CN116143805B

CN116143805B - Nitrogen-containing heterocyclic biaryl compounds, preparation method and application

Info

Publication number: CN116143805B
Application number: CN202210388385.8A
Authority: CN
Inventors: 万惠新; 王亚周; 查传涛; 马金贵
Original assignee: Shanghai Lingda Biomedical Co ltd
Current assignee: Shanghai Lingda Biomedical Co ltd
Priority date: 2021-09-17
Filing date: 2022-04-13
Publication date: 2025-10-17
Anticipated expiration: 2042-04-13
Also published as: CN116143805A

Abstract

本发明公开了一类含氮杂环联芳基类化合物、制备方法和用途，具体为一种如通式I所示的嘧啶并杂环类化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用，其中各基团的定义如说明书中所述。 The present invention discloses a class of nitrogen-containing heterocyclic biaryl compounds, preparation methods and uses, specifically a pyrimidoheterocyclic compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, a preparation method and pharmaceutical use thereof, wherein the definitions of the various groups are as described in the specification.

Description

Nitrogen-containing heterocyclic biaryl compounds, preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a nitrogen-containing heterocyclic biaryl compound, a compound for inhibiting activity of Ras mutein, a preparation method and application.

Background

Ras is the first oncogene identified in human tumors, and was first discovered in two murine sarcoma viruses. The Ras gene family has three members, HRas, KRas, NRas, respectively. In human tumors, KRas mutations are most common, accounting for about 85%. Previous studies have shown that KRas mutations are oncogenic because of missense mutations at codon 12, altering the structure of the KRas protein and allowing it to remain active. Ras plays a major role in signaling pathway in activating kinases that control gene transcription, thereby regulating cell differentiation and proliferation, and is intimately involved in tumor cell survival, proliferation, migration, metastasis, and angiogenesis. It is counted that a high proportion of KRas mutations occur in malignant tumors such as pancreatic cancer, colorectal cancer, ovarian cancer, cholangiocarcinoma and the like. However, targeting drugs for common proto-oncogenes such as EGFR, BCL, etc. have been developed for several generations since the first discovery of KRas oncogenes, but targeting drugs for KRas have not been successfully developed all the time. Targeting drugs against KRas pathway mutant tumors have been mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but have had little effect. In recent years, inhibitors against KRas specific gene mutations have been developed as hot spots, although some inhibitors have gradually moved from preclinical hatching to clinical studies, such as KRas ^G12C inhibitor AMG510, MRTX1257, etc., and have shown some efficacy in early clinical trials. The first clinical data of the global first-line KRas ^G12C inhibitor AMG510 was formally published by the american clinical oncology institute held at month 6 of 2019, in which the drug AMG510 was shown to be able to prevent tumor growth in most non-small cell lung and colorectal cancer patients with KRas mutations.

However, the KRAS inhibitor is limited to KRAS ^G12C mutant patients, and the research and development of a large number of mutant inhibitor drugs except KRAS ^G12C have not been broken through, such as high-frequency KRAS ^G12D、KRas^G12V、KRas^G13D and other mutations. Therefore, finding and searching for a targeted drug with high specificity and excellent pharmaceutical properties for a specific mutant gene other than KRas ^G12C is a great hotspot in the industry. Through the long-term efforts of the inventor, a KRAS mutation inhibitor with novel structure and action mechanism is discovered, and particularly has better drug-forming property on KRAS ^G12D mutation.

Disclosure of Invention

The invention aims to solve the technical problem of lack of KRAS ^G12D inhibitors in the prior art, and provides a nitrogen-containing heterocyclic biaryl compound, a preparation method and application. The nitrogen-containing heterocyclic biaryl compound provided by the invention is a brand-new KRAS ^G12D inhibitor, shows good inhibition activity, has good inhibition activity on tumor cells and good drug-forming property, and has wide drug development prospect.

The invention solves the technical problems by the following technical proposal:

The invention provides a nitrogen-containing heterocyclic biaryl compound shown in a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,

Wherein R ¹ is selected from substituted or unsubstituted piperazine or piperidine, the substituent is selected from one or more of halogen, cyano, hydroxy, amino, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkylcyano, C ₁-C₆ alkylhydroxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, and the substituents form a 3-10 membered carbocyclic or heterocyclic ring system between each other, the ring system including spiro, bridged, fused, and the like;

R ² is selected from substituted or unsubstituted C ₁-C₆ alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-12 membered cycloalkyl or heterocycloalkyl substituted alkyl, said substituents being selected from halogen, cyano, hydroxy, amino, monoalkylamino, dialkylamino, C ₁-C₆ alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 6-12 membered "containing 0 to 3 heteroatoms" independently selected from N, O, P, S containing 0 to 3 heteroatoms saturated or partially unsaturated spiro, bridged, fused ring, etc.;

L is selected from a bond, CHR ⁵、O、S、NR⁵;R⁵ is selected from an alkyl group of H, C ₁-C₆;

ar is selected from substituted or unsubstituted 5-12 membered aryl or heteroaryl, and the substituent R ³ is selected from one or more of hydrogen, halogen, cyano, hydroxy, nitro, substituted or unsubstituted amino, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, and the like;

M is N or CR ⁴;R⁴ is selected from F, CN, cl, C ₁-C₆ alkyl, etc., when M is N, W and W1 are each independently selected from N, C-F, C-Cl, C-H, C-CN, C-C ₁-C₆ alkyl, etc., when M is CR ⁴, W, W1 are each independently selected from N, C-F, C-Cl, C-H, C-CN, C-C ₁-C₆ alkyl, etc.;

the hetero atoms in the heterocyclic ring system, the heterocycloalkyl group and the heteroaryl group are independently selected from N, O, P, S, and the number of the hetero atoms is 1-3.

In some preferred embodiments, the nitrogen-containing heterocyclic biaryl compounds of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,

R ² is selected from the group consisting of substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted 5-12 membered aryl or heteroaryl, substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl substituted alkyl, wherein when R ² is substituted, the substituent is one or more R ^2-1, and wherein R ^2-1 is independently selected from the group consisting of halogen, cyano, hydroxy, amino, monoalkylamino, dialkylamino, dialkylaminoC ₁-C₆ alkyl-, C ₁-C₆ alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 6-12 membered "saturated or partially unsaturated spiro ring, bridged ring, fused ring containing 0-3 heteroatoms" independently selected from N, O, P, S, and the like, and wherein R ^2-1 may be further substituted with halogen, cyano, hydroxy, amino, monoalkylamino, dialkylamino, dialkylaminoC ₁-C₆ alkyl, C ₁-C₆, 5-8 membered cycloalkyl, 5-8 membered heteroaryl, or the like;

In some preferred embodiments of the invention, the substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl substituted alkyl is substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl-C ₁-C₃ alkyl-, preferably substituted or unsubstituted C ₃-C₈ cycloalkyl-C ₁-C₃ alkyl-, substituted or unsubstituted C ₅-C₁₂ heterocycloalkyl-C ₁-C₃ alkyl-;

In some preferred embodiments of the invention, R ^2-1 is 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, preferably 3-6 membered cycloalkyl, 5-12 membered heterocycloalkyl;

In one embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is characterized in that M is N, W1 is selected from N, C-F, C-Cl, C-H, C-CN, C-C ₁-C₆ alkyl and W is selected from N;

In one embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is characterized in that M is N, W1 is selected from N, W is selected from C-F, C-Cl, C-H, C-CN, C-C ₁-C₆ alkyl, R ¹ is selected from: the hydrogen on any carbon atom of the R ¹ group may be substituted by halogen, hydroxy, C ₁-C₆ alkyl;

In one embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is characterized in that M is CR ⁴,R⁴, preferably CN, F, W and W1 are each independently selected from N, C-F, C-Cl, C-H, C-CN, C-C ₁-C₆ alkyl, etc.;

In one embodiment of the invention, the nitrogen-containing heterocyclic biaryl compound shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof is characterized in that Ar is selected from benzene rings, naphthalene rings, wherein Ar can be substituted by one or more different R ³, R ³ is selected from halogen, hydroxyl, amino, cyano, C ₁-C₆ alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C ₂-C₆ alkenyl and C ₂-C₆ alkynyl, L is selected from CH ₂、O、NH、S;R² is selected from substituted or unsubstituted C ₁-C₆ alkyl, and the substituent is selected from halogen, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, C ₁-C₆ alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 6-12 membered saturated or partially unsaturated fused ring containing 0-3 heteroatoms, bridged ring, fused ring, etc.;

In one embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound shown in formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, is characterized in that R ³ -Ar is selected from

L is selected from-O-;

r ² is selected from

Wherein m, n are each selected from integers from 1 to 3, ry is selected from alkyl substituted amino, 3-10 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl, heteroaryl, R ^p and R ^q are each selected from hydrogen, halogen, alkyl or alkoxy of C ₁-C₆, hydroxy, amino, or R ^p and R ^q form a 3-10 membered carbocyclic or heterocyclic ring system;

In some preferred embodiments Ry is selected from 5-8 membered cycloalkyl or heterocycloalkyl, preferably

In some preferred embodiments, rp and Rq form a three membered carbocyclic ring with the attached carbon atom;

In some preferred embodiments, R ^p and R ^q are methyl;

In some preferred embodiments, the alkyl groups of the mono-, di-, alkyl-substituted amino groups are preferably C1-C6 alkyl groups;

in one embodiment of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof, has the following structure:

Thus, throughout this specification, one skilled in the art may select the groups and substituents thereof in the nitrogen-containing heterocyclic biaryl compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, to provide a stable nitrogen-containing heterocyclic biaryl compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, including but not limited to the compounds described in the examples of the invention.

The nitrogen-containing heterocyclic biaryl compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, described herein, may be synthesized by methods that include methods similar to those known in the chemical arts, the steps and conditions of which may be referenced in the art for similar reactions, particularly in light of the description herein. The starting materials are typically from commercial sources, such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SCIFINDER, REAXYS on-line databases).

In the present invention, the nitrogen-containing heterocyclic biaryl compound shown in formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, may be prepared by peripherally modifying the prepared nitrogen-containing heterocyclic biaryl compound shown in formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof, by a conventional method in the art, to obtain other nitrogen-containing heterocyclic biaryl compounds shown in formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomer, torsion isomers, solvates, polymorphs or prodrugs thereof.

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula I, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.

The invention also provides a preparation method of the nitrogen-containing heterocyclic biaryl compound shown in the formula I, which comprises the following steps:

a) Carrying out substitution reaction on a compound of the general formula (A) and R ¹ -H under alkaline conditions to generate a compound of the general formula (B);

b) Carrying out substitution reaction or metal catalytic coupling reaction on the compound of the general formula (B) and R ² -L-H under alkaline conditions to generate a compound of the general formula (C);

c) The compound of the general formula (C) and arylboric acid or arylborate or arylmetal reagent (Ar-M) are subjected to a transition metal catalytic coupling reaction to generate the general formula (I).

X is halogen, and the definition of each other group is as described above;

Preferably, each of said steps a), b), c) is performed in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.

Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof, and the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.

Preferably, the transition metal catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium (Pd ₂(dba)₃), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃)₄), palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, bis (triphenylphosphine) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof, and the catalyst ligand is selected from the group consisting of tri-t-butylphosphine, tri-t-butyltetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or a combination thereof.

The necessary starting materials or reagents for preparing the compounds of formula I are commercially available or may be prepared by synthetic methods known in the art. The compounds of the invention may be prepared as free bases or as salts thereof with acids, as described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and has all of the pharmaceutical activity of the parent compound. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent for the organic base, and processing according to conventional methods.

Examples of salt formation include salt formation with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, euryalonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, or trimethylacetic acid.

The nitrogen-containing heterocyclic biaryl compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, may have one or more chiral carbon atoms, and thus may be isolated as optically pure isomers, e.g., pure enantiomers, or racemates, or mixed isomers. Pure single isomers may be obtained by separation methods in the art, such as chiral crystallization to form salts, or chiral preparative column separation.

The chemicals used in the synthetic routes described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, including t-butoxycarbonyl (Boc). The above-described methods may additionally include steps prior to or subsequent to the steps specifically described herein, and suitable protecting groups may be added or removed to provide the subject compounds. In addition, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.

It is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:

The invention provides a pharmaceutical composition comprising an effective amount of a nitrogen-containing heterocyclic biaryl compound represented by formula I as described above, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and (one or more) pharmaceutically acceptable carrier (pharmaceutical excipients). For example, such pharmaceutical compositions may comprise one or more additional nitrogen-containing heterocyclic biaryl compounds of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof. In the pharmaceutical composition, the nitrogen-containing heterocyclic biaryl compound shown in the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can be used in an amount effective for treatment.

The invention provides a pharmaceutical composition for treating tumors, which consists of a nitrogen-containing heterocyclic biaryl compound shown in the general formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof and a pharmaceutically acceptable carrier.

It is a further object of the present invention to provide the use of the above compounds. The technical scheme for achieving the purpose is as follows:

The invention also provides an application of the nitrogen-containing heterocyclic biaryl compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof in preparing Ras mutein inhibitor, wherein the Ras mutein inhibitor can be KRAS ^G12D, can be used in a mammalian organism, can also be used in vitro, mainly used for experimental purposes, for example, can be used as a standard sample or a reference sample for comparison, or can be prepared into a kit according to a conventional method in the field for providing rapid detection for the inhibition effect of Ras mutein.

The invention also provides an application of the nitrogen-containing heterocyclic biaryl compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof in preparing medicines, wherein the medicines can be medicines for treating diseases related to activity or expression quantity of Ras muteins, or the medicines can be medicines for treating tumors. The Ras mutein may be KRAS ^G12D. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

Another aspect of the invention relates to a method for preventing and/or treating a disease associated with activity or expression of a Ras mutein comprising administering to a patient a therapeutically effective amount of the nitrogen-containing heterocyclic biaryl compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional, solvate, polymorph or prodrug thereof.

Another aspect of the present invention relates to a method for preventing and/or treating tumors comprising administering to a patient a therapeutically effective amount of the nitrogen-containing heterocyclic biaryl compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

Another aspect of the invention relates to a medicament for preventing and/or treating a disease or tumor associated with activity or expression of a Ras mutein, which comprises the nitrogen-containing heterocyclic biaryl compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

The nitrogen-containing heterocyclic biaryl compound shown in the general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof is used for preparing medicaments for treating diseases related to activity or expression quantity of Ras mutant proteins, in particular to medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

The invention relates to a compound with the structural characteristics of a general formula I, which can inhibit various tumor cells, especially can efficiently kill tumors related to abnormal KRAS ^G12D mutant protein signal paths, and is a therapeutic drug with a brand-new action mechanism.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can include one or more of binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, binders, disintegrants, lubricants, anti-adherent agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch, celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, gum powders, malt, gelatin, talc, adjuvants such as cocoa butter and suppository waxes, oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycol compounds such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic salts, ringer's solution, ethanol, phosphate buffer solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coating materials, sweeteners, flavoring agents and fragrances, preservatives and antioxidants.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical dosage forms of the compounds of the present invention may be provided in the form of immediate release, controlled release, sustained release or target drug release systems. For example, common dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and freeze-dried formulations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special bottles (SPECIAL FLASK). Pharmaceutical dosage forms often consist of a drug, excipients and a container/sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and may provide a means to achieve a desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the manufacturing steps. Pharmaceutically acceptable excipients are present in this field and include those listed in the various pharmacopoeias. (see U.S. Pharmacopeia (U.S.Pharmacopeia, USP), japanese Pharmacopeia (Japanese Pharmacopoeia, JP), european Pharmacopeia (European Pharmacopoeia, EP) and British Pharmacopeia (British pharmacopoeia, BP); U.S. food and drug administration (the U.S. food and Drug Administration, www.fda.gov) drug evaluation and research center (Centerfor Drug Evaluation AND RESEARCH, CEDR) publications, for example, inactive ingredient Guide (INACTIVE INGREDIENT Guide, 1996); handbook of drug additives written by Ash and Ash (Handbook ofPharmaceutical Additives,2002, incorporated information resources, inc. (Synapse Information Resources, inc., endiott NY; etc.).

Pharmaceutical dosage forms of the compounds of the present invention may be manufactured by any of the methods well known in the art, for example by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, grinding, emulsifying, (nano/micro) encapsulating, packaging, or lyophilizing processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.

The pharmaceutical compositions of the invention may be administered topically or systemically, e.g. for enteral, such as rectal or oral administration, or for parenteral administration to a mammal (especially a human), and comprise a therapeutically effective amount of a compound according to the invention, a stereoisomer or a pharmaceutically acceptable salt thereof as active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. A therapeutically effective amount of the active ingredient is defined as above and below and depending on the species, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated and mode of administration of the mammal, for enteral administration, such as oral administration, the compounds of the invention can be formulated in a wide variety of dosage forms.

The pharmaceutical compositions and dosage forms may comprise one or more compounds of the present invention, stereoisomers thereof, or one or more pharmaceutically acceptable salts thereof, as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid forms of preparation include powders, tablets, pills, troches, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is a mixture with the finely divided active component. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. Formulations of the active compounds may include an encapsulating material as a carrier providing a capsule in which the active ingredient with or without the carrier is surrounded by a carrier to which it is bound.

Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted to liquid form preparations shortly before use. The emulsion may be prepared in solution, for example in an aqueous propylene glycol solution, or may contain an emulsifier such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water with binders such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose and other commonly used suspending agents. Solid form preparations include solutions, suspensions and emulsions which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures, but melt and/or dissolve in the rectal cavity to release the drug.

The compounds of the invention may also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intra-arterial, intra-osseous, intramuscular, intra-cerebral, extra-cerebral, intra-synovial, intra-sternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions of the invention may be in the form of sterile injectable or infusible preparations, e.g., as sterile aqueous or oleaginous suspensions. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable or infusible formulation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1, 3-butanediol. Other examples of acceptable vehicles and solvents that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant. Solutions for parenteral use may also include suitable stabilizers and, if desired, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and salts thereof and sodium EDTA alone or in combination. The parenteral solution may also contain preservatives such as benzalkonium chloride, parahydroxybenzoic acid or propyl parahydroxybenzoate and chlorobutanol.

For inhalation or nasal administration, suitable pharmaceutical formulation chamber particles, aerosols, powders, mists or droplets, for example, have an average size of about 10 microns or less in diameter. For example, compositions for inhalation may be prepared in saline as solutions, using benzyl alcohol or other suitable preservatives, absorption promoters for improving bioavailability, fluorocarbon and/or other solubilizing or dispersing agents known in the art.

The pharmaceutical compositions of the present invention may also be administered topically to the skin or mucosa. For topical application, the pharmaceutical composition may be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.

The pharmaceutical compositions may be formulated in a suitable ointment comprising the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water. Or the pharmaceutical compositions may be formulated as suitable lotions or emulsions comprising the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may also be administered topically to the lower intestinal tract in rectal suppository formulations or in suitable enema formulations. Suitable pharmaceutical excipients (e.g. carriers) and methods for preparing pharmaceutical dosage forms are described in standard reference textbooks in the pharmaceutical formulation arts (Remington's Pharmaceutical Sciences, mack Publishing Company)

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.

Terminology

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

The definition of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY TH ED." vols.a (2000) andB (2001), plenum Press, newYork. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -.

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl, C _1-6 alkyl or C _1-C₆ alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1,2, 3,4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the C ₁-C₆ alkyl in the group "halo-C ₁-C₆ alkyl" is understood to be C ₁-C₆ alkylene (e.g., methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, 2-methylbutylene, 1-ethylpropylene, 1, 2-dimethylpropylene, neopentylene, or 1, 1-dimethylpropylene, etc.).

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.

The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.

The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C ₁～C₆ alkyl" or "C _1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl, and "C _1-4 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl (i.e., propyl, including n-propyl and isopropyl), C ₄ alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine, "hydroxy" means an-OH group, "hydroxyalkyl" means an alkyl group as defined below substituted by a hydroxy (-OH), "carbonyl" means a-C (=o) -group, "nitro" means-NO ₂, "cyano" means-CN ", amino" means-NH ₂, "substituted amino" means an amino group substituted by one or two of an alkyl, alkylcarbonyl, aralkyl, heteroaralkyl group, e.g., a mono-alkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino group, "carboxy" means-COOH ", an" acyl "means a-C (=o) H group, a" sulfonyl "means-S (=o) ₂ -group, a" sulfoxide "means-S (=o) -group, a" sulfonyl "means-S (=o) ₂ H group, a-C (=o) ₂ H group, a-NH-C (=o) means-NH-24, a" means-C (=o) H group, a "C (=o) H-group, a" means-C (=o) H group, a "C (=o) ₂ -group, a" means-C (=o) H group, a "C (=o) means" C (=o) H.

In the present application, as part of a group or other groups (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and linked to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.

The term "alkylene" as used herein refers to a saturated, branched or straight chain or cyclic hydrocarbon group of the number of carbon atoms (typically 1-6 carbon atoms) and having two monovalent radical centers derived from the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH ₂ -), ethylene { including 1, 2-ethylene (-CH ₂CH₂ -), 2-dimethylene (-CH (CH ₃) -) }, propylene { including 2-methylpropylene (-CH (CH ₃)CH₂ -), isopropylene (-C (CH ₃)₂ -)), 1, 3-propylene (-CH ₂CH₂CH₂ -) }, butylene { including 1, 4-butylene (-CH ₂CH₂CH₂CH₂ -) }.

In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.

In the present application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by single bonds, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

In the present application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.

In the present application, as part of a group or other group, the term "heterocyclyl" means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specifically indicated in the present specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system, a nitrogen, carbon or sulfur atom in a heterocyclic group of which may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

In the present application, the term "heterocycloalkyl" as part of a group or other group means a stable 3-to 20-membered saturated cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specifically indicated in the present specification, a heterocycloalkyl group may be either a monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic or higher ring system, which may include fused, bridged or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl"). The heterocycloalkyl bicyclic ring system may include one or more heteroatoms in one or both rings, and is saturated for purposes of the present application, a heterocycloalkyl group is preferably a stable 4-to 12-membered saturated monocyclic, bicyclic, bridged or spiro ring group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 7-membered saturated monocyclic, bicyclic, bridged or spiro ring group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, in particular, the 4-to 7-membered heterocycloalkyl group may contain 3, 4, 5 or 6 carbon atoms and one or two of the heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 7, in particular the heterocycloalkyl group may contain 3, 5 or 6 carbon atoms and the total number of heteroatoms or heteroatom-containing groups ("the total number of heteroatoms may be 3, 5 or 6 heteroatoms").

In the present application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized and the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is an open-ended limitation and does not exclude other aspects, i.e. it includes the content indicated by the invention.

Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.

The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.

In addition, unless explicitly stated otherwise, the description used in this invention ". In the broad sense, it is to be understood that each individual described is independent of the others and may be independently the same or different. In more detail, the description "..independently" may mean that specific options expressed between the same symbols in different groups do not affect each other, or that specific options expressed between the same symbols in the same groups do not affect each other.

Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedMeaning that the corresponding group is linked to other fragments, groups in the compound through this site.

In the present application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

"Stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.

"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like, organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

"Polymorphs" refer to the different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.

In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Or the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The application also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted into the biologically active compound of the present application under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the application. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present application. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present application, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods of prodrug preparation can be referenced Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990;Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475.

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

The "tumor", "cell proliferation abnormality related disease", and the like of the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.

The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e. causing regression of the state of the disease or condition, or

(Iv) Alleviating symptoms caused by the disease or condition.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The skilled artisan is familiar with the techniques of administration that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman,The Pharmacological Basis ofTherapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.

It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include-C (O) -R "(wherein" R "is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, t.w. and p.g.m. wuts, protective Groups in Organic Synthesis, (1999), 4th Ed, wiley. The protecting group may also be a polymeric resin.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects of providing the nitrogen-containing heterocyclic biaryl compound which can be used as a KRAS ^G12D inhibitor and can be used for preparing anti-tumor medicaments and preventing and/or treating tumors.

Detailed Description

The inventor has prepared a class of benzothiazolyl biaryl compounds with novel structure shown in formula I through long-term and intensive research, and found that the compounds have better KRAS ^G12D protein inhibition activity, and the compounds have quite excellent (IC ₅₀ even less than 10 nM) inhibition activity on cell proliferation and downstream signal pERK related to KRAS ^G12D under extremely low concentration (which can be as low as less than 100 nM), so that the compounds can be used for treating related diseases such as tumors caused by KRAS ^G12D mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

Preparation of intermediate A1 7-bromo-2, 4, 6-trichloro-8-fluoroquinoline-3-cyano

Step one methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate (710 mg,2.51 mmol) and cyanoacetic acid (213 mg,2.51 mmol) were dissolved in acetonitrile (10 mL), pyridine (1.98 g,25.1 mmol) was added, cooled to about 5 ℃, phosphorus oxychloride (1.17 g,7.53 mmol) was added dropwise and stirred at room temperature for 2 hours, poured into water, pH was adjusted to about 5, filtered and dried to give a yellow solid intermediate product (510 mg). LC-MS [ M-H ] ^-:m/z 349.1.

Step two, the intermediate compound (100 mg,0.29 mmol) is added into the existing ethanol (2 mL) solution of sodium ethoxide (20 mg,0.86 mmol), heated and refluxed overnight, dried by spin, added with water, and adjusted to pH about 4 by hydrochloric acid, and solid is separated out, the crude solid product is filtered, and dried to obtain a pale yellow intermediate product (45 mg). LC-MS [ M+H ] ⁺:m/z 316.9/318.9.

Step three the above intermediate compound (370 mg,1.16 mmol) was suspended in phosphorus oxychloride POCl ₃ (10 mL), one drop of N, N-dimethylformamide DMF was added, heated under reflux overnight, dried by spinning, the residue was dissolved in dichloromethane DCM (10 mL) and added dropwise to saturated aqueous sodium bicarbonate NaHCO ₃ and the pH was kept basic, and extracted three times with DCM (30 mL). The combined organic phases were dried over anhydrous magnesium sulfate MgSO ₄, filtered, and concentrated under reduced pressure to give intermediate A1 (298 mg) as a yellow solid. LC-MS [ M+H ] ⁺:m/z 352.8/354.8.¹H NMR(400MHz,DMSO-d₆): δ8.43 (s, 1H).

Intermediate A2:7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

Step one 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.5 g,5.62 mmol) and urea (2.7 g,44.9 mmol) were mixed and heated to 200 ℃ and reacted for 4 hours. Cooled to room temperature, then water (50 mL) was added, heated to 100 ℃ and stirred for an additional hour, filtered while hot. The solid was slurried with ethyl acetate (50 mL), and the filtered solid was dried to afford a reddish brown intermediate product (1.3g).LC-MS[M-H]^-:m/z 292.9.¹H NMR(400MHz,DMSO-d₆):δ11.50-11.3(dt,2H),7.83(s,1H).

Step two, the intermediate compound (413 mg,1.41 mmol) was suspended in POCl ₃ (20 mL), three drops of N, N-dimethylaniline were added, heated to reflux overnight, dried by spinning, the residue was dissolved in DCM (10 mL) and added dropwise to saturated aqueous NaHCO ₃ and the pH was kept at 7-8, and extracted three times with DCM (30 mL). The combined organic phases were dried over MgSO ₄, filtered and concentrated under reduced pressure to give intermediate A2 (219 mg) as a yellow solid. LC-MS [ M+H ] ⁺:m/z328.8/330.8.¹H NMR(400MHz,DMSO-d₆): delta 8.05 (s, 1H).

Intermediate A3:7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

Step one methyl 4-amino-6-chloro-5-fluoronicotinate (500 mg,2.45 mmol) and cyanoacetic acid (208 mg,2.45 mmol) were dissolved in acetonitrile (10 mL), pyridine (19.4 g,24.5 mmol) was added, cooled to about 5 ℃, phosphorus oxychloride (1.12 g,7.35 mmol) was added dropwise and stirred at room temperature for 2 hours, poured into water, after pH was adjusted to about 6, a solid was precipitated, the solid crude product was filtered, and dried to give a yellow intermediate product (530 mg). LC-MS [ M+H ] ⁺:m/z 272.1.

Step two, naH (60%, 200mg,5.0 mmol) was added to a DMF (10 mL) solution of the above intermediate compound (500 mg,1.84 mmol) under ice-bath cooling, the reaction was warmed to room temperature and stirred overnight, water was added to quench, pH was adjusted to around 4 with 4M aqueous hydrochloric acid, solid precipitated, the crude solid product was filtered, and dried to give a yellow intermediate product (200 mg). LC-MS [ M+H ] ⁺:m/z 240.

Step three, the intermediate compound (150 mg,0.63 mmol) was suspended in POCl ₃ (10 mL), one drop of DMF was added, and the mixture was heated to reflux overnight. After completion of the assay, the reaction was dried by spinning, the residue was dissolved in DCM (10 mL) and added dropwise to saturated aqueous NaHCO ₃ and the pH was kept at 7-8 and extracted three times with DCM (20 mL). The combined organic phases were dried over MgSO ₄, filtered and concentrated under reduced pressure to give intermediate A3 (219 mg) as a yellow solid. LC-MS [ M+H ] ⁺:m/z 276.1.¹H NMR(400MHz,DMSO-d₆): delta 8.55 (s, 1H).

Referring to the synthetic route and method of patent WO2021041671A1, the following intermediate compounds A4, B1-B6 and C1 are prepared;

referring to the synthetic route and process of patent WO2021106231A1, the following intermediates C2, C3 and C4 were prepared;

Examples general preparation method

In a first step, intermediate compound A (1 eq.) is dissolved in an appropriate solvent and amine or alcohol intermediate R ¹ -H (1.05 eq.) and organic base (3.5 eq.) are added. The reaction was slowly warmed to room temperature and stirred overnight. LC-MS monitors the reaction completely, water is added into the reaction solution, the water phase is extracted three times by ethyl acetate, the extract is dried by anhydrous sodium sulfate, the concentration is reduced, the remainder is separated and purified to obtain the target product, and the structure is confirmed by nuclear magnetism and mass spectrum.

And secondly, dissolving amine or alcohol intermediates R ² -Y-H (1 eq.) in a proper solvent, adding inorganic base (2 eq.) under low-temperature cooling, stirring for half an hour, and then adding the intermediates of the general formula (B) of the first step. The reaction was then stirred at room temperature overnight. TLC monitors the reaction completely, after adding water for quenching, the reaction is concentrated under reduced pressure, the remainder is prepared and separated and purified by silica gel column chromatography or HPLC to obtain the target compound, and nuclear magnetism and mass spectrum are adopted to confirm the structure.

And thirdly, dissolving the product C (1 eq.) and aryl boric acid (ester) or aryl metal reagent (1.2 eq.) in a proper solvent under the protection of nitrogen, adding a transition metal catalyst (0.1 eq.) and inorganic base (2 eq.) to react for several hours at 80-100 ℃, cooling to room temperature, pouring the reaction liquid into water, and extracting with ethyl acetate. The organic phase is washed by saturated saline, and after concentration, the crude product is prepared, separated and purified by silica gel column chromatography or HPLC to obtain the target compound, and the structure is confirmed by nuclear magnetism and/or mass spectrum.

EXAMPLE 14- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinoline-3-cyano

In the first step, 7-bromo-2, 4, 6-trichloro-8-fluoroquinoline-3-cyano (298 mg,0.84 mmol) was dissolved in dichloromethane DCM (15 mL), followed by the addition of tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (178 mg,0.84 mmol) and triethylamine TEA (0.5 mL,4.20 mmol) and stirred at room temperature overnight. The reaction solution was dried by spin to give a crude product, which was purified by silica gel column chromatography to give a yellow solid product (265 mg). ESI-MS m/z 529.1/531.1[ M+H ] ⁺.

In a second step sodium hydride NaH (20 mg,0.50 mmol) was dissolved in tetrahydrofuran THF (10 mL), cooled to zero, added (hexahydro-1H-pyrrolin-7A-yl) methanol (71 mg,0.50 mmol), stirred for half an hour, then the intermediate product of the previous step (220 mg,0.417 mmol) was added, stirred at room temperature for 2H, quenched with saturated ammonium chloride NH ₄ Cl in water (50 mL), extracted three times with ethyl acetate (50 mL), the combined organic phases dried and the crude product concentrated under reduced pressure was purified by silica gel column chromatography (DCM/MeOH=30:1) to give the yellow solid product (260 mg). LC-MS [ M+H ] ⁺:m/z 636.0.

In the third step, to a solution of the above intermediate (103 mg,0.16 mmol) in 1, 4-dioxane/water (12 mL/4 mL) was added boric acid ester B1 (50 mg,0.16 mmol), tetrakis (triphenylphosphine) palladium (24 mg,0.02 mmol) and sodium carbonate powder (Na ₂CO₃) (56 mg,0.53 mmol) at room temperature, and the reaction mixture was stirred under argon at 100℃overnight. After completion of the reaction, ethyl acetate was extracted, and the organic phase was washed with saturated brine, dried over anhydrous Na ₂SO₄, filtered, concentrated under reduced pressure, and purified by flash column chromatography on silica gel to give a yellow solid product (85 mg). LC-MS m/z 743.3[ M+H ] ⁺.

In the fourth step, trifluoroacetic acid (3 mL) was added to a solution of the intermediate (80 mg,0.11 mmol) in Dichloromethane (DCM) (6 mL) under ice-bath cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by HPLC to give a pale yellow solid product (47mg).LC-MS m/z:599.1[M+H]⁺.¹H-NMR(400MHz,CDCl₃):δ9.15(s,1H),8.62(m,1H),8.15-8.06(m,2H),7.58-7.61(m,1H),7.50-7.43(m,2H),7.25(m,1H),4.77-4.30(m,4H),3.97(m,J＝12.8Hz,2H),3.80-3.25(m,6H),2.35-1.86(m,12H).

Starting with intermediate A1, intermediates B and C and commercially available piperidine/piperazine derivative reagents, the following example compounds were obtained by analogy with reference to example 1 using the general preparation of the examples:

EXAMPLE 13 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoro-2- ((hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinazolin-7-yl) naphthalen-2-ol

The same procedures as in reference example 1 were repeated except for using intermediate A2 as a starting material to give example compound 13 (pale yellow solid ,12mg).ESI-MS m/z:574.1[M+H]⁺.¹H-NMR(400MHz,CDCl3):δ9.17(s,1H),8.65(m,1H),8.15-8.03(m,2H),7.65(m,1H),7.50-7.23(m,2H),6.89(m,1H),4.75-4.71(m,2H),4.61-4.52(m,2H),3.92(m.s,2H),3.86(m.d,J＝13.2Hz,2H),3.70-3.60(m,2H),3.27-3.22(m,2H),2.35-2.06(m,8H),2.05-1.86(m,4H).

Starting with intermediate A2, intermediates B and C and commercially available reagents, the following example compounds were obtained by analogy with the example general preparation procedure, with reference to example 1:

EXAMPLE 18 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (3-hydroxynaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -1, 6-naphthyridine-3-cyano

Using the intermediate A3, intermediates B and C and commercially available reagents as starting materials, example 18 (white solid) was prepared according to the procedure analogous to example 1 using the example general preparation method ,13mg).ESI-MS m/z:565.3[M+H]⁺.¹H-NMR(400MHz,CD3OD)δ9.01(s,1H),8.42(m,2H),7.92-8.00(m,1H),7.56(dd,J＝7.2,8.0Hz,1H),7.46-7.52(m,1H),7.27-7.35(m,2H),6.79(dd,J＝1.2,7.2Hz,1H),4.70-4.73(m,2H),4.55-4.62(m,2H),3.92(m,2H),3.83(d,J＝13.2Hz,2H),3.61-3.68(m,2H),3.22-3.26(m,2H),2.11-2.35(m,8H),1.89-2.07(m,4H).

Starting from intermediate A3, intermediates B and C and commercially available reagents, the following example compounds were obtained in the same manner as in reference to example 1:

EXAMPLE 31 4- (4- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) -8-fluoro-2- ((hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7 yl) naphthalen-2-ol

Example 31 (pale yellow solid) was prepared in the same manner as in example 1 using intermediate A4 as a starting material ,5mg).ESI-MS m/z:527.3[M+H]⁺.¹H-NMR(400MHz,CD₃OD)δ9.01(s,1H),8.42(m,2H),7.92-8.00(m,1H),7.56(dd,J＝7.2,8.0Hz,1H),7.46-7.52(m,1H),7.27-7.35(m,2H),6.79(dd,J＝1.2,7.2Hz,1H),4.59-4.68(m,4H),4.00(s,2H),3.85-3.92(m,2H),3.66-3.73(m,2H),3.19-3.26(m,2H),3.01(s,1H),1.94-2.23(m,10H).

Starting with intermediate A4, intermediates B and C and commercially available reagents, the following example compounds were obtained by the procedure analogous to example 1, using the general procedure of the example preparation:

Starting with intermediate A2, intermediates B and C and other commercially available reagents, the following example compounds were obtained by the general preparation procedure of the examples, in analogy to example 1:

test example 1 test of the Effect of the inventive Compounds on KRAS ^G12D -mediated ERK phosphorylation Capacity

Test method 1) AGS cells (ATCC) expressing KRAS ^G12D were cultured in DMEM medium containing 10% fetal bovine serum, 10mM HEPES and penicillin/streptomycin, seeded in 96-well plates at a density of 40,000 cells/well and attached for 12-14 hours. 2) After 3 hours, the medium was removed, 150. Mu.L of 4.0% formaldehyde was added, and the plate was incubated at room temperature for 20 minutes. 3) The plates were washed with PBS and infiltrated with 150. Mu.L ice-cold methanol for 10 min. 4) Binding of non-specific antibodies to the plates was blocked with 100 μl of blocking buffer for 1 hour at room temperature. Phosphorylation of ERK was detected using p-ERK specific antibodies, GAPDH as an internal standard. Primary antibody information and experimental conditions were as follows, p-ERK (Cell signaling) diluted 1:500 in blocking buffer+ 0.05%tween 20;GAPDH diluted 1:500 in blocking buffer+0.05%

In tween 20. The antibody was incubated for 2h at room temperature, PBS+0.05% Tween20, and the plate was washed. The secondary antibodies used to display primary antibodies were added as anti-rabbit-680 to be diluted 1:1000 in blocking buffer+0.05% tween20, anti-mouse-800 to be diluted 1:1000 in blocking buffer+0.05% tween20 and incubated for 1 hour at room temperature. 5) Plates were washed with PBS +0.05% tween20, 100 μl PBS was added to each well and the plates were read. 6) The phosphorylated ERK (Thr ²⁰²/Tyr²⁰⁴) signal for each well was normalized with GAPDH signal and the percentage of DMSO control value was calculated. IC ₅₀ values were calculated by four parameter dose-response curve fitting.

As a result, most of the compounds of the examples provided herein have significant inhibitory effect on phosphorylated ERK levels in AGS cells, IC ₅₀ is less than 10,000nM, IC ₅₀ of some examples is less than 1000nM, and IC ₅₀ of some examples is even less than 100nM. (D represents IC ₅₀. Gtoreq.10,000 nM, C represents 1,000 nM. Ltoreq.IC ₅₀ <10,000nM, B represents 100nM. Ltoreq.IC ₅₀ <1,000nM, A represents IC ₅₀ <100 nM)

Test example two, test example Compounds for BaF3-KRAS-G12D cell proliferation inhibition Activity

The test adopts CellTiter-Glo (CTG) kit provided by Promega company, which is a method for detecting cell viability by a homogenization method, and the cell viability of the cultured cells is determined by quantifying ATP.

1. Experimental reagent consumable ：RPMI1640(Hyclone,SH30809.01),Fetal Bovine Serum(FBS,Gibco,10099-141),Phosphate Buffered Saline(PBS,Solarbio,P1020-500),Celltiter Glo assay kit(Promega,G7573),Blank 96-cell culture plate(Thermo,165305)

2. Laboratory equipment CO2 incubator (Thermo Scientific, model 3100 Series), microscope (OLYMPUS, CKX41 SF), multifunctional microplate reader (BMG,Plus), biosafety cabinet (Thermo, model 1300series A2)

3. Cell proliferation experiments all cell lines were grown in complete medium at 37℃under 5% CO 2. Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%. The cell density was adjusted using complete medium and then seeded into 96 well cell culture plates with 90 μl total of 3000 cells per well. Cells in 96-well plates were incubated at 37 ℃ under 5% co 2. A 10-fold drug solution was prepared and then transferred from 10 μl of each serial diluted compound to the corresponding experimental well of a 96-well cell plate, the initial concentration of compound test 10um, 3-fold dilution, 9 concentrations, three multiplex wells were set for each drug concentration. Cells in the dosed 96-well plates were incubated at 37 ℃ under 5% co2 for a further 72 hours before CTG analysis. The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes. An equal volume of CTG solution was added to each well. Cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal. Using Luminescence Read Mode, read Luminescence (Luminescence) and collect data.

4. Analysis of data were analyzed using GRAPHPAD PRISM 7.0.0 software, and non-linear S-curve regression was used to fit the data to yield a dose-response curve, and IC50 values were calculated therefrom. Cell viability (%) = (Lum _{Drug to be tested}-Lum_{culture broth control})/(Lum_{Cell control}-Lum_{culture broth control}) ×100%. (A represents IC ₅₀ <1000nM, B represents 1000 nM. Ltoreq.IC ₅₀ <10000nM, C represents IC ₅₀. Gtoreq.10000 nM)

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A nitrogen-containing heterocyclic biaryl compound shown in a general formula I, or pharmaceutically acceptable salts thereof, or enantiomers and diastereomers thereof,

Wherein, the

W1 is selected from N, W is selected from C-F, C-Cl, C-H, C-CN and C-C ₁-C₆ alkyl, M is CR ⁴,R⁴ is selected from CN;

R ¹ is selected from

R ³ -Ar is selected from

L is selected from-O-;

r ² is selected from Wherein m and n are each independently selected from integers of 1-3, ry is selected from C1-C6 alkyl substituted amino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, rp and Rq form a3 membered carbocyclic ring, and R2 isWhen R ³ -Ar is selected from

2. A nitrogen-containing heterocyclic biaryl compound shown in a general formula I, or pharmaceutically acceptable salts thereof, or enantiomers and diastereomers thereof,

Wherein, the

W1 is C-Cl, W is C-F, M is CR ⁴,R⁴ selected from CN;

r ¹ is

Ar is substituted or unsubstituted phenyl, naphthyl or benzothiazolyl, wherein the substituent R ³ is independently selected from one or more of hydrogen, halogen, hydroxy, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl and 3-membered cycloalkyl;

r ² is selected from substituted C ₁-C₆ alkyl, said substituents being independently selected from one or more of mono-C1-C6 alkylamino, di-C1-C6 alkylamino;

Or R ² is selected from substituted 3-membered cycloalkyl-C ₁-C₃ alkyl-, the substituents are independently selected from one or more of C ₁-C₆ alkyl, the substituents are further substituted with mono-C1-C6 alkylamino, di-C1-C6 alkylamino, 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, the heteroatoms in the heterocycloalkyl are independently selected from N or O, the number of heteroatoms is 1-3;

Or R ² is selected from substituted or unsubstituted or 5-12 membered heterocycloalkyl-C ₁-C₃ alkyl-, said substituents are independently selected from one or more of halogen, C ₁-C₆ alkyl, said substituents are optionally further substituted with cyano, said heteroatoms in said heterocycloalkyl are independently selected from N, the number of heteroatoms is 1-3;

l is selected from O;

the nitrogen-containing heterocyclic biaryl compound shown in the general formula I does not contain the following compounds:

3. the nitrogen-containing heterocyclic biaryl compound of the general formula I as described in claim 2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer thereof,

Wherein, the

W1 is C-Cl, W is C-F, M is CR ⁴,R⁴ selected from CN;

r ¹ is

r ² is selected from Wherein m, n are each selected from integers from 1 to 3, ry is selected from C1-C6 alkyl substituted amino, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl, rp and Rq form a 3 membered carbocyclic ring;

l is selected from O;

4. the nitrogen-containing heterocyclic biaryl compound of the general formula I as described in claim 2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer thereof,

R ³ -Ar is selected from

L is selected from-O-;

r ² is selected from Wherein m, n are each selected from integers from 1 to 3, ry is selected from C1-C6 alkyl substituted amino, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl, rp and Rq form a 3 membered carbocyclic ring.

5. The nitrogen-containing heterocyclic biaryl compound as described in any one of the claim 1, 4, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer thereof,

Ry is selected from 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl;

Or alternatively Is that

6. The nitrogen-containing heterocyclic biaryl compound of the general formula I as described in claim 1 or 4, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof,

Ry is selected from

7. A nitrogen-containing heterocyclic biaryl compound, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, characterized in that the compound has the following structure:

8. A pharmaceutical composition comprising an effective amount of the nitrogen-containing heterocyclic biaryl compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer thereof, and a pharmaceutically acceptable carrier.

9. Use of a nitrogen-containing heterocyclic biaryl compound as described in any one of claims 1-7 or a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer thereof or a pharmaceutical composition as described in claim 8 for the preparation of a medicament;

The medicine is a tumor therapeutic medicine, and the tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma and pancreatic cancer.

10. Use of a nitrogen-containing heterocyclic biaryl compound as described in any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, or a pharmaceutical composition as described in claim 8, for the preparation of a Ras mutein inhibitor, wherein the Ras mutein is KRAS ^G12D.