Novel ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP-1) inhibitors and uses thereof

Abstract

The present invention discloses a novel type of highly active ENPP-1 inhibitor for treating various diseases, particularly cancer. These inhibitors of the present invention are small molecules. One of the novel structural features is the incorporation of a sulfoximine-type moiety located between the tail and core moieties. Methods of treatment, pharmaceutical compositions, and uses thereof are also disclosed.

Description

[Technical Field]

[0001] The present disclosure relates to novel compounds of formula I that inhibit the ENPP-1 protein and thus have potential use in immunotherapy for the treatment of disease. The invention also discloses synthetic methods for making the compounds, pharmaceutical compositions thereof, and potential uses in the treatment of many diseases, particularly cancer. [Background technology]

[0002] One strategy for cancer treatment, particularly cancer immunotherapy, has been reported to be enhancing the body's anti-tumor immune response. A recent study in Nat Cancer 1, 184-196 (2020) reported that inhibiting a protein known as ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP-1), which is known to negatively regulate innate immune signaling, can enhance the immune response2 as part of cancer treatment.

[0003] In journal publications a) J Hematol Oncol 13, 81 (2020) b) Molecules.24(22), 4192 (2019) c) Cell Chemical Biology 27, 1347-1358 (2020), the role of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway has been elucidated. The cGAS-STING pathway is important for interferon (IFN) production and T cell priming, making it a promising candidate for cancer immunotherapy. It has now been shown that cGAMP (cyclic GMP-AMP) hydrolysis by ENPP-1 attenuates cGAS-STING signaling. Therefore, inhibiting ENPP-1 reduces cGAMP hydrolysis, thereby enhancing cGAS-STING signaling and enhancing the host immune response. A review in Trends in Biochemical Science, 46(6), 446-460 (2021) points out that in addition to being an important IFN signaling pathway, cGAS-STING is also deeply involved in autophagy.

[0004] ENPP-1 plays a regulatory role in immune cells, including neutrophils, macrophages, dendritic cells, natural killer cells, and B lymphocytes. ENPP-1 expression is upregulated in M2 macrophages in the presence of cancer, promoting tumor growth and metastasis. The role of ENPP-1 in cancer is illustrated by the observation that, for example, tumor metastasis from breast cancer to bone is enhanced by overexpression of ENPP-1.

[0005] ENPP-1 belongs to the phosphodiesterase family. Patent Publication WO2018119328A1 reviews the roles and types of various phosphodiesterases. Phosphodiesterases are a type of enzyme that catalyzes the hydrolysis of phosphodiester bonds. In some instances, phosphodiesterases are associated with viral infections, and their inhibition correlates with reduced viral replication. In some instances, the phosphodiesterase family further includes cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, restriction endonucleases, and small molecule phosphodiesterases. J Biol Chem 280(24), 22962 (2005) and Biochemistry Moscow 75, 1-6 (2010) support the molecular functions of phosphodiesterases, nucleases (DNases, RNases), nucleotidases, and phosphatases, based on their chemical similarities. In another example, phosphodiesterases are associated with bacterial infections, such as those caused by Gram-negative or Gram-positive bacteria. In some cases, the bacteria are Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium Francisella, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae. Therefore, inhibitors of phosphodiesterases could have an impact on the treatment of many diseases. Highly specific inhibitors that inhibit specific phosphodiesterases, such as ENPP-1, are greatly needed in industry.

[0006] There are several prior arts that disclose ENPP-1 inhibitors with different structures and various potencies. The main features of the recently reported prior art documents are: a) ENPP-1 inhibitors mainly target cancer diseases; b) the inhibitor structure has at least three basic components consisting of a tail, a core, and a zinc-binding domain (the domain is also called a moiety), as exemplified in Formula II-X; c) some of these structures have a linking group (linker) between the core and the zinc-binding moiety, and / or some structures have a linker between the core and the tail moiety.

[0007] The structures of certain prior art compounds related to ENPP-1 inhibition are shown in Scheme 1. The scaffolds represented by Formulae II-V are not completely similar, but they contain a tail, a core, and a zinc-binding moiety. Some of the scaffolds have only one linker, while others have two. The ENPP-1 inhibitory activity of compounds represented by Formulae II-V has been disclosed in the respective literature for cancer treatment. JPEG2025527243000001.jpg68152

[0008] Patent Publication US20220135598A1 discloses inhibitor structures that conform to Formula II, in which the tail moiety is primarily a quinoline or substituted quinoline moiety with specific substitutions on the quinoline ring, the core moiety is a cyclic ring or a fused spiro ring, and the linker moiety L connecting the core moiety and the zinc binding moiety is a bond, a linear or branched C1-C6 alkylene, or a linear or branched C2-C6 alkylene. and the zinc-binding moiety is -NRcS(O)2NH2, -NRcS(O)2CH3, -SON2NH2, -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. Rc is defined as hydrogen, alkyl, substituted cycloalkyl, substituted alkylene, and substituted heteroaryl.

[0009] Patent Publication WO2020160333A1 discloses inhibitor structures conforming to Formula III, in which an additional linker L is added between the core portion and the tail portion. 1The key feature is the presence of a linker, L2, between the core and the zinc-binding domain. The zinc-binding group is disclosed as a phosphorus-containing group or urenyl. The core moiety can be aryl. Additionally, linker L1 has been explored as a linking moiety including, without limitation, alkyl, alkenylene, alkynylene, arylene, aralkylene, and functional groups such as amide, ureylene, imide, epoxy, epithio, epidioxy, carbonyldioxy, alkyldioxy, epoxyimino, epimino, and carbonyl. Patent Publication WO2019051269A1 discloses a structure as depicted in Formula-IV, where the linker between the core and X, designated L, can be a (C1-6) alkyl linker or a substituted (C1-6) alkyl linker, optionally substituted with a heteroatom or a linking functional group such as an ester (-CO2-), an amide (-CONH), a carbamate (-OCONH), an ether (-O-), a thioether (-S-), and / or an amino group. The tail portion is based on a quinazoline moiety, and the core portion, designated C, is an aromatic ring. The zinc-binding portion, designated X, is based on a phosphate, sulfonamide, or ureylene moiety.

[0010] Patent Publication WO2021225969A1 discloses a structure as depicted in Figure V, where L is a bond, -O-, -C(O)-, -NR6c-, or -OCR7c-*, and * represents the attachment point containing the zinc binding moiety. W in Figure V includes both a core group and a zinc binding moiety linked via a linker L. The core group is an aryl or heteroaryl moiety. The zinc binding moiety is a sulfoximine moiety having only hydrogen atoms as substituents on the nitrogen atom of the sulfoximine group. R6c and R7c are each independently hydrogen or C1-3 alkyl, where a1 and a2 are each independently 0, 1, 2, or 3.

[0011] Patent Publication WO2021226136A1 discloses a structure similar to that depicted in Formula-IV for ENPP-1 inhibition.

[0012] Patent Publication WO199046778A1 discloses a structure as depicted in Formula-VI, in which there are two linkers designated L and L1, and which have a sulfonamide-type terminal group for ENPP-1 inhibition. X is -NR7-, -O-, -S-, -S(=O)-, -S(=O)2-, or -CR8R9-; 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, or heteroaryl. R8 and R9 are independently hydrogen, deuterium, halogen, -CN, substituted alkoxy, -NO2, substituted amino, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl. JPEG2025527243000002.jpg69141

[0013] Patent Publication US20190282703A1 discloses a structure as shown in Formula VII, where there is a single linker, L as specified, 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 together form an oxo.

[0014] Patent Publication WO2021158829A1 discloses a structure as depicted in Formula VIII, where L is selected from the group consisting of C-C alkyl and C-C alkenyl, and Y is selected from the group consisting of -CRR-, -NR-, -N(CH)O-, -O-, -S-, -S(O)-, -S(O)2, aryl, and heteroaryl, where m is 2 or 3, for the treatment of cancer, bacterial diseases, or viral diseases. R, R, and R are independently selected from the group consisting of hydrogen and lower alkyl, or an isomer, hydrate, solvate, polymorph, tautomer, or pharmaceutically acceptable salt thereof. JPEG2025527243000003.jpg84154

[0015] Patent Publication WO2020140001A1 discloses quinazoline-based structures, as depicted in Formula-IX, that inhibit ENPP-1 enzyme activity and are therefore useful in the treatment of diseases. JPEG2025527243000004.jpg94159

[0016] Other relevant prior art documents that disclose specific compounds as ENPP-1 inhibitors whose structures do not fit the tail-core-zinc binding domain description shown in Figures II-IX are listed below.

[0017] Patent Publication WO2022056068A1 discloses small molecule ENPP-1 inhibitors for treating various cardiac diseases. Patent Publication WO2019023635A1 discloses novel ENPP-1 inhibitors and stimulators of interferon gene (Sting) modulators in the substituted 3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,5-c]pyridine series as cancer immunotherapeutic agents. Patent Publication WO2021053507A1 discloses 2-amino-S6-substituted thiopurine compounds as inhibitors of ENPP-1 for the treatment of cancer, infectious diseases, and other related conditions.

[0018] Furthermore, ENPP-1 inhibitors are also involved in DNA damage repair processes (see US20220135598A1). Patent Publications WO2019023635A1 and WO2021158829A1 describe ENPP-1 as an attractive drug target for the development of novel anticancer, cardiovascular, diabetes, obesity, and antifibrotic drugs. Patent Publications WO2022056068A1 and WO199046778A1 describe that ENPP-1 modulators are also useful against bacteria and fungi.

[0019] In Patent Publication WO2022125613A1, certain phosphonates are shown to be inhibitors of not only ENPP-1 but also CdnP. Cyclic dinucleotide phosphodiesterase (CdnP, also known as Rv2837c) is a phosphodiesterase that controls cyclic dinucleotide signaling in intracellular infections of M. tuberculosis. The structure of the phosphonates disclosed in the '613 patent application is also classified as a tail-core-zinc-binding domain and is represented as Formula X. JPEG2025527243000005.jpg80143

[0020] The primary therapeutic use or purpose behind ENPP-1 inhibitors is to provide treatment to patients or subjects suffering from cell proliferative disorders and cancers, including, but not limited to, glioma, glioblastoma multiforme, paraganglioma, supraventricular primitive neuroectodermal tumor, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, cholangiocarcinoma, colon cancer, chondrosarcoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), and other solid tumors. Due to the lack of targeted therapeutic agents for these cancers and cell proliferative disorders, there is currently an ongoing search for therapeutic agents, particularly novel ENPP-1 inhibitors that may exhibit selectivity for these adverse conditions and diseases.

[0021] The above brief review of tail-core-zinc-binding group structures describes scaffolds with potentially high efficacy in inhibiting ENPP-1, which enhances immune activity. However, none of these structures appear to be clinically proven. Literature reports do not reveal any drawbacks to these structures. Newer structures are still needed to address the urgent need to combat different types of cancer or carcinoma. Thus, the present invention discloses novel structures of highly effective molecules for use against one or more types of malignant tumors. Summary of the Invention

[0022] The present disclosure relates to compounds of Formula I that are potent inhibitors of ENPP-1 protein and therefore have potential use, for example, in immunotherapy for disease treatment. The present invention also discloses synthetic methods for producing these compounds and in vitro biological activity results that demonstrate the potential use of these inhibitors in the treatment of various diseases, including cancer. Specifically, the present invention discloses compounds of Formula I or pharmaceutically acceptable salts, hydrates, solvates, tautomers, and isomers thereof. JPEG2025527243000006.jpg121158 wherein formula I comprises moieties A and B constituting the tail moiety, moiety C constituting the core moiety, a sulfoximine-type group R2-S(=W)(=N) connecting the tail moiety and the core moiety, and a zinc-binding group (ZBG), The moiety A can be one or more R 3 X1, X2 and X3 are CH, N, CR', with the proviso that no two or more of X1, X2 and X3 are simultaneously N; Moiety B is a C6 aryl or 5-6 membered heteroaryl optionally substituted with one or more R4 groups, and the two shared atoms between moiety B and moiety A are fused to moiety A from a pair of carbon atoms or a pair of atoms where one atom is nitrogen and the other is carbon; the moiety C is selected from the group of structures consisting of (i), (ii), (iii), (iv), (v) and (vi); where L1 is connected to (i) at a variable position on the ring, wherein E1 is connected to the sulfur atom of the R2-S(=W)(=N) group and the linker (L1) is connected to the "a" atom of the zinc binding group (ZBG); JPEG2025527243000007.jpg87123n>1 R 1 n=0, 1, 2, 3, 4, with the proviso that the groups may be the same or different; R 1 , R 3 , R 4groups selected from the group consisting of R', halo, 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, where Ar = aryl, substituted aryl, heteroaryl or substituted heteroaryl; E1 = -(CH2) y -where y=0, 1 or 2, L1=-(CH2) y1 , NR", O or S, C1-6 straight chain alkyl, branched chain alkyl, -(CH2) y1 cycloalkyl, where y1=0, 1, 2 or 3; where R" = H, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, substituted aryl, halogenated alkyl; X4, X5 and X6 = CH, N or CR'; Moiety A is connected to the nitrogen atom of the R2-S(=W)(=N) group, where S is a chiral sulfur atom, N is nitrogen, W is O or NH; R2 is selected from the group consisting of C1-6 straight chain, branched, cycloalkyl, alkenyl, alkylene, alkynyl, halo, aryl, heteroaryl, heterocycle, substituted aryl, CF3, CHF2, CH2F, CN, and 2-6 membered alkylene groups, one end of which is bonded to the sulfur atom and the other end of which is bonded to moiety C at a position alpha to the carbon atom of moiety C that is bonded to the sulfur atom when y=0, thereby forming a ring structure; and ZBG shown in structure (vii) JPEG2025527243000008.jpg69143(iv) where a = S, P, C, or B atom, b1, b2 = O, S, NH or CH2, b3 = O, S, NH, CH2 or NH2O and m1, m2, and m3 = 0, 1, provided that only one of m1, m2, and m3 can be 0 at a given instance.

[0023] In one aspect, a general method for preparing compounds and intermediates required for the synthesis of compounds of Formula I is disclosed.

[0024] The compounds of Formula I inhibit the function of phosphodiesterase enzymes selected from the group consisting of ENPP-1, cyclic nucleotide phosphodiesterase, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNase, RNases, restriction endonucleases, and small phosphodiesterases.

[0025] Isomers of Compound I are selected from the group consisting of stereoisomers of Formula I and positional isomers resulting from the linkage of sulfoximine-type fragments of Formula I.

[0026] The stereoisomer is selected from the group consisting of the (R) isomer of Formula I, the (S) isomer of Formula I, and combinations thereof.

[0027] Regioisomers of Formula I are selected from the group consisting of molecules in which the core and tail moieties of Formula I are attached to the sulfoximine-type group at the sulfur and nitrogen atoms, respectively, and molecules in which the core and tail moieties of Formula I are attached to the sulfoximine-type group at the nitrogen and sulfur atoms, respectively.

[0028] Results from in vitro assays indicate that these compounds may be useful in treating diseases such as cancer by inhibiting phosphodiesterases such as ENPP-1. DETAILED DESCRIPTION OF THE INVENTION

[0029] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. In this specification and the claims that follow, reference will be made to terms that are defined to have the following meanings:

[0030] definition As used herein, unless otherwise specified, "alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 14 carbon atoms, and in some embodiments 1 to 6 carbon atoms. The term "alkyl" includes, by way of example, straight-chain and branched hydrocarbyl groups such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl ((CH)C-), n-pentyl (CHCHCHCHCHCH-), neopentyl ((CH)CCH-).

[0031] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms, no ring heteroatoms, and either a single ring or multiple rings, including fused, bridged, and spirocyclic ring systems. For multiple ring systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is to a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups containing multiple bicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like.

[0032] "Aryl" refers to an aromatic group having 5 to 14 carbon atoms, no ring heteroatoms, and either a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). For multiple ring systems, including fused, bridged, and spiro ring systems, with aromatic and non-aromatic rings that do not have 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-tetrahydronaphthalen-2-yl is an aryl group because the point of attachment is at the 2-position of the aromatic phenyl ring).

[0033] As used herein, "alkenyl" refers to an alkyl group having at least one site of olefinic unsaturation (i.e., having at least one site of formula C=C) and having the specified number of carbon atoms (i.e., C-C 10 "C" means 2 to 10 carbon atoms. Alkenyl groups may be in the "cis" or "trans" configuration, or in the "E" or "Z" configuration. Preferred alkenyl groups are those having 2 to 20 carbon atoms ("C2-C2M alkenyl"), 2 to 8 carbon atoms ("C2-C8 alkenyl"), 2 to 6 carbon atoms ("C2-C6 alkenyl"), or 2 to 4 carbon atoms ("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.

[0034] As used herein, "alkylene" refers to the same residues as alkyl, but has divalency. Preferred alkylene groups are those having 1 to 6 carbon atoms ("C-C alkylene"), 1 to 5 carbon atoms ("C-C alkylene"), 1 to 4 carbon atoms ("C-C alkylene"), or 1 to 3 carbon atoms ("C-C alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-).

[0035] As used herein, "alkynyl" refers to an alkyl group having at least one site of acetylenic unsaturation (i.e., having at least one site of formula C≡C) and having the specified number of carbon atoms (i.e., C-C 10 "C-C" refers to an unsaturated, linear or branched monovalent hydrocarbon chain, or combinations thereof, having 2 to 10 carbon atoms. Preferred alkynyl groups are those having 2 to 20 carbon atoms ("C-C alkynyl"), 2 to 8 carbon atoms ("C-C alkynyl"), 2 to 6 carbon atoms ("C-C alkynyl"), or 2 to 4 carbon atoms ("C-C 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.

[0036] "Halo" or "halogen" refers to elements in the Group 17 series with atomic numbers 9-85. Preferred halogen groups include fluoro, chloro, bromo, and iodo. When a residue is substituted with one or more halogens, it may be referred to using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to an aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may, but need not, be the same halo groups; 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 called a "perhaloalkyl." A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen is present in place of each H in the hydrocarbon forming the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0037] "Heteroaryl" refers to and includes unsaturated aromatic cyclic groups having 1 to 10 ring carbon atoms and at least one ring heteroatom, including, but not limited to, a heteroatom such as nitrogen, oxygen, and sulfur, where 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 a ring carbon or ring heteroatom. A heteroaryl can include additional fused rings (e.g., 1 to 3 rings), including additional fused aryl, heteroaryl, cycloalkyl, and / or heterocyclyl rings. Examples of heteroaryl groups include imidazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyloxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, and pyrrolopyrimidinyl. and the like, but are not limited to phenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, purinyl, benzofuranyl, furopyridinyl, benzoxazolyl, benzothiophenyl, benzothiazolyl, oxazolopyridinyl, thiazolopyridinyl, thienopyridinyl, quinolinyl, quinolonyl, naphthyridinyl, quinazolinyl, pyridopyrimidinyl, cinnolinyl, or pyridopyridazinyl.

[0038] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms, such as nitrogen, sulfur, or oxygen, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heterocyclyl group can have a single ring or multiple condensed rings. A heterocycle having one or more rings can be fused, spirocyclic, bridged, or any combination thereof. In a fused ring system, 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, azepanyltetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

[0039] "Optionally / optionally substituted" means, unless otherwise specified, that a group is unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, which substituents can 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.

[0040] A "medicament" or "pharmaceutical composition" refers to an administrable form of a pharmaceutical preparation comprising at least one pharmaceutically active ingredient and one or more pharmaceutically acceptable carriers.

[0041] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0042] As used herein, "therapy" or "treatment" refers to an approach to obtain 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: reducing symptoms caused by a disease, improving the quality of life of a person suffering from a disease, reducing the dosage of other drugs required to treat the disease, slowing the progression of the disease, and / or extending the survival of an individual. With respect to cancer or other unwanted cell proliferation, beneficial or desired results include shrinking a tumor (reducing tumor size), slowing the rate of tumor growth (e.g., inhibiting tumor growth), reducing the number of cancer cells, inhibiting, delaying, or partially slowing, preferably stopping, cancer cell invasion into peripheral organs, inhibiting (delaying, preferably stopping) tumor metastasis, inhibiting tumor growth, preventing or delaying tumor onset and / or recurrence, and / or alleviating to some extent one or more symptoms associated with cancer. In some embodiments, beneficial or desired results include preventing or delaying the onset and / or recurrence of unwanted cell proliferation, etc.

[0043] As used herein, "delaying the onset of disease" means delaying, preventing, slowing, retarding, stabilizing, and / or postponing the onset of a disease (such as cancer). This delay can be of varying lengths of time depending on the history of the disease and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can essentially encompass prevention of an individual from developing the disease. For example, late-stage cancer, such as the development of metastases, can be delayed.

[0044] As used herein, an "effective amount" or "effective dosage" of a compound or a salt thereof, or a pharmaceutical composition refers to an amount sufficient to bring about beneficial or desired results.

[0045] As used herein, the term "individual" refers to a mammal, including a human. An individual includes, but is not limited to, a human, a cow, a horse, a cat, a dog, a rodent, or a primate. In some embodiments, the individual is a human. An individual (such as a human) may have advanced disease or a low level of disease, such as a low tumor burden. In some embodiments, the individual is in an early stage of a proliferative disease (such as cancer). In some embodiments, the individual is in an advanced stage of a proliferative disease (such as advanced cancer).

[0046] In some embodiments, sarcoma and carcinoma are cancers that can be treated as solid tumors, while leukemia is a cancer that can be treated as liquid tumors.The present invention can treat various types of cancer, including but not limited to adrenocortical carcinoma, bladder cancer, brain tumor, 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 cancer, Hodgkin's lymphoma, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, sarcoma, skin cancer, and thyroid cancer.Breast cancer is classified into breast cancer (ER-negative or ER-positive), breast adenocarcinoma, primary ductal carcinoma, ductal carcinoma (ER-positive, ER-negative, or HER2-positive), triple-negative breast cancer (TNBC), HER2-positive breast cancer, or luminal breast cancer.Breast cancer is not classified. In some embodiments, the basal-like TNBC, immunomodulatory TNBC, mesenchymal TNBC (mesenchymal or mesenchymal stem-like), or luminal androgen receptor TNBC is triple-negative breast.In some embodiments, the prostate adenocarcinoma is prostate cancer.Ovarian adenocarcinoma, lung cancer, adenocarcinoma, non-small cell lung cancer, mucoepidermoid carcinoma, undifferentiated large cell carcinoma, colon adenocarcinoma, colon cancer, metastatic colorectal cancer, colon adenocarcinoma, astrocytoma, glioblastoma, medulloblastoma, neuroblastoma or meningioma, gastric cancer, cholangiocarcinoma or hepatoblastoma, hepatocellular carcinoma, liver cancer, medullary thyroid carcinoma or follicular thyroid carcinoma, papillary thyroid carcinoma, uterine serous papillary carcinoma or uterine clear cell carcinoma, gallbladder adenocarcinoma or squamous gallbladder carcinoma. Other therapeutic uses of the compounds include cancer, renal cell carcinoma or urothelial cell carcinoma, adrenocortical carcinoma, fibrosarcoma or Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma, basal cell carcinoma, melanoma or squamous cell carcinoma, tracheal carcinoma, laryngeal carcinoma, nasopharyngeal carcinoma and oropharyngeal carcinoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma or multiple myeloma.

[0047] Molecular biology of ENPP-1 Ectonucleotide pyrophosphatase / phosphodiesterase family member 1 (ENPP-1) is a 925 amino acid protein with a molecular weight of 104,924 Da. This protein is primarily present in the extracellular space, lysosomal membranes, and plasma membranes. ENPP-1, a member of the nucleotide pyrophosphatase / phosphodiesterase family, is a homodimer that requires a zinc ion as a coenzyme for biological function. The molecular functions of ENPP-1 protein have been reported to include 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 hydrolyzes ATP, GTP, CTP, TTP, and UTP to their respective monophosphates, releasing pyrophosphate and diadenosine polyphosphate. The ENPP-1 protein has been implicated in several biological processes, including the generation of precursor metabolites, the metabolism of phosphate-containing compounds, the regulation of nucleotide sugar availability in the endoplasmic reticulum and Golgi apparatus, the regulation of purinergic signaling, endocytosis, immune response, and nucleoside triphosphate catabolism. One of the key functions of ENPP-1 has been reported to be the hydrolysis of 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173 / STING. Hydrolysis of cyclic GMP-AMP reduces the expression of downstream components of the STING pathway, which are important for maintaining immune function. Therefore, ENPP-1-mediated inactivation of the STING pathway leads to immunosuppression and enhanced tumor cell metastasis.

[0048] ENPP-1 belongs to the phosphodiesterase class, a class of enzymes that catalyze the hydrolysis of phosphodiester bonds. In some instances, phosphodiesterases are associated with viral infections, and their inhibition correlates with reduced viral replication.

[0049] In some embodiments, the class of phosphodiesterases further includes cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxins, sphingomyelin phosphodiesterases, DNases, RNases, restriction endonucleases, and small phosphodiesterases.

[0050] In another example, phosphodiesterase is associated with bacterial infection, such as infection from gram-negative or gram-positive bacteria. In some cases, the bacteria is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhoeae. Therefore, inhibitors of phosphodiesterase may have an impact on the treatment of many diseases.

[0051] Crystallographic information of protein-ligand complexes Six crystal structures have been reported for the ENPP-1 protein. 2YS0, 6WET, 6WEU, 6WEV, 6WEW, and 6WFJ are the PDB codes reported for ENPP-1. Of the available PDB structures, 6WEV was used for in silico studies. The resolution of this protein is reported to be 2.90 Å. 6WEV is the target considered for performing in silico studies. ENPP-1 protein complexed with N-{[1-(6,7-dimethoxy-5,8-dihydroquinazolin-4-yl)piperidin-4-yl]methyl}sulfuric diamide (PDB ID: 6WEV) contains additional coenzymes, including 2-acetamido-2-deoxy-β-D-glucopyranose, phosphate ions, calcium ions, and zinc ions. The zinc ions play an important role in the catalytic activation of ENPP-1. Therefore, the interaction of drug candidates with the zinc ions is important for eliciting enzyme inhibition.

[0052] Molecular Docking - Methodology Molecular docking studies were performed using the AutoDock4Zn program, which incorporates improved force field parameters to address the coordination properties of small molecules and zinc ions. This program captures the energetic and geometric aspects of the interaction between small molecules and zinc ions. The previous AutoDock force field considered van der Waals terms, hydrogen bonding terms, Coulomb electrostatic terms, desolvation terms, and ligand torsional entropy terms to describe the interaction between the ligand and receptor. However, the previous AutoDock force field was inappropriate for dealing with zinc ions because the van der Waals equilibrium distances of the atoms involved in zinc coordination are significantly larger than the coordination distances, and there are no specific terms for metal coordination. Therefore, we added potential energy terms related to the pairwise interactions of each atom type involved in zinc ion coordination to the current AutoDock force field.

[0053] Molecular docking results Structural features relevant to ENPP-1 inhibitors are classified into the zinc-binding head or group, core, and tail. Of these three segments, the zinc-binding head plays a key role in ENPP-1 inhibition by coordinating with the zinc ion present in the catalytic site of the enzyme. The core and tail segments firmly anchor the compound in the binding pocket. Inhibitor design began with these three structural elements in mind. ENPP-1 cocrystallized with an inhibitor reported to have good potency was used for docking studies. The active site residues of the ENPP-1 protein include D218, F257, L290, K295, D326, S325, K338, W322, F321, Y371, Y340, P323, T356, D376, H380, and the zinc ion. The inhibitors were redocked into the enzyme's binding pocket, and the binding profiles were visualized. Previously available docking studies of ENPP-1 have emphasized that the closer the zinc-binding head of an inhibitor is to the zinc atom present in the catalytic site, the greater the degree of enzyme inhibition. This observation was taken into account in the redocking study. The zinc-binding head of the reference compound was found to be closely associated with the zinc ion present in the active site.

[0054] ENPP-1 inhibitors The compounds of the present invention are potent inhibitors of ENPP-1. The structure of the molecules is represented by Formula I. The present invention discloses a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or isomer thereof: JPEG2025527243000009.jpg115162 wherein formula I has moieties A and B constituting a tail moiety, moiety C constituting a core moiety, a sulfoximine-type group R2-S(=W)(=N) connecting the tail moiety and the core moiety, and a zinc binding group (ZBG), The moiety A can be one or more R 3 X1, X2 and X3 are CH, N, CR', with the proviso that no two or more of X1, X2 and X3 are simultaneously N; Moiety B is a C6 aryl or 5-6 membered heteroaryl optionally substituted with one or more R4 groups, and the two shared atoms between moiety B and moiety A are fused to moiety A from a pair of carbon atoms or a pair of atoms where one atom is nitrogen and the other is carbon; the moiety C is selected from the group of structures consisting of (i), (ii), (iii), (iv), (v) and (vi); where L1 is connected to (i) at a variable position on the ring, Here, E1 is connected to the sulfur atom of the R2-S(=W)(=N) group, and the linker (L1) is connected to the "a" atom of the zinc binding group (ZBG). JPEG2025527243000010.jpg84129 R if n>1 1 n=0, 1, 2, 3, 4, with the proviso that the groups may be the same or different; R 1 , R 3 , R 4 groups selected from the group consisting of R', halo, 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 Ar = aryl, substituted aryl, heteroaryl or substituted heteroaryl; E1 = -(CH2) y -where y=0, 1 or 2, L1=-(CH2) y1 , NR", O or S, C1-6 straight chain alkyl, branched chain alkyl, -(CH2) y1 cycloalkyl, where y1=0, 1, 2 or 3; where R" = H, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, substituted aryl, halogenated alkyl; X4, X5 and X6 = CH, N or CR'; Moiety A is connected to the nitrogen atom of the R2-S(=W)(=N) group, where S is a chiral sulfur atom, N is nitrogen, W is O or NH; R2 is selected from the group consisting of C1-6 straight chain, branched, cycloalkyl, alkenyl, alkylene, alkynyl, halo, aryl, heteroaryl, heterocycle, substituted aryl, CF3, CHF2, CH2F, CN, and 2-6 membered alkylene groups, one end of which is bonded to the sulfur atom and the other end of which is bonded to moiety C at a position alpha to the carbon atom of moiety C that is bonded to the sulfur atom when y=0, thereby forming a ring structure; and ZBG shown in structure (vii) JPEG2025527243000011.jpg55142 (vi) where a = S, P, C, or B atom, b1, b2 = O, S, NH or CH 2、 b3 = O, S, NH, CH2 or NH2O and m1, m2, m (3)の m1, m2, m3 = 0, 1, provided that only one of them can be 0 in any given instance.

[0055] Zinc-binding domain (ZBG) The zinc binding moiety (ZBG) is linked to the core via a linker L1 which may or may not be present. In one embodiment, the zinc binding moiety is formed from the structure group consisting of: JPEG2025527243000012.jpg51162

[0056] Sulfoximine-type fragments One of the key features of the structure depicted in Formula I is the presence of a sulfoximine-type fragment located between the tail and core. Sulfoximine-based structures have steadily gained popularity in pharmaceutical science. One recent publication is "Application of sulfoximines in medicinal chemistry from 2013 to 2020," European Journal of Medicinal Chemistry 209, 112885 (2021). Another publication, "Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry," J. Med. Chem. 63 (23), 14243-14275 (2020), also discusses the limitations of this functional group. The sulfoximine-type fragments of interest in this disclosure are shown below as sulfoximines and sulfondiimines. JPEG2025527243000013.jpg63163

[0057] Sulfondiimines are isosteres of sulfoximines, and in this disclosure, both are referred to as sulfoximine-type fragments. The nitrogen of the NH group in sulfondiimines is connected to sulfur via a double bond, and is equivalent in volume to the O atom present in sulfoximine. In this disclosure, R1x has the same meaning as the R2 group in Figure I, and R2x and R3x have the same meanings as the core and tail portions of Figure I, respectively. In none of the ENPP-1 inhibitors reported to date is the sulfoximine-type fragment located between the core and tail portions of the inhibitor molecule. In this disclosure, the sulfoximine-type fragment is represented as the R2-S(=W)(=N) group.

[0058] In one embodiment, the R2 group of the sulfoximine-type fragment is selected from the list of radicals consisting of methyl, cyclopropyl, cyclopropylmethyl, ethyl, propyl, isopropyl, phenyl, and benzyl.

[0059] Preferred sulfoximine-type fragments corresponding to the formula R2-S(=W)(=N) are as follows: JPEG2025527243000014.jpg33163

[0060] Tail part The tail portion in Figure I is attached to the nitrogen atom of the sulfoximine-type fragment, which is attached to the sulfur atom via a double bond, and portion A is attached to the nitrogen atom of the sulfoximine-type fragment. In one embodiment, the tail moiety comprising moieties A and B, which together comprise the X1, X2, X3, R3 and R4 groups, is selected from the group consisting of: The number of ring substituents R3 and R4 on each of moieties A and B can be 0, 1 or more. When more than one ring substituent is present, such ring substituents can be the same or different.

[0061] Core part The core moiety, referred to as moiety C, comprises the L1, X4, X5, X6=, R1, L2 groups, which together are selected from the group consisting of: JPEG2025527243000016.jpg170163JPEG2025527243000017.jpg184164

[0062] In most of these structures, one end of the core moiety is bound to a ZBG, and the other end of the core moiety, indicated by a wavy line, is bound to a sulfoximine-type fragment, particularly a sulfur atom of the sulfoximine-type fragment. In some of the core moiety structures shown below, the designation "linker" refers to a sulfoximine-type fragment; the connection between the core moiety and the tail moiety via the nitrogen atom attached to the sulfur is not shown in the structures shown below. JPEG2025527243000018.jpg28114

[0063] In one embodiment, the core moiety together with the sulfoximine-type fragment is selected from the group consisting of: JPEG2025527243000019.jpg100165

[0064] Isomers of Formula I Stereoisomers and specific constitutional isomers stereoisomer Compounds corresponding to Formula I exhibit optical activity due to the presence of an asymmetric sulfur atom, resulting in two non-superimposable mirror images. The two forms of such compounds are known as enantiomers and are classified as levorotalis (l-isomer) or dextrorotalis (d-isomer), depending on their left (-) or right (+) rotation of plane-polarized light, respectively. Stereoisomers of Formula I are selected from the group consisting of the (R)-isomer of Formula I, the (S)-isomer of Formula I, and combinations thereof.

[0065] When both isomers exhibit different activities, or when only one isomer exhibits activity and the other does not, or when one isomer exhibits positive activity and the other negative activity, chiral separation of such racemates is important in the pharmaceutical industry to remove unwanted isomers from the composition and achieve better therapeutic activity. When the racemate exhibits the same activity as the individual isomers, separation is not necessary. Possible enantiomers of the present invention are exemplified below. JPEG2025527243000020.jpg75124

[0066] Constitutional isomers (also called positional isomers) The presence of an N-substituted sulfoximine linker also provides the opportunity to generate positional or constitutional isomers. One positional isomer results from changes in the linkage between the core and tail moieties of the sulfoximine-type fragment of Formula I. These structures differ from each other depending on the orientation of the sulfoximine linker. To illustrate constitutional isomers of Formula I, Structure P1, shown below, shows the N-substituted sulfoximine linker attached to the tail moiety via the nitrogen atom of the sulfoximine linker and to the core moiety via the sulfur atom of the sulfoximine linker. Unlike Structure P1, Structure P2 shows the N-substituted sulfoximine linker attached to the core moiety via the N atom of the sulfoximine linker and to the tail moiety via the sulfur atom of the sulfoximine linker. JPEG2025527243000021.jpg66131

[0067] Synthesis of Compounds of Formula I General synthetic scheme for embodiments of the present invention represented by formula I A retrosynthetic strategy for preparing compounds of formula I is to prepare aryl sulfoximines starting from appropriately substituted aryl alkyl sulfides by oxidation of the sulfide group with phenyl iodoacetate in the presence of ammonium carbamate. The preferred alkyl substituent is methyl. All sulfoximine derivatives were synthesized from the corresponding sulfides in the presence of an ammonia source and mild oxidizing reagents. JPEG2025527243000022.jpg49163 The R group on the sulfide is found in the sulfoximine molecules listed below. JPEG2025527243000023.jpg102152

[0068] The arylmethyl sulfoximine molecule is then coupled with a halo compound in the presence of base to form a tail-sulfoximine-core structure functionalized with a zinc-binding polar group. The products of the present invention are generally combinations of (R) and (S) enantiomers or racemates, and are optionally resolved into the enantiomers. JPEG2025527243000024.jpg96146

[0069] General Procedure: Substituted thioanisoles were treated with diacetoxyiodobenzene (PhI(OAc)2) and ammonium carbamate (NH4(CO2NH2)2) to synthesize sulfoximines. The corresponding sulfoximines were treated with base followed by 4-chloro-6,7-dimethoxyquinazoline to afford the respective sulfoximine-quinazoline conjugates. In the final step, various zinc binding groups (ZBGs) were inserted onto the phenyl ring attached to the sulfoximine via functionalization, as shown in Example 1.

[0070] Example 1: Synthesis of {4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]-phenyl}phosphonic acid (SAPTI012S001) Step 1: 4-Bromothioanisole (1.0 equiv.) was dissolved in MeOH (0.2 M) in RBF, and diacetoxyiodobenzene (PhI(OAc)2) (3.0 equiv.) followed by ammonium carbamate (NH4(CO2NH2)) (4.0 equiv.) was added portionwise under N2 atmosphere. After 2 h, the same amounts of (PhI(OAc)2) and (NH4(CO2NH2)) were added again to obtain the maximum yield. After completion of the reaction, methanol was removed under reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine. The organic layer was concentrated and purified by column chromatography using 10-15% EtOAc in hexane as an eluent. The product, 1-bromo-4-(S-methanesulfonimidoyl)benzene (SAPTI012S001 / IM1), was confirmed by LCMS; yield: 95%. LCMS: [M+H] = 234, 236 (isotopic peaks). JPEG2025527243000025.jpg106153 Step-2: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in DMF (0.2 M) in RBF and cooled to 0 °C in an ice bath. Then, NaH (2.0 equiv.) was added followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv.) under a N2 atmosphere. The temperature of the reaction mixture was slowly raised to 100 °C and stirred for 8 h. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography using 30% EtOAc in hexane as the eluent. The product, 4-{[(4-bromophenyl)(methyl)oxo-λ6-sulfanylidene]amino}-6,7-dimethoxyquinazoline (SAPTI012S001 / IM2), was confirmed by LCMS; yield: 40%. LCMS: [M+H] = 422, 424 (isotopic peaks). Step 3: 4-{[(4-bromophenyl)(methyl)oxo-λ6-sulfanylidene]amino}-6,7-dimethoxyquinazoline (1.0 equiv.), diethyl phosphite (2.0 equiv.), DIPEA (1.5 equiv.), Pd(OAc)2 (5 mol%), and XPhos (10 mol%) were transferred to a sealed tube and dissolved in ethanol (0.2 M). The reaction mixture was degassed under N2 atmosphere and stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography using 3-4% DCM in hexane as the eluent. The product, diethyl (4-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)phosphonate (SAPTI012S001 / IM3), was confirmed by LCMS; yield: 80%. LCMS: [M+H] = 480 Step-4. Diethyl (4-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)phosphonate (1.0 equiv.) was dissolved in 0.2 M dry CHCl3 in RBF, then TMSBr (4.0 equiv.) was added at 0°C over 10 min and the reaction mass was stirred at room temperature for 4 h. After completion of the reaction, it was diluted with methanol, concentrated under reduced pressure and recrystallized from a mixed solvent of MeOH, DCM and acetone. The pure product {4-[N-(6,7-dimethoxyquinazolin-4-)-S-methanesulfonimidoyl]phenyl}phosphonic acid (SAPTI012S001) was confirmed by HNMR and LCMS; yield-50%, purity-92% LCMS: [M+H] = 424. 1 H-NMR: 8.70 ppm (s, 1H); 8.16 ppm (d, 2H); 7.95 ppm (d, 2H); 7.67 ppm (s, 1H); 7.21 ppm (s, 1H); 3.99 ppm (s, 6H, OCH3); 3.85 ppm (s, 3H, SCH3).

[0071] Example 2: Synthesis of {3-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]-phenyl}phosphonic acid (SAPTI012S002). Step-1: 3-Bromothioanisole (1.0 equiv.) was dissolved in MeOH (0.2 M) in RBF, and diacetoxyiodobenzene (PhI(OAc)2) (3.0 equiv.) followed by ammonium carbamate (NH4(CO2NH2)) (4.0 equiv.) was added portionwise under N2 atmosphere. After 2 h, the same amount of (PhI(OAc)2) and (NH4(CO2NH2)) was added again to obtain the maximum yield. After the reaction was completed, methanol was distilled off under reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine. The organic layer was concentrated and purified by column chromatography using 10-15% EtOAc in hexane as the eluent. The product, 1-bromo-3-(S-methanesulfonimidoyl)benzene (SAPTI012S002 / IM1), was confirmed by LCMS; yield -85%. LCMS: [M+] = 234; 236 (isotopic peak). JPEG2025527243000026.jpg123157 Step 2: 1-Bromo-3-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in DMF (0.2 M) in RBF and cooled to 0 °C in an ice bath. Then, NaH (2.0 equiv.) and 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv.) were added under a N2 atmosphere, and the reaction mixture was slowly heated to 100 °C and stirred for 8 h. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography using 30% EtOAc in hexane as the eluent. The product, 4-{[(3-bromophenyl)(methyl)oxo-λ6-sulfanylidene]amino}-6,7-dimethoxyquinazoline (SAPTI012S002 / IM2), was confirmed by LCMS; yield—42%. LCMS: [M+] = 422; 424 (isotopic peak) Step 3: 4-{[(3-bromophenyl)(methyl)oxo-λ6-sulfanylidene]amino}-6,7-dimethoxyquinazoline (1.0 equiv.), diethyl phosphite (2.0 equiv.), DIPEA (1.5 equiv.), Pd(OAc)2 (5 mol%), and XPhos (10 mol%) were transferred to a sealed tube and dissolved in ethanol (0.2 M). The reaction mixture was degassed under N2 atmosphere and stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography using 3-4% DCM in hexane as the eluent. The product, diethyl (3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)phosphonate (SAPTI012S002 / IM3), was confirmed by LCMS; yield: 80%. LCMS: [M+H] = 479. Step-4. Diethyl (3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)phosphonate (1.0 equiv.) was dissolved in 0.2 M dry CHCl3 in RBF, then TMSBr (4.0 equiv.) was added at 0°C over 10 min, and the reaction mass was stirred at room temperature for 4 h. After completion of the reaction, it was diluted with methanol, concentrated under reduced pressure, and then recrystallized from a mixed solvent of MeOH, DCM, and acetone. The pure product {3-[N-(6,7-dimethoxyquinazolin-4-)-S-methanesulfonimidoyl]phenyl}phosphonic acid (SAPTI012S002) was obtained. 1 Confirmed by H-NMR and LCMS; yield-44%, purity-97%. LCMS: [M+H] = 424. 1 8.25 ppm (d, 1H, CH); 8.04 ppm (dd, 1H, CH); 7.82 ppm (m, 1H, CH); 7.69 ppm (s, 1H, CH); 7.24 ppm (s, 1H, CH); 4.01 ppm (s, 3H, OCH3); 4.00 ppm (s, 3H, OCH3); 3.92 ppm (s, 3H, SCH3).

[0072] Example 3: Synthesis of common intermediate (SAPTI012S003 / IM4) 4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]aniline Step-1: 4-(methylsulfanyl)aniline (1.0 equiv.) in DCM solution was treated with N-ethyl,N,N-diisopropylamine (2.0 equiv.) at 0°C, followed by the dropwise addition of Boc-anhydride (1.2 equiv.) at the same temperature. The temperature was slowly raised to room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After the completion of the reaction of 4-(methylsulfanyl)aniline, the reaction mass was further diluted with DCM and washed with water and brine. The organic layer was concentrated and purified by column chromatography using 10-15% EtOAc in hexane as the eluent. The isolated spot was less polar than the starting material and was used in the next step without purification; yield - 81%. JPEG2025527243000027.jpg113154 Step-2: tert-Butyl [4-(methylsulfanyl)phenyl]carbamate (1.0 equiv.) was dissolved in MeOH (0.2 M) in RBF, followed by the addition of diacetoxyiodobenzene (PhI(OAc)2) (3.0 equiv.) and then ammonium carbamate (NH4(CO2NH2)) (4.0 equiv.) portionwise under N2 atmosphere. After 2 h, the addition of the same amounts of (PhI(OAc)2) and (NH4(CO2NH2)) was repeated to obtain the maximum yield. After the reaction was completed, methanol was removed under reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine. The organic layer was concentrated and purified by column chromatography using 10-15% EtOAc in hexane as the eluent. The product, tert-butyl [4-(S-methanesulfonimidoyl)phenyl]carbamate (SAPTI012S003 / IM2), was confirmed by LCMS; yield 90%. LCMS: [M+H] = 271. Step-3: tert-Butyl [4-(S-methanesulfonimidoyl)phenyl]carbamate (1.0 equiv.) was dissolved in DMF (0.2 M) in RBF and cooled to 0 °C in an ice bath. Then, NaH (2.0 equiv.) and 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv.) were added under N2 atmosphere, and the temperature of the reaction mixture was slowly raised to 100 °C and stirred for 8 h. After completion of the reaction, the mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography using 30% EtOAc in hexane as the eluent. The product tert-butyl (3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)carbamate (SAPTI012S003 / IM3) was confirmed by LCMS; yield - 36%. LCMS: [M+H] = 459. Step-4: tert-Butyl (3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)carbamate (1.0 equiv.) was dissolved in 0.2 M dry DCM in RBF, then trifluoroacetic acid (10.0 equiv.) was added at room temperature and stirred for 4 hours. The crude reaction mixture was concentrated under reduced pressure to remove DCM and excess TFA. The TFA salt of the free amine was neutralized with triethylamine to give the free amine (4-[N-(6,7-dimethoxyquinazolin-4-)-S-methanesulfonimidoyl]aniline) (SAPTI012S003 / IM4), which was confirmed by crude LCMS. The free amine in the crude mixture was subjected to further reaction without purification. LCMS: [M+H] = 359.

[0073] Example 4: Synthesis of N-{4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]phenyl}sulfuric diamide (SAPTI012S003) JPEG2025527243000028.jpg61136 (4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]aniline) (1.0 equiv.) was dissolved in dry THF (0.2 M) in RBF, then TEA (2.0 equiv.) and chlorosulfonamide (1.5 equiv.) were added under N2 atmosphere, and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, THF was evaporated under reduced pressure, and the crude product was purified by column chromatography using DMC and MeOH (3-4%) as eluent. The product, N-{4-[N-(6,7-dimethoxyquinazoline-4-)-S-methanesulfonimidoyl]phenyl}sulfuric diamide, was confirmed by LCMS. Yield: 50%, Purity: 90%. LCMS: [M+H] = 408. 1 7.96 ppm (d,2H,CH); 7.69 ppm (s,1H,CH); 7.46ppm(s,2H,NH2); 7.34 ppm (d, 2H, CH); 7.21 ppm (s, 1H, CH); 3.94 ppm (s, 3H, OCH3); 3.90 ppm (s, 3H, OCH3); 3.69 ppm (s, 3H, SCH3).

[0074] Example 5: Synthesis of 1-(3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)-phenylurea (SAPTI012S004) JPEG2025527243000029.jpg68168 Step-1: A DCM solution of (4-[N-(6,7-dimethoxyquinazolin-4-yl)-S-methanesulfonimidoyl]aniline) (1.0 equiv.) was treated with benzoyl isocyanate (1.5 equiv.) at room temperature for 12 h. After completion of the reaction, the mass was further diluted with DCM and washed with water and brine. The organic layer was concentrated under reduced pressure and purified by column chromatography using 10-15% DCM in MeOH as the eluent. The product N-((3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)carbomoyl)benzamide (SAPTI012S004 / IM5) was isolated in 33% yield. Step-2: N-((3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenyl)carbomoyl)benzamide (1.0 equiv.) was treated with 1.0 N aqueous KOH at 95° C. for 3 hours. Then the reaction mixture was further diluted with water and extracted with DCM. The organic layer was concentrated and purified by column chromatography using 3-4% DCM in MeOH as the eluent. The product 1-(3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonimidoyl)phenylurea (SAPTI012S004) was confirmed by LCMS; yield—66%, purity—95%. LCMS: [M+H] = 402. 1 7.89 ppm (d, 2H, CH); 7.67 ppm (d, 2H, CH); 7.57 ppm (s, 1H, CH); 7.15 ppm (s, 1H, CH); 6.27 ppm (s, 2H, NH2); 3.93 ppm (s, 3H, OCH3); 3.92 ppm (s, 3H, OCH3); 3.62 ppm (s, 3H, SCH3).

[0075] Example 6: Synthesis procedure for SAPTI012S005 The previous intermediate SAPTI012S002 / IM1 (1.0 equiv.) was dissolved in dry 1,4-dioxane (0.2 M). B2(Pin)2 (1.4 equiv.) KOAc (3.5 equiv.) followed by PdCl2(dppf) complex (5 mol%) was added. The reaction mixture was purged with nitrogen for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 8 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S005 was confirmed by LCMS and 1H NMR; yield 40%. LCMS: [M+H] = 388.

[0076] Example 7: Synthesis procedure for SAPTI012S006. The previous intermediate SAPTI012S001 / IM1 (1.0 equiv.) was dissolved in dry 1,4-dioxane (0.2 M). KOAc (3.5 equiv.), B2(Pin)2 (1.4 equiv.), followed by PdCl2(dppf) complex (5 mol%) were added. The reaction mixture was purged with N2 for 10 min. The temperature was then slowly raised to 100 °C and stirred at the same temperature for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S002 was confirmed by LCMS and H NMR; yield 40%; LCMS: [M+H] = 388.

[0077] Example 8: Synthesis procedure for SAPTI012S007 Step 1: The previous intermediate SAPTI012S003 / IM2 (1.0 equiv.) in DCM solution was treated with benzylthioisocyanate (1.5 equiv.) at room temperature for 12 hours. After completion of the reaction, the mass was further diluted with DCM and washed with water and brine. The combined organic layer was concentrated under reduced pressure and purified by column chromatography using DCM and MeOH as eluents (10-15%). The product SAPTI012S007 / IM1 was confirmed by LCMS; yield - 33%. LCMS: [M+1] = 522. Step-2: Intermediate SAPTI012S007 / IM1 (1.0 equiv.) was treated with 1.0 N aqueous KOH at 95 °C for 3 h. Then the reaction mixture was further diluted with water and extracted with DCM. The organic layer was concentrated and purified by column chromatography using DCM and MeOH as eluents (3-4%). The product SAPTI012S007 was confirmed by LCMS and 1H NMR; yield - 66%. LCMS: [M+H] = 418.

[0078] Example 9: Synthesis procedure for SAPTI012S008 Step 1: The previous intermediate SAPTI012S001 / IM1 (1.0 equiv.) was dissolved in DMF (0.2 M), then sodium thiomethoxide (1.6 equiv.) was added at room temperature, and the resulting mixture was stirred at 100 °C for 8 h. After the reaction was complete, the reaction mixture was quenched with MeOH and the solvent was evaporated on a rotary evaporator until DMF was completely removed. The reaction mixture was dissolved again in sufficient DCM and washed with water and brine. The organic layer was concentrated to obtain the crude reaction mixture, which was purified by silica gel column chromatography using DCM and MeOH as eluents (0–5%). The product SAPTI012S008 / IM1 was confirmed by LCMS; yield: 70. [M+H] = 390 Step 2: Intermediate SAPTI012S008 / IM1 (1.0 equiv.) was dissolved in MeOH (0.2 M), followed by the addition of diacetoxyiodobenzene (PhI(OAc)2) (1.5 equiv.) and ammonium carbamate (NH4(CO2NH2)) (2.0 equiv.) in small portions. The reaction progress was monitored by TLC and LCMS. If starting material remained after 2 h, another 0.5 equiv. of PhI(OAc)2 and 0.6 equiv. of NH4(CO2NH2) were added to maximize the yield. After completion of the reaction, methanol was removed under reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine. The combined organic layer was concentrated and purified by column chromatography using EtOAc and hexane as eluents (85-90%). SAPTI012S008 was confirmed by LCMS and 1H NMR; yield: 30%. LCMS: [M+H] = 421

[0079] Example 10: Synthesis procedure for SAPTI012S009 Triphosgene (1.1 equiv.) was dissolved in DCM (0.2 M), and the reaction mixture was cooled to 0 °C under a nitrogen atmosphere. Aniline (1.0 equiv.) was then slowly added to the reaction mixture, and stirring was continued at room temperature for approximately 2 h. The starting material SAPTI012S003 / IM2 amine (1.0 equiv.) was then added at room temperature and stirred for approximately 2–3 h. The reaction progress was monitored by TLC. The reaction mixture was then quenched with aqueous NaHCO3 at 0 °C and extracted with DCM. The combined organic layers were evaporated under reduced pressure to obtain the crude product. The crude product was purified using column chromatography eluting with EtOAc and hexane. The product SAPTI012S009 was confirmed by LCMS and 1H NMR; yield: 67%. LCMS: [M+H] = 478.

[0080] Example 11: Synthesis procedure for SAPTI012S010 Step 1: tert-Butyl [3-(S-methanesulfonimidoyl)phenyl]carbamate (1.0 equiv.) was dissolved in DMF (0.2 M) and cooled to 0 °C in an ice bath. Then, NaH (2.0 equiv.) and 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv.) were added under a N2 atmosphere. The temperature of the reaction mixture was slowly raised to 100 °C and stirred for 8 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography using EtOAc and hexane as the eluent (60-70%). The product SAPTI012S010 / IM1 was confirmed by LCMS; yield - 36%. LCMS: [M+H] = 459. Step-2: Intermediate SAPTI012S010 / IM1 (1.0 equiv.) was dissolved in 0.2 M dry DCM in RBF, and then trifluoroacetic acid (10 V) was added at room temperature and stirred for 4 hours. The crude reaction mixture was concentrated under reduced pressure to remove DCM and excess TFA. The TFA salt of the free amine was then neutralized with triethylamine to give the free amine SAPTI012S010 / IM2, which was confirmed by LCMS of the crude product. The free amine in the crude mixture was subjected to further reaction without further purification. LCMS: [M+H] = 359. Step-3: Intermediate SAPTI012S010 / IM2 (1.0 equiv.) was dissolved in dry THF (0.2 M) in RBF, then TEA (2.0 equiv.) and chlorosulfonamide (1.5 equiv.) were added under N2 atmosphere, and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, THF was distilled off under reduced pressure, and the crude product was purified by column chromatography using DMC and MeOH as eluents (3-4%). The product SAPTI012S010 was confirmed by LCMS and 1H NMR; yield - 50%. LCMS: [M+H] = 438.

[0081] Example 12: Synthesis procedure for SAPTI012S011 Step-1: The previous intermediate SAPTI012S010 / IM2 (1.0 equiv.) in DCM solution was treated with benzyl isocyanate (1.5 equiv.) at room temperature for 12 hours. After completion of the reaction, the mass was further diluted with DCM and washed with water and brine. The combined organic layer was concentrated under reduced pressure, and the crude was purified by column chromatography using DCM and MeOH as eluents (10-15%). The product SAPTI012S011 / IM1 was confirmed by LCMS; yield - 57%. LCMS: [M+H] = 506 Step-2: Intermediate SAPTI012S011 / IM1 (1.0 equiv.) was treated with 1.0 N aqueous KOH at 95 °C for 3 h. Then the reaction mixture was further diluted with water and extracted with DCM. The organic layer was concentrated and purified by column chromatography using DCM and MeOH as eluents (3-4%). The product SAPTI012S011 was confirmed by LCMS, 1H NMR; yield - 67%. LCMS: [M+H] = 402.

[0082] Example 13: Synthesis procedure for SAPTI012S012 Step 1: t-Butyl [3-(S-methanesulfonimidoyl)phenyl]methylcarbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and then 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min, followed by the addition of Pd(OAc)2 (5 mol%) and slowly warming to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S012 / IM1 was confirmed by LCMS; yield 28%. LCMS: [M+H] = 473 Step-2: Intermediate SAPTI012S012 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0°C in an ice bath. HCl (10 vol.) in dioxane was added dropwise and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S012 / IM2 was confirmed by LCMS and used without further purification; yield - 64%. LCMS: [M+H] = 373 Step-3: The HCl salt of SAPTI012S012 / IM2 (1.0 equiv.) was dissolved in water and AcOH (1:1), followed by the addition of sodium cyanate (1 equiv.) portionwise at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with water and brine, passed through anhydrous sodium sulfate, evaporated under reduced pressure, and purified by reverse-phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S012 was confirmed by LCMS and 1H NMR; yield: 30%. LCMS: [M+H] = 416

[0083] Example 14: Synthesis procedure for SAPTI012S013 Step 1: t-Butyl [3-(S-methanesulfonimidoyl)phenyl]methylcarbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and then 4-chloro-8-methoxyquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min, followed by the addition of Pd(OAc)2 (5 mol%) and slowly warming to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S013 / IM1 was confirmed by LCMS; yield 64%. LCMS: [M+H] = 443 Step-2: Intermediate SAPTI012S013 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0 °C in an ice bath. Then, HCl in dioxane (10 vol.) was added dropwise and stirred at room temperature for 5 hours or more. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S013 / IM2 was confirmed by LCMS and used without further purification; yield - 91%. LCMS: [M+H] = 343 Step-3: The HCl salt of SAPTI012S013 / IM2 (1.0 equiv.) was dissolved in water, and AcOH (1:1) followed by sodium cyanate (1 equiv.) was added portionwise at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, evaporated under reduced pressure, and purified by reverse-phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S013 was confirmed by LCMS and 1H NMR; yield: 20%. LCMS: [M+H] = 386

[0084] Example 15: Synthesis procedure for SAPTI012S014 Step 1: 4-(S-methanesulfonimidoyl)benzonitrile (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%) and Cs2CO3 (1.4 equiv.) were added, followed by 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.), and the solution was purged with N2 for 10 min. Then, Pd(OAc)2 (5 mol%) was added, and the temperature was raised to 100 °C. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S014 / IM1 was confirmed by LCMS; yield 27%. LCMS: [M+H] = 369 Step-2: SAPTI012S014 / IM1 (1.0 equiv.) was dissolved in 1N KOH (10V), and the resulting mixture was stirred at 60°C for 4 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM several times. The aqueous layer was acidified with 1N HCl until the aqueous layer became an acidic solution, and extracted with DCM. The organic layer was collected and concentrated to obtain a crude mixture. The crude mixture was purified by silica gel column chromatography using DCM and MeOH (0-10%) as eluents. The product SAPTI012S014 was confirmed by LCMS and 1H NMR; yield 42%. LCMS [M+H] = 388.

[0085] Example 16: Synthesis procedure for SAPTI012S015 Step-1: tert-Butyl {[3-(S-methanesulfonimidoyl)phenyl]methyl}carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF and added with DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and then 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.). ) Add the solution N2 After purging with HCl for 10 min, Pd(OAc)2 (5 mol%) was added and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C for 6 h under a N2 atmosphere. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S015 / IM1 was confirmed by LCMS; yield 47%. LCMS: [M+H] = 473 Step-2: Intermediate SAPTI012S015 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0°C in an ice bath. Then, HCl in dioxane (10 vol.) was added dropwise and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S015 / IM2 was confirmed by LCMS and used without further purification; yield - 98%. LCMS: [M+H] = 373 Step-3: SAPTI012S015 / IM2 (1.0 equiv.) was dissolved in water and AcOH (1:1), followed by the addition of sodium cyanate (1 equiv.) portionwise at 0 °C, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, evaporated under reduced pressure, and purified by reverse-phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S015 was confirmed by LCMS and 1H NMR; yield: 32%. LCMS: [M+H] = 416

[0086] Example 17: Synthesis procedure for SAPTI012S016 The previous intermediate SAPTI012S014 / IM1 (1.0 equiv.) was dissolved in isopropyl alcohol (10 v.), followed by the addition of NaOH (1 equiv.), and the resulting mixture was stirred at 80 °C for 12 h. After the reaction was complete, the reaction mixture was evaporated to remove isopropyl alcohol from the reaction mixture. The resulting crude product was diluted with water and extracted multiple times with DCM. The combined organic layers were concentrated to give the crude mixture. The product was purified by silica gel column chromatography using DCM and MeOH (0-10%) as eluents. The product SAPTI012S016 was confirmed by LCMS and 1H NMR; yield 50%. LCMS [M+H] = 387

[0087] Example 18: Synthesis procedure for SAPTI012S017 Step 1: 4-(S-methanesulfonimidoyl)benzonitrile (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-8-methoxyquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min, followed by Pd(OAc)2 (5 mol%) and slowly heated to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 8 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S017 / IM1 was confirmed by LCMS; yield 78%. LCMS: [M+H] = 339 Step 2: To the intermediate SAPTI012S017 / IM1 (1.0 equiv.) dissolved in isopropyl alcohol (10 v), NaOH (1 equiv.) was added, and the resulting mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was evaporated to remove isopropyl alcohol from the reaction mixture. The resulting crude product was diluted with water and extracted multiple times with DCM. The combined organic layers were concentrated to obtain a crude mixture. This crude product was purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S017 was confirmed by LCMS and 1H NMR; yield 13%. LCMS [M+H] = 357

[0088] Example 19: Synthesis procedure for SAPTI012S018 Step 1: 4-(S-methanesulfonimidoyl)benzonitrile (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Then, Pd(OAc)2 (5 mol%) was added, the temperature was slowly raised to 100 °C, and the reaction mixture was stirred at 100 °C under N2 atmosphere for 8 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S018 / IM1 was confirmed by LCMS; yield 96%. LCMS: [M+H] = 368 Step 2: To the intermediate SAPTI012S018 / IM1 (1.0 equiv.) dissolved in isopropyl alcohol (10 v), NaOH (1 equiv.) was added, and the resulting mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was evaporated to remove isopropyl alcohol from the reaction mixture. The resulting crude product was diluted with water and extracted multiple times with DCM. The combined organic layers were concentrated to obtain the crude mixture. The product was purified by silica gel column chromatography using DCM and MeOH (0-10%) as eluents. The product SAPTI012S018 was confirmed by LCMS and 1H NMR; yield 58%. LCMS [M+H] = 386

[0089] Example 20: Synthesis procedure for SAPTI012S019 Step 1: 4-(S-methanesulfonimidoyl)benzonitrile (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Then, Pd(OAc)2 (5 mol%) was added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 8 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0–5%) as eluents. The product SAPTI012S019 / IM1 was confirmed by LCMS; yield 95%. LCMS: [M+H] = 312 Step-2: Intermediate SAPTI012S019 / IM1 (1.0 equiv.) was dissolved in isopropyl alcohol (10 v), and then NaOH (1 equiv.) was added. The resulting mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was evaporated to remove isopropyl alcohol from the reaction mixture. The resulting crude product was diluted with water and extracted multiple times with DCM. The combined organic layers were concentrated to obtain a crude mixture. The product was purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S019 was confirmed by LCMS and 1H NMR; yield 78%. LCMS [M+H] = 329

[0090] Example 21: Synthesis procedure for SAPTI012S020 Step 1: 4-(S-methanesulfonimidoyl)benzonitrile (1.0 equiv.) was dissolved in toluene (0.2 M) in a RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-8-methoxyquinoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 8 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product (SAPTI012S20 / IM1) was confirmed by LCMS; yield 89%. LCMS: [M+H] = 338 Step-2: Intermediate SAPTI012S020 / IM1 (1.0 equiv.) was dissolved in isopropyl alcohol (10 v), and then NaOH (1 equiv.) was added. The resulting mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was evaporated to remove isopropyl alcohol from the reaction mixture. The resulting crude product was diluted with water and extracted multiple times with DCM. The combined organic layers were concentrated to obtain a crude mixture. The product was purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S020 was confirmed by LCMS and 1H NMR; yield 13%. LCMS [M+H] = 356

[0091] Example 22: Synthesis procedure for SAPTI012S021 Step 1: tert-Butyl {[3-(S-methanesulfonimidoyl)phenyl]methyl}carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Then, Pd(OAc)2 (5 mol%) was added, and the temperature was raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S021 / IM1 was confirmed by LCMS; yield 64%. LCMS: [M+H] = 369 Step-2: Intermediate SAPTI012S021 / IM1 (1.0 equiv.) was dissolved in 1N KOH (10V), and the resulting mixture was stirred at 60°C for 4 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted multiple times with DCM. The aqueous layer was acidified with 1N hydrochloric acid until acidic, and the resulting solution was extracted with DCM. The organic layer was collected and concentrated to give a crude mixture. The product was purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S021 was confirmed by LCMS and 1H NMR; yield 40%. LCMS [M+H] = 388

[0092] Example 23: Synthesis procedure for SAPTI012S022 The previous intermediate SAPTI012S021 / IM1 (1.0 equiv.) was dissolved in isopropyl alcohol (10 v.), followed by the addition of NaOH (1 equiv.), and the resulting mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was evaporated to remove isopropyl alcohol from the reaction mixture. The resulting crude product was diluted with water and extracted multiple times with DCM. The combined organic layers were concentrated to give the crude mixture. The product was purified by silica gel column chromatography using DCM and MeOH (0-10%) as eluents. The product SAPTI012S022 was confirmed by LCMS and 1H NMR; yield 40%. LCMS [M+H] = 387

[0093] Example 24: Synthesis procedure for SAPTI012S023 Step 1: tert-Butyl {[3-(S-methanesulfonimidoyl)phenyl]methyl}carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Next, Pd(OAc)2 (5 mol%) was added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product (SAPTI012S023 / IM1) was confirmed by LCMS; yield 64%. LCMS: [M+H] = 473 Step-2: Intermediate SAPTI012S023 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0°C in an ice bath. Then, dioxane-HCl (10 vol.) was added dropwise and stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and washed with ether. The hydrochloride salt of the product was dissolved in DCM and washed with water and NaHCO3 solution. The organic layer was concentrated and purified by silica gel chromatography. The product SAPTI012S023 was confirmed by LCMS and used without further purification; yield - 74%. LCMS: [M+H] = 373

[0094] Example 25: Synthesis procedure for SAPTI012S024 Step 3: SAPTI012S023 (1.0 equiv.) was dissolved in water and AcOH (1:1), followed by the addition of sodium cyanate (1.0 equiv.) portionwise at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was purified by reverse-phase column chromatography using water and MeOH as the eluent (20-30%). The product SAPTI012S024 was confirmed by LCMS and H NMR; yield: 30%. LCMS: [M+H] = 416

[0095] Example 26: Synthesis procedure for SAPTI012S025 Step 1: Dipropan-2-yl{2-[4-(S-methanesulfonimidoyl)phenyl]ethyl}phosphonate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 was then added, slowly heated to 100 °C, and stirred under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S025 / IM1 was confirmed by LCMS; yield 20%. LCMS: [M+H] = 536 Step-2: SAPTI012S025 / IM1 (1.0 equiv.) was dissolved in CHCl3 (0.2 M) in a sealed tube and cooled to 0°C in an ice bath. HBr (10 vol.) was added under N2 atmosphere and stirred at 60°C for 5 hours. After completion of the reaction, the reaction mixture was evaporated to dryness and purified by reversed-phase C18 column chromatography using 0.1% phosphoric acid in water and MeOH as the eluent (10-15%). The product SAPTI012S025 was confirmed by 1H NMR and LCMS; yield - 15%. LCMS: [M+H] = 452

[0096] Example 27: Synthesis procedure for SAPTI012S026 Step 1: 6-Bromo-1-imino-4,4-dimethyl-1,2,3,4-tetrahydro-1-benzothiopyran-1-one (1.0 equiv.) was dissolved in DMF (0.2 M) and cooled to 0 °C in an ice bath. Next, NaH (2.0 equiv.) and then 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv.) were added under a N2 atmosphere. The temperature of the reaction mixture was slowly raised to 100 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by silica gel column chromatography using EtOAc and hexane as eluents (0.5-10%). The product SAPTI012S026 / IM1 was confirmed by LCMS; yield - 40%. LCMS: [M+H] = 477. Step-2: Intermediate SAPTI012S026 / IM1 (1.0 equiv.) was dissolved in EtOH (0.2 M) in a sealed tube. XPhos (7.5 mol%), DIPEA (1.4 equiv.), and diethyl phosphite (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 was then added, and the temperature was slowly raised to 100 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by column chromatography using DCM and MeOH (0-5%) as eluents. Intermediate SAPTI012S026 / IM2 was confirmed by LCMS; yield 80%. LCMS: [M+H] = 534 Step-3: Intermediate SAPTI012S026 / IM2 (1.0 equiv.) was dissolved in DCM (0.2 M) in RBF and cooled to 0 °C in an ice bath. Trimethylsilyl bromide (10 vol.) was then added under N2 atmosphere and stirred at room temperature for at least 12 h. After completion of the reaction, the reaction mixture was evaporated to dryness and purified by reverse-phase column chromatography using 0.1% phosphoric acid in water and MeOH as the eluent (10-15%). The pure product SAPTI012S026 was confirmed by 1H NMR and LCMS; yield - 44%. LCMS: [M+H] = 478

[0097] Example 28: Synthesis procedure for SAPTI012S027 Step 1: Dipropan-2-yl[3-(S-benzenesulfonimidoyl)propyl]phosphonate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 was then added, slowly heated to 100 °C, and stirred under N2 for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product (SAPTI012S027 / IM1) was confirmed by LCMS; yield 20%. LCMS: [M+H] = 536 Step-2: Intermediate SAPTI012S027 / IM1 (1.0 equiv.) was dissolved in CHCl3 (0.2 M) in a sealed tube and cooled to 0 °C in an ice bath. HBr (10 V) was added under N2 atmosphere and stirred at 60 °C for 5 h. After completion of the reaction, the reaction mixture was evaporated to dryness and purified by reversed-phase C18 column chromatography using 0.1% phosphoric acid in water and MeOH as the eluent (10-15%). The product SAPTI012S027 was confirmed by 1H NMR and LCMS; yield - 15%. LCMS: [M+H] = 452

[0098] Example 29: Synthesis procedure for SAPTI012S028 Step 1: 1-Bromo-5-(S-methanesulfonimidoyl)naphthalene (1.0 equiv.) was dissolved in THF (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added and purged with N2 for 10 min. Pd(OAc)2 was then added, and the reaction mixture was slowly heated to 100 °C under N2 atmosphere and stirred for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S028 / IM1 was confirmed by LCMS; yield 65%. LCMS: [M+H] = 473 Step 2: Intermediate SAPTI012S028 / IM1 (1.0 equiv.) was dissolved in EtOH (0.2 M) in a sealed tube. XPhos (7.5 mol%), DIPEA (1.4 equiv.), and diethyl phosphite (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 was then added, and the temperature was slowly raised to 100 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by column chromatography using DCM and MeOH (0-5%) as eluents. Intermediate SAPTI012S028 / IM2 was confirmed by LCMS; yield 80%. LCMS: [M+H] = 530 Step-3: Intermediate SAPTI012S028 / IM2 (1.0 equiv.) was dissolved in DCM (0.2 M) in RBF and cooled to 0 °C in an ice bath. Trimethylsilyl bromide (10 V) was then added under N2 atmosphere and stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was evaporated to dryness and purified by reversed-phase column chromatography using 0.1% phosphoric acid in water and MeOH as the eluent (10-15%). The pure product SAPTI012S028 was confirmed by 1H NMR and LCMS; yield - 44%. LCMS: [M+H] = 474

[0099] Example 30: Synthesis procedure for SAPTI012S029 Step 1: tert-Butyl [5-(S-methanesulfonimidoyl)naphthalen-1-yl]carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the reaction mixture was purged with N2 for 10 min. Pd(OAc)2 was then added, and the reaction mixture was slowly heated to 100 °C under a N2 atmosphere. Stirring was continued at 100 °C for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S029 / IM1 was confirmed by LCMS; yield 71%. LCMS: [M+H] = 509 Step-2: Intermediate SAPTI012S029 / IM1 (1.0 equiv.) was dissolved in dioxane (0.2 M) in RBF and cooled to 0°C in an ice bath. Then, hydrochloric acid (10 vol.) in dioxane was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was evaporated to dryness, washed with diethyl ether, quenched with 10% NaHCO3 solution, and extracted multiple times with DCM. The combined organic layer was concentrated and carried to the next step without purification. The product SAPTI012S029 / IM2 was confirmed by LCMS; yield - 65%. LCMS: [M+H] = 409 Step-3: Intermediate SAPTI012S029 / IM2 (1.0 equiv.) was dissolved in AcOH / HO (1:1) (0.5 M) in RBF, then NaOCN (1.0 equiv.) was added at 0 °C and the reaction mass was stirred at room temperature for 3 h. After completion of the reaction, it was quenched with diluted NaOH and extracted multiple times with DCM. The combined organic layer was concentrated under reduced pressure and purified by neutral alumina column chromatography using DCM and MeOH as eluents (10-15%). The pure product SAPTI012S029 was confirmed by 1H NMR and LCMS; yield - 44%. LCMS: [M+H] = 452

[0100] Example 31: Synthesis procedure for SAPTI012S030 Step 1: tert-Butyl N-[3-(cyclopentylsulfonimidoyl)phenyl]carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Then, Pd(OAc)2 (5 mol%) was added, and the temperature was raised to 100 °C. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product (SAPTI012S030 / IM1) was confirmed by LCMS; yield 63%. LCMS: [M+H] = 513 Step-2: SAPTI012S030 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0°C in an ice bath. Then, HCl in dioxane (10 vol.) was added dropwise and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S030 / IM2 was confirmed by LCMS and used without further purification; yield - 72%. Step-3: The HCl salt of SAPTI012S030 / IM2 (1.0 equiv.) was dissolved in water and AcOH (1:1), followed by the addition of sodium cyanate (1 equiv.) portionwise at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, evaporated under reduced pressure, and purified by reverse-phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S030 was confirmed by LCMS and 1H NMR; yield: 30%. LCMS: [M+H] = 456

[0101] Example 32: Synthesis procedure for SAPTI012S031 Step 1: Diethyl {4-[S-(propane-2-)sulfonimidoyl]phenyl}phosphonate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 was then added, and the reaction mixture was slowly heated to 100 °C and stirred under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S031 / IM1 was confirmed by LCMS; yield 20%. LCMS: [M+H] = 508 Step-2: Intermediate SAPTI012S031 / IM1 (1.0 equiv.) was dissolved in CHCl3 (0.2 M) in a sealed tube and cooled to 0 °C in an ice bath. HBr (10 vol.) was added under N2 atmosphere and stirred at 60 °C for 5 h. After completion of the reaction, the reaction mixture was evaporated to dryness and purified by reversed-phase C18 column chromatography using 0.1% phosphoric acid in water and MeOH as the eluent (10-15%). The product SAPTI012S031 was confirmed by 1H NMR and LCMS; yield - 15%. LCMS: [M+H] = 452

[0102] Example 33: Synthesis procedure for SAPTI012S032 Step 1: tert-Butyl N-[3-(propan-2-ylsulfonimidoyl)phenyl]carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S032 / IM1 was confirmed by LCMS; yield 30%. LCMS: [M+H] = 485 Step-2: Intermediate SAPTI012S032 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0 °C in an ice bath. Then, dioxane HCl (10 vol.) was added dropwise and stirred at room temperature for 5 hours or more. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The hydrochloride salt of SAPTI012S032 / IM2 was confirmed by LCMS and used without further purification. Step-3: The HCl salt of SAPTI012S032 / IM2 (1.0 equiv.) was dissolved in water, and AcOH (1:1) followed by sodium cyanate (1 equiv.) was added portionwise at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, evaporated under reduced pressure, and purified by reverse-phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S032 was confirmed by LCMS and 1H NMR; yield: 65%. LCMS: [M+H] = 428

[0103] Example 34: Synthesis procedure for SAPTI012S033 Step 1: tert-Butyl N-[3-(propan-2-ylsulfonimidoyl)phenyl]carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. Then, DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S033 / IM1 was confirmed by LCMS; yield 61%. LCMS: [M+H] = 487 Step-2: Intermediate SAPTI012S033 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0 °C in an ice bath. HCl in dioxane (10 vol.) was then added dropwise and stirred at room temperature for 5 hours or more. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S033 / IM2 was confirmed by LCMS and used without further purification; yield - 72%. Step-3: The HCl salt of SAPTI012S033 / IM2 (1.0 equiv.) was dissolved in water, and AcOH (1:1) followed by sodium cyanate (1 equiv.) was added portionwise at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, evaporated under reduced pressure, and purified by reverse-phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S033 was confirmed by LCMS and 1H NMR; yield: 30%. LCMS: [M+H] = 430

[0104] Example 35: Synthesis procedure for SAPTI012S034. Step 1: tert-Butyl [4-(S-benzenesulfonimidoyl)phenyl]carbamate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Then, Pd(OAc)2 (5 mol%) was added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S034 / IM1 was confirmed by LCMS; yield 30%. LCMS: [M+H] = 521 Step-2: Intermediate SAPTI012S034 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0 °C in an ice bath. HCl in dioxane (10 vol.) was then added dropwise and stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S034 / IM2 was confirmed by LCMS and used without further purification; yield - 60%. Step-3: The HCl salt of SAPTI012S034 / IM2 (1.0 equiv.) was dissolved in water and AcOH (1:1), followed by the addition of sodium cyanate (1 equiv.) portionwise at 0 °C, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and extracted multiple times with DCM. The combined organic layers were washed with brine, passed through anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was then purified by reverse-phase column chromatography using water and MeOH as the eluent (20-30%). The product SAPTI012S034 was confirmed by LCMS and 1H NMR; yield: 55%. LCMS: [M+H] = 464

[0105] Example 36: Synthesis procedure for SAPTI012S035 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-8-methoxyquinazoline (1.5 equiv.) were added, and the solution was purged with N2 for 10 min. Next, Pd(OAc)2 (5 mol%) was added, the temperature was raised to 100 °C, and the reaction mixture was stirred at 100 °C for 16 h under a N2 atmosphere. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S035 / IM1 was confirmed by LCMS; yield 35%. LCMS: [M+H] = 393 Step 2: Intermediate SAPTI012S035 / IM1 (1.0 equiv.) was dissolved in dry 1,4-dioxane (0.2 M). B2(Pin)2 (1.4 equiv.) KOAc (3.5 equiv.) followed by PdCl2(dppf) complex (5 mol%) was added. The reaction mixture was purged with N2 for 10 min, then the temperature was slowly raised to 100 °C and stirred at the same temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S035 was confirmed by LCMS and 1H NMR; yield 40%. LCMS: [M+H] = 358.

[0106] Example 37: Synthesis procedure for SAPTI012S036 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-bromo-6,7-dimethoxyquinoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S036 / IM1 was confirmed by LCMS; yield 65%. LCMS: [M+H] = 422 Step 2: Intermediate SAPTI012S036 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M), B2(Pin)2 (1.4 equiv.), KOAc (3.5 equiv.), and then PdCl2(dppf) complex (5 mol%) were added. The reaction mixture was purged with nitrogen for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S036 was confirmed by LCMS and 1H NMR; yield 45%. LCMS: [M+H] = 387.

[0107] Example 38: Synthesis procedure for SAPTI012S037 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF, followed by the addition of DPE Phos (7.5 mol%), CsCO (1.4 equiv.), and then 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 equiv.). The solution was purged with N for 10 min, after which Pd(OAc) (5 mol%) was added and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S037 / IM1 was confirmed by LCMS; yield 43%. LCMS: [M+H] = 365 Step 2: Intermediate SAPTI012S037 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M), B2(Pin)2 (1.4 equiv.), KOAc (3.5 equiv.), and then PdCl2(dppf) complex (5 mol%) were added. The reaction mixture was purged with N2 for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S037 was confirmed by LCMS and 1H NMR; yield 55%. LCMS: [M+H] = 331.

[0108] Example 39: Synthesis procedure for SAPTI012S038 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and then 4-chloro-6-fluoroquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S038 / IM1 was confirmed by LCMS; yield 34%. LCMS: [M+H] = 381 Step 2: Intermediate SAPTI012S038 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M), followed by the addition of B2(Pin)2 (1.4 equiv.), KOAc (3.5 equiv.), and PdCl2(dppf) complex (5 mol%). The reaction mixture was purged with N2 for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S038 was confirmed by LCMS and 1H NMR; yield 50%. LCMS: [M+H] = 346.

[0109] Example 40: Synthesis procedure for SAPTI012S039 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-5-methoxyquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S039 / IM1 was confirmed by LCMS; yield 76%. LCMS: [M+H] = 393 Step 2: Intermediate SAPTI012S039 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M), followed by the addition of B2(Pin)2 (1.4 equiv.), KOAc (3.5 equiv.), and PdCl2(dppf) complex (5 mol%). The reaction mixture was purged with N2 for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S039 was confirmed by LCMS and 1H NMR; yield 25%. LCMS: [M+H] = 358.

[0110] Example 41: Synthesis procedure for SAPTI012S040 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (1.5 equiv.) were added. The solution was purged with N2 for 10 min, after which Pd(OAc)2 (5 mol%) was added and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S040 / IM1 was confirmed by LCMS; yield 34%. LCMS: [M+H] = 394 Step 2: Intermediate SAPTI012S040 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M). B2(Pin)2 (1.4 equiv.) KOAc (3.5 equiv.) followed by PdCl2(dppf) complex (5 mol%) was added. The reaction mixture was purged with N2 for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S040 was confirmed by LCMS and 1H NMR; yield 30%. LCMS: [M+H] = 359.

[0111] Example 42: Synthesis procedure for SAPTI012S041 Step 1: 1-Bromo-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloroquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S041 / IM1 was confirmed by LCMS; yield 92%. LCMS: [M+H] = 363 Step 2: Intermediate SAPTI012S041 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M). Then, B2(Pin)2 (1.4 equiv.) KOAc (3.5 equiv.) and PdCl2(dppf) complex (5 mol%) were added. The reaction mixture was purged with N2 for 10 min. The temperature was then slowly raised to 100 °C and stirred at that temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S041 was confirmed by LCMS and 1H NMR; yield 25%. LCMS: [M+H] = 328.

[0112] Example 43: Synthesis procedure for SAPTI012S042 Step 1: Methyl [4-(S-methanesulfonimidoyl)phenyl]acetate (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF. DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-8-methoxyquinazoline (1.5 equiv.) were added. The solution was purged with N2 for 10 min. Pd(OAc)2 (5 mol%) was then added, and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S042 / IM1 was confirmed by LCMS; yield 79%. LCMS: [M+H] = 416 Step-2: A (0.2 M) solution of SAPTI012S042 / IM1 in aqueous NH4OH (28-30%) was stirred at room temperature (25 °C) for 16 h. The solvent was then evaporated to give a crude reaction mixture, which was purified by flash column chromatography using MeOH in DCM as the solvent and neutral alumina as the stationary phase (0-5%). The product SAPTI012S042 was confirmed by LCMS and 1H NMR; yield 34%. LCMS: [M+H] = 401

[0113] Example 44: Synthesis procedure for SAPTI012S043 Step 1: 2-Bromo-1-fluoro-4-(S-methanesulfonimidoyl)benzene (1.0 equiv.) was dissolved in toluene (0.2 M) in RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv.), and 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv.). The solution was purged with N2 for 10 min, followed by the addition of Pd(OAc)2 (5 mol%) and the temperature was slowly raised to 100 °C. The reaction mixture was stirred at 100 °C for 16 h under a N2 atmosphere. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH (0-5%) as eluents. The product SAPTI012S043 / IM1 was confirmed by LCMS; yield 31%. LCMS: [M+H] = 441 Step 2: Intermediate SAPTI012S043 / IM1 (1.0 equiv.) was dissolved in dry dioxane (0.2 M), B2(Pin)2 (1.4 equiv.), KOAc (3.5 equiv.), and then PdCl2(dppf) complex (5 mol%) were added. The reaction mixture was purged with N2 for 10 min, then the temperature was slowly raised to 100 °C and stirred at that temperature for 8 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S043 was confirmed by LCMS / H NMR; yield 40%. LCMS: [M+H] = 406

[0114] The characteristic data of the compound are as follows: Table 1: H NMR and LCMS data for compounds of the present invention [Table 1] JPEG2025527243000070.jpg252162JPEG2025527243000071.jpg233162JPEG2025527243000072.jpg251162JPEG2025527243000073.jpg23816 1JPEG2025527243000074.jpg246162JPEG2025527243000075.jpg221161JPEG2025527243000076.jpg216162JPEG2025527243000077.jpg45162

[0115] Optical resolution of the (R) and (S) enantiomeric mixture of the present invention: The mixture of (R) and (S) enantiomers / racemates of the present invention can be separated into the individual enantiomers using analytical or / and preparative chiral chromatography (HPLC). The compound of Example 7 was subjected to chiral separation and its activity value is shown in Table 3.

[0116] ENPP-1 inhibition assay Assay method: 3 nM human ENPP-1 prepared at pH 7.4 was incubated with 5 μM cGAMP substrate, test sample prepared in pH 7.4 buffer, and 40 μM HSA. The reaction was incubated at room temperature for 3 hours. After incubation, the contents were heated to 95°C for 10 minutes to terminate the reaction. 10 μl of this solution was added to a 384-well plate, to which 10 μl of AMP Glo Reagent-1 was added, followed by incubation at 25°C for 60 minutes. After incubation, 20 μl of AMP detection solution was added to each well along with the enzyme reaction mixture, followed by incubation at 25°C for 60 minutes. Luminescence signals (RLU) were recorded using a SpectraMax I3X plate reader.

[0117] The luminescence signal is measured as a function of inhibitor concentration. If the inhibitor molecule is active, the luminescence reading (called OD) decreases with increasing inhibitor concentration. The percent inhibition is calculated using the following formula: Percent inhibition = ((OD of control - OD of sample) / OD of control) x 100

[0118] In the present disclosure, the IC50 value of an inhibitor molecule is measured as the concentration of the inhibitor that inhibits 50% of the proliferation of human ENPP-1. A graph is drawn with the inhibitor concentration on the X-axis versus the inhibition rate on the Y-axis, and the slope is measured as the IC50 value.

[0119] Some compounds of the present invention were subjected to ENPP-1 inhibition assay to identify IC50 values and / or inhibition rates. The metabolic stability of these compounds was also measured.

[0120] The results of the ENPP-1 inhibition assay for several compounds are shown in Table 1. The data presented in Table 1 indicate that many of the lead molecules of the present invention inhibit the function of phosphodiesterase enzymes such as ENPP-1 and have promising efficacy in treating diseases such as cancer.

[0121] In some aspects, the present invention provides methods of treating cancer in an individual in need thereof, the methods comprising administering to the individual an effective amount of a compound of the present invention, or a salt thereof.

[0122] In some respects, the present invention provides a method of treating a disease or disorder associated with the ENPP-1 enzyme in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of the present invention or a salt thereof.

[0123] The compounds detailed herein or salts thereof can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. [Table 2] JPEG2025527243000079.jpg34158

[0124] One of the enantiomers of the compound of formula I is less active than the other. The codes SAPTI012S006-E1 and SAPTI012S006-E2 refer to the two enantiomers of SAPTI012S006. The enantiomers are separated by chiral HPLC. The enantiomers have not yet been assigned a Cahn Ingold Prelog configuration (R or S). [Table 3]

[0125] In another embodiment of the invention, there is provided the use of a compound of formula I 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 defined by formula I.

[0126] In one embodiment, the pharmaceutical formulation containing the compound of Formula I or its salt 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 nanoparticle formulation.

[0127] In one embodiment, the pharmaceutical formulation containing the compound of formula I or a salt thereof is adapted for oral, rectal, topical or intravenous administration, and optionally contains any one or more pharmaceutically acceptable carriers, adjuvants or vehicles (excipients).

[0128] The compound of Formula I or its salts may be formulated with a suitable carrier and provided in a delivery form including, but not limited to, tablets, caplets, capsules, cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasts (poultices), patches, powders, patches, packs, creams, solutions, patches, aerosols (e.g., nasal sprays 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.

[0129] In one embodiment, the compound of Formula I is formulated for oral administration and can be administered in any conventional formulation, for example, in the form of a solid formulation such as a tablet, powder, granule, capsule, etc.; an aqueous formulation; an oily suspension; or a liquid formulation such as a syrup or elixir. In one embodiment, the compound of Formula I is formulated for parenteral administration and can be administered as an aqueous or oily suspension injection or nasal drops. When preparing parenteral formulations using the compound of Formula I, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers, etc. can be optionally used.

[0130] For example, when administered orally in the form of a tablet or capsule, the compound of formula I can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Powders are prepared by comminuting the compound of formula I to a suitable size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, for example, starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents can also be present.

[0131] Capsules are produced by preparing a powder mixture as described above and filling formed gelatin sheaths. Lubricants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before filling. Disintegrants or solubilizers such as agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.

[0132] Furthermore, if 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 β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding lubricants and disintegrating agents, and pressing into tablets. Powder mixtures are prepared by mixing the suitably comminuted compound with the above-mentioned diluents or bases, optionally with binders such as carboxymethylcellulose, alginates, gelatin, or polyvinylpyrrolidone; solution retardants such as paraffin; resorption accelerators such as quaternary salts; and / or adsorbents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be moistened with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials, and forced through a screen. Instead of granulating, the powder mixture can be run through a tablet machine, resulting in imperfect slugs of granules. The granules can be lubricated by the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent sticking to the tablet-forming dies. 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 the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a sugar or polymeric coating, and a polish coat of wax can be provided, and dyes can be added to these coatings to distinguish different unit dosages.

[0133] Oral preparations such as solutions, syrups, and elixirs can be prepared in dosage unit form containing a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, and elixirs can be prepared by using a non-toxic alcoholic vehicle. Suspensions can be prepared by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives such as peppermint oil, natural sweeteners, and artificial sweeteners such as saccharin, can also be added.

[0134] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. Formulations of the compound of Formula I can also be prepared so as to prolong or sustain the release of the compound, for example, by coating or embedding particulate matter in polymers, waxes, etc.

[0135] The compound of formula I or a salt, solvate, or hydrate 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, phosphatidylcholines, and the like.

[0136] The compound of Formula I or its salt, solvate, or hydrate can also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are bound.The compound can also be bound to a soluble polymer as a targetable drug carrier.Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues.In addition, the compound can be bound to a group of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate, and crosslinked or amphiphilic block copolymers of hydrogels.

[0137] Pharmaceutical formulations adapted for transdermal administration can be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the compound of formula I can be delivered from the patch by iontophoresis, as described in Pharmaceutical Research, 3(6), 318 (1986).

[0138] Pharmaceutical preparations suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.When formulated into ointments, active ingredients can be used with either a paraffinic ointment base or a water-miscible ointment base.Alternatively, active ingredients can be incorporated into creams using an oil-in-water cream base or a water-in-oil cream base.

[0139] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

[0140] Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include coarse powder having a particle size in the range 20 to 500 microns, which may be 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 to the nose. Formulations wherein the carrier is a liquid, suitable for administration as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.

[0141] 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.

[0142] Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions containing suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. Injection solutions and suspensions can be prepared from sterile powders, granules, or tablets.

[0143] The formulations described herein may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavorings.

[0144] The therapeutically effective amount of a compound of Formula I will depend on many 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, the route of administration, and is ultimately at the discretion of the attending physician or veterinarian. An effective amount of a salt or hydrate thereof can be determined as a fraction of the effective amount of the compound of Formula I or its salt, solvate, or hydrate per se.

[0145] Embodiments of the present invention provide for administering a compound of Formula I to a healthy individual or a patient with cancer disease, alone or in combination with another agent that (a) is effective against cancer disease, (b) improves immune response and robustness, or (c) reduces inflammation and / or pain.

[0146] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art that certain changes and modifications can be made therein without departing from the spirit or scope of the appended claims. The foregoing merely illustrates the principles of the present invention. All examples and conditional language incorporated herein are intended primarily to aid the reader in understanding the principles of the present invention and the concepts contributed by the inventors to further develop this technology, and are not intended to be limited to such specifically incorporated examples and conditions. Therefore, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof. wherein Formula I has moieties A and B constituting the tail portion, moiety C constituting the core portion, a sulfoximine-type group R2-S(=W)(=N) connecting the tail portion to the core portion, and a zinc binding group (ZBG), The moiety A can be one or more R 3 is a 6-membered aryl or heteroaryl optionally substituted with a group; X 1 , X 2 and X 3 X, provided that two or more of them are not N at the same time. 1 , X 2 and X 3 are CH, N, CR', Moiety B is a C6 aryl or 5-6 membered heteroaryl optionally substituted with one or more R4 groups, and moiety B is fused to moiety A such that the two shared atoms between moiety B and moiety A come from a pair of carbon atoms or a pair of atoms where one atom is nitrogen and the other is carbon; the moiety C is selected from the group of structures consisting of (i), (ii), (iii), (iv), (v) and (vi); where L1 is connected to (i) at a variable position on the ring, wherein E1 is connected to the sulfur atom of the R2-S(=W)(=N) group and the linker (L1) is connected to the "a" atom of the zinc binding group (ZBG); R if n>1 1 n=0, 1, 2, 3, 4, with the proviso that the groups are the same or different; R 1 , R 3 , R 4 The groups include R', halo, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF 3 , CHF 2 , C.H. 2 F, OCF 3 and C.H. 2 Ar, where R' = H, CN, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, CH 2 Ar and Ar=aryl, substituted aryl, heteroaryl, or substituted heteroaryl; E1 = -(CH 2 ) y -where y=0, 1 or 2, L1 = -(CH 2 ) y1 , NR", O or S, C1-6 straight chain alkyl, branched chain alkyl, -(CH 2 ) y1 cycloalkyl, where y1=0, 1, 2 or 3; where R" = H, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, substituted aryl, halogenated alkyl; X 4 , X 5 and X 6 = CH, N or CR', Moiety A is connected to the nitrogen atom of the R2-S(=W)(=N) group, where S is a chiral sulfur atom, N is nitrogen, W is O or NH; R2 is C1-6 straight chain, branched, cycloalkyl, alkenyl, alkylene, alkynyl, halo, aryl, heteroaryl, heterocyclic, substituted aryl, CF 3 , CHF 2 , C.H. 2 selected from the group consisting of F, CN and 2- to 6-membered alkylene groups, one end of which is bonded to the sulfur atom and the other end of which is bonded to moiety C at a position α to the carbon atom of moiety C bonded to the sulfur atom when y=0, thereby forming a ring structure; and ZBG is shown in structure (vii), (vi) where a = S, P, C, or B atom, b1, b2 = O, S, NH or CH 2 and b3 = O, S, NH, CH 2 or NH 2 O, Then, in a given instance, m 1 , m 2 , m 3 m, provided that exactly one of 1 , m 2 , m 3 =0, 1.

2. 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

3. 10. The compound of claim 1, wherein the compound inhibits the function of a phosphodiesterase enzyme.

4. 4. The compound of claim 3, wherein the phosphodiesterase enzyme is selected from the group consisting of ENPP-1, cyclic nucleotide phosphodiesterase, phospholipase C and D, autotaxin, sphingomyelin phosphodiesterase, DNase, RNase, restriction endonucleases, small phosphodiesterases, and combinations thereof.

5. 2. The compound of claim 1, wherein the isomer is a stereoisomer of formula I.

6. 6. The compound of claim 5, wherein the stereoisomer is selected from the group consisting of an enantiomer and a racemate.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient and / or diluent.

8. 10. A method for treating glioma, glioblastoma multiforme, paraganglioma, supraventricular primitive neuroectodermal tumor, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), other solid tumors, and mycobacterial diseases, comprising administering the pharmaceutical composition of claim 7 to a human in need thereof.

Images