Novel small molecule drug conjugates of gemcitabine derivatives

Abstract

This invention provides a novel small molecule drug conjugate for use in the treatment or prevention of cancer and other proliferative conditions characterized by cells expressing cytochrome P450 1B1 and its allele variants. [Solution] A compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof is provided. TIFF2026090362000235.tif36128 (wherein the formula, the effector is the part of (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine)

Description

[Technical Field]

[0001] Priority application This application claims priority to U.S. Provisional Application No. 62 / 625,779, filed on 2 February 2018, which is incorporated herein by reference in its entirety.

[0002] Field of Invention The present invention relates to novel small molecule drug conjugates (SMDCs) for use in the treatment or prevention of cancer and other proliferative conditions characterized, for example, by cells expressing cytochrome P450 1B1 (CYP1B1) and its allele variants. The present invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapies, for example, in the treatment or prevention of cancer or other proliferative conditions, and methods for treating cancer or other conditions in human or non-human animal patients. Other aspects of the present invention are further disclosed herein. [Background technology]

[0003] Background of the Invention CYP1B1 is a member of the dioxin-inducible CYP1 gene family, which also includes CYP1A1 and CYP1A2, as described by Sutter et al. (J Biol. Chem., May 6; 269(18):13092-9, 1994) (Non-Patent Literature 1). CYP1B1 is a hemthiolate monooxygenase enzyme capable of metabolizing and activating a variety of substrates, including steroids, xenobiotics, drugs, and / or SMDCs. The CYP1B1 protein is frequently expressed in a wide range of primary and metastatic human cancers of various tissue types, while it is either absent or expressed at negligible levels in normal tissues (McFadyen MC, Melvin WT and Murray GI, "Cytochrome P450 Enzymes: Novel Options for Cancer Therapeutics", Mol Cancer Ther., 3(3): 363-71, 2004 (Non-patent Literature 2); McFadyen MC and Murray GI, "Cytochrome P450 1B1: a Novel Anticancer Therapeutic Target", Future Oncol., 1(2): 259-63, 2005 (Non-patent Literature 3)).

[0004] More specifically, CYP1B1 has been shown to be expressed in cancers of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovaries, prostate, and skin, but not in the corresponding normal tissues. For example, Barnett, et al. in Clin. Cancer Res., 13(12): 3559-67, 2007 (Non-patent Literature 4) reported that CYP1B1 is overexpressed in glial tumors including glioblastoma, anaplastic astrocytoma, oligodendroglioma, and anaplastic oligodendroglioma, but not in unaffected brain tissue; Carnell, et al., in Int. J. Radiat. Oncol. Biol. Phys., 58(2): 500-9, 2004 (Non-patent Literature 5) reported that CYP1B1 is overexpressed in prostate adenocarcinoma, but not in corresponding normal prostate tissue; Carnell, et al., 2004 (ibid.) also showed that CYP1B1 is expressed in bladder cancer (n=22, 100%); Downie, et al., in Clin. Cancer Res., Increased expression of CYP1B1 in primary and metastatic ovarian cancer was reported by 11(20): 7369-75, 2005 (Non-Patent Literature 6) and McFadyen, et al., in Br. J. Cancer, 85(2): 242-6, 2001 (Non-Patent Literature 7), but not in normal ovarian tissue; Gibson, et al., in Mol. Cancer Ther., 2(6): 527-34, 2003 (Non-Patent Literature 8) and Kumarakulasingham, et al., in Clin. Cancer Res., 11(10): 3758-65, 2005 (Non-Patent Literature 9), which reported that CYP1B1 is overexpressed in colonic adenocarcinoma compared to the corresponding normal tissue.

[0005] Several studies have shown that CYP1B1 is overexpressed in breast cancer compared to the corresponding normal tissue (e.g., Murray GI, Taylor MC, McFadyen MC, McKay JA, Greenlee WF, Burke MD and Melvin WT, "Tumor-Specific Expression of Cytochrome P450 CYP1B1", Cancer Res., 57(14): 3026-31, 1997 (Non-patent Literature 10); Haas S, Pierl C, Harth V, Pesch B, Rabstein S, Bruning T, Ko Y, Hamann U, Justenhoven C, Brauch H and Fischer HP, "Expression of Xenobiotic and Steroid Hormone Metabolizing Enzymes in Human Breast Carcinomas". Int. J. Cancer, 119(8): 1785-91, 2006 (Non-patent Literature 11); McKay JA, Murray GI, See Ah-See AK, Greenlee WF, Marcus CB, Burke MD, and Melvin WT, "Differential Expression of CYP1A1 and CYP1B1 in Human Breast Cancer", Biochem. Soc. Trans., 24(2): 327S, 1996 (Non-Patent Document 12).

[0006] Everett, et al., in J. Clin. Oncology, 25: 18S, 2007 (Non-patent Literature 13) reported that CYP1B1 is overexpressed in malignant melanoma and disseminated disease, but not in normal skin. Chang, et al., in Toxicol. Sci., 71(1): 11-9, 2003 (Non-patent Literature 14) reported that the CYP1B1 protein is not present in normal liver, but Everett, et al., 2007 (ibid.) confirmed the overexpression of CYP1B1 in stage IV melanoma metastasis to the liver, but not in adjacent normal liver tissue.

[0007] Greer, et al., in Proc. Am. Assoc. Cancer Res., 45: 3701, 2004 (Non-patent Literature 15) reported that CYP1B1 is overexpressed during malignant progression in head and neck squamous cell carcinoma, but not in normal epithelium.

[0008] According to McFadyen, et al., in Br. J. Cancer, 91(5): 966-71, 2004 (Non-patent document 16), CYP1B1 was detected in kidney cancer but not in the corresponding normal tissue.

[0009] Murray, et al., 2004 (ibid.) showed overexpression of CYP1B1 in lung cancer cells compared to normal lung tissue using immunohistochemical testing. Su, et al., in Anti-Cancer Res., 2, 509-15, 2009 (Non-patent document 17) showed overexpression of CYP1B1 in advanced stage IV non-small cell lung cancer compared to the disease in early stages using immunohistochemical testing.

[0010] As is evident from the numerous disclosures cited above, CYP1B1 expression is characteristic of various different cancers and other proliferative states, and CYP1B1 expression can be used to define such various cancers and other states. Since normal (non-cancerous) cells do not express significant levels of CYP1B1, it can naturally be expected that compounds that are cytotoxic to CYP1B1-expressing cells but substantially non-cytotoxic to normal cells would have utility as targeted anticancer agents in cancers characterized by CYP1B1 expression. "Targeted" means that such compounds can be delivered systemically, are thought to be activated only in the presence of cancerous cells expressing CYP1B1, and remain substantially non-toxic to the rest of the body.

[0011] Furthermore, it is known that several cytochrome P450 enzymes metabolize and detoxify various anticancer drugs. McFadyen, et al. (Biochem Pharmacol. 2001, Jul 15; 62(2): 207-12 (Non-Patent Literature 18)) demonstrated a significant decrease in docetaxel sensitivity in CYP1B1-expressing cells compared to non-CYP1B1-expressing cells. This finding suggests that the presence of CYP1B1 in cells can reduce their sensitivity to several cytotoxic drugs. Therefore, CYP1B1-activated SMDCs may be useful in treating cancers where drug resistance is mediated by CYP1B1.

[0012] Furthermore, the CYP1B1 gene is highly pleomorphic in cancer, and several single nucleotide polymorphisms within the CYP1B1 gene have been identified that alter the expression and / or activity of the encoded protein. Of these, the CYP1B1*3(4326C>G; L432V) allele was characterized by both increased expression of CYP1B1 for several substrates and enzyme kinetics, as described by Sissung, et al. in Mol Cancer Ther., 7(1): 19-26, 2008 (Non-Patent Literature 19) and the references cited herein. This finding suggests that not only CYP1B1, but also allele variants of the enzyme, may contribute to SMDC activation and cancer targeting.

[0013] SMDCs have been investigated as a means of reducing the undesirable toxicity or some other negative attributes of a drug without loss of efficacy. SMDCs are drugs that are chemically modified to be inactive, but after administration, are metabolized or otherwise converted to the active form of the drug in the body. The overexpression of CYP1B1 in primary tumors and metastatic diseases compared to normal tissue presents a tremendous opportunity for the development of CYP1B1-activated SMDCs for targeted cancer therapy, as outlined by McFadyen et al., Mol Cancer Ther., 3(3), 363-71, 2004 (Non-Patent Literature 20). Indeed, the discovery and development of CYP1B1-activated SMDCs for targeted cancer therapy may offer significant pharmacological advantages over existing clinically used non-targeted cytochrome P450-activated SMDCs such as cyclophosphamide, ifosfamide, dacarbazine, and procarbazine, which are activated by cytochrome P450 expressed in normal tissues, as outlined by Patterson LH and Murray GI in Curr Pharm Des., 8(15): 1335-47, 2002 (Non-Patent Literature 21).

[0014] The use of so-called "trigger-linker-effector" chemistry in SMDC design requires activation of the trigger to initiate linker fragmentation and release the effector (typically an active drug), while the bioactivity of the effector is masked in the SMDC form. Selective SMDC modular design targeting tumor-expressing cytochrome P450s such as CYP1B1 requires (1) identification of a selective trigger moiety, (2) the use of a biostable linker that efficiently fragments (usually by aromatic hydroxylation) following trigger activation, and (3) a suitable effector or drug that does not interfere with the efficiency of the triggering process.

[0015] WO 99 / 40944 (Patent Document 1) describes an SMDC containing a drug moiety bound to a carrier framework, the described SMDC being activated via hydroxylation by CYP1B1 to release the drug moiety.

[0016] WO 2010 / 125350 (Patent Document 2) also describes an SMDC that is activated via hydroxylation by CYP1B1 and releases the drug portion.

[0017] Therefore, there remains a strong need for novel SMDCs that are useful for patients who require them. [Prior art documents] [Patent Documents]

[0018] [Patent Document 1] WO 99 / 40944 [Patent Document 2] WO 2010 / 125350 [Non-patent literature]

[0019] [Non-Patent Document 1] Sutter et al. (J Biol. Chem., May 6; 269(18):13092-9, 1994) [Non-licensed document 2] McFadyen MC, Melvin WT and Murray GI, "Cytochrome P450 Enzymes: Novel Options for Cancer Therapeutics", Mol Cancer Ther., 3(3): 363-71, 2004 [Non-licensed document 3] McFadyen MC and Murray GI, "Cytochrome P450 1B1: a Novel Anticancer Therapeutic Target", Future Oncol., 1(2): 259-63, 2005

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[0020] The present invention provides a described SMDC having novel structural and functional features, which were developed to meet the unaddressed needs of patients requiring these SMDCs.

[0021] In particular, the present invention provides a novel phosphoramidate SMDC having both novel structural and functional characteristics. The SMDCs disclosed herein are designed to release gemcitabine derivatives at specific cancer target sites that overexpress cytochrome P450. In another aspect, the SMDCs disclosed herein are also designed to protect the SMDC gemcitabine derivative moiety from cancer resistance mechanisms by incorporating the structural characteristics of a phosphoramidate or phosphorodiamidate as part of the SMDC molecule.

[0022] According to a first aspect, the present invention relates to a compound of formula (I): TIFF2026090362000001.tif36128 or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein, -L- is, within the -L- effector, -(C1-C5)alkylene-O-C(O)-effector, -(C3-C5)alkenylene-O-effector, as defined by TIFF2026090362000002.tif36128, A is -(C1-C5)alkylene-O-C(O)-; E is -O-, -O-C(O)N(H)-, -O-C(S)N(H)-, or -S-, or -S-C(O)N(H)-; D is -(C1-C5)alkylene- or -(C3-C5)alkenylene-; Y 1 is C=C, carbon or nitrogen, and when Y 1 is nitrogen, Z 1 does not exist; Each of Y 4 and Y 5 is independently carbon or nitrogen, and when Y 3 is nitrogen, Z 3 does not exist, and when Y 4 is nitrogen, Z 5 does not exist; Y 2 is C or N, and when Y 2 is nitrogen, Z 2 does not exist; Y 5 is an oxygen, carbon, nitrogen, or sulfur atom, and when Y 5 is an oxygen or sulfur atom, Z 6 does not exist; Z 1 and Z 2Each of these, if present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may independently be substituted with 1 to 3 halos; Z 3 , Z 4 , and Z 5 hydrogen, alkyl, deuterated alkyl, C 1~6 Alkoxy, deuterated C 1~6 Each alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, alkylamino, aralkylamino, arylamino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano moieties are independently selected, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; Z 1 , Z 2 , or Z 4 Provided that at least one of them is H; Z 6 The group is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, and aralkyl, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; each Z 8These are independently hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, unsubstituted deuterated C1-C6 alkoxy, substituted C1-C6 alkoxy, and substituted deuterated C1-C6 alkoxy, wherein the substituted alkyl, alkoxy and deuterated alkoxy are substituted with one or more groups selected from amino, monosubstituted or disubstituted amino, cyclic C1-C5 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholino, thiol, thioether, tetrazole, carboxylic acid, ester, amide, monosubstituted or disubstituted amide, N-bonded amide, N-bonded sulfonamide, sulfoxy, sulfonate, sulfonyl, sulfoxy, sulfinate, sphinyl, phosphonooxy, phosphate, or sulfonamide, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl may be substituted with 1 to 3 halos; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine.

[0023] Another aspect of the present invention relates to the compounds of the present invention described herein, or pharmaceutically acceptable salts, esters, amides, or solvates thereof, for use as medicinal agents.

[0024] Another aspect of the present invention relates to the compounds of the present invention described herein, or pharmaceutically acceptable salts, esters, amides, or solvates thereof, for use in methods of treating or prophylactic conditions.

[0025] Another aspect of the present invention relates to a method of treatment or prevention, comprising administering a therapeutically or prophylactically useful amount of one of the compounds of the present invention described herein to a patient in need.

[0026] Another aspect of the present invention relates to a method of treatment or prevention comprising administering a therapeutically or prophylactically useful amount of one of the compounds of the present invention described herein to a patient in need thereof, wherein the proliferative state is a cancer selected from cancers of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovary, pancreas, prostate, or skin.

[0027] Another aspect of the present invention relates to a method for treating or prophylactic a proliferative condition, comprising administering a therapeutically or prophylactically useful amount of one of the compounds of the present invention described herein, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof, to a subject in need.

[0028] Another aspect of the present invention relates to the use of the compounds of the present invention described herein, or their pharmaceutically acceptable salts, esters, amides, or solvates, for the preparation of medical agents for use in methods of treating or preventing proliferative conditions.

[0029] Another aspect of the present invention relates to a method for diagnosing a patient for the presence of tumor cells expressing the CYP1B1 enzyme, comprising: (a) administering a specific SMDC disclosed in any of the embodiments described herein to the patient; (b) determining the amount of the corresponding hydroxylated metabolite subsequently produced; and (c) correlating the amount with the presence or absence of tumor cells in the patient.

[0030] Another aspect of the present invention is, (1) Identify the presence of a tumor in the patient; (2) To treat a patient identified as being in need of treatment by administering a therapeutically or prophylactically useful amount of one of the compounds of the present invention described herein, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof. Regarding methods.

[0031] [Invention 1001] Compound of formula (I): TIFF2026090362000003.tif38128 or its pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers: During the ceremony, -L- is within the -L- effect pedal, -(C1~C5) Alkilen-OC(O)- effect pedal, -(C3~C5) Alkenylene-O- effect pedal, Defined as TIFF2026090362000004.tif41128, A is -(C1~C5)alkylene-OC(O)-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, or -S-, or -SC(O)N(H)-; D is either -(C1~C5)alkylene- or -(C3~C5)alkenne-; Y 1 C=C, carbon, or nitrogen, Y 1 If it is nitrogen, then Z 1 It does not exist; Y 4 and Y 5 Each of them is independently either carbon or nitrogen, Y 3 If it is nitrogen, then Z 3 Y does not exist. 4 If it is nitrogen, then Z 5 It does not exist; Y 2 is C or N; Y 5 is an oxygen, carbon, nitrogen, or sulfur atom, Y 5 If it is an oxygen or sulfur atom, then Z 6 It does not exist; Z 1 and Z 2Each of these, if present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may independently be substituted with 1 to 3 halos; Z 3 , Z 4 , and Z 5 hydrogen, alkyl, deuterated alkyl, C 1~6 Alkoxy, deuterated C 1~6 Each alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano moieties are independently selected, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; Z 1 , Z 2 , or Z 4 Provided that at least one of them is H; Z 6 The group is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, and aralkyl, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; each Z 8These are independently hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, unsubstituted deuterated C1-C6 alkoxy, substituted C1-C6 alkoxy, and substituted deuterated C1-C6 alkoxy, wherein the substituted alkyl, alkoxy, and deuterated alkoxy are substituted with one or more groups selected from amino, monosubstituted or disubstituted amino, cyclic C1-C5 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholino, thiol, thioether, tetrazole, carboxylic acid, ester, amide, monosubstituted or disubstituted amide, N-bonded amide, N-bonded sulfonamide, sulfoxy, sulfonate, sulfonyl, sulfoxy, sulfinate, sphinyl, phosphonooxy, phosphate, or sulfonamide, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl may be substituted with 1 to 3 halos; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine. [Invention 1002] Y 3 and Y 4 A compound of the present invention 1001, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein each of the atoms is carbon. [Invention 1003] Z 3 , Z 4 , and Z 5 Each of these compounds is selected from halo, unsubstituted C1-C3 alkyl, substituted C1-C3 alkyl, unsubstituted C1-C3 alkoxy, substituted C1-C3 alkoxy, unsubstituted deuterated C1-C3 alkoxy, or substituted C1-C3 alkoxy, and each alkyl and alkoxy moiety can be independently substituted with 1 to 3 halos, or any of the compounds of the present invention described above, or pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers thereof. [Invention 1004] Z 3 , Z 4 , and Z 5Each of these is selected from bromo, chloro, fluoro, methyl, deuterated methyl (which may be substituted with 1 to 3 halos), methoxy (which may be substituted with 1 to 3 halos), or deuterated methoxy, and is one of the compounds of the present invention described above, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof. [Invention 1005] Equation (Ia): Any of the compounds of the present invention described above, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, having TIFF2026090362000005.tif31128: During the ceremony, L, Y 1 , Y 2 , Y 5 , Z 3 , Z 4 , Z 5 , and Z 6 Each of these is defined in any of invention 1001 to 1004, The effector is the part that is (i) a phosphate derivative of gemcitabine, or (ii) a salt form of a phosphate derivative of gemcitabine. [Invention 1006] Formulas (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib- x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii): Any of the compounds of the present invention having TIFF2026090362000006.tif88128 or TIFF2026090362000007.tif198128, or any pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any of the above formulas: During the ceremony, Z 3 and Z 5 Each of these is independently a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; Z 4 If present, these are a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; -L-Effector is -(C1~C3)Alkilen-OC(O)-Effector, The filename is TIFF2026090362000008.tif33128. D is -(C1~C3)alkylene-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, -S-, or -SC(O)N(H)-; A is -(C1~C3)alkylene-OC(O)-; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine. [Invention 1007] The aforementioned effector is defined by formula (b), (c), (d), or (e): This is from TIFF2026090362000009.tif89136. During the ceremony, G is either -N(H)- or -O-; M is -OH, -O-aryl, -O-(C1~C5)alkyl-heterocycloalkyl, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 + And, M 2 is, -O - Na + , -O - Et3NH + , -O - K + , -O - NH4 + , or NC(R x R y )C(O)XR z And, X is -O- or -N(R d )-; R a is H; R b is -O-R b’ and when G is -N(H)-, R b’ is aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, cycloalkyl, alkoxyalkyl, acyloxyalkyl, alkylthioalkyl, alkylthiocarbonylalkyl, -alkyl-C(=O)-O-R d , -alkyl-O-C(=O)-R d , or -alkyl-C(R e )R f ; and any of the alkyl, heteroaryl or aryl moieties of R b may be substituted with halo, alkyl, or alkoxy; or when G is -O-, R b is M 2 ; R c is aryl, -C(O)-aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, cycloalkyl, alkoxyalkyl, acyloxyalkyl, alkylthioalkyl, alkylthiocarbonylalkyl, -alkyl-C(=O)-O-R d , -alkyl-O-C(=O)-R d , or -alkyl-C(R e )R f ; and any of the alkyl, heteroaryl, or aryl moieties of R c may be substituted with halo, alkyl, or alkoxy, and any of the alkyl, heteroaryl, or aryl moieties of R c may be substituted with halo, alkyl, or alkoxy; R d is H or alkyl; R e is -alkylthio-(C1-C 25 )alkyl or -alkyloxy-(C1-C 25 )alkyl; R f is -alkylthio-(C1~C 25 )alkyl or -alkyloxy-(C1~C 25 ) is alkyl; R x and R y Each is independently H, or an alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl, or R x and R y These, together with the carbon atoms to which they are bonded, form cycloalkyl, aryl, or heteroaryl groups; R z is a -(C1~C6) alkyl which may be substituted with a heterocycloalkyl or aryl. Any of the compounds of the present invention described above, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof. [Invention 1008] Any of the compounds of the present invention described above, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein the linker region (L) is -C(H)2-OC(O)-. [Invention 1009] Formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi ), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx): Compounds of the present invention 1001 having TIFF2026090362000010.tif123158TIFF2026090362000011.tif121150, or pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers of any of the above formulas: During the ceremony, Z 3 , Z 4 , and Z 5Each of these is independently a methyl, halo, methoxy, or deuterated methoxy that may be substituted with 1 to 3 halos; R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; R e is H, halo, alkyl, -(C1~C5)alkyl, or -(C1~C5)alkoxy; R z is a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; M is -OH, -O-aryl, -O-(C1~C5)alkyl-heterocycloalkyl, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 +で be. [Invention 1010] - The effect pedal has the following structure: It has one of TIFF2026090362000012.tif163157, In the formula, M is -O-(C1~C3)alkyl-N-morpholino, -O aryl, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 + The compounds of any of the present invention 1001 to 1006, or their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers. [Invention 1011] In the formula, M is -O-(CH2)3-N-morpholino, -O aryl, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 +The compound of the present invention 1010. [Invention 1012] Z 3 , Z 5 , and Z 4 Any of the compounds of the present invention described above, or pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers thereof, which, if present, are methoxy or deuterated methoxy, which may be substituted with 1 to 3 halos, respectively. [Invention 1013] Z 3 and Z 5 However, each is independently bromo or fluoro, and Z 4 A compound of any of the present invention 1001 to 1011, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, which, if present, is a methoxy or deuterated methoxy which may be substituted with 1 to 3 halos. [Invention 1014] The following structure: A compound of the present invention 1001 having one of TIFF2026090362000013.tif154166TIFF2026090362000014.tif196166TIFF2026090362000015.tif105166, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any one of compounds 1 to 15. [Invention 1015] A composition comprising any of the compounds of the present invention described above together with a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt, ester, amide, or solvate of any of the compounds of the present invention described above together with the pharmaceutically acceptable carrier. [Invention 1016] A compound according to any of the invention 1001 to 1014, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in pharmaceuticals. [Invention 1017] A compound according to any of the present invention 1001 to 1014, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in a method of treating or prophylactic conditions. [Invention 1018] The compound, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in a method of treatment or prevention of the present invention 1017, wherein the proliferative state is a cancer selected from cancers of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovary, pancreas, prostate, or skin. [Invention 1019] Use of any compound from the present invention 1001 to 1014, or a pharmaceutically acceptable salt, ester, amide, or solvate, for the preparation of a medical agent for use in a method of treating or prophylactic conditions. [Invention 1020] A method for diagnosing a patient for the presence of tumor cells expressing the CYP1B1 enzyme, (a) A step of administering one of the specific compounds 1001 to 1014 of the present invention to the patient. (b) A step of determining the amount of the corresponding hydroxylated metabolite that is subsequently produced; and (c) A step of correlating the amount with the presence or absence of tumor cells in the patient. Methods that include... [Invention 1021] (1) Identify the presence of a tumor in the patient; (2) To treat a patient identified as being in need of treatment by administering a therapeutically or prophylactically useful amount of any of the compounds 1001 to 1014 of the present invention, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof. method. Further aspects and embodiments of the present invention can be found in the following description.

[0032] Brief explanation of the drawing Figure 1a shows the mechanism of CYP1B1-induced 3-hydroxylation of (5,7-di(methoxy)benzofuran-2-yl)methyl(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (I), followed by 1,4-elimination, and the spontaneous release of cytotoxic effector molecules. Figure 1b of TIFF2026090362000016.tif67143 illustrates the mechanism of CYP1B1-induced 4-hydroxylation of (5,7-di(methoxy)benzofuran-2-yl)methyl(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxyl-methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (I), followed by 1,6 elimination, and the spontaneous release of cytotoxic effector molecules. Figure 1c in TIFF2026090362000017.tif68142 illustrates the mechanism of spontaneous release of cytotoxic effector molecules via CYP1B1-induced 6-hydroxylation of (5,7-di(methoxy)benzofuran-2-yl)methyl(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxyl-methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (I), followed by 1,8 elimination. Figure 1d in TIFF2026090362000018.tif69142 illustrates the mechanism of spontaneous release of a cytotoxic effector molecule via CYP1B1-induced C-6 dealkylation of (5,6,7-tri(methoxy)benzofuran-2-yl)methyl(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxyl-methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate(II), followed by 1,6 elimination. TIFF2026090362000019.tif69142 [Modes for carrying out the invention]

[0033] Detailed description of the invention SMDCs are disclosed in which the effector molecule is a molecule that has pharmacological function.

[0034] These effector molecules are chemically modified by reacting them to form the compound of formula (I). Hydroxylation of the compound of formula (I), for example, CYP1B1-induced hydroxylation, allows for the release of the effector molecule by the breakdown of the compound of formula (I) resulting from hydroxylation or hydroxylation via epoxide formation. Alternatively, dealkylation of the compound of formula (II), for example, CYP1B1-induced dealkylation, allows for the release of the effector molecule by the breakdown of the compound of formula (II).

[0035] In summary, the structure of the compound of formula (I) can be considered to consist of three parts: a trigger region, a linker, and an effector molecule. The trigger typically acts as a substrate for CYP1B1-induced hydroxylation and includes the bicyclic part shown on the left side of formula (I) and its substituents, i.e., Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 It can generally be understood that these parts include the remaining carbon atoms to which some of these parts are bonded, and the parts of the compound that include those parts.

[0036] The trigger region of the compound is bound via a linker region containing L, which in turn is bound to the effector molecule labeled as such. In the following discussion, several terms will be used, and these terms should be understood to have the meanings provided below unless otherwise indicated in the context.

[0037] Where chemical structures are shown or described, unless otherwise explicitly stated, all carbon atoms are assumed to have hydrogen substitutions to match a valence of 4. For example, for the chemical moiety -C(C)3, nine hydrogens are implied, and therefore the structure is -C(CH3)3. Certain atoms in a structure may also be described using letterforms, for example, -CH2CH2-, indicating that they have one or more hydrogens as substituents (clearly defined hydrogens). It is understood by those skilled in the art that the aforementioned descriptive techniques are common in the field of chemistry to provide conciseness and simplicity in describing otherwise complex structures.

[0038] Unless otherwise indicated, the chemical moieties listed in the definition of the variable of formula (I) and all its embodiments should be read from left to right, with the right side directly bonded to the defined parent structure. However, the chemical moieties (e.g., -alkyloxy-(C1~C)) should be read from left to right. 25 When a bond point is shown to the left of an alkyl group, the left side of this chemical moiety is directly bonded to the defined parent moiety.

[0039] When considering the general description of compounds disclosed herein for the purpose of constructing compounds, it is assumed that such constructions will result in the creation of stable structures. That is, those skilled in the art will recognize some theoretical constructions that are not typically considered stable compounds (i.e., sterically practical and / or synthetically viable).

[0040] The compounds described herein, and their pharmaceutically acceptable salts or other derivatives thereof, may optionally exist in isotopically labeled forms in which one or more atoms of the compound are replaced by atoms having the same atomic number but with atomic masses different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, for example, 2 H (deuterium), 3 H (tritium), 13 C,14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl is an example. The isotope-labeled compounds described herein, and their pharmaceutically acceptable salts, esters, SMDCs, solvates, hydrates, or other derivatives, can generally be prepared by performing the procedures disclosed in the following scheme and / or examples, using readily available isotope-labeled reagents instead of unlabeled reagents. Where a particular hydrogen position is replaced with "D" or "deuterium," it should be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position. In one embodiment, one or more sp of the compounds disclosed herein 3 One or more hydrogen atoms bonded to a carbon atom are replaced by deuterium. In another embodiment, one or more sp atoms of the compound disclosed herein 2 One or more hydrogen atoms bonded to a carbon atom are replaced by deuterium.

[0041] "Optional" or "optional" means that the event or situation described thereafter may or may not occur, and that the description includes examples of when such event or situation occurs and examples of when it does not. A person skilled in the art will understand that with respect to any molecule described as containing one or more optional substituents, it means that only sterically practical and / or synthetically viable compounds are included. "May be substituted" means substituted or unsubstituted and refers to all subsequent modifying phrases in the term unless otherwise specified. Thus, for example, in the term "optionally substituted arylalkyl," both the "alkyl" and "aryl" parts of the molecule may be substituted or unsubstituted.

[0042] Unless otherwise specified, the term "may be substituted" applies to the chemical part immediately preceding it. For example, if a variable group (e.g., R) is defined as an aryl, a may-substituted alkyl, or a cycloalkyl, only the alkyl group may be substituted.

[0043] A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. It will be understood that pharmaceutically acceptable salts are non-toxic. Further information on appropriate pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th sup.th ed., Mack Publishing Company, Easton, Pa., 1985, or in SM Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977; 66:1-19, both of which are incorporated herein by reference.

[0044] Non-limiting examples of pharmaceutically acceptable acid addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; as well as organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxybenzoyl benzoic acid. Examples include those formed using tansulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid.

[0045] Non-limiting examples of pharmaceutically acceptable base addition salts include those formed when acidic protons present in the parent compound are replaced by ionic forms of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred salts are ammonium, potassium, sodium, calcium, and magnesium salts. The aforementioned salts may be substituted if possible. Non-limiting examples of substituted salts include alkylated ammonium salts, such as triethylammonium salt. Non-limiting examples of pharmaceutically acceptable salts derived from non-toxic organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, and polyamine resins. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0046] All compounds disclosed herein include either their free base form or their pharmaceutically acceptable salts, regardless of whether it is stated herein that these compounds may exist as their pharmaceutically acceptable salts.

[0047] The term "SMDC" refers to a small molecule drug conjugate. An SMDC is a drug that is covalently bonded to another chemical part for a specific application.

[0048] As used herein, “treating” a disease, disorder or syndrome, or “treatment” of a disease, disorder or syndrome, includes (i) preventing the disease, disorder or syndrome from occurring in humans, i.e., preventing the development of clinical symptoms of the disease, disorder or syndrome in animals that are potentially exposed to or susceptible to the disease, disorder or syndrome, but have not yet experienced or exhibited symptoms of the disease, disorder or syndrome; (ii) inhibiting the disease, disorder or syndrome, i.e., preventing its occurrence; and (iii) reducing the disease, disorder or syndrome, i.e., causing regression of the disease, disorder or syndrome. As is known in the art, adjustments may be necessary for systemic versus localized delivery, age, weight, overall health status, sex, diet, administration timing, drug interactions, and severity of the condition, and these adjustments will be verifiable by those skilled in the art through routine experiments.

[0049] All compounds disclosed herein may exist as single stereoisomers (including single enantiomers and single diastereomers), racemates, mixtures of enantiomers and diastereomers, and polymorphs. Examples of stereoisomers of the compounds disclosed herein include geometric isomers and optical isomers, such as atropisomers. The compounds disclosed herein may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, as well as geometric isomers, are intended to be within the scope of the compounds disclosed herein.

[0050] Furthermore, the compounds of this disclosure may exist in a non-solvated form and in a solvated form with a pharmaceutically acceptable solvent, such as water or ethanol. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds of this disclosure.

[0051] Alkyl, as used herein, means a saturated hydrocarbyl group that may be linear, cyclic, or branched (typically linear unless otherwise indicated in the context). If an alkyl group has one or more unsaturated sites, these may be composed of carbon-carbon double or carbon-carbon triple bonds. If an alkyl group contains a carbon-carbon double bond, this results in an alkenyl group; the presence of a carbon-carbon triple bond results in an alkynyl group. In one example, alkyl, alkenyl, and alkynyl groups contain 1 to 25 carbon atoms. In another example, alkyl, alkenyl, and alkynyl groups contain 1 to 10 carbon atoms. In yet another example, alkyl, alkenyl, and alkynyl groups contain 1 to 6 carbon atoms. In yet another example, alkyl, alkenyl, and alkynyl groups contain 1 to 4 carbon atoms. In yet another example, alkyl, alkenyl, and alkynyl groups contain 1 to 3 carbon atoms. In yet another example, alkyl, alkenyl, and alkynyl groups contain 1 to 2 carbon atoms. In yet another example, alkyl contains 1 carbon atom. It should be understood that the lower limit for alkenyl and alkynyl groups is two carbon atoms, while the lower limit for cycloalkyl groups is three carbon atoms.

[0052] Alkyl, alkenyl, or alkynyl groups can be substituted, for example, once, twice, or three times, i.e., once, i.e., one or more hydrogen atoms of the alkyl group are formally replaced. Examples of such substituents include halos (e.g., fluoro, chloro, bromo, and iodine), aryl, hydroxy, nitro, amino, alkoxy, alkylthio, carboxy, cyano, thio, formyl, esters, acyl, thioacyl, amides, sulfonamides, and carbamates.

[0053] -(C3~C5)alkenylene means a divalent alkene group with a length of 3 to 5 carbon atoms that can be bonded to another atom, as in the case of -(C3~C5)alkenylene-O- or -(C3~C5)alkenylene-OC(O)N(H)-. -(C3~C5)alkenylene- may also be substituted with 1 to 4 C1 to C6 alkyl groups.

[0054] Carboxy, as used herein, means the functional group CO2H, which may be in the deprotonated form (CO2 - ).

[0055] Halo or halogen means fluoro, bromo, chloro, or iodo, respectively.

[0056] Acyl and thioacyl mean the functional groups of the formula -C(O)-alkyl or -C(S)-alkyl, respectively, where alkyl is as defined above.

[0057] Ester means a functional group containing the moiety -OC(=O)-.

[0058] Amide means a functional group containing the moiety -N(H)C(=O)-, where each of the indicated hydrogen atoms may be replaced by alkyl or aryl.

[0059] Carbamate means a functional group containing the moiety -N(H)C(=O)O-, where each of the indicated hydrogen atoms may be replaced by alkyl or aryl.

[0060] Sulfonamide means a functional group containing the moiety -SO2N(H)2-, where each of the indicated hydrogen atoms may be independently replaced by alkyl or aryl.

[0061] Alkyloxy (synonymous with alkoxy) and alkylthio moieties are of the formula -O-alkyl and -S-alkyl, respectively, where alkyl is as defined above.

[0062] Et3NH + refers to the structure TIFF2026090362000020.tif17128.

[0063] Alkenyloxy, alkynyloxy, alkenylthio, and alkynylthio belong to the formulas -O-alkenyl, -O-alkynyl, -S-alkenyl, and S-alkynyl, where alkenyl and alkynyl are defined above.

[0064] Deuterated alkyl is used herein to mean an alkyl group as defined herein, in which one or more hydrogen atoms of the alkyl group are replaced by deuterium. If there are more than one deuterated alkyl group in the molecules disclosed herein, each deuterated C1-C6 alkyl group may be the same or different.

[0065] In this specification, a deuterated C1-C6 alkyl group is defined as a C1-C6 alkyl group in which one or more hydrogen atoms of the C1-C6 alkyl group are replaced by deuterium. If there are more than one deuterated C1-C6 alkyl group in the molecules disclosed herein, each deuterated C1-C6 alkyl group may be the same or different.

[0066] In this specification, a deuterated alkoxy is defined as an -O-alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by deuterium. If there are more than one deuterated alkyl group in the molecules disclosed herein, each deuterated C1-C6 alkyl group may be the same or different.

[0067] In this specification, a deuterated C1-C6 alkoxy means an O-C1-C6 alkyl group in which one or more hydrogen atoms of a C1-C6 alkyl group are replaced by deuterium. If there are more than one deuterated C1-C6 alkyl groups in the molecules disclosed herein, each deuterated C1-C6 alkyl group may be the same or different.

[0068] Deuterated methoxy is -OCD 1~3 This is what is meant in this specification. -OCD 1~3It should be understood that this means including one of -OCH2D, -OCHD2, or -OCD3. If there is more than one deuterated methoxy group in the molecules disclosed herein, each deuterated methoxy group may be the same or different.

[0069] In this specification, the amino group means a group of formulas -N(R)2 in which each R is independently hydrogen, alkyl, or aryl. For example, R may be an unsaturated unsubstituted C1-6 alkyl, e.g., methyl or ethyl. In another example, two R groups bonded to a nitrogen atom N are bonded together to form a ring. One example of two R groups bonded to a nitrogen atom N is when -RR- forms an alkylenedi radical, which typically arises formally from an alkane with two hydrogen atoms removed from its terminal carbon atoms, thereby forming a ring with the nitrogen atom of the amine. As is well known, the diradical in a cyclic amine does not necessarily have to be alkylene, and morpholine (-RR- is -(CH2)2O(CH2)2-) is one such example in which a cyclic amino substituent can be prepared.

[0070] References to aminos in this specification should also be understood to include quaternized or protonated derivatives of amines obtained from compounds containing such amino groups. Examples of the latter may be understood to be salts, such as hydrochloride salts.

[0071] In this specification, aryl means a group formally formed by removing a hydrogen atom from an aromatic compound.

[0072] Allirenedi radicals are formally generated from an aromatic moiety by the removal of two hydrogen atoms and may be monocyclic, e.g., phenylene, unless otherwise specifically indicated in the context. As is known to those skilled in the art, heteroaromatic moieties are subsets of aromatic moieties that contain one or more heteroatoms, typically O, N, or S, instead of one or more carbon atoms and any hydrogen atoms bonded thereto. Exemplary heteroaromatic moieties include pyridine, furan, pyrrole, thiophene, and pyrimidine. Further examples of heteroaromatic rings include pyridyl; pyridazine (two nitrogen atoms adjacent to each other in an aromatic six-membered ring); pyrazine (two nitrogen atoms arranged 1,4 in a six-membered aromatic ring); pyrimidine (two nitrogen atoms arranged 1,3 in a six-membered aromatic ring); and 1,3,5-triazine (three nitrogen atoms arranged 1,3,5 in a six-membered aromatic ring).

[0073] Aryl or arylene radicals can be substituted once or multiple times with electron-withdrawing groups.

[0074] Non-limiting examples of electron-withdrawing groups include cyano(-CN), haloalkyl, amide, nitro, keto(-COR), alkenyl, alkynyl, and quaternary amino(-N) groups. + Examples include R3), esters, amides (-C(O)NR2), N-linked amides (-NR-C(=O)-R), N-linked sulfonamides (-NR-S(=O)2R), sulfoxys (-S(=O)2OH), sulfonates (S(=O)2OR), sulfonyls (S(=O)2R), and sulfonamides (-S(=O)2-NR2), where each R is a C1-C6 alkyl group, C3-C 20 Heterocyclic group, or C3~C 20Independently selected from the aryl group, the C1-C6 alkyl group includes ethers, aminos, monosubstituted or disubstituted aminos, cyclic C1-C5 alkylaminos, imidazolyls, C1-C6 alkylpiperazinyls, morpholinos, thiols, thioethers, tetrazoles, carboxylic acids, esters, amides, monosubstituted or disubstituted amides, N-linked amides (-NR-C(=O)-R), N-linked sulfonamides (-NR-S(=O)2-R), sulfoxys (-S( It may be substituted with one or more groups selected from (-O)(2OH), sulfonate (S(=O)2OR), sulfonyl (S(=O)2R), sulfoxy (S(=O)OH), sulfinate (S(=O)OR), sulfinyl (S(=O)R), phosphonooxy (-OP(=O)(OH)2), phosphate (OP(=O)(OR)2), and sulfonamide (-S(=O)2-NR2), where each R is a C1-C6 alkyl group, C3-C 20 Heterocyclic group, or C3~C 20 The aryl group is independently selected. In another example, each R is a C1-C6 alkyl group (based on the definition of alkyl above, C1-C6 alkyl groups include unsubstituted C1-C6 alkoxy and substituted C1-C6 alkoxy groups). In another example, each R is a C1-C6 alkyl, an unsubstituted C1-C6 alkoxy, or a substituted C1-C6 alkoxy, where the substituted alkyl or substituted alkoxy are ethers, -OH aminos, monosubstituted or disubstituted aminos, cyclic C1-C5 alkylaminos, imidazolyls, C1-C6 alkylpiperazinyls, morpholinos, thiols, thioethers, tetrazoles, carboxylic acids, esters, amides, monosubstituted or disubstituted amides, N-bonded amides (-NR-C(=O)-R), and N-bonded sulfonamides. The molecule is substituted with one or more groups selected from (-NR-S(=O)2-R), sulfoxy(-S(=O)2OH), sulfonate(S(=O)2OR), sulfonyl(S(=O)2R), sulfoxy(S(=O)OH), sulfinate(S(=O)OR), sulfinyl(S(=O)R), phosphonooxy(-OP(=O)(OH)2), phosphate(OP(=O)(OR)2), and sulfonamide(-S(=O)2-NR2), where each R is a C1-C6 alkyl group, C3-C 20 Heterocyclic group, or C3~C20 It is independently selected from the aryl group.

[0075] The composition and variability of these three regions of the compound of formula (I): the trigger, linker, and effector regions, are described below.

[0076] The trigger region of the compound of formula (I) generally includes a conjugated bicyclic moiety containing a six-membered ring fused to a five-membered ring.

[0077] While not constrained by theory, the activity of compounds of formula (I) as substrates for hydroxylation by CYP1B1, for example, is thought to be achieved to some extent by the structure of the hydroxylation-prone trigger moiety, which leads to the spontaneous disintegration of the compound via one of the elimination processes of 1,4, 1,6, or 1,8, depending on where the hydroxylation occurs, as shown in Figure 1. Furthermore, -OCH3 is thought to be metabolized normally via hydroxylation, followed by O-dealkylation. However, deuterated methoxy may confer enhanced stability to CYP-based hydroxylation and O-dealkylation via kinetic isotope effects. Thus, the adjacent aromatic CH bond becomes a site for CYP-based hydroxylation, which leads to the spontaneous disintegration of the compound via 1,4, 1,6, or 1,8 elimination.

[0078] From the structure of the compound of formula (I), one will notice that, due to the conjugation of carbon atoms, one of three mechanisms for the spontaneous decomposition of the compound can occur independently of the properties of the substituents on the trigger region. Therefore, as will be discussed below, a wide variety of properties for this region of the compound of formula (I) can be permitted.

[0079] In one embodiment of the compound of formula (I), Y 2 C is Y 3 is C(H). In another embodiment of the compound of formula (I), Y 3 and Y 4 Each of them is C(H). In another embodiment of the compound of formula (I), Y 2C is Y 3 and Y 4 is C(H). In another embodiment of the compound of formula (I), Y 2 C is Y 1 , Y 3 And, Y 4 is C(H).

[0080] In another embodiment of the compound of formula (I), Y 1 is N, and Y 2 C is Y 3 is C(H) and Y 4 is C(H) and Y 5 is S. In another embodiment of the compound of formula (I), Y 1 is N, and Y 2 is N, and Y 3 is C(H) and Y 4 is C(H) and Y 5 is C(H). In another embodiment of the compound of formula (I), Y 1 is C(H) and Y 2 C is Y 3 is C(H) and Y 4 is C(H) and Y 5 is N(CH3). In another embodiment of the compound of formula (I), Y 1 is C(H) and Y 2 is N, and Y 3 is C(H) and Y 4 is C(H) and Y 5 is N. In another embodiment of the compound of formula (I), Y 1 is N, and Y 2 is N, and Y 3 is C(H) and Y 4 is C(H) and Y 5 is N. In another embodiment of the compound of formula (I), Y 1 C is Y 2 C is Y 3 is C(H) and Y 4 is C(H) and Y 5 is S. In another embodiment of the compound of formula (I), Y 1 is N, and Y 2 C is Y 3is C(H) and Y 4 is C(H) and Y 5 is O. In another embodiment of the compound of formula (I), Y 1 is C(H) and Y 2 C is Y 3 is C(H) and Y 4 is C(H) and Y 5 It is O.

[0081] substituent Z 1 , Z 2 and Z 4 In general, these are as described herein. However, at least one of these parts is a hydrogen atom to give the site for hydroxylation of the compound. In some embodiments of the compound of formula (I), Z 2 or Z 4 One of them is hydrogen. In other embodiments, Z 2 and Z 4 is hydrogen. In any of these embodiments, Z 2 or Z 4 is a hydrogen atom, or Z 2 and Z 4 Both are hydrogen atoms, or Z 2 Z 4 If it is not a hydrogen atom, then Z 1 Z may be hydrogen. In certain embodiments of the compound of formula (I), 1 , Z 2 and Z 4 Each of them is a hydrogen atom.

[0082] In another aspect of equation (I), Z 3is selected from hydrogen alkyl, deuterated alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halo, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthioxy, alkenylthioxy, alkynylthioxy, arylthioxy, aralkylthioxy, amino, hydroxy, thio, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos. In another embodiment of formula (I), Z 3 is halo. In another embodiment of formula (I), Z 3 is methyl. In another embodiment of formula (I), Z 3 is methoxy. In another embodiment of formula (I), Z 3 is bromo.

[0083] In another embodiment of formula (I), Z 5 is selected from hydrogen alkyl, deuterated alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halo, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthioxy, alkenylthioxy, alkynylthioxy, arylthioxy, aralkylthioxy, amino, hydroxy, thio, carboxy, formyl, nitro, and cyano. In another embodiment of formula (I), Z 5 is halo. In another embodiment of formula (I), Z 5 is methyl. In another embodiment of formula (I), Z 5 is methoxy. In another embodiment of formula (I), Z 5 is bromo.

[0084] In another embodiment of formula (I), Z 3 and Z 5Each of these is selected from alkyl hydrogen, deuterated alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos. In another embodiment of formula (I), Z 3 and Z 5 Each of these is selected from alkyl, deuterated alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos. In another embodiment of formula (I), Z 3 and Z 5 These are deuterated C1-C6 alkoxy compounds, respectively. In another embodiment of formula (I), Z 3 and Z 5 These are C1-C6 alkoxys, respectively. In another embodiment of formula (I), Z 3 and Z 5 These are each C1-C6 alkyl groups. In another embodiment of formula (I), Z 3 and Z 5 These are C1-C3 alkoxys, respectively. In another aspect of formula (I), Z 3 and Z 5 These are each C1-C3 alkyl groups. In another embodiment of formula (I), Z 3 and Z 5 These are hydrogen atoms. In another aspect of equation (I), Z 3 and Z 5These are halos, respectively. In another aspect of equation (I), Z 3 and Z 5 These are each bromo. In another aspect of equation (I), Z 3 and Z 5 These are each deuterated methoxy. In another embodiment of formula (I), Z 3 and Z 5 Each of these is methoxy. In another aspect of formula (I), Z 3 and Z 5 Each of these is methyl. In another aspect of formula (I), Z 3 and Z 5 These are -OCD respectively. 1~3 Therefore, in another aspect of equation (I), Z 3 and Z 5 These are each -OCD3.

[0085] In another aspect of equation (I), Z 3 and Z 5 Each of these is independently selected from halo, methyl, methoxy, or deuterated methoxy.

[0086] One aspect of the present invention is a compound of formula (I): With respect to TIFF2026090362000021.tif32128 or its pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, During the ceremony, -L- is an effect pedal containing -(C1~C5) Alkilen-OC(O)- effect pedals and -(C3-C5) Alkenylene-O- effect pedals. Defined as TIFF2026090362000022.tif35128, A is -(C1~C5)alkylene-OC(O)-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, -S-, or -SC(O)N(H)-; D is either -(C1~C5)alkylene- or -(C3-C5)alkenne-; Y 1 C=C, carbon, or nitrogen, Y 1If it is nitrogen, then Z 1 It does not exist; Y 4 and Y 5 Each of them is independently either carbon or nitrogen, Y 3 If it is nitrogen, then Z 3 Y does not exist. 4 If it is nitrogen, then Z 5 It does not exist; Y 2 is C or N, and Y 2 If it is nitrogen, then Z 2 It does not exist; Y 5 is an oxygen, carbon, nitrogen, or sulfur atom, Y 5 If it is an oxygen or sulfur atom, then Z 6 It does not exist; Z 3 , Z 4 , and Z 5 Each of these is independently selected from hydrogen, alkyl, deuterated alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; Z 1 , Z 2 , or Z 4 Provided that at least one of them is H; Z 6 The group is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, and aralkyl, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; each Z 8These are independently hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, unsubstituted deuterated C1-C6 alkoxy, substituted C1-C6 alkoxy, and substituted deuterated C1-C6 alkoxy, wherein the substituted alkyl, alkoxy, and deuterated alkoxy are substituted with one or more groups selected from amino, monosubstituted or disubstituted amino, cyclic C1-C5 alkylamino, imidazolyl, C1-C6 alkylpiperazinyl, morpholino, thiol, thioether, tetrazole, carboxylic acid, ester, amide, monosubstituted or disubstituted amide, N-bonded amide, N-bonded sulfonamide, sulfoxy, sulfonate, sulfonyl, sulfoxy, sulfinate, sphinyl, phosphonooxy, phosphate, or sulfonamide, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl may be substituted with 1 to 3 halos; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine.

[0087] In formula (I), or in other embodiments thereof of pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, the effector is the portion of (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine.

[0088] In formula (I), or in other embodiments of its pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, Y 3 and Y 4 Each of these is carbon.

[0089] In formula (I), or in other embodiments thereof of pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, Z 3 , Z 4 and Z 5Each of these is selected from halo, unsubstituted C1-C3 alkyl, substituted C1-C3 alkyl, unsubstituted C1-C3 alkoxy, substituted C1-C3 alkoxy, unsubstituted deuterated C1-C3 alkoxy, or substituted C1-C3 alkoxy, and each alkyl and alkoxy moiety can be independently substituted with 1 to 3 halos.

[0090] In formula (I), or in other embodiments thereof of pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, Z 3 , Z 4 and Z 5 Each of these is selected from bromo, chloro, fluoro, methyl (which may be substituted with 1 to 3 halos), deuterated methyl, methoxy (which may be substituted with 1 to 3 halos), or deuterated methoxy.

[0091] Another form of equation (I) is equation (Ia): With respect to compounds containing TIFF2026090362000023.tif25128, or their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, During the ceremony, L, Y 1 , Y 2 , Y 5 , Z 3 , Z 4 , Z 5 , Z 6 And the effects are defined as in any form of equation (I).

[0092] Other forms of formulas (I) and (Ia) are (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii): With regard to compounds having one or more of TIFF2026090362000024.tif78128TIFF2026090362000025.tif195122, or pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers of any of the above formulas, During the ceremony, Z 3 and Z 5 Each of these is independently a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; Z 4 If present, these are a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; -L-Effector is -(C1~C3)Alkilen-OC(O)-Effector, The filename is TIFF2026090362000026.tif28128. D is -(C1~C3)alkylene-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, -S-, or -SC(O)N(H)-; A is -C(H)2-OC(O)-; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine.

[0093] In compounds having formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), or in other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, the linker region (L) is -C(H)2-OC(O)-.

[0094] L represents the linking region, which is described in more detail below. Each of the following embodiments of L (linking region) may be a separate embodiment relating to the trigger region and the effector, respectively, including any combination of trigger region and effector, to the extent that it is chemically possible. Various embodiments of the linker region are described below.

[0095] In other embodiments of formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), including the sub-embodiments of these formulas above, the linker region (L) is -(C1~C5)alkylene-OC(O)-.

[0096] In other embodiments of formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), including the sub-embodiments of these formulas above, the linker region (L) is -(C3~C5)alkenylene-OC(O)-.

[0097] In other forms of formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), including the subforms of these formulas above, the linker region (L) is: The filename is TIFF2026090362000027.tif32128. During the ceremony, A is -(C1~C5)alkylene-OC(O); X is -O-; D is either -(C1~C5)alkylene- or -(C3~C5)alkenne-; each Z 8 This is defined as in any aspect of this specification.

[0098] In other forms of formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), including the subforms of these formulas above, the linker region (L) is: The filename is TIFF2026090362000028.tif28128. During the ceremony, A is -(C1~C2)alkylene-OC(O)-; X is -O-; D is either -(C1~C2)alkylene- or -(C3~C4)alkenne-; each Z 8 This is defined as in any aspect of this specification.

[0099] In other forms of formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), including the subforms of these formulas above, the linker region (L) is: The filename is TIFF2026090362000029.tif23128. During the ceremony, A is -(C1~C2)alkylene-OC(O)-.

[0100] In other forms of formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), including the subforms of these formulas above, the linker region (L) is: The filename is TIFF2026090362000030.tif22128. During the ceremony, A is -(C1~C2)alkylene-OC(O)-; D is -CH2- or -CH2-C(H)=C(H-).

[0101] In another embodiment, the phosphoramidate derivative of gemcitabine has an α-amino acid moiety bonded to the P atom, and the other hydroxyl groups on the P atom are in free base form. In another embodiment, the phosphoramidate derivative of gemcitabine has an α-amino acid moiety bonded to the P atom, and the other hydroxyl groups on the P atom are in salt form. In another embodiment, the phosphoramidate derivative of gemcitabine has an α-amino acid moiety bonded to the P atom, and the other hydroxyl groups on the P atom are solubilizing groups, such as heterocycloalkylalkyl groups. In another embodiment, the phosphoramidate derivative of gemcitabine has an aryl-O moiety and an α-amino acid moiety bonded to the P atom. In another embodiment, the α-amino acid derivative may be a naturally occurring or non-naturally occurring amino acid in any of the above embodiments.

[0102] Compounds having formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii), or other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, the effector is of formula (b), (c), (d), or (e): This is from TIFF2026090362000031.tif83128. During the ceremony, G is either -N(H)- or -O-; M is -OH, -O-aryl, -O-(C1~C5)alkyl-heterocycloalkyl, -O - Na+, -O - Et3NH + , -O - K +、 or -O - NH4 + and; M 2 is, -O - Na + , -O - Et3NH + , -O - K + , or -O - NH4 + , NHC(R x R y )C(O)XR z and; X is -O- or -N(R d )-and; R a H is; R b is -OR b ' and if G is -N(H)-, then R b’These include aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, cycloalkyl, alkoxyalkyl, acyloxyalkyl, alkylthioalkyl, alkylthiocarbonylalkyl, -alkyl-C(=O)-OR d ,-alkyl-OC(=O)-R d , or -alkyl-C(R e )R f And R b The alkyl, heteroaryl, or aryl moiety may be substituted with a halo, alkyl, or alkoxy; Or, if G is -O-, then R b is M 2 and; R c These include aryl, -C(O)-aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, cycloalkyl, alkoxyalkyl, acyloxyalkyl, alkylthioalkyl, alkylthiocarbonylalkyl, and -alkyl-C(=O)-OR d ,-alkyl-OC(=O)-R d , or -alkyl-C(Re)R f And R c The alkyl, heteroaryl, or aryl moiety of R may be substituted with a halo, alkyl, or alkoxy. c The alkyl, heteroaryl, or aryl moiety may be substituted with a halo, alkyl, or alkoxy; R d is H or alkyl; R e is -alkylthio-(C1~C 25 )alkyl or -alkyloxy-(C1~C 25 ) is alkyl; R f is -alkylthio-(C1~C 25 )alkyl or -alkyloxy-(C1~C 25 ) is alkyl; R x and R yEach is independently H, or an alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl, or R x and R y These, together with the carbon atoms to which they are bonded, form cycloalkyl, aryl, or heteroaryl groups; R z This is a -(C1~C6) alkyl which may be substituted with a heterocycloalkyl or aryl group.

[0103] Formula (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib -xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), (Ib-xviii), (Ic-i), (Ic-ii), (Ic-iii) In other aspects of (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx) (including the respective sub-parts of these formulas described herein), - The effect pedal has the following structure: It has one of TIFF2026090362000032.tif147148, In the formula, M is -O-(C1~C3)alkyl-N-morpholino, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 + That is the case.

[0104] Other embodiments of the compound having formula (I) are the following: (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx): With respect to one or more of TIFF2026090362000033.tif116148TIFF2026090362000034.tif114141, or any pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers of any of the above formulas, During the ceremony, Z 3 , Z 4 , and Z 5 Each of these is independently a methyl, halo, methoxy, or deuterated methoxy that may be substituted with 1 to 3 halos; R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; R e is H, halo, alkyl, -(C1~C5)alkyl or -(C1~C5)alkoxy; R z is a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; M is -OH, -O-aryl, -O-(C1~C5)alkyl-heterocycloalkyl, -O - Na+, -O - Et3NH + , -O - K + , -O - NH4 + or NC(R x R y )C(O)XR z That is the case.

[0105] In any of the formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx), or in other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, R a is a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; M is -O-(C1~C5)alkyl-heterocycloalkyl, -O - Na+, -O - Et3NH + , -O - K + , -O - NH4 + , or NC(R x R y )C(O)XR z That is the case.

[0106] In any of the formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx), or in other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; R zis a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; M is -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 + That is the case.

[0107] In any of the formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx), or in other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; R z is a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; M is Et3NH + That is the case.

[0108] In any of the formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx), or in other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; R z is a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; M is -O-(C1~C5)alkyl-heterocycloalkyl.

[0109] In any of the formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx), or in other embodiments of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, R b is a -(C1-C5) alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl; R z is a -(C1~C5)alkyl which may be substituted with a heterocycloalkyl or aryl; M is NC(R x R y )C(O)XR z That is the case.

[0110] Formula (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (I b-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), (Ib-xviii), (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v) , (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx) (including sub-forms of these formulas above), or other forms of pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers thereof, Z 3 , Z 5 , and Z 4 If present, these are methoxy or deuterated methoxy, respectively.

[0111] Formulas (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii) (including the sub-formulas of these formulas above), or other forms of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, Z 3 , Z 5 , and Z 4 Each of these, if present, may be substituted with 1 to 3 halos, and the effector is as defined in any of the embodiments described herein.

[0112] Formula (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (I b-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), (Ib-xviii), (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v) , (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx) (including sub-forms of these formulas above), or other forms of pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers thereof, Z 3 and Z 5 These are independently bromo or fluoro, and Z 4 This is a methoxy or deuterated methoxy molecule, which, if present, may be substituted with 1 to 3 halos.

[0113] Formula (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (I b-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), (Ib-xviii), (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v) , (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx) (including sub-forms of these formulas above), or other forms of pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers thereof, Z 3 and Z 5These are, independently, bromo or fluoro; Z 4 if present, is methoxy or deuterated methoxy which may be substituted with 1 to 3 halos; the effector is as defined in any embodiment described herein.

[0114] Formula (I), (Ia), (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib-x), (Ib-xi), (Ib-xi i), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), (Ib-xviii), (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi ), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx) (including sub-forms of these formulas above), or in other forms of their pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers, the effector has the following structure: It has one of TIFF2026090362000035.tif147148, In the formula, M is -O-(C1~C3)alkyl-N-morpholino, -O aryl, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 + In another embodiment, M is -O-(CH2)3-N-morpholino, -O aryl, -O - Na+, -O - Et3NH + , -O - K + , or -O - NH4 + That is the case.

[0115] Compounds of another embodiment of formula (I) are one or more of compounds 1 to 22 described in the examples herein, or pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers of any one or more of compounds 1 to 22.

[0116] The gemcitabine portion of the compound of formula (I) is the portion that provides the desired target-directed effect in cells, typically cells expressing CYP1B1. In all embodiments of formula (I), the linker portion of formula (I) is directly bound to the amino group-containing base of the effector component of formula (I). When released, the effector molecule has a recognizable pharmacological effect on the cell from which it is released.

[0117] Effector molecules have either cell proliferation inhibitory or cytotoxic effects on cells (e.g., CYP1B1-expressing cells) that act to trigger their release. As is well known, cytotoxic molecules are those that are toxic to cells, while cell proliferation inhibitors are those that inhibit cell proliferation and / or replication.

[0118] For use in accordance with the present invention, the compounds described herein, or their physiologically acceptable salts, solvates, esters, or amides, can be provided as pharmaceutical formulations comprising the compounds, or their physiologically acceptable salts, esters, amides, or other physiologically functional derivatives, together with one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic and / or prophylactic components. Any carrier is acceptable in the sense that it is compatible with the other components of the formulation and is not harmful to its recipient.

[0119] Examples of physiologically acceptable salts of the compounds according to the present invention include organic carboxylic acids, such as acetic acid, lactic acid, tartaric acid, maleic acid, citric acid, pyruvic acid, oxalic acid, fumaric acid, oxaloacetic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and acid addition salts formed using inorganic acids, such as hydrochloric acid, sulfur, phosphoric acid, and sulfamic acid.

[0120] The determination of physiologically acceptable esters or amides, particularly esters, is well within the skill of those skilled in the art.

[0121] It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvates of the compounds described herein, and these may be used in any of the uses / methods described herein. The term solvate is used herein to refer to a complex of a solute, e.g., a compound or a salt of a compound, and a solvent. When the solvent is water, the solvate may be called a hydrate, e.g., monohydrate, dihydrate, trihydrate, etc., depending on the number of water molecules present per molecule of the substrate.

[0122] The compounds of the present invention can exist in various stereoisomers, and it will be recognized that the compounds of the present invention as defined above include all stereoisomers and mixtures thereof, including enantiomers and racemic mixtures. The present invention, within its scope, includes the use of any such stereoisomer or mixture of stereoisomers, including individual enantiomers of the compound of formula (I) and complete or partial racemic mixtures of such enantiomers.

[0123] It will be understood by those skilled in the art that anti-cancer SMDCs, such as those described herein, can be targeted to specific tumors by conjugating them with tumor-targeting moieties, such as tumor-targeting peptides, for example, small molecule peptides identified through the development of phage display peptide libraries. Such peptides or other moieties can aid in the targeting of conjugates containing them to specific cancers, particularly solid tumors. Therefore, providing compounds of the present invention conjugated with such conjugates, i.e., tumor-targeting moieties, forms a further aspect of the present invention, as well as compositions, uses, and methods described herein that include or involve the use of such conjugates.

[0124] The compounds of the present invention can be prepared using readily available reagents and techniques in the art and / or exemplary methods described below. The compounds of the present invention have been found to be cytotoxic in cells expressing the CYP1B1 enzyme, but substantially non-toxic in normal cells that do not express CYP1B1. The compounds of the present invention may also be cytotoxic in cells expressing the CYP1A1 enzyme. Therefore, in practice, the compounds of the present invention are non-toxic prodrugs that are converted into cytotoxic agents (typically by CYP1B1).

[0125] Preferably, the compounds of the present invention are defined below, or have a cytotoxic IC50 concentration of less than 10 μM, preferably less than 5 μM, for example, less than 1.0 μM or 0.5 μM. 50 It has a value.

[0126] In some embodiments, the cytotoxicity of the compounds of the present invention can be measured by incubating the compounds at various serial dilutions with cells engineered to express CYP1B1. Preferably, the cells may be Chinese hamster ovary (CHO) cells, which may contain recombinant CYP1B1 and cytochrome P-450 reductase (CPR). High levels of functional enzyme, when co-expressed with human P-450 reductase, can be achieved using amplification of the dihydrofolate reductase (DHFR) gene. Typically, engineered cells can be incubated with the compound and, after a suitable period (e.g., 96 hours), further incubated with a suitable assay reagent (e.g., 1.5 hours) to provide an indicator of the number of viable cells in the culture. A suitable assay reagent is MTS (see below), which is bioreduced by the cells to a formazan product soluble in tissue culture medium. The absorbance of the formazan product can be directly measured at 510 nm, and the quantitative formazan product, measured by the amount of absorbance at 490 nm or 510 nm, is directly proportional to the number of viable cells in culture. For comparison, the IC of the compound of the present invention... 50 The values ​​can also be measured in cells that do not contain CYP1B1 (e.g., Chinese hamster ovary cells), for example, wild-type CHO cells. The compounds of the present invention can appropriately have at least 10-fold selectivity for CYP1B1-expressing cells, and “fold selectivity” refers to the IC50 of a given compound in non-CYP1-expressing cells. 50 The IC values ​​of the same compound in CYP1B1-expressing cells 50 It is defined as the quotient of the values.

[0127] In some embodiments, the cytotoxicity of the compounds of the present invention can also be measured by incubating the compounds at various serial dilutions with primary head and neck tumor cells derived from patients with head and neck squamous cell carcinoma.

[0128] In some embodiments, the in vivo efficacy of the compounds of the present invention can be measured by subcutaneously transplanting primary head and neck squamous cell carcinoma tumor cells constitutively expressing CYP1B1 into the flank of nude mice to generate a xenograft model of a primary human tumor, and then measuring the effect of SMDC therapy on tumor growth.

[0129] In some embodiments, the in vivo pharmacokinetic parameters (AUC, concentration, t) of the compound of the present invention are... max , t 1 / 2 This can be measured in the plasma and tissues of rodents and non-rodent species, including mice, rats, dogs, and monkeys.

[0130] Accordingly, the present invention also encompasses the use of one or more of the compounds of the present invention, including the aforementioned pharmaceutically acceptable esters, amides, salts, solvates, and SMDCs, for use in the treatment of the human or animal body, particularly by the treatment or prevention of proliferative conditions in humans and non-human animals, such as proliferative disorders or diseases, including proliferative conditions characterized by cells expressing CYP1B1 in certain aspects of the present invention. More specifically, the present invention encompasses the use of one or more of the compounds of the present invention for the treatment of cancer characterized by CYP1B1 expression in certain aspects of the present invention.

[0131] In this specification, “proliferative state” means a disease or disorder characterized by unwanted or uncontrolled cell proliferation of undesirable, excessive, or abnormal cells, such as neoplastic or hyperplastic proliferation, whether in vitro or in vivo. Examples of proliferative states include pre-malignant and malignant cell proliferations, including malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis.

[0132] In certain aspects of the present invention, the proliferative state may be characterized by cells expressing CYP1B1.

[0133] The proliferative state may be selected from cancers of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovaries, prostate, and skin. In some embodiments, the proliferative state may include solid tumors.

[0134] Another embodiment relates to a method for treating or prophylactic a proliferative condition, comprising administering a therapeutically or prophylactically useful amount of a compound according to formula (I), including all embodiments of formula (I), or a pharmaceutically acceptable salt, ester, amide, or solvate thereof, to a subject, wherein the proliferative condition is cancer of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovary, prostate, and skin.

[0135] In this specification, “treatment” means treatment by a therapy that achieves a certain desirable therapeutic effect on a proliferative condition, whether in humans or in non-human animals (for example, in veterinary applications), including inhibition of the progression of the disorder, improvement of the disorder, or cure of the condition, including reduction of the rate of progression, cessation of the rate of progression, etc. Treatment as a preventive measure is also included. References to prevention or prevention in this specification do not indicate or require complete prevention of the condition; instead, the manifestation of its symptoms may be reduced or delayed through prevention or prevention according to the present invention. In this specification, “therapeutic effective dose” means an amount of one or more compounds of the present invention, or a pharmaceutical formulation containing one or more such compounds, that is effective in producing such a therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0136] Therefore, the compounds of the present invention can be used as anticancer agents. The term "anticancer agent" as used herein means a compound that treats cancer (i.e., a compound useful in the treatment of cancer). The anticancer effects of the compounds of the present invention may arise through one or more mechanisms, including regulation of cell proliferation, inhibition of angiogenesis, inhibition of metastasis, inhibition of invasion, or promotion of apoptosis.

[0137] It will be recognized that the appropriate dosage of the compounds of the present invention may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risks or adverse side effects of the treatment of the present invention. The selected dosage level depends on various factors, including the activity of the particular compound, the route of administration, the time of administration, the elimination rate of the compound, the duration of treatment, other drugs, compounds, or materials used in combination, as well as the patient's age, sex, weight, condition, overall health, and medical history. While the amount and route of administration of the compound are ultimately at the discretion of the physician, the dosage should generally achieve a local concentration at the site of action to achieve the desired effect.

[0138] In vivo administration can be performed as a single dose, continuously or intermittently, throughout the entire course of treatment. Methods for determining the most effective means of administration and dosage are well known to those skilled in the art and vary depending on the formulation used in the therapy, the purpose of the therapy, the target cells being treated, and the subject being treated. Single or multiple doses may be administered at dose levels and patterns selected by the treating physician.

[0139] Pharmaceutical formulations may be suitable for oral, topical (including transdermal, buccal, and sublingual), rectal, or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), nasal, and, for example, intrapulmonary administration by inhalation. Where appropriate, the formulations may be conveniently provided in separate dosing units and may be prepared by any method well known in the field of pharmacy. These methods typically involve mixing the active compound with a liquid carrier or a finely ground solid carrier or both, and then, if necessary, forming the product into the desired formulation.

[0140] Pharmaceutical formulations suitable for oral administration, where the carrier is solid, are most preferably provided as unit-dose formulations such as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be manufactured by compression or molding with optionally one or more auxiliary components. Compressed tablets can be prepared by mixing the active compound in a free-flowing form, such as powder or granules, with optionally a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant, and compressing it in a suitable machine. Molded tablets can be manufactured by molding the active compound using an inert liquid diluent. Tablets can optionally be coated, and if not coated, they can optionally be cut. Capsules can be prepared by filling capsule shells with the active compound, either alone or in a mixture with one or more auxiliary components, and then sealing them in a conventional manner. Cachet formulations are similar to capsules, where the active compound is sealed in a rice paper wrapper with optional auxiliary components. The active compound can also be formulated as a dispersible granule, which can, for example, be suspended in water before administration or sprinkled on food. The granules can be packaged in sachets. Formulations suitable for oral administration, in which the carrier is liquid, can be provided as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0141] Formulations for oral administration include controlled-release dosage forms, such as tablets in which the active compound is formulated in a suitable controlled-release matrix or coated with a suitable controlled-release film. Such formulations may be particularly convenient for prophylactic use.

[0142] Pharmaceutical formulations suitable for rectal administration, in which the carrier is solid, are most preferably provided as unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can conveniently be formed by mixing a softened or molten carrier with an active compound, followed by cooling and molding in a mold.

[0143] Suitable pharmaceutical formulations for parenteral administration include sterile solutions or suspensions of the active compound in an aqueous or oily vehicle.

[0144] Injectable preparations can be adapted for bolus injection or continuous infusion. Such preparations are conveniently provided in unit-dose or multi-dose containers, which are sealed after introduction of the preparation until needed for use. Alternatively, the active compound may be in powder form, consisting of a suitable vehicle before use, such as sterile, pyrogen-free water.

[0145] The active compound can also be formulated as a long-acting depot preparation, which can be administered by intramuscular injection or, for example, by subcutaneous or intramuscular implantation. The depot preparation may contain, for example, a suitable polymeric or hydrophobic material or an ion exchange resin. Such long-acting formulations are particularly convenient for prophylactic use.

[0146] Formulations suitable for intrapulmonary administration via the buccal oral cavity are provided such that particles containing the active compound, preferably having a diameter in the range of 0.5 to 7 microns, are delivered into the bronchial trees of the recipient.

[0147] One possibility is that such a formulation may be in the form of a finely crushed powder, which may be conveniently provided in a perforated, preferably gelatinous, capsule for use in an inhalation device, or as an autopropelled formulation comprising the active compound, a suitable liquid or gaseous propellant, and optionally other components, such as a surfactant and / or a solid diluent. Suitable liquid propellants include propane and chlorofluorocarbons, and a suitable gaseous propellant is carbon dioxide. Autopropelled formulations may also be used in which the active compound is prepared in the form of droplets of a solution or suspension.

[0148] Such self-propelled formulations are similar to those known in the art and can be prepared by established procedures. Preferably, they are supplied in a container provided with either a manually operated valve or an automatically functioning valve having the desired spray characteristics; advantageously, the valves are of the metering type, delivering a fixed amount, e.g., 25 to 100 microliters, with each of their operations.

[0149] As a further possibility, the active compound may also be in the form of a solution or suspension for use in an atomizer or nebulizer, where accelerated airflow or ultrasonic agitation is used to generate a fine liquid mist for inhalation.

[0150] Preparations suitable for nasal administration include those generally similar to those for intrapulmonary administration. When compounded, such preparations should preferably have a particle diameter in the range of 10 to 200 microns to allow retention in the nasal cavity; this can be achieved, as appropriate, by using a powder of appropriate particle size or by selecting an appropriate valve. Other suitable preparations include coarse powders with a particle diameter in the range of 20 to 500 microns for administration by rapid inhalation through the nostril from a container held close to the nose, and nasal sprays containing 0.2 to 5% w / v of the active compound in an aqueous or oily solution or suspension.

[0151] It should be understood that, in addition to the carrier components described above, the pharmaceutical preparations may include one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and substances included for the purpose of making the preparation isotonic with the blood of the target recipient.

[0152] Pharmaceutically acceptable carriers are well known to those skilled in the art and are not limited to, but include 0.1 M, preferably 0.05 M, phosphate buffer or 0.8% physiological saline. Furthermore, pharmaceutically acceptable carriers may also be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, e.g., olive oil, and injectable organic esters, e.g., ethyl oleate. Aqueous carriers include water, alcohol / aqueous solutions, emulsions, or suspensions, including physiological saline and buffering media. Parenteral vehicles include sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, Ringer's lactate solution, or non-volatile oils. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, and inert gases, may also be present.

[0153] Formulations suitable for topical formulations may be provided, for example, as gels, creams, or ointments.

[0154] Liquid or powder formulations may also be provided that can be sprayed or sprinkled directly onto the area to be treated, such as a wound or ulcer. Alternatively, the formulation can be sprayed or sprinkled onto a carrier, such as a bandage, gauze, or mesh, and then applied to the area to be treated.

[0155] For therapeutic formulations for veterinary use, the formulation may conveniently be either a powder or a liquid concentrate. Following the conventions of standard veterinary formulations, conventional water-soluble excipients, such as lactose or sucrose, can be incorporated into the powder to improve its physical properties. Therefore, a particularly suitable powder of the present invention comprises 50-100% w / w, preferably 60-80% w / w, of the active ingredient and 0-50% w / w, preferably 20-40% w / w, of conventional veterinary excipients. These powders can be added to animal feed as an intermediate premix or diluted in animal drinking water.

[0156] The liquid concentrate of the present invention appropriately contains the compound or its derivatives or salts, and may optionally contain a veterinarily acceptable water-miscible solvent, such as polyethylene glycol, propylene glycol, glycerol, glycerol formal, or such solvent mixed with ethanol up to 30% v / v. The liquid concentrate can be administered into the drinking water of an animal.

[0157] Generally, suitable doses of one or more compounds of the present invention range from about 1 μg to about 5000 μg / kg of body weight per day, for example, 1, 5, 10, 25, 50, 100, 250, 1000, 2500, or 5000 μg / kg per day. If the compound is a salt, solvate, SMDC, etc., the amount administered can be calculated based on the parent compound, and therefore the actual weight used may increase proportionally.

[0158] In some embodiments, one or more compounds of the present invention can be used in combination therapy for the treatment of the above-described proliferative conditions, i.e., in combination with other therapeutic agents. Examples of such other therapeutic agents include, but are not limited to, topoisomerase inhibitors, alkylating agents, antimetabolites, DNA binding agents, and microtubule inhibitors (tubulin targeting agents), such as cisplatin, cyclophosphamide, etoposide, irinotecan, fludarabine, 5-FU, taxane, or mitomycin C. Other therapeutic agents will be apparent to those skilled in the art. In the case of active compounds combined with other therapies, two or more therapies can be administered via separate routes, each with a different dosing schedule.

[0159] The combination of the drugs listed above and the compounds of the present invention will be at the physician's discretion, and the physician will select the dosage using the common general knowledge of physicians and dosing regimens known to those skilled in the art.

[0160] When the compounds of the present invention are administered in combination therapy with one, two, three, four, or more other therapeutic agents, preferably one or two, preferably one other therapeutic agent, the compounds may be administered simultaneously or sequentially. When administered sequentially, they may be administered at short intervals (e.g., over 5 to 10 minutes) or at longer intervals (e.g., separated by 1, 2, 3, or 4 hours, or longer if necessary), and the exact dosing regimen should be in line with the characteristics of the therapeutic agents.

[0161] The compounds of the present invention can also be administered in conjunction with non-chemotherapy, such as radiotherapy, photodynamic therapy, gene therapy, surgery, and restricted diets.

[0162] Another aspect of the present invention relates to a method for diagnosing a patient for the presence of tumor cells expressing the CYP1B1 enzyme, comprising: (a) administering one or more compounds of the present invention to the patient; (b) determining the amount of the corresponding hydroxylated metabolite subsequently produced; and (c) correlating the amount with the presence or absence of tumor cells in the patient.

[0163] Another aspect of the present invention is, (1) Identify the presence of a tumor in the patient; (2) Treating a patient identified as being in need of treatment by administering a therapeutically or prophylactically useful amount of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof. Regarding methods, in one embodiment, tumors can be identified by using tumor biomarkers. Tumor biomarkers can also be useful in confirming specific diagnoses, for example, in determining whether a tumor is of primary or metastatic origin. To make this distinction, chromosomal changes observed in cells located at the primary tumor site can be screened against those observed at secondary sites. If the changes are consistent, the secondary tumor can be identified as metastatic; on the other hand, if the changes are different, the secondary tumor can be identified as a different primary tumor.

[0164] In another embodiment, tumors can be identified by biopsy. Non-limiting examples of biopsies that can be used include fine-needle aspiration biopsy, core needle biopsy, vacuum-assisted biopsy, image-guided biopsy, surgical biopsy, incisional biopsy, endoscopic biopsy, and bone marrow biopsy.

[0165] In another embodiment, tumor identification may also be done by magnetic resonance imaging (MRI), a test that uses a magnetic field to produce detailed images of the body.

[0166] In another embodiment, tumor identification may be performed by a bone scan. In yet another embodiment, tumor identification may be performed by a computed tomography (CT) scan, also known as a CAT scan.

[0167] In another embodiment, tumor identification may also be performed by an integrated PET-CT scan, which combines images from positron emission tomography (PET) scans and computed tomography (CT) scans performed simultaneously using the same machine.

[0168] In another embodiment, tumor identification may also be performed by ultrasound, which is an imaging technique that uses high-frequency sound waves to pinpoint the location of tumors within the body.

[0169] In a more specific form, as a form of personalized medicine, companion diagnostics that can be used to assist in treating patients can be obtained from Ventana Medical Systems, Inc., a member of the Roche Group, located at 1910 Innovation Park Drive, Tuscon, AZ 85755.

[0170] The following examples and schemes illustrate general synthetic procedures for the compounds disclosed herein. The synthesis of the compounds disclosed herein is not limited by these examples and schemes. Those skilled in the art will know that other procedures can be used to synthesize the compounds disclosed herein, and that the procedures described in the examples and schemes are only one such procedure. In the following description, those skilled in the art will recognize that specific reaction conditions, reagents added, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure.

[0171] Preparation of compounds general principles 1 H, 13 C, and 31P nuclear magnetic resonance (NMR) spectra were recorded using one of the Bruker Avance DPX 400 MHz spectrometers in the indicated solvent. Chemical shifts are expressed in ppm. Signal splitting patterns are described as singleline (s), broad singleline (bs), doubleline (d), tripleline (t), quadrupleline (q), multiline (m), or a combination thereof. Low-resolution electrospray (ES) mass spectra were recorded using a Bruker MicroTof mass spectrometer in positive ion mode, with methanol / water (95:5) or water-acetonitrile (1:1) + 0.1% formic acid as the mobile phase. High-resolution electrospray measurements were performed using a Bruker MicroTof mass spectrometer. LC-MS analysis was performed using an Agilent HPLC 1100 (Phenomenex Gemini column 5μ C18 110Å 50×3.0mm, eluted with (0-20% MeOH / H2O)) and a diode array detector in series with a Bruker Microtof mass spectrometer. Column chromatography was performed using silica gel (230-400 mesh) or RediSep (登録商標) The reactions were carried out using 0.4, 12, 40, or 80 g silica pre-packed columns. All starting materials were commercially available and used without further purification. All reactions were carried out under dry and inert conditions unless otherwise noted.

[0172] Methods for the preparation and / or separation and isolation of single stereoisomers from racemic or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R) and (S) isomers can be separated by chiral synthones or by the formation of diastereoisomer salts or complexes, for example by crystallization, as is known to those skilled in the art; or by the formation of diastereoisomer derivatives, for example by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example by enzymatic oxidation or reduction, followed by separation of the modified enantiomer from the unmodified enantiomer; or by gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica bound to a chiral ligand, or in the presence of a chiral solvent. If a desired enantiomer is converted to another chemical entity by one of the above separation procedures, it will be recognized that further steps may be required to liberate the desired enantiomer form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by asymmetric transformation, by converting one enantiomer to another. For enantiomer mixtures enriched with a specific enantiomer, the enantiomer of the main component can be further enriched by recrystallization (with a decrease in yield).

[0173] The following examples illustrate general synthetic procedures for the compounds disclosed herein. The synthesis of the compounds disclosed herein is not limited by these examples and schemes. Those skilled in the art will know that other procedures can be used to synthesize the compounds disclosed herein, and that the procedures described in the examples and schemes are only one such procedure. In the following description, those skilled in the art will recognize that specific reaction conditions, reagents added, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. Unless otherwise specified, the intermediate compounds in the following examples, without description of how they were prepared, are either commercially available to those skilled in the art, or can be synthesized by those skilled in the art using commercially available precursor molecules and synthetic methods known in the art.

[0174] Unless otherwise specified, the intermediate compounds in the following examples, without any explanation of how they were manufactured, are either commercially available to those skilled in the art, or can be synthesized by those skilled in the art using these materials.

[0175] Typical preparation examples of trigger precursors The trigger precursor molecules for the compounds of the present invention can be prepared by the following synthetic schemes and by making any necessary modifications to the starting materials, reagents, and / or reaction conditions known to a skilled medicinal chemist in order to arrive at the compounds of the present invention. The synthetic precursor molecules for these schemes are either commercially available or their preparations are known in the art.

[0176] Preparation Example 1 Benzofuran trigger precursors Z 3 , Z 4 and Z 5 A benzofuran trigger precursor (i), as defined herein, can be produced using the following scheme: The synthesis of benzofuran-2-carboxylate is widely known, and many methods exist for the synthesis of intermediates such as (ib). Thus, a appropriately substituted salicylaldehyde starting material (ia) can be reacted with a haloacetate such as ethyl-2-bromoacetate, followed by cyclization of the formylphenoxyacetic acid derivative intermediate [see H. Dumont and S. Kostanecki, “Zur kenntnis der cumaron-gruppe”, Chemische Berichte, vol. 42, no. 1, pp. 911-915, 1909]. Cyclization can be carried out in an alcoholic solution in the presence of a basic catalyst such as sodium ethanolate, 1,8-diazobicyclo-[5.4.0]-7-undecane, or potassium carbonate. Subsequently, the resulting ester can be further functionalized or converted into a desired trigger precursor using known methods for the reduction of carboxylate esters to primary alcohols, such as metal hydride reducing agents (LiAlH4, LiBEt3H, or NaBH4).

[0177] Preparation Example 2 Benzo[b]thiophene trigger precursor Z 3 , Z 4 and Z 5 A benzo[b]thiophene trigger precursor (iii), as defined herein, can be manufactured using one of the following schemes: Scheme (ii) Alternatively, the benzothiophene-2-yl alcohol of formula (ii) can be conveniently prepared from the substituted salicylaldehyde derivative of formula (ii-e) (see scheme above). Alkylation with dimethylthiocarbamoyl chloride, followed by a Newman-Kwart rearrangement, yields the intermediate of formula (ii-g). Alkaline work-up can yield the free thiophenol of formula (ii-h), which can then undergo alkylation / cyclization using standard procedures. The ester intermediate (ii-i) can then be reduced to alcohol (ii) using methods commonly used for the reduction of carboxylate esters to primary alcohols, such as LAH in tetrahydrofuran.

[0178] Preparation Example 3 1H-benzo[d]imidazole trigger precursor Z 3 , Z 4 and Z 5 The 1H-benzo[d]imidazole trigger precursor, as defined herein, can be prepared using the following scheme, similar to that described by Borchardt et. al. “Preparation of tetrahydropyranones as hepatitis C virus RNA-dependent RNA polymerase inhibitors”, WO 2004 / 074270. Scheme (iii) A suitably substituted 2-halo-nitrobenzene (iii) can be reacted with methylamine to form an aminonitro intermediate, which can then be reduced using a known method for the conversion of nitroarenes to aniline, such as zinc and an acid source, e.g., HCl, to obtain compound (iii-b). Compound (iii-b) can then be converted to the target alcohol (vi) by heating with a reagent such as hydroxyacetic acid.

[0179] Preparation Example 4 1H-indole trigger precursor Z 3 , Z 4 and Z 5 A 1H-indole trigger precursor, as defined herein, can be prepared using the following scheme, similar to that described by Condie et al. in Tetrahedron, (2005), 61(21), 4989-5004. Scheme (iv) A properly substituted benzaldehyde starting material (iv-a) can be reacted with a 2-azidoacetate reagent and then heated at a high temperature in an inert solvent such as ortho-dichlorobenzene to yield an indole ester intermediate (iv-b). The indole (iv-b) can then be alkylated with an alkyl halide such as methyl iodide and a suitable base such as NaH to yield the second-to-last trigger (iv-c), which can then be reduced to a primary alcohol target (vii) using a method commonly used for the reduction of carboxyl esters to primary alcohols, such as lithium aluminum hydride in tetrahydrofuran.

[0180] Preparation Example 5 Benzothiazole trigger precursor Z 3 , Z 4 and Z 5 A benzothiazole trigger precursor, as defined herein, can be manufactured using any of the following schemes. Appropriately substituted aniline can be iodinated and then acylated to the intermediate (vb), which is done by using standard methods known to perform such conversions, such as N-iodosuccinimide, followed by reaction with acetyl chloride. Acetamide (vb) can be converted to the corresponding thioacetamide using a reagent such as Lawson's reagent, and then cyclized using either a base or copper(I) iodide to yield thiazole (vc). Next, the 2-methyl group can be oxidized to the corresponding carboxylic acid (vd) using an oxidizing agent such as potassium permanganate. The subsequent conversion to a primary alcohol (ix) can be carried out using the conditions described above.

[0181] Preparation Example 6 Benzoxazole trigger precursor Z 3 , Z 4 and Z 5 A benzoxazole trigger precursor, as defined herein, can be manufactured using any of the following schemes. Appropriately substituted aniline can be iodized and then acylated to the intermediate (vI-b), which is done by using standard methods for which such conversions are known, such as N-iodosuccinimide, followed by reaction with acetyl chloride. The acetamide (vI-c) can be cyclized to yield the oxazole (vI-d). The subsequent conversion to the primary alcohol (vi) can be carried out using the above conditions.

[0182] Examples of synthesis of compounds of the present invention The compounds of the present invention can be prepared according to the following synthesis schemes I and II, and by making any necessary modifications to the starting materials, reagents, and / or reaction conditions known to a skilled medicinal chemist in order to arrive at the compounds of the present invention. The synthetic precursor molecules for these schemes are either commercially available or their preparations are known in the art.

[0183] Synthesis Scheme I TIFF2026090362000042.tif66128 Synthesis Scheme 1 R a , R b , and R c As defined herein, such phosphoramidate analogs can be prepared using well-known and established literature methods for the synthesis of nucleoside phosphates and phosphonate analogs, starting from the advanced intermediates described herein (see Pradere et al. Chem. Rev. 2014, 114, 9154-9218).

[0184] Synthesis Scheme II Alternatively, a phosphoramidate analog of gemcitabine SMDC can be prepared by starting from the evolved intermediate 8 using a procedure similar to that described by Slusarczyk et. al. in J. Med. Chem., 2014, 57, 1531-1542. Thus, the C-4' alcohol can be selectively protected with a protecting group such as tert-butylcarbonate to yield intermediate compound 13. The C-5' primary alcohol group can then be phosphorylated according to the method described by Baraniak et. al. in Bioorg. Med. Chem. Lett., 2014, 22, 2133-2140.

[0185] Synthesis Scheme III Gemcitabine SMDC phosphorodiamidate analogs can be prepared according to the procedures described in the literature, such as those described by McGuigan in J. Med. Chem. 2011, 54, 8632.

[0186] Synthesis of intermediate compounds Compound A: (5,7-dibromobenzofuran-2-yl)methanol TIFF2026090362000045.tif17128 Process A: Synthesis of Int A-1 TIFF2026090362000046.tif251283,5-dibromo-2-hydroxybenzaldehyde (400 g, 1.44 mol) and 2-ethyl bromo (360 g, 2.16 mol) were dissolved in DMF (1800 mL), to which anhydrous potassium carbonate (590 g, 4.29 mol) was added all at once at room temperature. The mixture was heated to 100 °C and magnetically stirred at this temperature overnight. The mixture was cooled to room temperature, and the solid was removed by filtration. The filtration cake was washed with ELISA (500 mL x 3), and the filtrate was concentrated under reduced pressure using a rotary evaporator to remove the ELISA. The residue was poured into ice water (w / w=1 / 1, 4 L), which formed a yellow solid. The solid was collected by filtration and washed three times with MeOH (200 mL). The solid was dried under reduced pressure to obtain 240 g of compound Int A-1, which was used directly in the next step. f = 0.5 (petroleum ether: SiO = 20:1).

[0187] Step B: Synthesis of compound A TIFF2026090362000047.tif23128Int A-1 (120 g, 0.35 mol) was added in small amounts (5 g each) to a chilled solution of MeOH (1000 mL) and THF (1000 mL) to NaBH4 (52.8 g, 1.39 mol), maintaining the reaction temperature between 5 and 10°C. The resulting mixture was stirred for 3 hours, then the ice bath was removed and the reaction was allowed to reach room temperature over 16 hours. The mixture was poured into ice / water (w / w=1 / 1, 3 L) and concentrated to remove most of the organic solvent. The mixture was extracted with SiO2 (800 mL x 3), and the mixed organic washing solution was extracted three times with saturated brine (400 mL). The organic phase was separated and dried over anhydrous sodium sulfate. This process was repeated, and the two reaction products were mixed, concentrated, and 120 g of crude compound A was obtained, which was used directly in the next step. R f =0.4 (Petroleum ether: SiO = 5:1) TIFF2026090362000048.tif11128

[0188] Compound B: (5,7-dimethoxybenzofuran-2-yl)methanol Synthesis of Compound B TIFF2026090362000049.tif18128 TIFF2026090362000050.tif22128 Compound A (60 g, 0.20 mol), NaOMe (600 mL, 30% w / w, purchased from Alfa), and DMF (6 g, 0.08 mol) were mixed with CuBr (8 g, 0.056 mol) under nitrogen at room temperature. The mixture was then stirred at 80°C for 4 hours. The reaction mixture was cooled to 0°C, and then H2O (500 mL) was added to the mixture at 0°C. The mixture was filtered through a Celite pad, and the filtrate was extracted three times with DCM (500 mL). The mixed DCM extract was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a brown solid. This process was repeated, and the two reaction products were mixed, concentrated, and obtained an oil, which was purified by column chromatography (petroleum ether: siRNA = 5:1 to 0:1) to obtain 60 g of Compound B as a yellow solid. f (Petroleum ether: SiO = 5:1) = 0.4 TIFF2026090362000051.tif11130

[0189] Compound C: (5,7-bis(methoxy-d3)benzofuran-2-yl)methanol TIFF2026090362000052.tif18128 Process A: Synthesis of Int C-1 TIFF2026090362000053.tif221285-Methoxysalicylicaldehyde (200 g, 1.31 mol) and anhydrous NaOAc (172 g, 2.10 mol) were mixed in AcOH (1.5 L), to which Br2 (270 g, 1.71 mol) was added dropwise over 1 hour at 0-5°C (ice bath) under nitrogen using a dropping funnel. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into ice water (w / w=1 / 1, 2 L) and stirred for 15 minutes. The mixture was then filtered. The filtrate was washed with water (400 mL x 3) and then dried under vacuum (oil pump) at 45°C for 2 days to obtain Int C-1 (200 g) as a yellow solid. TIFF2026090362000054.tif11137

[0190] Process B: Synthesis of Int C-2 TIFF2026090362000055.tif25128 To a 1000 mL dry DMF mixture of Int C-1 (200 g, 0.87 mol) and anhydrous K2CO3 (360 g, 2.61 mol), 217 g (1.30 mol) of ethyl 2-bromoethyl acetate was added all at once under nitrogen at room temperature, and the mixture was stirred at room temperature for 10 minutes, then heated to 100 °C and stirred for 6 hours. The mixture was cooled to room temperature and concentrated. The residue was poured into water (1 L) and stirred for 20 minutes. The mixture was filtered, the filtrate was washed with water (500 mL x 3), and the mixture was dried under vacuum (oil pump) to obtain Int C-2 (105.4 g) as a brown solid. TIFF2026090362000056.tif17143

[0191] Process C: Synthesis of Int C-3 To a solution of C-2 (120 g, 0.40 mol) in DCM (700 mL), a solution of BBr3 (350 g, 1.4 mol) in DCM (500 mL) was added dropwise over 30 minutes at -70°C under nitrogen, while maintaining the temperature below -60°C. The reaction mixture was warmed to 0°C and stirred at 0°C for 3 hours. The reaction mixture was slowly poured into ice water (w / w=1 / 1, 1 L) and then extracted with DCM (800 mL x 2). The mixed organic phase was washed with saturated brine (800 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 150 mm, diameter: 50 mm, silica gel of 100-200 mesh, petroleum ether / alkyl = 20 / 1, 10 / 1, 5 / 1) to obtain Int C-3 (42 g) as a white solid. TIFF2026090362000058.tif17143

[0192] Process D: Synthesis of Int C-4 In a solution of Int C-3 (95 g, 0.33 mol) in dry acetone (2 L), K2CO3 (115 g, 0.83 mol) and CD3I (97 g, 0.67 mol) were added all at once, and the mixture was heated under reflux for 12 hours. The mixture was cooled, filtered, and the solid was washed with acetone (300 mL x 3). The mixed organic layer was evaporated to obtain Int C-4 (81 g) as a yellow solid. TIFF2026090362000060.tif17143

[0193] Process E: Synthesis of Int C-5 A mixture of C-4 (70g, 0.071 mol), bis(pinacorato)diborone (89g, 0.35 mol), KOAc (68.6g, 0.70 mol), and Pd(dppf)Cl2 (16.8g, 0.023 mol) in DMSO (800 mL) was degassed under nitrogen for 15 minutes, and then heated overnight at 80°C under nitrogen. The reaction mixture was poured into water (1.5 L) and extracted with pharmaceutically acceptable phosphate (600 mL x 3). The organic extract was washed with saturated brine (800 mL x 2), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated to obtain the residue, which was purified by silica gel column chromatography (column height: 80 mm, diameter: 28 mm, silica gel of 100-200 mesh, petroleum ether / toluene = 20 / 1, 10 / 1, 5 / 1) to obtain Int C-5 (53 g) as a pale solid. TIFF2026090362000062.tif11148

[0194] Process F: Synthesis of Int C-6 TIFF2026090362000063.tif23128 Int C-5 (58 g, 0.17 mol) was added in 600 mL of THF / MeOH (v / v=1 / 2) solution to 30% H2O2 (200 mL) all at once at 0°C. The mixture was stirred at the same temperature for 2 hours. Saturated aqueous solution Na2S2O3 (500 mL) was added and the mixture was stirred for another hour. The reaction was confirmed by potassium iodide starch test paper to determine whether the H2O2 had been destroyed. The mixture was extracted with siRNA (500 mL x 3), the mixed extract was washed with brine (500 mL), dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated to obtain Int C-6 (25.4 g) as a white solid. TIFF2026090362000064.tif17143

[0195] Process G: Synthesis of Int C-7 TIFF2026090362000065.tif21128 Compound Int C-6 (27 g, 0.113 mol) was dissolved in acetone (800 mL) and anhydrous K2CO3 (38.8 g, 0.282 mol) and CD3I (32.8 g, 0.226 mol) were added. The reaction mixture was heated under reflux for 12 hours, then cooled and filtered. The solid was washed with acetone (400 mL x 3), and the mixed organic extract was evaporated under vacuum to obtain 22 g of compound Int C-7 as a white solid. TIFF2026090362000066.tif17143

[0196] Step H: Synthesis of compound C To a solution of C-7 (16 g, 0.062 mol) in anhydrous THF (400 mL), LiAlH4 (4.8 g, 0.125 mol) was added over 10 minutes at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with water (100 ml), and the resulting suspension was filtered. The filtrate was concentrated to obtain compound C (8.5 g) as a white solid. TIFF2026090362000068.tif11128

[0197] Compound D: 5-methoxy-7-methylbenzofuran-2-yl)methanol TIFF2026090362000069.tif18128 Process A: Synthesis of Int D-1 TIFF2026090362000070.tif231282.0 g (7.0 mmol) of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (prepared in a manner similar to that described for ethyl ester Int C-2), CH3B(OH)2 (0.42 g, 7.0 mmol), and Na2CO3 (2.2 g, 20.7 mmol) were mixed in a dioxane (80 mL) / H2O (10 mL) solution, to which Pd(PPh3)4 (0.8 g, 0.7 mmol) was added. The mixture was refluxed overnight and then cooled to room temperature. The reaction mixture was poured into H2O and extracted with SiO2. The organic extract was washed with brine and dried over MgSO4. The solution was concentrated to obtain a residue, which was purified by silica gel column to obtain 320 mg of the Int D-1 compound.

[0198] Step B: Synthesis of compound D To a suspension of LiAlH4 (0.22 g, 5.79 mmol) in THF (15 mL), a solution of Int D-1 (0.32 g, 1.45 mmol) in THF (15 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, then poured into H2O, extracted with siRNA, washed the organic phase with brine, dried over MgSO4, concentrated to obtain a residue, which was purified by silica gel column to obtain 260 mg of compound D. TIFF2026090362000072.tif17143

[0199] Compound E: (7-Cyclopropyl-5-methoxybenzofuran-2-yl)methanol TIFF2026090362000073.tif20128 Step A: Synthesis of Compound E TIFF2026090362000074.tif271282.0 g (7.0 mmol) of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (prepared in a manner similar to that described for ethyl ester Int C-2), cyclopropylboronic acid (0.6 g, 8.0 mmol), and Na2CO3 (2.2 g, 20.7 mmol) were mixed in a dioxane (80 mL) / H2O (10 mL) solution to which Pd(PPh3)4 (0.8 g, 0.7 mmol) was added. The mixture was refluxed overnight and then cooled. The reaction mixture was poured into H2O and extracted with siRNA (3 × 20 mL). The mixed organic extract was washed with brine, dried over MgSO4, concentrated to obtain a residue, which was purified by silica gel column to obtain 200 mg of the desired ester. A suspension of LiAlH4 (0.12 g, 3.25 mmol) in THF (5 mL) was added dropwise to a solution of ester (0.20 g, 0.813 mmol) in THF (5 mL) at 0°C, and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was poured into H2O, extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated to obtain the residue, which was purified by silica gel column to obtain compound E (0.15 g). TIFF2026090362000075.tif17143

[0200] Compound F: (7-isopropyl-5-methoxybenzofuran-2-yl)methanol Synthesis of compound F TIFF2026090362000076.tif19128 TIFF2026090362000077.tif291282.0 g (7.0 mmol) of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (prepared in a manner similar to that described for ethyl ester Int C-2), cyclopropylboronic acid (0.6 g, 8.0 mmol), and Na2CO3 (2.2 g, 20.7 mmol) were mixed in a dioxane (80 mL) / H2O (10 mL) solution to which Pd(PPh3)4 (0.8 g, 0.7 mmol) was added. The mixture was refluxed overnight and then cooled. The reaction mixture was poured into H2O and extracted with siRNA (3 × 20 mL). The mixed organic extract was washed with brine, dried over MgSO4, concentrated to obtain a residue, which was purified by silica gel column to obtain 500 mg of the desired ester. A mixture of olefin ester (0.5 g, 2.29 mmol) and Pd / C (0.1 g) in ethanol (20 mL) was hydrogenated at room temperature for 2 hours under a hydrogen pressure of 50 psi. The mixture was filtered and evaporated to obtain 400 mg of the desired compound. A solution of intermediate ester (0.50 g, 2.01 mmol) in THF (15 mL) was added dropwise to a suspension of LiAlH4 (0.305 g, 8.04 mmol) in THF (15 mL) at 0°C and stirred at 0°C for 30 minutes. The reaction mixture was poured into water and extracted with RINKAN. The organic extract was washed with brine, dried over MgSO4, concentrated to obtain a residue, which was purified by silica gel column to obtain 350 mg of compound F. TIFF2026090362000078.tif17143

[0201] Compound G: (5-methoxy-7-phenylbenzofuran-2-yl)methanol Synthesis of compound G TIFF2026090362000079.tif26128 TIFF2026090362000080.tif25128 Pd(PPh3)4 (0.17 g, 0.15 mmol) was added to a solution of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (1.5 mmol), phenylboronic acid (0.18 g, 1.5 mmol), and Na2CO3 (0.48 g, 4.5 mmol) in dioxane (20 mL) / H2O (5 mL). The mixture was refluxed under N2 for 1 hour. The reaction mixture was poured into H2O and extracted with RINKAN. The organic extract was washed with brine, dried over MgSO4, and concentrated to obtain 200 mg of crude coupling product, which was redissolved in 15 mL of THF and added dropwise to a suspension of LiAlH4 (0.23 g, 5.96 mmol) in THF (15 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then poured into water and extracted with toluene (3 × 10 mL). The organic extract was washed with brine, dried over MgSO4, and then concentrated to obtain the residue, which was purified by silica gel column to obtain 300 mg of compound G. TIFF2026090362000081.tif24143

[0202] Compound H: (7-(dimethylamino)-5-methoxybenzofuran-2-yl)methanol Synthesis of compound H TIFF2026090362000082.tif18128 TIFF2026090362000083.tif27128 To a solution of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (3.0 g, 10 mmol), dimethylamine (0.57 g, 13 mmol), and Cs2CO3 (12.3 g, 37 mmol) in dioxane (80 mL), Pd2(dba)3 (0.75 g, 0.82 mmol) and 450 mg (1.50 mmol) of (2-biphenyl)di-tert-butylphosphine (JohnPhos) were added. The mixture was refluxed overnight under N2 and then cooled. The reaction mixture was poured into H2O and then extracted with RINKAN (3 × 20 mL). The organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum to obtain 700 mg of the desired amino ester. A suspension of LiAlH4 (0.32 g, 8.43 mmol) in THF (30 mL) was added dropwise to a solution of the above-mentioned amino ester (0.70 g, 2.81 mmol) in THF (30 mL) at 0°C, and the mixture was stirred for 30 minutes. The reaction mixture was poured into H2O and extracted with HCl. The organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum to obtain the residue, which was purified by silica gel column chromatography to obtain compound H (0.39 g). TIFF2026090362000084.tif17143

[0203] Compound I: (5-Methoxy-7-(methyl(phenyl)aminobenzofuran-2-yl)methanol Synthesis of Compound I TIFF2026090362000085.tif22128 TIFF2026090362000086.tif26128 To a solution of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (3.0 g, 10 mmol), N-methylaniline (1.36 g, 12 mmol), and Cs2CO3 (12.3 g, 37 mmol) in dioxane (80 mL), Pd2(dba)3 (0.75 g, 0.82 mmol) and X-Phos (0.43, 1.44 mmol) were added. The mixture was refluxed overnight under N2. The reaction mixture was cooled, then poured into water, and extracted with siRNA. The organic extract was washed with brine, dried over MgSO4, concentrated to obtain a residue, which was purified by silica gel column to obtain 1.1 g of the desired CN coupling product, which was used directly in the next step. A suspension of LiAlH4 (0.20 g, 5.77 mmol) in THF (20 mL) was added dropwise to a solution of the above ester (0.60 g, 1.92 mmol) in THF (20 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then poured into H2O and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to obtain compound I (0.35 g) as a white solid. TIFF2026090362000087.tif23143

[0204] Compound J: (5-Methoxy-7-(4-methylpiperazine-l-yl)benzofuran-2-yl)methanol A two-step procedure similar to that described for the synthesis of compound I, using N-methylpiperazine as the amine. (TIFF2026090362000088.tif28128) TIFF2026090362000089.tif17143

[0205] Compound K: (5-methoxy-7-morpholinobenzofuran-2-yl)methanol A two-step procedure similar to that described for the synthesis of compound I, using morpholine as the amine. (TIFF2026090362000090.tif23128) TIFF2026090362000091.tif17143

[0206] Compound L: 4-(2-(hydroxymethyl)-5-methoxybenzofuran-7-yl)thiomorpholine 1,1-dioxide A two-step procedure similar to that described for the synthesis of compound I, using thiomorpholine 1,1-dioxide as the amine. (TIFF2026090362000092.tif26128) TIFF2026090362000093.tif17143

[0207] Compound M: (7-(1,1-difluoroethyl)-5-methoxybenzofuran-2-yl)methanol TIFF2026090362000094.tif18128 Process A: Preparation of Int M-1 TIFF2026090362000095.tif28128 To a 100 mL solution of methyl 7-bromo-5-methoxybenzofuran-2-carboxylate (2.85 g, 10 mmol), (1-ethoxy)-tributylstannane (6.31 g, 17.5 mmol) and PdCl2(PPh)3 (0.7 g, 1.0 mmol) were added. The mixture was stirred overnight at 50°C under N2. The reaction mixture was poured into H2O and extracted with siRNA. The organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum to obtain a 2.0 g residue, which was used directly in the next step without further purification.

[0208] Step B: Preparation of Int M-2 TIFF2026090362000096.tif28128 Int M-1 (2.0 g, 7.25 mmol) was added to a 100 mL solution of dioxane with 2 M HCl (9 mL, 18 mmol). The mixture was stirred at room temperature for 30 minutes and then diluted with siRNA. The organic phase was washed twice with saturated NaHCO3, then with water, and then with brine. The organic matter was dried over MgSO4 and concentrated under vacuum to obtain 1.2 g of Int M-2, which was used directly in the next step without purification.

[0209] Process C: Preparation of Int M-3 A solution of Int M-2 (0.9 g, 0.88 mmol) in DAST (6 mL) was stirred overnight at 60°C. The reaction mixture was cooled and treated very slowly with 1 mL of water. The resulting mixture was extracted with siRNA (3 × 20 mL), the organic extract was washed with brine, and dried with MgSO4. By evaporation of the solvent, 450 mg of Int M-3 was obtained as an off-white solid.

[0210] Step D: Preparation of compound M To a suspension of LiAlH4 (0.18 g, 4.93 mmol) in THF (20 mL), a solution of Int M-3 (0.45 g, 1.67 mmol) in THF (20 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then poured into H2O and extracted with RINKAN. The organic extract was washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to obtain compound M (0.27 g) as a white solid. TIFF2026090362000099.tif17143

[0211] Compound N: (5,7-dimethylbenzofuran-2-yl)methanol TIFF2026090362000100.tif15128 Process A: Preparation of Int N-1 TIFF2026090362000101.tif311282,4-dimethylphenol (80 g, 0.66 mol) was dissolved in CH3CN (2000 mL), to which Et3N (248 g, 2.46 mol) and MgCl2 (93 g, 0.99 mol) were added all at once at room temperature. The mixture was stirred at room temperature for 1 hour, and then (CH2O) nThe mixture was added. The resulting mixture was heated under reflux and stirred overnight. The mixture was cooled to room temperature and then poured into a stirred 5% HCl (500 mL) solution. The mixture was extracted with HCl (3 × 400 mL). The mixed organic extract was washed with brine (300 mL) and separated. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (column height: 50 cm, diameter: 20 cm, 100-200 mesh silica gel, petroleum ether / HCl = 10 / 1) to obtain Int N-1 (58 g) as a yellow solid. TIFF2026090362000102.tif11128

[0212] Step B: Preparation of Int N-2 TIFF2026090362000103.tif31128Int A mixture of N-1 (58 g, 0.386 mol) and K2CO3 (160 g, 1.16 mol) in DMF (1.2 L) was to be mixed with methyl 2-bromoacetate (88.2 g, 0.58 mol) all at once at room temperature under N2. The mixture was stirred at room temperature for 10 minutes, then heated to 100°C and stirred overnight. The suspension was cooled to room temperature and filtered. The filtered cake was washed with phenylethylamine (500 mL x 3), and the filtrate was concentrated to remove most of the phenylethylamine. The resulting DMF solution was poured into ice water (w / w=1 / 1) (1 L) and stirred at room temperature for 20 minutes. The brown solid was collected by filtration. The filtered cake was washed with water (200 mL), then dried under high vacuum (using a vacuum dryer with P2O5; a pressure of <10 Pa was generated by an oil pump) to obtain crude Int N-2, which was then washed with PE / EA (v / v=5 / 1, 600 mL). The residual solvent was removed using a rotary evaporator to obtain pure Int N-2 (40 g) as a brown solid. TIFF2026090362000104.tif16144

[0213] Step C: Preparation of compound N Int N-2 (12 g, 60 mmol) was added dropwise to a stirred suspension of LAH (4.5 g, 118 mmol) in anhydrous THF (100 mL) under N2 conditions at 4°C (ice bath). The mixture was stirred at 0°C for 1 hour, and then quenched by dropwise adding water (50 mL), taking care to control the internal temperature to below 10°C. The suspension was filtered, and the filter cake was washed with THF (100 mL). The filtrate was concentrated, and the residue was washed with petroleum ether / alkyl=8 / 1 to obtain compound N (8 g) as a white solid. TIFF2026090362000106.tif17144LCMS: Purity: 98.4%; MS calculated value: 176.1; MS measured value: 159.1 [M-OH]. Melting point: 96.4℃~97.1℃.

[0214] Compound O: (4-((5,7-dimethoxybenzofuran-2-yl)methoxy)phenyl)methanol TIFF2026090362000107.tif15128 Process A: Synthesis of Int O-1 Compound B (30.0 g, 0.144 mol), ethyl 4-hydroxybenzoate (28.7 g, 0.173 mol), and PPh3 (18.8 g, 0.187 mol) were added dropwise to a suspension of these compounds in anhydrous THF (300 mL) (32.2 g, 0.187 mol) in DEAD form over 30 minutes at 4°C (ice water batch). After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. The mixture was poured into water and extracted with DCM (200 mL x 3). The mixed organic extract was dried over Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (column height: 20 cm, diameter: 5 cm, 100-200 mesh silica gel, petroleum ether / siRNA = 5 / 1) to obtain crude Int O-1 (20 g, 85%) as an off-white solid. 1 The purity of the 1H NMR spectrum was obtained. TIFF2026090362000109.tif23144

[0215] Step B: Synthesis of compound O To a suspension of LAH (2.87 g, 0.075 mol) in anhydrous THF (200 mL), Int O-1 (18 g, 0.050 mol) was gradually added over 30 minutes at 4°C (ice bath) under nitrogen. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. Water (3 ml) was added dropwise at 0°C, followed by 15% NaOH aqueous solution (3 ml) and H2O (15 ml). After stirring for 30 minutes, MgSO4 (40 g) was added, and the mixture was stirred for another 30 minutes. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (column height: 20 cm, diameter: 5 cm, 100-200 mesh silica gel, petroleum ether / siRNA = 5:1) to obtain compound O (11 g) as an off-white solid. TIFF2026090362000111.tif36143

[0216] Compound P: (4-((5,7-bis(methoxy-d 3 benzofuran-2-yl methoxyphenyl methanol A two-step procedure similar to that described for the synthesis of compound O, using compound C as the starting material (TIFF2026090362000112.tif19128). TIFF2026090362000113.tif23143

[0217] Compound Q: (4-((5-methoxy-7-methylbenzofuran-2-yl)methoxy)phenyl)methanol A two-step procedure similar to that described for the synthesis of compound O, using compound D as the starting material (TIFF2026090362000114.tif19128). TIFF2026090362000115.tif30143 Melting point: 101.6℃~102.3℃

[0218] Compound R: (4-((5,7-dimethylbenzofuran-2-yl)methoxy)phenyl)methanol TIFF2026090362000116.tif19128 A two-step procedure similar to that described for the synthesis of compound N, using compound N as the starting material. TIFF2026090362000117.tif30143 Melting point: 133.8℃~135.6℃

[0219] Compound S:(E)-3-(5,7-dimethylbenzofuran-2-yl)propa-2-en-1-ol TIFF2026090362000118.tif19128 Process A: Preparation of Int S-1 TIFF2026090362000119.tif29128 Compound N (30 g, 0.170 mol) was dissolved in acetonitrile (300 mL), to which IBX (104.3 g, 0.340 mol) was added. The mixture was heated under reflux and stirred overnight. The mixture was cooled to room temperature and filtered. The filtered cake was washed with phenylethylamine (100 mL), and the solvent was concentrated to obtain Int S-1 (27 g) as a colorless oil. TIFF2026090362000120.tif11143

[0220] Step B: Preparation of Int S-2 TIFF2026090362000121.tif24128 Triethyl phosphonoacetate (31.2 g, 0.139 mol) was added to a mixture of NaH (3.3 g, 0.139 mol) and THF (50 mL) at 0°C (ice bath). After addition, the mixture was stirred at 0°C for 1 hour. Then, a solution of Int S-1 (22 g, 0.126 mol) in THF (150 mL) was added dropwise at 0°C, and the mixture was warmed to ambient temperature overnight. The solvent was poured into ice water and extracted with ELISA (200 mL). The organic extract was dried over anhydrous Na2SO4 and concentrated to obtain 16.5 g of Int S-2 as a white solid. TIFF2026090362000122.tif17143

[0221] Step C: Preparation of compound S To a stirring solution of Int S-2 (21 g, 0.086 mol) in anhydrous THF (200 mL) at 4°C (ice bath), DIBAL-H (206 mL, 0.206 mol) was added dropwise under nitrogen to maintain the reaction temperature at -78°C to -65°C. The mixture was then warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (20 mL), anhydrous MgSO4 (200 g) was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed with siRNA (200 mL x 2). The solvent was concentrated to obtain 10.4 g of compound S. TIFF2026090362000124.tif30143 Melting point: 104.6℃~106.3℃

[0222] Compound T:(E)-3-(5-methoxy-7-methylbenzofuran-2-yl)propa-2-en-1-ol A two-step procedure similar to that described for the synthesis of compound S, using compound D as the starting material (TIFF2026090362000125.tif19128). TIFF2026090362000126.tif30143

[0223] Compound U:(E)-3-(5,7-bis(methoxy-d3)benzofuran-2-yl)propa-2-en-1-ol A two-step procedure similar to that described for the synthesis of compound S, using compound C as the starting material (TIFF2026090362000127.tif19128). TIFF2026090362000128.tif24143 Melting point: 86.5℃~87.0℃

[0224] Compound V: (5,6,7-trimethoxybenzofuran-2-yl)methanol TIFF2026090362000129.tif20128 Process A: Synthesis of Int V-1 To a solution containing 150.0 g (0.77 mol) of 2,3,4-trimethoxybenzaldehyde in 1000 mL of DCM, 300.0 g (1.74 mol) of m-CPBA was added in five portions (30 g each) at 0°C to 10°C (ice bath). After addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered to remove the solid, and the filtrate was washed with NaHCO3 aqueous solution (400 mL x 3), water (300 mL), and brine (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, and the mixture was filtered. By concentrating the filtrate, a dark yellow oil was obtained, which was dissolved in EtOH (600 mL) and treated all at once with 10% KOH aqueous solution (500 mL). The mixture was stirred at 50°C for 4 hours. Next, the mixture was cooled, acidified to pH=1 with 1M HCl, and extracted with DCM (500 mL x 3). The mixed organic extract was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by silica gel chromatography (column height: 50 cm, diameter: 20 cm, silica gel of 100-200 mesh, petroleum ether / alkyl = 30 / 1, 20 / 1, 15 / 1, 10 / 1) to obtain Int V-1 (79.0 g) as yellow oil. TIFF2026090362000131.tif11143

[0225] Process B: Synthesis of Int V-2 A mixture of Int V-1 (74 g, 400 mmol), HMTA (67.6 g, 480 mmol), and TFA (500 mL) was refluxed under N2 for 20 hours. The solution was cooled to room temperature and concentrated under vacuum. Toluene (200 mL) was added to the residue, and the solution was further concentrated to remove trace amounts of TFA. The residual oil was treated with THF (300 mL) and 2 M HCl (300 mL), then heated under reflux for 2 hours. The solution was cooled to room temperature and extracted with DCM (300 mL x 3). The mixed organic layers were washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by silica gel chromatography (column height: 50 cm, diameter: 20 cm, silica gel of 100-200 mesh, petroleum ether / alkyl = 30 / 1, 20 / 1, 15 / 1, 10 / 1) to obtain Int V-2 (36.0 g) as a yellow solid. TIFF2026090362000133.tif11142

[0226] Process C: Synthesis of Int V-3 To a solution of Int V-2 (36 g, 0.17 mol) in anhydrous DMF (200 mL), K2CO3 (46.9 g, 0.34 mol) and methylbromoacetate (28.4 g, 0.19 mol) were added at room temperature. The resulting solution was heated to 110 °C and stirred for 6 hours. The suspension was cooled and filtered through a Celite pad. The filtrate cake was washed with SiO2 (500 mL), and the filtrate was concentrated. The residual oil was purified by silica gel chromatography (column height: 30 cm, diameter: 10 cm, 100-200 mesh silica gel, petroleum ether / SiO2 = 15 / 1, 10 / 1, 5 / 1) to obtain Int V-3 (14 g) as a white solid. TIFF2026090362000135.tif11128

[0227] Step D: Synthesis of compound V TIFF2026090362000136.tif29128 Compound Int V-3 (14 g, 52.63 mmol) was dissolved in anhydrous MeOH (100 mL) and NaBH4 (10 g, 263.16 mmol) was added in 10 portions (1 g each) at 0-10°C (ice bath). The resulting mixture was stirred at 30°C for 3 hours. The suspension was filtered, and the filtrate was concentrated to obtain 10.6 g of compound V as a white solid. MP: 68.2°C-68.7°C. TIFF2026090362000137.tif17143

[0228] Compound W: (4,5,7-trimethoxybenzofuran-2-yl)methanol A three-step procedure similar to that described for the synthesis of compound V, using 2,4,5-trimethoxybenzaldehyde as the starting material, as described in TIFF2026090362000138.tif25128. TIFF2026090362000139.tif24144

[0229] Compound X: (5,7-dimethoxy-3-methylbenzofuran-2-yl)methanol TIFF2026090362000140.tif25128 Process A: Synthesis of Int X-1 TIFF2026090362000141.tif321282-Hydroxy-5-methoxyacetophenone (200 g, 1200 mmol) and anhydrous NaOAc (104 g, 1264 mmol) were added all at once to 2000 mL of AcOH at room temperature. Then, bromine (199 g, 1.264 mol) in 300 mL of AcOH was added dropwise using a dropping funnel over 2 hours at room temperature, maintaining the internal reaction temperature at 15-25°C (water bath). After the addition was complete, the mixture was stirred at room temperature for 16 hours, then poured into ice water (w / w=1 / 1, 8 L) and stirred for 1 hour. The mixture was then filtered, the filtered cake was washed with water (3 × 1 L), and then air-dried for 2 days to obtain Int X-1 (210 g) as a yellow solid. TIFF2026090362000142.tif11128

[0230] Process B: Synthesis of Int X-2 Int X-1 (100 g, 0.408 mol) and 2-bromoacetonitrile (73 g, 0.612 mol) were mixed in DMF (1 L), to which K2CO3 (169 g, 1.224 mol) was added all at once at room temperature. The mixture was then heated to 80°C under N2 and stirred overnight. The suspension was cooled to room temperature and poured into 2000 mL of ice / water / brine (v / v / v=1 / 1 / 2), and the mixture was extracted with ELISA (3 × 1000 mL). The mixed organic extract was washed with water (3 × 1000 mL) and then with brine (3 × 1000 mL), and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated. The residue was purified using a silica gel column (column height: 60 cm, diameter: 20 cm, silica gel of 100-200 mesh, petroleum ether / sorbate = 5 / 1-3 / 1) to obtain Int X-2 (38 g) as a yellow solid. TIFF2026090362000144.tif17143

[0231] Process C: Synthesis of Int X-3 TIFF2026090362000145.tif29128 Int X-2 (50 g, 188 mmol) was added all at once to a MeOH / MeCN (600 mL, v / v=1 / 1) solution at room temperature with K2CO3 (182 g, 1316 mmol). The mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was poured into water (800 mL) and extracted with siRNA (3 × 400 mL). The mixed organic extracts were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated. The residue was redissolved in 1 M HCl (500 mL) and MeOH (100 mL). The mixture was heated at 80°C for 2 hours, then the reaction was cooled and filtered. The solid was washed with water (800 mL × 3) and then dried to obtain Int X-3 (34.3 g) as a white solid. TIFF2026090362000146.tif11128

[0232] Process D: Synthesis of Int X-4 To a mixture of Int X-3 (35 g, 117 mmol) in anhydrous DCM (500 mL), a solution of DIBAL-H (257 mL, 1 M in toluene, 257 mmol) was added dropwise over 1 hour at -70°C (dry ice-acetone bath) under N2. During the addition, the temperature of the system rose to -65°C, and the mixture was stirred at -70°C for 2 hours. The mixture was warmed to 0°C, quenched with water (100 mL), and filtered. The organic phase was separated, and the aqueous phase was extracted with DCM (2 × 100 mL). The mixed organic phase was washed with saturated brine (2 × 100 mL), dried over anhydrous Na₂SO₄, and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (column height: 30 cm, diameter: 15 cm, silica gel of 100-200 mesh, petroleum ether / SiO₂ = 10 / 1-3 / 1) to obtain Int X-4 (9.8 g) as a yellow solid. TIFF2026090362000148.tif17144

[0233] Step E: Synthesis of compound X A mixture of Int X-4 (19.5 g, 71.9 mmol), NaOMe (212 mL, 25% w / v in MeOH), and anhydrous DMF (2.2 g, 29.6 mmol) was mixed with CuBr (3.0 g, 21.2 mmol) under nitrogen at room temperature. The reaction mixture was heated to 80°C-90°C for 3 hours. After the reaction mixture was cooled to 0°C, H2O (500 mL) was added. The mixture was extracted with DCM (2 × 300 mL), the mixed organic extract was dried over anhydrous Na2SO4, and filtered. The filtrate was vacuum-concentrated using a rotary evaporator, and the residue was purified by silica gel chromatography (column height: 30 cm, diameter: 10 cm, silica gel of 100-200 mesh, petroleum ether / dimethyl = 10 / 1-3 / 1) to obtain compound X (8.4 g) as a yellow solid. TIFF2026090362000150.tif24144 Melting point: 71.9℃~73.8℃.

[0234] Compound Y: 1-(5,7-dimethoxybenzofuran-2-yl)ethane-1-ol TIFF2026090362000151.tif20128 Process A: Synthesis of Int Y-1 A solution of compound B (10.0 g, 48.03 mmol) and IBX (26.9 g, 96.06 mmol) was dissolved in 150 mL of acetonitrile and stirred at 80°C for 4 hours under a nitrogen blanket. The suspension was cooled, filtered, and the filtered cake was washed with 100 mL of siRNA. The filtrate was concentrated to obtain 9.8 g of Int Y-1 as a yellow solid.

[0235] Step B: Synthesis of compound Y To a solution containing 3.0 g (14.5 mmol) of compound Y in 50 mL of THF at 80°C, MeMgBr (7.3 mL, 21.9 mmol, 3 M in ether) was added dropwise at 0°C. The reaction mixture was stirred for 10 minutes, and then quenched with saturated NH4Cl solution (20 mL). The resulting organic layer was extracted with siRNA (100 mL x 2), the mixed organic extract was dried over Na2SO4, filtered, and concentrated to obtain 3.2 g of compound Y as a brown oil. TIFF2026090362000154.tif11128

[0236] Compound Z: (5,7-dimethoxybenzo[b]thiophen-2-yl)methanol TIFF2026090362000155.tif20128 Process A: Synthesis of Int Z-1 TIFF2026090362000156.tif31128 To a solution of 3,5-dibromo-2-hydroxybenzaldehyde (12 g, 42.8 mmol) in 100 mL of THF at 0°C, NaH (1.9 g, 47.6 mmol) was added in five separate additions. The reaction mixture was stirred at 0°C to 20°C for 1 hour, then recooled and treated with a solution of dimethylthiocarbamoyl chloride (6.52 g, 52.7 mmol) in 20 mL of THF. Once the reaction was complete, a saturated aqueous solution of NH4Cl (100 mL) was added, and the resulting mixture was extracted with siRNA (100 mL x 2). The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:siRNA = 50:1 to 20:1) to obtain 9.0 g of Int Z-1 as a yellow solid. TIFF2026090362000157.tif11128

[0237] Process B: Synthesis of Int Z-2 Compound Int Z-1 (5.0 g, 13.6 mmol) in a 100 mL round-bottom flask was stirred at 150°C for 3 hours, then cooled and purified by column chromatography (petroleum ether: dimethyl = 5:1) to obtain 3 g of Int Z-2 as a yellow solid. TIFF2026090362000159.tif5153

[0238] Process C: Synthesis of Int Z-3 To a solution containing 3 g (8.17 mmol) of Int Z-2 in 50 mL of MeOH, 1.8 g (45 mmol) of NaOH in 50 mL of H2O was added. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was neutralized by the addition of 10% citric acid (50 mL) and extracted with siRNA (50 mL x 2). The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain Int Z-3 (2 g, crude) as a yellow oil, which was used in the next step without further purification.

[0239] Process D: Synthesis of Int Z-4 To a solution containing 2 g (6.76 mmol) of Int Z-3 in 80 mL of DMF, ethyl bromoacetate (1.13 g, 6.76 mmol) and K2CO3 (2.8 g, 20.3 mmol) were added. The resulting mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was then cooled, treated with 100 mL of water, and extracted with 2 × 100 mL of phenylethylamine. The organic extract was dried and concentrated to obtain a residue, which was purified by column chromatography (petroleum ether:phenylethylamine = 100:1) to yield Int Z-4 (2.0 g) as a white solid. TIFF2026090362000162.tif17144

[0240] Process E: Synthesis of Int Z-5 In a 250 mL round-bottom flask, a slurry containing LiAlH4 (0.42 g, 11 mmol) in THF (80 mL) was added dropwise at 0 °C to a THF (20 mL) solution of Int Z-4 (2 g, 5.5 mmol). The reaction mixture was stirred at 0 °C for 1 hour, then slowly quenched with H2O (0.45 mL), followed by NaOH (15%, 0.45 mL) and H2O (1.3 mL). Solid MgSO4 was added, and the mixture was filtered. The filtrate was concentrated to obtain Int Z-5 (1.4 g) as a white solid.

[0241] Process F: Synthesis of Int Z-6 To a solution containing Int Z-5 (1.4 g, 4.35 mmol) in NaOMe / MeOH (40 mL), DMF (0.13 g, 1.74 mmol) and CuBr (0.19 g, 1.31 mmol) were added. The resulting mixture was stirred at 100 °C for 12 hours, then cooled and treated with 50 mL of water. The mixture was extracted with 50 mL of DCM and then dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated to leave a residue, which was purified by column chromatography (petroleum ether / SiO₂ = 20:1) to obtain 1.1 g of compound Z as a white solid. TIFF2026090362000165.tif17144 [Examples]

[0242] Example 1 Preparation of (5,7-dimethoxybenzofuran-2-yl)methyl(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(((hydroxy(((S)-1-(methylamino)-1-oxopropan-2yl)amino)phosphoryl)oxy)-methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (compound 1) TIFF2026090362000166.tif23128 Process A: Synthesis of Int 1-1 Compound B (60 g, 0.29 mol) and TEA (31 g, 0.30 mol) were stirred in anhydrous THF (500 mL) (in an ice bath), to which 4-nitrophenyl chloroformate (60 g, 0.30 mol) in anhydrous THF (300 mL) was added dropwise at 0°C. The reaction mixture was then stirred at 20°C for 12 hours, after which the solvent was evaporated. The crude residue was washed with MTBE (150 mL x 3) and then filtered. The filtrate was discarded, and the filtrate cake was dissolved in ELISA (2000 mL) and water (1000 mL). The organic phase was separated and washed with water (1000 mL x 2), then brine (500 mL), and then dried over anhydrous Na2SO4. The filtrate was concentrated to obtain 85 g of Int 1-1. TIFF2026090362000168.tif17143

[0243] Process B: Synthesis of Int 1-2 To a solution of gemcitabine hydrochloride (140 g, 460 mmol) in pyridine (2000 mL) (ice bath), TIPDSCl (176 g, 560 mmol) was added dropwise at 0°C under N2. The reaction mixture was stirred at 20°C for 12 hours. Pyridine was removed under vacuum, the residue was dissolved with siRNA (1500 mL), and washed with water (800 mL x 3). The organic layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain 250 g of compound 1-2 as a white solid, which was used directly in the next step. TIFF2026090362000170.tif17143

[0244] Process C: Synthesis of Int i-3 Compound Int 1-1 (85 g, 0.224 mol) was added all at once to a stirred suspension in THF (800 mL) with compound 1-2 (116 g, 0.23 mol) under nitrogen. The resulting solution was heated under reflux at 100 °C for 12 hours. The mixture was cooled, the solvent was evaporated to remove the residue, which was dissolved in SiO2 (500 mL) and washed with water (200 mL x 3). The organic phase was separated, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash chromatography to obtain 90 g of compound Int 1-3 as a foam. f =(petroleum ether: SiO = 1:1) = 0.4.

[0245] Process D: Synthesis of Int 1-4 Compound Int 1-3 (90 g, 0.12 mol) was dissolved in MeOH (1000 mL) and treated all at once with NH4F (22.5 g, 2.46 mol). The resulting solution was stirred at 20°C for 12 hours, then the solvent was evaporated to obtain the residue. The residue was dissolved in ELISA (1000 mL), washed with water (500 mL x 3), then dried over anhydrous Na2SO4, and concentrated to obtain the residue. The residue was covered with HPLC-grade MeOH (1000 mL) and then filtered. The filtered cake was washed with HPLC-grade MeOH (200 mL x 2). The filtered cake was then covered with HPLC-grade MeOH (1500 mL) and heated at 80°C to produce a solution. The solution was cooled to room temperature over 12 hours to allow precipitation. The precipitate was filtered, washed with HPLC-grade MeOH (150 mL x 3), and the solid was dried at 45°C for 6 days to obtain 35 g of Int 1-4 as a white solid. f (DCM / MeOH=15 / 1)=0.3. HPLC: t=2.40 min; Purity: 99.71%. TIFF2026090362000173.tif30144

[0246] Process E: Synthesis of Int 1-5 TIFF2026090362000174.tif27143 Int 1-4 (2.0 g, 4.0 mmol) was added to a dry 100 mL round-bottom flask with trimethyl phosphate (10 ml). The slurry was stirred at room temperature under nitrogen until a homogeneous solution was formed. The resulting reaction mixture was then cooled to -10°C in an ice water salt bath and stirred for 10 minutes. Phosphorus oxychloride (2.8 g, 18 mmol) was added dropwise over 10 minutes. After the addition was complete, the reaction mixture was stirred for a further 3 hours at -10°C. The reaction mixture was then treated dropwise with deionized water (200 mL) at 0°C. During the addition, a yellow solid was formed, which was subsequently filtered and washed with water (10 mL x 3). The yellow solid was dissolved in acetonitrile / water (20 mL, 1 / 1) and the pH was adjusted to 8 with dimethyl phosphate. The mixture was purified by preparative HPLC to obtain 1.0 g of Int 1-5 as a white solid. HPLC purity: 99.83%. TIFF2026090362000175.tif30143

[0247] Step A: Synthesis of Compound 1 To a solution of 1.0 g, 1.7 mmol of compound 1-5 (2S)-2-amino-N-methyl-propanamide HPLC purity = 99%. TIFF2026090362000177.tif36143

[0248] Example 2 Preparation of (5,7-dimethoxybenzofuran-2-yl)methyl(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(((hydroxy(((S)-3-methyl-1-(methylamino)-1-oxobutan-2-yl)amino)-phosphoryl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (compound 2) TIFF2026090362000178.tif21128 Step A: Synthesis of Compound 2 TIFF2026090362000179.tif23144 To a solution of Int 1-5 (2.0 g, 3.5 mmol) and (2S)-2-amino)-N-methyl-propanamide (2.8 g, 21.5 mmol) in dioxane (40 mL), DCC (5.6 g, 27.1 mmol) and 0.1 mL siRNA were added. The resulting reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated and purified by preparative HPLC (Phenomenex Luna C18 250*50 mm*10 μm; eluate = 10 mM NH4HCO3-MeCN) to obtain a white solid. This solid was added to 30 mL of MeOH, then filtered and washed with MeOH (10 mL x 2). The filtrate was concentrated to obtain 80 mg of compound 10 as a white solid. HPLC: t=2.8 min; purity: 97.9%. TIFF2026090362000180.tif30143

[0249] Example 3 Preparation of (5,7-dimethoxybenzofuran-2-yl)methyl(1-((2R,4R,5R)-5-((((((S)-1-(dimethylamino)-1-oxopropan-2-yl)amino)(hydroxy)phosphoryl)oxy)methyl)-3,3-difluoro-4-hydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (compound 3) TIFF2026090362000181.tif22128 Step A: Synthesis of Compound 3 To a solution of TIFF2026090362000182.tif23143Int 1-5 (1.00 g, 1.73 mmol) and (2S)-2-amino-N,N-dimethyl-propanamide (800.0 mg, 6.89 mmol) in dioxane / H2O (12 mL / 3 mL), DCC (2.00 g, 9.69 mmol) and 0.1 mL TEA were added. The resulting reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated and purified by preparative HPLC (Phenomenex Luna C18 250*50 mm*10 μm; eluate = 10 mM NH4HCO3-MeCN) to obtain compound 3 (100 mg) as a white solid. HPLC purity: approximately 99.1%. TIFF2026090362000183.tif30143

[0250] Example 4 Preparation of benzyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-L-valinate (compound 4) TIFF2026090362000184.tif20128 Step A: Synthesis of Compound 4 To a solution of 1-5 (200.0 mg, 0.290 mmol) and L-valinebenzyl ester (447 mg, 1.18 mmol) in dioxane / H2O (4 mL / 1 mL), DCC (341 mg, 1.65 mmol) and 1 mL of triethylamine were added. The colorless reaction mixture, which immediately formed a precipitate, was stirred at 80°C for 16 hours. The reaction mixture was cooled and then filtered. The filtrate cake was washed with 5 mL of MeOH. The filtrate was concentrated and then purified by preparative HPLC (Waters Xbridge 150*25 mm*5 μm; eluate = 10 mM NH4HCO3-MeCN). The clean fraction was lyophilized to obtain compound 4 (60 mg) as a white solid. TIFF2026090362000186.tif36143

[0251] The following compounds can be prepared using the same procedure as described in Example 4: Compound 5: Benzyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-L-alaninate TIFF2026090362000187.tif58144

[0252] Example 5 Preparation of (5,7-dimethoxybenzofuran-2-yl)methyl(1-((2R,4R,5R)-5-(((benzamido-(mercapto)phosphoryl)oxy)methyl)-3,3-difluoro-4-hydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (compound 6) TIFF2026090362000188.tif20128 Process A: Synthesis of Int 5-1 To a solution of Int 1-4 (5.0 g, 10.1 mmol) in dioxane (120 mL) and water (30 mL), Boc2O (3.3 g, 15.1 mol) and Na2CO3 (5.5 g, 51.9 mol) were added in one step. The mixture was stirred at 20°C for 48 hours. After this time, TLC (DCM / MeOH = 20 / 1, product: Rf = 0.4) indicated that the reaction was complete. Water (500 mL) was added, and the mixture was extracted with 800 mL of siRNA. The organic extract was washed with water (500 mL) and brine (500 mL), then dried over Na2SO4, and concentrated to dryness under reduced pressure. The mixture was then purified by MPLC to obtain compound Int 5-1 (3.0 g) as a white solid. TIFF2026090362000190.tif23143

[0253] Process B: Synthesis of Int 5-2 TIFF2026090362000191.tif22148 A mixture of compound Int 5-1 (700 mg, 1.1 mmol) and MeCN (30 mL) was mixed with 320 mg (1.2 mmol) of N-(2-sulfide-1,3,2-oxatiaphosphoran-2-yl)benzamide [Baraniak et al Bioorg. Med. Chem. Lett. 22, (2014) 2133-2140] and DBU (232 g, 1.5 mmol), and the mixture was stirred at 40°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1~30:1) to obtain compound Int 5-2 (450 mg) as a red solid. TIFF2026090362000192.tif30144

[0254] Step C: Synthesis of compound 6 TIFF2026090362000193.tif22149 Compound Int 5-2 (130 mg, 163 µm) was dissolved in DCM (5 mL) and TFA (765 mg, 6.7 mmol) was added all at once. The resulting solution was stirred at 20°C for 4 hours, and the solvent was evaporated to obtain the residue. This residue was purified by preparative HPLC (Phenomenex Luna C18(2) 5 μm 2.0 * 50 mm; eluate = 10 mM NH4HCO3-MeCN) to obtain compound 6. HPLC: t = 2.11 min; purity: 92.4%. TIFF2026090362000194.tif36143

[0255] Example 6 Preparation of (5,7-dimethoxybenzofuran-2-yl)methyl(1-((2R,4R,5R)-5-(((benzamido-(hydroxy)phosphoryl)oxy)methyl)-3,3-difluoro-4-hydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-yl)carbamate (compound 7) TIFF2026090362000195.tif21128 Process A: Synthesis of Int 6-1 5.80 g (47.88 mmol, 1.00 equivalent) and 9.97 g (47.88 mmol, 1.00 equivalent) of benzamide in 60 mL of CCl4 were heated at 80°C for 2.5 hours. The reaction mixture was cooled to 25°C. Formic acid (2.53 g, 52.67 mmol, 1.10 equivalent) was then added dropwise. After stirring for 1 hour, the resulting precipitate was collected by filtration. The collected solid was washed with 10 mL of CCl4 and dried under vacuum to obtain 8.0 g of Int 10⁻¹ as a white powder. TIFF2026090362000197.tif17143

[0256] Step B: Synthesis of Compound 7 Compound Int 6-1 (500 mg, 2.10 mmol) was added all at once to a solution of Int 1-4 (1.04 g, 2.10 mmol, 1.00 equivalent) and NMI (900.46 mg, 6.30 mmol, 3.00 equivalent) in ACN (10.00 mL) at 0°C under nitrogen. The resulting mixture was stirred at 25°C for 16 hours. Water (1 mL) was added to quench the reaction, and the mixture was purified by preparative HPLC (Phenomenex Luna C18 250*50 mm*10 μm; eluate = 10 mM NH4HCO3-MeCN) to obtain 30 mg of compound 7 as a white solid. TIFF2026090362000199.tif24143

[0257] Example 7 Preparation of benzyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (compound 8) TIFF2026090362000200.tif30128 Process A: Synthesis of Int 7-1 To a solution containing 12.4 g (58.68 mmol) of phenylphosphodichloride and L-alanine benzyl ester HCl (12.7 g, 58.68 mmol, 1.00 equivalent) in 15 mL of DCM at -70°C, 16.3 mL (117.36 mmol, 2.00 equivalent) of TEA in 5 mL of DCM was added over 0.5 hours. The reaction mixture was slowly warmed to 20°C and stirred for a further 0.5 hours. The mixture was stirred for 4 hours, then concentrated and filtered. The filtrate was washed with ether, concentrated, and the residue was purified by silica gel chromatography (petroleum ether:MTBE = 5:1 to 1:1) to obtain Int 7-1 (14.10 g) as a colorless oil. TIFF2026090362000202.tif17144

[0258] Step B: Synthesis of Compound 8 Int 8-1 in 3 mL of THF was added to a 4 mL solution of Int 1-4 (200 mg, 402 umol) and 402 mg (2.81 mmol, 7.00 equivalents) of NMI at 30°C in 4 mL of THF (4 mL). The mixture was stirred at 15°C for 16 hours, then filtered and concentrated to obtain the residue, which was purified by preparative HPLC (neutral). The desired fraction was evaporated by freeze-drying to obtain 18 mg of compound 8 as a white solid. TIFF2026090362000204.tif30144

[0259] The following compounds can be prepared using the same procedure as described in Example 7: Compound 9: Isopropyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)-methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate TIFF2026090362000205.tif67143 Compound 10: Isopropyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(naphthalene-l-yloxy)phosphoryl)-L-alaninate TIFF2026090362000206.tif73143

[0260] Example 8 Preparation of 2-morpholinoethyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (compound 11) TIFF2026090362000207.tif30128 Process A: Synthesis of Int 8-1 To a 0°C solution containing 2-morpholinoethanol (20.4 g, 155.4 mmol) and N-Boc-L-alanine (30.0 g, 158.5 mmol) in 1.7 L of 700 mL of DCM, a mixture of DCC (41.5 g, 201.4 mmol) and DMAP (2.5 g, 20.6 mmol) dissolved in 300 mL of DCM was added. The mixture was stirred at 25°C for 16 hours, and the solid was removed by filtration. The filtrate was extracted with water (500 mL x 2), the mixed organic extract was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate: 5 / 1-1 / 4) to obtain 50 g of Int 13-1 as a white oil. TIFF2026090362000209.tif17143

[0261] Process B: Synthesis of Int 8-2 A solution containing 0.0 g (140.6 mmol) of Int 8-1 was added to the mixture, and a saturated solution of HCl with SiO (400.0 mL) was added to the mixture. The mixture was stirred at 20°C for 3 hours, then the solid was filtered and washed with SiO (100 mL) to obtain Int 9-2 (32 g) as a white solid. TIFF2026090362000211.tif17143

[0262] Step C: Synthesis of compound 11 TIFF2026090362000212.tif78151 Int 1-4 (200.0 mg, 402.1 umol) was added to a solution of TMP (2 mL) with phenylphosphodichloride (594 mg, 2.8 mmol) in TMP (0.5 mL) at 0°C. The mixture was stirred at -10°C for 16 hours, and then treated with Int 13-2 (1.9 g, 8.0 mmol) in a single dose at -10°C. Then, triethylamine (1.7 g, 16.9 mmol) in TMP (1 mL) was added dropwise, and the mixture was stirred at -10°C for 2 hours. The solid precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 30%~55%, 10 min) to obtain 46.5 mg of compound 11 as a white solid. TIFF2026090362000213.tif29143

[0263] The following compounds can be prepared using the same procedure as described in Example 8: Compound 12: 1-Methylpiperidine-4-yl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate TIFF2026090362000214.tif66143

[0264] Example 9 Preparation of ethyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(((S)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)-L-alaninate (compound 13) TIFF2026090362000215.tif32128 Step A: Preparation of Compound 13 To a solution of 1-4 (200.0 mg, 0.402 mmol) in 2 mL of TMP at -10°C, POCl3 (308.3 mg, 2.0 mmol, 5 equivalents) in 0.5 mL of TMP was added. The mixture was stirred at -10°C for 3 hours. L-Alanine ethyl ester (1.8 g, 8.0 mmol, 20.0 equivalents) was added to the mixture all at once at -10°C, followed by the dropwise addition of Et3N (1.4 g, 13.7 mmol, 34.0 equivalents) in 0.5 mL of TMP. The mixture was stirred at -10°C for 0.5 hours, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 25%~55%, 12 min) to obtain 33.3 mg of compound 13 as a white solid. TIFF2026090362000217.tif24144

[0265] The following compounds can be prepared using the same procedure as described in Example 9: Compound 14: Benzyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(((S)-1-ethoxy-1-oxopropane-2-yl)amino)phosphoryl)-L-alaninate (Compound 14) TIFF2026090362000218.tif69143

[0266] Example 10 Preparation of benzyl((((2R,3R,5R)-5-(4-((((5,7-dimethoxybenzofuran-2-yl)methoxy)carbonyl)amino)-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(pyridine-3-yloxy)phosphoryl)-L-alaninate (compound 15) TIFF2026090362000219.tif31128 Step A: Preparation of Compound 15 TIFF2026090362000220.tif25138Int 1-4 (500.0 mg, 1.01 mmol) in a 3 mL trimethyl phosphate solution at -10°C was mixed with POCl3 (469 μL, 5.0 mmol, 5 equivalents) in 2 mL of trimethyl phosphate. The mixture was stirred at -10°C for 1 hour. L-alanine benzyl ester HCl (1.7 g, 8.1 mmol, 20.0 equivalents) was added to the mixture all at once at -10°C, followed by the dropwise addition of a TMP (5 mL) mixture of Et3N (4.5 mL, 32.3 mmol, 32.0 equivalents) and 3-hydroxypyridine (768 mg, 8.07 mmol, 8.00 equivalents). The mixture was stirred at -10°C for 0.5 hours, and then stirred at 15°C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 25%~55%, 12 min) to obtain 37 mg of compound 15 as a white solid. TIFF2026090362000221.tif43143

[0267] Example 11 Cytotoxicity of SMDCs in primary human tumor cell lines Cytotoxicity of SMDCs in primary human head and neck squamous cell carcinoma tumor cell line (UT-SCC-14) constitutively expressing CYP1B1 Greer, et al., in Proc. Am. Assoc. Cancer Res., 45: 3701, 2004 reported that CYP1B1 is overexpressed during malignant progression of head and neck squamous cell carcinoma (HNSCC), but not in normal epithelium. The primary UT-SCC-14 tumor cell line was isolated from a cancer patient with HNSCC (see, e.g., Yaromina et. al., Radiother Oncol., 83: 304-10, 2007, and Hessel et al., Int J Radiat Biol., 80; 719-27, 2004). The patient was a 25-year-old male with HNSCC characterized by the following clinicopathological parameters: location, tongue scc; T3, N1, M0; site, tongue; lesion, primary; grade G2. The UT-SCC-14 cell line constitutively expresses CYP1B1 at both mRNA and protein levels and was used to demonstrate the cytotoxicity of the compound in cancer cells derived from human cancers characterized by CYP1B1 overexpression (Greer, et al., in Proc. Am. Assoc. Cancer Res., 45: 3701, 2004).

[0268] UT-SCC-14 tumor cells: Following the method of the literature (the content of which is incorporated herein by reference, Hessel et al., Int J Radiat Biol., 80; 719-27, 2004), fetal bovine serum (50 ml), non-essential amino acids (100 ×, 5 ml), and sodium pyruvate (100 mmol dm³) were administered along with penicillin 100 IU / ml / streptomycin (100 ug / ml, 5 ml). -3(5 ml), L-glutamine (200 mmol dm³) -3 HNSCC cell lines were grown under standard cell culture conditions in EMEM (500 ml) supplemented with 5 ml of [unclear].

[0269] SMDC cytotoxic IC in primary head and neck tumor cell lines 50 Determining the value UT-SCC-14 tumor cell suspension, with 2000 cells per well in a 96-well plate, was prepared by adding fresh medium if necessary to a total volume of 100 μl per well. The cells were incubated in an incubator for 4 hours. After 4 hours, the adhesion of cells to the bottom of the 96-well plate was confirmed under a microscope. The medium was then removed and replaced with fresh medium containing the stock solution of the test compound in ethanol, resulting in a final volume of 100 μl per well, with the following final concentrations: 0, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 μmol dm³. -3 The results were obtained. It was found that a final ethanol concentration of 0.2% did not affect the growth characteristics of the UT-SCC-14 cell line. UT-SCC-14 cells were incubated with the test compound for 72 hours, then all were aspirated and replaced with 100 μl of fresh medium to compensate for medium loss due to evaporation. Cells were incubated with 20 μL of MTS assay reagent for 1.5 hours, and absorbance per well at 510 nm was measured using a plate reader. (a) Cells + medium, (b) Cells + medium containing 0.2% ethanol, (c) Medium alone, and (d) 0.2% ethanol and 0-100 μmol dm³ -3 For a series of controls, including culture media containing test compound concentrations within a specified range, the mean absorbance and standard deviation were calculated for each test compound concentration. Cytotoxic IC 50 The values ​​were calculated from a plot of test compound concentrations against cell proliferation percentage (100% cell proliferation corresponds to untreated control cells).

[0270] Cytotoxic IC 50The value is defined herein as the concentration of a compound that kills 50% of UT-SCC-14 tumor cells. Commercially available MTS assays are uniform colorimetric methods for determining the number of viable cells in proliferation, cytotoxicity, or chemosensibility assays.

[0271] In the above assay, cytotoxic IC50 with a concentration of less than 1 μM was observed. 50 The compound of the present invention having a value is considered to be active.

[0272] The above disclosures have been described in some detail as examples and illustrations for the purpose of clarity and understanding. The invention has been described in relation to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Accordingly, it should be understood that the above description is intended to be illustrative and not limiting. Therefore, the scope of the invention should not be determined in relation to the above description, but rather in relation to the appended claims below and the entire scope of equivalents to which such claims are granted.

Claims

1. Compound of formula (I): or its pharmaceutically acceptable salts, esters, amides, solvates, or stereoisomers: During the ceremony, -L- is used within the -L- effect pedal, -(C 1 ~C 5 )Alkilen-OC(O)-effector, -(C 3 ~C 5 ) Alkenylene-O-Effector, Defined as, A is -(C 1 ~C 5 ) is alkylene-OC(O)-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, or -S-, or -SC(O)N(H)-; D is -(C 1 ~C 5 ) alkylene- or -(C 3 ~C 5 ) alkenylene-; Y 1 C=C, carbon, or nitrogen, Y 1 If it is nitrogen, then Z 1 It does not exist; Y 4 and Y 5 Each of them is independently either carbon or nitrogen, Y 3 If it is nitrogen, then Z 3 Y does not exist. 4 If it is nitrogen, then Z 5 It does not exist; Y 2 is C or N; Y 5 is an oxygen, carbon, nitrogen, or sulfur atom, Y 5 If it is an oxygen or sulfur atom, then Z 6 It does not exist; Z 1 and Z 2 Each of these, if present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may independently be substituted with 1 to 3 halos; Z 3 , Z 4 , and Z 5 Hydrogen, alkyl, deuterated alkyl, C 1～6 Alkoxy, deuterated C 1～6 Each alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano moieties are independently selected, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; Z 1 , Z 2 , or Z 4 Provided that at least one of them is H; Z 6 The elements are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, and aralkyl, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; each Z 8 These are independently hydrogen and unsubstituted C 1 ~C 6 Alkyl, substituted C 1 ~C 6 Alkyl, unsubstituted C 1 ~C 6 Alkoxy, unsubstituted deuterated C 1 ~C 6 alkoxy, substituted C 1 ~C 6 Alkoxy and substituted deuterated C 1 ~C 6 The alkoxy is an alkoxy, and the substituted alkyl, alkoxy, and deuterated alkoxy are amino, monosubstituted or disubstituted amino, and cyclic C 1 ~C 5 Alkylamino, imidazolyl, C 1 ~C 6 Substituted with one or more groups selected from alkylpiperazinyl, morpholino, thiol, thioether, tetrazole, carboxylic acid, ester, amide, monosubstituted or disubstituted amide, N-bonded amide, N-bonded sulfonamide, sulfoxy, sulfonate, sulfonyl, sulfoxy, sulfinate, sphinyl, phosphonooxy, phosphate, or sulfonamide, each alkyl, alkenyl, alkynyl, alkoxy, and aryl may be substituted with 1 to 3 halos; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine.

2. Y 3 and Y 4 The compound according to claim 1, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein each of the atoms is carbon.

3. Z 3 , Z 4 , and Z 5 These are Halo and Unsubstituted C, respectively. 1 ~C 3 Alkyl, substituted C 1 ~C 3 Alkyl, unsubstituted C 1 ~C 3 alkoxy, substituted C 1 ~C 3 Alkoxy, unsubstituted deuterated C 1 ~C 3 Alkoxy or substituted C 1 ~C 3 A compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, selected from alkoxys, wherein each alkyl and alkoxy moiety can be independently substituted with 1 to 3 halos.

4. Z 3 , Z 4 , and Z 5 Each of the above is selected from bromo, chloro, fluoro, methyl, deuterated methyl which may be substituted with 1 to 3 halos, methoxy which may be substituted with 1 to 3 halos, or deuterated methoxy, and is a compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

5. Equation (Ia): A compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof: During the ceremony, L, Y 1 , Y 2 , Y 5 , Z 3 , Z 4 , Z 5 , and Z 6 Each of these is defined in any one of claims 1 to 4, The effector is the part that is (i) a phosphate derivative of gemcitabine, or (ii) a salt form of a phosphate derivative of gemcitabine.

6. Formulas (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib- x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii): A compound according to any one of the above claims, having, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any of the above formulas: During the ceremony, Z 3 and Z 5 Each of these is independently a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; Z 4 If present, these are a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; -L-Effector is -(C 1 ~C 3 ) Alkilen-OC(O)-effector, And, D is -(C 1 ~C 3 ) is alkylene-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, -S-, or -SC(O)N(H)-; A is -(C 1 ~C 3 ) is alkylene-OC(O)-; The effector is the part that is (i) a phosphoramidate derivative of gemcitabine, (ii) a salt form of a phosphoramidate derivative of gemcitabine, or (iii) a phosphorodiamidate derivative of gemcitabine.

7. The aforementioned effector is given by formula (b), (c), (d), or (e): It is, During the ceremony, G is either -N(H)- or -O-; M is -OH, -O-aryl, -O-(C 1 ~C 5 )alkyl-heterocycloalkyl, -O - Na+, -O - Et 3 NH + 、-O - K + 、 or -O - NH 4 + and M 2 is, -O - Na + , -O - Et 3 NH + , -O - K + , -O - NH 4 + , or NC(R x R y )C(O)XR z And, X is -O- or -N(R d )- and, R a H is; R b is -OR b’ And if G is -N(H)-, then R b’ These include aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, cycloalkyl, alkoxyalkyl, acyloxyalkyl, alkylthioalkyl, alkylthiocarbonylalkyl, -alkyl-C(=O)-OR d ,-alkyl-OC(=O)-R d , or -alkyl-C(R e )R f And R b The alkyl, heteroaryl, or aryl portion may be substituted with a halo, alkyl, or alkoxy; Or, if G is -O-, then R b is M 2 And; R c These include aryl, -C(O)-aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, cycloalkyl, alkoxyalkyl, acyloxyalkyl, alkylthioalkyl, alkylthiocarbonylalkyl, and -alkyl-C(=O)-OR d ,-alkyl-OC(=O)-R d , or -alkyl-C(R e )R f And R c The alkyl, heteroaryl, or aryl portion of the R may be substituted with a halo, alkyl, or alkoxy. c The alkyl, heteroaryl, or aryl moiety of the above may be substituted with a halo, alkyl, or alkoxy; R d is H or alkyl; R e is -alkylthio-(C 1 ~C 25 )alkyl or -alkyloxy-(C 1 ~C 25 ) is alkyl; R f is -alkylthio-(C 1 ~C 25 )alkyl or -alkyloxy-(C 1 ~C 25 ) is alkyl; R x and R y Each is independently H, or an alkyl or alkoxyaryl which may be substituted with a heterocycloalkyl, or R x and R y These, together with the carbon atoms to which they are bonded, form cycloalkyl, aryl, or heteroaryl groups; R z (C) may be substituted with a heterocycloalkyl or aryl group. 1 ~C 6 ) is alkyl, A compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

8. The linker region (L) is -C(H) 2 A compound according to any one of the above claims, which is -OC(O)-, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

9. Formulas (Ic-i), (Ic-ii), (Ic-iii), (Ic-iv), (Ic-v), (Ic-vi), (Ic-vii), (Ic-viii), (Ic-ix), (Ic-x), (Ic-xi ), (Ic-xii), (Ic-xiii), (Ic-xiv), (Ic-xv), (Ic-xvi), (Ic-xvii), (Ic-xviii), (Ic-xix), or (Ic-xx): A compound according to claim 1 having, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any of the above formulas: During the ceremony, Z 3 , Z 4 , and Z 5 Each of these is independently a methyl, halo, methoxy, or deuterated methoxy that may be substituted with 1 to 3 halos; R b (C) may be substituted with a heterocycloalkyl group. 1 ~C 5 ) alkyl or alkoxyaryl; R e H, halo, alkyl, -(C 1 ~C 5 )alkyl, or -(C 1 ~C 5 ) is an alkoxy; R z (C) may be substituted with a heterocycloalkyl or aryl group. 1 ~C 5 ) is alkyl; M is -OH, -O-aryl, -O-(C 1 ~C 5 ) Alkyl-heterocycloalkyl, -O - Na+, -O - Et 3 NH + , -O - K + , or -O - NH 4 +で be.

10. - The effect pedal has the following structure: Having one of the following, In the formula, M is -O-(C 1 ~C 3 )alkyl-N-morpholino, -O aryl, -O - Na+, -O - Et 3 NH + , -O - K + , or -O - NH 4 + The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

11. In the formula, M is -O-(CH 2 ) 3 -N-morpholino, -Oaryl, -O - Na+, -O - Et 3 NH + , -O - K + , or -O - NH 4 + The compound according to claim 10.

12. Z 3 , Z 5 , and Z 4 The compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein, if present, each is a methoxy or deuterated methoxy which may be substituted with 1 to 3 halos.

13. Z 3 and Z 5 However, each is independently bromo or fluoro, and Z 4 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, which, if present, is a methoxy or deuterated methoxy which may be substituted with 1 to 3 halos.

14. The following structure: A compound according to claim 1 having one of the above, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any one of compounds 1 to 15.

15. A composition comprising a compound according to any one of the above claims together with a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt, ester, amide, or solvate of a compound according to any one of the above claims together with a pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in pharmaceuticals.

17. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in a method of treating or prophylactic a proliferative condition.

18. The compound, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in a method of treatment or prevention according to claim 17, wherein the proliferative state is a cancer selected from cancers of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovary, pancreas, prostate, or skin.

19. Use of any one of the compounds according to claims 1 to 14, or pharmaceutically acceptable salts, esters, amides, or solvates, for the preparation of a medical agent for use in a method of treating or prophylactic conditions.

20. A method for diagnosing a patient for the presence of tumor cells expressing the CYP1B1 enzyme, (a) A step of administering a specific compound according to any one of claims 1 to 14 to the patient, (b) A step of determining the amount of the corresponding hydroxylated metabolite that is subsequently produced; and (c) A step of correlating the amount with the presence or absence of tumor cells in the patient. Methods that include...

21. (1) Identify the presence of a tumor in the patient; (2) To treat a patient identified as being in need of treatment by administering a therapeutically or prophylactically useful amount of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof. method.

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