Traizolo quinozoline derivatives and a method of synthesizing the same thereof

Abstract

The present invention provides an efficient, cost-effective, and scalable process for synthesizing novel [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives using α, β- unsaturated keto / ester methyleneindolinones and inorganic azides in the presence of copper catalysts. The process involves a tandem [3+2] cycloaddition and ring expansion under mild, 5 aerobic conditions, delivering high yields (38-95%) across a broad substrate scope. The method is compatible with electron-donating and electron-withdrawing substituents, demonstrating versatility and sustainability. The reaction proceeds at room temperature, adheres to green chemistry principles, and is scalable to gram quantities without compromising efficiency. The synthesized derivatives hold potential for applications in 0 antibacterial, anticancer, antifungal, and other pharmaceutical treatments, addressing current gaps in triazoloquinazoline synthesis.

Description

TRAIZOLO QUINOZOLINE DERIVATIVES AND A METHOD OF SYNTHESIZING THE SAME THEREOF FIELD OF THE INVENTION

[0001] The present invention relates to the field of medicinal and synthetic organic chemistry, specifically to the synthesis of novel heterocyclic compounds. More particularly, the invention provides a cost-effective and efficient process for the preparation of [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives using copper catalysts and inorganic azides under mild conditions. The synthesized compounds have potential applications in the pharmaceutical industry for therapeutic treatments such as antibacterial, anticancer, anti-HIV, antifungal, and cardiovascular agents. BACKGROUND OF THE INVENTION

[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0003] The development of heterocyclic compounds has always been a focus in medicinal and synthetic chemistry due to their significant biological and pharmaceutical applications. Among these, triazoles and quinazolines have emerged as highly important scaffolds. Triazoles are known for their therapeutic properties such as antibacterial, antifungal, anti-HIV, and anticancer activities, while quinazoline derivatives are widely used for their anti-inflammatory, anticancer, and cardiovascular effects. However, combining these two structures into a single fused system, like triazoloquinazoline, offers the potential to amplify their biological properties. Despite this promise, research in this area remains limited.

[0004] One major limitation in the existing approaches is the lack of efficient synthetic methods for triazoloquinazoline derivatives. While triazole and quinazoline derivatives have been individually well-studied, synthetic approaches for their combined framework, such as [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one , are scarce. The methods that do exist primarily focus on other isomers like [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one or [1,2,3]triazolo[1,5- a]quinoxalin-4(5H)-one, leaving the synthesis of [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one largely unexplored.

[0005] Another drawback in the prior art is the complexity of existing methods, which often involve multiple steps requiring the isolation and purification of intermediates. Such multi-step protocols not only increase the time and cost of synthesis but also reduce the overall efficiency and scalability of the process. This is a significant limitation for their practical application in pharmaceutical and industrial settings.

[0006] In addition, current methods rely on expensive and hazardous reagents, such as diazo compounds and hypervalent iodine(III) reagents, or require harsh conditions like high temperatures and prolonged reaction times. These factors make the processes less sustainable and environmentally unfriendly. Moreover, the safety concerns associated with handling reactive intermediates like azides further complicate large-scale production.

[0007] Another challenge is the low yields and narrow substrate scope observed in previous methods. Many approaches fail to accommodate substrates with diverse functional groups, such as electron-donating or electron-withdrawing substituents, limiting the structural diversity of the final compounds. This restricts the ability to tailor the properties of these derivatives for specific biological applications.

[0008] Scalability is also a major concern. Existing methods are often limited to small- scale reactions, which poses challenges when translating these processes to industrial or gram-scale synthesis. The inability to scale up reactions efficiently hampers their broader utility in pharmaceutical development.

[0009] Furthermore, while triazole and quinazoline frameworks have individually shown great potential, the biological applications of their fused derivatives, such as triazoloquinazolines, remain largely unexplored. This gap exists primarily due to the lack of efficient synthetic strategies that can deliver these compounds in sufficient quantities for detailed pharmacological studies.

[0010] Given these shortcomings, there is a growing need for synthetic methods that are efficient, economical, and scalable while adhering to the principles of green chemistry. Such methods should utilize readily available and inexpensive starting materials, operate under mild reaction conditions, and deliver products with high yields. Additionally, the ability to accommodate diverse substrates and ensure safety in handling reactive intermediates like azides is critical for the practical application of these methods. Addressing these issues will enable the preparation of structurally diverse [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, facilitating their exploration for therapeutic applications such as antibacterial, anticancer, and anti-HIV agents.

[0011] In view of the above, there is an urgent need for improved methodologies that overcome the limitations of the prior art. A streamlined, cost-effective, and sustainable approach to synthesizing [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives is essential to unlock their full potential in pharmaceutical research and drug development. OBJECTIVE OF THE INVENTION

[0012] The primary objective of the present invention is to develop an efficient, cost- effective, and scalable process for synthesizing [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives with broad substrate scope and high yields.

[0013] Another objective of the present invention is to design and develop a new, one- pot synthetic method for [1,2,3]triazolo[1,5-c]quinazoline derivatives by utilizing α, β- unsaturated keto / ester methyleneindolinones and inorganic azides as starting materials in the presence of a copper catalyst.

[0014] Another objective of the present invention is to employ copper-based catalysts (e.g., CuBr) to facilitate a sequential [3+2] cycloaddition reaction and ring expansion under mild, aerobic conditions.

[0015] Another objective of the present invention is to carry out the reaction at room temperature and atmospheric pressure and using molecular oxygen as a terminal oxidant, adhering to green chemistry principles to avoid hazardous, expensive, or specialized reagents.

[0016] Another objective of the present invention is to ensure the versatility of the process by accommodating various electron-donating groups (e.g., methyl, methoxy) and electron-withdrawing groups (e.g., halogens, nitro, trifluoromethyl) on the indolinone scaffold; N-protected and N-unprotected substrates and substrates containing ester, ketone, and aldehyde functional groups.

[0017] Another objective of the present invention is to optimize reaction conditions to deliver the desired [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one products in high yields (up to 95%) with excellent regioselectivity, minimizing the formation of undesired isomers.

[0018] Another objective of the present invention is to develop a process that can be scaled up to gram quantities without compromising efficiency, yield, or safety, making it suitable for industrial and pharmaceutical applications.

[0019] Another objective of the present invention is to optimize conditions for handling azide reagents (e.g., sodium azide) safely, addressing concerns related to large-scale use of azides in synthetic processes.

[0020] Another objective of the present invention is to confirm the structure of synthesized compounds using techniques such as NMR, FTIR, HRMS, and X-ray crystallography, ensuring reliability and reproducibility of the process.

[0021] Another objective of the present invention is to produce structurally diverse [1,2,3]triazolo[1,5-c]quinazoline derivatives for potential therapeutic applications, including but not limited to Antibacterial agents, Anticancer treatments, Anti-HIV therapies, Antifungal agents and Cardiovascular treatments.

[0022] Another objective of the present invention is to provide sufficient quantities of triazoloquinazoline derivatives for further biological evaluation, enabling their exploration as lead molecules for pharmaceutical applications.

[0023] Another objective of the present invention is to develop an environmentally sustainable process by minimizing waste generation, using safe, inexpensive reagents and solvents and reducing energy consumption through mild reaction conditions.

[0024] Another objective of the present invention is to overcome limitations of existing methods, such as multistep synthesis, use of expensive or hazardous reagents, poor yields, limited substrate scope, and scalability issues. SUMMARY OF THE INVENTION

[0025] The present invention relates to novel [1,2,3]triazolo[1,5-c]quinazolin-5(6H)- one derivatives by using NaN3and alkene carboxylate derivatives in the presence of copper catalyst via sequential [3+2] cycloaddition and ring expansion reactions and a method of preparing the same thereof. Several of these derivatives were prepared in good yields and also demonstrated in gram scale application. This is a new process for delivering a new class of heterocycles, which can show promising therapeutic applications in pharmaceutical industry.

[0026] In an aspect, present invention discloses a process for synthesizing [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, comprising the steps of: i. reacting α, β-unsaturated keto / ester methyleneindolinone with an inorganic azide, ii. reacting the selected compounds under the influence of a copper catalyst in a polar solvent at room temperature, iii. performing sequential [3+2] cycloaddition followed by ring expansion, isolating the resultant [1,2,3]triazolo[1,5-c]quinazoline derivatives; wherein the reaction is carried out at room temperature using a suitable solvent to obtain [1,2,3]triazolo[1,5-c]quinazoline derivatives.

[0027] In an aspect, the present invention discloses In another embodiment, the present invention provides a compound of the formula [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, wherein the derivatives is obtained using NaN3and alkene carboxylate derivatives in the presence of copper catalyst via sequential [3+2] cycloaddition and ring expansion reactions:

[0028] inventive subject matterwill of preferred embodiments. FIGURES OF THE INVENTION

[0029] Figure 1 displays the Isomers of triazoloquinozoline

[0030] Figure 2 shows the state of the art for [1,2,3]-triazolo [1,5-a] quinoxalin-4(5H)- one synthesis and present study.

[0031] Figure 3 shows the Crystal structure of compound 3a. DETAILED DESCRIPTION OF THE INVENTION

[0032] The following is a full description of the disclosure's embodiments. The embodiments are described in such a way that the disclosure is clearly communicated. The level of detail provided, on the other hand, is not meant to limit the expected variations of embodiments; rather, it is designed to include all modifications, equivalents, and alternatives that come within the spirit and scope of the current disclosure as defined by the attached claims. Unless the context indicates otherwise, the term "comprises" and variants such as "comprises" and "comprising" throughout the specification are to be read in an open, inclusive meaning, that is, as "including, but not limited to."

[0033] When "one embodiment" or "an embodiment" is used in this specification, it signifies that a particular feature, structure, or characteristic described in conjunction with the embodiment is present in at least one embodiment. As a result, the expressions "in one embodiment" and "in an embodiment" that appear throughout this specification do notnecessarily refer to the same embodiment. Furthermore, in one or more embodiments, the specific features, structures, or qualities may be combined in any way that is appropriate.

[0034] Unless the content clearly demands otherwise, the singular terms "a," "an," and "the" include plural referents in this specification and the appended claims. Unless the content explicitly mandates differently, the term "or" is normally used in its broad definition, which includes "and / or."

[0035] All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0036] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

[0037] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0038] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.

[0039] It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method or a device. In this specification, theseimplementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.

[0040] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing. Definitions:

[0041] For the purpose of the present invention, heterocyclic compounds may be defined as organic compounds containing a ring structure composed of at least one heteroatom (e.g., N, O, S).

[0042] For the purpose of the present invention, Triazole may be defined as a five- membered heterocyclic ring containing three nitrogen atoms.

[0043] For the purpose of the present invention, Quinazoline may be defined as a bicyclic structure comprising two fused benzene and pyrimidine rings.

[0044] For the purpose of the present invention, Triazoloquinazoline may be defined as a fused heterocyclic compound integrating both triazole and quinazoline frameworks.

[0045] For the purpose of the present invention, [1,2,3]-Triazole may be defined as a specific triazole isomer where the three nitrogen atoms occupy positions 1, 2, and 3 in the ring.

[0046] For the purpose of the present invention, [1,5-c]-Quinazoline may be defined as a specific arrangement where the triazole is fused at positions 1 and 5 of the quinazoline ring.

[0047] For the purpose of the present invention, Cycloaddition may be defined as a chemical reaction that forms a ring by the addition of unsaturated molecules.

[0048] For the purpose of the present invention, Ring Expansion may be defined as a reaction in which a smaller ring structure expands to form a larger ring.

[0049] For the purpose of the present invention, Copper Catalysts may be defined as a Copper-based compounds that accelerate chemical reactions.

[0050] For the purpose of the present invention, Inorganic Azides may be defined as Azides such as sodium azide (NaN3) used in cycloaddition reactions.

[0051] For the purpose of the present invention, Electron-Withdrawing Groups may be defined as a substituent that pull electron density away from a molecule, such as NO2, CF3, or halogens.

[0052] For the purpose of the present invention, Electron-Donating Groups may be defined as a substituent that donate electron density to a molecule, such as methyl (CH3) or methoxy (-OCH3).

[0053] For the purpose of the present invention, Substrate Scope may be defined as the range of starting materials that can undergo a specific reaction successfully.

[0054] For the purpose of the present invention, Solvent may be defined as a medium in which chemical reactions take place, such as DMSO or DMF.

[0055] For the purpose of the present invention, Gram-Scale Synthesis may be defined as the production of chemical compounds in quantities suitable for laboratory-scale applications.

[0056] For the purpose of the present invention, Yield may be defined as an amount of product obtained from a reaction, expressed as a percentage.

[0057] For the purpose of the present invention, Pharmacological Applications may be defined as therapeutic uses of compounds in treating diseases.

[0058] For the purpose of the present invention, Regioselectivity may be defined as a preference of a chemical reaction to occur at a specific position on a molecule.

[0059] For the purpose of the present invention, Mild Conditions may be defined as a reaction condition that occur at low temperature and atmospheric pressure.

[0060] For the purpose of the present invention, Green Chemistry may be defined as an Environmentally friendly chemical processes that minimize waste and energy consumption.

[0061] In a general embodiment, the present invention provides a novel, efficient, and cost-effective process for synthesizing [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives. The method involves the reaction of α, β-unsaturated keto / ester methyleneindolinone compounds with inorganic azides (e.g., NaN3) in the presence of copper catalysts under mild, aerobic conditions.

[0062] The process further utilizes a tandem [3+2] cycloaddition followed by a ring expansion to deliver the desired derivatives in high yields (38-95%). The substrate scope includes a variety of electron-donating and electron-withdrawing substituents, demonstrating versatility and scalability, including gram-scale synthesis. The synthesized derivatives hold significant potential for therapeutic applications in pharmaceutical industries, including antibacterial, anticancer, and antifungal treatments.

[0063] In an embodiment, the present invention relates to a novel [1,2,3]triazolo[1,5- c]quinazolin-5(6H)-one derivatives by using inorganic azides and alkene carboxylatederivatives in the presence of copper catalyst via sequential [3+2] cycloaddition and ring expansion reactions.

[0064] Several of these derivatives were prepared in good yields and also demonstrated in gram scale application. This is a new process for delivering a new class of heterocycles, which can show promising therapeutic applications in pharmaceutical industry.

[0065] In an embodiment, present invention discloses a process for synthesizing [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, comprising the steps of: iv. reacting α, β-unsaturated keto / ester methyleneindolinone with an inorganic azide, v. reacting the selected compounds under the influence of a copper catalyst in a polar solvent at room temperature, vi. performing sequential [3+2] cycloaddition followed by ring expansion, isolating the resultant [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives; wherein the reaction is carried out at room temperature using a suitable solvent to obtain [1,2,3]triazolo[1,5-c]quinazoline derivatives.

[0066] In another embodiment, the inorganic azide is selected from the group consisting of sodium azide (NaN3), trimethylsilyl azide (TMS-N3), diphenyl phosphoryl azide, para-toluenesulfonyl azide, and 4-acetamidobenzenesulfonyl azide.

[0067] In another embodiment, the copper catalyst is selected from the group consisting of CuBr, CuI, Cu(OAc)2, CuCl, Cu(OTf)2, and CuBr2.

[0068] In another embodiment, the reaction is optimized using 10 mol% CuBr and DMSO solvent.

[0069] In another embodiment, the solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane (DCM), chloroform, acetonitrile (ACN), tetrahydrofuran (THF), methanol, ethanol, ethyl acetate, dimethoxyethane (DME), and combinations there of.

[0070] In another embodiment, the reaction is carried out under aerobic conditions, and molecular oxygen acts as the terminal oxidant.

[0071] In another embodiment, the α, β-unsaturated keto / ester methyleneindolinone comprises electron-donating or electron-withdrawing substituents selected from the group consisting of methyl, methoxy, halogens (Cl, Br, I, F), nitro (-NO2), and trifluoromethyl (- CF3) groups.

[0072] In another embodiment, the yield of the [1,2,3]triazolo[1,5-c]quinazolin-5(6H)- one derivatives ranges between 38% and 95%.

[0073] In an exemplary embodiment, said method is applicable to alkenes bearing electron-withdrawing groups such as nitro, CN, CHO, COR, F, Cl, and Br.

[0074] In another embodiment, the reaction time is 24 hours to achieve maximum yield.

[0075] In some embodiment, the process can be scaled up to gram quantities, ensuring industrial applicability.

[0076] In some embodiment, the synthesized derivatives may have potential applications as antibacterial, anti-HIV, anticancer, antiallergic, antifungal, cardiovascular, and antitrypanosomal agents.

[0077] In some embodiment, the process is effective for substrates with diverse functional groups, including electron-donating and electron-withdrawing substituents.

[0078] In another embodiment, the present invention provides a compound of the formula [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, wherein the derivatives is obtained using NaN3and alkene carboxylate derivatives in the presence of copper catalyst via sequential [3+2] cycloaddition and ring expansion reactions:

[0079] N-unprotected indolinone substrates participate successfully in the reaction.

[0080] In another embodiment, a new class of [1,2,3]triazolo[1,5-c]quinazolin-5(6H)- one derivatives with potential applications is disclosed.

[0081] In some embodiments, the derivatives are substituted with functional groups selected from electron-donating groups, electron-withdrawing groups, halogens, and alkyl or aryl esters.

[0082] In some embodiments, the derivatives are suitable for therapeutic applications selected from antibacterial, anti-HIV, anticancer, antiallergic, antifungal, cardiovascular, antitrypanosomal, and antileishmanial agents.

[0083] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions, or examples, which are included toenable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art. EXAMPLES

[0084] The present invention is further explained in the form of the following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention (Figure 1). Example 1: A) General experimental procedure for the azidation reaction of of α, β- unsaturated keto-carboxylic acid (1) with sodium Azide:

[0085] In a with acrylic esterssubstituted oxindole 1 (1 equiv.), sodium azide (1.1 equiv.), and CuBr (10 mol%). After pouring DMSO solvent, the reaction mixture was stirred at room temperature for 24 h in open conditions After 24 h, the reaction mixture was partitioned into water and EtOAc, and extracted with EtOAc five times. The combined EtOAc extracts were washed with cold water repeatedly then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PET ether / EtOAc: 50:50) to afford the desired product (Figure 2). Example 2: X-ray crystal structures and data:ORTEP of 3a (CCDC= 2323714) showing thermal ellipsoids at the 50% probability level.Example 3: Crystallographic parameters of 3a: Parameters 3a (2323714) Empirical formula C12H10N4O3Example 4: Crystal preparation:

[0086] The crystals are grown by the simple recrystallization method where pure compounds isolated after column chromatography are dissolved in ethyl acetate, and kept at room temperature for 10 days to get the pure crystals. More information on crystal structures can also be obtained from the Cambridge Crystallographic Data Centre (CCDC) with deposition numbers 2323714 (3a). Example 5: Analytical data:Example 6: Ethyl-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3a):

[0087] Prepared according to the general procedure A, using ethyl-2-(2-oxoindolin-3- ylidene)acetate (108 mg, 0.5 mmol) to afford ethyl-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5- c]quinazoline-1-carboxylate 3a (122 mg, 95%) as a whitle solid. Melting point: 273-275oC.1H NMR (400 MHz, DMSO-d6) δ 9.13 – 9.11 (m, 1H), 7.71 – 7.67 (m, 1H), 7.44 – 7.37 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-D6) δ 161.2, 142.5, 136.8, 136.4, 132.8, 127.3, 123.5, 116.1, 109.8, 61.4, 14.2. FTIR (neat): 3482, 3435, 3056, 1764, 1711, 1160 cm-1. HRMS (ESI) m / z calculated for C12H11N4O3(M+H)+: 259.0831, found: 259.0828. Example 7: Ethyl-8-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3b):

[0088] Prepared according to the general procedure A, using ethyl-2-(6-methoxy-2- oxoindolin-3-ylidene)acetate (123 mg, 0.5 mmol) to afford ethyl-8-methoxy-5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3b (94 mg, 65%) as a grey solid. Melting point: 276°C-279°C.1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.10 (d, J = 9.1 Hz, 1H), 7.04 (dd, J = 9.1, 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H),3.88 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO) δ 162.5, 161.3, 142.7, 138.6, 137.0, 131.6, 129.2, 111.5, 103.2, 99.5, 61.2, 55.7, 14.2. FTIR (neat): 3565, 3215, 2920, 1762, 1716, 1281 cm-1. HRMS (ESI) m / z calculated for C13H13N4O4(M+H)+: 289.0937, found: 289.0926.Example 8: Ethyl-9- oxo- [1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3c):

[0089] Prepared according to the general procedure A, using ethyl-2-(5-methoxy-2- oxoindolin-3-ylidene)acetate(123.62 mg, 0.5 mmol) to afford ethyl 9-methoxy-5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3c (86.5 mg, 60 %) as a white solid. Melting point: 245°C-247°C.1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 7.40 – 7.31 (m, 2H), 4.47 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.3, 155.1, 142.3, 136.8, 132.8, 130.5, 121.1, 117.4, 110.4, 109.8, 61.5, 55.6, 14.2. FTIR (neat): 2919, 2848, 2308, 1739, 1471, 1110 cm-1. HRMS (ESI) m / z calculated for C13H13N4O4(M+H)+: 289.0937, found: 289.0935.

[0090] Example 9 :Ethyl-9-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3d): Prepared according to the general procedure A, using ethyl-2-(5-methyl-2- oxoindolin-3-ylidene)acetate (115.6 mg, 0.5 mmol) to afford ethyl 9-methyl-5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3d (92.5 mg, 68%) as a orange solid. Melting point: 268°C-272°C.1H NMR (400 MHz, Acetone-d6 + 1drop DMSO-d6) δ 12.11 (s, 1H), 9.03 (s, 1H), 7.48 (dd, J = 8.4, 1.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, Acetone-d6 + 1drop DMSO-d6) δ 162.3, 143.4, 135.3, 134.5, 134.1, 134, 128.2, 116.8, 62.1, 21.1, 14.6. FTIR (neat): 3155, 2918, 2851, 1734, 1440, 1110 cm-1. HRMS (ESI) m / z calculated for C13H13N4O3(M+H)+: 273.0987, found: 273.0987.Example 10: Ethyl-7-methyl- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3e):

[0091] Prepared according to the general procedure A, using ethyl-2-(7-methyl-2-oxoindolin- 3-ylidene)acetate (115.6 mg, 0.5 mmol) to afford ethyl-7-methyl-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3e (66.7 mg, 49 %) as a white solid. Melting point: 292°C-296°C.1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 9.06 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 1H), 7.32 (t, J = 8 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.35 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).13C{1H} NMR (101 MHz, DMSO) δ 161.3, 142.9, 136.9, 134.8, 134.2, 132.8, 125.2, 125.0, 123.3, 110.0, 61.4, 18.0, 14.2. FTIR (neat): 3204, 1731, 1555, 1501, 1308, 1200 cm-1. HRMS (ESI) m / z calculated for C12H13N4O3(M+H)+: 273.0987, found: 273.0984.Example 11: Ethyl-9- [1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3f):

[0092] Prepared according to the general procedure A, using ethyl-2-(5-chloro-2-oxoindolin- 3-ylidene)acetate (125.8 mg, 0.5 mmol) to afford ethyl-9-chloro-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3f (95 mg, 65%) as a yellowish orange solid. Melting point: 234°C-237°C.1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.24 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.8, 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).113C{1H} NMR (100 MHz, DMSO) δ 161.2, 142.3, 136.0, 135.5, 133.2, 132.6, 127.3, 126.4, 118.1, 111.3, 61.7, 14.1. FTIR (neat): 2980, 2924, 2853, 1719, 1617, 1113 cm-1. HRMS (ESI) m / z calculated for C12H10ClN4O3(M+H)+: 293.0441, found: 293.0429.Example 12: Ethyl 8-chloro-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3g):

[0093] Prepared according to the general procedure A, using ethyl-2-(6-chloro-2-oxoindolin- 3-ylidene)acetate (125.8 mg, 0.5 mmol) to afford ethyl-8-chloro-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3g (130 mg, 89 %) as a light brown solid. Melting point: 262°C-266°C.1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.15 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 8.8, 1.6 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO) δ 161.2, 142.4, 137.7, 137.0, 136.3, 133.0, 129.1, 123.6, 115.4, 109.0, 61.5, 14.1. FTIR (neat): 3057, 2984, 2934, 1765, 1743, 1292 cm-1. HRMS (ESI) m / z calculated for C12H10ClN4O3(M+H)+: 293.0441, found: 293.0446. Example 13: Ethyl-10-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3h):

[0094] Prepared according to the general procedure A, using ethyl-2-(4-chloro-2-oxoindolin- 3-ylidene)acetate (125.8 mg, 0.5 mmol) to afford ethyl-10-chloro-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3h (91 mg, 62 %) as a grey solid. Melting point: 308°C-312°C.1H NMR (400 MHz, DMSO-d6) δ 7.58 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 9.7, 8.2 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 163.1, 143.0, 135.7, 132.0, 130.3, 129.6, 123.9, 117.1, 114.8, 109.5, 61.7, 13.9. FTIR (neat): 3436, 2984, 2934, 1734, 1580, 1145 cm-1. HRMS (ESI) m / z calculated for C12H10ClN4O3(M+H)+: 293.0441, found: 293.0433.Example 14: Ethyl-9-bromo-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3i):

[0095] Prepared according to the general procedure A, using ethyl-2-(5-bromo-2-oxoindolin- 3-ylidene)acetate (148 mg, 0.5 mmol) to afford ethyl-9-bromo-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3i (96 mg, 57 %) as a grey solid. Melting point: 277°C-280°C.1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 9.34 (d, J = 6.8 Hz, 1H), 7.87 (dd, J = 8.7, 2.2 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.1, 142.3, 135.8, 135.7, 135.3, 133.2, 129.3, 118.2, 115.1, 111.7, 61.6, 14.1. FTIR (neat): 3274, 2921, 1719, 1558, 1469, 1191 cm-1. HRMS (ESI) m / z calculated for C12H10BrN4O3(M+H)+: 336.9936, found: 336.9940.Example 15: Ethyl-9-iodo-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3j):

[0096] Prepared according to the general procedure A, using ethyl-2-(5-iodo-2-oxoindolin-3- ylidene)acetate (171.5 mg, 0.5 mmol) to afford ethyl-9-iodo-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3j (160 mg, 83 %) as a yellow solid. Melting point: 273°C-275°C.1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 9.52 (d, J = 1.9 Hz, 1H), 8.00 (dd, J = 8.6, 1.9 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.1, 142.3, 140.8, 136.0, 135.6, 135.2, 133.1, 118.9, 112.1, 86.9, 61.6, 14.2. FTIR (neat): 2921, 2849, 2349, 1716, 1469, 1116 cm-1. HRMS (ESI) m / z calculated for C12H10IN4O3(M+H)+: 384.9797, found: 384.9797.Example 16: Ethyl-9-fluoro-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3k):

[0097] Prepared according to the general procedure A, using ethyl-2-(5-fluoro-2-oxoindolin- 3-ylidene)acetate (117.6 mg, 0.5 mmol) to afford ethyl-9-fluoro-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3k (85.8 mg, 62 %) as a white solid. Melting point: 260°C-263°C.1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.94 (dd, J = 10.2, 2.8 Hz, 1H), 7.61 (ddd, J = 8.1, 5.4, 1.5 Hz, 1H), 7.50 – 7.39 (m, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO) δ 161.2, 158.6, 156.3, 142.3, 136.3, 133.2 (d, J = 6.8 Hz), 120.9, 120.6, 118.2 (d, J = 8.7 Hz), 112.8 (d, J = 27.4 Hz), 112.7 – 112.51 (m), 110.9, 61.7, 14.1. FTIR (neat): 3275, 2986, 1778, 1729, 1594, 1291 cm-1. HRMS (ESI) m / z calculated for C12H10FN4O3(M+H)+: 277.0737, found: 277.0740.Example 17: Ethyl-5-oxo-7-(trifluoromethyl)-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline- 1-carboxylate (3l):

[0098] Prepared according to the general procedure A, using ethyl-2-(2-oxo-7- (trifluoromethyl)indolin-3-ylidene)acetate (142.61 mg, 0.5 mmol) to afford ethyl-5-oxo-7- (trifluoromethyl)-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3l (128.86 mg, 79 %) as a white solid. Melting point: 205°C-207°C.1H NMR (400 MHz, DMSO-d6) δ 9.51 (d, J = 7.4 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO) δ 161.2, 142.4, 135.9, 133.4, 133.3, 132.0, 130.3, 130.2, 130.2, 130.1, 127.1, 124.4, 123.1, 121.7, 119.0, 116.0, 115.6, 115.3, 115.0, 112.2, 61.7, 39.5, 14.1.19F NMR (377 MHz, DMSO) δ -59.43(s, 3F). FTIR (neat): 3249, 2919, 2850, 1750, 1701, 1123 cm-1. HRMS (ESI) m / z calculated for C13H10F3N4O3(M+H)+: 327.0705, found: 327.0702.Example 18: Ethyl-9-nitro-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3m):

[0099] Prepared according to the general procedure A, using ethyl-2-(5-nitro-2-oxoindolin- 3-ylidene)acetate (131 mg, 0.5 mmol) to afford ethyl-9-nitro-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3m (124 mg, 82%) as a white solid. Melting point: 260°C-264°C.1H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 10.15 (d, J = 2.5 Hz, 1H), 8.53 (dd, J = 9.1, 2.6 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO) δ 161.08, 142.5, 142.4, 141.3, 136.1, 133.5, 127.5, 123.6, 117.3, 110.2, 61.9, 14.1. FTIR (neat): 2920, 2850, 2116, 1716, 1610, 1115 cm-1. HRMS (ESI) m / z calculated for C12H10N5O5(M+H)+: 304.0682, found: 304.0682.Example 19: Methyl-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3n):

[0100] Prepared according to the general procedure A, using methyl-2-(2-oxoindolin-3- ylidene)acetate (101.6 mg, 0.5 mmol) to afford methyl-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5- c]quinazoline-1-carboxylate 3n (105 mg, 86 %) as a brown solid. Melting point: 254°C-256°C.1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.11 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 20.0, 8.0 Hz, 2H), 3.99 (s, 3H).13C{1H} NMR (100 MHz, DMSO) δ 161.7, 142.5, 136.9, 136.4, 132.9, 132.7, 127.3, 123.6, 116.1, 109.8, 52.5. FTIR (neat): 2921, 2872, 2307, 1732, 1614, 1199, cm-1. HRMS (ESI) m / z calculated for C11H9N4O3(M+H)+: 245.0674, found: 245.0663.Example 20: Methyl-9-chloro-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3o):

[0101] Prepared according to the general procedure A, using methyl-2-(5-chloro-2- oxoindolin-3-ylidene)acetate (118.8 mg, 0.5 mmol) to afford methyl-9-chloro-5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3o (85.5 mg, 61 %) as a yellow solid. Melting point: 268°C-270°C.1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.21 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.8, 1.6 Hz, 1H), 7.44 (dd, J = 8.6, 3.3 Hz, 1H), 4.01 (s, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.7, 142.2, 136.1, 135.3, 133.0, 132.7, 127.3, 126.3, 118.0, 111.2, 52.6. FTIR (neat): 2922, 2857, 2308, 1714, 1616, 1196 cm-1. HRMS (ESI) m / z calculated for C11H8ClN4O3(M+H)+: 279.0285, found: 279.0285.Example 21: Methyl-8-chloro-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3p):

[0102] Prepared according to the general procedure A, using methyl-2-(6-chloro-2- oxoindolin-3-ylidene)acetate (118.8 mg, 0.5 mmol) to afford methyl-8-chloro-5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3p (92.5 mg, 66 %) as a grey solid. Melting point: 246°C-248°C.1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 9.16 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.7, 1.7 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 4.00 (s, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.6, 142.4, 137.7, 137.0, 136.4, 132.8, 129.1, 123.7, 115.4, 109.0, 52.6. FTIR (neat): 2919, 2849, 1717, 1612, 1438, 1175 cm-1. HRMS (ESI) m / z calculated for C11H8ClN4O3(M+H)+: 279.0285, found: 279.0289.Example 22: Methyl-9-iodo-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3q):

[0103] Prepared according to the general procedure A, using methyl-2-(5-iodo-2-oxoindolin- 3-ylidene)acetate (164.5 mg, 0.5 mmol) to afford methyl-9-iodo-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3q (155.5 mg, 83 %) as a white solid. Melting point: 252°C-254°C.1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 9.53 (d, J = 1.9 Hz, 1H), 8.00 (dd, J = 8.6, 1.9 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 4.01 (s, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 142.5, 141.1, 136.2, 136.0, 135.5, 133.1, 118.4, 112.2, 87.2, 52.8. FTIR (neat): 3369, 2923, 2854, 1710, 1643, 1113 cm-1. HRMS (ESI) m / z calculated for C11H8IN4O3(M+H)+: 370.9641, found: 370.9630. Example 23: Methyl-9- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3r):

[0104] Prepared according to the general procedure A, using methyl-2-(5-fluoro-2- oxoindolin-3-ylidene)acetate (110.59 mg, 0.5 mmol) to afford methyl-9-fluoro-5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3r (88.5 mg, 68 %) as a yellow solid. Melting point: 252°C-256°C.1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.93 (dt, J = 11.8, 5.9 Hz, 1H), 7.66 – 7.58 (m, 1H), 7.46 (dd, J = 9.1, 4.9 Hz, 1H), 4.00 (s, 3H).13C{1H} NMR (100 MHz, DMSO) δ 161.7, 158.6, 156.2, 148.9, 142.2, 136.3, 133.2, 132.9, 120.9, 120.6, 118.2 (d, J = 8.6 Hz), 112.7 (d, J = 27.1 Hz), 112.4 (m), 110.8, 52.6. FTIR (neat): 3216, 2953, 2924, 1626, 1479, 1173 cm-1. HRMS (ESI) m / z calculated for C11H8FN4O3(M+H)+: 263.0580, found: 263.0584.Example 24: Methyl-5-oxo-7-(trifluoromethyl)-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline- 1-carboxylate (3s):

[0105] Prepared according to the general procedure A, using methyl-2-(2-oxo-7- (trifluoromethyl)indolin-3-ylidene)acetate (135.6 mg, 0.5 mmol) to afford methyl-5-oxo-7- (trifluoromethyl)-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3s (101 mg, 65 %) as a grey solid. Melting point: 223°C-226°C.1H NMR (400 MHz, DMSO-d6) δ 9.48 (d,J = 8.0 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 4.00 (s, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.8, 142.8, 136.1, 132.9, 131.8, 130.0 (d, J = 5.2 Hz), 124.6, 122.4, 112.2, 52.6. FTIR (neat): 3344, 2948, 2836, 1649, 1451,1016 cm-1. HRMS (ESI) m / z calculated for C12H8F3N4O3(M+H)+: 313.0548, found: 313.0547.Example 25: 5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1-carbaldehyde (3t):

[0106] Prepared according to the general procedure A, using 2-(2-oxoindolin-3- ylidene)acetaldehyde (86.5 mg, 0.5 mmol) to afford 5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5- c]quinazoline-1-carbaldehyde 3t (48 mg, 45 %) as a grey solid. Melting point: 223°C-225°C.1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.38 (s, 1H), 9.07 (dd, J = 8.4, 1.3 Hz, 1H), 7.83 – 7.71 (m, 1H), 7.51 – 7.39 (m, 2H).13C{1H} NMR (100 MHz, DMSO-d6) δ 185.8, 142.6, 140.9, 136.8, 136.3, 133.7, 127.0, 123.7, 116.1, 109.9. FTIR (neat): 3320, 2921, 2852, 1734, 1616,1466 cm-1. HRMS (ESI) m / z calculated for C10H6N4NaO2(M+Na)+: 237.0388, found: 237.0388.Example 26: 1-acetyl-[1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one (3u):

[0107] Prepared according to the general procedure A, using 3-(2-oxopropylidene)indolin-2- one (93.6 mg, 0.5 mmol) to afford 1-acetyl-[1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one 3u (47 mg, 41 %) as a grey solid. Melting point: 277°C-279°C.1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 7.79 – 7.64 (m, 1H), 7.42 (dd, J = 13.2, 8.1 Hz, 2H), 2.82 (s, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 193.0, 142.6, 140.7, 136.5, 135.6, 133.2, 127.4, 123.4, 116.0, 110.1, 28.8. FTIR (neat): 3387, 2918, 2851, 1735, 1658, 1476 cm-1. HRMS (ESI) m / z calculated for C11H9N4O2(M+H)+: 229.0726, found: 229.0725.Example 27: 1-benzoyl-[1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one (3v):

[0108] Prepared according to the general procedure A, using 3-(2-oxo-2- phenylethylidene)indolin-2-one (124.6 mg, 0.5 mmol) to afford 1-benzoyl- [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one 3v (80 mg, 55 %) as a white solid. Melting point: 234°C-237°C.1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.92 (dd, J = 8.2, 1.1 Hz, 1H), 8.08 (dd, J = 5.1, 3.3 Hz, 2H), 7.77 – 7.68 (m, 2H), 7.61 (dd, J = 10.6, 4.7 Hz, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.43 – 7.35 (m, 1H).13C{1H} NMR (100 MHz, DMSO-d6) δ 187.6, 142.6, 140.0, 137.6, 137.3, 136.5, 133.3, 133.1, 130.4, 128.4, 126.7, 123.5, 116.1, 110.1. FTIR (neat): 3112, 2916, 2858, 1748, 1660, 1174 cm-1. HRMS (ESI) m / z calculated for C16H11N4O2(M+H)+: 291.0884, found: 291.0882.Example 28: 1-(4-chlorobenzoyl)-[1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one (3w):

[0109] Prepared according to the general procedure A, using 3-(2-(4-chlorophenyl)-2- oxoethylidene)indolin-2-one (141 mg, 0.5 mmol) to afford 1-(4-chlorobenzoyl)- [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one 3w (80 mg, 49 %) as a white solid. Melting point: 288°C-290°C.1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.98 (dd, J = 8.2, 1.0 Hz, 1H), 8.19 – 8.08 (m, 2H), 7.78 – 7.67 (m, 3H), 7.52 – 7.39 (m, 2H).13C{1H} NMR (100 MHz, DMSO-d6) δ 186.4, 142.6, 139.8, 138.3, 137.6, 136.6, 136.3, 133.3, 132.3, 128.6, 126.8,123.5, 116.2, 110.1. FTIR (neat): 2917, 2852, 1736, 1657, 1298, 1083 cm-1. HRMS (ESI) m / z calculated for C16H9ClN4NaO2(M+Na)+: 347.0312, found: 347.0311.Example 29: 1-(4-methylbenzoyl)- c]quinazolin-5(6H)-one (3x):

[0110] Prepared according to the general procedure A, using 3-(2-oxo-2-(p- tolyl)ethylidene)indolin-2-one (131 mg, 0.5 mmol) to afford 1-(4-methylbenzoyl)- [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one 3x (60 mg, 39 %) as a white solid. Melting point: 276°C-278°C.1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.89 (dd, J = 8.2, 1.1 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.76 – 7.67 (m, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.41 (dd, J = 13.9, 4.6 Hz, 3H), 2.44 (s, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 186.4, 142.6, 139.8, 138.3, 137.6, 136.6, 136.3, 133.3, 132.3, 128.6, 126.8, 123.5, 116.2, 110.1. FTIR (neat): 3388, 2918, 2851, 1734, 1599, 1172 cm-1. HRMS (ESI) m / z calculated for C17H13N4O2(M+H)+: 305.1038, found: 305.1043.Example 30: ethyl 6-butyl-5-oxo- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3y):

[0111] Prepared according to the general procedure A, using ethyl-2-(1-butyl-2-oxoindolin-3- ylidene)acetate (136 mg, 0.5 mmol) to afford ethyl 6-butyl-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3y (85 mg, 54%) as a white solid. Melting point: 238°C-240°C.1H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J = 8.1, 1.2 Hz, 1H), 7.89 – 7.78 (m, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.40 – 4.25 (m, 2H), 1.78 – 1.67 (m, 2H), 1.51 – 1.37 (m, 5H), 0.96 (t, J = 7.3 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.2, 143.1, 136.3, 135.7, 133.2, 132.6, 128.0, 123.6, 115.7,110.6, 61.5, 43.7, 19.4, 14.1, 13.7.FTIR (neat): 2959, 2871, 1719, 1609, 1485, 1466, 1190 cm-1. HRMS (ESI) m / z calculated for C16H19N4O3(M+H)+: 315.1379, found: 315.1457. Example 31: ethyl 6- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate (3z) :

[0112] Prepared according to the general procedure A, using ethyl (1-methyl-2-oxoindolin-3- ylidene)acetate (115.62 mg, 0.5 mmol) to afford ethyl 6-methyl-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3z (52 mg, 38 %) as a white solid. Melting point: 212°C-215°C.1H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J = 8.1, 1.3 Hz, 1H), 7.84 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.57 – 7.48 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) 161.2, 143.3, 137.3, 135.7, 133.2, 132.7, 127.7, 123.8, 115.9, 110.4, 61.5, 39.5, 31.4, 14.1. FTIR (neat): 2951, 2863, 2360, 1729, 1469, 1171 cm-1. HRMS (ESI) m / z calculated for C13H12N4NaO3(M+Na)+: 295.0807, found: 295.0806. EtO2C N N OExample 32: ethyl6-benzyl-5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate (3aa) :

[0113] Prepared according to the general procedure A, using ethyl(1-benzyl-2-oxoindolin-3- ylidene)acetate (153.67 mg, 0.5 mmol) to afford ethyl 6-butyl-5-oxo-5,6-dihydro- [1,2,3]triazolo[1,5-c]quinazoline-1-carboxylate 3aa (91 mg, 52 %) as a white solid. Melting point: 239°C-241°C.1H NMR (400 MHz, DMSO-d6) δ 9.32 (dd, J = 8.3, 1.4 Hz, 1H), 7.76 – 7.65 (m, 1H), 7.48 (dd, J = 7.9, 5.8 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 5.62 (s, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, DMSO-d6) δ 161.3, 143.9, 136.5, 136.1, 135.3, 133.1, 132.8, 128.7, 127.9, 127.5, 126.6, 123.9, 116.2, 110.9, 61.5, 47.2, 39.5, 14.2. FTIR (neat): 3057,1720, 1609, 1559, 1296, 1105, 1041 cm-1. HRMS (ESI) m / z calculated for C19H17N4O3(M+H)+: 349.1301, found: 349.1300 Results

[0114] Initially, a control experiment was performed using ethyl (2-oxoindolin-3- ylidene)acetate and TMS-N3in the absence of any metal catalyst led to no reaction (Table 1, entry 1),This reaction in the presence of 10 mol% of CuBr or CuI at room temperature for 24 hours resulted in no reaction (Table 1, entry 2 and 3). Interestingly, this reaction with NaN3in the absence of any catalyst afforded only a 29% yield (Table 1, entry 4). Then, the same reaction was performed under aerobic conditions in the presence 50 mol% CuBr or CuI as a catalyst afforded ethyl 5-oxo-5,6-dihydro carboxylate 3a at 95% or 74% yield (Table 1, entry 5,6). The structure of product 3a was confirmed by X-ray analysis (Figure 3, CCDC No 2323714). Whereas under inert condition, the reaction yield was decreased to 31% (Table 1, entry 7). Other copper catalysts such as Cu(OAc)2, CuCl, Cu(OTf)2, CuBr2and CuBr were also investigated for this reaction to get the best yield (table 1, entries 8-12). Among all the Cu-catalysts, CuBr proved to be the best catalyst to produce product 3a at 95% yield when DMSO was used as a solvent. The decrease in CuBr catalyst loading to 10 mol% and 5 mol%, this reaction afforded 95% and 50% of the product 3a after 24 hrs (Table 1, entries 12 and 13).

[0115] Decreasing the reaction time from 24 hrs to 20 hrs resulted in a lower yield of product 3a (Table 1, entry 14). Other solvents were inefficient for this transformation and afforded lower yield of product 3a (Table 1, entries 15-17). Other metal catalysts such as FeCl2and FeCl3gave lower yields, up to 78% (Table 1, entire 18-19).

[0116] With an optimized catalyst and protocol, next attention turned to the substrate scope (Scheme 1). First, substitution on aryl ring of ethyl-2-(2-oxoindolin-3-ylidene)acetate derivatives were examined.Table 1. Optimization of reaction conditionsaSolvent Yieldb(eq.) (mol%) of 3a17 NaN3(1.2) CuBr (10) 1,2-DME 80aReaction(0.023 mmol, l0 mol%) in DMSO (2.0 mL) were stirred at r.t. for 24 hrs. n.d.= not detected. r.t.= room temperature.bIsolated yields.c1.0 equiv. TBHP added as an additive.dUnder N2.e20 hrs.

[0117] It was found that ethyl-2-(2-oxoindolin-3-ylidene)acetate containing both electron- donating and electron-withdrawing substituents performed well under the reaction conditions, resulting in the corresponding ethyl 5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline-1- carboxylate. The unsubstituted ethyl-2-(2-oxoindolin-3-ylidene)acetate afforded the corresponding product 3a exclusively with a 95% yield. The other isomer 4a was not observed in these reaction conditions. Then, we moved to electron donating substituents such as OMe at C-6 and C-5 positions, Me at C-5 and C-7, which affords the corresponding products 3b, 3c, 3d and 3e in good yield with high regioselectivity (Scheme 1). Next we moved to halogen substitution on aryl ring of ethyl-2-(2-oxoindolin-3-ylidene)acetate. The chlorine substitution in C-5, C-6 and C-4 afforded the corresponding product 3f, 3g and 3h with yields of 65%, 89% and 62% respectively (Scheme 1). Other halogen substitutions for ethyl-2-(2-oxoindolin-3-ylidene)acetate, at C-5 position, such as Br, I, F, afforded the corresponding product 3i, 3j and 3k at 57%, 83% and 62% yield respectively (Scheme 1). Furthermore, the electron withdrawing substituents such as -CF3at C-7 position and -NO2at C-5 position successfully afforded the respective products 3l and 3m in 79% and 82% yield (Scheme 1). Subsequently, the effect of ester substitution was studied. Other ester groups such as methoxy ester provided good to excellent yield of products 3n-3s (Scheme 1). This reaction with (2-oxoindolin-3-ylidene)acetaldehyde and the ketone substituted (2- oxopropylidene)indolin-2-one under the optimized reaction conditions, led to the desired product 3t and 3u in 45% and 41% yield (Scheme 1). Moreover, this reaction with aromatic ketones such as (2-oxo-2-phenylethylidene)indolin-2-one and also with an electron withdrawing group such as Cl at para-position of the phenyl ring and an electron donating group such as Me at para position of phenyl yield the corresponding products 3v-3x in good to moderate yield (Scheme 1).Scheme 1. Substrate scope for sequential reaction of (3+2)-cycloaddition and ring-expansion Reaction conditions: compound 1 (0.5 mmol, 1.0 eq.), 2 (0.6 mmol, 1.2 eq.) and CuBr (0.05 mmol, 10 mol%) in DMSO (2.0 mL) were stirred at rt for 24 h in a reaction vial in open condition.

[0118] The influence of N-substituents of the indolinone motif was investigated by using substrates with N-Butyl, N-Methyl, N-Benzyl (Scheme 2) to afford the respective products 3y–3aa in 38 to 54% yield. All of the above substrates revealed that both N-protected and N- unprotected ethyl-2-(2-oxoindolin-3-ylidene)acetate could successfully take part in the dipolar cycloaddition reaction and rearrangement to afford the desired product 3.

[0119] To evaluate the scalability of this method, we performed the reaction on a gram scale. Despite challenges associated with scaling up of azide reaction, subjecting 3.5 mmol of ethyl- (2-oxo-7-(trifluoromethyl)indolin-3-ylidene)acetate to the optimized reaction conditionsusing a simple batch setup proceeded efficiently, resulting in 74% yield of 3m (850 mg in 24 h).

[0120] In summary, the present invention provides a novel, one-pot and efficient method for the synthesis of 5-oxo-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline. The method is based on the copper-promoted reaction of α, β-unsaturated keto / ester methyleneindolinone with sodium azide at room temperature through an azide-alkene cyclization and ring expansion / rearrangement reaction. The generality of this method was demonstrated with a variety of α, β-unsaturated keto / ester methyleneindolinone and generated diverse 5-oxo-5,6- dihydro-[1,2,3]triazolo[1,5-c]quinazoline derivatives upto 95% yield.

[0121] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention. ADVANTAGES OF THE PRESENT INVENTION

[0122] Efficient and Cost-Effective: The method uses inexpensive and readily available starting materials and catalysts, ensuring economic feasibility.

[0123] Mild Conditions: The reaction proceeds at room temperature under aerobic conditions, reducing energy consumption and improving safety.

[0124] High Yields: The process delivers yields ranging between 38% and 95%, demonstrating excellent efficiency.

[0125] Versatility: The method accommodates a wide range of functional groups, showcasing broad substrate scope.

[0126] Environmentally Friendly: By using molecular oxygen as a terminal oxidant and avoiding hazardous reagents, the process adheres to green chemistry principles.

[0127] Scalability: The method is scalable to gram quantities, making it suitable for pharmaceutical applications.

[0128] Pharmaceutical Potential: The synthesized triazoloquinazoline derivatives are structurally diverse and hold significant promise for therapeutic applications, including antibacterial, antifungal, and anticancer treatments.

Claims

We Claim:

1. A process for synthesizing [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, comprising the steps of: a) reacting α, β-unsaturated keto / ester methyleneindolinone with an inorganic azide, b) reacting the selected compounds under the influence of a copper catalyst in a polar solvent at room temperature, c) performing sequential [3+2] cycloaddition followed by ring expansion, d) isolating the resultant [1,2,3]triazolo[1,5-c]quinazoline derivatives. wherein the reaction is carried out at room temperature using a suitable solvent to obtain [1,2,3]triazolo[1,5-c]quinazoline derivatives.

2. The process as claimed in claim 1, wherein the inorganic azide is selected from the group consisting of sodium azide (NaN3), trimethylsilyl azide (TMS-N3), diphenyl phosphoryl azide, para-toluenesulfonyl azide, and 4-acetamidobenzenesulfonyl azide.

3. The process as claimed in claim 1, wherein the copper catalyst is selected from the group consisting of CuBr, CuI, Cu(OAc)2, CuCl, Cu(OTf)2, and CuBr2.

4. The method as claimed in claim 1, wherein the reaction is optimized using 10 mol% CuBr and DMSO solvent.

5. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dichloromethane (DCM), chloroform, acetonitrile (ACN), tetrahydrofuran (THF), methanol, ethanol, ethyl acetate, dimethoxyethane (DME), and combinations thereof.

6. The process as claimed in claim 1, wherein the reaction is carried out under aerobic conditions, and molecular oxygen acts as the terminal oxidant.

7. The process as claimed in claim 1, wherein the α, β-unsaturated keto / ester methyleneindolinone comprises electron-donating or electron-withdrawing substituents selected from the group consisting of methyl, methoxy, halogens (Cl, Br, I, F), nitro (-NO2), and trifluoromethyl (-CF3) groups.

8. The process as claimed in claim 1, wherein the yield of the [1,2,3]triazolo[1,5- c]quinazoline derivatives ranges between 38% and 95%.

9. The method as claimed in claim 1, wherein the reaction time is 24 hours to achieve maximum yield.

10. A compound of the formula [1,2,3]triazolo[1,5-c]quinazolin-5(6H)-one derivatives, wherein the derivatives is obtained using NaN3and alkene carboxylate derivatives in the presence of copper catalyst via sequential [3+2] cycloaddition and ring expansion reactions:

11. The compound as claimed in claim 10, the inorganic azide is selected from the group consisting of NaN3, trimethylsilyl azide (TMS-azide), diphenyl phosphoryl azide, para-toluenesulfonyl azide, 4-Acetamidobenzenesulfonyl azide, etc.

12. The compound as claimed in claim 10, wherein said alkene carboxylate is having electro withdrawing group and wherein, said alkene carboxylate is selected from the group consisting of nitro, CN, CHO, CO-R, F, Cl, Br, or a combination thereof.

13. The compound as claimed in claim 10, said copper catalyst is selected from the group consisting of metal-catalyst.

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