WO2024127343A1

WO2024127343A1 - Inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase 1 (enpp-1)

Info

Publication number: WO2024127343A1
Application number: PCT/IB2023/062767
Authority: WO
Inventors: Ganapathy Bhotla Venkata RAMANARAYANAN; Perumal SARAVANAN; Vadivelu Saravanan; Kulkarni NAGARAJ
Original assignee: Sravathi Ai Technology Private Limited
Priority date: 2022-12-16
Filing date: 2023-12-15
Publication date: 2024-06-20

Abstract

The present invention discloses a novel type of highly potent ENPP-1 inhibitors for the treatment of various diseases particularly, cancer. The compounds of the invention have tail, core, and zinc binding portions (ZBP), where the key feature includes positioning of a sulfoximine-type moiety and an amino nitrogen atom specified as G₁ or G₂ fragment in a saturated cyclic ring in the core part. Synthesis of compounds of formula (1), pharmaceutical compositions and use thereof are also disclosed.

Description

INHIBITORS OF ECTONUCLEOTIDE PYROPHOSPHATASE / PHOSPHODIESTERASE 1 (ENPP-1) RELATED APPLICATIONS This invention claims the benefit of priority to the Indian provisional patent application No. 202241072781 filed on the 16th of December 2022, titled “INHIBITORS OF ECTONUCLEOTIDE PYROPHOSPHATASE / PHOSPHODIESTERASE 1 (ENPP-1)” and it is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present disclosure relates to novel compounds of formula 1, which inhibit ENPP-1 protein and hence have the potential for use in immunotherapy for disease treatment. The invention also discloses synthetic methods for making the compounds, their pharmaceutical compositions, and potential uses in the treatment of many diseases, particularly cancer. BACKGROUND OF THE INVENTION One of the reported strategies in the treatment of cancer, particularly cancer immunotherapy is to potentiate anti-tumour immune responses of the human body. A recent journal publication, viz., Nature Cancer, 1(2), 184–196- doi:10.1038/s43018-020-0028-4, also reports that by inhibiting a protein known as Ectonucleotide Pyrophosphatase / Phosphodiesterase 1 (ENPP- 1), which is known to negatively regulate innate immune signalling, thus enhancing the immune responses as part of a treatment of cancer disease. In journal publications, viz., a) J Hematol Oncol 2020, 13, 81 -https://doi.org/10.1186/s13045- 020-00916-z; b) Molecules 2019, 24, 4192 - doi:10.3390/molecules24224192 and c) Cell Chemical Biology 2020, 27, 1347–1358, the role of cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway has been disclosed. The cGAS-STING pathway has a promising role in cancer immunotherapy as it has been recognized that it is important in interferon (IFN) production and T cell priming and it acts a link between the cGAS-STING pathway and ENPP-1. It now emerges that hydrolysis of cGAMP (cyclic GMP- AMP) by ENPP-1 attenuates cGAS-STING signaling. Therefore, inhibition of ENPP-1 would decrease hydrolysis of cGAMP resulting in enhancement of cGAS-STING signaling, with concomitant increase in the immune responses of the body. In a review article in Trends in Biochemical Science, Volume 46, Issue 6, June 2021, Pages 446-460, it is pointed out that in addition to the crucial IFN signaling, cGAS-STING is much involved in autophagy. ENPP-1 plays a regulatory function in immune cells such as neutrophils, macrophages, dendritic cells, natural killer cells, and B lymphocytes. ENPP-1 expression is heightened in M2 macrophages in the presence of cancer and promotes tumor growth and spread. The role of ENPP-1 in cancer is exemplified by the observations of enhanced tumor metastasis to the bone from breast cancer, for example, by over-expression of ENPP-1. ENPP-1 belongs to the family of Phosphodiesterase. A patent publication, WO2018119328A1 reviews the roles and types of different phosphodiesterases. Phosphodiesterases comprise a class of enzymes that catalyze the hydrolysis of a phosphodiester bond. In some instances, phosphodiesterase has been linked with viral infection and its inhibition has been correlated with a reduction in viral replication. In some instances, the class of phosphodieserases further comprises cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and small- molecule phosphodiesterases. In another instance, phosphodiesterase is linked with a bacterial infection, e.g., an infection from a Gram-negative bacterium or a Gram-positive bacterium. In some cases, the bacterium is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae. Hence inhibitors of phosphodiesterases would potentially impact treatment of many diseases. Inhibitors which have high specificity in inhibiting a particular phosphodiesterase, for example ENPP-1, are much needed in the industry. There are several prior art reports which disclose ENPP-1 inhibitors with different structures of varied potency. The key features of the recently reported references of prior art are a) ENPP- 1 inhibitors predominantly target cancer diseases b) structures of the inhibitors possess at least three basic components comprising a tail, a core and zinc binding domain, as exemplified in formulae X-XI and c) some of these structures have linking groups (linkers) between the core and zinc binding portions and/or some structures have linkers between the core and tail parts. Structures of compounds of certain prior art inventions relevant to ENPP-1 inhibition are highlighted in Scheme 1. Though the scaffolds represented in Figures III-VI are not exactly similar, they contain tail, core, and zinc binding portions. Some of the scaffolds have only one linker and others two linkers. ENPP-1 inhibitory activity of the compounds of structures of Formulas III-VI is disclosed in the respective literature references for cancer treatment. Scheme 1

Formula III Formula IV Formula-V Formula-VI US20220135598A1 WO2020160333A1 WO2019051269A1 WO2021225969A1 Patent publication, US20220135598A1 discloses inhibitor structure conforming to the Formula 1II where tail part is primarily quinoline or substituted quinoline moiety with specific substitutions on the quinoline ring, core part is a cyclic ring or fused spiro ring; linker part L which links the core part with the zinc binding portion can be a bond, linear or branched C1- C6 alkylene or linear or branched C2-C6 alkenylene; and zinc binding portion is — NRcS(O)2NH 2, —NRcS(O)2CH3, —SO2NH2, —NRcC(O)CH3, —C(O)OH, —CONH2, NRcCONH2, — CONH(OH), —B(OH)2, —P(O)(OH)2, —SO2OH, —NRcS(O)2CF3, —NRcS(O)2NHCH3, or —NR1CH2C6-aryl-S(O)2NH2. Patent publication WO2020160333A1 discloses inhibitor structure conforming to the Formula 1V, where the presence of an additional linker L¹ between core part and tail part is a key feature. The linker L2 is present between the core and zinc binding domain. Zinc binding group has been disclosed as phosphorus-containing group or urenyl. The core part could be aryl. Further, linker L1 is explored as alkyl, alkenylene, alkynylene, arylene, alarylene, aralkylene and linking moieties containing functional group including without limitation: amido, ureylene, imide, epoxy, epithio, epidioxy, cabonyldioxy, alkyldioxy, epoxyimino, epimino, and carbonyl. Patent publication, WO2019051269A1 discloses a structure as depicted in Formula-V, wherein linker between core and X was termed as L, which can be a (Ci- 6)alkyl linker or a substituted (Ci-6)alkyl linker, optionally substituted with a heteroatom or linking functional group, such as an ester (-CO2-), amido (CONH), carbamate (OCONH), ether (-0-), thioether (-S-) and/or amino group. The tail part is based on quinazoline moiety and core part represented as C is an aromatic ring. The zinc binding portion represented as X was based on phosphoric acid or sulfonamide or ureylene moieties. Patent publication, WO2021225969A1 discloses a structure as depicted in Figure-VI, where L is a bond, -O-, -C(O)-, -NR6c-, or -OCR7c-*, wherein * represents the point of attachment to portion containing zinc binding portion. W in Figure-VI contains both the core group and zinc binding portion connected though the linker L. The core group is an aryl or heteroaryl moiety. The zinc binding portion is a sulfoximine moiety with only a hydrogen atom as the substituent on the nitrogen atom of the sulfoximine group. a1 and a2 are independently 0 , 1, 2 or 3. Patent publication, WO2021226136A1 discloses a structure akin to the one depicted in Formula-V for ENPP-1 inhibition. Patent publication, WO2019046778A1 discloses a structure as depicted in Formula-VII, where there are two linkers named L and L1 and with a sulfonamide type end group for ENPP-1 inhibition.

Formula-VII Formula-VIII 7 (US 20190282703A1) Where X is -NR -, -O- -CR⁸R⁹-; L is a bond

-CR¹⁰R¹¹-; and L1 is a bond or -CR¹³R¹⁴ Patent publication, US20190282703A1 discloses a structure as depicted in Formula-VIII, where there is single linker, L as specified and a sulfonamide end group and a monocyclic tail group. Patent publication, WO2021158829A1 discloses a structure as depicted in Formula 1X where L is selected from the group consisting of an C1-C5 alkyl, and C1-C5 alkenyl; and where Y is selected from the group consisting of -CR4R5-, -NR6-, -N(CH2)mO-, -O-, -S-, - S(O)-, -S(O)2, aryl, and heteroaryl; wherein m is 2 or 3 for treatment of cancer, bacterial or viral diseases

Formula IX (WO2021158829A1) Patent publication, WO2020140001A1 discloses a structure as depicted in Formulae-X and X1 where X is N or CH; Z is NH, O, S, SO, or S02; and Q is -B(OH)2 or -P(0)(Ra)(Rb).

Formulae X and XI (WO2020140001A1) Other related prior art references which disclose certain compounds as ENPP-1 inhibitors having structures not falling in the tail-core-zinc binding part description given in figures III- X1 are mentioned below. WO2022056068A1 discloses small molecule ENPP-1 inhibitors for treating a variety of cardiac conditions. Patent publication, WO2019023635A1 discloses substituted -3H-imidazo[4,5-c] pyridine and 1H-pyrrolo[2,5-c] pyridine series of novel ENPP- 1 inhibitors and stimulator for interferon genes (sting) modulator as cancer immune therapeutics. A patent publication, WO2021053507A1 discloses 2-amino-S6-substituted thiopurine compounds as inhibitors of the ENPP-1 for treatment of cancer, infectious disease, and other conditions associated. Additionally, ENPP-1 inhibitors play a role in DNA damage repair process (See reference US20220135598A1). The patent publication, WO2019023635 mentions that ENPP-l is an attractive druggable target for the development of novel anticancer, cardiovascular, diabetes, obesity, and anti-fibrotic therapeutics. Patent publication, WO2022056068A1 mentions that modulators of ENPP-1 may also be useful against bacteria and fungi. In a patent publication, WO2022125613A1, certain phosphonates are disclosed as inhibitors of not only ENPP-1 but also CdnP. Cyclic di-nucleotide phosphodiesterase (CdnP, also known as Rv2837c) is a phosphodiesterase in regulating cyclic dinucleotide signaling during intracellular infections of M. tuberculosis. The structure of the phosphonates disclosed in ‘613 patent application also may be classified as tail-core-zinc binding domain and be represented as Formula XII.

Formula XII In a recent review article, by J. Choi in Bull. Korean Chem. Soc. 2022, 1, progress in the discovery of small molecule ENPP1 inhibitors, has been discussed. The molecules reviewed in the article cover a wide range of molecules having groups such as sulfamides, sulfonamides, sulfamates, sulfonates, sulfonimidamides, sulfoximine end groups, boronic acids and certain phosphonates. The review points out that inhibition of ENPP1 is a promising approach that may result in optimal STING activation. Successful regulation of ENPP1 might provide a chance to expand the scope of cancer immunotherapy. The main therapeutic use or purpose behind ENPP-1 inhibitors is to provide treatment to patients or subjects suffering from cell proliferative diseases and cancers including, without limitation, glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumours, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), and other solid tumours. The non-availability of targeted treatments for these cancers and cell proliferative diseases is driving the current continued search of therapeutic agents, particularly new ENPP-1 Inhibitors that could show selectivity to some of these adverse conditions and diseases. The brief overview given above on structures with tail-core-zinc binding group describes scaffolds of potentially high potency for inhibition of ENPP-1 to boost immune activity. However, none of these structures seem to be clinically proven. The shortcomings of these structures are not clear from the literature reports. Newer structures are still needed to address the dire need to fight diverse types of cancer or carcinoma. Accordingly, the present invention discloses a novel structure for highly efficacious molecules for use against one or more types of maladies. SUMMARY OF THE INVENTION The present disclosure relates to compounds of formula 1, which are potent inhibitors of ENPP- 1 protein and hence have the potential for use as for example, in immune therapy for disease treatment. The invention also discloses synthetic methods for making these compounds and invitro bioactivity results to indicate the potential use of these inhibitors in treatment of various diseases including cancer. Specifically, the invention discloses a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isomer thereof.

wherein the formula 1 comprises portion A, portion B, portion C and Zinc-binding portion (ZBP) with portions A and B constituting tail part of the formula 1, wherein, the portion A is a six-membered aryl or heteroaryl, which is optionally substituted with (R²)n groups and where X₁, X₂ and X₃ is CH, N, CR' with the proviso that not more than two of X₁, X₂ and X₃ is simultaneously N, where n = 0, 1, 2 or 3, wherein, R² is selected from a group consisting of R', F, Cl, Br, I, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH2Ar and where Ar = aryl, substituted aryl, heteroaryl, or substituted hetero aryl; the portion B is C6 aryl or 5-6 membered heteroaryl, optionally substituted with (R¹)n groups, wherein the portion B is fused to the portion A where the two shared atoms between the portions B and A come from a pair of carbon atoms or from a pair of atoms, where one of the atoms is nitrogen and the other is carbon; wherein n = 0, 1, 2 or 3 and wherein, R¹ is selected from a group consisting of R', F, Cl, Br, I, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, - NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH₂Ar and where Ar = aryl, substituted aryl, heteroaryl, or substituted hetero aryl; the portion C constitutes the core part of the formula 1 and is a 4 or a 6 membered saturated cyclic ring having as part of the ring, sulphur, or nitrogen atoms from G1 and G2 fragments, where G1 and G2 fragments are selected from a group consisting of

with the proviso that the G1 and G2 fragments are not the same simultaneously, where the nitrogen atom of G2 fragment is bonded to a zinc binding portion (ZBP) through a linker (L2)q and the nitrogen atom of G1 fragment is bonded to the carbon atom located between the bridge head atom and the X3 atom of the portion A through a linker (L₁)p, where L₁ is -CH₂- when p = 0,1,2 or 3 and where L₂ is -CH₂- when q = 0, 1, 2 or 3 with the proviso that when boronic acid type ZBP is present, the value of q is equal to 2 or 3. the ZBP is selected from a group consisting of

^, where, R⁵, R⁶ and R⁸ are alkyl or aryl groups and R7 is H, alkyl, or aryl group. In one aspect, a general method of preparation of compounds and intermediates required for synthesis of compound of formula 1 is disclosed. The compound represented by formula 1, inhibits function of phosphodiesterase enzyme which is selected from a group consisting of ENPP-1, cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and small-molecule phosphodiesterases. Invitro assay results point to the potential of these compounds in inhibiting phosphodiesterase such as ENPP-1 and hence in treatment of diseases such as cancer. DETAILED DESCRIPTION It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to the terms that shall be defined to have the following meanings. Definitions As used herein unless otherwise specified, "alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. The term "alkyl" includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃-), ethyl (CH₃CH₂-), n-propyl (CH₃CH₂CH₂-), isopropyl ((CH₃)₂CH-), n-butyl (CH₃CH₂CH₂CH₂-), isobutyl ((CH₃)₂CHCH₂-), sec-butyl ((CH₃)(CH₃CH₂)CH-), t-butyl ((CH₃)₃C-), n-pentyl(CH₃CH₂CH₂CH₂CH₂-), and neopentyl ((CH3)3CCH2-). "Cycloalkyl" refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8- tetrahydronaphthalene-5- yl). The term "Cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. "Aryl" refers to an aromatic group of from 5 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthyl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "Aryl" or "Ar" applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene- 2- yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring). “Alkenyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and having the number of carbon atoms designated (i.e., C₂-C₁₀ means two to ten carbon atoms). The alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C2M alkenyl”), having 2 to 8 carbon atoms (a “C2- C₈ alkenyl”), having 2 to 6 carbon atoms (a “C₂-C₆ alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof, and the like. “Alkylene” as used herein refers to the same residues as alkyl but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1- C₃ alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), butylene (— CH2CH2CH2CH2—), and the like. “Alkynyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C₂-C₁₀ means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C2M alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like. “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or thee (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl (—CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy “Heteroaryl” refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulphur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom. Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl oxazolyl, isoxazolyl, 1,3,4- oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzoimidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, purinyl, benzofuranyl, furopyridinyl, benzooxazolyl, benzothiophenyl, benzothiazolyl, oxazolopyridinyl, thiazolopyridinyl, thienopyridinyl, quinolinyl, quinolonyl, naphthyridinyl, quinazolinyl, pyridopyrimidinyl, cinnolinyl or pyridopyridazinyl and the like. “Heterocycle” or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulphur, or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heterocyclyl group may have a single ring or multiple condensed rings but excludes heteroaryl groups. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like. “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents. A “medicament” or “pharmaceutical composition” refers to a pharmaceutical formulation in administrable form comprising at least one pharmaceutically active ingredient and one or more pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals. In reference to cancers or other unwanted cell proliferation, beneficial or desired results include shinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer. In some embodiments, beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation. As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late-stage cancer, such as development of metastasis, may be delayed. As used herein, an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. As used herein, the term “individual” is a mammal, including humans. An individual includes, but is not limited to human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human. The individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden. In some embodiments, the individual is at an early stage of a proliferative disease (such as cancer). In some embodiments, the individual is at an advanced stage of a proliferative disease (such as an advanced cancer). In some aspects, sarcomas and carcinomas are cancer that may be treated as solid tumors whereas leukemia are the cancer that may be treated as liquid tumors. Present invention may treat different types of cancers that include, but are not limited to, adrenocortical cancer, bladder cancer, brain tumors, breast cancer, prostate cancer, colorectal cancer, colon cancer, endometrial cancer, gallbladder cancer, gastric cancer, head and neck cancer, hematopoietic cancer, kidney cancer, leukemia, oral cancer, uterine carcinoma, hodgkin lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, sarcoma, skin cancer and thyroid cancer. The breast cancer is classified as carcinoma of breast (ER negative or ER positive), mammary adenocarcinoma, primary breast ductal carcinoma, mammary ductal carcinoma (ER positive, ER negative or HER2 positive), triple negative breast cancer (TNBC), HER2 positive breast cancer or luminal breast cancer. The breast cancer is unclassified. In some cases, a basal-like TNBC, an immunomodulatory TNBC, mesenchymal TNBC (mesenchymal or mesenchymal stem-like) or a luminal androgen receptor TNBC are triple negative breast. In some embodiments, prostate adenocarcinoma is prostate cancer. Other therapeutic use of the compounds including the ovary adenocarcinoma, lung carcinoma, adenocarcinoma, non-small lung carcinoma, mucoepidermoid, anaplastic large cell cancer, the colon adenocarcinomas, colon carcinoma, metastatic colorectal cancer, colon adenocarcinoma, astrocytoma, glioblastoma, meduloblastoma, neuroblastoma or meningioma, stomach cancer, cholangiocarcinoma or hepatoblastoma, hepatocellular carcinoma, liver cancer, medullary thyroid cancer or follicular thyroid cancer, papillary thyroid carcinomas, uterine papillary serous carcinoma or uterine clear cell carcinoma, gallbladder adenocarcinoma or squamous cell gallbladder carcinoma, renal cell carcinoma or urothelial cell carcinoma, adrenal cortical carcinoma, fibrosarcoma or Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma, basal cell carcinoma, melanoma or squamous carcinoma, cancer of the trachea, laryngeal cancer, nasopharyngeal cancer and oropharyngeal cancer, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mantle cell lymphoma or multiple myeloma. Molecular Biology of ENPP-1 Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP-1) is a 925 amino acid length protein having a molecular mass of 104924 Da. This protein is predominantly found in the extracellular space, lysosomal membrane and in the plasma membrane. The ENPP-1 protein which belongs to the nucleotide pyrophosphatase/phosphodiesterase family is a homodimer that requires zinc ion as a cofactor for eliciting biological function. The molecular functions reported for ENPP-1 protein are nucleic acid binding, exonuclease activity, phosphodiesterase I activity, 3'-phosphoadenosine 5'-phosphosulfate binding, ATP binding, calcium ion binding, cyclic-GMP-AMP hydrolase activity, dTTP diphosphatase activity, exonuclease activity, insulin receptor binding, NADH pyrophosphatase activity, nucleic acid binding, nucleoside-triphosphate diphosphatase activity, nucleotide diphosphatase activity, phosphodiesterase I activity, polysaccharide binding, protein homodimerization activity, scavenger receptor activity, zinc ion binding and nucleotide diphosphatase activity. ENPP-1 protein is involved in the hydrolysis of ATP, GTP, CTP, TTP and UTP to their respective monophosphates with release of pyrophosphate and diadenosine polyphosphates. The involvement of ENPP-1 protein is identified in several biological processes such as generation of precursor metabolites, metabolism of phosphate containing compounds, regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, regulation of purinergic signalling, endocytosis, immune responses, and nucleoside triphosphate catabolic process. One of the critical functions of ENPP-1 is reported to be the hydrolysis of 2',3'- cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING. The hydrolysis of cyclic GMP-AMP leads to the reduced expression of STING pathway downstream components, which are crucial for the maintenance of immune functions. Hence, ENPP-1 mediated STING pathway inactivation leads to immune suppression and enhanced tumour cell metastasis. ENPP-1 belongs to the class of Phosphodiesterases. Phosphodiesterases comprise a class of enzymes that catalyze the hydrolysis of a phosphodiester bond. In some instances, phosphodiesterase has been linked with viral infection and its inhibition has been correlated with a reduction in viral replication. In some instances, the class of phosphodiesterases further comprises cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and small- molecule phosphodiesterases. In another instance, phosphodiesterase is linked with a bacterial infection, e.g., an infection from a Gram-negative bacterium or a Gram-positive bacterium. In some cases, the bacterium is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae. Hence inhibitors of phosphodiesterases would potentially impact treatment of many diseases. Crystallographic Information on protein-ligand complex 6 crystal structures are reported for ENPP-1 protein. 2YS0, 6WET, 6WEU, 6WEV, 6WEW and 6WFJ are the reported PDB codes for ENPP-1. Out of the available PDB structures 6WEV was considered for insilico studies. The resolution of this protein was reported to be 2.90 Å. 6WEV is the target considered for the execution of insilico studies. The ENPP-1 protein complexed with N-{[1-(6,7-dimethoxy-5,8-dihydroquinazolin-4-yl) piperidin-4- yl]methyl}sulfuric diamide (PDB ID: 6WEV) has additional cofactors such as 2-acetamido-2- deoxy-beta-D-glucopyranose, phosphate ion, calcium ion and zinc ions. Zinc ions play essential role in the catalytic activation of ENPP-1. Hence the interaction of drug candidate molecules with zinc ions is critical for eliciting enzyme inhibition. Molecular Docking – Methodology Molecular docking studies were executed by AutoDock4Zn program, which incorporates improved force field parameters for addressing the co-ordination properties of zinc ions with the small molecules. The energetic and geometric components of zinc ion interactions with small molecules are captured in this program. Traditional autodock force field accounts for van der Waals, hydrogen bond, Coulomb electrostatic, desolvation and ligand torsional entropy terms for describing the interactions between ligand and receptor. But the traditional autodock forcefield is inadequate for handling zinc ions as van der Waals equilibrium distances for the atoms involved in zinc coordination are significantly larger than the coordination distances and lack of specific terms for metal co-ordination. Hence potential energy term associated with the pairwise interactions of each atom type involved in zinc ion co-ordination is added to the current autodock forcefield. Other tools for molecular docking may also be used instead of AutoDock4Zn. Molecular Docking Results The structural features associated with ENPP-1 inhibitors are categorized as zinc binding head or group, core, and tail parts. Out of the three portions, the presence of zinc binding portion plays vital role in the ENPP-1 inhibition as this group co-ordinates with the zinc ion present in the catalytic site of enzyme. The core and tail groups anchor the compound tightly in the binding pocket. The inhibitor design was initiated by considering these three structural elements. ENPP-1 co-crystalized with the inhibitor reported to have good potency was considered for the docking studies. The active site residues of ENPP-1 protein include D218, F257, L290, K295, D326, S325, K338, W322, F321, Y371, Y340, P323, T356, D376, H380 and Zn ions. The re-docking of the inhibitor to the binding pocket of enzyme was performed to visualize the binding profile. Prior art available on ENPP-1 docking studies emphasize that the closeness of zinc binding head of inhibitor to zinc atoms present in the catalytic site results in the higher degree of enzyme inhibition. This observation was taken into consideration for the redocking studies. The zinc binding portion of the reference compound was found to have a close association with the zinc ions present in the active site. Inhibitors of ENPP-1 The inventive compounds of the present invention are potential inhibitors of ENPP-1. The structure of the molecules is represented in the formula 1. The present invention discloses a compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or isomer thereof.

f^ormula 1 wherein the formula 1 comprises portion A, portion B, portion C and zinc-binding portion (ZBP), where the respective portions and key functional groups are described as under. Zinc binding portion (ZBP) The zinc binding portion (ZBP) is selected from a group consisting of

^, where, R⁵, R⁶, R⁸ are alkyl or aryl groups and R7 is H, alkyl, or aryl groups. The zinc binding portion (ZBP) is linked to the core part via the linker (L₂)q and G2 and the core part is linked HO OH B to the tail part via G1 and the linker (L₁)p respectively. When the ZBP is or 6 _{H O} B ^OR the ZBP is known as boronic acid type. When this boronic acid type ZBP is present in the formula 1, q = 2 or 3. Sulfoximine -type fragment One of the notable features of the structure depicted by formula 1 is the presence of a sulfoximine-type fragment positioned in the saturated ring of the core part in the form of fragment G1 or G2 of formula 1. Sulfoximine based structures are steadily gaining popularity in medicinal science. One of the recent references is “Application of sulfoximines in medicinal chemistry from 2013 to 2020”, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2020.112885. In another journal publication titled, “Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry” J. Med. Chem.2020, 63, 23, 14243– 14275; https://doi.org/10.1021/acs.jmedchem.0c00960, the limitations of this functional group is also discussed. The sulfoximine-type fragments of interest in this disclosure are given immediately below as sulfoximines and sulfondiimines.

The sulfondiimines are isosteres of sulfoximines, and both fall under sulfoximine-type fragments in this disclosure. The nitrogen of NH group in sulfondiimine is bonded to sulphur though a double bond and is isosteric with O atom present in sulfoximine. In the present disclosure, the R1x and R2x of sulfoximine group are part of a cyclic ring (four or six or eight- membered) of the core part of Formula 1. None of the hitherto published ENPP-1 inhibitors have the sulfoximine-type fragment as part of core part of the inhibitor molecules. Tail part Portions A and B constitute the tail part of the formula 1, wherein, the portion A is a six-membered aryl or heteroaryl, which is optionally substituted with (R²)n groups and where X₁, X₂ and X₃ is CH, N, CR' with the proviso that not more than two of X1, X2 and X3 is simultaneously N, where n = 0, 1, 2 or 3, wherein, R² is selected from a group consisting of R', F, Cl, Br, I, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF₃, CHF₂, CH₂F, OCF₃, SCF₃ and CH2Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH2Ar and where Ar = aryl, substituted aryl, heteroaryl, or substituted hetero aryl; the portion B is C6 aryl or 5-6 membered heteroaryl, optionally substituted with (R¹)n groups, wherein the portion B is fused to the portion A where the two shared atoms between the portions B and A come from a pair of carbon atoms or from a pair of atoms, where one of the atoms is nitrogen and the other is carbon; wherein n = 0, 1, 2 or 3 and wherein, R1 is selected from a group consisting of R', F, Cl, Br, I, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH2Ar and where Ar = aryl, substituted aryl, heteroaryl, or substituted hetero aryl; The portion A of the tail part of formula 1 is bonded to the core part at a nitrogen atom of either the sulfoximine-type fragment, the nitrogen of which is bonded to the sulphur atom though a double bond or to nitrogen atom of a tertiary amino nitrogen fragment, both the fragments being present,in the saturated cyclic ring of the portion C of formula 1 (See Structures 2 and 3).

Tail part of formula 1 In one embodiment, the tail part comprising portions A & B which contain X1, X2, X3, (R¹)n and (R²)_n groups together is selected from a group consisting of

The number of ring substituents R¹ and R² on the portions B and A respectively may be 0, 1 or more. When more than one ring substituent is present, such ring substituents may be the same or different. The Core Part

Portion C of the core part In one embodiment, the portion C is a six-membered saturated ring. In another embodiment, the portion C is a symmetrically substituted saturated six-membered ring characterized by a plane of symmetry. In one embodiment, the portion C is a four-membered saturated ring. In another embodiment, the portion C is a symmetrically substituted saturated four-membered ring characterized by a plane of symmetry. In yet another embodiment, the portion C is an eight-membered saturated ring. In an additional embodiment, the portion C is a symmetrically substituted saturated eight- membered ring characterized by a plane of symmetry The core part comprises portion C; the zinc binding portion (ZBP) is bonded to the portion C via the linker (L₂)q - G2 fragment. Preferably, the portion C contains a six-membered cyclic group with no substitution on any of the methylene groups and G1 and G2 fragments. The G1 and G2 fragments are selected from a group consisting of sulfoximine fragment and an amino nitrogen atom, illustrated as

. In all embodiments, G1 and G2 fragments are not the same simultaneously. In one embodiment, G2 and G1 fragments occur in the cyclic ring of the portion C as sulfoximine fragment and the amino nitrogen atom respectively where the nitrogen of the sulfoximine fragment is bonded to a ZBP via linker, (L1)p; the amino nitrogen is bonded to the tail part via linker, (L₂)q. This is illustrated as Structure 2, when p and q are equal to zero.

Structure 2 In another embodiment, G2 and G1 fragments occur together in the cyclic ring as an amino nitrogen and sulfoximine groups respectively where the amino nitrogen is bonded to the ZBP via linker, (L1)p and the sulfoximine nitrogen is bonded to the tail part via linker, (L2)q, respectively. This is illustrated as Structure 3 when p and q are equal to zero.

Structure 3 The linkers L₁ and L₂ are defined as follows. L₁ is -CH₂- when p = 0,1,2 or 3 and L₂ is also -CH2- when q = 0, 1, 2 or 3; with the proviso that when boronic acid type ZBP is present in formula 1, the value of q is ≥ 2. In one embodiment, the portion C is a four-membered saturated ring with G1 and G2 fragments occupying the opposite vertices of the four-membered ring. Whether the ring size of portion C is 4, 6 or 8, the attachments of G2 and G1 remain the same and are with ZBP and tail part, respectively. In a preferred embodiment, the substitutions in 4, 6 or 8-membered saturated ring present in the core part should be symmetrical such that a plane of symmetry is maintained within the core part. As the requirement is to maintain a plane of symmetry for the core part, the number of substitutions are even in number and can be a maximum of 4, 8 and 12 substitutions in 4, 6 and 8 membered saturated rings, respectively. The symmetrical substitutions in 4, 6 or 8-membered saturated ring present in the core part are selected from the group consisting of alkyl, aryl, halo, cyano, alkoxy, aryloxy, amino, substituted amino and a combination thereof. Synthesis of compounds of formula 1 General Strategy of Synthesis of sulfoximine based inventive Examples of the invention represented by formula 1 The strategy for preparing the inventive examples based on formula 1 resides on the preparation of the intermediate IM3 or IM4 which is then modified though appropriate reagents to incorporate various zinc binding portions or groups to obtain the inventive examples. 1) General procedure-1 for the synthesis of various sulfoximines, including the intermediate IM3

Step-1: Substituted quinazolin-4(3H)-one (1.0 equiv.) where (R¹)_n is (OMe)_2, was dissolved in toluene (0.2M) in round bottom flask (RBF), followed by cooling to 0 ^oC with ice bath. Then DIPEA (1.5 equiv.), and POCl3 were added dropwise and stirred for 15 mins at the same 0 ^oC. Then temperature was slowly raised to 100 ^oC and stirred for 3h. After completion of reaction, toluene was removed under reduced pressure, and the reaction mixture dissolved in EtOAc and washed with cold water and dilute NaHCO3 solution. The organic layer was concentrated to get pure compound and used in further steps without any further purification. The identified compound was confirmed by LCMS and purity of the compound was confirmed by HPLC. Step-2: Thiomorpholine (1.5 equiv.) was dissolved in dry THF (0.2M) in RBF and cooled to 0 °C with ice bath. Then NaH (1.2 equiv.) was added portion wise and stirred for 15 min, followed by addition of substituted 4-chloroquinazoline (1.0 equiv.) under N2 atmosphere. The temperature of reaction mixture was slowly raised to 100 °C and stirred over 6h. After completion of reaction, solvents were removed under reduced pressure, and the reaction mixture was dissolved in dichloromethane (DCM) and washed with water and brine solution. The organic layer was concentrated and purified by column chomatography by using EtOAc & Hexane as eluents (60-70%). The N-C coupled products were confirmed with LCMS and HPLC. Step-3: N-C coupled products (1.0 equiv.) was dissolved in MeOH (0.2M) in RBF, then Diacetoxyiodobenzene (PhI(OAc)₂) (1.5 equiv.), followed by portion wise addition of ammonium carbamate (NH4(CO2NH2)) (1.0 equiv.) under N2 atmosphere. After 2 h again the addition of same amount of (PhI(OAc)2) and (NH4(CO2NH2) was repeated to get maximum yield. After completion of reaction, methanol was removed under reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine solution. The organic layer was concentrated and purified with column chomatography by using DCM & methanol as eluents (85-90%). All the final sulfoximine compounds were confirmed with LCMS and HPLC and taken to next step. 2) General procedure-2 for the synthesis of urea and thiourea derivatives from sulfoximines .

4-(quinazolin-4-yl)-1-imino-1λ⁶-thiomorpholin-1-one (sulfoximines) (1.0 equiv.) was dissolved in AcOH/H2O (1:1) (0.5M) in a round bottom flask (RBF), followed by addion of NaOCN or NaSCN (2.2 equiv.) at 0°C for 10 min and the reaction mass stirred over 3 h at room temperature. After completion of reaction, the mixture was quenched with dilute NaOH and extracted with DCM. The organic layer again was washed with water and brine solution. The combined organic layer was concentrated and purified by column chomatography using DCM & MeOH as eluent (10-15%). The identity of all the final products were confirmed with LCMS, HNMR, and the purity confirmed with HPLC.

3) General procedure for the synthesis of common intermediate (IM4) for SAPTI012SU005 & SAPTI012SU006

Step-1: tert-butyl thiomorpholine-4-carboxylate (1.0 equiv.) was dissolved in MeOH (0.2M) in RBF, then Diacetoxyiodobenzene (PhI(OAc)2) (1.5 equiv.) was added followed by Ammonium carbamate (NH4(CO2NH2)) (2.0 equiv.) portion wise under N2 atmosphere. If starting material was still present even after 2 h, the addition of (PhI(OAc)₂) and (NH₄(CO₂NH₂) was repeated to get maximum yield. After completion of reaction, methanol was removed under reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine solution. The organic layer was concentrated and purified by column chomatography using EtOAc & Hexane as a mobile phase. The product tert-butyl 1- imino-1-oxo-1λ⁶-thiomorpholine-4-carboxylate (IM1’) was confirmed by LCMS (M+H) = 235; yield (88%). Step-2: tert-Butyl 1-imino-1-oxo-1λ6-thiomorpholine-4-carboxylate IM1’ (1.0 equiv.) and 4- chloro-6,7-dimethoxyquinazoline (1.2 equiv.) were dissolved in toluene (0.2M) in RBF under N2 atmosphere. Pd(OAc)2 (0.05 equiv.), DPPE (0.075 equiv.), and Cs2CO3 (1.4equiv.) were added to the above reaction mixture under N₂ atmosphere and the reaction was subjected to reflux for about 6 h. After completion of the reaction, toluene was removed under reduced pressure and dissolved in EtOAc followed by washing with water and brine solution. The organic layer was concentrated and purified by column chomatography using EtOAc/ Hexane as a mobile phase. The product IM2’ was confirmed by LCMS (M+H) = 423; Yield (29%). Step-3: IM2’ (1.0 equiv.) was dissolved with DCM (0.2M) in RBF followed by addition of Trifluoroacetic acid (TFA) dropwise into the reaction media under ice cold condition. The reaction was allowed to stir at room temperature up to the exhaustion of IM2’. After completion of the reaction, excess of TFA was quenched with saturated NaHCO3 solution and the product was extracted with DCM. The organic layer was washed with water & brine solution. The product 1-[(6,7-dimethoxyquinazolin-4-yl)imino]-1λ6-thiomorpholin-1-one, IM4 was confirmed by LCMS. Yield (65%) LCMS; M+.=323, rt-3.8 4) Synthesis of 1-[(6,7-dimethoxyquinazolin-4-yl) imino]-1-oxo-1λ⁶-thiomorpholine-4- carboxamide (SAPTI012SU005)

1-[(6,7-dimethoxyquinazolin-4-yl)imino]-1λ6-thiomorpholin-1-one (IM4) (1.0 equiv.) was taken in an RBF. Added glacial acetic acid-water mixture (1:1 ratio) into the above reaction vessel followed by NaOCN (1.2 equiv. ) portion wise into the reaction medium. The reaction was allowed to stir at room temperature for about 2h. After completion of the reaction the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. Now the organic layer was washed again with water and brine solution. The combined organic layer was concentrated and purified by column chomatography using neutral alumina as stationary phase and DCM/MeOH as mobile phase. The product 1-[(6,7-dimethoxyquinazolin- 4-yl) imino]-1-oxo-1λ6-thiomorpholine-4-carboxamide (SAPT1012SU005) was confirmed with LCMS (M+H) = 366; Yield (54%). 5) Synthesis of 1-[(6,7-dimethoxyquinazolin-4-yl)imino]-1-oxo-1λ⁶-thiomorpholine-4- sulfonamide

IM4 (1eq) was dissolved with DCM (0.2M) in RBF, and Et3N was added dropwise followed by sulfomyl chloride (1.5 equiv.) portion wise into the reaction media under cold condition. The reaction was allowed to stir at RT for about 12h. After completion of the reaction the reaction mixture was further diluted with DCM and washed with water and brine solution. The combined organic layer was concentrated and purified by column chomatography with neutral alumina as stationary phase and DCM/MeOH as mobile phase. The product 1-[(6,7-dimethoxy quinazolin-4-yl)imino]-1-oxo-1λ6-thiomorpholine-4-sulfonamide (SAPT1012SU006) was confirmed with LCMS (M+H) = 366; Yield (54%). 6) Synthesis of example compound with the number SAPTI012SU007 from intermediate IM3

IM3 (1 eq.) was dissolved with DMF (0.2M) in RBF, and NaH (1.5 eq.) was added dropwise at 0 ºC followed by sulfomyl chloride (1.5 eq.) portion wise into the reaction media under cold condition. The reaction was allowed to stir at 110 ºC for about 4h. After completion of the reaction the reaction mixture was further diluted with DCM and washed with water and brine solution. The combined organic layer was concentrated and purified by column chromatography with neutral alumina as stationary phase and DCM/MeOH as mobile phase. The product N-[4-(6,7-dimethoxyquinolin-4-yl)-1-oxo-1λ6-thiomorpholin-1-ylidene]urea (SAPT1012SU007) was confirmed with LCMS (M+H) = 465. 7) Synthesis of SAPTI012SU008 from intermediate IM3A

The intermediate IM3A was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3. The starting material was 6,7-dimethoxyquinolin-4-ol. The final compound SAPTI012SU008 was synthesised from intermediate IM3A by using NaOCN as reagent, the reaction procedure similar to that mentioned in the general procedure- 2. 8) Synthesis of SAPTI012SU009 from intermediate IM3B

IM3B was prepared similar to the general procedure described for the intermediate, IM3, where the starting material was the fluorinated compound, fluoro substituted quinazolin-4(3H)-one. The final compound SAPTI012SU009 was synthesised from intermediate IM3B by using NaOCN as reagent using the reaction procedure similar to that mentioned in the general procedure-2. 9) Synthesis of SAPTI012SU010 from intermediate IM3C

IM3C was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was 7-methyl-3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one. The final compound SAPTI012SU010 was synthesised from intermediate IM3C by using NaOCN as reagent, the reaction procedure similar to that mentioned in the general procedure-2. 10) Synthesis of SAPTI012SU011 from intermediate IM3D

I_M3D ^{SAPTI012SU011} IM3D was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was fluoro and methoxy substituted quinazolin- 4(3H)-one. The final compound SAPTI012SU011 was synthesised from intermediate IM3D by using NaOCN as reagent, the reaction procedure similar to that mentioned in the general procedure-2. 11) Synthesis of SAPTI012SU012 from intermediate IM3E

I_M3E SAPTI012SU012 IM3E was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was 8-methoxypyrido[3,4-d]pyrimidin-4(3H)- one. The final compound SAPTI012SU012 was synthesised from intermediate IM3E by using NaOCN as reagent according to the reaction procedure similar to that mentioned in the general procedure-2.

IM3F was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was 7-methoxyquinazolin-4(3H)-one. The final compound SAPTI012SU013 was synthesised from intermediate IM3F by using NaOCN as reagent according to the reaction procedure similar to that mentioned in the general procedure- 2. 13) Synthesis of SAPTI012SU014 from intermediate IM3G

IM3G was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was 5-methoxyquinazolin-4(3H)-one. The final compound SAPTI012SU014 was synthesised from intermediate IM3G by using NaOCN as reagent according to the reaction procedure similar to that mentioned in the general procedure- 2. 14) Synthesis of SAPTI012SU015 from intermediate IM3H

IM3H was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was 8-methoxycinnolin-4(3H)-one. The final compound SAPTI012SU015 was synthesised from intermediate IM3H by using NaOCN as reagent according to the reaction procedure similar to that mentioned in the general procedure- 2. 15) Synthesis of SAPTI012SU016 from intermediate IM3I

IM3I was prepared by a procedure similar to the general procedure-1 described for the intermediate, IM3, where the starting material was quinazolin-4(3H)-one. The final compound SAPTI012SU016 was synthesised from intermediate IM3I by using NaOCN as reagent according to the reaction procedure similar to that mentioned in the general procedure-2. 16) Synthesis of SAPTI012SU017 from intermediate IM3

3 equivalents of Boc-L-leucine were dissolved with DCM (0.2M) in RBF, followed by 3 equivalent of DCC were added at 0 ºC and the mixture were stirred over 30 min at same temperature followed by sulfoximine IM3 was also added at same temperature and raised the temperature to RT and stirred for 12h. After completion of the reaction the reaction mixture was further diluted with DCM and washed with water and brine solution. The combined organic layer was concentrated to get crude reaction mass. The expected product was identified in LCMS, and the crude was taken for further deprotection.

SAPTI012SU017 The crude reaction mass from previous reaction was dissolved in 4M dioxane HCl and the reaction mixtures was stirred for 1 hr at room temperature. After completion of the reaction the reaction mixture was further diluted with DCM and washed with water and NaHCO₃ solution. The combined organic layer was concentrated to get crude reaction mass. And the pure compound was isolated using column chromatography by using DCM/MeOH as mobile phase. The product SAPTI012SU017 was confirmed with LCMS and taken further for biological study. General procedure for incorporation of (L1)p and (L2)q linkers. The L1 linker is introduced by treating thiomorpholine or thiomorpholine sulfoximine with alkyl halides which is already attached with ring A at appropriate position. The L2 linker is introduced by treating amine or sulfoximine with alkyl halides or functionalized carboxylic acids or aldehydes which are already connected with zinc binding portion (ZBP). ENPP-1 Inhibition Assay Assay method: Human ENPP-1 at 3nM prepared in pH 7.4 was incubated with 5µM cGAMP substrate with the test samples prepared in buffer with pH 7.4 along with 40µM HSA. The reaction was incubated at RT for 3hs. Post incubation, the reaction was stopped by heating the contents at 95ºC for 10mins.10µl of the solution was added to 384-well plate to which 10µl of AMP Glo reagent-1 was added and incubated for 60mins at 25ºC. After the incubation, 20µl of AMP detection solution was added to each well with the enzyme reaction and incubated for 60 mins at 25ºC. The luminescence signal (RLU) was recorded using SpectraMax I3X plate reader. The luminescence signal is measured as a function of concentration of the inhibitor. If the inhibitor molecule is active, as the concentration of the inhibitor increases, the luminescence value (referred to as OD) decreases. % Inhibition is then calculated as % Inhibition = ((OD of Control – OD of sample)/OD of Control) x 100 In this disclosure, the IC50 value of an inhibitor molecule is measured as the concentration of inhibitor which inhibits growth of 50% of the human ENPP-1. A graph of inhibitor concentration on X-axis vs. percentage inhibition on Y-axis is drawn and the slope is measured as the IC50 value. Several inventive compounds are subjected to ENPP-1 inhibition assay to identify the IC50 values and/or % inhibition. The metabolic stability of some of these compounds has also been measured. The results of the ENPP-1 inhibition assay of several compounds are shown in Tables 1 and Table 2. From the data presented in Table 1, certain lead molecules of the present invention inhibit function of phosphodiesterase enzyme, such as ENPP-1, with promising potency for treatment of diseases such as cancer. Table 1 further contains the ¹H-NMR and/or LCMS characterization data for the examples of compounds (S. Nos .1 to 17) of the invention. TABLE 1: ENPP-1 inhibition IC50 values of intermediates and compounds of the invention

Additionally, Table 2 contains the activity values for compounds having S. No.7 to S. No 17. TABLE 2: ENPP-1 inhibition IC50 values of compounds having S. No.7 to S. No.17

In one aspect, the present invention provides a method of treating cancer in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound or salt thereof of the present invention. In another aspect, the present invention provides method of treating a disease or disorder associated with ENPP-1 enzyme in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound or salt thereof of the present invention. A compound or salt thereof detailed herein, or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical or transdermal delivery form. In another embodiment of the invention, there is provided a use of a compound of formula 1 in the manufacture of a medicament for use in the treatment of cancer. In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in formula 1. In one embodiment, the pharmaceutical formulation containing a compound of formula 1 or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nano-particle formulation. In one embodiment, the pharmaceutical formulation containing a compound of formula 1 or a salt thereof is a formulation adapted for oral, rectal, topical, or intravenous formulation, wherein the pharmaceutical formulation optionally comprises any one or more of a pharmaceutically acceptable carrier, adjuvant, or vehicle. A compound as represented by formula 1 or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules, cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. In one embodiment, the compounds of formula 1 are formulated for oral administration, and can be administered as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir. In one embodiment, the compounds of formula 1 are formulated for parenteral administration and can be administered as an aqueous or oily suspension injectable, or a nasal drop. Upon preparation of a parenteral formulation with a compound of formula 1, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers, and the like may be arbitrarily used. For instance, for oral administration in the form of a tablet or capsule, the compound of formula 1 can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound of formula 1 to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present. Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch , gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated , for example, by preparing a powder mixture, granulating, or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound , suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin , a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing though a screen. As an alternative to granulating , the powder mixture can be run though the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared though the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added. Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulations of compounds of formula 1 can also be prepared to prolong or sustain the release of the compound, as for example by coating or embedding particulate material in polymers, wax or the like. The compounds of formula 1 or salts, solvates, or hydrates thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of formula 1 or salts, solvates, or hydrates thereof, may also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropyl-methacrylamidephenol. polyhydroxyethylaspartamide-phenol, or poly- ethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period. For example, the compounds of formula 1 may be delivered from a patch by iontophoresis as described in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas. Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation though the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators. Pharmaceutical formulations adapted for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. In addition to the ingredients particularly mentioned above, the formulations described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. A therapeutically effective amount of a compound of formula 1 will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation , and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. An effective amount of a salt or hydrate thereof may be determined as a proportion of the effective amount of the compound of Formula 1 or salts, solvates or hydrates thereof per se. Embodiments of the present invention provide administration of a compound of formula 1 to a healthy or a patient with cancer disease, either as a single agent or in combination with (a) another agent that is effective in cancer disease (b) another agent that improves immune response and robustness, or (c) another agent that reduces inflammation and/or pain. Even though the foregoing invention has been described in some detail by way of illustration and examples for purposes of clarity of understanding, it is readily apparent to those skilled in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. The preceding merely illustrates the principles of the invention. All the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art and are to be construed as being without limitation to such specifically recited examples and conditions. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein.

Claims

We Claim: 1. A compound of formula 1 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or isomer thereof,

f^ormula 1 wherein the formula 1 comprises portion A, portion B, portion C and zinc-binding portion (ZBP) with portions A and B together constituting tail part of the formula 1, wherein, the portion A is a six-membered aryl or heteroaryl, which is optionally substituted with (R²)n groups and where X1, X2 and X3 is CH, N, CR' with the proviso that not more than two of X1, X₂ and X3 is simultaneously N, wherein, R² is selected from a group consisting of R', F, Cl, Br, I, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH₂Ar and where Ar = aryl, substituted aryl, heteroaryl, or substituted hetero aryl and n = 0, 1,2 or 3; the portion B is C6 aryl or 5-6 membered heteroaryl, optionally substituted with (R¹)n groups, wherein the portion B is fused to the portion A where the two shared atoms between the portions B and A come from a pair of carbon atoms or from a pair of atoms, where one of the atoms is nitrogen and the other is carbon; wherein, R¹ is selected from a group consisting of R', F, Cl, Br, I, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF₃, CHF₂, CH₂F, OCF₃, SCF₃ and CH₂Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH2Ar and where Ar = aryl, substituted aryl, heteroaryl, or substituted hetero aryl and n = 0,1,2 or 3; the portion C constitutes core part of the formula 1 and is an unsubstituted or a symmetrically substituted 4 or 6 or 8 membered saturated cyclic ring having as part of the ring G1 and G2 fragments, where G1 and G2 fragments are selected from the group consisting of

with the proviso that the G1 and G2 fragments are not the same simultaneously, where the nitrogen atom of G2 fragment is bonded to a zinc binding portion (ZBP) through a linker (L2)q and the nitrogen atom of G1 fragment is bonded to the carbon atom located between the bridge head atom and X3 atom of the portion A through a linker (L1)p, where L1 is -CH₂- when p = 0,1,2 or 3 and where L₂ is -CH₂- when q = 0, 1,

2 or 3 with the proviso that when boronic acid type ZBP is present, the value of q is equal to 2 or

3. the Zinc binding portion (ZBP) is selected from a group consisting of

^, where, R⁵, R⁶, R⁸ are alkyl or aryl group and R7 is H, alkyl or aryl group. 2. The compound as claimed in Claim 1, wherein the compound is selected from a group consisting of N , e 3. The compound as claimed in Claim 1, wherein the compound inhibits function of phosphodiesterase enzyme.

4. The compound as claimed in Claim 3, wherein the phosphodiesterase enzyme is selected from a group consisting of ENPP-1, cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endoculeases, and small-molecule phosphodiesterases.

5. A pharmaceutical composition comprising a compound as claimed in Claim 1 and a pharmaceutically acceptable carrier or excipient and/or diluent.

6. A method of treating a glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumours, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), other solid tumours and mycobacterial diseases which comprises administering to a human in need thereof, a pharmaceutical composition according to Claim 5.