WO2024028727A1 - Nouveaux inhibiteurs d'ectonucléotide pyrophosphatase/phosphodiestérase 1 (enpp-1) et leurs utilisations - Google Patents

Nouveaux inhibiteurs d'ectonucléotide pyrophosphatase/phosphodiestérase 1 (enpp-1) et leurs utilisations Download PDF

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WO2024028727A1
WO2024028727A1 PCT/IB2023/057701 IB2023057701W WO2024028727A1 WO 2024028727 A1 WO2024028727 A1 WO 2024028727A1 IB 2023057701 W IB2023057701 W IB 2023057701W WO 2024028727 A1 WO2024028727 A1 WO 2024028727A1
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Ganapathy Bhotla Venkata RAMANARAYANAN
Vadivelu Saravanan
Perumal SARAVANAN
Unni AMBILI
Bharti NIVEDITA
Kulkarni NAGARAJ
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Sravathi Ai Technology Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65128—Six-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • NOVEL ECTONUCLEOTIDE PYROPHOSPHATASE / PHOSPHODIESTERASE 1 (ENPP-1) INHIBITORS AND USES THEREOF DESCRIPTION Field of the invention The present disclosure relates to novel compounds of Formula I, 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-tumor immune responses of the human body.
  • the cGAS- STING pathway has a promising role in cancer immunotherapy as it is important in interferon (IFN) production and T cell priming. 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, 46(6), 446-460 (2021), it is pointed out that in addition to the crucial IFN signaling, cGAS-STING is much involved in autophagy.
  • IFN interferon
  • 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.
  • phosphodiesterase has been linked with viral infection and its inhibition has been correlated with a reduction in viral replication.
  • the class of phosphodiesterase further comprises cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, restriction endonucleases, and small- molecule phosphodiesterases.
  • Literature J Biol Chem 280(24), 22962(2005) and Biochemistry Moscow 75, 1–6 (2010) supports the molecular functions with chemical similarity between phosphodiesterase, nuclease (DNases, RNases), nucleotidase, phosphatase.
  • phosphodiesterase is linked with a bacterial infection, e.g., an infection from a Gram- negative bacterium or a Gram-positive bacterium.
  • the bacterium is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
  • Inhibitors which have high specificity in inhibiting a particular phosphodiesterase, for example ENPP-1, are much needed in the industry.
  • 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 (domain is also referred as part), as exemplified in formulae II-X and c) some of these structures have linking groups (linkers) between the core and zinc binding part 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 formulae II-V are not exactly similar, they contain tail, core, and zinc binding parts.
  • the Rc is defined as hydrogen, alkyl, substituted cycloalkyl, substituted alkylene and substituted heteroaryl.
  • Patent publication WO2020160333A1 discloses inhibitor structure conforming to the Formula III, where the presence of an additional linker L 1 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.
  • linker L1 is explored as alkyl, alkenylene, alkynylene, arylene, aralkylene and linking moieties containing functional group including without limitation: amido, ureylene, imide, epoxy, epithio, epidioxy, cabonyldioxy, alkyldioxy, epoxyimino, epimino, and carbonyl.
  • WO2019051269A1 discloses a structure as depicted in Formula-IV, wherein linker between core and X was termed as L, which can be a (C1- 6)alkyl linker or a substituted (C1-6)alkyl linker, optionally substituted with a heteroatom or linking functional group, such as an ester (-CO2-), amido (-CONH), carbamate (-OCONH), ether (-O-), 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 part represented as X was based on phosphoric acid or sulfonamide or ureylene moieties.
  • Patent publication, WO2021225969A1 discloses a structure as depicted in Figure-V, where L is a bond, -O-, -C(O)-, -NR6c-, or -OCR7c-*, wherein * represents the point of attachment containing zinc binding part.
  • W in Figure-V contains both the core group and zinc binding part connected through the linker L.
  • the core group is an aryl or heteroaryl moiety.
  • the zinc binding part is a sulfoximine moiety with only a hydrogen atom as the substituent on the nitrogen atom of the sulfoximine group.
  • the R6c, R7c are each independently hydrogen or C1-3 alkyl wherein a1 and a2 are independently 0, 1, 2 or 3.
  • Patent publication, WO2021226136A1 discloses a structure akin to the one depicted in Formula-IV for ENPP-1 inhibition.
  • Patent publication, WO2019046778A1 discloses a structure as depicted in Formula-VI, where there are two linkers named L and L1 and with a sulfonamide type end group for ENPP-1 inhibition.
  • L is a bond or - CR10R11-; and L1 is a bond or -CR13R14-.
  • R7 is hydrogen, -CN, substituted alkoxy, substituted ester, substituted carbonyl, substituted amide, substituted sulfoxide, substituted sulfone, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • R8 and R9 are independently hydrogen, deuterium, halogen, -CN, substituted alkoxy, -NO2, substituted amino, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl.
  • Formula-VI Formula-VII (WO2019046778A1) (US20190282703A1)
  • Patent publication, US20190282703A1 discloses a structure as depicted in Formula-VII, where there is single linker, L as specified and a sulfonamide end group and a monocyclic tail group.
  • L is defined as -(CR3R4)n— where X is —N— or —CH—. R3 and R4 on the same carbon are taken together to form an oxo.
  • Patent publication, WO2021158829A1 discloses a structure as depicted in Formula VIII 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.
  • R4, R5 and R6 are independently selected from the group consisting of hydrogen and lower alkyl; or an isomer, hydrate, solvate, polymorph, tautomer or a pharmaceutically acceptable salt thereof.
  • Formula VIII Patent publication, WO2020140001A1 discloses quinazoline based structure as depicted in Formulae-IX that inhibit ENPP-1 enzymatic activity and are therefore useful for the treatment of diseases.
  • Formulae IX (WO2020140001A1)
  • Other related prior art references which disclose certain compounds as ENPP-1 inhibitors of structures not falling in the tail-core-zinc binding part description given in figures II-IX 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).
  • Patent publications, WO2019023635A1, WO2021158829A1 mentions that ENPP-l is an attractive druggable target for the development of novel anticancer, cardiovascular, diabetes, obesity and anti-fibrotic therapeutics.
  • Patent publications, WO2022056068A1, WO2019046778A1 mentions that modulators of ENPP-1 may also be useful against bacteria and fungi.
  • WO2022125613A1 certain phosphonates have been shown 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 can be classified as tail-core-zinc binding domain and may be represented as Formula X.
  • ENPP-1 inhibitors 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.
  • 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, chondrosar
  • the present disclosure relates to compounds of Formula I, 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.
  • the invention discloses a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isomer thereof.
  • the compound represented by formula I 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, R ases, restriction endonucleases, and small-molecule phosphodiesterases.
  • the isomer of compound I is selected from a group consisting of stereoisomer of the Formula I and positional isomer arising from linkage of sulfoximine-type fragment of the formula I.
  • the stereoisomer is selected from a group consisting of (R) isomer of the formula I, (S) isomer of the Formula I and a combination thereof.
  • the positional isomer of Formula I is selected from a group consisting of a molecule where the core and the tail parts of the Formula I are bonded to the sulfoximine-type group at the sulphur and the nitrogen atoms respectively and a molecule where the core and the tail parts of the Formula I are bonded to the sulfoximine-type group at the nitrogen and the sulphur atoms respectively.
  • 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.
  • phosphodiesterase such as ENPP-1
  • 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.
  • 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.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8- tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • 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 anthryl).
  • a single ring e.g., phenyl
  • multiple condensed (fused) rings e.g., naphthyl or anthryl.
  • 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 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.
  • Preferred alkenyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 2 M alkenyl”), having 2 to 8 carbon atoms (a “C 2 - C 8 alkenyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkenyl”).
  • alkenyl examples 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.
  • Preferred alkylene groups are those having 1 to 6 carbon atoms (a “C 1 -C 6 alkylene”), 1 to 5 carbon atoms (a “C 1 -C 5 alkylene”), 1 to 4 carbon atoms (a “C 1 -C 4 alkylene”) or 1 to 3 carbon atoms (a “C 1 - C 3 alkylene”).
  • alkylene include, but are not limited to, groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), butylene (— CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkynyl 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., C 2 -C 10 means two to ten carbon atoms).
  • Preferred alkynyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 2 M alkynyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkynyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkynyl”).
  • alkynyl examples 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.
  • 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 three (“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 (—CF 3 ).
  • 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 (—OCF 3 ).
  • 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 sulfur, 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.
  • 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, o
  • 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, sulfur 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.
  • 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.
  • 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.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • 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.
  • “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • 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.
  • beneficial or desired results include shrinking 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.
  • beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation.
  • “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.
  • an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • the term “individual” is a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
  • the individual is human.
  • the individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden.
  • the individual is at an early stage of a proliferative disease (such as cancer).
  • the individual is at an advanced stage of a proliferative disease (such as an advanced cancer).
  • sarcomas and carcinomas are cancer that may be treated as solid tumours whereas leukemia are the cancer that may be treated as liquid tumours.
  • Present invention may treat different types of cancers that include, but are not limited to, adrenocortical cancer, bladder cancer, brain tumours, 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, ovarian cancer, sarcoma, skin cancer and thyroid cancer.
  • adrenocortical cancer bladder cancer, brain tumours, 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, 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.
  • a basal- like TNBC, an immunomodulatory TNBC, mesenchymal TNBC (mesenchymal or mesenchymal stem-like) or a luminal androgen receptor TNBC are triple negative breast.
  • prostate adenocarcinoma is prostate cancer.
  • 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.
  • ENPP-1 belongs to the class of Phosphodiesterases.
  • Phosphodiesterases comprise a class of enzymes that catalyze the hydrolysis of a phosphodiester bond.
  • phosphodiesterase has been linked with viral infection and its inhibition has been correlated with a reduction in viral replication.
  • the class of phosphodiesterases further comprises cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and small- molecule phosphodiesterases.
  • phosphodiesterase is linked with a bacterial infection, e.g., an infection from a Gram-negative bacterium or a Gram-positive bacterium.
  • the bacterium is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae.
  • 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 in-silico studies. The resolution of this protein was reported to be 2.90 ⁇ .
  • 6WEV is the target considered for the execution of in-silico 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.
  • ENPP-1 inhibitors are categorized as zinc binding head or group, core, and tail part. Out of the three parts, the presence of zinc binding head plays vital role in the ENPP-1 inhibition as this group co-ordinates with the zinc ion present in catalytic site of enzyme. The core and tail parts anchor the compound tightly in the binding pocket. The inhibitor design was initiated by considering these 3 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, F 3 21, 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 head 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 I.
  • the present invention discloses a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or isomer thereof.
  • the zinc-binding part is formed from a group of structures consisting of Sulfoximine-type fragment
  • 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 209, 112885 (2021).
  • sulfoximine-type fragments of interest in this disclosure are given immediately below as sulfoximines and sulfondiimines.
  • x S u S fu ol xfo i m xi im n e in ses SulfondiiminesS S ulfondiimines 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 through a double bond and is isosteric with O atom present in sulfoximine.
  • the R1x has the same meaning as the R2 groups of the Figure I, R2x and R3x have the same meaning as core and tail parts of the Figure I respectively.
  • None of the hitherto reported ENPP-1 inhibitors have the sulfoximine-type fragment positioned between core and tail parts of the inhibitor molecules.
  • the R2 group of the sulfoximine-type fragment is selected from the list of radicals consisting of methyl, cyclopropyl, cyclopropyl methyl, ethyl, propyl, isopropyl, phenyl, and benzyl.
  • the tail part of Figure I is bonded to the nitrogen atom of the sulfoximine-type fragment, where the nitrogen is bonded to the sulphur atom through a double bond and the portion A is bonded to the nitrogen atom of the sulfoximine-type fragment.
  • the tail part comprising portions A & B which contain X1, X2, X3, R3 and R4 groups together is selected from the group consisting of
  • the number of ring substituents R3 and R4 on the portions A and B respectively may be 0, 1 or more. When more than one ring substituent is present, such ring substituents may be the same or different.
  • one end of the core part is bonded to the ZBG and the other end of the core part shown by wavy lines is bonded to sulfoximine-type fragment, particularly the sulfur atom of the sulfoximine-type fragment.
  • the label, “Linker” is the sulfoximine- type fragment and the linkage of the core to the tail part through the nitrogen atom bonded to the sulphur is not shown in the structures immediately given below.
  • the core part along with the sulfoximine-type fragment is selected from the group consisting of Isomer of Formula I Stereoisomers and certain constitutional isomers Stereoisomers
  • the compounds corresponding to Formula I exhibit optical activity due to presence of asymmetric sulphur atom resulting in two non-superimposable mirror-image forms.
  • the two forms of such compounds are known as enantiomers and classified as levorotary (l-isomer) or dextrorotary (d-isomer) depending on the rotation of plane-polarized light in a left (-) or right (+) -handed manner, respectively.
  • Stereoisomer of figure I is selected from a group consisting of (R) isomer of the formula I, (S) isomer of the Formula I and a combination thereof.
  • both isomers have different activity or when only one of the isomer is showing activity and other is not showing any activity or when one is showing positive and other is showing negative activity, the chiral separation of such racemic drugs in pharmaceutical industries is important in order to remove unwanted isomer from composition and to achieve better therapeutic activity. If racemic is showing same activity as individual isomers, then no separation is required.
  • the possible enantiomers of the invention are illustrated through an example below.
  • the structure P2 represents the attachment of N-substituted sufoximine linker to the core part via N atom of the sulfoximine linker and to the tail part via S atom of the sulfoximine linker.
  • e P1 P2 Positional Isomers Synthesis of compounds of Formula I General Scheme of Synthesis of inventive Examples of the invention represented by Formula I
  • the retrosynthetic strategy for the preparation of compounds represented by Formula I is to prepare aryl sulfoximine starting from a suitably substituted aryl alkyl sulfide through oxidation of the sulfide group using phenyl iodoacetate in the presence of ammonium carbamate.
  • the preferred alkyl substituent is methyl.
  • the aryl methyl sulfoximine molecule is then coupled to a halo compound in the presence of base to form the tail-sulfoximine-core structure which is then functionalized to have a zinc binding polar group.
  • the products of the present invention are generally combination of (R) and (S) enantiomers or racemates and optionally resolved into the enantiomers.
  • Ge neral Procedure Substituted thioanisoles were treated with diacetoxyiodobenzene (PhI(OAc)2 and ammonium carbamate (NH4(CO2NH2) for the synthesis of sulfoximine.
  • Example 1 Synthesis of ⁇ 4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]- phenyl ⁇ phosphonic acid (SAPTI012S001)
  • Step-1 4-bromothioanisole (1.0 equivalent) was dissolved in MeOH (0.2M) in RBF, then Diacetoxyiodobenzene (PhI(OAc)2) (3.0 equivalent), followed by Ammonium carbamate (NH4(CO2NH2) (4.0 equivalent) were added portion wise under N2 atmosphere. After 2 hours again repeated the addition of same amount of (PhI(OAc)2) and (NH4(CO2NH2) to get maximum yield.
  • Step-2 1-bromo-4-(S-methanesulfonimidoyl) benzene (1.0 equivalent) was dissolved in DMF (0.2M) in RBF and cooled to 0 °C with ice bath. Then NaH (2.0 equivalent) followed by 4- chloro-6,7-dimethoxyquinazoline (1.1 equivalent) were added under N2 atmosphere. Temperature of reaction mixture slowly was raised to 100 °C and stirred over 8hr. After completion of reaction, mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified with column chromatography by using 30% of EtOAc in hexane as eluent.
  • Step-3 4- ⁇ [(4-bromophenyl)(methyl)oxo- ⁇ 6-sulfanylidene]amino ⁇ -6,7- dimethoxyquinazoline (1.0 equivalent), diethylphosphite (2.0 equivalent), DIPEA (1.5 equivalent), Pd(OAc)2 (5 mol%) and XPhos (10 mol%) were transferred to seal tube and dissolved with ethanol (0.2M).
  • the reaction mixture was de-gassed under N2 atmosphere and stirred at 80 °C over 16 hr. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step-1 3-bromothioanisole (1.0 equivalent) was dissolved in MeOH (0.2M) in RBF, then Diacetoxyiodobenzene (PhI(OAc)2) (3.0 equivalent), followed by Ammonium carbamate (NH4(CO2NH2) (4.0 equivalent) were added portion wise under N2 atmosphere. After 2 hours again repeated the addition of same amount of (PhI(OAc)2) and (NH4(CO2NH2) to get maximum yield. After completion of reaction, methanol was removed under reduced pressure, and the reaction mixture dissolved in EtOAc and washed with water and brine solution. The organic layer was concentrated and purified with column chromatography by using 10-15% of EtOAc in hexane as eluent.
  • Step-3 4- ⁇ [(3-bromophenyl)(methyl)oxo- ⁇ 6-sulfanylidene]amino ⁇ -6,7- dimethoxyquinazoline (1.0 equivalent), diethylphosphite (2.0 equivalent), DIPEA (1.5 equivalent), Pd(OAc)2 (5 mol%) and XPhos (10 mol%) were transferred to seal tube and dissolved with ethanol (0.2M).
  • the reaction mixture was de-gassed under N2 atmosphere and stirred at 80 °C over 16 hr. After completion of reaction, the reaction mixture was quenched with water and extracted with ethylacetate.
  • Step-4 diethyl(3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl) phosphonate (1.0 equivalent) was dissolved in 0.2M dry CHCl3 in RBF followed by added TMSBr (4.0 equivalent) at 0°C over 10 min and the reaction mass stirred at room temperature over 4 hr. After the completion of the reaction, diluted with methanol and concentrated under reduced pressure followed by recrystallization with solvent mixture of MeOH, DCM, and acetone.
  • Example 3 Synthesis of common intermediate (SAPTI012S003/IM4) 4-[N-(6,7-dimethoxy quinazoline-4-)-S-methanesulfonimidoyl]aniline
  • Step-1 4-(methylsulfanyl)aniline (1.0 equivalent) in DCM solution was treated with N-ethyl, N,N-diisopropylamine (2.0 equivalent) at 0 °C followed by Boc-Anhydride (1.2 equivalent) was added at same temperature as dropwise. Temperature was raised slowly to room temperature and reaction mixture was stirred over 12hr at RT. After completion of 4- (methylsulfanyl)aniline, the reaction mass was further diluted with DCM and washed with water and brine solution.
  • Step-2 tert-butyl [4-(methylsulfanyl)phenyl]carbamate (1.0 equivalent) was dissolved in MeOH (0.2M) in RBF, then Diacetoxyiodobenzene (PhI(OAc)2) (3.0 equivalent), followed by Ammonium carbamate (NH4(CO2NH2) (4.0 equivalent) were added portion wise under N2 atmosphere.
  • Step-3 tert-butyl [4-(S-methanesulfonimidoyl)phenyl]carbamate (1.0 equivalent) was dissolved in DMF (0.2M) in RBF and cooled to 0 °C with ice bath. Then NaH (2.0 equivalent) followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 equivalent) were added under N 2 atmosphere, and the temperature of reaction mixture slowly raised to 100 °C and stirred over 8hr. After completion of reaction, mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified with column chromatography by using 30% of EtOAc in hexane as eluent.
  • Example 4 Synthesis of N- ⁇ 4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl] phenyl ⁇ sulfuric diamide (SAPTI012S003) (4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfon imidoyl]aniline) (1.0 equivalent) was dissolved in dry THF (0.2M) in RBF, followed by added TEA (2.0 equivalent) and chlorosulfonamide (1.5 equivalent) under N2 atmosphere and the reaction mixture was stirred over 16hr at room temperature.
  • SAPTI012S003 4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfon imidoyl]aniline
  • Example 5 Synthesis of 1-(3-(N-(6,7-dimethoxyquinazoline-4-yl)-S-methylsulfonimidoyl)- phenyl urea (SAPTI012S004)
  • Step-1 (4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]aniline) (1.0 equivalent) in DCM solution was treated with Benzoyl isocyanate (1.5 equivalent) at room temperature over 12hr. After completion of reaction, the mass was further diluted with DCM and washed with water and brine solution. The organic layer concentrated under reduced pressure and purified with column chromatography by using 10-15% of DCM in MeOH as eluent.
  • Example 6 Synthetic procedure for the synthesis of SAPTI012S005
  • the previous intermediate SAPTI012S002/IM1 (1.0 eq.) was dissolved in dry 1,4-dioxane (0.2M), then B2(Pin)2 (1.4 eq.) KOAc (3.5 eq.), followed by PdCl2(dppf) complex (5 mol%) were added and the reaction mixture was purged with N2 for 10 mins, later slowly raise the temperature to 100 °C, and stirred at same temperature for 8 hours.
  • the reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%).
  • Example 12 Synthetic procedure for the synthesis of SAPTI012S011 Ph S tep-1: The previous intermediate SAPTI012S010/IM2 (1.0 eq.) in DCM solution was treated with Benzyl isocyanate (1.5 eq.) at room temperature for 12 hours. After completion of reaction, the mass was further diluted with DCM and washed with water and brine solution. The combined organic layer was concentrated under reduced pressure and the crude was purified with column chromatography by using DCM & MeOH as eluent (10-15%). The product SAPTI012S011/IM1 was confirmed with LCMS; yield-57%.
  • Example 13 Synthetic procedure for the synthesis of SAPTI012S012 Step-1: t-butyl [3-(S-methanesulfonimidoyl)phenyl]methylcarbamate (1.0 eq.) was dissolved in toluene (0.2M) in RBF, then DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.) followed by 4-chloro- 6,7-dimethoxyquinazoline (1.5 eq.) were added and the solution was purged with N2 for 10 mins, then Pd(OAc)2 (5 mol%) was added and slowly raise the temperature to 100 °C. The reaction mixture stirred under N2 atmosphere at 100 °C for 6 hours.
  • reaction mixture was quenched with water and extracted with DCM multiple time, the combined organic layer was washed with water and brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • reaction mixture was quenched with water and extracted with DCM multiple times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • the product SAPTI012S013 was confirmed with LCMS and 1H NMR; yield: 20%.
  • Example 16 Synthetic procedure for the synthesis of SAPTI012S015 Step-1: tert-butyl ⁇ [3-(S-methanesulfonimidoyl)phenyl]methyl ⁇ carbamate (1.0 eq.) was dissolved in toluene (0.2M) in RBF, then DPE Phos (7.5 mol%), Cs 2 CO 3 (1.4 eq.) followed by 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.) were added and the solution was purged with N2 for 10 mins, then Pd(OAc)2 (5 mol%) was added and slowly raise the temperature to 100 °C. The reaction mixture stirred under N2 atmosphere at 100 °C for 6 hours.
  • reaction mixture was quenched with water and extracted with DCM multiple time, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • reaction mixture evaporated to remove isopropyl alcohol from the reaction mixture.
  • Resulting crude was diluted with water and extracted with DCM multiple times, the combined organic layer was concentrated to get crude mixture.
  • the crude was purified with silica gel column chromatography by using DCM & MeOH as eluent (0-10%).
  • reaction mixture diluted with water and extracted with DCM multiple times. Now aqueous layer was acidified with 1 N HCl till aqueous layer become acidic resulting solution extracted with DCM and this organic layer was collected and concentrated to get crude mixture, and the Product was purified with silica gel column chromatography by using DCM & MeOH as eluent (0- 10%).
  • Step-3 The SAPTI012S023 (1.0 eq.) was dissolved in water and AcOH (1:1) followed by sodium cyanate (1.0 eq.) was added portion wise at 0 °C and reaction was stirred at RT for 2 hours. After the completion of reaction, the reaction mixture was quenched with water and extracted with DCM multiple time, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure to get crude and the crude was and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • reaction mixture was evaporated to dryness, and purified with reversed phase C18 column chromatography by using 0.1% phosphoric acid in water and MeOH as eluent (10-15%).
  • the product SAPTI012S027 was confirmed with 1H NMR and LCMS; yield-15%.
  • reaction mixture was quenched with water and extracted with DCM multiple time, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • Step-3 The HCl salt of SAPTI012S032/IM2 (1.0 eq.) was dissolved in water and AcOH (1:1) followed by sodium cyanate (1 eq.) was added portion wise at 0 °C and reaction was stirred at RT for 2 hours.
  • reaction mixture was quenched with water and extracted with DCM multiple time, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • Step-2 The intermediate SAPTI012S033/IM1 (1.0 eq.) was dissolved in 1,4-Dioxane (0.2M) in RBF and cooled to 0 °C with ice bath. Then Dioxane HCl (10 vol.) was added dropwise and stirred for over 5 hours at RT. After completion of reaction, the reaction mixture was evaporated to dryness, washed with ether. The HCl salt of SAPTI012S033/IM2 was confirmed with LCMS and used without further purification; yield-72%.
  • Step-3 The HCl salt of SAPTI012S033/IM2 (1.0 eq.) was dissolved in water and AcOH (1:1) followed by sodium cyanate (1 eq.) was added portion wise at 0 °C and reaction was stirred at RT for 2 hours. After the completion of reaction, the reaction mixture was quenched with water and extracted with DCM multiple times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure and purified by reversed phase column chromatography by using water and MeOH as an eluent (20-30%).
  • reaction mixture was quenched with water and extracted with DCM multiple times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulphate and evaporated under reduced pressure, followed by the crude was purified wit reverse phase column chromatography by using water and MeOH as an eluent (20-30%).
  • reaction mixture was stirred under N2 atmosphere at 100 °C for 16 hours. After completion of reaction, the reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%). The product SAPTI012S036/IM1 was confirmed with LCMS; yield 65%.
  • reaction mixture stirred under N2 atmosphere at 100 °C for 16 hours. After completion of reaction, the reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%). The product SAPTI012S037/IM1 was confirmed with LCMS; yield 43%.
  • reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%).
  • the product SAPTI012S038/IM1 was confirmed with LCMS; yield 34%.
  • reaction mixture was stirred under N2 atmosphere at 100 °C for 16 hours. After completion of reaction, the reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%). The product SAPTI012S039/IM1 was confirmed with LCMS; yield 76%.
  • reaction mixture stirred under N2 atmosphere at 100 °C for 16 hours. After completion of reaction, the reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%). The product SAPTI012S040/IM1 was confirmed with LCMS; yield 34%.
  • reaction mixture stirred under N2 atmosphere at 100 °C for 16 hours. After completion of reaction, the reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%). The product SAPTI012S041/IM1 was confirmed with LCMS; yield 92%.
  • Step-1 2-bromo-1-fluoro-4-(S-methanesulfonimidoyl)benzene (1.0 eq.) was dissolved in toluene (0.2M) in RBF, then DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.) followed by 4-chloro- 6,7-dimethoxyquinazoline (1.5 eq.) were added and the solution was purged with N2 for 10 mins, then Pd(OAc)2 (5 mol%) was added and temperature was raised slowly to 100 °C. The reaction mixture was stirred under N2 atmosphere at 100 °C for 16 hours.
  • reaction mixture was filtered through a pad of celite, and filtrate was evaporated and purified with silica gel column chromatography by using DCM & MeOH as eluent (0-5%).
  • the product SAPTI012S043/IM1 was confirmed with LCMS; yield 31%.
  • Optical resolution of mixtures of (R) and (S) enantiomers of this invention Mixtures of (R) and (S) enantiomers/racemates of this invention are separated into individual enantiomers by using analytical or/and preparative chiral chromatography (HPLC). The compound of Example 7 was subjected to chiral separation and their activity values are given in Table 3.
  • ENPP-1 Inhibition Assay Assay method Human ENPP-1 at 3nM prepared in pH 7.4 was incubated with 5 ⁇ M cGAMP substrate with the test samples prepared in buffer with pH 7.4 along with 40 ⁇ M HSA. The reaction was incubated at RT for 3hrs.
  • the reaction was stopped by heating the contents at 95oC for 10mins.10 ⁇ l of the solution was added to 384-well plate to which 10 ⁇ l of AMP Glo reagent-1 was added and incubated for 60mins at 25oC. After the incubation, 20 ⁇ l 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 ((OD of Control – OD of sample)/OD of Control) x 100
  • 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.
  • 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 Table 1.
  • the present invention provides 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.
  • 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.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • SAPTI012S006-E1 and SAPTI012S006-E2 refer to the two enantiomers of SAPTI012S006.
  • the enantiomers are separated by chiral HPLC.
  • the enantiomers are yet to be assigned the Cahn Ingold Prelog configurations (R or S).
  • Table 3 ENPP-1 inhibition IC50 values of enantiomers of SAPTI012S006
  • a use of a compound of Formula I in the manufacture of a medicament for use in the treatment of cancer.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formula I.
  • the pharmaceutical formulation containing a compound of Formula I or a salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • the pharmaceutical formulation containing a compound of Formula I 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 I 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.
  • suitable carriers 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.
  • the compounds of Formula I 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.
  • the compounds of Formula I are formulated for parenteral administration and can be administered as an aqueous or oily suspension injectable, or a nasal drop.
  • a parenteral formulation with a compound of Formula I Upon preparation of a parenteral formulation with a compound of Formula I, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used.
  • the compound of Formula I 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 I 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 colouring agents 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.
  • suitable binders, lubricants, disintegrating agents and colouring 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 alginate, 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 through a screen.
  • the powder mixture can be run through 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 flavoured aqueous solution, while elixirs are prepared through 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, flavour additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulations of compounds of Formula I 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 I 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, stearyl amine or phosphatidylcholines.
  • the compounds of Formula I or salts, solvates or hydrates thereof may also be delivered by the use of 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, pyran copolymer, polyhydroxypropyl-methacrylamidephenol. polyhydroxyethylaspartamide-phenol, or poly- ethyleneoxidepolylysine substituted with palmitoyl residues.
  • 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.
  • compositions 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.
  • the compounds of Formula I 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.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • 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 through 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.
  • compositions 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.
  • sterile liquid carrier for example water for injections
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • 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 I 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 3administration, 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 I or salts, solvates or hydrates thereof per se.
  • Embodiments of the present invention provide administration of a compound of Formula I 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau type d'inhibiteurs d'ENPP-1 hautement puissants pour le traitement de diverses maladies, en particulier le cancer. Ces inhibiteurs selon l'invention sont à petites molécules. L'une des nouvelles caractéristiques structurales est l'incorporation d'une fraction de type sulfoximine qui est positionnée entre les parties queue et noyau. L'invention concerne également une méthode de traitement, des compositions pharmaceutiques et leur utilisation.
PCT/IB2023/057701 2022-08-01 2023-07-28 Nouveaux inhibiteurs d'ectonucléotide pyrophosphatase/phosphodiestérase 1 (enpp-1) et leurs utilisations WO2024028727A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019051269A1 (fr) * 2017-09-08 2019-03-14 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs d'enpp1 et leur utilisation pour le traitement du cancer
WO2020160333A1 (fr) * 2019-02-01 2020-08-06 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs d'enpp1 et méthodes de modulation de réponse immunitaire
WO2021225969A1 (fr) * 2020-05-04 2021-11-11 Volastra Therapeutics, Inc. Inhibiteurs imino sulfanone de l'enpp1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019051269A1 (fr) * 2017-09-08 2019-03-14 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs d'enpp1 et leur utilisation pour le traitement du cancer
WO2020160333A1 (fr) * 2019-02-01 2020-08-06 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs d'enpp1 et méthodes de modulation de réponse immunitaire
WO2021225969A1 (fr) * 2020-05-04 2021-11-11 Volastra Therapeutics, Inc. Inhibiteurs imino sulfanone de l'enpp1

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