94 g, 98.14% yield) as a colorless liquid.
And 4, step 4: synthesis of Compound 4-4
To a reaction flask at room temperature was added crude 4-3 (1.90 g), meOH (20.00 mL) and K as described above 2 CO 3 (3.07 g), dimethyl (1-diazo-2-oxopropyl) phosphonate (2.17 mL) was added slowly with stirring at 0 ℃ and the reaction was allowed to return to room temperature for 12h. Adding EA and water, extracting, drying, and concentrating. The concentrate was purified by a silica gel column (PE. PE: EA =2 1) to obtain the objective product 4-4 (1.25 g, yield 67.36%) as a pale yellow liquid.
And 5: synthesis of Compounds 4 to 5
At room temperature, compound 4-4 (65.77 mg), compound 1-9 (100.00 mg), cuI (7.48 mg), pdCl were added to a reaction flask 2 (PPh 3 ) 2 (18.39 mg), TEA (0.05 mL), and DMF (1.00 mL) were allowed to react for 0.5h under nitrogen at 40 ℃ after nitrogen substitution. The reaction mixture was extracted with water and EA, dried and concentrated. The concentrate was purified (DCM: meOH = 12) to give the target compound 4-5 (23.00 mg, 22.49% yield) as a yellow solid. ESI-MS m/z of 780[ 2 ], [ M ] +H] + 。
Step 6: synthesis of Compounds 4-6
The above-mentioned compound 4-5 (23.00 mg), THF (1.00 mL) and triethylamine trihydrofluoride salt (0.05 mL) were charged into a reaction flask at room temperature and reacted at room temperature for 0.3h. The reaction was directly concentrated to give crude target compound 4-6 as a yellow oil, which was used directly in the next reaction. ESI-MS m/z:666[ 2 ], [ M ] +H] + 。
And 7: synthesis of Compound 4
The crude 4-6 (20.00 mg), DCM (1.00 mL) and TFA (1.00 mL) were added to the flask at room temperature and reacted for 0.3h at room temperature. The solvent was first spun dry, dissolved in DCM, adjusted to pH =8 with aqueous sodium bicarbonate solution in ice bath, extracted with DCM and MeOH, dried organic phase and concentrated. The concentrate was purified by Pre-TLC separation (DCM: meOH: ammonia =10 =18.93％)。ESI-MS m/z:566[M+H] + 。 1 H NMR(500MHz,MeOD)δ7.84(dd,J＝15.5,7.5Hz,1H),7.73(dd,J＝8.1,4.2Hz,1H),7.48-7.36(m,3H),7.26-7.16(m,2H),7.11(d,J＝2.1Hz,1H),5.19(dd,J＝55.7,5.1Hz,1H),4.58-4.41(m,2H),3.73-3.55(m,4H),3.22-3.08(m,1H),3.07-2.92(m,2H),2.70(dd,J＝12.0,6.5Hz,2H),2.61(t,J＝11.7Hz,1H),2.19(dtd,J＝27.6,13.8,6.7Hz,1H),2.02(ddd,J＝21.0,13.2,6.6Hz,1H),1.89(d,J＝22.9Hz,4H),1.20(d,J＝3.6Hz,2H),0.94(dd,J＝14.2,11.7Hz,2H)。
The following examples were synthesized using the methods described above, or analogous methods using the corresponding intermediates.
Pharmacological experiment
Example 1 cellular p-ERK detection assay
Two KRas-G12D mutant tumor cells AGS (
CRL-1739 TM ) Or Panc 04.03 (` H `)>
CRL-2555 TM ) By 5X 10 4 Cell density per well was plated in 96-well plates and incubated overnight in a cell incubator. After the cells were attached, the test compound was added to 96-well plates at final concentrations of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and after 3h of incubation, the protein lysate of each processed cell sample in the 96-well plate was extracted using a lyss buffer (50. Mu.L) in an MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit, the protein lysate was quantified using the BCA method, and the protein sample concentration was diluted to 0.1. Mu.g/. Mu.L using the lyss buffer. Adding 25 ul/well of protein diluent into a 96-well MSD detection plate, incubating at room temperature for 3h, adding 25 muL of detection antibody solution, continuing to incubate at room temperature for 1h, washing the plate, and adding 150 muL of 1 × read buffer T. Plate readings were performed on a SECTOR Imager and raw data was collected.
p-ERK% value = ((2 × phosphorylation signal value)/(phosphorylation signal value + total signal value)) × 100
The percent p-ERK inhibition was calculated according to the following formula:
percent inhibition = (maximum-measured value)/(maximum-Blank) × 100
("maximum" from 0.1% DMSO control well, "Blank" from Blank control well, "measured" from compound treated well).
Curve fitting and IC acquisition using GraphPad Prism software 50 The value is obtained.
TABLE 1
Example 2: cell proliferation Assay (AGS)
AGS (KRas-G12D mutant tumor cells) (II)
CRL-1739 TM ) By 1 × 10 3 Cell density per well was plated on low adsorption 96-well plates and incubated overnight in a cell incubator. After the cells adhere to the wall, adding a compound to be detected into a 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05 and 0nM (the final concentration of DMSO is 0.5%), culturing at 37 ℃ for 96 hours, adding 50 mu L of Cell-titer GLO working solution into each well, shaking and mixing uniformly, incubating at room temperature for 10min, reading a Luminescence value of Luminescence in a multifunctional microplate reader, and calculating and converting the Luminescence value data into inhibition percentage. And calculating the percentage of inhibition of cell proliferation according to the following formula:
percent inhibition = (max-measured)/(max-Blank) × 100
("maximum" from 0.1% DMSO control well, "Blank" from Blank control well, "measured" from compound treated well).
Curve fitting and IC acquisition using GraphPad Prism software 50 The value is obtained.
TABLE 2
Claims (15)
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,
X 1 selected from the group consisting of CR 6 Or N; r is 6 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, haloElement, C 2-6 Alkenyl, substituted C 2-6 Alkenyl radical, C 3-6 Cycloalkyl or substituted C 3-6 A cycloalkyl group;
X 2 selected from the group consisting of CR 7 Or N; r is 7 Selected from H, halogen, cyano or C 1-6 An alkyl group;
X 3 selected from the group consisting of CR 8 Or N; r 8 Selected from H, halogen, cyano or C 1-6 An alkyl group;
l is selected from the group consisting of a bond, O, NR 9 Or C 1-4 Alkylene of the said C 1-4 Alkylene is optionally substituted by one or more R 9 Substitution; r 9 Selected from H, halogen, cyano or C 1-6 Alkyl, or two R on the same carbon atom 9 Together with the atoms to which they are attached form a 3-6 membered cycloalkyl group;
R 1 selected from the group consisting of absent, or R 1 、R 7 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo;
R 2 selected from absent, or R 2 、R 8 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo;
R 3 selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by one or more R 10 Substitution;
R 4 selected from H, halogen, C 1-6 Alkyl OR-OR 11 Said R is 11 Is selected from C 1-6 Alkyl or C 3-8 Cycloalkyl radical, R 11 Optionally substituted by one or more groups selected from hydroxy, halogen, C 1-3 Alkyl radical, C 1-3 Alkoxy or cyclopropyl;
R 5 selected from aryl or heteroaryl, said aryl or heteroaryl being optionally further substituted by one or more R 10 Substitution;
R 10 selected from H, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (= O) R a 、-C 0-6 alkylene-S (= O) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (= O) R a 、-C 0-6 alkylene-C (= O) OR a 、-C 0-6 alkylene-C (= O) N (R) a ) 2 、
C 2-6 Alkenyl radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl), said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R a Substituted;
each R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Alkyl halidesBase, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
and the compound of the formula (I) is not
2. A compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof, selected from compounds of the formula:
preferably, it is
Wherein the substituents are as defined in claim 1.
3. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof of claim 1 wherein R is 5 Is selected from
/>
4. A compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to one of claims 1-3, wherein L is a bond and R is 3 Is cycloalkyl, said cycloalkyl being further substituted by one or more R 10 Substitution; the R is 10 Is selected from-C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl radical, -C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 or-C 0-6 Alkylene- (5-to 14-membered heteroaryl), said-C 0-6 Alkylene- (3-to 14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R a Substituted; said R is a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 A haloalkoxy group.
5. A compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1-3 wherein L is selected from the group consisting of a bond and C 1-4 Alkylene of the R 3 Selected from heterocyclyl or heteroaryl, said heterocyclyl or heteroaryl being optionally further substituted by one or more R 10 Substitution; the R is 10 Selected from H, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a or-C 0-6 alkylene-NR a C(O)N(R a ) Said R is a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl or C 1-6 A haloalkyl group.
6. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, of any one of claims 1-5 wherein R 1 、R 7 Together with the atoms to which they are attached form a substituent or notA substituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo.
7. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, of any one of claims 1-5 wherein R 1 Is absent.
8. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, of any one of claims 1-5 wherein R 2 、R 8 Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C 1-6 Alkyl or oxo.
9. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R is 2 Is absent.
10. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein R is 4 Is halogen, preferably F.
11. A compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
12. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-10, or a stereoisomer, tautomer, deuteron, or pharmaceutically acceptable salt thereof.
13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for the manufacture of a medicament.
14. The use according to claim 13, wherein the manufacture of a medicament is for the manufacture of a medicament for the treatment and/or prevention of a disease mediated by KRAS G12D.
15. The use of claim 14, wherein the KRAS G12D mediated disease is a cancer 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, schwannoma, lung squamous cell carcinoma, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
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