Substituted 4-heteroatom-isoquinolone compounds, process of preparation and applications thereof

Abstract

The present disclosure generally relates to substituted heteroaromatic compounds. The invention relates to novel substituted 4-heteroatom-isoquinolone compounds, and isomers, derivatives, analogues and / or salt forms thereof of formula I; and its process of preparation thereof. Furtherore, the present invention relates to a process of preparation of various drugs / APIs / alkaloids e.g. Ampikin APIs such as CX-614, CX-554, DRF-2655, ITF-296, ITF-1129, Raititrexed, Deoxyvasicinone family of quinazolinone alkaloids, etc. using said formula I compound as starting material. The compound of formula I acts as antimalarial agent, anticancer agent, neuroprotective agent and so on. Formula I

Description

[0001] SUBSTITUTED 4-HETEROATOM-ISOQUINOLONE COMPOUNDS, PROCESS OF PREPARATION AND APPEICATIONS THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present disclosure generally relates to synthetic substituted heteroaromatic compounds. The invention relates to novel substituted 4-heteroatom-isoquinolone compounds, and isomers, derivatives, analogues and / or salt forms thereof of formula I; and a process of preparation thereof via intramolecular decarboxylative C(sp3)-X (X = O, N, S) bond formation. Further, the present invention relates to a process of preparation of various drugs / APIs / alkaloids e.g. Ampikin APIs such as CX-614, CX-554, DRF-2655, ITF-296, ITF-1129, Raititrexed, Deoxyvasicinone family of quinazolinone alkaloids, etc. using said formula I compound as starting material. The compound of formula I acts as antimalarial agent, anticancer agent, neuroprotective agent and so on.

[0004] BACKGROUND OF THE INVENTION

[0005] Heterocyclic compounds continue to play very important role in modern drug discovery due to their contribution to specific interactions with the targeted proteins and desirable physicochemical properties. Depending on the targeted interactions and program needs, different heterocyclic compounds can be designed. Isoquinolinones (l-oxo-1,2- dihydroisoquinolines) can be considered as one of the important heterocyclic compounds, and these are a class of fused heterocycles that are of increasing interest in pharmaceutical chemistry and can be regarded as intermediates for the synthesis of isoquinoline and dihydroisoquinoline ring systems which display a large spectrum of biological activity. The isocarbostyril skeleton is also a common building block of a wide variety of benzo[c]phenanthridine alkaloidse. Moreover, the isoquinolinone cores not only are important pharmacophores in biologically active compounds but also versatile building blocks to access more complex derivatives (refer, Xianhai Huang et al., Bioorganic & Medicinal Chemistry Letters 27 (2017) 5344-5348).

[0006] To date numerous processes for the elaboration of said heterabicyclic framework have been reported but few have demonstrated broad synthetic and pharmacologoical utility. One of the articles by Deb, M. L. et al., Angew. Chem., Int. Ed. 2013, 52, 9791 reported a copper- mediated intramolecular a-functionalization of tertiary amines through CH bond oxidative activation (benzylic and non-benzylic) to synthesize diverse dihydro- 1,3 -oxazines through CO bond formation. Another article by B. Francesca et al., J. Med. Chem, 38 (1995), 38, p. 130-136 reported nitro ester 3-[(nitrooxy)alkyl]-2Z7-l,3-benzoxazin-4(3J7)-one compounds derived from 3-[(nitrooxy)alkyl]-2if-l,3-benzoxazin4(3H)-ones (6a-q) wherein said 6a-q compounds are prepared using methyl salicylic esters (2a — o), which were converted to first 2-hydroxy-N-(hydroxyalkyl)benzamides (3a-o) followed by to the corresponding 3- substituted-2,3-dihydro-4H-l,3-benzoxazin-4(3H)-ones (4a — o) via two-step procedure involving a cyclization with paraformaldehyde under acidic conditions and the hydrolysis of the intermediate. However, these articles / methods suffer from limitations or disadvantages such as use of toxic chemicals / metals, higher temperature requirement, lesser selectivity, restricted to CO bond formation only hence less tunability and applicability, etc.

[0007] Therefore, there is an unmet need to provide an effective and alternative substituted isoquinolone compounds with high scale production, better tunability for formation of different heterobonds (-O-, -N-, -S-, etc.) in heterocylic compound and with better activity. Addressing all said problems, inventors of present application provide novel substituted 4- heteroatom-isoquinolone compounds and process of preparation thereof for further applications in preparation of various drugs / APIs / alkaloids. Also, these novel compounds may possess therapueric activity in terms of antimalarial agent, anticancer agent, neuroprotective agent and so on.

[0008] OBJECTIVES OF THE INVENTION

[0009] An objective of the present invention is to provide a substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I.

[0010] Another objective of the present invention is to provide a substituted 4-heteroatom- isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula IA, IB, IC, ID or IE.

[0011] Another objective of present invention is to provide process of preparation of substituted 4- heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I from compound of formula II as starting material. Yet nother objective of the present invention is to provide novel substituted amino acid based compound of formula II, which is used as starting material in preparation of formula I compounds.

[0012] Yet another objective of the present invention is to provide substituted 4-heteroatom- isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, IA, IB, IC, ID or IE, useful in the preparation of different drugs / APIs / alkaloids having isoquinolone moiety.

[0013] SUMMARY OF THE INVENTION

[0014] In an aspect, the present invention relates to a process for the preparation of substituted 4- heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, the formula I is represented as:

[0015] Formula I wherein R1to R4may be same or different, and are independently selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un) substituted heteroaryl(C5-C12), (un) substituted protecting group, (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12), (un)substituted alkylene(C2-C12) hydroxyl, amino, nitro, halo, oxyalkyl, haloalkyl, aminocarbonyl alkyl, trifluoroalkyl, oxyalkyl (un)substituted-heteroaryl, (un) substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted hetero arylether, heteroalkylene, arylalkyl, alkylaryl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether-

[0016] (un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl- thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylamino sulfonylamino , dialkylamino sulfonylamino , alkylaminocarbonylamino , alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate;

[0017] R5, and R6may be same or different, and are independently selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cll), (un)substituted heteroaryl(C5-C12), (un) substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted protecting group, (un)substituted alkylene(C2-C12), (un)substitutedalkyl-thio- (un)substitutedalkyl, alkylaryl, arylalkyl, (un)substituted alkylene(C2-C12) hydroxyl, alkylamino, aminoalkyl, alkylamido, alkylheteroaryl, alkyloxynitro, (un)substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, heteroalkylene, alkylaryl, arylalkyl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl-ether- (un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl,

[0018] (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-

[0019] (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl, , alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate, optionally R5and R6together forms a cyclic ring which may be further substituted with R* substituent or forms further cylic ring(s) ranging from 1-3; the dashed bond between X and carbon is either single bond or double bond; and “X” is a heteroatom selected from oxygen, nitrogen, and sulphur, which may optionally be substituted with (un)substituted alkyl(Cl to C21), (un) substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un)substituted heteroaryl(C5-C12), (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un) substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12) and (un)substituted allyl(C2-C12); the process comprising the steps of: a) preparing a reaction mixture comprising a substituted natural or synthetic amino acid compound of formula II without prefunctionalization, an organophotoredox catalyst, an oxidant, and a solvent,

[0020] Formula II wherein R1-R6 and X are the same as defined above; b) stirring the reaction mixture of step a) under irradiation of visible light source at temperature in the range of 25 to 35 °C for time period in the range of 20 to 72 h to obtain a (crude) compound of formula I; and c) optionally washing, separating, drying and purifying the compound of step b) to obtain the pure compound of formula I.

[0021] ABBREVIATIONS:

[0022] ACN = Acetonitrile, THF = Tetrahydrofuran, DCM = Dichloromethane, RFTA = Riboflavin tetraacetate, APS = Ammonium persulfate, KPS = Potassium persulfate, MeOH = Methanol, DTBP = Di-tert-butyl Peroxide, HOBt = Hydroxybenzotriazole, DIPEA = A,A-Diisopropylethylamine, EDC.HC1 = N-Ethyl-N'-(3- dimethylaminopropyl)carbodiimide hydrochloride, PC-A = (Ir[dF(CF3)ppy]2(dtbpy))PF6 ([4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine-Nl,Nr]bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate), PC-B = 9- Mesityl-10-methylacridinium tetrafluoroborate, PC-C = 4CzIPN (1, 2,3,5- Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene), and (DHQ)iPyr = Hydroquinine 2,5- diphenyl-4,6-pyrimidinediyl diether.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] “Membered ring” or “cyclic ring” as used herein means any cyclic structure with carbon, hydrogen and heteroatom (N, O, S, P, Si, B, etc.) in saturated or unsaturated cyclic ring form e.g. cyclic ring may be 4 to 10-membered ring. Thus, by way of example and not limitation, those membered rings include cyclohexyl, pyridinyl, pyranyl, thiopyranyl, etc. which are 6- membered rings, cyclopentyl, pyrrolyl, furanyl, thienyl, pyrrolidine, pyrrole, tetrahydrofuran, furan, phospholane, phosphole, silacyclopentane, silole, tetrahydrothiophene, thiophene, etc.

[0025] “Alkylamine” as used herein means an — N(alkyl)xHygroup, moiety or substituent where x and y are independently selected from the group x=l, y=l and x=2, y=O. Alkylamine includes those — N(alkyl)xHygroups wherein x=2 and y=0 and the alkyl groups taken together with the nitrogen atom to which they are attached form a cyclic ring system.

[0026] “Alkylaryl” as used herein means substituent, moiety or group where alkyl moiety is bonded to aryl moiety i.e. -aryl-alkyl, where aryl and alkyl groups are as described above, e.g. - C6H4-CH3 or -C6H4-CH2CH(CH3).

[0027] The protecting groups that may form the protective derivatives of the above substituents may be found in sources such as Greene and Wuts, above. Optional substituents include those selected from the group consisting of halogen, — CN, — NH2, — OH, — N(CH3)2, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone, those selected from the group consisting of halogen, — CN, — NH2, — OH, NH(CH3), — N(CH3)2, — CO2H, — CO2alkyl, — C(=O)NH2, — C(=O)NHalkyl, — C(=O)N(alkyl)2, — S(=O)2NH2, — S(=O)2NH(alkyl), — S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, — S-alkyl and-S(=O)2alkyl or those selected from the group consisting of halogen, — CN, — NH2, —OH, — NH(CH3), — N(CH3)2, — CH3, — CH2CH3, — CF3, — OCH3, and — OCF3. “Heterocycle” or “heterocyclic” as used herein means a cycloalkyl or aromatic ring system wherein one or more, typically 1, 2 or 3, but not all of the carbon atoms comprising the ring system are replaced by a heteroatom which is an atom other than carbon, including, N, O, S, Se, B, Si, P, typically N, O or S wherein two or more heteroatoms may be adjacent to each other or separated by one or more carbon atoms, typically 1-17 carbon atoms, 1-7 atoms or 1-3 atoms. “Heteroarylalkyl” as used herein means a substituent, moiety or group where a heteroaryl moiety is bonded to an alkyl moiety, i.e., -alkyl-heteroaryl, where alkyl and heteroaryl groups are as described above.

[0028] “Alkylheteroaryl” as used herein means substituent, moiety or group where heteroaryl moiety is bonded to alkyl moiety, i.e., heteroaryl-alkyl, where heteroaryl and alkyl groups are as described above.

[0029] “Haloalkyl” as used herein means an alkyl substituent moiety or group in which one or more of its hydrogen atoms are replaced by one or more independently selected halide atoms. Haloalkyl includes C1-C4 haloalkyl. Example but non-limiting Ci-C4haloalkyls are — CH2CI, CH2Br, — CH2I, — CHBrCl, — CHC1— CH2C1 and — CHC1— CH2I. “Haloalkylene” as used herein means an alkylene substituent, moiety or group in which one or more hydrogen atoms are replaced by one or more halide atoms. Haloalkylene includes Ci- Ce haloalkylenes or C1-C4 haloalky lenes.

[0030] “Acetal”, “thioacetal”, “ketal”, “thioketal” and the like as used herein means a moiety, group or substituent comprising or consisting of a carbon to which is bonded two of the same or different heteroatoms wherein the heteroatoms are independently selected S and O. For acetal the carbon has two bonded oxygen atoms, a hydrogen atom and an organic moiety. For ketal, the carbon has two bonded oxygen atoms and two independently selected organic moieties where the organic moiety is as described herein alkyl or optionally substituted alkyl group. For thioacetals and thioketals one or both of the oxygen atoms in acetal or ketal, respectively, is replaced by sulfur.

[0031] As used herein, the term “alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group. Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, propan- 1,3 -diyl, propan- 1,2-diyl, butan-l,4-diyl, butan-l,3-diyl, butan-l,2-diyl, 2-methyl-propan-l,3-diyl, and the like. As used herein, the term “alkylamino” refers to a group of formula — NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “alkoxycarbonyl” refers to a group of formula — C(O)O-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylcarbonyl” refers to a group of formula — C(O)-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylcarbonylamino” refers to a group of formula — NHC(O)-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylsulfonylamino” refers to a group of formula — NHS(O)2-alkyl, wherein the alkyl group is as defined above. As used herein, the term “aminosulfonyl” refers to a group of formula — S(O)2NH2. As used herein, the term “alkylaminosulfonyl” refers to a group of formula — S(O)2NH( alkyl), wherein the alkyl group is as defined above. As used herein, the term “dialkylaminosulfonyl” refers to a group of formula — S(O)2N(alkyl)2, wherein each alkyl group independently is as defined above.

[0032] As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula — NHC(0)NH2. As used herein, the term “alkyl aminocarbonylamino” refers to a group of formula — NHC(O)NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “dialkylaminocarbonylamino” refers to a group of formula — NHC(O)N(alkyl)2, wherein each alkyl group independently is as defined above. As used herein, the term “alkylcarbamoyl” refers to a group of formula — C(O) — NH(alkyl), wherein the alkyl group is as defined above.

[0033] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has (R)-configuration or (S)-configuration.

[0034] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Example prototropic tautomers include ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H — and 3H-imidazole, 1H — , 2H — and 4H-l,2,4-triazole, 1H — and 2H — isoindole, and 1H — and 2H-pyrazole.

[0035] The expressions, “ambient temperature”, “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature from about 20° C. to about 30°

[0036] C.

[0037] In an embodiment, the present invention relates to a process of preparation of substituted 4- heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I via intramolecular decarboxylative C(sp3)-X (X = O, N, S) bond formation, the formula I is represented as: Formula I wherein R1to R4may be same or different, and are independently selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un) substituted heteroaryl(C5-C12), (un) substituted protecting group, (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12), (un)substituted alkylene(C2-C12) hydroxyl, amino, nitro, halo, oxyalkyl, haloalkyl, aminocarbonyl alkyl, trifluoroalkyl, oxyalkyl (un)substituted-heteroaryl, (un) substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted hetero arylether, heteroalkylene, arylalkyl, alkylaryl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether-

[0038] (un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl- thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylamino sulfonylamino , dialkylamino sulfonylamino , alkylaminocarbonylamino , alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate;

[0039] R5, and R6may be same or different, and are independently selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un)substituted heteroaryl(C5-C12), (un) substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted protecting group, (un)substituted alkylene(C2-C12), (un)substitutedalkyl-thio- (un)substitutedalkyl, alkylaryl, arylalkyl, (un)substituted alkylene(C2-C12) hydroxyl, alkylamino, aminoalkyl, alkylamido, alkylheteroaryl, alkyloxynitro, (un)substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, heteroalkylene, alkylaryl, arylalkyl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl-ether- (un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl,

[0040] (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-

[0041] (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl, , alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate, optionally R5, and R6together forms a cyclic ring which may be further substituted with R* substituent or forms further cylic ring(s) ranging from 1-3; the dashed bond between X and carbon is either single bond or double bond; and

[0042] “X” is a heteroatom selected from oxygen, nitrogen, and sulphur, which may optionally be substituted with (un)substituted alkyl(Cl to C21), (un) substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un)substituted heteroaryl(C5-C12), (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un) substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12) and (un)substituted allyl(C2-C12); the process comprising the steps of: a) preparing a reaction mixture comprising a substituted natural or synthetic amino acid compound of formula II without prefunctionalization, an organophotoredox catalyst, an oxidant, and a solvent,

[0043] Formula II wherein R1-R6 and X are the same as defined above; b) stirring the reaction mixture of step a) under irradiation of visible light source at temperature in the range of 25 to 35 C for time period in the range of 20 to 72 hrs to obtain (crude) compound of formula I; and c) optionally washing, separating, drying and purifying the compound of step b) to obtain the pure compound of formula I.

[0044] In another embodiment, the visible light source is having the wavelength in the range of 390-490nm.

[0045] In another embodiment, the organophotoredox catalyst is selected from but not limited to Riboflavin tetraacetate (RFTA), (Ir[dF(CF3)ppy]2(dtbpy))PF6 ([4,4'-Bis(l,l- dimethylethyl)-2,2 '-bipyridine-N 1 ,N l']bi s [3 , 5 -difluoro-2- [5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C]Iridium(III) hexafluorophosphate) as PC-A, 9-Mesityl-10-methylacridinium tetrafluoroborate as PC-B, and 4CzIPN (l,2,3,5-Tetrakis(carbazol-9-yl)-4,6- dicyanobenzene) as PC-C. In another embodiment, the oxidant is selected from but not limited to ammonium persulfate (APS), potassium persulfate (KPS), di-terZ-butyl peroxide (DTBP), PIDA ((Diacetoxyiodo)benzene), PIFA ((Bis(trifluoroacetoxy)iodo)benzene), Benzoyl peroxide, Chloranil, 2, 3 -Diehl oro-5, 6-di cyano- 1,4-benzoquinone (DDQ), and salt sodium chlorite (NaCICh).

[0046] In another embodiment, the solvent is selected from acetonitrile (CAN), tetrahydrofuran (THF), dichloromethane (DCM), methanol (MeOH), dimethylsulfoxide (DMSO), dimethylformamide (DMF), Dioxane, Toluene, dichloroethane (DCE), benzene, and chloroform.

[0047] In another embodiment, the visible light source is selected from but not limited to blue LEDs, red LEDs, green LEDs, white LEDs, UV light and Sun light.

[0048] In optional or some embodiments, the washing and separation of (crude) compound is done by diluting it with ethyl acetate and washed with saturated aqueous NaHCOs solution, followed by extracting the aqueous phase with ethyl acetate at least three times and the combined organic phase was washed with brine to obtain separated compound (by removal of impurities, side products and unreacted starting materials).

[0049] In optional or some embodiments, the organic phases obtained after drying and separation is dried over anhydrous Na2SO4, followed by evaporating the solvent under reduced pressure.

[0050] In optional or some embodiments, the purification is done by silica gel column chromatography using ethyl acetate and petroleum ether as eluents to obtain compound I in pure form.

[0051] In another embodiment, the yield of substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, IA, IB, IC, ID or IE (before or after step c) is in range of 71-85%.

[0052] In another embodiment, the selectivity of formation of said compound isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, IA, IB, IC, ID or IE is in range of 70-95%. In another embodiment, the conversion of starting materials into said compound isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, IA, IB, IC, ID or IE is in range of 60-90%.

[0053] In another embodiment, the compound of formula I, IA, IB, IC, ID or IE as synthesized herein is optionally purified by literature methods known to a person skilled in the art e.g. drying, evaporation, concentration methods, chromatographic techniques (conventional or advanced such as column chromatography, flash chromatography, HPLC, etc.) and so on.

[0054] In another embodiment, the compound obtained by the process provides single isomeric compound (ee) or mixture of isomeric forms / compounds from a single reaction / process.

[0055] In another embodiment, the process for synthesis of compound of formula I may be done in batch mode or in continuous mode.

[0056] In another embodiment, the amount / concentration of compound of formula II for the preparation of formula I is in range of 10 mmol to 100 mmol.

[0057] In another embodiment, the amount / concentration of salicylic acid for the preparation of formula II is in range of 10 mmol to 500 mmol.

[0058] In another embodiment, the amount / concentration of photoredox catalyst used in step a) is in range of 0. Immol to 1.0 mmol.

[0059] In another embodiment, the amount / concentration of oxidant used in step a) is in range of 10 mmol to 100 mmol.

[0060] In another embodiment, the amount / concentration of solvent used in step a) is in range of 2 mL to 1000 mL.

[0061] In another embodiment, when X is oxygen and R6is hydrogen, then at least one of R1, R2, R3, and R4is not hydrogen in said formula I.

[0062] In optional or some embodiments, the aromatic carbons connected with Rl, R2, R3, and R4 groups may be replaced with heteroatom selected from -N, -S, and -O. In optional or some embodiments, the R1 with R2 or R2 with R3 or R3 with R4 or R1 with R3 or R2 with R4 forms together a cyclic ring which may be further substituted.

[0063] In another embodiment, the protecting group is selected from but not limited to p- methoxybenzyl (PMB), tert-butyloxycarbonyl (boc), boc-NH group, and so on.

[0064] In some embodiments, the cyclic ring is selected from unsaturated cyclic ring or saturated cyclic ring, wherein the saturated cyclic ring is C3-C10 cycloalkyl ring or C3-C10 cycloheteroalkyl ring, and the unsaturated cyclic ring is C3-C10 aryl ring or C3-C10 heteroaryl ring.

[0065] In some embodiments, the R* substituent is selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un) substituted aryl(C5-Cll), (un)substituted heteroaryl(C5-C12), (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12), (un)substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, heteroalkylene, arylalkyl, heteroarylalkyl, (un) substituted halo, nitro, (un)substitutedalkyl- ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl,

[0066] (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-

[0067] (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl,

[0068] (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, amino sulfonylamino, aminocarbonylamino , alkylamino sulfonyl amino , dialkylamino sulfonylamino , alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate.

[0069] In some embodiments, the substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, is represented by the formulas IA: Formula I A wherein Rl to R4 and X are the same as defined under formula I explained above; the dashed bond between X and carbon is either single bond or double bond; and Rl’, R2’ and R3’ are independently the same as defined under formula I explained above under Rl, R5 or R6.

[0070] In some embodiments, the substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, is represented by the formulas IB:

[0071] Formula IB wherein Rl to R4 and X are the same as defined under formula I explained above; the dashed bond between X and carbon is either single bond or double bond; and Rl’, R2’, R3’ and R4’ are independently the same as defined under formula I explained above under Rl, R5 or R6.

[0072] In some embodiments, the substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, is represented by the formulas IC:

[0073] Formula IC wherein Rl to R4 and X are the same as defined under formula I explained above; the dashed bond between X and carbon is either single bond or double bond; and Rl’ and R2’ are independently the same as defined under formula I explained above under Rl, R5 or R6.

[0074] In some embodiments, the substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, is represented by the formulas ID:

[0075] Formula ID wherein Rl to R4 and X are the same as defined under formula I explained above; the dashed bond between X and carbon is either single bond or double bond; and Rl’, R2’, R3’, R4’, and R5’ are independently the same as defined under formula I explained above under Rl, R5 or R6. In some embodiments, the substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, is represented by the formulas IE: Formula IE wherein R1 to R4 and X are the same as defined under formula I explained above; the dashed bond between X and carbon is either single bond or double bond; and Rl’, R2’, R3’, and R4’ are independently the same as defined under formula I explained above under Rl, R5 or R6.

[0076] In specific embodiment, the Rl to R4 are independently selected from hydrogen, halo, (un)substituted Cl-ClOalkyl, amino, hydroxyl, (un)substituted Cl-ClOalkoxy, nitro, -CF3, -NH-CO-alkyl(Cl-C8), (un) substituted C5-C10aryl, and (un) substituted C6-C10heteroaryl.

[0077] In specific embodiment, the R5 and R6 are independently selected from hydrogen, (un)substituted Cl-ClOalkyl, alkylaryl, alkylthioalkyl, alkylhydroxyl, alkylheteroaryl, alkyl-substituedaryl, alkylamide, alkyl-SH, alkylamino, alkyloxy-substitutedaryl, alkyloxynitro, (un) substituted C5-C10aryl, and (un)substituted C6-C10heteroaryl.

[0078] In specific or optional embodiment, R5 and R6 together forms a cycloalkyl ring wherein the number of carbons in said cycloalkyl ring is in the range of 3 to 8.

[0079] In another embodiment, the process provides compound, isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I selected from:

[0080] The general synthetic scheme for preparation of formula I is provided herein:

[0081] In another embodiment, the present invention is to provide a substituted 4-heteroatom- isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, IA, IB, IC, ID or IE to act as therapeutic agent in terms of antimalarial agent, anticancer agent, anti-inflammatory, anticancer, anti-diabetes, anti-thrombotic, anti-obesity, anti-ischaemic and neuro-protective properties, antibacterial, antiviral, antifungal, neuroprotective agent and so on. In another aspect, the present invention is to provide substituted 4-heteroatom-isoquinolone compound and isomer, derivative, racemate, analogue and / or pharmaceutically acceptable salt form thereof of formula I, IA, IB, IC, ID or IE, useful in the preparation of different drugs / APIs / alkaloids having isoquinolone moiety. In another embodiment, the drugs / APIs / alkaloids having isoquinolone moiety is selected from but not limited to:

[0082] In another embodiment, the present invention provides a process of preparation of CX-614 Drug molecule using compound of formula I, the synthetic scheme of the same is provided below as Scheme 2:

[0083] In another embodiment, the present invention provides a process of preparation of CX-558 Drug molecule using compound of formula I, the synthesis of the same is provided below as Scheme 3:

[0084] In another embodiment, the present invention is to provide novel substituted amino acid based compound of formula II, which is used as starting material in preparation of formula I compounds.

[0085] The novel compounds based on formula II are selected from but not limited to:

[0086] In a nutshell, the present invention provides a protocol for the intramolecular decarb oxylative C(sp3)-X (X = O, N, S) bond formation by using organophotoredox catalysis. The protocol is operationally simple and uses mild reaction condition. The method has been established for the construction of C-O, C-N and C-S bond using commercially available salicylic acids and natural / unnatural amino acids without any prefunctionalization to achieve pharmacologically important scaffolds. The application of the protocol has been demonstrated in synthesis of Ampikin APIs such as CX-614, CX-554, DRF-2655, ITF-296, ITF-1129, Raititrexed. Slight modification in the substrate provided smooth access to Deoxy vasicinone family of quinazolinone alkaloids, EXAMPLES

[0087] Procurement details: All chemicals & materials used in present invention are obtained from different vendors such as Setlab India, Vijay Chemicals India, Anand Agencies India, TCI India, Sigma Aldrich India, BLD Pharma India, Avra chemicals India, Spectrochem India and Lobachem India. Example 1 : General procedure of synthesis of compound of formula III (this is starting material for synthesis of compound of formula II) :

[0088] |V(1 equiv.) V (1.2 equiv.) wherein R1-R6 and X are same as defined above in the description. To a solution of salicylic acid analogues IV (1 equiv.) in DCM (10 mL for 1 g of acid) was added, EDC.HC1 (1.2 equiv.) and HOBt (1.2 equiv.) followed by DIPEA (3 equiv.) at 0 °C with continuous stirring for 10 minutes. Later, a solution of amino acid methyl ester hydrochloride V (1.2 equiv.) in DCM (2 mL) was added drop wise at 0°C to reaction mixture in five minutes with continuous stirring. The reaction mixture was allowed to warm to temperature of 30°C and stirred overnight (for 10 h). After completion of reaction (checked by TLC), it was quenched with saturated aqueous NH4CI (10 mL), & extracted with DCM (3x15 mL). The combined organic layers were washed with saturated aqueous NaHCCL solution (3x20 mL) and brine (20mL), dried over anhydrous NaiSCL & concentrated in vacuo. The crude products were purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents to obtain corresponding product (III) in yields of 70- 90%.

[0089] Example IA: Typical experimental procedure for the synthesis of representative compound methyl (2-hydroxybenzoyl)prolinate:

[0090] To the solution of salicylic acid (1g, 7.24 mmol, 1 equiv.) in DCM (20 mL) was added EDC.HC1 (1.66 g, 8.69 mmol, 1.2 equiv.) and HOBt (1.17 g, 8.69 mmol, 1.2 equiv.), followed by DIPEA (2.80 g, 3.79 mL, 21.73 mmol, 3 equiv.) at 0 °C with continuous stirring for 10 minutes. Then a solution of proline methyl ester hydrochloride (1.43 g, 8.69 mmol, 1.2 equiv.) in DCM (5 mL) was added drop wise at 0 °C to the reaction mixture in five minutes with continuous stirring. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of reaction (checked by TLC), it was quenched with saturated aqueous NH4CI (10 mL) solution, and extracted with DCM (3 x 15 mL). The combined organic layers were washed with saturated aqueous NaHCOs solution (3 x 15 mL) and brine (15 mL), dried over anhydrous NaiSCL and concentrated in vacuo. The crude product was purified by silica gel column chromatography using ethyl acetate and petroleum ether (4:6) as eluents to obtain corresponding product Illa in 81 % yield as a thick oil (1.46 g).

[0091] Examples of prepared compounds according to example IA:

[0092] Example IB: Alternative method: General procedure of synthesis of compound of formula III (this is starting material for synthesis of compound of formula II) :

[0093] To a stirred and ice-cold solution of salicylic acid analogues IV (1 equiv.) in anhydrous DCM (10 mL for 1 g of acid) was added thionyl chloride dropwise (2 equiv.) followed by catalytic amount of DMF (10 pL). The reaction temperature was increased to room temperature and stirring was continue for 4 h. The solvent was removed by vacuum to afford the corresponding acid chloride. Later, fresh anhydrous DCM (10 mL for 1 g of acid) was added and reaction mixture cool to 0°C. After five-minute stirring at 0°C, a solution of amino acid methyl ester hydrochloride V (1.2 equiv.) in DCM (2 mL) containing TEA (3 equiv.) was added and reaction mixture was allowed to warm at temperature of 30°C & stirred overnight (for 10 h). After completion of reaction (checked by TLC), it was quenched with saturated aqueous NaHC03 solution (3x20 mL) & extracted with DCM (3x15 mL). The combined organic layers were washed with saturated brine (20mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude products were purified by silica gel column chromatography using ethyl acetate & petroleum ether as eluents to obtain product in yield of 70-90%.

[0094] Example 2: General procedure of synthesis of compound of formula II from compound of formula III (formula II is starting material for synthesis of compound of formula I):

[0095] To the solution of ester III (1 equiv.) in THF / water (1: 1) [10 mL for 1 g of ester] was added aqueous 2 N NaOH (2 equiv.) drop wise at room temperature with continuous stirring and the reaction mixture was stirred until complete consumption of the starting material (checked by TLC). THF was then removed in vacuo followed by dilution with water (5 mL for 1 g scale) and addition of ethyl acetate (10 mL for 1 g scale). The organic layer was separated and the aqueous layer was acidified with citric acid up to pH 2 and extracted with ethyl acetate (15 mL X 3 for 1 g). The ethyl acetate layer was separated, dried over anhydrous NaiSCL and concentrated in vacuo to obtain the corresponding amino acids in quantitative yields (more than 95%).

[0096] 2A: Typical experimental procedure for the synthesis of representative compound II:

[0097] To the solution of ester III (1 g, 4.016 mmol, 1 equiv.) in THF / water (1: 1, 10 mL) was added aqueous NaOH (321 mg, 4 mL 2 N, 2 mmol, 2 equiv.) drop wise at room temperature with continuous stirring and the reaction mixture was stirred until complete consumption of the starting material (checked by TLC). THF was then removed in vacuo followed by dilution with water (10 mL) and addition of ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was acidified with citric acid up to pH 2 and extracted with ethyl acetate (15 mL X 3). The ethyl acetate layer was separated, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the corresponding amino acid Ha in 93% yield as a white solid (878 mg).

[0098] Example 3: General procedure of synthesis of compound of formula I from compound of formula II:

[0099] An oven dried schlenk tube containing a stirring bar, RFTA (5 mol%), KPS (1 equiv.) and salicylic acid (II, 1 equiv.) was evacuated well, flushed and refilled with argon. Anhydrous DCM was added via syringe and the reaction mixture was stirred under irradiation of 30 W blue LEDs (approximately 5 cm away from the light source) over 24h at temperature of 30°C. After completion of reaction, the mixture was diluted with ethyl acetate & washed with saturated aqueous NaHCOs solution. The aqueous phase was extracted with ethyl acetate three times and combined organic phase was washed with brine. The united organic phases were dried over anhydrous NaiSCh. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents to obtain compound I in 71-85% yields.

[0100] Typical experimental procedure for the synthesis of representative compound 1,2,3,3a- tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one (la):

[0101] An oven dried schlenk tube containing stirring bar, RFTA (6.94 mg, 0.012 pmol mol%), KPS (68.93 mg, 0.2553 mmol, 1 equiv.) and salicylic acid (60 mg, 0.2553 mmol, 1 equiv.) was evacuated, flushed and refilled with argon. Anhydrous DCM (2 ml) was added via syringe and the reaction mixture was stirred under irradiation of 30 W blue LEDs (approximately 5 cm away from the light source) over 24 h at room temperature. After completion of reaction (checked by TLC), the mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCOs solution. The aqueous phase was extracted with ethyl acetate (10 mL X 3) three times and the combined organic extracts were washed with brine. The combined organic phases were dried over anhydrous NaiSCX. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using ethyl acetate and petroleum ether (3:7) as eluents to obtain la with 85% of yield (41 mg).

[0102] ADVANTGAES OF THE INVENTION:

[0103] • Provides substituted isoquinolone compounds with high scale production, better tunability for formation of different heterobonds (-O-, -N-, -S-, etc.) in heterocylic compound and with better activity.

[0104] • Provides effective substituted 4-heteroatom-isoquinolone compounds for further application in preparation of various drugs / APIs / alkaloids.

[0105] • The process is scalable and preferable for the bulk scale synthesis.

Claims

CLAIMS:

1. A process for the preparation of a substituted 4-heteroatom-isoquinolone compound, isomer, derivative, racemate, analogue or pharmaceutically acceptable salt form thereof of formula I, the formula I is represented by:Formula Iwherein R1to R4may be same or different, and are independently selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un)substituted heteroaryl(C5-C12), (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted protecting group, (un) substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12), (un)substituted alkylene(C2-C12) hydroxyl, amino, nitro, halo, -CF3, oxyalkyl, haloalkyl, aminocarbonyl alkyl, trifluoroalkyl, oxyalkyl (un)substituted-heteroaryl, (un)substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, heteroalkylene, arylalkyl, alkylaryl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl,(un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylamino sulfonylamino , dialkyl amino sulfonylamino , alkylaminocarbonylamino , alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate;R5, and R6may be same or different, and are independently selected from hydrogen, (un)substituted alkyl(Cl to C21), (un)substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cll), (un)substituted heteroaryl(C5-C12), (un)substituted protecting group, (un)substituted cycloalkyl(C3-C12), (un) substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12), (un)substitutedalkyl-thio- (un)substitutedalkyl, alkylaryl, arylalkyl, (un)substituted alkylene(C2-C12) hydroxyl, alkylamino, aminoalkyl, alkylamido, alkylheteroaryl, alkyloxynitro, (un)substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un)substituted alkylether, (un)substituted arylether, (un) substituted hetero arylether, heteroalkylene, alkylaryl, arylalkyl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl- ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether-(un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl, , alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylamino sulfonylamino , dialkylamino sulfonylamino , alkylaminocarbonylamino , alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate, optionally R5, and R6together forms a cyclic ring which is substituted with R* substituent or forms a cylic ring(s) ranging from 1-3; the dashed bond between X and carbon is either single bond or double bond; and“X” is a heteroatom selected from oxygen, nitrogen, and sulphur, which is optionally be substituted with (un)substituted alkyl(Cl to C21), (un) substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cll), (un)substituted heteroaryl(C5-C12), (un)substituted cycloalkyl(C3-C12), (un) substituted alkenyl(C2-C12), (un)substituted alkynyl(C2-C12), (un)substituted alkylene(C2-C12) and (un) substituted allyl (C2-C 12); the process comprising steps of:a) preparing a reaction mixture comprising a substituted natural or synthetic amino acid compound of formula II without prefunctionalization, an organophotoredox catalyst, an oxidant, and a solvent,Formula II;b) stirring the reaction mixture of step a) under irradiation of visible light source at temperature in the range of 25 to 35 °C for time period in the range of 20 to 72 hrs to obtain a (crude) compound of formula I; and c) optionally washing, separating, drying and purifying the compound of step b) to obtain the pure compound of formula I.

2. The process as claimed in claim 2, wherein the visible light source is having a wavelength in the range of 390-490 nm; wherein the organophotoredox catalyst is selected from riboflavin tetraacetate (RFTA), (Ir[dF(CF3)ppy]2(dtbpy))PF6 ([4,4'- Bis(l,l-dimethylethyl)-2,2'-bipyridine-Nl,Nr]bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate) as PC-A, 9-Mesityl-10- methylacridinium tetrafluoroborate as PC-B, and 4CzIPN (l,2,3,5-Tetrakis(carbazol-9- yl)-4,6-dicyanobenzene) as PC-C; and wherein the oxidant is selected from ammonium persulfate (APS), potassium persulfate (KPS), di-terZ-butyl peroxide (DTBP), ((Diacetoxyiodo)benzene), ((Bis(trifluoroacetoxy)iodo)benzene), benzoyl peroxide, chloranil, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), and sodium chlorite salt (NaCICh).

3. The process as claimed in claim 1, wherein the solvent is selected from acetonitrile (CAN), tetrahydrofuran (THF), dichloromethane (DCM), methanol (MeOH), dimethylsulfoxide (DMSO), dimethylformamide (DMF), dioxane, Toluene, dichloroethane (DCE), benzene, and chloroform; and wherein the visible light source is selected from blue LED, red LED, green LED, white LED, UV light and sun light.

4. The process as claimed in claim 1, wherein the washing and separation of the compound as obtained in step b) is done by diluting with ethyl acetate and washed with saturated aqueous NaHCCE solution, followed by extracting the aqueous phase with ethyl acetateat least three times, and the combined organic phase was washed with brine to obtain separated compound by removal of impurities, side products and unreacted starting materials.

5. The process as claimed in claim 1, wherein the aromatic carbon connected with R1, R2, R3, and R4is replaced with heteroatom selected from -N, -S, and -O; and wherein the R1with R2or R2with R3or R3with R4or R1with R3or R2with R4forms together a cyclic ring which is further substituted.

6. The process as claimed in claim 1 or 4, wherein the cyclic ring is selected from unsaturated cyclic ring and saturated cyclic ring, wherein the saturated cyclic ring is C3- C10 cycloalkyl ring or C3-C10 cycloheteroalkyl ring, and the unsaturated cyclic ring is C3-C10 aryl ring or C3-C10 heteroaryl ring; and wherein the R* substituent is selected from hydrogen, (un)substituted alkyl(Cl to C21), (un) substituted alkoxy(Cl to C21), (un)substituted aryl(C5-Cl l), (un)substituted heteroaryl(C5-C12), (un)substituted cycloalkyl(C3-C12), (un)substituted alkenyl(C2-C12), (un)substituted alkynyl(C2- C12), (un)substituted alkylene(C2-C12), (un)substituted allyl(C2-C12), (un)substituted cyclic ring(C3-C12), silyl, alkylsilyl, (un) substituted alkylether, (un)substituted arylether, (un)substituted heteroarylether, heteroalkylene, arylalkyl, heteroarylalkyl, (un)substituted halo, nitro, (un)substitutedalkyl-ether-(un)substitutedaryl, (un)substitutedalkyl-ether-(un)substitutedheteroaryl, (un)substitutedalkyl-ether- (un)substitutedalkyl, (un)substitutedalkyl-thio-(un)substitutedaryl,(un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylamino sulfonyl, aminosulfonylamino, aminocarbonylamino , alkylamino sulfonyl amino , dialkylamino sulfonylamino , alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate, and carbonate.

7. The process as claimed in claim 1, wherein the substituted 4-heteroatom-isoquinolone compound of formula I, is selected from compound of formula IA, IB, IC, ID and IE, represented by:Formula IA, wherein R1’, R2’ and R3’ are same as any of R1, R5andR6of formula I, respectively;Formula IB, wherein R1’, R2’, R3’ and R4’ are independentlysame as any of R1, R5and R6of formula I, respectively;Formula IC, wherein R1’, and R2’ are independently same as anyof R1, R5and R6of formula I, respectively;Formula ID, wherein R1’, R2’, R3’, R4’ andR5’ are independentlysame as any of R1, R5and R6of formula I, respectively; andR1R1OFormula IE, wherein R1’, R2’, R3’, R4’ and R5’ are independentlysame as any of R1, R5and R6of formula I, respectively.

8. The process as claimed in claim 1, wherein the R1 to R4 are independently selected from hydrogen, halo, (un)substituted (Cl-ClO)alkyl, amino, hydroxyl, (un)substituted Cl- ClOalkoxy, nitro, -CF3, -NH-CO-alkyl(Cl-C8), (un)substituted (C5-C10)aryl, and (un)substituted (C6-C10)heteroaryl; wherein the R5 and R6 are independently selected from hydrogen, (un)substituted (Cl-ClO)alkyl, alkylaryl, alkylthioalkyl, alkylhydroxyl, alkylheteroaryl, alkyl-substituedaryl, alkylamide, alkyl-SH, alkylamino, alkyloxy- substitutedaryl, alkyloxy nitro, (un)substituted (C5-C10)aryl, and (un)substituted (C6- C10)heteroaryl; and wherein the R5 and R6 together forms a cycloalkyl ring wherein number of carbon in said cycloalkyl ring is in the range of 3 to 8.

9. The process as claimed in claim 1, wherein the compound is selected from the group consisting of: a) 7 -bromo- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one,b) 7 -iodo- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one, c) 5,7-di-tert-butyl-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9- one, d) 7-amino-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, e) 5-hydroxy-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, f) 7-nitro-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, g) 7-(trifluoromethyl)- 1,2,3, 3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin- 9-one, h) N-(9-oxo-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-7- yl)acetamide, i) 2-(2-(methylthio)ethyl)-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, j) 2-(hydroxymethyl)-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, k) 2-( 1 -hydroxyethyl)-2,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, l) 2-(3 -methylbutan-2-yl)-2 ,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, m) 2-((lH-indol-3-yl)methyl)-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, n) 2-(4-oxo-3,4-dihydro-2H-benzo[e][l,3]oxazin-2-yl)acetamide, o) 3 -(4-oxo-3 ,4-dihydro-2H-benzo [e] [ 1 ,3 ] oxazin-2-yl)propanamide, p) 2-(mercaptomethyl)-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, q) 2-(4-aminobutyl)-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, r) 5 a, 6, 8 ,9-tetrahydro-7H, 11 H-benzo [e]pyrido [2, 1 -b] [ 1 ,3 ] oxazin- 11 -one, s) 2,3-dihydro-5H,10aH-benzo[e]thiazolo[2,3-b][l,3]oxazin-5-one, t) 5a,6-dihydro-llH,13H-benzo[5,6][l,3]oxazino[3,2-b]isoquinolin-13-one, u) 2,2a-dihydro-lH,8H-azeto[2,l-b]benzo[e][l,3]oxazin-8-one, v) 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] thiazin-9-one, w) 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one, x) 7-fluoro-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one,y) 7-chloro- 1 ,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2, 1 -b] [ 1 ,3]oxazin-9-one, z) 7 -methyl- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one, aa) 6-methoxy-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, bb) l,2,3,3a-tetrahydro-HH-naphtho[2,3-e]pyrrolo[2,l-b][l,3]oxazin-l 1-one, cc) 2-methyl-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, dd) 2,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, ee) 2-(sec -butyl) -2,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, f f) 2-isobutyl-2,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, gg) 2-benzyl-2,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, hh) 2-(4-hydroxybenzyl)-2,3 -dihydro -4H-benzo [e] [ 1 ,3 ] oxazin-4-one, ii) 5 a, 6, 7 ,8 ,9, 10-hexahydro- 12H-benzo [5 ,6] [1,3] oxazino [3 ,2-a] azepin- 12-one, jj ) 2,3,11,11 a- tetrahydro- 1 H,5H-benzo [f]pyrrolo [2, 1 -c] [ 1 ,4] oxazepin-5-one, kk) 6-iodo- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one,11) 6-methyl- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one, mm) tert-butyl (9-oxo- 1,2,3, 3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-7- yl)carbamate, nn) 6-nitro-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, oo) 6-(trifluoromethyl)- 1,2,3, 3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, pp) 7-phenyl-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, qq) 7-(2,4-difluorophenyl)- 1,2,3, 3a-tetrahydro-9H-benzo[e]pyrrolo[2,l- b] [ 1 ,3]oxazin-9-one, rr) l,2,3,l la-tetrahydro-5H-benzo[4,5]thieno[2,3-e]pyrrolo[2,l-b][l,3]oxazin-5- one, ss) 2-methyl-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, tt) 3-(4-methoxybenzyl)-2, 3-dihydro-4H-benzo[e][l,3]oxazin-4-one,uu) 3-(4-methoxybenzyl)-2-methyl-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, vv) 2-isobutyl-3-(4-methoxybenzyl)-2,3-dihydro-4H-benzo[e][l,3]oxazin-4-one, ww) 3-(4-methoxybenzyl)-2-(2-(methyl-hydroxymethyl)ethyl)-2,3-dihydro-4H- benzo [e] [ 1 ,3 ] oxazin-4-one, xx) 2-benzyl-3 -(4-methoxybenzyl)-2,3 -dihydro-4H-benzo [e] [ 1 ,3 ] oxazin-4-one, yy) 2-((lH-indol-3-yl)methyl)-3-(4-methoxybenzyl)-2,3-dihydro-4H- benzo [e] [ 1 ,3 ] oxazin-4-one, zz) 3 a-methyl- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] oxazin-9-one, aaa) 3-hydroxy-l,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,l-b][l,3]oxazin-9-one, bbb) 6,7,8 ,9-tetrahydro- 11 H-pyrido [2, 1 -b] quinazolin- 11 -one (Mackinazolinone) , ccc) 2,3 -dihydropyrrolo [2, 1 -b] quinazolin-9( 1 H)-one (Deoxy vasicinone) , ddd) 6-fluoro-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one, eee) 6-methyl-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one, fff) 6-methoxy-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one, ggg) 3 a-methyl- 1 ,2,3 ,3 a-tetrahydro-9H-benzo [e]pyrrolo [2, 1 -b] [ 1 ,3 ] thiazin-9-one, hhh) 5a,6,8,9-tetrahydro-7H,l lH-benzo[e]pyrido[2,l-b][l,3]thiazin-l 1-one, and iii) 4-phenyl-2,3,3a,4-tetrahydropyrrolo[2,l-b]quinazolin-9(lH)-one.

10. The process as claimed in claim 1, wherein the compound acts as intermediate for the preparation of drug, API, and alkaloid having isoquinolone moiety, selected from: a) 2,3 -dihydropyrrolo [2, 1 -b] quinazolin-9( 1 H)-one, b) 2-methylquinazolin-4(3H)-one, c) 5a,6,7,8-tetrahydro-10H-[l,3]dioxolo[4',5':4,5]benzo[l,2-e]pyrrolo[2,l- b][l,3]oxazin- 10-one, d) 2,3,6a,7,8,9-hexahydro-l lH-[l,4]dioxino[2',3':4,5]benzo[l,2-e]pyrrolo[2,l- b][l,3]oxazin-l 1-one,e) 2-ethoxy-3-(4-(2-(4-oxo-2H-benzo[e][l,3]oxazin-3(4H)- yl)ethoxy)phenyl)propanoic acid, f) 2-(4-oxo-2H-benzo[e][l,3]oxazin-3(4H)-yl)ethyl nitrate, g) 2-(6-methyl-4-oxo-2H-benzo[e][l,3]oxazin-3(4H)-yl)ethyl nitrate, and h) (5-(methyl((2-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)methyl)amino)thiophene-2-carbonyl)glutamic acid.

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