Novel exonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) inhibitor and application thereof

Abstract

The invention discloses a novel efficient ENPP-1 inhibitor which is used for treating various diseases, especially cancers. Such inhibitors are small molecules. Wherein a new structural feature is incorporation of a sulfoximine group located between the tail and the core portion. 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 can inhibit ENPP-1 protein, and the compounds have the potential to be applied in disease treatment immunotherapy. The present invention further discloses a synthetic method for preparing the compounds, pharmaceutical compositions thereof, and potential uses in the treatment of many diseases (especially cancer). Background Art

[0002] It is reported that one of the strategies for treating cancer, especially cancer immunotherapy, is to enhance the body's anti-tumor immune response. A recent journal article, Nat Cancer, Vol. 1, pp. 184-196 (2020), also reported that by inhibiting a protein called "ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP-1)" (ENPP-1 is known to negatively regulate innate immune signals), the immune response is enhanced 2 as part of the treatment of cancer diseases.

[0003] In the journal literature, i.e. a) J Hematol Oncol, Vol. 13, p. 81 (2020); b) Molecules, Vol. 24, No. 22, p. 4192 (2019); c) Cell Chemical Biology, Vol. 27, pp. 1347-1358

[0004] (2020). The cGAS STING pathway is important for interferon (IFN) production and T cell activation, and therefore has the potential to play a role in cancer immunotherapy. It has been found that the hydrolysis of cGAMP (cyclic GMP-AMP) by ENPP-1 attenuates cGAS-STING signaling. Therefore, inhibition of ENPP-1 will reduce the hydrolysis of cGAMP and promote enhanced cGAS-STING signaling, accompanied by an increase in the body's immune response. In a review article in Trends in Biochemical Science, Vol. 46, No. 6, pp. 446-460 (2021), it is pointed out that in addition to the critical IFN signaling, cGAS-STING is also widely involved in the autophagy process.

[0005] ENPP-1 plays a regulatory role in immune cells such as neutrophils, macrophages, dendritic cells, natural killer cells and B lymphocytes. When cancer occurs, the expression of ENPP-1 in M2 macrophages increases and aggravates the growth and spread of tumors. In the observation of breast cancer, it was found that ENPP-1 may promote the development of cancer. For example, through the overexpression of ENPP-1, the metastasis of tumors to bones is enhanced.

[0006] ENPP-1 belongs to the phosphodiesterase family. Patent W02018119328A1 reviews the roles and types of different phosphodiesterases. Phosphodiesterases are a class of enzymes that catalyze the hydrolysis of phosphodiester bonds. In some cases, phosphodiesterases are associated with viral infections, and inhibition of phosphodiesterases can reduce viral replication. In some cases, this class of phosphodiesterases also includes cyclic nucleotide phosphodiesterases, phospholipase C and D, spinosin, sphingomyelin phosphodiesterases, restriction endonucleases, and small molecule phosphodiesterases. The literature "Journal of Biological Chemistry" (J Biol Chem) Vol. 280, No. 24, p. 22962 (2005) and "Moscow Biochemistry" (Biochemistry Moscow) Vol. 75, pp. 1-6 (2010) supports the molecular function of the chemical similarity between phosphodiesterases and nucleases, nucleotidases, and phosphatases. In some examples, the bacteria is Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novo, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae or Neisseria gonorrhoeae. Therefore, phosphodiesterase inhibitors will have a potential impact on the treatment of many diseases. The industry is in urgent need of an inhibitor with high specificity in inhibiting a specific phosphodiesterase (such as ENPP-1). Some prior art reports disclose ENPP-1 inhibitors with different structures and different potencies. The main features of the recently reported prior art references are as follows: a) ENPP-1 inhibitors are mainly targeted at cancer diseases; b) as shown in formula 11-X, the structure of the inhibitor has at least three basic components, including a tail, a core and a zinc binding domain (the domain is also called a part); c) some of these structures have a connecting group (linker) between the core and the zinc binding part, and / or some structures have a linker between the core and the tail.

[0007] Scheme 1 highlights the structures of some prior art inventions related to ENPP-1 inhibition. Although the scaffolds represented by formula II-V are not completely similar, they all contain a tail, a core, and a zinc binding portion. Some of the scaffolds include only one linker, while others have two linkers. The ENPP-1 inhibitory activity of the compounds of formula II-V has been disclosed in the relevant literature on cancer treatment.

[0008] Solution 1

[0009]

[0010] Patent document US20220135598Al discloses the structure of the inhibitor, which conforms to formula II, wherein the tail part is mainly quinoline or substituted quinoline part, there is a specific substituted quinoline molecule on the quinoline ring, and the core part is a cyclic or fused spiro ring; the linker part L connecting the core part and the zinc binding part can be a bond, a linear or branched C1-C6 olefin or a linear or branched C2-C6 olefin; the zinc binding part is NRcS(O)2NH2, -NRcS(O)2CH3, -SO2NH2, -NRcC(O)CH3, -C(O)OH, -CONH2, NRcCONH2, -CONH(OH), -B(OH)2, -P(O)(OH)2, -SO2OH, -NRcS(O)2CF3, -NRcS(O)2CF3, NRcS(O)2NHCH3, or -NR1CH2C6-aryl-S(O)2NH2. Rc is defined as hydrogen, alkyl, substituted cycloalkyl, substituted alkylene and substituted heteroaryl.

[0011] Patent document WO2020160333A1 discloses an inhibitor structure conforming to formula III, the main feature of which is that there is an additional linker L1 between the core part and the tail. The linker L2 is located between the core and the zinc binding domain. The disclosed zinc binding group is a phosphorus-containing group or a urea group. The core part can be an aryl group. In addition, the linker L1 can also be an alkyl, alkenyl, alkynyl, aryl, aralkyl and a linker molecule containing functional groups, which include but are not limited to: amino, urea, imine, epoxy, epithio, epidioxy, carbone dioxy, alkyl dioxy, epoxy imino, epidioxy and carbonyl.

[0012] Patent document WO2019051269Al discloses a structure as shown in Formula-IV, wherein the linker between the core and X is called L, and the linker can be a (Cl-6) alkyl linker or a substituted (Cl-6) alkyl linker, optionally substituted by a heteroatom or a connecting functional group, such as an ester (-CO2-), an amino group (-CONH), a carbamate (-OCONH), an ether (-O-), a thioether (-S-) and / or an amino group. The tail is based on a quinazoline molecule, and the core part is represented by C, which is an aromatic ring. The zinc binding part represented by X is based on a phosphoric acid or sulfonamide or urea group.

[0013] Patent document WO2021225969Al discloses a structure as shown in Figure-V, wherein L is a bond, -0-, -C(O)-, -NR6c- or -OCR7c-*, where * represents a connection point containing a zinc binding portion. W in Figure-V comprises a core group and a zinc binding portion connected by a linker L. The zinc binding site is a sulfoximine group, and there is only one hydrogen atom as a substituent on the nitrogen atom of the sulfoximine group. R6c and R7c are each independently hydrogen or Cl-3 alkyl, wherein a1 and a2 are independently 0, 1, 2 or 3.

[0014] Patent document WO2021226136Al discloses an ENPP-1 inhibitory structure similar to that described in Formula-IV.

[0015] Patent document WO2019046778Al discloses a structure as shown in Formula-VI, in which there are two linkers named L and Ll, and with sulfonamide end groups for inhibiting ENPP-1. Wherein X is -NR7-, -O-, -S-, -S(=O)-, -S(=O)2- or -CR8R9-; L is a bond or -CR10R11-; L1 is a bond or -CR13R14-. R7 is hydrogen, -CN, substituted alkoxy, substituted ester, substituted carbonyl, substituted amide, substituted sulfoxide, substituted sulfone, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. R8 and R9 are independently hydrogen, deuterium, halogen, -CN, substituted alkoxy, -NO2, substituted amino, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl.

[0016]

[0017] Patent document US20190282703A1 discloses a structure as shown in Formula VII, wherein there is a single linker L (as described), a sulfonamide terminal group and a monocyclic tail terminal group. L is defined as -(CR3R4)n-, where X is -N- or -CH-. R3 and R4 on the same carbon are combined to form an oxo group.

[0018] Patent document WO2021158829A1 discloses a structure as shown in formula VIII, wherein L is selected from a group consisting of a Cl-C5 alkyl group and a Cl-C5 alkenyl group; Y is selected from a group consisting of -CR4R5-, -NR6-, -N(CH2)m0-, -0-, -S-, -S(O)-, -S(0)2, aryl and heteroaryl groups; wherein m is 2 or 3, and is used to treat cancer, bacterial or viral diseases. R4, R5 and R6 are independently selected from a group including hydrogen and a lower alkyl group; or an isomer, hydrate, solution, polymorph, homologue or pharmaceutically acceptable salt thereof.

[0019]

[0020] Patent document WO2020140001Al discloses a quinazoline-based structure as shown in Formula-IX, which can inhibit the activity of ENPP-1 enzyme and can therefore be used to treat diseases.

[0021]

[0022] Other relevant prior art references are mentioned below which disclose certain compounds as ENPP-1 inhibitors whose structures do not conform to the description of the zinc binding portion of the tail core given in Figures I-IX.

[0023] WO2022056068Al discloses small molecule ENPP-1 inhibitors for treating various heart diseases. Patent document WO2019023635Al discloses novel ENPP-1 inhibitors and interferon gene stimulators (STING) regulators of substituted-3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,5-c]pyridine series as cancer immunotherapy. Patent document WO2021053507 Al discloses 2-amino-S6-substituted thiopurine compounds as ENPP-1 inhibitors for treating cancer, infectious diseases and other related diseases.

[0024] In addition, ENPP-1 inhibitors can also play a role in the DNA damage repair process (see reference US20220135598Al). Patent documents WO2019023635Al and WO2021158829Al disclose that ENPP-1 is an attractive drug target for the development of new anti-cancer, cardiovascular, diabetes, obesity and anti-fibrosis therapies. Patent documents WO2022056068Al and WO2019046778Al disclose that ENPP-1 regulators can also be used to fight bacteria and fungi.

[0025] In patent document WO2022125613Al, certain phosphonates are not only inhibitors of ENPP-1, but also inhibitors of CdnP. Cyclic dinucleotide phosphodiesterase (CdnP, also known as Rv2837c) is a phosphodiesterase that regulates cyclic dinucleotide signaling during intracellular infection of Mycobacterium tuberculosis. The phosphonate structure disclosed in the '613 patent application can also be classified as a tail core zinc binding domain, which can be represented by Formula X.

[0026]

[0027] The primary therapeutic use or purpose of ENPP-1 inhibitors is to provide treatment for patients or subjects suffering from cell proliferative diseases and cancers, including but not limited to glioma, glioblastoma multiforme, paraganglioma, epiblast primitive neuroectodermal tumor, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic bile duct carcinoma (IHCC), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD) and other solid tumors. Since there are currently no targeted therapeutic drugs for these cancers and cell proliferative diseases, people are currently exploring therapeutic drugs, especially new ENPP-1 inhibitors that can show selectivity for some of these adverse symptoms and diseases.

[0028] The above briefly summarizes the structures with tail zinc binding groups, describing the potential high-efficiency scaffolds with the ability to inhibit ENPP-1 and enhance immune activity. However, none of these structures appear to have been clinically validated. The shortcomings of these structures are not clear in the literature reports. There is still a need for updated structures to meet the urgent needs of combating different types of cancer. Therefore, the present invention discloses a novel structure of high-efficiency molecules for combating one or more types of diseases. Summary of the invention

[0029] The present disclosure relates to compounds of formula I, which are effective inhibitors of ENPP-1 proteins and thus have the potential for immunotherapy, such as for the treatment of diseases. The present invention also discloses synthetic methods for preparing these compounds and in vitro biological activity results to 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, isomers thereof.

[0030]

[0031] Wherein, Formula I includes the A part and the B part which together constitute the tail part, the C part which constitutes the core part, the sulfoximine type group R2-S(=W)(=N) connecting the tail part and the core part, and the zinc binding group (ZBG), wherein,

[0032] The A moiety is a six-membered aromatic or heteroaromatic group, which may be optionally replaced by one or more R 3 Group substitution, where X1, X2 and X3 are CH, N, CR', but no more than two of X1, X2 and X3 can be N at the same time;

[0033] The B moiety is a C6 aryl or a 5-6 membered heteroaryl, optionally substituted by one or more R 4A radical substitution in which the moiety B is fused to the moiety A and the two common atoms between the moieties B and A are from a pair of carbon atoms or from a pair of atoms in which one atom is nitrogen and the other is carbon;

[0034] The C moiety is selected from the group consisting of structures (i), (i), (ii), (iv), (v) and (vi), wherein L1 is attached to (i) at a variable position of the ring;

[0035] 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);

[0036]

[0037] n=0,1,2,3,4, provided that when n>1, the R groups may be the same or different;

[0038] R 1 , R 3 , R 4 The group is selected from the group consisting of R', halogen, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, wherein R'=H, CN, C1-6 straight chain alkyl, branched alkyl, cycloalkyl, CH2Ar, wherein Ar=aryl, substituted aryl, heteroaryl or substituted heteroaryl;

[0039] E1=-(CH2) y - where y = 0, 1, 2 or 3;

[0040] L1=-(CH2) y1 、NR", O or S, C1-6 straight chain alkyl, branched chain alkyl, (CH2) y1 Cycloalkyl, wherein y1=0, 1, 2 or 3;

[0041] Wherein R"=H, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, substituted aryl, halogenated alkyl;

[0042] X4, X5 and X6 = CH, N or CR';

[0043] The A part is connected to the nitrogen atom of the R2-S(=W)(=N) group

[0044] Where S is a chiral sulfur atom,

[0045] N is nitrogen,

[0046] W is O or NH;

[0047] R2 is selected from the group consisting of C1-6 straight chain, branched chain, cycloalkyl, olefin group, olefin group, alkynyl, halo, aryl, heteroaryl, heterocyclic, substituted aryl, CF3, CHF2, CH2F, CN and 2-6 membered olefin groups, one end of which is bonded to the sulfur atom and the other end is bonded to the C part at the alpha position of the carbon atom of the C part bonded to the sulfur atom

[0048] When y=O, a ring structure is formed and

[0049] As shown in structure (vii), ZBG

[0050]

[0051] Where a = S, P, C or B atom;

[0052] b1, b2 = O, S, NH or CH2.

[0053] b3=O、S、NH、CH2 or NH2O

[0054] And m1, m2 and m3 = 0, 1, provided that only one of m1, m2 and m3 can be 0 in a given instance. In one aspect, the present invention discloses a general method for preparing compounds and intermediates required for compounds of formula I. The compounds represented by formula I can inhibit the function of phosphodiesterases selected from ENPP-1, cyclic nucleotide phosphodiesterases, phospholipase C and D, autotaxin, sphingomyelin phosphodiesterase, deoxyribonuclease, ribonuclease, restriction endonuclease, small molecule phosphodiesterase and combinations thereof. The isomers of the compound I are selected from stereoisomers of formula I and a group consisting of positional isomers generated by connecting sulfoximine-type fragments of formula I.

[0055] The stereoisomer is selected from the group consisting of the (R) isomer of Formula I, the (S) isomer of Formula I, and combinations thereof.

[0056] Positional isomers of formula I can be selected from molecules wherein the core and tail of formula I are bonded to the sulfinyl imide group at sulfur atom and nitrogen atom, respectively, and molecules wherein the core and tail of formula I are bonded to the sulfinyl imide group at nitrogen atom and sulfur atom, respectively.

[0057] In vitro test results show that these compounds have the potential to inhibit phosphodiesterases such as ENPP-1 and therefore can be used to treat diseases such as cancer. DETAILED DESCRIPTION

[0058] It should be understood that the terms used herein are only used to describe specific embodiments and are not intended to limit the scope of the present invention. In this specification and the appended claims, reference will be made to terms having the following meanings.

[0059] definition

[0060] Unless otherwise indicated, "alkyl" as used herein refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 14 carbon atoms, and in certain embodiments, a monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. For example, the term "alkyl" includes straight and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2-) and neopentyl ((CH3)3CCH2-). "Cycloalkyl" refers to a saturated or partially saturated cyclic group consisting of 3 to 14 carbon atoms, free of cyclic heteroatoms, having a monocyclic or polycyclic ring, including fused rings, bridged rings and spiro ring systems. For polycyclic systems having aromatic rings and non-aromatic rings with acyclic heteroatoms, the term "cycloalkyl" applies when the point of attachment is on a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl). The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc.

[0061] "Aryl" refers to an aromatic group of 5 to 14 carbon atoms, free of cyclic heteroatoms, having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthracenyl). For polycyclic ring systems, including fused, bridged, and spirocyclic ring systems having aromatic and nonaromatic rings and no annular impurity atoms, 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 its point of attachment is at the 2 position of the aromatic phenyl ring).

[0062] As used herein, "alkenyl" refers to an unsaturated linear or branched monovalent hydrocarbon chain or combinations thereof having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having a specified number of carbon atoms (i.e., C2-C 10Meaning 2 to 10 carbon atoms). Alkenyl can be "cis" or "trans" configuration, or alternatively "E" or "Z" configuration. Preferred alkenyls are those having 2-20 carbon atoms ("C2-C24 alkenyl"), 2-8 carbon atoms ("C2-C8 alkenyl"), 2-6 carbon atoms ("C2-C6 alkenyl"), or 2-4 carbon atoms ("C-C4 alkenyl"). Examples of alkenyl include, but are not limited to, vinyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, homologues and isomers thereof.

[0063] As used herein, "alkylene" refers to a residue identical to an alkyl group but having divalence. Preferred alkylene groups are those having 1 to 6 carbon atoms ("C1-C6 alkylene"), 1 to 5 carbon atoms ("C1-C5 alkylene"), 1 to 4 carbon atoms ("C1-C4 alkylene"), or 1 to 3 carbon atoms ("C1-C5 alkylene"). Examples of alkylene groups include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-).

[0064] As used herein, "alkynyl" refers to an unsaturated straight or branched monovalent hydrocarbon chain or a combination thereof, having at least one acetylenic unsaturation site (i.e., having at least one moiety of the formula C=C) and having the specified number of carbon atoms (i.e., C2-C10 means 2-10 carbon atoms). Preferred alkynyl groups are those having 2-20 carbon atoms ("C2-C2m alkynyl"), having 2-8 carbon atoms ("C2-C8 alkynyl"), having 2-6 carbon atoms ("C2-C6 alkynyl"), or having 2-4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or ethynyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof.

[0065] "Halogen" refers to an element of the 17th group series with an atomic number of 9 to 85. Preferred halogen groups include fluorine, chlorine, bromine and iodine. When a residue is substituted with more than one halogen, it can be indicated by using a prefix corresponding to the number of halogen moieties attached, such as dihaloaryl, dihaloalkyl, trihaloaryl, etc. Refers to aryl and alkyl substituted with two or three halogen groups, which can be but not necessarily the same halogen: thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. Alkyl groups in which each hydrogen is replaced by a halogen group are referred to as "perhaloalkyl". Preferred perhaloalkyl groups are trifluoroalkyl (CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each H in the hydrocarbon that constitutes the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-CF3).

[0066] "Heteroaryl" refers to and includes an unsaturated aromatic cyclic group with 1 to 10 annular carbon atoms and at least one annular heteroatom, wherein the annular heteroatom includes but is not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl can be connected to the rest of the molecule at the annular carbon or annular heteroatom. Heteroaryl can contain other fused rings (e.g., 1 to 3 rings), including other fused aryl, heteroaryl, cycloalkyl and / or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, thienyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, benzothiazolyl, oxazolopyridinyl, thiazole "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated non-aromatic group having 1 to 10 annular carbon atoms and 1 to 4 annular heteroatoms (e.g., nitrogen, sulfur or oxygen, etc.), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocyclic group can have a single ring or multiple fused rings. A heterocyclic ring comprising more than one ring can be fused, spirocyclic or 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, azetidinyl, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

[0067] Unless otherwise indicated, "optionally substituted" means that the group can be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for the group, wherein the substituents can be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the 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.

[0068] "Medicament" or "pharmaceutical composition" refers to a pharmaceutical preparation in an administrable form comprising at least one pharmaceutically active ingredient and one or more pharmaceutically acceptable carriers.

[0069] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a component of a pharmaceutical preparation 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.

[0070] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result (including a clinical result). For example, a beneficial or desired result includes, but is not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of a person suffering from the disease, reducing the dose of other drugs required to treat the disease, delaying the progression of the disease, and / or prolonging the survival of an individual. With respect to cancer or other unwanted cell proliferation, a beneficial or desired result includes shrinking a tumor (reducing the size of the tumor); reducing the growth rate of a tumor (e.g., inhibiting tumor growth); reducing the number of cancer cells; inhibiting, delaying, or slowing down the infiltration of cancer cells into peripheral organs to a certain extent; inhibiting (slowing down and preferably stopping to a certain extent) tumor metastasis; inhibiting tumor growth; preventing or delaying the occurrence and / or recurrence of a tumor; and / or alleviating one or more symptoms associated with cancer to a certain extent. In certain embodiments, a beneficial or desired result includes preventing or delaying the occurrence and / or recurrence of a disease, such as unnecessary cell proliferation.

[0071] As used herein, "delaying the progression of a disease" means delaying, hindering, slowing, slowing, stabilizing and / or postponing the progression of a disease (e.g., cancer). Such delays may be of varying lengths, depending on the disease and / or the medical history of the individual being treated. For those skilled in the art, a sufficient or significant delay may actually include prevention, i.e., the individual will not develop the disease. For example, advanced cancer (e.g., the progression of metastases) may be delayed.

[0072] As used herein, an "effective dose" or "effective amount" of a compound or salt thereof or pharmaceutical composition refers to an amount sufficient to produce a beneficial or desired effect.

[0073] As used herein, the term "subject" refers to a mammal, including humans. The subject includes, but is not limited to, humans, cattle, horses, cats, dogs, rodents, or primates. In certain embodiments, the subject is a human. The subject (e.g., a human) may have an advanced disease or a less severe disease, such as a lower tumor burden. In certain embodiments, the subject is in the early stages of a proliferative disease (e.g., cancer). In certain embodiments, the subject is in the late stages of a proliferative disease (e.g., advanced cancer).

[0074] In some aspects, sarcomas and carcinomas are cancers that can be treated as solid tumors, while leukemias are cancers that can be treated as liquid tumors. The present invention can treat different types of cancers, including but not limited to adrenocortical carcinoma, bladder cancer, brain tumors, breast cancer, prostate cancer, colorectal cancer, colon cancer, endometrial cancer, gallbladder cancer, gastric cancer, head and neck cancer, hematopoietic cancer, kidney cancer, leukemia, oral cancer, uterine cancer, Hodgkin lymphoma, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, sarcomas, skin cancer and thyroid cancer. Breast cancer is divided into breast cancer (ER negative or ER positive), breast adenocarcinoma, primary breast ductal carcinoma, breast 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 examples, basal-like TNBC, immune-modulated TNBC, mesenchymal TNBC (mesenchymal or mesenchymal stem-like) or luminal androgen receptor TNBC all belong to triple negative breast cancer. In certain embodiments, prostate adenocarcinoma refers to prostate cancer. Other therapeutic uses of the compounds include ovarian adenocarcinoma, lung cancer, adenocarcinoma, non-small lung cancer, mucinous adenocarcinoma, asexual large cell carcinoma, colon adenocarcinoma, colon cancer, metastatic colorectal cancer, colon adenocarcinoma, astrocytoma, glioblastoma, medulloblastoma, neuroblastoma or meningioma, gastric cancer, bile duct cancer or hepatoblastoma, hepatocellular carcinoma, liver cancer, medullary thyroid cancer, liver cancer, medullary thyroid cancer or follicular thyroid cancer, papillary thyroid cancer, uterine papillary serous carcinoma clear cell carcinoma of the uterus, adenocarcinoma of the gallbladder or squamous cell carcinoma of the gallbladder, 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, laryngeal, nasopharyngeal and oropharyngeal cancers, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma or multiple myeloma.

[0075] Molecular biology of ENPP-1

[0076] Ectonucleotide pyrophosphatase / phosphodiesterase family member 1 (ENPP-1) is a 925 amino acid long protein with a molecular weight of 104924 Da. The protein is mainly found in the extracellular space, lysosomal membranes, and plasma membranes. The ENPP-1 protein belongs to the nucleotide pyrophosphatase / phosphodiesterase family and is a homodimer that requires zinc ions as a cofactor to initiate biological functions. The molecular functions of the ENPP-1 protein are reported to include nucleic acid binding, exonuclease activity, phosphodiesterase I activity, 3'-phosphoadenosine-5'-sulfate phosphate binding, ATP binding, calcium ion binding function, cyclic-GMP-AMP hydrolase activity, dTTP diphosphatase activity, exonuclease activity, insulin receptor binding, nucleic acid binding, nucleoside-triphosphate diphosphatase activity, nucleotide diphosphatase activity, phosphodiesterase I activity, polysaccharide binding, protein homodimerization activity, scavenger receptor activity, zinc ion binding, and nucleotide diphosphatase activity. ENPP-1 protein is involved in the hydrolysis of ATP, GTP, CTP, TTP and UTP into their respective monophosphates, and releases pyrophosphate and di-adenosine polyphosphate. ENPP-1 protein is involved in a variety of biological processes, such as the generation of precursor metabolites, metabolism of phosphate-containing compounds, regulation of nucleotide sugar availability in the endoplasmic reticulum and Golgi apparatus, regulation of purine signaling, endocytosis, immune response and nucleoside triphosphate catabolism. It is reported that one of the key functions of ENPP-1 is the hydrolysis of 2',3'cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173 / STING. The hydrolysis of cyclic GMP-AMP leads to a decrease in the expression of downstream components of the STING pathway, which is essential for maintaining immune function. Therefore, it can be seen that ENPP-1-mediated inactivation of the STING pathway leads to immunosuppression and enhanced tumor cell metastasis.

[0077] ENPP-1 belongs to the class of phosphodiesterases. Phosphodiesterases include a class of enzymes that catalyze the hydrolysis of phosphodiester bonds. In some instances, phosphodiesterases can lead to viral infection, and inhibition of phosphodiesterases can reduce viral replication. In some cases, the phosphodiesterase class also includes cyclic nucleotide phosphodiesterases, phospholipase C and D, autotaxin, sphingomyelin phosphodiesterases, DNA enzymes, RNA enzymes, restriction endonucleases, and small molecule phosphodiesterases.

[0078] In another case, phosphodiesterase can cause bacterial infection, for example, infection with Gram-negative bacteria or Gram-positive bacteria. In some examples, the bacteria are Listeria monocytogenes, Mycobacterium tuberculosis, Novi, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae or Neisseria gonorrhoeae. Therefore, phosphodiesterase inhibitors will have a potential impact on the treatment of many diseases.

[0079] Crystallographic information on protein-ligand complexes

[0080] ENPP-1 protein has been reported to have 6 crystal structures. 2YSO, 6WET, 6WEU, 6WEV, 6WEW, and 6WFJ are the reported PDB codes for ENPP-1. Among the available PDB structures, 6WEV was considered for silica studies. The resolution of the protein was reported as 2.90 Å. 6WEV was the target considered for silica studies. ENPP-1 protein complexed with N-{[1-(6,7-dimethoxy-5,8-dihydroquinazolin-4-yl)piperidin-4-yl]methyl}diamide sulfate (PDB ID: 6WEV) also has other cofactors such as 2-acetamido-2-deoxy-β-D-glucopyranose, phosphate ions, calcium ions, and zinc ions. Zinc ions play an important role in the catalytic activation of ENPP-1. Therefore, the interaction of candidate drug molecules with zinc ions is essential to elicit enzyme inhibition.

[0081] Molecular Docking - Methodology

[0082] Molecular docking studies were performed by the AutoDock4Zn program, which incorporates improved force field parameters to address the coordination properties of zinc ions with small molecules. The energetic and geometrical components of the interaction between zinc ions and small molecules are captured in this program. Traditional autodock force fields, including van der Waals force fields, hydrogen bonding force fields, Coulomb electrostatic force fields, desolvation force fields, and ligand torsion entropy force fields, are used to describe the interactions between ligands and receptors. However, traditional autodock force fields are not sufficient to handle zinc ions because the van der Waals equilibrium distances of zinc-coordinated atoms are much larger than the coordination distances and they lack specific terms for metal coordination. Therefore, we have incorporated potential energy terms associated with each type of atomic pairing interaction in the coordination of zinc ions into the current autodock force field.

[0083] Molecular docking results The structural features associated with ENPP-1 inhibitors can be divided into the zinc binding head or group, the core, and the tail. Among the three parts, the presence of the zinc binding head plays a crucial role in the inhibition of ENPP-1 as this group coordinates the zinc ion in the catalytic site of the enzyme. The core and tail hold the compound tightly in the binding pocket. The design of the inhibitors starts from these 3 structural elements. While performing the docking studies, the co-crystals of ENPP-1 with inhibitors reported to have good potency were considered. The active site residues of ENPP-1 protein include D218, F257, L290, K295, D326, S325, K338, W322, F321, Y371, Y340, P323, T356, D376, H380 and the zinc ion. The inhibitors were re-docked with the binding pocket of the enzyme to observe their binding. The prior art on the docking studies of ENPP-1 emphasizes that the zinc ion binds very tightly to the enzyme. The closer the zinc-binding head of the inhibitor is to the zinc atom present in the catalytic site, the higher the degree of inhibition of the enzyme. This observation was taken into account while conducting the re-docking study. It was found that the zinc-binding head of the reference compound binds tightly to the zinc ion in the active site.

[0084] ENPP-1 inhibitors

[0085] The compound disclosed in the present invention is a potential inhibitor of ENPP-1. The molecular structure is shown in Formula I.

[0086] The present invention discloses a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or isomer thereof.

[0087]

[0088] Wherein, Formula I includes the A part and the B part which together constitute the tail part, the C part which constitutes the core part, the sulfoximine type group R2-S(=W)(=N) connecting the tail part and the core part, and the zinc binding group (ZBG), wherein,

[0089] The A moiety is a six-membered aromatic or heteroaromatic group, which may be optionally replaced by one or more R 3 Group substitution, where X1, X2 and X3 are CH, N, CR', but no more than two of X1, X2 and X3 can be N at the same time;

[0090] The B moiety is a C6 aryl or a 5-6 membered heteroaryl, optionally substituted by one or more R 4 A radical substitution in which the moiety B is fused to the moiety A and the two common atoms between the moieties B and A are from a pair of carbon atoms or from a pair of atoms in which one atom is nitrogen and the other is carbon;

[0091] The C moiety is selected from the group consisting of structures (i), (i), (ii), (iv), (v) and (vi), wherein L1 is attached to (i) at a variable position of the ring;

[0092] 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);

[0093]

[0094] n=0,1,2,3,4, provided that when n>1, the R groups may be the same or different;

[0095] R 1 , R 3 , R 4 The group is selected from the group consisting of R', halogen, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, wherein R'=H, CN, C1-6 straight chain alkyl, branched alkyl, cycloalkyl, CH2Ar, wherein Ar=aryl, substituted aryl, heteroaryl or substituted heteroaryl;

[0096] E1=-(CH2) y - where y = 0, 1, 2 or 3;

[0097] L1=-(CH2) y1 、NR", O or S, C1-6 straight chain alkyl, branched chain alkyl, (CH2) y1 Cycloalkyl, wherein y1=0, 1, 2 or 3;

[0098] Wherein R"=H, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, substituted aryl, halogenated alkyl; X4, X5 and X6=CH, N or CR';

[0099] The A part is connected to the nitrogen atom of the R2-S(=W)(=N) group

[0100] Where S is a chiral sulfur atom,

[0101] N is nitrogen,

[0102] W is O or NH;

[0103] R2 is selected from the group consisting of C1-6 straight chain, branched chain, cycloalkyl, olefin group, olefin group, alkynyl, halo, aryl, heteroaryl, heterocyclic, substituted aryl, CF3, CHF2, CH2F, CN and 2-6 membered olefin groups, one end of which is bonded to the sulfur atom and the other end is bonded to the C part at the alpha position of the carbon atom of the C part bonded to the sulfur atom

[0104] When y=O, a ring structure is formed and

[0105] As shown in structure (vii), ZBG

[0106]

[0107] Where a = S, P, C or B atom;

[0108] b1, b2 = O, S, NH or CH2;

[0109] b3=O, S, NH, CH2 or NH2O;

[0110] And m1, m2 and m3 = 0, 1, provided that only one of m1, m2 and m3 can be 0 in a given instance.

[0111] Zinc binding domain

[0112] In one embodiment, the zinc binding moiety comprises the following group of structures, the structure comprising:

[0113]

[0114] One of the important features of the structure described in Formula I of sulfoximine-type fragment is that there is a sulfoximine-type fragment between the tail and the core part. Structures based on sulfoximine are gradually gaining popularity in medical science. A recent reference is "Application of sulfoximine in medicinal chemistry from 2013 to 2020", published in the European Journal of Medicinal Chemistry, Vol. 209, p. 112885 (2021). In another journal article entitled "Sulfoximine: A rising star in modern drug discovery? The current status and prospects of an emerging functional group in medicinal chemistry", published in the Journal of Medicinal Chemistry, Vol. 63, No. 23, pp. 14243-14275 (2020), the limitations of the functional group are also discussed. Sulfoximine-type fragments related to the present disclosure are shown below, and the fragments include sulfoximine and sulfodiimine.

[0115]

[0116] Sulfadiimines are allotropes of sulfoximines, and both are classified as sulfoximine-type fragments in the present disclosure. The nitrogen of the NH group in the sulfadiimines is double-bonded to sulfur and is in the same position as the oxygen atom in the sulfoximine. In the present disclosure, R1x has the same meaning as the R2 group in Figure 1, and R2x and R3x have the same meaning as the core and tail in Figure 1, respectively. None of the ENPP-1 inhibitors reported to date have a sulfoximine-type fragment located between the core and tail of the inhibitor molecule. The sulfoximine-type fragment is represented in the present disclosure as the R2-S(=W)(=N) group.

[0117] In one embodiment, the R2 group of the sulfoximine-type fragment is selected from methyl, cyclopropyl, cyclopropylmethyl, ethyl, propyl, isopropyl, phenyl and benzyl.

[0118] Preferred sulfoximine-type fragments corresponding to the formula R2-S(=W)(=N) are as follows:

[0119]

[0120] Tail part

[0121] The tail of Figure I is bonded to the nitrogen atom of the sulfoximine-type fragment, wherein the nitrogen is bonded to the sulfur atom via a double bond, and the portion A is bonded to the nitrogen atom of the sulfoximine-type fragment.

[0122] In one embodiment, the tail is composed of two parts, A and B, which together contain X1, X2, X3, R3 and R4 groups, such groups are selected from the following groups:

[0123]

[0124] The number of ring substituents R3 and R4 on moiety A and moiety B, respectively, may be 0, 1 or more. When more than one ring substituent is present, these ring substituents may be the same or different.

[0125] Core part

[0126] The core part, referred to as part C, comprises together L1, X4, X5, X6=, R1, L2 groups and is selected from

[0127]

[0128] For most of these structures, one end of the core moiety is bonded to ZBG, and the other end of the core moiety, shown by a wavy line, is bonded to a sulfoximine-type fragment, particularly a sulfur atom of the sulfoximine-type fragment.

[0129] In the partial structure of the core portion shown below, the label "Linker" is a sulfoximine type fragment, and the connection of the core portion to the tail via the sulfur-bonded nitrogen atom is not shown in the structure shown below.

[0130]

[0131] In one embodiment, the core portion together with the sulfoximine-type fragment is selected from:

[0132]

[0133] Isomers of Formula I

[0134] Stereoisomers and certain structural isomers

[0135] Stereoisomers

[0136] The compounds corresponding to Formula I exhibit optical activity due to the presence of an asymmetric sulfur atom, resulting in two non-superimposable mirror-image forms. The two forms of such compounds are called enantiomers and are classified as left-handed (l-isomers) or right-handed (d-isomers) according to the rotation of plane polarized light in a left-handed (-) or right-handed (+) manner, respectively. The stereoisomers of Figure I are selected from (R) isomers of Formula I, (S) isomers of Formula I, and combinations thereof.

[0137] When two isomers have different activities, or when only one isomer shows activity and the other does not show any activity, or when one shows positive activity and the other shows negative activity, in order to remove the unwanted isomer from the composition and obtain better therapeutic activity, chiral separation of such racemic drugs in the pharmaceutical industry is extremely critical. If the racemate shows the same activity as the individual isomers, no separation is required. The enantiomers to which the present invention may be applied are illustrated by the following examples.

[0138]

[0139] Structural isomers (also called positional isomers)

[0140] The presence of N-substituted sulfoximine linkers also provides the opportunity to generate positional or structural isomers. One of the positional isomers comes from the change in the connection of the sulfoximine-type fragment of Formula I to the core and tail. These structures are different from each other due to the orientation of the sulfonyl imide linker. To illustrate the structural isomers of Formula I, the structure P1 presented below shows that the N-substituted sulfoximine linker is connected to the tail via the nitrogen atom of the sulfoximine linker and is connected to the core part via the S atom of the sulfoximine linker. Unlike structure P1, structure P2 shows that the N-substituted sulfoximine linker is connected to the core part via the nitrogen atom of the sulfoximine linker and is connected to the tail part via the sulfur atom of the sulfoximine linker.

[0141]

[0142] Synthesis of compounds of formula I

[0143] The general synthesis scheme of the present invention shown in Formula I

[0144] The retrosynthetic strategy for preparing compounds represented by formula I is to prepare the aryl sulfoximine starting from an appropriately substituted arylalkyl sulfide by oxidation of the sulfide group using phenyl iodoacetate in the presence of ammonium carbamate. The preferred alkyl substituent is methyl.

[0145] All sulfoximine derivatives were synthesized from the corresponding sulfides in the presence of an ammonia source and a mild oxidant.

[0146]

[0147] The R group on the sulfide is found in the derivatized sulfoximine molecules listed below.

[0148]

[0149] The arylmethylsulfoximine molecule is then coupled with a halogenated compound in the presence of a base to form a tail-sulfoximine-core structure which is then functionalized to have a zinc-binding polar group. The product of the invention is typically a composition of (R) and (S) enantiomers or racemates and is optionally resolved into the enantiomers.

[0150]

[0151] General procedure: The sulfoximines were synthesized by treating the substituted thioanisole with diacetoxyiodobenzene (Ph(OAc)2 and ammonium carbamate (NH4(CO2NH2)). The resulting sulfoximine was treated with a base followed by 4-chloro-6,7-dimethoxyquinazoline to afford the corresponding sulfoximine-quinazoline coupling product. In the last step, various zinc binding groups (ZBG) were inserted onto the benzene ring attached to the sulfoximine by functionalization, see Example 1.

[0152] Example 1: Synthesis of {4-[N-(6,7-dimethoxyquinazoline-4-)-S-methylsulfoniminoyl]phenyl}phosphonic acid (SAPTI012S001)

[0153] Step 1: 4-Bromothioanisole (1.0 eq.) was dissolved in MeOH (0.2 M) in a RBF, and then diacetoxyiodobenzene (Phl(OAc)2) (3.0 eq.) and ammonium carbamate (NH4(C02NH2) (4.0 eq.) were added portionwise under nitrogen atmosphere. After 2 hours, the addition of equal amounts of (Phl(OAc)2) and (NH4(CO2NH2) was repeated again to obtain maximum yield. After completion of the reaction, methanol was removed by reduced pressure, and the reaction mixture was dissolved in EtOAc and washed with water and brine solution. The organic layer was concentrated and purified by column chromatography using 10-15% EtOAc in hexane as the eluent. The product 1-bromo-4-(S-methylsulfonylimide)benzene (SAPTI012S001 / IM1) (yield: 95%) was confirmed by LCMS.

[0154] LCMS: [M+H]=234,236 (isotope peak).

[0155]

[0156] Step 2: 1-bromo-4-(S-methylsulfonylimino)benzene (1.0 eq.) was dissolved in DMF (0.2 M) in a RBF and cooled to 0°C with an ice bath. NaH (2.0 eq.) was then added under nitrogen, followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 eq.). The temperature of the reaction mixture was slowly raised to 100°C and stirred for 8 hours. After the reaction was complete, 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 eluent. LCMS was used to confirm the product 4-{[(4-bromophenyl)(methyl)oxo-6-sulfenyl]amino}-6,7-dimethoxyquinazoline (SAPTI012S001 / IM2) (yield: 40%).

[0157] LCMS: [M+H]=422,424 (isotope peak).

[0158] Step 3: 4-{[(4-bromophenyl)(methyl)oxo-6-sulfylidene]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 with ethanol (0.2 M). The reaction mixture was degassed under nitrogen and stirred at 80 ° C for 16 hours. After the reaction was completed, 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. LCMS was used to confirm the product (4-(N-(6,7-dimethoxyquinazoline-4-yl)-S-methylsulfonylimino)phenyl)phosphonic acid diethyl ester (SAPTI012S001 / IM3) (yield: 80%)

[0159] LCMS: [M+H]=480.

[0160] Step 4: Diethyl (4-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonyliminoyl)phenyl)phosphonate (1.0 eq.) was dissolved in 0.2 M anhydrous CHCl3 in RBF, and TMSBr (4.0 eq.) was added at 0°C for 10 min. The reaction mass was stirred at room temperature for 4 h. After completion of the reaction, it was diluted with methanol and concentrated under reduced pressure, and then recrystallized from a solvent mixture of MeOH, DCM, and acetone. The pure product {4-[N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonyliminoyl]phenyl}phosphonic acid (SAPTI012S001) (yield: 50%, purity: 92%) was confirmed by HNMR and LCMS

[0161] LCMS: [M+H]=424.

[0162] 1 H-NMR: 8.70ppm (s, 1H); 8.16ppm (d, 2H); 7.95ppm (d, 2H); 7.67ppm (s, 1H); 7.21ppm (s, 1H); 3.99ppm (s, 6H, OCH3); 3.85ppm (s, 3H, SCH3).

[0163] Example 2: Synthesis of {3-[N-(6,7-dimethoxyquinazoline-4-)-S-methylsulfonylimino]phenyl}phosphonic acid (SAPTI012S002).

[0164] Step 1: 3-Bromothioanisole (1.0 equiv) was dissolved in MeOH (0.2 M) in a RBF, and then diacetoxyiodobenzene (PhI(OAc)2) (3.0 equiv) was added portionwise under nitrogen atmosphere, followed by ammonium carbamate (NH4(CO2NH2) (4.0 equiv). After 2 hours, the addition of equal amounts of (PhI(OAc)2) and (NH4(CO2NH2) was repeated again to obtain 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 solution. 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-methylsulfonylimide)benzene (SAPTI012S002 / IM1) (yield: 85%) was confirmed by LCMS.

[0165] LCMS: [M+] = 234, 236 (isotope peaks).

[0166]

[0167] Step 2: 1-Bromo-3-(S-methylsulfonylimino)benzene (1.0 eq.) was dissolved in a RBF solution of DMF (0.2 M) and cooled to 0 ° C with an ice bath. NaH (2.0 eq.) was then added under nitrogen, followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 eq.), and the temperature of the reaction mixture was slowly raised to 100 ° C and stirred for 8 hours. After the reaction was completed, 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 eluent. LCMS was used to confirm the product 4-{[(3-bromophenyl)(methyl)oxo-6-sulfenyl]amino}-6,7-dimethoxyquinazoline (SAPTI012S002 / IM2) (yield: 42%).

[0168] LCMS: [M+] = 422; 424 (isotope peak).

[0169] Step 3: 4-{[(3-bromophenyl)(methyl)oxo-6-sulfanyl]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 with ethanol (0.2 M). The reaction mixture was degassed under nitrogen and stirred at 80 ° C for 16 hours. After the reaction was completed, 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 (3-(N-(6,7-dimethoxyquinazoline-4-yl)-S-methylsulfonylimino)phenyl)phosphonic acid diethyl ester (SAPTI012S002 / IM3) was confirmed by LCMS (yield 80%).

[0170] LCMS: [M+H]=479.

[0171] Step 4: Diethyl (3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonyliminoyl)phenyl)phosphonate (1.0 equiv) was dissolved in 0.2 M anhydrous CHCl3 in RBF, and then TMSBr (4.0 equiv) was added at 0°C for 10 minutes and stirred at room temperature for 4 hours to react. After the reaction was completed, it was diluted with methanol and concentrated under reduced pressure, and then recrystallized from a solvent mixture of MeOH, DCM and acetone. The pure product {3-[N-(6,7-dimethoxyquinazolin-4-)-S-methylsulfonyliminoyl]phenyl}phosphonic acid (SAPTI012S002) was confirmed by 1HNMR and LCMS (yield: 44%, purity: 97%)

[0172] LCMS: [M+H]=424.

[0173] 1 H-NMR: 8.80ppm(s,1H,CH); 8.35ppm(d,1H,CH); 8.25ppm(d,1H,CH); 8.04ppm(dd,1H,CH); 7.82ppm(m,1H,CH) ;7.69ppm(s,1H,CH);7.24ppm(s,1H,CH);4.01ppm(s,3H,OCH3);4.00ppm(s,3H,OCH3);3.92ppm(s,3H,SCH3).

[0174] Example 3: Synthesis of Common Intermediate (SAPTI012S003 / IM4) 4-[N-(6,7-dimethoxyquinazoline-4-)-S-methylsulfonylimino]aniline Step-1: 4-(Methylthio)aniline (1.0 eq.) in DCM solution was treated with N-ethyl, N,N-diisopropylamine (2.0 eq.) at 0°C and then Boc-anhydride (1.2 eq.) was added dropwise 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 completion of 4-(methylthio)aniline, the reaction mass was further diluted with DCM and washed with water and brine solution. The organic layer was concentrated and purified by column chromatography using 10-15% EtOAc in hexane as eluent. The isolated spot was non-polar compared to the starting material and was used in further steps without purification (yield: 81%).

[0175]

[0176] Step 2: Tert-butyl [4-(methylthio)phenyl]carbamate (1.0 equiv) was dissolved in MeOH (0.2 M) in a RBF, and then diacetoxyiodobenzene (PhI(OAc)2) (3.0 equiv) was added in portions under nitrogen, followed by ammonium carbamate (NH4(CO2NH2) (4.0 equiv). After 2 hours, the addition of equal amounts of (PhI(OAc)2) and (NH4(CO2NH2) was repeated again to obtain 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 solution. 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-methylsulfonylimino)phenyl]carbamate (SAPTI012S003 / IM2) (yield: 90%) was confirmed by LCMS. LCMS: [M+H]=271.

[0177] Step 3: tert-Butyl [4-(S-methylsulfonyl imide) phenyl] carbamate (1.0 equiv) was dissolved in DMF (0.2M) in a RBF and cooled to 0°C with an ice bath. NaH (2.0 equiv) was then added under nitrogen, followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv), and the temperature of the reaction mixture was slowly raised to 100°C and stirred for 8 hours. After the reaction was complete, 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 eluent. LCMS was used to confirm the product (tert-butyl 3-(N-(6,7-dimethoxyquinazoline-4-yl) S-methylsulfonyl imide) phenyl) carbamate (SAPTI012S003 / IM3) (yield: 36%).

[0178] LCMS: [M+H]=459.

[0179] Step 4: tert-Butyl (3-(N-(6,7-dimethoxyquinazoline-4-yl)-S-methylsulfonyliminoyl)phenyl)carbamate (1.0 eq) was dissolved in 0.2 M anhydrous DCM in a RBF, then trifluoroacetic acid (10.0 eq) was added and stirred for 4 hours at room temperature. 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-dimethoxyquinazoline-4-)-S-methylsulfonyliminoyl]aniline) (SAPTI012S003 / IM4) and confirmed by LCMS of the crude product. The free amine in the crude mixture was reacted further without purification.

[0180] LCMS: [M+H]=359.

[0181] Example 4: Synthesis of N-{4-[N-(6,7-dimethoxyquinazoline-4-)-S-methylsulfonylimino]phenyl}sulfuric acid diamide (SAPTI012S003)

[0182]

[0183] (4-[N-(6,7-dimethoxyquinazoline-4-)-S-methylsulfonylimino]aniline) (1.0 equiv) was dissolved in anhydrous THF (0.2 M) in a RBF, and then TEA (2.0 equiv) and chlorosulfonamide (1.5 equiv) were added under nitrogen, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, THF was removed under reduced pressure, and the crude product was purified by column chromatography using DMC and MeOH as eluents (3-4%). ​​LCMS was used to confirm the product N-{4-[N-(6,7-dimethoxyquinazoline-4-)-S-methylsulfonylimino]phenyl}sulfuric acid diamide (yield: 50%, purity: 90%).

[0184] LCMS: [M+H]=408.

[0185] 1 H-NMR: 8.42ppm(s,1H,CH); 8.63ppm(s,1H,NH); 7.96ppm(d,2H,CH); 7.69ppm(s,1H,CH); 7.46ppm(s,2H,NH2) ;7.34ppm(d,2H,CH);7.21ppm(s,1H,CH);3.94ppm(s,3H,OCH3);3.90ppm(s,3H,OCH3);3.69ppm(s,3H,SCH3).

[0186] Example 5: Synthesis of 1-(3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonylimino)phenylurea (SAPTI012S004)

[0187]

[0188] Step 1: (4-[N-(6,7-dimethoxyquinazoline-4-yl)-S-methylsulfonylimino]aniline) (1.0 eq.) in DCM solution was treated with benzoyl isocyanate (1.5 eq.) at room temperature for 12 hours. After completion of the reaction, the material was further diluted with DCM and washed with water and brine solution. The organic layer was concentrated under reduced pressure and purified by column chromatography using 10-15% DCM-MeOH solution as eluent. The product N-((3-(N-(6,7-dimethoxyquinazoline-4-yl)-S-methylsulfonylimino)phenyl)carbamoyl)benzamide (SAPTI012S004 / IM5) was isolated (yield: 33%).

[0189] Step 2: N-((3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonylimino)phenyl)carbamoyl)benzamide (1.0 equiv) was treated with 1.0 N aqueous KOH at 95 °C for 3 hours. The reaction mixture was then 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 eluent. The product 1-(3-(N-(6,7-dimethoxyquinazolin-4-yl)-S-methylsulfonylimino)phenylurea (SAPTI012S004) was confirmed by LCMS (yield: 66%, purity: 95%).

[0190] LCMS: [M+H]=402.

[0191] 1 H-NMR: 9.72ppm(s,1H,NH); 8.36ppm(s,1H,CH); 7.89ppm(d,2H,CH); 7.67ppm(d,2H,CH); 7.57ppm(s,1H,CH); 7.15ppm(s,1H,CH); 6.27ppm(s,2H,NH2); 3.93ppm(s,3H,OCH3); 3.92ppm(s,3H,OCH3); 3.62ppm(s,3H,SCH3).

[0192] Example 6: Synthesis procedure of SAPTI012S005

[0193]

[0194] The previous intermediate SAPTI012S002 / IM1 (1.0 eq) was dissolved in dry 1,4-dioxane (0.2 M), then B2(Pin)2 (1.4 eq), KOAc (3.5 eq) were added, followed by PdCl2(dppf) complex (5 mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 8 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S005 (yield: 40%) was confirmed by LCMS and 1H NMR.

[0195] LCMS: [M+H]=388.

[0196] Example 7: Synthesis procedure of SAPTI012S006

[0197]

[0198] The previous intermediate SAPTI012S001 / IM1 (1.0 eq) was dissolved in anhydrous 1,4-dioxane (0.2 M), then KOAc (3.5 eq), B2(Pin)2 (1.4 eq) were added, followed by PdCl2(dppf) complex (5 mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 6 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S002 (yield: 40%) was confirmed by LCMS and 1H NMR.

[0199] LCMS: [M+H]=388.

[0200] Example 8: Synthesis procedure of SAPTI012S007

[0201]

[0202] Step 1: the previous intermediate SAPTIO12S003 / IM2 (1.0 equivalent) in the DCM solution was treated at room temperature for 12 hours with benzoylthioisocyanate (1.5 equivalent). After the reaction was completed, the material was further diluted with DCM and washed with water and saline solution. The organic layer merged was concentrated under reduced pressure, and purified by column chromatography using DCM and MeOH as eluent (10-15%). LCMS was used to confirm product SAPTIO12S007 / IM1 (yield: 33%).

[0203] LCMS: [M+1]=522.

[0204] Step 2: Intermediate SAPTI012S007 / IM1 (1.0 equivalent) was treated with 1.0N KOH aqueous solution at 95°C for 3 hours. The reaction mixture was then 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%).

[0205] LCMS: [M+H]=418.

[0206] Example 9: Synthesis procedure of SAPTI012S008

[0207]

[0208] Step 1: The previous intermediate SAPTI012S001 / IM1 (1.0 equivalent) was dissolved in DMF (0.2M), then sodium thiomethoxide (1.6 equivalent) was added at room temperature, and the resulting mixture was stirred at 100°C for 8 hours. After the reaction was completed, the reaction mixture was quenched with MeOH, and the solvent was evaporated on a rotary evaporator until the DMF was completely removed. The reaction mixture was dissolved again in sufficient DCM and washed with water and brine solution. The organic layer was concentrated to obtain a crude reaction mixture, and the crude product was purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S008 / IM1 (yield: 70.6%) was confirmed by LCMS.

[0209] LCMS: [M+H]=390.

[0210] Step 2: Intermediate SAPTI012S008 / IM1 (1.0 eq.) was dissolved in MeOH (0.2 M), followed by the addition of diacetoxyiodobenzene (Phl(OAc)2) (1.5 eq.) and ammonium carbamate (NH4(C02NH2) (2.0 eq.), and the reaction progress was monitored by TLC and LCMS. If the starting material still remained after 2 hours, 0.5 eq. of PhI(OAc)2 and 0.6 eq. of NH4(CO2NH2) were added again to obtain maximum yield. After completion of the reaction, methanol was removed under reduced pressure, the reaction mixture was dissolved in EtOAc, washed with water and brine solution. The combined organic layers were concentrated and purified by column chromatography using EtOAc and hexane as eluents (85-90%), and the product SAPTI012S008 (yield: 30%) was confirmed by LCMS and 1H NMR. LCMS: [M+H]=421.

[0211] Example 10: Synthesis procedure of SAPTI012S009

[0212]

[0213] Triphosgene (1.1 equivalents) was dissolved in DCM (0.2M), and the reaction mixture was then cooled to 0°C under nitrogen, followed by slow addition of aniline (1.0 equivalents), and continued stirring at room temperature for about 2 hours. Starting material SAPTI012S003 / IM2 amine (1.0 equivalents) was then added at room temperature and stirred for about 2-3 hours. The reaction progress was monitored by TLC, and the reaction mixture was subsequently quenched with NaHCO3 aqueous solution at 0°C and extracted with DCM. The combined organic layers were evaporated under reduced pressure to give a crude product. The crude product was purified by column chromatography using EtOAc and hexane as eluents. Product SAPTI012S009 was confirmed by LCMS and 1H NMR (yield: 67%).

[0214] LCMS: [M+H]=478.

[0215] Example 11: Synthesis procedure of SAPTI012S010

[0216]

[0217] Step 1: tert-Butyl [3-(S-methylsulfonylimino)phenyl]carbamate (1.0 equiv.) was dissolved in DMF (0.2 M) and then cooled to 0 ° C with an ice bath. NaH (2.0 equiv.) was then added under nitrogen, followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv.), and the temperature of the reaction mixture was slowly raised to 100 ° C and stirred for 8 hours. After the reaction was complete, 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 eluents (60-70%). The product SAPTI012S010 / IM1 was confirmed by LCMS (yield: 36%).

[0218] LCMS: [M+H]=459.

[0219] Step 2: In RBF, intermediate SAPTI012S010 / IM1 (1.0 equivalent) was dissolved in 0.2M anhydrous DCM, then trifluoroacetic acid (10V) 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 obtain the free amine SAPTI012S010 / IM2, and confirmed with crude LCMS. The free amine in the crude mixture was further reacted without further purification.

[0220] LCMS: [M+H]=359.

[0221] Step 3: In RBF, the intermediate SAPTI012S010 / IM2 (1.0 equivalent) was dissolved in anhydrous THF (0.2M), then TEA (2.0 equivalent) and chlorosulfonamide (1.5 equivalent) were added under nitrogen, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, THF was removed 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%).

[0222] LCMS: [M+H]=438.

[0223] Example 12: Synthesis procedure of SAPTI012S011

[0224]

[0225] Step 1: The previous intermediate SAPTI012S010 / IM2 (1.0 eq.) in DCM solution was treated with benzyl isocyanate) (1.5 eq.) at room temperature for 12 hours. After completion of the reaction, the material was further diluted with DCM and washed with water and brine solution. The combined organic layers were concentrated under reduced pressure and the crude product was purified by column chromatography using DCM and MeOH as eluents (10-15%). The product SAPTI012S011 / IM1 was confirmed by LCMS (yield: 57%).

[0226] LCMS: [M+H]=506.

[0227] Step 2: Intermediate SAPTI012S011 / IM1 (1.0 equivalent) was treated with 1.0N KOH aqueous solution at 95°C for 3 hours. The reaction mixture was then 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%).

[0228] LCMS: [M+H]=402.

[0229] Example 13: Synthesis procedure of SAPTI012S012

[0230]

[0231] Step 1: In a RBF, a solution of tert-butyl [3-(S-methylsulfonylimino)phenyl]methylcarbamate (1.0 eq.) was dissolved in toluene (0.2 M), followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.), the solution was purged with nitrogen for 10 minutes, 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 6 hours under nitrogen. 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 SAPTI012S012 / IM1 (yield: 28%) was confirmed by LCMS.

[0232] LCMS: [M+H]=473.

[0233] Step 2: The intermediate SAPTI012S012 / IM1 (1.0 equiv) was dissolved in 1,4-dioxane (0.2 M) in a RBF and cooled to 0 °C with an ice bath, then HCl dioxane solution (10 vol) was added dropwise and stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S012 / IM2 was confirmed by LCMS and was further used without further purification (yield: 64%). LCMS: [M+H] = 373.

[0234] Step 3: The HCl salt of SAPTI012SO12 / IM2 (1.0 equivalent) was dissolved in water and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent) and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with water and brine solution and 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%).

[0235] LCMS: [M+H]=416.

[0236] Example 14: Synthesis procedure of SAPTI012S013

[0237]

[0238] Step 1: tert-Butyl [3-(S-methylsulfonylimino)phenyl]methylcarbamate (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-8-methoxyquinazoline (1.5 eq.), the solution was purged with nitrogen for 10 minutes, 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 6 hours under nitrogen. 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 SAPTI012S013 / IM1 (yield: 64%) was confirmed by LCMS.

[0239] LCMS: [M+H]=443.

[0240] Step 2: The intermediate SAPTI012S013 / IM1 (1.0 equiv) was dissolved in 1,4-dioxane (0.2 M) in a RBF and cooled to 0°C with an ice bath. Then HCl dioxane solution (10 volumes) was added dropwise and stirred at room temperature for more than 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S013 / IM2 was confirmed by LCMS and used further without further purification (yield: 91%). LCMS: [M+H]=343.

[0241] Step 3: The HCl salt of the SAPTI012SO13 / IM2 (1.0 equivalent) was dissolved in water, and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent), and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with a saline solution and evaporated under reduced pressure through anhydrous sodium sulfate, 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%).

[0242] LCMS: [M+H]=386.

[0243] Example 15: Synthesis procedure of SAPTI012S014

[0244]

[0245] Step 1: 4-(S-methylsulfonylimide)benzonitrile (1.0 eq) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%) and Cs2CO3 (1.4 eq), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq), and the solution was purged with nitrogen for 10 minutes. Pd(OAc)2 (5 mol%) was then added and the temperature was raised to 100°C. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S014 / IM1 (yield: 27%) was confirmed by LCMS.

[0246] LCMS: [M+H]=369.

[0247] Step 2: SAPTI012SO14 / IM1 (1.0 equivalent) 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 for many times, and the aqueous layer was acidified with 1N HCl until the aqueous layer became an acidic solution, extracted with DCM and the organic layer was collected and concentrated to obtain a crude mixture. The crude product was purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S014 was confirmed by LCMS and 1H NMR (yield: 42%).

[0248] LCMS [M+H]=388.

[0249] Example 16: Synthesis procedure of SAPTI012S015

[0250]

[0251] Step 1: Tert-butyl {[3-(S-methylsulfonylimino)phenyl]methyl}carbamate (1.0 eq) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq), the solution was purged with nitrogen for 10 minutes, 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 for 6 hours under nitrogen. After the reaction was completed, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S015 / IM1 (yield: 47%) was confirmed by LCMS.

[0252] LCMS: [M+H]=473.

[0253] Step 2: The intermediate SAPTI012S015 / IM1 (1.0 equiv) was dissolved in 1,4-dioxane (0.2 M) in a RBF and cooled to 0°C with an ice bath. Then HCl dioxane solution (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 HCl salt of SAPTI012S015 / IM2 was confirmed by LCMS and used further without further purification (yield: 98%). LCMS: [M+H]=373.

[0254] Step 3: SAPTI012S015 / IM2 (1.0 equivalent) was dissolved in water, and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent), and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulfate and 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%).

[0255] LCMS: [M+H]=416.

[0256] Example 17: Synthesis procedure of SAPTI012S016

[0257]

[0258] The previous intermediate SAPTI012S014 / IM1 (1.0 equivalent) was dissolved in isopropanol (10V), then NaOH (1 equivalent) was added, and the resulting mixture was stirred at 80°C for 12 hours. After the reaction was complete, the reaction mixture was evaporated to remove isopropanol from the reaction mixture. The resulting crude product was diluted with water and extracted with DCM several times, and 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 SAPTI012S016 was confirmed by LCMS and 1H NMR (yield: 50%).

[0259] LCMS [M+H]=387.

[0260] Example 18: Synthesis procedure of SAPTI012S017

[0261]

[0262] Step 1: 4-(S-methylsulfonylimide)benzonitrile (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-8-methoxyquinazoline (1.5 eq.), the solution was purged with nitrogen for 10 minutes, 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 for 8 hours under nitrogen. 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 SAPTI012S017 / IM1 (yield: 78%) was confirmed by LCMS.

[0263] LCMS: [M+H]=339.

[0264] Step 2: Add intermediate SAPTI012S017 / IM1 (1.0 equivalent) dissolved in isopropanol (10V), then add NaOH (1 equivalent), and stir the resulting mixture at 80°C for 12 hours. After the reaction is complete, evaporate the reaction mixture to remove isopropanol from the reaction mixture. The resulting crude product is diluted with water and extracted with DCM several times, and the combined organic layers are concentrated to obtain a crude mixture. The crude product is purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S017 is confirmed by LCMS and 1H NMR (yield: 13%).

[0265] LCMS [M+H]=357.

[0266] Example 19: Synthesis procedure of SAPTI012S018

[0267]

[0268] Step 1: 4-(S-methylsulfonylimide)benzonitrile (1.0 eq) was dissolved in toluene (0.2 M) in a RBF, then DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq) and 4-chloro-6,7-dimethoxyquinazoline (1.5 eq) were added, and the solution was purged with nitrogen for 10 minutes. Pd(OAc)2 (5 mol%) was then added and the temperature was slowly raised to 100°C, and then the reaction mixture was stirred at 100°C under nitrogen for 8 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S018 / IM1 (yield: 96%) was confirmed by LCMS.

[0269] LCMS: [M+H]=368.

[0270] Step 2: Add intermediate SAPTI012S018 / IM1 (1.0 equivalent) dissolved in isopropanol (10V), then add NaOH (1 equivalent), and stir the resulting mixture at 80°C for 12 hours. After the reaction is complete, evaporate the reaction mixture to remove isopropanol from the reaction mixture. The resulting crude product is diluted with water and extracted with DCM several times, and the combined organic layers are concentrated to obtain a crude mixture. The product is purified by silica gel column chromatography using DCM and MeOH as eluents (0-10%). The product SAPTI012S018 is confirmed by LCMS and 1H NMR (yield: 58%).

[0271] LCMS: [M+H]=386.

[0272] Example 20: Synthesis procedure of SAPTI012S019

[0273]

[0274] Step 1: 4-(S-methylsulfonylimino)benzonitrile (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 eq.), and the solution was purged with nitrogen 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 nitrogen for 8 h. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S019 / IM1 (yield: 95%) was confirmed by LCMS.

[0275] LCMS: [M+H]=312.

[0276] Step 2: The intermediate SAPTI012S019 / IM1 (1.0 eq.) was dissolved in isopropanol (10 V), then NaOH (1 eq.) was added, and the resulting mixture was stirred at 80 ° C for 12 hours. After the reaction was completed, the reaction mixture was evaporated to remove isopropanol from the reaction mixture. The resulting crude product was diluted with water and extracted with DCM several times, and 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%).

[0277] LCMS [M+H]=329.

[0278] Example 21: Synthesis procedure of SAPTI012S020

[0279]

[0280] Step 1: 4-(S-methylsulfonylimino)benzonitrile (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-8-methoxyquinoline (1.5 eq.), and the solution was purged with nitrogen for 10 minutes. 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 for 8 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product (SAPTI012S20 / IM1) was confirmed by LCMS (yield: 89%).

[0281] LCMS: [M+H]=338.

[0282] Step 2: The intermediate SAPTI012S020 / IM1 (1.0 equivalent) was dissolved in isopropanol (10V), then NaOH (1 equivalent) was added, and the resulting mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was evaporated to remove isopropanol from the reaction mixture. The resulting crude product was diluted with water and extracted with DCM several times, and 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%).

[0283] LCMS [M+H]=356.

[0284] Example 22: Synthesis procedure of SAPTI012S021

[0285]

[0286] Step 1: Tert-butyl {[3-(S-methylsulfonylimino)phenyl]methyl}carbamate (1.0 eq) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq), and the solution was purged with nitrogen for 10 minutes. Pd(0Ac)2 (5 mol%) was then added and the temperature was raised to 100°C. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S021 / IM1 (yield: 64%) was confirmed by LCMS.

[0287] LCMS: [M+H]=369.

[0288] Step 2: The intermediate SAPTI012S021 / IM1 (1.0 equivalent) 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 then acidified with 1N HCl until the aqueous layer became acidic, the resulting solution was extracted with DCM, the organic layer was collected and concentrated to give a crude mixture, and 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%).

[0289] LCMS [M+H]=388.

[0290] Example 23: Synthesis procedure of SAPTI012S022

[0291]

[0292] The previous intermediate SAPTI012S021 / IM1 (1.0 equivalent) was dissolved in isopropanol (10V), then NaOH (1 equivalent) was added, and the resulting mixture was stirred at 80°C for 12 hours. After the reaction was complete, the reaction mixture was evaporated to remove isopropanol from the reaction mixture. The resulting crude product was diluted with water and extracted with DCM several times, and 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 SAPTI012S022 was confirmed by LCMS and 1H NMR (yield 40%).

[0293] LCMS [M+H]=387.

[0294] Example 24: Synthesis procedure of SAPTI012S023

[0295]

[0296] Step 1: Dissolve tert-butyl {[3-(S-methylsulfonylimino)phenyl]methyl}carbamate (1.0 eq) in toluene (0.2 M) in a RBF, then add DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq), followed by 4-chloro-6,7-dimethoxyquinazoline (1.5 eq), and purge the solution with nitrogen for 10 minutes. Then add Pd(0Ac)2 (5 mol%) and slowly heat to 100°C, and stir the reaction mixture at 100°C under nitrogen for 6 hours. After the reaction is complete, the reaction mixture is filtered through a celite pad, the filtrate is evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). LCMS is used to confirm the product (SAPTI012S023 / IM1) (yield: 64%).

[0297] LCMS: [M+H]=473.

[0298] Step 2: The intermediate SAPTI012S023 / IM1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.2 M) in a RBF and cooled to 0°C with an ice bath. Then HCl dioxane solution (10 volumes) was added dropwise and stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was evaporated to dryness and washed with ether. The HCl 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 further without further purification (yield: 74%). LCMS: [M+H]=373.

[0299] Example 25: Synthesis procedure of SAPTI012S024.

[0300]

[0301] Step 3: SAPTI012S023 (1.0 equivalent) was dissolved in water, and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1.0 equivalent), and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude product, and the crude product was purified by reverse phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S024 was confirmed by LCMS and 1H NMR (yield: 30%).

[0302] LCMS: [M+H]=416.

[0303] Example 26: Synthesis procedure of SAPTI012S025

[0304]

[0305] Step 1: Dissolve dipropan-2-yl {2-[4-(S-methylsulfonylimino)phenyl]ethyl}phosphonate (1.0 eq.) in RBF solution of toluene (0.2 M), then add DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.), and purge the solution with nitrogen for 10 minutes. Then add Pd(OAc)2 and slowly heat to 100°C and stir under nitrogen for 6 hours. After completion of the reaction, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S025 / IM1 (yield 20%) was confirmed by LCMS. LCMS: [M+H]=536.

[0306] Step 2: In a sealed tube, SAPTI012SO25 / IM1 (1.0 equivalent) was dissolved in CHCl3 (0.2M) and cooled to 0°C with an ice bath, then HBr (10 volumes) was added under nitrogen and stirred at 60°C for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and purified by reverse phase C18 column chromatography using 0.1% aqueous phosphoric acid and MeOH as eluents (10-15%). The product SAPTI012S025 was confirmed by 1H NMR and LCMS (yield: 15%).

[0307] LCMS: [M+H]=452.

[0308] Example 27: Synthesis procedure of SAPTI012S026

[0309]

[0310] 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 (0.2M) and then cooled to 0°C with an ice bath. NaH (2.0 equiv) was then added under nitrogen, followed by 4-chloro-6,7-dimethoxyquinazoline (1.1 equiv), and the temperature of the reaction mixture was slowly raised to 100°C and stirred for 12 hours. After the reaction was complete, 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 (05-10%). The product SAPTI012S026 / IM1 (yield: 40%) was confirmed by LCMS.

[0311] LCMS: [M+H]=477.

[0312] Step 2: In a sealed tube, the intermediate SAPTI012S026 / IM1 (1.0 equivalent) was dissolved in EtOH (0.2M), and then XPhos (7.5mol%), DIPEA (1.4 equivalents) were added, followed by diethyl phosphite (1.5 equivalents), and the solution was purged with nitrogen for 10 minutes. Pd(OAc)2 was then added, the temperature was slowly raised to 100°C, and stirred for 16 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was evaporated and purified by column chromatography using DCM and MeOH as eluents (0-5%). Intermediate SAPTI012S026 / IM2 (yield: 80%) was confirmed by LCMS.

[0313] LCMS: [M+H]=534.

[0314] Step 3: In RBF, intermediate SAPTI012S026 / IM2 (1.0 equivalent) was dissolved in DCM (0.2M) and cooled to 0°C with an ice bath. Trimethylsilyl bromide (10 volumes) was then added under nitrogen and stirred at room temperature for more than 12 hours. After the reaction was complete, the reaction mixture was evaporated to dryness and purified by reverse phase column chromatography using 0.1% phosphoric acid in water and MeOH as eluents (10-15%). The pure product SAPTI012S026 was confirmed by 1H NMR and LCMS (yield: 44%).

[0315] LCMS: [M+H]=478.

[0316] Example 28: Synthesis procedure of SAPTI012S027

[0317] Step 1: Dissolve [3-(S-benzenesulfonylimino)propyl]phosphonic acid dipropyl-2-yl ester (1.0 eq.) in toluene (0.2 M) in RBF, then add DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.), and purge the solution with nitrogen for 10 minutes. Then add Pd(OAc)2 and slowly heat to 100°C and stir under nitrogen for 6 hours. After completion of the reaction, the reaction mixture was filtered through a celite pad, 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%).

[0318] LCMS: [M+H]=536.

[0319]

[0320] Step 2: In a sealed tube, the intermediate SAPTI012S027 / IM1 (1.0 equivalent) was dissolved in CHCl3 (0.2M) and cooled to 0°C with an ice bath, then HBr (10V) was added under nitrogen and stirred at 60°C for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and purified by reverse phase C18 column chromatography using 0.1% aqueous phosphoric acid and MeOH as eluents (10-15%). The product SAPTI012S027 was confirmed by 1H NMR and LCMS (yield: 15%).

[0321] LCMS: [M+H]=452.

[0322] Example 29: Synthesis procedure of SAPTI012S028

[0323] Step 1: 1-Bromo-5-(S-methylsulfonylimino)naphthalene (1.0 eq.) was dissolved in THF (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.) and purged with nitrogen for 10 minutes. Pd(OAc)2 was then added, and the reaction mixture was slowly heated to 100°C under nitrogen and stirred for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S028 / IM1 (yield 65%) was confirmed by LCMS.

[0324] LCMS: [M+H]=473.

[0325]

[0326] Step 2: In a sealed tube, the intermediate SAPTI012S028 / IM1 (1.0 equivalent) was dissolved in EtOH (0.2M), and then XPhos (7.5mol%), DIPEA (1.4 equivalents) were added, followed by diethyl phosphite (1.5 equivalents), and the solution was purged with nitrogen for 10 minutes. Pd(OAc)2 was then added, the temperature was slowly raised to 100°C, and stirred for 16 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was evaporated and purified by column chromatography using DCM and MeOH as eluents (0-5%). Intermediate SAPTI012S028 / IM2 (yield: 80%) was confirmed by LCMS.

[0327] LCMS: [M+H]=530.

[0328] Step 3: In RBF, intermediate SAPTI012S028 / IM2 (1.0 equivalent) was dissolved in DCM (0.2M) and cooled to 0°C with an ice bath. Then trimethylsilyl bromide (10V) was added under nitrogen and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and purified by reverse phase column chromatography using 0.1% phosphoric acid in water and MeOH as eluents (10-15%). Pure product SAPTI012S028 was confirmed by 1H NMR and LCMS (yield: 44%).

[0329] LCMS: [M+H]=474.

[0330] Example 30: Synthesis procedure of SAPTI012S029

[0331]

[0332] Step 1: Dissolve tert-butyl [5-(S-methylsulfonylimino)naphthalene-1-yl]carbamate (1.0 eq.) in toluene (0.2 M) in a RBF, then add DPE phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.), and purge the reaction mixture with nitrogen for 10 minutes. Pd(OAc)2 was then added, and the reaction mixture was slowly heated to 100°C under nitrogen conditions and continued to stir at 100°C for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S029 / IM1 (yield 71%) was confirmed by LCMS.

[0333] LCMS: [M+H]=509.

[0334] Step 2: In RBF, intermediate SAPTI012S029 / IM1 (1.0 equivalent) was dissolved in dioxane (0.2M) and cooled to 0°C with an ice bath. Then HCl dioxane solution (10 volumes) was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was evaporated to dryness, washed with ether, quenched with 10% NaHCO3 solution, and extracted with DCM many times. The combined organic layer was concentrated and used for the next step without purification. The product SAPTI012S029 / IM2 (yield: 65%) was confirmed with LCMS.

[0335] LCMS: [M+H]=409.

[0336] Step 3: Intermediate SAPTI012S029 / IM2 (1.0 eq) was dissolved in AcOH / H2O (1:1) (0.5 M) in RBF, then NaOCN (1.0 eq) was added at 0°C and the reaction mass was stirred at room temperature for 3 hours. After completion of the reaction, it was quenched with dil NaOH and extracted with DCM several times. The combined organic layers were 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%).

[0337] LCMS: [M+H]=452.

[0338] Example 31: Synthesis procedure of SAPTI012S030

[0339]

[0340] Step 1: In a RBF, tert-butyl N-[3-(cyclopentylsulfonylimino)phenyl]carbamate (1.0 eq.) was dissolved in toluene (0.2 M), followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.), and the solution was purged with nitrogen for 10 minutes. Pd(OAc)2 (5 mol%) was then added and the temperature was raised to 100°C. The reaction mixture was stirred at 100°C under nitrogen for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product (SAPTI012S030 / IM1) was confirmed by LCMS (yield 63%).

[0341] LCMS: [M+H]=513.

[0342] Step 2: SAPTI012S030 / IM1 (1.0 eq.) was dissolved in 1,4-dioxane (0.2 M) in a RBF and cooled to 0°C with an ice bath. Then HCl dioxane solution (10 vols) was added dropwise and stirred at room temperature for 5 hours. After the reaction was complete, 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%).

[0343] Step 3: The HCl salt of SAPTI012SO30 / IM2 (1.0 equivalent) was dissolved in water, and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent), and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with brine solution and evaporated under reduced pressure through anhydrous sodium sulfate, 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%).

[0344] LCMS: [M+H]=456.

[0345] Example 32: Synthesis procedure of SAPTI012S031

[0346]

[0347] Step 1: Diethyl {4-[S-(propane-2-)sulfonylimino]phenyl}phosphonate (1.0 eq) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq), and the solution was purged with nitrogen for 10 min. Pd(OAc)2 was then added and the reaction mixture was slowly heated to 100 °C and stirred for 6 h under nitrogen. 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 (yield 20%) was confirmed by LCMS. LCMS: [M+H]=508.

[0348] Step 2: The intermediate SAPTI012S031 / IM1 (1.0 equivalent) was dissolved in CHCl3 (0.2M) in a sealed tube and cooled to 0°C with an ice bath, then HBr (10 volumes) was added under nitrogen and stirred at 60°C for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and purified by reverse phase C18 column chromatography using 0.1% phosphoric acid in water and MeOH as eluents (10-15%). The product SAPTI012S031 was confirmed by 1H NMR and LCMS (yield: 15%).

[0349] LCMS: [M+H]=452.

[0350] Example 33: Synthesis procedure of SAPTI012S032

[0351] Step 1: In a RBF, tert-butyl N-[3-(propane-2-ylsulfonylimino)phenyl]carbamate (1.0 equiv) was dissolved in toluene (0.2 M), followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv), and the solution was purged with nitrogen for 10 minutes. 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 for 6 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S032 / IM1 (yield: 30%) was confirmed by LCMS.

[0352] LCMS: [M+H]=485.

[0353]

[0354] Step 2: Intermediate SAPTI012S032 / IM1 (1.0 eq) was dissolved in 1,4-dioxane (0.2 M) in a RBF and cooled to 0°C with an ice bath. Then HCl dioxane solution (10 vol) was added dropwise and stirred at room temperature for more than 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness and washed with ether. The HCl salt of SAPTI012S032 / IM2 was confirmed by LCMS and used without further purification (yield: 72%).

[0355] Step 3: The HCl salt of SAPTI012S032 / IM2 (1.0 equivalent) was dissolved in water, and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent), and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with brine solution and evaporated under reduced pressure through anhydrous sodium sulfate, and purified by reverse phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S032 was confirmed by LCMS and 1HNMR (yield: 65%).

[0356] LCMS: [M+H]=428.

[0357] Example 34: Synthesis procedure of SAPTI012S033

[0358] Step 1: tert-Butyl N-[3-(propan-2-ylsulfonylimino)phenyl]carbamate (1.0 equiv) was dissolved in a RBF solution of toluene (0.2 M), followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv), and the solution was purged with nitrogen for 10 minutes. 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 nitrogen for 6 hours. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S033 / IM1 (yield 61%) was confirmed by LCMS.

[0359] LCMS: [M+H]=487.

[0360]

[0361] Step 2: Intermediate SAPTI012S033 / IM1 (1.0 equiv) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0°C with an ice bath. Then HCl dioxane solution (10 vol) was added dropwise and stirred at room temperature for more than 5 hours. After the reaction was complete, 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%.

[0362] Step 3: The HCl salt of SAPTI012S033 / IM2 (1.0 equivalent) was dissolved in water and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent), and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulfate and 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 1HNMR (yield: 30%).

[0363] LCMS: [M+H]=430.

[0364] Example 35: Synthesis procedure of SAPTI012S034.

[0365] Step 1: tert-Butyl [4-(S-benzenesulfonyl imino) phenyl] carbamate (1.0 equiv) was dissolved in a RBF solution of toluene (0.2 M), followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 equiv), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 equiv), and the solution was purged with nitrogen for 10 minutes. 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 for 16 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S034 / IM1 (yield: 30%) was confirmed by LCMS.

[0366] LCMS: [M+H]=521.

[0367]

[0368] Step 2: Intermediate SAPTI012S034 / IM1 (1.0 equiv) was dissolved in 1,4-dioxane (0.2 M) in RBF and cooled to 0°C with an ice bath. Dioxane.HCl (10 vol) was then 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 SAPTI012S034 / IM2 was confirmed by LCMS and used without further purification; yield -60%.

[0369] Step 3: The HCl salt of SAPTI012S034 / IM2 (1.0 equivalent) was dissolved in water and AcOH (1:1) was added in batches at 0°C, followed by sodium cyanate (1 equivalent) and stirred at room temperature for 2 hours to react. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM several times, the combined organic layer was washed with brine solution and passed through anhydrous sodium sulfate and evaporated under reduced pressure, and then the crude product was purified by reverse phase column chromatography using water and MeOH as eluents (20-30%). The product SAPTI012S034 was confirmed by LCMS and 1H NMR (yield: 55%).

[0370] LCMS: [M+H]=464.

[0371] Example 36: Synthesis procedure of SAPTI012S035

[0372]

[0373] Step 1: 1-Bromo-4-(S-methylsulfonylimino)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-8-methoxyquinazoline (1.5 eq.), and the solution was purged with nitrogen for 10 minutes. Pd(OAc)2 (5 mol%) was subsequently added and the temperature was raised to 100°C, and the reaction mixture was stirred at 100°C under nitrogen for 16 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S035 / IM1 (yield: 35%) was confirmed by LCMS.

[0374] LCMS: [M+H]=393.

[0375] Step 2: The intermediate SAPTI012S035 / IM1 (1.0 eq) was dissolved in anhydrous 1,4-dioxane (0.2 M), and then B2(Pin)2 (1.4 eq), KOAc (3.5 eq) were added, followed by PdCl2(dppf) complex (5 mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S035 was confirmed by LCMS and 1H NMR (yield: 40%).

[0376] LCMS: [M+H]=358.

[0377] Example 37: Synthesis procedure of SAPTI012S036

[0378]

[0379] Step 1: 1-Bromo-4-(S-methylsulfonylimide)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-bromo-6,7-dimethoxyquinoline (1.5 eq.), the solution was purged with nitrogen for 10 minutes, 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 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S036 / M1 was confirmed by LCMS (yield: 65%).

[0380] LCMS: [M+H]=422.

[0381] Step 2: The intermediate SAPT1012S036 / IM1 (1.0 equivalent) was dissolved in anhydrous dioxane (0.2M), then B2(Pin)2 (1.4 equivalent), KOAc (3.5 equivalent), followed by PdCl2(DPP1) complex (5mol%), the reaction mixture was purged with nitrogen for 10 minutes, then slowly warmed to 100°C and stirred at the same temperature for 5 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S036 was confirmed by LCMS and 1H NMR (yield: 45%).

[0382] LCMS: [M+H]=387.

[0383] Example 38: Synthesis procedure of SAPTI012S037

[0384]

[0385] Step 1: 1-Bromo-4-(S-methylsulfonylimide)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 eq.), the solution was purged with nitrogen 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 for 16 h under nitrogen. 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 SAPTI012S037 / IM1 (yield: 43%) was confirmed by LCMS.

[0386] LCMS: [M+H]=365.

[0387] Step 2: The intermediate SAPTI012S037 / IM1 (1.0 eq.) was dissolved in anhydrous dioxane (0.2 M), and then B2(Pin)2 (1.4 eq.), KOAc (3.5 eq.) were added, followed by PdCl2(dppf) complex (5 mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S037 (yield: 55%) was confirmed by LCMS and 1H NMR.

[0388] LCMS: [M+H]=331.

[0389] Example 39: Synthesis procedure of SAPTI012S038

[0390]

[0391] Step 1: 1-Bromo-4-(S-methylsulfonylimide)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-6-fluoroquinazoline (1.5 eq.), the solution was purged with nitrogen for 10 minutes, 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 for 16 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S038 / IM1 (yield: 34%) was confirmed by LCMS.

[0392] LCMS: [M+H]=381.

[0393] Step 2: The intermediate SAPTI012S038 / IM1 (1.0 eq) was dissolved in anhydrous dioxane (0.2 M), and then B2(Pin)2 (1.4 eq), KOAc (3.5 eq) were added, followed by PdCl2(dppf) complex (5 mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S038 was confirmed by LCMS and 1H NMR (yield: 50%).

[0394] LCMS: [M+H]=346.

[0395] Example 40: Synthesis procedure of SAPTI012S039

[0396]

[0397] Step 1: 1-Bromo-4-(S-methylsulfonylimide)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-5-methoxyquinazoline (1.5 eq.), and the solution was purged with nitrogen for 10 minutes, 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 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S039 / IM1 (yield: 76%) was confirmed by LCMS.

[0398] LCMS: [M+H]=393.

[0399] Step 2: The intermediate SAPTI012S039 / IM1 (1.0 equivalent) was dissolved in anhydrous dioxane (0.2M), and then B2(Pin)2 (1.4 equivalent), KOAc (3.5 equivalent) were added, followed by PdCl2(dppf) complex (5mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S039 was confirmed by LCMS, 1H NMR (yield: 25%).

[0400] LCMS: [M+H]=358.

[0401] Example 41: Synthesis procedure of SAPTI012S040

[0402] Step 1: 1-Bromo-4-(S-methylsulfonylimide)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (1.5 eq.), the solution was purged with nitrogen 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 for 16 h under nitrogen. 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 SAPTI012S040 / IM1 (yield: 34%) was confirmed by LCMS.

[0403] LCMS: [M+H]=394.

[0404]

[0405] Step 2: The intermediate SAPTI012S040 / IM1 (1.0 equivalent) was dissolved in anhydrous dioxane (0.2M), and then B2(Pin)2 (1.4 equivalent)\KOAc (3.5 equivalent) was added, followed by PdCl2(dppf) complex (5mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S040 was confirmed by LCMS and 1H NMR (yield: 30%).

[0406] LCMS: [M+H]=359.

[0407] Example 42: Synthesis procedure of SAPTI012S041

[0408] Step 1: 1-Bromo-4-(S-methylsulfonylimide)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloroquinazoline (1.5 eq.), and the solution was purged with nitrogen for 10 minutes, 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 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, the filtrate was evaporated, and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S041 / IM1 (yield: 92%) was confirmed by LCMS.

[0409] LCMS: [M+H]=363.

[0410]

[0411] Step 2: The intermediate SAPTI012S041 / IM1 (1.0 equivalent) was dissolved in anhydrous dioxane (0.2M), and then B2(Pin)2 (1.4 equivalent), KOAc (3.5 equivalent) were added, followed by PdCl2(dppf) complex (5mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then the temperature was slowly raised to 100°C and stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S041 was confirmed by LCMS, 1H NMR (yield 25%).

[0412] LCMS: [M+H]=328.

[0413] Example 43: Synthesis procedure of SAPTI012S042

[0414]

[0415] Step 1: Methyl [4-(S-methylsulfonylimino)phenyl]acetate (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-8-methoxyquinazoline (1.5 eq.), and the solution was purged with nitrogen for 10 minutes, 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 6 hours under nitrogen. After the reaction was complete, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S042 / IM1 (yield: 79%) was confirmed by LCMS.

[0416] LCMS: [M+H]=416.

[0417] Step 2: A solution of SAPTI012S042 / IM1 in aqueous solution (0.2 M). Stir NH4OH (28-30%) at room temperature (25°C) for 16 hours. Then evaporate the solvent to obtain a crude reaction mixture, which is purified by flash column chromatography using neutral alumina as the stationary phase. MeOH-DCM solution (0-5%) is used as a solvent. The product SAPTI012S042 is confirmed by LCMS and 1H NMR (yield: 34%). LCMS: [M+H] = 401

[0418] Example 44: Synthesis procedure of SAPTI012S043

[0419]

[0420] Step 1: 2-Bromo-1-fluoro-4-(S-methylsulfonylimino)benzene (1.0 eq.) was dissolved in toluene (0.2 M) in a RBF, followed by the addition of DPE Phos (7.5 mol%), Cs2CO3 (1.4 eq.), followed by the addition of 4-chloro-6,7-dimethoxyquinazoline (1.5 eq.), the solution was purged with nitrogen for 10 minutes, 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 for 16 hours under nitrogen. After the reaction was complete, the reaction mixture was filled with a celite pad, and the filtrate was evaporated and purified by silica gel column chromatography using DCM and MeOH as eluents (0-5%). The product SAPTI012S043 / M1 was confirmed by LCMS (yield: 31%).

[0421] LCMS: [M+H]=441.

[0422] Step 2: The intermediate SAPTI012S043 / IM1 (1.0 equivalent) was dissolved in anhydrous dioxane (0.2M), and then B2(Pin)2 (1.4 equivalent), KOAc (3.5 equivalent) were added, followed by PdCl2(dppf) complex (5 mol%), and the reaction mixture was purged with nitrogen for 10 minutes, then slowly heated to 100°C and stirred at the same temperature for 8 hours. After the reaction was completed, the reaction mixture was filtered through a celite pad, 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 1HLCMS1H NMR (yield: 40%).

[0423] LCMS: [M+H]=406.

[0424] The characterization data of the compounds are as follows:

[0425] Table 1: 1H NMR and LCMS data of compounds of the present invention

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435] Optical resolution of the (R) and (S) enantiomeric mixture of the present invention:

[0436] The mixture of (R) and (S) enantiomers / racemates of the present invention is separated into the individual enantiomers by using analytical and / or preparative chiral chromatography (HPLC). The chiral separation of the compound of Example 7 is carried out and its activity values ​​are shown in Table 3.

[0437] ENPP-1 Inhibition Assay Method: 3nM human ENPP-1 prepared at pH 7.4 was incubated with 5μM cGAMP substrate and test article prepared in pH 7.4 buffer and 40μM HSA. The reaction was incubated for 3 hours at room temperature. After incubation, the reaction was terminated by heating the contents at 95°C for 10 minutes. 10μL of the solution was added to a 384-well plate, 10μL of Amp Glo reagent 1 was added to it, and incubated at 25°C for 60 minutes. After incubation, 20μL of AMP detection solution was added to each well with enzyme reaction and incubated at 25°C for 60 minutes. The luminescence signal (RLU) was recorded using a SpectraMax I3X microplate reader.

[0438] The luminescence signal is measured as a function of the inhibitor concentration. If the inhibitor molecule is active, the luminescence value (called OD) decreases as the inhibitor concentration increases. The inhibition % is calculated as:

[0439] Inhibition % = ((OD of control - OD of sample) / OD of control) × 100

[0440] In the present disclosure, the IC50 value of an inhibitor molecule refers to the inhibitor concentration that inhibits 50% of the growth of human ENPP-1. The slope of the plot is the IC50 value, with the X-axis representing the inhibitor concentration and the Y-axis representing the inhibition percentage.

[0441] Several compounds of the invention were subjected to ENPP-I inhibition assays to determine IC50 values ​​and / or % inhibition. The metabolic stability of some of the compounds was also determined.

[0442] Table 1 lists the ENPP-1 inhibition test results of several compounds. From the data listed in Table 1, it can be seen that many lead molecules of the present invention can inhibit the function of phosphodiesterase (such as ENPP-1) and are expected to be used in the treatment of diseases such as cancer.

[0443] In certain aspects, the present invention provides a method for treating cancer in an individual, wherein the method comprises administering to the individual an effective amount of a compound of the present invention or a salt thereof.

[0444] In certain aspects, the present invention provides a method of treating a disease or disorder associated with an ENPP-1 enzyme in a subject, wherein the method comprises administering to the subject an effective amount of a compound of the present invention or a salt thereof.

[0445] The compounds or salts thereof described herein may be administered by a variety of routes including oral, mucosal (eg, nasal, sublingual, vaginal, buccal or rectal), parenteral (eg, intramuscular, subcutaneous or intravenous), topical or transdermal.

[0446] Table 2: ENPP-1 inhibition IC50 values ​​of the compounds of the present invention

[0447]

[0448]

[0449] One enantiomer 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 were separated by chiral HPLC. The enantiomers have not been assigned a Cahn Ingold Prelog configuration (R or S).

[0450] Table 3: IC5 values ​​of ENPP-1 inhibition of SAPTI012S006 enantiomers

[0451] Code Sample properties IC50 value range SAPTI012S006 Racemic <100nM SAPTI012S006-E1 Enantiomer E1 >100nM SAPTI012S006-E2 Enantiomer E2 <100nM

[0452] In another embodiment of the present invention, there is provided a use of a compound of formula I in the preparation of a medicament for treating cancer. In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and an effective dose of a compound defined in formula I.

[0453] In one embodiment, the pharmaceutical formulation comprising a compound of Formula I or a salt thereof is a formulation suitable for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In another embodiment, the formulation is a nanoparticle formulation.

[0454] In one embodiment, the pharmaceutical preparation containing the compound of formula I or its salt is a preparation suitable for oral, rectal, topical or intravenous injection, wherein the pharmaceutical preparation optionally comprises any one or more of a pharmaceutically acceptable carrier, adjuvant or carrier.

[0455] The compounds represented by Formula I or salts thereof can be formulated with suitable carriers to form the following preparations, including but not limited to tablets, caplets, capsules, cachets, troches, lozenges, chewing gums, dispersions, suppositories, ointments, cataplasms (creams), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0456] In one embodiment, the compound of formula I is formulated for oral administration and can be administered as a conventional formulation, such as any dosage form of a solid agent, such as a tablet, powder, granule, capsule, etc.; an aqueous agent; an oily suspension; or a liquid agent such as a syrup and an elixir. In one embodiment, the compound of formula I is formulated for parenteral administration and can be administered as an injectable aqueous or oily suspension or nasal drop. When preparing parenteral formulations with the compound of formula I, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers, etc. can be used arbitrarily.

[0457] For example, for oral administration in tablet or capsule dosage form, 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 pulverizing the compound of formula I to a suitable fine particle size and mixing with a similarly pulverized pharmaceutical carrier, such as an edible carbohydrate (e.g., starch or mannitol). Flavoring agents, preservatives, dispersants, and coloring agents may also be added.

[0458] Capsules are prepared by preparing a powder mixture as described above and filling the formed gelatin sheath. Before the filling operation, glidants and lubricants (such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol) can be added to the powder mixture. Disintegrants or solubilizers (such as agar, calcium carbonate or sodium carbonate) can also be added to improve the availability of the drug when the capsule is ingested.

[0459] In addition, when needed or necessary, applicable binders, lubricants, disintegrants and colorants can also be incorporated into the mixture. The applicable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include but are not limited to starch, methyl cellulose, agar, bentonite, xanthan gum, etc. For example, tablets are prepared by preparing a powder mixture, granulating or slugging, adding lubricants and disintegrants and pressing into tablets. The powder mixture is prepared by mixing the appropriately crushed compound with a diluent or base as described above, and optionally mixed with a binder such as carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone, a solution blocker such as paraffin, a reabsorption promoter such as a quaternary salt and / or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, Acadia mucus or a solution of cellulose or polymeric material and forcing it through a screen. As an alternative to granulation, the powder mixture can be broken into incompletely formed slugs of granules by a tablet press. The granules can be lubricated by adding stearic acid, stearate, talc or mineral oil to prevent adhesion to the tablet forming die. The lubricated mixture is then pressed into tablets. The compounds of the present invention can also be combined with a free-flowing inert carrier and directly pressed into tablets without granulation or slugging steps. A transparent or opaque protective coating can be provided, which consists of a sealing coating of shellac, a coating of sugar or polymeric material and a polishing coating of wax. Dyes can be added to the coating to distinguish different unit doses.

[0460] Oral liquids such as solutions, syrups and elixirs can be prepared in dosage units so that a certain amount of the compound contains a predetermined amount. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while elixirs are prepared by using a non-toxic alcohol carrier. Suspensions can be prepared by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.

[0461] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. For formulations of the compound of formula I, the release time of the compound may also be prolonged or sustained by coating or embedding particulate materials in polymers, waxes or similar substances.

[0462] The compound of formula I or its salt, solubilizer or hydrate can also be administered in the form of liposome delivery system, such as small monoamide vesicles, large monoamide vesicles and multiamide vesicles. Liposomes can be formed by a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine, etc.

[0463] Formula I compound or its salt, solution or hydrate can also be delivered by coupling the compound molecule to a carrier using a monoclonal antibody as a separate carrier. These compounds can also be combined with soluble polymers as targeted drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl-methacrylamide phenol. Polyhydroxyethyl asparagine-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compound can be coupled to a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as crosslinked or amphiphilic block copolymers of polylactic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

[0464] Pharmaceutical preparations suitable for transdermal administration can be made into discrete patches, intended to maintain close contact with the epidermis of the user for a long time. For example, the compound of Formula I can be released from the patch by iontophoresis, as shown in "Pharmaceutical Research" (Pharmaceutical Research) Vol. 3, No. 6, p. 318 (1986). Pharmaceutical preparations suitable for topical application can be formulated into ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. When formulated into ointments, active ingredients can be used together with paraffin or water miscible ointment bases. Alternatively, active ingredients can be formulated in creams with oil-in-water cream bases or water-in-oil bases.

[0465] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

[0466] Pharmaceutical preparations suitable for nasal administration (where the carrier is a solid) include coarse powders with particle sizes ranging, for example, from 20 to 500 microns, which are administered in the same manner as snuff, i.e., by rapid inhalation through the nasal cavity from a powder container held close to the nasal cavity. Suitable preparations for nasal sprays or drops in which the carrier is a liquid include aqueous or oily solutions of the active ingredient.

[0467] Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists which can be administered by various types of metered-dose, dosed pressurized aerosols, nebulizers or pneumoperitoneum machines.

[0468] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended user; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations can be stored in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0469] In addition to the ingredients particularly mentioned above, the formulations described herein may include other conventional formulations having regard to the type of formulation concerned, for example, formulations suitable for oral administration may include flavoring agents.

[0470] 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 exact condition to be treated and its severity, the nature of the formulation and the route of administration, and will ultimately be determined by the attending physician or veterinarian. The effective amount of a salt or hydrate thereof can be determined as a ratio of the effective amount of the compound of formula I or its salt, solvate or hydrate itself.

[0471] Embodiments of the present invention provide for administering a compound of Formula I to a healthy or cancer patient as a single agent or in combination with (a) another drug effective against cancer, (b) another drug that improves immune response and robustness, or (c) another drug that reduces inflammation and / or pain.

[0472] Although the foregoing invention has been described in detail by way of illustration and example for the purpose of clearly illustrating the present invention, it is obvious to those skilled in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. The foregoing merely illustrates the principles of the present invention. All examples and conditional language described herein are intended to help the reader understand the principles of the present invention and the concepts contributed by the inventors to promote the development of the art, and should not be construed as limiting the present invention to the above examples and conditions. Therefore, the scope of the present invention is not 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, in, Formula I includes part A and part B that together constitute the tail, part C that constitutes the core, a sulfoximine group R2-S(=W)(=N) connecting the tail and the core, and a zinc binding group (ZBG), wherein, The A moiety is a six-membered aromatic or heteroaromatic group, which may be optionally replaced by one or more R 3 Group substitution, where X1, X2 and X3 are CH, N, CR', but no more than two of X1, X2 and X3 can be N at the same time; The B moiety is a C6 aryl or a 5-6 membered heteroaryl, optionally substituted by one or more R 4 A radical substitution in which the moiety B is fused to the moiety A and the two common atoms between the moieties B and A are from a pair of carbon atoms or from a pair of atoms in which one atom is nitrogen and the other is carbon; The C moiety is selected from the group consisting of structures (i), (i), (ii), (iv), (v) and (vi), wherein L1 is attached to (i) at a variable position of 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); n=0,1,2,3,4, provided that when n>1, the R groups may be the same or different; R 1 , R 3 , R 4 The group is selected from the group consisting of R', halogen, OR', OAr, SR', SAr, NHAr, NR'R', CN, SCN, -NHCOR', COR', COOR', COOAr, CF3, CHF2, CH2F, OCF3, SCF3 and CH2Ar, wherein R'=H, CN, C1-6 straight chain alkyl, branched alkyl, cycloalkyl, CH2Ar, wherein Ar=aryl, substituted aryl, heteroaryl or substituted heteroaryl; E1=-(CH2) y - where y = 0, 1, 2 or 3; L1=-(CH2) y1 、NR", O or S, C1-6 straight chain alkyl, branched chain alkyl, (CH2) y1 Cycloalkyl, wherein y1=0, 1, 2 or 3; Wherein R"=H, C1-6 straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, substituted aryl, halogenated alkyl; X4, X5 and X6 = CH, N or CR'; The A part 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, olefin, olefin, alkynyl, halo, aryl, heteroaryl, heterocyclic, substituted aryl, CF3, CHF2, CH2F, CN and 2-6 membered olefin groups, one end of which is bonded to the sulfur atom and the other end is bonded to the C portion at the alpha position to the carbon atom of the C portion bonded to the sulfur atom; When y=O, a ring structure is formed and ZBG as shown in structure (vii); 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 in a given instance.

2. The compound according to claim 1, wherein the compound is selected from the following groups, the group comprising:

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

4. The compound of claim 3, wherein the phosphodiesterase is selected from the group consisting of ENPP-1, cyclic nucleotide phosphodiesterase, phospholipase C and D, autotaxin, sphingomyelin phosphodiesterase, deoxyribonuclease, ribonuclease, restriction endonuclease, small molecule phosphodiesterase, and combinations thereof.

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

6. The compound according to claim 5, wherein the stereoisomer is selected from enantiomers and racemates.

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. A method for treating glioma, glioblastoma multiforme, paraganglioma, supratentorial primitive neuroectodermal tumor, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic bile duct carcinoma (IHCC), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), other solid tumors and mycobacterial diseases, the method comprising administering a pharmaceutical composition according to claim 7 to a population of patients.

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