Nitrogen-containing heterocyclic co-aryl compounds, methods of making and uses thereof

Abstract

The application discloses a kind of nitrogen-containing heterocyclic aryl compounds, preparation method and purposes, specifically, a kind of pyrimidine and heterocyclic compound as shown in general formula I, or its pharmaceutically acceptable salt, or its enantiomer, diastereoisomer, tautomer, torsion isomer, solvate, polymorph or prodrug, its preparation method and pharmaceutical application, wherein the definition of each group is described in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and in particular, relates to a class of nitrogen-containing heterocyclic aryl compounds, compounds with inhibitory activity of Ras mutant proteins, preparation methods and uses. BACKGROUND

[0002] 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, namely HRas, KRas and NRas. In human tumors, KRas mutation is the most common, accounting for about 85%. Previous studies have shown that KRas mutation can cause cancer because of a missense mutation in the 12th codon, which changes the structure of KRas protein and keeps it in an activated state. The role of Ras in signal pathway transmission is mainly to activate the kinase that controls gene transcription, thereby regulating cell differentiation and proliferation, and is closely related to tumor cell survival, proliferation, migration, metastasis and angiogenesis. According to statistics, a high proportion of KRas mutations occur in malignant tumors such as pancreatic cancer, colorectal cancer, ovarian cancer and cholangiocarcinoma. However, more than thirty years have passed since the first discovery of the KRas oncogene, and the targeting drugs of common proto-oncogenes such as EGFR and BCL have undergone several generations, but the targeting drugs for KRas have never been successfully developed. For a long time, the targeting drugs for KRas pathway mutant tumors have mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but the effect is very small. In recent years, the development of inhibitors targeting specific KRas gene mutations has become a hot spot, although some inhibitors have gradually moved from preclinical incubation to clinical research, such as KRas G12C inhibitors AMG510, MRTX1257, and have shown some efficacy in early clinical trials. The first clinical data of the global first KRas G12C inhibitor AMG510 was finally released at the American Society of Clinical Oncology in June 2019, and in this clinical study, Amgen's AMG510 showed that it could stop the tumor growth of most non-small cell lung cancer and colorectal cancer patients with KRas mutations.

[0003] However, the current KRas inhibitors are still limited to KRas G12C mutant patients, and a large number of KRas G12C mutation inhibitors have not yet been developed, such as high KRas G12D , KRas G12V , KRas G13D mutations. Therefore, it is necessary to discover and find specific and excellent KRas G12CTargeted drugs for specific mutant genes other than EGFR, HER2, ALK and ROS1 have become a hot spot in the industry. After long-term efforts of the inventors, a new type of KRas mutant inhibitor with novel structure and mechanism of action is discovered, especially for KRas G12D mutants, which has good drugability. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the problem of lack of KRas G12D inhibitors in the prior art; and to provide a class of nitrogen-containing heterocycle-linked aryl compounds, a preparation method and uses. The nitrogen-containing heterocycle-linked aryl compound provided by the present application is a new type of KRas G12D inhibitor, which shows good inhibitory activity; it has good inhibitory activity on tumor cells and good drugability, and has broad prospects for drug development.

[0005] The present application solves the above technical problems by the following technical solutions:

[0006] The present application provides a nitrogen-containing heterocycle-linked aryl compound having a general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof,

[0007]

[0008] wherein R 1 is selected from substituted or unsubstituted piperazine or piperidine, and the substituents are selected from one or more of the following groups: halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylcyano, C1-C6 alkylhydroxyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, and the above substituents form a 3-10 membered carbocyclic or heterocyclic ring system, which includes spiro, bridged, fused, and the like;

[0009] R 2 is selected from substituted or unsubstituted C1-C6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-12 membered cycloalkyl or heterocycloalkyl substituted alkyl; and the substituents are selected from the following groups: halogen, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, C1-C6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 6-12 membered "containing 0-3 heteroatoms independently selected from N, O, P, S" containing 0-3 heteroatoms saturated or partially unsaturated spiro, bridged, fused, and the like;

[0010] L is selected from a chemical bond, CHR 5 , O, S, NR 5 ; R5 H, C1-C6 alkyl;

[0011] Ar is selected from substituted or unsubstituted 5-12 membered aryl or heteroaryl, said substituents R 3 selected from one or more of the following: hydrogen, halogen, cyano, hydroxyl, nitro, substituted or unsubstituted amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, and the like;

[0012] M is N or CR 4 ; R 4 selected from F, CN, Cl, C1-C6 alkyl, and the like; when M is N, W and W1are independently selected from N, C-F, C-Cl, C-H, C-CN, C-C1-C6 alkyl, and the like; when M is CR 4 , W, W1are independently selected from N, C-F, C-Cl, C-H, C-CN, C-C1-C6 alkyl, and the like;

[0013] the heteroatoms in the heterocyclic ring system, heterocycloalkyl, heteroaryl are independently selected from N, O, P, S, and the number of heteroatoms is 1-3.

[0014] In some preferred embodiments, the nitrogen-containing heterocyclic biaryl compounds as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof,

[0015]

[0016] wherein, R 1 selected from substituted or unsubstituted piperazine or piperidine, said substituents selected from one or more of the following: halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylcyano, C1-C6 alkylhydroxyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, and the above substituents form 3-10 membered carbocyclic or heterocyclic ring system, said ring system includes spiro, bridged, fused, and the like, between two of the above substituents;

[0017] R 2 selected from substituted or unsubstituted C1-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; said R 2 when substituted, said substituents are one or more R 2-1 , said R 2-1independently selected from halogen, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, dialkylamino C1-C6 alkyl-, C1-C6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 6-12 membered "containing 0-3 heteroatoms independently selected from N, O, P, S" saturated or partially unsaturated spiro, bridged, fused, etc. rings; said R 2-1 may be further substituted by halogen, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, dialkylamino C1-C6 alkyl-, C1-C6 alkyl, 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered aryl or heteroaryl;

[0018] L is selected from a bond, CHR 5 , O, S, NR 5 ; R 5 is selected from H, C1-C6 alkyl;

[0019] Ar is selected from substituted or unsubstituted 5-12 membered aryl or heteroaryl, said substituents R 3 are selected from one or more of the following: hydrogen, halogen, cyano, hydroxyl, nitro, substituted or unsubstituted amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, etc.

[0020] M is N or CR 4 ; R 4 is selected from F, CN, Cl, C1-C6 alkyl, etc.; when M is N, W and W1 are independently selected from N, C-F, C-Cl, C-H, C-CN, C-C1-C6 alkyl, etc.; when M is CR 4 , W, W1 are independently selected from N, C-F, C-Cl, C-H, C-CN, C-C1-C6 alkyl, etc.

[0021] The heteroatoms in the heterocyclic ring system, heterocycloalkyl, heteroaryl are independently selected from N, O, P, S, and the number of heteroatoms is 1-3.

[0022] In some preferred embodiments of the present application, the substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl substituted alkyl is substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl-C1-C3 alkyl-; preferably substituted or unsubstituted C3-C8 cycloalkyl-C1-C3 alkyl-, substituted or unsubstituted C5-C 12 heterocycloalkyl-C1-C3 alkyl-;

[0023] In some preferred embodiments of the present application, R 2-1When it is a 3-12 membered cycloalkyl group or a 3-12 membered heterocycloalkyl group, it is preferably a 3-6 membered cycloalkyl group or a 5-12 membered heterocycloalkyl group;

[0024] In a certain embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, is characterized in that M is N, W1 is selected from N, CF, C-Cl, CH, C-CN, C-C1-C6 alkyl and W is selected from N;

[0025] In a certain embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, is characterized in that M is N, W1 is selected from N, W is selected from CF, C-Cl, CH, C-CN, C-C1-C6 alkyl; R 1 Selected from: The above R 1 The hydrogen on any carbon atom of the group can be replaced by halogen, hydroxyl, or C1-C6 alkyl;

[0026] In one embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsoisomer, solvate, polymorph or prodrug thereof, is characterized in that M is CR 4 , R 4 Preferably, CN, F; W and W1 are independently selected from N, CF, C-Cl, CH, C-CN, C-C1-C6 alkyl, etc.;

[0027] In a certain embodiment of the present invention, the nitrogen-containing heterocyclic biaryl compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is characterized in that Ar is selected from a benzene ring, a naphthalene ring, and the above Ar can be replaced by one or more different R 3 Substituted, the R 3 is selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; L is selected from CH2, O, NH, S; R 2selected from the group consisting of: halo, cyano, hydroxy, amino, monoalkylamino, dialkylamino, C1-C6alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 6-12 membered saturated or partially unsaturated spiro, bridged, fused, etc. ring containing 0-3 heteroatoms;

[0028] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, is characterized in that R 3 -Ar is selected from

[0029] L is selected from -O-;

[0030] R 2 is selected from the group consisting of:

[0031] wherein m, n are independently selected from an integer from 1-3; Ryis selected from alkyl substituted amino, 3-10 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl, heteroaryl; R p and R q are independently selected from hydrogen, halo, C1-C6alkyl or alkoxy, hydroxy, amino, or R p and R q form a 3-10 membered carbocyclic or heterocyclic ring system;

[0032] In some preferred embodiments, Ryis selected from 5-8 membered cycloalkyl or heterocycloalkyl, preferably

[0033] In some preferred embodiments, Rpand Rqtogether with the carbon atom to which they are attached form a three-membered carbocyclic ring;

[0034] In some preferred embodiments, R p and R q are methyl;

[0035] In some preferred embodiments, the alkyl group in the monoalkylamino, dialkylamino, alkyl substituted amino is preferably C1-C6alkyl;

[0036] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, is characterized in that the compound has the structure:

[0037]

[0038]

[0039]

[0040] Thus, throughout this specification, those skilled in the art will recognize the imidazopyrimidines of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, described herein can be selected to provide stable imidazopyrimidines of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, including but not limited to the compounds described in the Examples herein.

[0041] The imidazopyrimidines of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, described herein can be synthesized by methods that include methods known in the chemical arts, and the steps and conditions can be adapted from the steps and conditions of analogous reactions in the art, particularly in light of the description herein. Starting materials are generally available from commercial sources, such as Aldrich, or readily produced using methods known to those skilled in the art (available through SciFinder, Reaxys online databases).

[0042] In the present application, the imidazopyrimidines of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, described herein can also be prepared from the imidazopyrimidines of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, described herein that have been prepared, by peripheral modification using methods conventional in the art.

[0043] In general, the compounds of the present application can be prepared by the methods described herein, unless otherwise specified, wherein the definitions of substituents are as described in Formula I. The following reaction schemes and examples are intended to further illustrate the present application.

[0044] The present application also provides a process for preparing the imidazopyrimidines of Formula I described herein, comprising steps a-c:

[0045] a) reacting a compound of general formula (A) with R 1 - H under basic conditions to form a compound of general formula (B);

[0046] b) reacting a compound of general formula (B) with R 2 - L-H under basic conditions or metal catalyzed coupling to form a compound of general formula (C);

[0047] c) coupling a compound of general formula (C) with aryl boronic acid or aryl boronic ester or aryl metal reagent (Ar-M) via transition metal catalyzed coupling to form general formula (I).

[0048]

[0049] X is halogen and the definitions of the other groups are as described above;

[0050] Preferably, each of the steps a), b), c) is carried out in a solvent and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

[0051] Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof; 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 hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or combinations thereof.

[0052] Preferably, the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(tri-o-tolylphosphine)dichloropalladium, 1,2-bis(diphenylphosphino)ethanedichloropalladium, or combinations thereof; the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-tolylphosphine, tricyclohexylphosphine, tri-o-tolylphosphine, or combinations thereof.

[0053] The necessary starting materials or reagents for preparing the compounds of Formula I are commercially available or prepared by synthetic methods known in the art. The compounds of the present application can be prepared as the free base or as an acid addition salt, as described in the Experimental Section below. The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein and having the same pharmaceutical activity as the parent compound. The pharmaceutically acceptable salts can be prepared by treatment of the free base with the appropriate acid in a suitable organic solvent according to conventional methods.

[0054] Examples of salt formation include: salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, toluenesulfonic acid, or trifluoroacetic acid.

[0055] The nitrogen-containing heterocyclic biaryl compounds of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, can have one or more chiral carbon atoms and thus can be isolated as optically pure isomers, such as pure enantiomers, or as racemates, or as mixtures of isomers. Pure single isomers can be obtained by separation methods known in the art, such as chiral crystallization or chiral preparative column separation.

[0056] The chemicals used in the synthetic routes described in this patent, including solvents, reagents, catalysts, and protecting groups, include tert-butyloxycarbonyl (Boc). The above methods can additionally include steps before or after the steps specifically described herein, and appropriate protecting groups can be added or removed to obtain the target compounds. In addition, the various synthetic steps can be performed in an alternate sequence or in the reverse order to give the end product.

[0057] Another object of the present application is to provide a medicament for treating or preventing tumors and a composition thereof. The technical solutions achieving the above object are as follows:

[0058] The present application provides a pharmaceutical composition comprising an effective amount of the nitrogen-containing heterocyclic ring bi-aryl compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier (pharmaceutical excipient). For example, the pharmaceutical composition can comprise one or more additional nitrogen-containing heterocyclic ring bi-aryl compounds of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof. In the pharmaceutical composition, the nitrogen-containing heterocyclic ring bi-aryl compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, can be present in a therapeutically effective amount.

[0059] The present application provides a pharmaceutical composition for treating tumors, which comprises the nitrogen-containing heterocyclic ring bi-aryl compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.

[0060] Another object of the present application is to provide a use of the above-mentioned compound. The technical solution to achieve the above-mentioned object is as follows:

[0061] The present application also provides a use of the above-mentioned nitrogen-containing heterocyclic ring bi-aryl compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, in the preparation of a Ras mutant protein inhibitor; in the use, the Ras mutant protein can be KRAS G12D ; the Ras mutant protein inhibitor can be used in vivo in a mammalian organism; it can also be used in vitro, mainly as an experimental use, for example, as a standard sample or a control sample to provide a comparison, or prepared into a kit according to the conventional method in the art, to provide a rapid detection of the inhibitory effect of the Ras mutant protein.

[0062] The present application also provides a use of the above-mentioned nitrogen-containing heterocyclic ring bi-aryl compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, in the preparation of a drug; the drug can be a drug for treating a disease related to the activity or expression amount of a Ras mutant protein; or, the drug can be a therapeutic drug for tumors. The Ras mutant protein can be KRAS G12DThe tumor can be independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, etc.

[0063] Another aspect of the present application relates to a method for preventing and / or treating a disease related to Ras mutant protein activity or expression, which comprises administering to a patient a therapeutically effective dose of the nitrogen-containing heterocyclic compound of the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, rotamer, solvate, polymorph or prodrug thereof.

[0064] Another aspect of the present application relates to a method for preventing and / or treating a tumor, which comprises administering to a patient a therapeutically effective dose of the nitrogen-containing heterocyclic compound of the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, rotamer, solvate, polymorph or prodrug thereof.

[0065] Another aspect of the present application relates to a medicament for preventing and / or treating a disease related to Ras mutant protein activity or expression, or a tumor, which comprises the nitrogen-containing heterocyclic compound of the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, rotamer, solvate, polymorph or prodrug thereof.

[0066] The nitrogen-containing heterocyclic compound of the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, rotamer, solvate, polymorph or prodrug thereof is used for preparing a medicament for treating a disease related to Ras mutant protein activity or expression, in particular a medicament for treating a tumor. The tumor can be independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, etc.

[0067] The present application relates to a compound having the structural characteristics of the general formula I, which can inhibit a variety of tumor cells, and can efficiently kill KRas G12D The tumor related to abnormal mutant protein signaling pathway is a new type of therapeutic drug with a new mechanism of action.

[0068] The pharmaceutical excipients can be those used in the pharmaceutical art. The excipients are used as a vehicle to provide a safe, stable and functional pharmaceutical composition, and can also provide a means to allow the active ingredient to be released at a desired rate or to be absorbed effectively by the subject after administration of the composition. The pharmaceutical excipients can be inert fillers or can provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following: binders, suspending agents, emulsifying agents, diluents, fillers, granulating agents, glidants, disintegrants, lubricants, antiadherents, flow-aids, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorants and sweeteners.

[0069] Substances which can serve as pharmaceutically-acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, 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 silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

[0070] The pharmaceutical compositions of the present application can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, dragee-making, encapsulating, entrapping or lyophilizing processes.

[0071] Pharmaceutical dosage forms of the compounds of the present application can be provided in immediate release, controlled release, sustained release or targeted 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 lyophilized formulations. Depending on the route of administration used, special devices can be required to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks. Pharmaceutical dosage forms often consist of the drug, excipients and a container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compounds of the present application to improve or facilitate the manufacture, stability, administration and safety of the drug, and can provide a means to obtain the desired drug release profile. The type of excipient added to the drug can therefore depend on various factors, such as the physical and chemical properties of the drug, the route of administration and the preparation steps. Pharmaceutical excipients exist in the art and include those listed in various pharmacopeias. (See U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and British Pharmacopoeia (BP); U.S. Food and Drug Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, such as the Inactive Ingredient Guide (1996); Handbook of Pharmaceutical Additives, Ash and Ash, eds., 2002, Synapse Information Resources, Inc., Endicott NY; etc.

[0072] Pharmaceutical dosage forms of the compounds of the present application can 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, sifting, emulsifying, (nano / micro)encapsulating, pan-coating, or lyophilizing processes. As described above, the compositions of the present application can include one or more than one physiologically acceptable inactive ingredient that facilitates the processing of the active molecules into formulations for pharmaceutical use.

[0073] The pharmaceutical composition of the present invention can be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and comprises a therapeutically effective amount of a compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined above and below and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated, and the mode of administration. For enteral administration, such as oral administration, the compounds of the present invention can be formulated into a wide variety of dosage forms.

[0074] The pharmaceutical compositions and dosage forms may contain one or more compounds of the present invention, their stereoisomers, or one or more pharmaceutically acceptable salts thereof as active ingredients. Pharmaceutically acceptable carriers may be solid or liquid. Solid formulations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. A solid carrier may also be one or more substances that act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is typically a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding properties in appropriate proportions and compacted into the desired shape and size. 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 compound may include an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without a carrier, is surrounded by a carrier associated therewith.

[0075] Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations that are intended to be converted into liquid form preparations shortly before use. Emulsions can be prepared in solutions, such as propylene glycol aqueous solutions, or can contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing fine particles of the active ingredient in water with a binder such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other commonly used suspending agents. Solid form preparations include solutions, suspensions, and emulsions and can contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0076] Exemplary compositions for rectal administration include suppositories, which can be prepared, for example, from a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters, or polyethylene glycols, which melt in the rectal cavity and release the drug as a result of the melting and / or dissolution.

[0077] The compounds of the present application can also be administered parenterally, e.g., by inhalation, injection or infusion, such as intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

[0078] Thus, for parenteral administration, the pharmaceutical composition of the present application can be in the form of a sterile injectable or infusible solution or suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. A sterile injectable or infusible formulation can also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition can be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that can be used in the pharmaceutical composition of the present application include, but are not limited to, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed 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 can also contain long-chain alcohol diluents or dispersants. Solutions for parenteral use can also include suitable stabilizing agents, and if desired, buffer substances. Suitable stabilizing agents include antioxidants such as, singly or in combination, sodium sulfite, sodium bisulfite or ascorbic acid, citric acid and its salts, and EDTA sodium salt. Parenteral solutions can also contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0079] For inhalation or nasal administration, suitable formulations are those room-temperature granules, aerosols, powders, mists, or drops, having an average diameter of about 10 microns or less. For example, compositions for inhalation can be prepared in solution form in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubility or dispersibility enhancers known in the art.

[0080] The pharmaceutical composition of the present application can also be administered topically to the skin or mucosa. For topical application, the pharmaceutical composition can be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.

[0081] The pharmaceutical compositions can be in a form suitable for topical administration, such as an ointment, cream, lotion, paste, gel or the like, in which the active ingredient is suspended or dissolved. Alternatively, the pharmaceutical compositions can be in a form suitable for administration by injection, such as an ampoule, syringeable liquid or the like. Suitable carriers and their formulation are described in standard reference texts, such as Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA.

[0082] It should be understood that all technical features of the above-mentioned and the technical features described in detail hereinafter (such as the examples) can be combined with each other to form new or preferred technical solutions within the scope of the present application. Due to the limited space, they are not listed one by one here.

[0083] The term

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless otherwise indicated, are incorporated by reference herein in their entirety.

[0085] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural

[0086] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THE ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purification can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0087] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0088] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0089] 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 shorthand notation does not include carbons that may be present in substituents of the group being described.

[0090] Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group 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 shorthand notation does not include carbons that may be present in substituents of the group.

[0091] In the present text, numerical ranges defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicate the integers within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

[0092] In various parts of the present application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group is to be understood as a connecting group. For example, if the structure requires a connecting group and the Markush group definition recited for that variable recites "alkyl" or "aryl", then it is to be understood that the "alkyl" or "aryl" represents a connecting alkylene group or arylene group, respectively.

[0093] In some specific structures, when an alkyl group is clearly indicated as a connecting group, then the alkyl group represents a connecting alkylene group, for example, the C1-C6 alkyl group in the group "halo-C1-C6 alkyl" is to be understood as a C1-C6 alkylene group (e.g., methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, t-butylene, isopentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, neopentylene, or 1,1-dimethylpropylene, etc.).

[0094] In addition to the foregoing, the following terms, as used in the specification and claims, have the meanings indicated below, unless specifically indicated otherwise.

[0095] The term "comprising" is a open term, i.e. including the indicated features but not excluding others.

[0096] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, including deuterium and variants of hydrogen, as long as the valency of the particular atom is not exceeded and the resulting compound is stable.

[0097] In general, the term "substituted" means that one or more hydrogen atoms on the given structure are replaced with a particular substituent group. Further, when the group is substituted with more than one of the recited substituent groups, the substituent groups are independent of each other, i.e., the more than one substituent groups can be different or the same. Unless otherwise indicated, a substituent group can be substituted at each substitutable position of the group. When more than one position is available for substitution on the given structure, the substituents can be the same or different at each position.

[0098] Throughout the specification, substituents of the compounds disclosed herein are disclosed by group or range. It is specifically intended that the present application include each and every independent combination of the members of these groups and ranges. For example, the terms "C1-C6 alkyl" or "C1-C6 alkyl" are intended to include each and every individual C1, C2, C3, C4, C5, and C6 alkyl.1-6 "alkyl" specifically means methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl, each of which is independently disclosed; "C 1-4 "alkyl" specifically means methyl, ethyl, C3alkyl (i.e., propyl, including n-propyl and isopropyl), C4alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl).

[0099] In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means the -OH group; "hydroxyalkyl" means an alkyl group as defined below, which is substituted with a hydroxy (-OH) group; "carbonyl" means the -C(=O)- group; "nitro" means -NO2; "cyano" means -CN; "amino" means -NH2; "substituted amino" means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylcarbonylamino, aralkylamino, heteroaralkylamino; "carboxy" means -COOH; "acyl" means the -C(=O)H group; "sulfone" means the -S(=O)2- group; "sulfoxide" means the -S(=O)- group; "sulfonyl" means the -S(=O)2H group; "urea" means -NH-C(=O)-NH2; "sulfonylurea" means the -S(=O)2-NH-C(=O)-NH2 group; "alkoxy" means an alkyl-O- group as defined below.

[0100] In the present application, the term "alkyl", as a group or part of a group (for example, in groups such as halo-substituted alkyl and the like), means a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, having from, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and being attached to the rest of the molecule by a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.

[0101] The term "alkylene" as used herein refers to a saturated, branched or straight chain or cyclic hydrocarbon group of the indicated number of carbon atoms (typically 1-6 carbon atoms) and having two monovalent radical centers derived from 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 (-CH2-), ethylene {including 1,2-ethylene (-CH2CH2-), 2,2-dimethylene (-CH(CH3)-)}, propylene {including 2-methylpropylene (-CH(CH3)CH2-), isopropylene (-C(CH3)2-), 1,3-propylene (-CH2CH2CH2-)}, butylene {including 1,4-butylene (-CH2CH2CH2CH2-)}.

[0102] In the present application, the term "alkenyl" as a group or part of a group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, from 2 to 14, preferably 2 to 10, more preferably 2 to 6 carbon atoms, and being attached 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-enyl, pent-1,4-dienyl, and the like.

[0103] In the present application, the term "alkynyl" as a group or part of a group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, from 2 to 14, preferably 2 to 10, more preferably 2 to 6 carbon atoms, and being attached to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1- en-4-ynyl, and the like.

[0104] In the present application, the term "cycloalkyl" as a group or part of a group refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which can include fused ring systems, bridged ring systems or spirocyclic ring systems, having from 3 to 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably having from 3 to 8 carbon atoms, and which is saturated or unsaturated and can be attached through a single bond via any suitable carbon atom to the rest of the molecule. Unless otherwise specifically noted in the specification, the carbon atoms in a cycloalkyl group can optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 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, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methano-1H-indenyl, and octahydro-2,5-methano-indenyl, and the like.

[0105] In the present application, the term "heterocyclyl" as a group or as part of a group refers to a stable 3- to 20-membered non-aromatic ring radical consisting of two to fourteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which can include fused, bridged, or spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical thereof can be optionally oxidized; the nitrogen atom(s) can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. The heterocyclyl radical can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl radical comprising fused rings, one or more of the rings can be an aryl or heteroaryl group as defined below, provided the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of this application, the heterocyclyl radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocyclyl radicals include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non-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, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0106] In the present application, the term "heterocycloalkyl" as a group or part of a group refers to a stable 3- to 20-membered saturated cyclic group consisting of 2-14 carbon atoms and 1-6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless stated otherwise specifically in the present description, the heterocycloalkyl group can be monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic or more ring ring system, which can include fused, bridged or spiro ring systems (e.g. a bicyclic system ("bicyclic heterocycloalkyl"). The bicyclic heterocycloalkyl ring system can include one or more heteroatoms in one or both rings; and is saturated. For the purposes of the present application, the heterocycloalkyl group is preferably a stable 4- to 12-membered saturated monocyclic, bicyclic, bridged or spiro group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4- to 7-membered saturated monocyclic, bicyclic, bridged or spiro group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. In particular, the 4- to 7-membered heterocycloalkyl group can contain 3, 4, 5 or 6 carbon atoms and one or two of the above-mentioned heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 7; more particularly, the heterocycloalkyl group can contain 3, 4 or 5 carbon atoms and one or two of the above-mentioned heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 6 ("4- to 6-membered heterocycloalkyl").

[0107] In the present application, the term "aryl" as a group or part of a group refers to 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, the aryl group can be a monocyclic, bicyclic, tricyclic or more ring ring system, and can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-lH-isoindolyl, 2-benzoxazolinonyl, 2H-l,4-benzoxazin-3(4H)-on-7-yl and the like.

[0108] In the present application, the term "arylalkyl" refers to an alkyl group as defined above which is substituted by an aryl group as defined above.

[0109] In the present application, the term "heteroaryl" as a group or as part of a group means a 5- to 16-membered, conjugated ring system having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the heteroaryl group is attached to the remainder of the molecule via a single bond through an atom of the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can optionally be oxidized; the nitrogen atoms can optionally be quaternized. For the purposes of the present application, the heteroaryl group is preferably a stable 5- to 12-membered aromatic radical containing 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic radical containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic radical containing 1 to 3 heteroatoms selected from the group consisting of 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, quinolyl, isoquinolyl, naphthylidinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, iso-thiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenarsenyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine and the like.

[0110] In the present application, the term "heteroarylalkyl" means an alkyl group as defined above which is substituted by a heteroaryl group as defined above.

[0111] It should be understood that, in the present application, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Furthermore, the term "comprising" is to be construed as open-ended, not closed, and thus includes both the recited steps and other steps as well.

[0112] Unless otherwise indicated, the present application employs conventional methods of mass spectroscopy, elemental analysis, and the like, following standard procedures of the art.

[0113] Unless otherwise indicated, the present application employs standard nomenclature used in analytical chemistry, organic synthesis chemistry, and optics. In certain instances, standard techniques are used for chemical synthesis, chemical analysis, and testing of luminescent device performance.

[0114] Also, it should be noted that the description employed in the present application "independently" should be interpreted broadly, unless otherwise explicitly indicated, and means that each individual described is independent of the other, and can be the same or different specific group. In more detail, the description "independently" can mean that the specific options expressed by the same symbol in different groups do not affect each other; or it can mean that the specific options expressed by the same symbol in the same group do not affect each other.

[0115] As will be understood by those skilled in the art, the use of means that the corresponding group is connected to other fragments, groups in the compound via the site.

[0116] In the present application, "optionally" or "may" means that the event or circumstance subsequently described can or can not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

[0117] The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally recognized as chemical entities that are embedded or appended to a molecule.

[0118] "Stereoisomer" means a compound composed of the same atoms, bonded by the same sequence of bonds, but having a different three-dimensional structure. The present application encompasses various stereo isomers and mixtures thereof.

[0119] When the compounds of the present application contain alkenyl double bonds, the compounds of the present application are intended to include both E- and Z- geometric isomers, unless otherwise indicated.

[0120] "Tautomer" means an isomer that differs from another compound only in the position of a proton. All tautomeric forms of the compounds of the present application are also intended to be included within the scope of the present application.

[0121] The compounds of the present application, or their pharmaceutically acceptable salts, can contain one or more chiral carbon atoms and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined, based on its stereochemistry, as either an (R)- or (S)-. The present application is intended to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present application can select either the racemate, diastereomer, or enantiomer as starting material or intermediate. The optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chromatography on chiral supports, among others.

[0122] Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gϋbitz 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.

[0123] In the present application, the term "pharmaceutically acceptable salt" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0124] "Pharmaceutically acceptable acid addition salt" refers to salts of the free base which retain the biological effectiveness and non-toxicity of the free amine and which are formed with inorganic acids or with organic acids. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, formic acid, acetic acid, 2,2-dichloroacetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, undecylenic acid, glycolic acid, gluconic acid, lactic acid, sebacic acid, adipic acid, glutaric acid, malonic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, 4-aminosalicylic acid, naphthalene-2-sulfonic acid, and the like. These salts can be prepared by methods known in the art.

[0125] "Pharmaceutically acceptable base addition salt" refers to salts of the free acid which retain the biological effectiveness and non-toxicity of the free acid and which are formed with inorganic or organic bases. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of 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, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, 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.

[0126] "Polymorph" refers to different solid crystalline phases of certain compounds of the application that arise due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the application can exist in more than one crystal form, and the present application is intended to cover all such polymorphs and mixtures thereof.

[0127] In general, crystallization will produce solvates of the compounds of the application. The term "solvate" as used throughout this application refers to an aggregate that comprises one or more molecules of a compound of the present application with one or more molecules of solvent. The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present application can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present application can form true solvates but in some cases can only retain a mixture of the solvent or water plus part of the solvent. The compounds of the present application can be reacted or precipitated out of a solvent or crystallized from a solvent. Solvates of the compounds of the present application are also within the scope of the present application.

[0128] The present application also includes prodrugs of the above-mentioned compounds. In the present application, the term "prodrug" means a compound that is convertible in vivo into a biologically active compound of the present application. Thus, the term "prodrug" refers to a pharmacologically acceptable metabolic precursor of a compound of the present application. When administered to a subject in need thereof, a prodrug can not be active but is converted in vivo to an active compound of the present application. Prodrugs are typically rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in the blood. Prodrug compounds often provide an advantage of solubility, tissue compatibility, or sustained release in a mammalian organism. Prodrugs include known amino- and carboxy-protecting groups. Specific methods for preparing prodrugs are described in Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R.B., et al., J. Med. Chem. 2000, 43, 475.

[0129] In the present application, "pharmaceutical composition" means a formulation of a compound of the present application with a medium generally accepted in the art for the delivery of biologically active compounds to mammals, e.g., humans. The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject and to enhance absorption into the body.

[0130] The term "pharmaceutically acceptable" as used herein means a substance (such as a carrier or diluent) that does not interfere with the effectiveness of the biological activity of a compound of the present application or the properties of the compound, and that is relatively non-toxic, i.e., the material is not deleterious to the individual to whom it is administered, or does not interact in a deleterious manner with any component of the composition.

[0131] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow regulating agent, sweetening agent, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor approved by a relevant government agency for use in humans or domestic animals.

[0132] The "tumor", "cell proliferation abnormality related disease" and the like described in the present application include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell 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.

[0133] The term "prevention", "prevent" and "preventing" used herein includes reducing the likelihood of the occurrence or aggravation of a disease or a disorder in a patient.

[0134] The term "treatment" and other similar synonyms used herein include the following meanings:

[0135] (i) preventing the disease or disorder from occurring in a mammal, in particular, when such mammal is predisposed or has yet to be diagnosed as having the disease or disorder;

[0136] (ii) inhibiting the disease or disorder, i.e., arresting its development;

[0137] (iii) relieving the disease or disorder, i.e., causing the state of the disease or disorder to regress; or

[0138] (iv) alleviating the symptoms of the disease or disorder.

[0139] The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" used herein refers to the amount of at least one agent or compound that, upon administration, is sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. For example, an "effective amount" for therapy is the amount of a composition comprising a compound disclosed herein that is needed to provide clinically significant relief of symptoms of a disorder. Techniques for determining appropriate dosages are known in the art, e.g., dose escalation studies.

[0140] The terms "administering," "administered," "administration," and the like, as used herein, refer to a method of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusion), topical administration, and transrectal administration. Those of skill in the art are well versed in administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 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.

[0141] The terms "pharmaceutical combination," "pharmaceutical co-administration," "co-administration," "administering another therapeutic agent," "administering another therapeutic agent(s)," and the like, as used herein, refer to co-administration of more than one active ingredient in which the active ingredients are combined or brought together in a single entity or a single dosage. The term "fixed combination" means that at least one compound described herein and at least one co-agent are both administered to a patient simultaneously in the form of a single entity or dosing form. The term "non-fixed combination" means that at least one compound described herein and at least one co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time periods.

[0142] Those skilled in the art will further appreciate that in the methods described below, the functional groups of intermediate compounds can need to be protected by appropriate protecting groups. Such functional groups include hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy 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 include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where "R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or aralkyl esters.

[0143] Protecting groups can 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 can also be a polymer resin.

[0144] Without deviating from the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0145] The reagents and raw materials used in the present application are commercially available.

[0146] The positive progress effect of the present application is that a nitrogen-containing heterocyclic biaryl compound is provided, which can be used as a KRAS G12D inhibitor; it can be used for preparing an antitumor drug, preventing and / or treating tumors. DETAILED DESCRIPTION

[0147] The inventors have prepared a novel benzothiazole-based biaryl compound having the structure shown in Formula I through long-term and in-depth research, and found that it has good KRAS G12D protein inhibitory activity, and the compound has quite excellent inhibitory activity on KRas G12D related cell proliferation and downstream signal pERK (IC 50 even less than 10 nM), and thus can be used for treating diseases related to KRas G12D mutation or abnormal expression, such as tumors. Based on the above findings, the inventors have completed the present application.

[0148] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, unless otherwise specified, are selected according to conventional methods and conditions, or according to the manufacturer's instructions. The experimental methods in the following examples, unless otherwise specified, are generally selected according to conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0149] Preparation of intermediate A1: 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile

[0150]

[0151] Step one: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid methyl ester (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 °C, and phosphorus oxychloride (1.17 g, 7.53 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, poured into water, and the pH was adjusted to about 5. The solid was filtered and dried to give the yellow solid intermediate product (510 mg). LC-MS [M-H] - : m / z 349.1.

[0152] Step two: The above intermediate compound (100 mg, 0.29 mmol) was added to a freshly prepared sodium ethoxide solution (20 mg, 0.86 mmol) in ethanol (2 mL) and heated to reflux overnight. The mixture was concentrated and water was added. The pH was adjusted to about 4 with hydrochloric acid. A solid precipitated, which was filtered and dried to give the yellow solid intermediate product (45 mg). LC-MS [M+H] + : m / z 316.9 / 318.9.

[0153] Step three: The above intermediate compound (370 mg, 1.16 mmol) was suspended in phosphorus oxychloride (10 mL) and one drop of N,N-dimethylformamide (DMF) was added. The mixture was heated to reflux overnight, concentrated, and the residue was dissolved in dichloromethane (DCM, 10 mL). The solution was added dropwise to saturated aqueous sodium bicarbonate (NaHCO3) solution and the pH was kept basic. The mixture was extracted with DCM (30 mL) three times. The combined organic phase was dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure to give the yellow solid intermediate Al (298 mg). LC-MS [M+H] + : m / z 352.8 / 354.8. 1 H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H).

[0154] Intermediate A2: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0155]

[0156] 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 °C for 4 hours. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was heated to 100 °C for another hour and filtered while hot. The solid was slurried with ethyl acetate (50 mL) and the filtered solid was dried to give the red-brown solid intermediate product (1.3 g). LC-MS [M-H] - : m / z 292.9.1 H NMR (400 MHz, DMSO-d6): δ 11.50-11.3 (dt, 2H), 7.83 (s, 1H).

[0157] Step two: The above intermediate compound (413 mg, 1.41 mmol) was suspended in POCl3(20 mL), three drops of N,N-dimethylaniline were added, heated to reflux overnight, rotary evaporated, the residue was dissolved in DCM (10 mL) and added dropwise into saturated aqueous NaHCO3solution, keeping pH to 7-8, extracted with DCM (30 mL) three times. The combined organic phase was dried over MgSO4, filtered, concentrated under reduced pressure to give yellow solid intermediate A2 (219 mg). LC-MS [M+H] + : m / z 328.8 / 330.8. 1 H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H).

[0158] Intermediate A3: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0159]

[0160] Step one: 4-amino-6-chloro-5-fluoronicotinic acid methyl ester (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 °C, dropwise added phosphorus oxychloride (1.12 g, 7.35 mmol), stirred at room temperature for 2 hours, poured into water, adjusted pH to about 6, solid precipitated, the solid crude product was filtered and dried to give yellow intermediate product (530 mg). LC-MS [M+H] + : m / z 272.1.

[0161] Step two: To the above intermediate compound (500 mg, 1.84 mmol) in DMF (10 mL) was added NaH (60%, 200 mg, 5.0 mmol) under ice-bath cooling, the reaction was raised to room temperature and stirred overnight, quenched with water, adjusted pH to about 4 with 4 M aqueous hydrochloric acid, solid precipitated, the solid crude product was filtered and dried to give yellow intermediate product (200 mg). LC-MS [M+H] + : m / z 240.

[0162] Step 3: The above intermediate compound (150 mg, 0.63 mmol) was suspended in POCl3(10 mL) with a drop of DMF, and heated to reflux overnight. After the reaction was confirmed to be complete, the reaction was concentrated under reduced pressure, and the residue was dissolved in DCM (10 mL) and added dropwise to saturated aqueous NaHCO3solution, and maintained at pH 7-8, and extracted with DCM (20 mL) three times. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give yellow solid intermediate A3 (219 mg). LC-MS [M+H] + : m / z 276.1. 1 H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H).

[0163] The following intermediate compounds A4, B1-B6 and C1 were prepared according to the synthetic routes and methods of patent WO2021041671A1;

[0164]

[0165]

[0166] The following intermediate compounds C2, C3 and C4 were prepared according to the synthetic routes and methods of patent WO2021106231A1;

[0167]

[0168] General preparation method of examples

[0169]

[0170] First step: The intermediate compound A (1 eq.) was dissolved in an appropriate solvent, and amine or alcohol intermediate R 1 -H (1.05 eq.) and an organic base (3.5 eq.). The reaction was slowly warmed to room temperature and stirred overnight. The reaction was monitored to be complete by LC-MS, and the reaction was added to water, and the aqueous phase was extracted with ethyl acetate three times, and the extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified to obtain the target product, and the structure was confirmed by nuclear magnetic resonance and mass spectrometry.

[0171] Second step: The amine or alcohol intermediate R 2 -Y-H (1 eq.) was dissolved in an appropriate solvent, and an inorganic base (2 eq.) was added at low temperature, and stirred for half an hour, and then the above first step product intermediate of general formula (B) was added. Then the reaction was stirred at room temperature overnight. The reaction was monitored to be complete by TLC, and after quenching with water, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography or HPLC preparation to obtain the target compound, and the structure was confirmed by nuclear magnetic resonance and mass spectrometry.

[0172] Third step: Dissolve the above general product C (1 eq.) and aryl boronic acid (ester) or aryl metal reagent (1.2 eq.) in a suitable solvent, add transition metal catalyst (0.1 eq.) and inorganic base (2 eq.), heat to 80-100 degrees for several hours, cool to room temperature, pour the reaction into water, and extract with ethyl acetate. Wash the organic phase with saturated brine, concentrate, and purify the crude product by silica gel column chromatography or HPLC preparative separation to obtain the target compound, and confirm the structure by nuclear magnetic resonance and / or mass spectrometry.

[0173] Example 1: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-7-(3- hydroxynaphthalen-1-yl)-2-((hexahydro-1H-pyrrolin-7a(5H)-yl)methoxy)quinoline- 3-carbonitrile

[0174]

[0175] First step: Dissolve 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile (298 mg, 0.84 mmol) in dichloromethane (DCM) (15 mL), then add 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 stir at room temperature overnight. Spin dry the reaction to obtain the crude product, and purify by silica gel column chromatography to obtain the yellow solid product (265 mg). ESI-MS m / z: 529.1 / 531.1 [M+H] + .

[0176] Second step: Dissolve sodium hydride (NaH) (20 mg, 0.50 mmol) in tetrahydrofuran (THF) (10 mL), cool to zero degrees, add (hexahydro-1H-pyrrolin-7a-yl)methanol (71 mg, 0.50 mmol), stir for half an hour, then add the intermediate product (220 mg, 0.417 mmol) from the previous step, stir at room temperature for 2 h, quench with saturated aqueous ammonium chloride (NH4Cl) (50 mL), then extract with ethyl acetate (50 mL) three times, dry the combined organic phase, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (DCM / MeOH = 30:1) to obtain the yellow solid product (260 mg). LC-MS [M+H] + : m / z 636.0.

[0177] Step 3: To a solution of the above intermediate (103 mg, 0.16 mmol) in 1,4-dioxane / water (12 mL / 4 mL) was added boronate B1 (50 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) and sodium carbonate powder (Na2CO3) (56 mg, 0.53 mmol) at room temperature. The reaction mixture was stirred at 100 °C under argon overnight. Upon completion, the reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the product (85 mg) as a yellow solid. LC-MS m / z: 743.3 [M+H] + .

[0178] Step 4: To a solution of the above intermediate (80 mg, 0.11 mmol) in dichloromethane (DCM) (6 mL) was added trifluoroacetic acid (3 mL) under ice-bath cooling. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by HPLC preparative purification to give the product (47 mg) as a light yellow solid. LC-MS m / z: 599.1 [M+H] + . 1 H-NMR (400 MHz, CDC13): δ 9.15 (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 = 12.8 Hz, 2H), 3.80-3.25 (m, 6H), 2.35-1.86 (m, 12H).

[0179] The following example compounds were obtained by using the general preparation method of the examples, by analogy with the procedure of Example 1, starting from intermediate Al, intermediate B and C, and commercially available piperidine / piperazine derivatives reagents:

[0180]

[0181]

[0182] Example 13: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-((hexahydro-1H-pyrrol-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

[0183]

[0184] Using intermediate A2 as the starting material, the same method as in Example 1 was used to obtain Example Compound 13 (light yellow solid, 12 mg). ESI-MS m / z: 574.1 [M+H] + . 1 H-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(ms,2H),3.86(md,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).

[0185] Using intermediate A2, intermediates B and C and commercially available reagents as raw materials, the following example compounds were obtained by the general preparation method of the examples and similar operations to Example 1:

[0186]

[0187]

[0188] Example 18: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-cyano

[0189]

[0190] Using Intermediate A3, Intermediates B and C, and commercially available reagents as starting materials, the general preparation method of Example 1 was employed, and Example 18 (white solid, 13 mg) was prepared using a similar procedure to Example 1. ESI-MS m / z: 565.3 [M+H] + . 1H-NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.42 (m, 2H), 7.92-8.00 (m, 1H), 7.56 (dd, J = 7.2, 8.0 Hz, 1H), 7.46-7.52 (m, 1H), 7.27-7.35 (m, 2H), 6.79 (dd, J = 1.2, 7.2 Hz, 1H), 4.70-4.73 (m, 2H), 4.55-4.62 (m, 2H), 3.92 (m, 2H), 3.83 (d, J = 13.2 Hz, 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).

[0191] The following example compounds were prepared by the same method as in Example 1, using intermediate A3, intermediate B and C, and commercially available reagents as starting materials:

[0192]

[0193]

[0194]

[0195] Example 31: 4-(4-(3,6-diazabicyclo[3.1.1]octan-3-yl)-8-fluoro-2-((hexahydro-1H-pyrrol- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0196]

[0197] Example 31 was prepared by the same method as in Example 1, using intermediate A4 as starting material (pale yellow solid, 5 mg). ESI-MS m / z: 527.3 [M+H] + . 1 H-NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.42 (m, 2H), 7.92-8.00 (m, 1H), 7.56 (dd, J = 7.2, 8.0 Hz, 1H), 7.46-7.52 (m, 1H), 7.27-7.35 (m, 2H), 6.79 (dd, J = 1.2, 7.2 Hz, 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).

[0198] Using intermediate A4, intermediates B and C and commercially available reagents, the general procedure of the examples, the following example compounds were obtained using similar procedures to those described in Reference Example 1:

[0199]

[0200]

[0201]

[0202]

[0203] Using intermediate A1, intermediates B and C and commercially available piperidine / piperazine derivative reagents, the general procedure of the examples, the following example compounds were obtained using similar procedures to those described in Reference Example 1:

[0204]

[0205]

[0206] Using intermediate A3, intermediates B and C and commercially available reagents, the following example compounds were obtained using similar procedures to those described in Reference Example 1:

[0207]

[0208]

[0209] Using intermediate A1, intermediates B and C and commercially available piperidine / piperazine derivative reagents, the general procedure of the examples, the following example compounds were obtained using similar procedures to those described in Reference Example 1:

[0210]

[0211]

[0212] Using intermediate A2, intermediates B and C and other commercially available reagents, the general procedure of the examples, the following example compounds were obtained using similar procedures to those described in Reference Example 1:

[0213]

[0214]

[0215] Using intermediate A1, intermediates B and C and commercially available piperidine / piperazine derivative reagents, the general procedure of the examples, the following example compounds were obtained using similar procedures to those described in Reference Example 1:

[0216]

[0217]

[0218]

[0219] Test Example 1: Effect of compounds of the application on KRas G12D mediated ERK phosphorylation

[0220] Test Method: 1) KRAS G12D expressing AGS cells (ATCC) were cultured in DMEM medium containing 10% fetal bovine serum, 10 mM HEPES and penicillin / streptomycin and seeded in 96-well plates at a density of 40,000 cells / well and allowed to adhere for 12-14 hours. 2) Example compound solutions were added at a final concentration of 0.5% DMSO and after 3 hours the medium was removed and 150 μL of 4.0% formaldehyde was added and the plates incubated at room temperature for 20 minutes. 3) The plates were washed with PBS and permeabilized with 150 μL of ice-cold methanol for 10 minutes. 4) The plates were blocked for 1 hour at room temperature with 100 μL of blocking buffer to prevent non-specific antibody binding. Phosphorylation of ERK was detected using a p-ERK specific antibody with GAPDH as an internal control. Primary antibody information and experimental conditions are as follows: p-ERK (Cell signaling) was diluted 1 :500 in blocking buffer + 0.05% tween 20; GAPDH was diluted 1 :500 in blocking buffer + 0.05%

[0221] tween 20. Antibodies were incubated for 2h at room temperature and plates were washed with PBS + 0.05% Tween 20. Secondary antibodies to visualize the primary antibodies were added as follows: anti-rabbit-680 was diluted 1 : 1000 in blocking buffer + 0.05% tween 20, anti-mouse-800 was diluted 1 : 1000 in blocking buffer + 0.05% tween 20 and incubated for 1 hour at room temperature. 5) Plates were washed with PBS + 0.05% Tween 20 and 100 μL PBS was added to each well and the plates were read. 6) The phosphorylated ERK (Thr 202 / Tyr 204 ) signal in each well was normalized to the GAPDH signal and the percentage of the DMSO control value was calculated. IC 50 values were calculated by four parameter dose-response curve fitting.

[0222] Results: The majority of the example compounds provided by the application showed a clear inhibition of the phosphorylated ERK level in AGS cells with IC 50 values of less than 10,000 nM, some examples had IC 50Less than 1000nM, IC of some embodiments 50 Even less than 100nM. (D represents IC 50 ≥10,000nM, C means 1,000nM≤IC 50 <10,000nM, B indicates 100nM≤IC 50 <1,000nM, A represents IC 50 <100nM)

[0223]

[0224]

[0225] Test Example 2: Test of the Inhibitory Activity of Example Compounds on BaF3-KRAS-G12D Cell Proliferation

[0226] This experiment used the CellTiter-Glo (CTG) kit provided by Promega, which is a homogenous cell viability detection method that determines the cell viability of cultured cells by quantifying ATP.

[0227] 1. Reagents and consumables: RPMI1640 (Hyclone, SH30809.01), Fetal Bovine Serum (FBS, Gibco, 10099-141), Phosphate Buffered Saline (PBS, Solarbio, P1020-500), CelltiterGlo assay kit (Promega, G7573), Blank 96-cell culture plate (Thermo, 165305)

[0228] 2. Experimental instruments and equipment: CO2 incubator (Thermo Scientific, Model 3100 Series), microscope (OLYMPUS, CKX41SF), multifunctional microplate reader (BMG, Plus), biological safety cabinet (Thermo, Model 1300 Series A2)

[0229] 3. Cell Proliferation Assay: All cell lines were cultured in complete medium at 37°C, 5% CO2. Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed by trypan blue exclusion to ensure viability was above 90%. Cell density was adjusted with complete medium and seeded into 96-well cell culture plates, with 90 μL seeded per well for a total of 3,000 cells. Cells in the 96-well plates were incubated at 37°C, 5% CO2. A 10x drug solution was prepared and 10 μL of each serially diluted compound was transferred to the corresponding wells of the 96-well plates. Compounds were tested starting at a 10 μM concentration and then diluted 3-fold over nine concentrations, with triplicate wells per drug concentration. Cells in the drug-treated 96-well plates were incubated at 37°C, 5% CO2 for 72 hours before CTG analysis. CTG reagent was thawed and the plates were 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. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal. Use Luminescence Read Mode to read the luminescence value and collect data.

[0230] 4. Data analysis: GraphPad Prism 7.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated based on this. Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%. (A represents IC 50 Value < 1000nM, B represents 1000nM ≤ IC 50 Value <10000nM, C represents IC 50 ≥10000nM)

[0231]

[0232]

[0233] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A nitrogen-containing heterocyclic biaryl compound having the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, in, W1 is selected from N; W is selected from CF, C-Cl, CH, C-CN, C-C1-C6 alkyl; M is CR 4 , R 4 Selected from CN; R 1 Selected from R 3 -Ar is selected from L is selected from -O-; R 2 Selected from wherein m and n are each selected from an integer of 1 to 3; Ry is selected from a C1-C6 alkyl-substituted amino group, a 3-10-membered cycloalkyl group, or a 3-10-membered heterocycloalkyl group; Rp and Rq form a 3-membered carbocyclic ring; and R2 is When R 3 -Ar is selected from 2. A nitrogen-containing heterocyclic biaryl compound having the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, in, W1 is C-Cl; W is CF; M is CR 4 , R 4 Selected from CN; R 1 for Ar is substituted or unsubstituted phenyl, naphthyl, benzothiazolyl; the substituent R 3 Independently selected from one or more of the following groups: hydrogen, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-membered cycloalkyl; R 2 Selected from substituted C1-C6 alkyl, wherein the substituents are independently selected from one or more of the following groups: mono-C1-C6 alkylamino, di-C1-C6 alkylamino; or R 2 Selected from substituted 3-membered cycloalkyl-C1-C3 alkyl-, wherein the substituents are independently selected from one or more of the following groups: C1-C6 alkyl; the substituents are further substituted by the following groups: 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, and the number of heteroatoms is 1-3; or R 2 Selected from substituted or unsubstituted or 5-12 membered heterocycloalkyl-C1-C3 alkyl-; the substituents are independently selected from one or more of the following groups: halogen, C1-C6 alkyl; the substituents are optionally further substituted by the following groups: cyano; the heteroatoms in the heterocycloalkyl are independently selected from N, and the number of heteroatoms is 1-3; L is selected from O; The nitrogen-containing heterocyclic biaryl compound represented by the general formula I does not include the following compounds:

3. The nitrogen-containing heterocyclic biaryl compound of formula I according to claim 2, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, in, W1 is C-Cl; W is CF; M is CR 4 , R 4 Selected from CN; R 1 for Ar is substituted or unsubstituted phenyl, naphthyl, benzothiazolyl; the substituent R 3 Independently selected from one or more of the following groups: hydrogen, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-membered cycloalkyl; R 2 Selected from wherein m and n are independently selected from integers of 1 to 3; Ry is selected from amino substituted with C1-C6 alkyl, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl; Rp and Rq form a 3-membered carbocyclic ring; L is selected from O; The nitrogen-containing heterocyclic biaryl compound represented by the general formula I does not include the following compounds:

4. The nitrogen-containing heterocyclic biaryl compound of formula I according to claim 2, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, characterized in that: R 3 -Ar is selected from L is selected from -O-; R 2 Selected from wherein m and n are independently selected from integers of 1-3; Ry is selected from amino substituted by C1-C6 alkyl, 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 according to any one of claims 1 and 4, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, characterized in that: Ry is selected from 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl; or for 6. The nitrogen-containing heterocyclic biaryl compound represented by the general formula I according to any one of claims 1 and 4, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, characterized in that: 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 according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, and a pharmaceutically acceptable carrier.

9. Use of the nitrogen-containing heterocyclic biaryl compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament; The drug is a drug for treating tumors; the tumors are independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, and pancreatic cancer.

10. Use of the nitrogen-containing heterocyclic biaryl compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or the pharmaceutical composition according to claim 8 in the preparation of a Ras mutant protein inhibitor; the Ras mutant protein is KRAS G12D .

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